chemotherapy induced cardiac toxicity
DESCRIPTION
Dr Salah Mabrouk Assiut university South Egypt Cancer Institute Tel (202) 01004081234 email: [email protected]TRANSCRIPT
آياته من النفس في ما عيناكا ولعل ترى لو عجاب عجبإذا بأسرار مشحون أعياكا والكون لها تفسيرا حاولت
الردى يد تخطفته للطبيب أرداكا قل من األمراض ياشافيعافاكا من الطب فنون عجزت ما بعد وعوفي نجا للمريض قل
علة من ال يموت للصحيح دهاكا قل ياصحيح بالمنايا منسوداني ) ( بديوي علي إبراهيم للشاعر
ChemotherapyInduced
Cardotoxicity
By Salah Mabrouk
Assisstant lecturer of
Medical OncologySECI Assiut University
Definition of cardotoxicity Chemotherapy induced cardotoxicity
ndash Anthracyclines Epidemiology Pathogenesis Risk factors Stages Diagnosis Prevention Treatment ndash Non-anthracyclines Incidence Pathogenesis Risk factors Diagnosis Prevention ampTreatment
Radiotherapy induced cardotoxicity
Definition of cardiac toxicity
Damage to the heart muscle by a toxin that may cause arrhythmias (changes in heart rhythm) or cardiomyopathy and heart failure
Anthracyclines
Epidemiology
bullFirst recognized Mid to late 1970rsquos
bullIncidence 18-65
bullMortality gt20
Anthracyclines
The most well-known is doxorubicin )Adriamycinreg(
Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone
Pathogenesis
Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative
metabolism4 Anthracycline affinity for cardiolipin results in drug
accumulation5 Genetic polymorphisms in NAD(P)H oxidase and
Doxorubicin efflux transporters
I- Free radical formation A- Enzymatic reaction in mitochondria
Quinone
Aminoresidue
Sugar residue
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
ChemotherapyInduced
Cardotoxicity
By Salah Mabrouk
Assisstant lecturer of
Medical OncologySECI Assiut University
Definition of cardotoxicity Chemotherapy induced cardotoxicity
ndash Anthracyclines Epidemiology Pathogenesis Risk factors Stages Diagnosis Prevention Treatment ndash Non-anthracyclines Incidence Pathogenesis Risk factors Diagnosis Prevention ampTreatment
Radiotherapy induced cardotoxicity
Definition of cardiac toxicity
Damage to the heart muscle by a toxin that may cause arrhythmias (changes in heart rhythm) or cardiomyopathy and heart failure
Anthracyclines
Epidemiology
bullFirst recognized Mid to late 1970rsquos
bullIncidence 18-65
bullMortality gt20
Anthracyclines
The most well-known is doxorubicin )Adriamycinreg(
Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone
Pathogenesis
Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative
metabolism4 Anthracycline affinity for cardiolipin results in drug
accumulation5 Genetic polymorphisms in NAD(P)H oxidase and
Doxorubicin efflux transporters
I- Free radical formation A- Enzymatic reaction in mitochondria
Quinone
Aminoresidue
Sugar residue
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Definition of cardotoxicity Chemotherapy induced cardotoxicity
ndash Anthracyclines Epidemiology Pathogenesis Risk factors Stages Diagnosis Prevention Treatment ndash Non-anthracyclines Incidence Pathogenesis Risk factors Diagnosis Prevention ampTreatment
Radiotherapy induced cardotoxicity
Definition of cardiac toxicity
Damage to the heart muscle by a toxin that may cause arrhythmias (changes in heart rhythm) or cardiomyopathy and heart failure
Anthracyclines
Epidemiology
bullFirst recognized Mid to late 1970rsquos
bullIncidence 18-65
bullMortality gt20
Anthracyclines
The most well-known is doxorubicin )Adriamycinreg(
Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone
Pathogenesis
Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative
metabolism4 Anthracycline affinity for cardiolipin results in drug
accumulation5 Genetic polymorphisms in NAD(P)H oxidase and
Doxorubicin efflux transporters
I- Free radical formation A- Enzymatic reaction in mitochondria
Quinone
Aminoresidue
Sugar residue
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Definition of cardiac toxicity
Damage to the heart muscle by a toxin that may cause arrhythmias (changes in heart rhythm) or cardiomyopathy and heart failure
Anthracyclines
Epidemiology
bullFirst recognized Mid to late 1970rsquos
bullIncidence 18-65
bullMortality gt20
Anthracyclines
The most well-known is doxorubicin )Adriamycinreg(
Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone
Pathogenesis
Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative
metabolism4 Anthracycline affinity for cardiolipin results in drug
accumulation5 Genetic polymorphisms in NAD(P)H oxidase and
Doxorubicin efflux transporters
I- Free radical formation A- Enzymatic reaction in mitochondria
Quinone
Aminoresidue
Sugar residue
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Anthracyclines
Epidemiology
bullFirst recognized Mid to late 1970rsquos
bullIncidence 18-65
bullMortality gt20
Anthracyclines
The most well-known is doxorubicin )Adriamycinreg(
Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone
Pathogenesis
Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative
metabolism4 Anthracycline affinity for cardiolipin results in drug
accumulation5 Genetic polymorphisms in NAD(P)H oxidase and
Doxorubicin efflux transporters
I- Free radical formation A- Enzymatic reaction in mitochondria
Quinone
Aminoresidue
Sugar residue
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Anthracyclines
The most well-known is doxorubicin )Adriamycinreg(
Other anthracyclines arendash Epirubicin (farmarubicinreg) ndash Daunorubicin (Cerubidinereg) ndash Idarubicin (Idamycinreg)ndash Mitoxantrone
Pathogenesis
Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative
metabolism4 Anthracycline affinity for cardiolipin results in drug
accumulation5 Genetic polymorphisms in NAD(P)H oxidase and
Doxorubicin efflux transporters
I- Free radical formation A- Enzymatic reaction in mitochondria
Quinone
Aminoresidue
Sugar residue
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Pathogenesis
Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative
metabolism4 Anthracycline affinity for cardiolipin results in drug
accumulation5 Genetic polymorphisms in NAD(P)H oxidase and
Doxorubicin efflux transporters
I- Free radical formation A- Enzymatic reaction in mitochondria
Quinone
Aminoresidue
Sugar residue
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Pathogenesis Multiple mechanisms appear to be involved1 Free Radical formation ndashEnzymatic reaction in mitochondria ndashNon-enzymatic reaction with Iron2 Cytochrome C release apoptotic signal3 Fewer antioxidant defenses highly oxidative
metabolism4 Anthracycline affinity for cardiolipin results in drug
accumulation5 Genetic polymorphisms in NAD(P)H oxidase and
Doxorubicin efflux transporters
I- Free radical formation A- Enzymatic reaction in mitochondria
Quinone
Aminoresidue
Sugar residue
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
I- Free radical formation A- Enzymatic reaction in mitochondria
Quinone
Aminoresidue
Sugar residue
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
I- Free radical formation Enzymatic reaction in mitochondria
Anthracyclines might undergo redox activation through their interaction with several flavoprotein oxidoreductases
This semiquinone can rapidly auto-oxidize using molecular oxygen )O2( as an electron acceptor returning to the parent compound which is then available for a new redox cycle
This reaction leads to the formation of superoxide anion )O2minus( Driven by superoxide dismutases )SOD( or spontaneously in acidic pH
superoxide anion is converted into hydrogen peroxide )H2O2( which in the presence of traces of transition metals such as iron or copper
will be converted to the very reactive oxidizing species hydroxyl radical )HO(
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
I- Free radical formation B- Non-enzymatic reaction with Iron
Anthracyclines can directly form complexes with ferrous iron displaced from its sites of storage within the cell
These complexes are apt to generate ROS in the presence or the absence of reducing components
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
bull Free radicals ndash Molecules containing an odd number of electrons bull H2O2 hydroxyl radicals ndash Are highly reactive and damaging to tissues such as proteins lipids and
nucleic acids leading to modifications that are more likely to have an effect on the nucleus the sarcoplasmic reticulum or the mitochondria ndash cellular organelles that are in close proximity to the site of generation of ROS
ndash Are countered by antioxidants and by intracellular enzymes (flavoenzyme) The heart is predisposed to oxidative stress because of relatively low levels of
antioxidant enzymes Mitochondria are particularly susceptible to free radical damage
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Cytochrome C release apoptotic signal
Apoptosis hypothesis for the cardiotoxicity of anthracyclines Apaf-1 Apoptotic protease activating factor-1
TNFFAS-R tumor necrosis factorFas receptor
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Risk factors for anthracycline-induced cardiotoxicity Treatment related Cumulative dose of anthracycline Dosing schedules Previous anthracycline therapy Radiation therapy Co-administration of additional potentially cardiotoxic agentsPatient related Age Preexisting cardiovascular disease or cardiac risk factors
(hypertension diabetes increasing total cholesterol Obesity and Smoking)
Gender female sex
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Treatment related risk factors 1- Cumulative dosebull Can occur at any dosebull Highly variable ndashSerious adverse effects may occur with small
dose ndashgtno adverse effects with very high dose bull The standard cumulative doses Doxorubicin 450ndash550 mgm2 Epirubicin 900ndash1000 mgm2 why
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Induction Treatment Of AMLInduction Treatment Of AML
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
bullADR amp DNR - 450 mgm2 if CPA is also given
- 550 mgm2 if not
bullIdarubicin 75 mgm2
bullMitoxantrone 140 mgm2
Cumulative doses of anthracyclines
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Doxorubicin versus Epirubicin cumulative doses on a mgm2 basis Epirubicin is less cardiotoxic than
doxorubicin and can therefore be administered at higher cumulative doses (up to a total of 900 mgm2 versus a total of 450 mgm2 for doxorubicin before cardiotoxicity limits further therapy)
However to achieve the same clinical benefit as doxorubicin epirubicin tends to be given at 25ndash50 higher doses which potentially negates the advantages of any higher cumulative dose threshold
van Dalenet al Cochrane Database Syst Rev (2006)
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Treatment related risk factors
2- Dosing schedule
bull Single large dose gt smaller frequent dosing
bull The dose every 3 weeks gt weekly doses
bull Bolus injection (peak levels) gt continuous infusion
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Treatment related risk factors 3- History of mediastinal irradiation bull Amplifies preexisting CAD bull Exacerbation of vascular injury bull Pericardial effusion bull Pericardial fibrosis (restrictive disease) bull Myocardial fibrosis (valvular disease)4-Administration of other cardiotoxic medications
(cyclophosphomides actinomycin D bleomycin cisplatin methotraxate trastuzumab)
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Barrett-Lee P J et al Ann Oncol 2009 0mdn728v1-728 doi101093annoncmdn728
Cumulative probability of developing doxorubicin-induced chronic heart failure [27]Patient related risk factors 1- Age of patient
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Patient related risk factors
2- Preexisting cardiovascular disease or cardiac risk factors
Hypertension
Diabetes
increasing total cholesterol)
Obesity
Smoking
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Patient related risk factors 3- Gender female sex
Controversy
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Clinical manifestation stages
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Type I and Type II Treatment-Related Cardiotoxicity
Type Indash Cumulative-dose related
ndash Irreversible (cell death)
ndash Typical biopsy changes
ndash Doxorubicin is the model
Type IIndash Not cumulative-dose related
ndash Largely reversible (cell dysfunction)
ndash Absence of anthracycline-like biopsy changes
ndash Trastuzumab is the model
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Clinical manifestation stagesAcute cardiotoxicity ECG changes and Arrhythmias
Subacute cardiotoxicity Pericarditis (infrequent) Myocarditis (infrequent)
Chronic cardiotoxicity Contractile dysfunction Heart failure
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Stagesbull Acute Toxicityndash Rarendash Directly connected with the administration of a
single dose or after a course of the antibioticbull Often asymptomatic and rarely fatalbull Synergistic action between drug and
hypokalemiabull Tends to be reversible and usually transientbull Result of an autonomic defect
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
ECG CHANGES AND ARRHYTHMIAS Occur during or within 24 hours of doxorubicin administration
The most common ECG abnormalities reported are 1 Nonspecific ST-T wave changes 2 Decreased QRS voltage3 Sinus tachycardia4 Supraventricular tachyarrhythmia 5 Premature ventricular and atrial contractions6 T-wave abnormalities7 QT interval prolongation8 Rarely sudden death and life-threatening ventricular arrhythmias
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
bull Subacute Toxicityndash Occurs days to weeks post treatmentndash Rare and often asymptomaticndash Includes
1 Toxic pericarditis 2 Toxic Myocarditis
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Chronic Cardiotoxicity Include
1 Contractile dysfunction (CHRONIC CARDIOMYOPATHY)
2 Heart failure This is the most severe form of doxorubicin
cardiotoxicity Cardiomyopathy is DOSE-RELATED Morphologic damage increases progressively
with increasing doses
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Diagnosis and monitoring Clinical picture Electrocardiogram )ECG) Echocardiogram Laboratory markers bull Troponin I amp T
bull B-type natriuretic peptide (BNP) Cardiac biopsy Multi Gated Acquisition )MUGA( scan
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Echocardiography Benefits Provides a wide spectrum of information on cardiac
morphology and function Does not expose patients to ionising radiation Tissue Doppler imaging may improve detection of systolic and
diastolic dysfunction Limitations Image quality limits use in some patients LVEF measurements time consuming and operator dependent Not sensitive for the early detection of preclinical cardiac
disease Both FS( fractional shortening ) and LVEF are affected by
preload and afterload
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Echocardiography
Nousiainen Eur J Haematol 62135-141 1999
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Biomarkers1 Cardiac troponin I (TnIampT) a contractile protein in the
myocardium2 B-type natriuretic peptide (BNP) cardiac hormone
Benefits Troponin is a highly specific and sensitive biomarker
for detection of myocardial damage Potentially useful screening tool It can be used to predict at a very early stage the
development of future ventricular dysfunction as well as its severity
Limitation Data regarding clinical value are limited
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Magnetic resonance imaging
Benefit Valuable tool to assess myocardial function and
damage
Limitations High costs of repeated examinations Limited availability
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Computed tomography
Benefits Image quality similar to magnetic resonance
imaging with Lower cost
Limitations High radiation dose Limited availability
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Scintigraphy
Benefit Sensitive method to detect myocyte damage
in patients after doxorubicin therapy
Limitation Larger prospective trials required to ascertain
potential role
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Multiple uptake gated acquisition scan (MUGA scan)
Benefits Well-established and well-validated method to
determine ejection fraction Can also assess regional wall motion and diastolic
function (nonstandard)
Limitations No information on valve function LVEF measurements are not sensitive for the early
detection of preclinical cardiac disease
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Endomyocardial biopsy
bull Microscope Changes1ndash Mitochondrial defects
2ndash Diminished cardiac myocyte calcium handling properties
3ndash Decreased vascularization4ndash Apoptosis5ndash Fibrosis causing increased cardiac stiffness
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Endomyocardial biopsy
Benefits Provides histological evidence of cardiotoxicity
Limitations Invasive Small sample of myocardium tested
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Prevention
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Prevention1 Screening for risk factors and prevention of cardiac
events
2 Dose limitation(lt 550mg m2 )
3 Dosing Schedules modification
4 Use different forms of athracyclines that cause less cardiotoxicity (Liposomal preparations)
5 Use agents to prevent the cardiotoxicity
6 Use cardioprotective agent (Dexrazoxane)
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Screening for risk factors and prevention of cardiac events
Assess for preexisting cardiac risk factors Reduce cardiac risk LVEF assessment
1 le 30rarrDonrsquot give anthracyclines
2 30ndash50rarr give with monitoring of LVEF
3 ge 50 rarrrepeat evaluation at 250ndash300 mgm2 and again at 450 mgm2 cumulative dose
bull A 10 decrease in LVEF or a drop from ge 50 to le 50 or from 30ndash50 to le 30 rarr stop anthracyclines
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Dose limitation keep the total lifetime cumulative dose below
the recommended threshold ndash 550 mgm2 for doxorubicin ndash 900 mgm2 for epirubicin ndash When combined with paclitaxel the cumulative
doxorubicin dose should not exceed 360 mgm2 and doxorubicin should be given before paclitaxel
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Dosing Schedules It should be as possible in
bull Smaller frequent dosing
bull Weekly doses
bull Continuous infusion controversy
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Liposomal preparations of athracyclines
Figure Liposomes ndash
)left( = aqueous soluble drug encapsulated in aqueous compartment )centre( = a hydrophobic drug in the liposome bilayer
)right( C = hydrophilic polyoxyethylene lipids incorporated into liposome
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Figure Accumulation of liposomes within solid tumours mdash )left( liposomes in normal tissue )right( liposome extravasation from the disorganised
tumour vasculature
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
There are two formulations of liposomal anthracyclines 1 Nonpegylated2 Pegylated
NB Peg =polyethylene glycol Non-toxic and non-immunogenic Hydrophilic (aqueous-soluble) Highly flexible ndash provides for surface treatment or
bioconjugation
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Types of liposomal anthracyclines includendash Liposomal daunorubicin (DaunoXomereg) ndash Pegylated liposomal doxorubicin
(Doxilreg or Caelyx reg)
Pegylated liposomal doxorubicin has shown a similar anti-cancer effect to doxorubicin but with less cardiac toxicity
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Liposomal preparations of athracyclines
(Caelyxreg) Liposomes are preferentially taken
up by tissues enriched in phagocytic reticuloendothelial cells
In many trials it appears to be as effective as standard doxorubicin
Side effects
mucositis and palmoplantar erythrodysesthesia
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Cardioprotective agent (Dexrazoxane= Cardioxanereg)
Dexrazoxane is an oral iron chelator It prevents the formation of the semiquinone-iron
which leads to reactive oxygen production It has been tested in multiple clinical trials and has
been shown to reduce cardiac toxicity The recommended dosage ratio of
dexrazoxanedoxorubicin is 101 doxorubicin should be given within 30 minutes of giving dexrazoxane
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Dexrazoxane
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
7
10
54
1
15
12
4
15
20
0 5 10 15 20 25
Doxo 500 mgm2
Doxo 1000 mgm2
Doxo bolus gt 550 mgm2
Doxo low dose weekly gt 600 mgm2
Doxo (400-499 mgm2) + Dexrazoxane
Dauno 500 mgm2
Dauno 1000 mgm2
Epirubicin lt 900 mgm2
Epirubicin 1000 mgm2
Anthracycline Cardiotoxicity Effects of Different Drugs Scheduling and Cardiac Protection with
Dexrazoxane
CHF ()
Hensley ML et al J Clin Oncol 1999 17(10)3333-3355
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
ASCO Recommendations
Not recommended for initial therapy Breast patients receiving more than 300
mgm2 of doxorubicin Consideration in patients with other
malignancies receiving more than 300 mgm2 of doxorubicin
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Dexrazoxane and response to chemotherapy
Some data suggests that dexrazoxane may decrease response to chemotherapy
One phase III trial published by Swain in 1997 showed a significant decrease in response in the dexrazoxane group
There has been no difference in overall survival or progression free survival in this trial
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
New prevention strategies In addition to new biomarkers for risk stratification
there are new potential approaches to prevention of anthracycline cardiotoxicity
These include
1 Angiotensin-converting enzyme (ACE) inhibitors
2 Angiotensin II receptor blockers (ARBs)
3 Carvedilol
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
They may prevent doxorubicin cardiotoxicity by reducing left ventricular remodelling and limiting oxidative stress
ACE inhibitors
Troponin positive patients followed for 12 months subsequent to chemotherapy treatmentdemonstrating a cardioprotective effect of enalapril as measured by preserved LVEF Orange boxes indicate patients with persistent troponin elevation and purple boxes aretroponin positive patients that returned to baseline
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Angiotensin receptor blockers ARBs have been found to have intrinsic
antioxidant and mediate a cardioprotection Nakamae and colleagues found that valsartan
significantly reduced changes in the left ventricular end-diastolic diameter
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Recovery of LV dysfunction with standard Recovery of LV dysfunction with standard HF therapyHF therapy
Jensen et al Annals of Oncology 2002 13499-709
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Carvedilol Carvedilol blocks beta1 beta2 and alpha1
adrenoceptors and has potent antioxidant and anti-apoptetic properties
Early research in animals has shown that the use of carvedilol can prevent chemotherapeutic cardiotoxicity
Kalay and associates conducted the first human clinical trial investigating the prophylactic use of carvedilol in this clinical setting
Further large randomised trials are needed
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Non-anthracycline
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
ANTINEOPLASTIC AGENT MAJOR CARDIAC SIDE EFFECT INCIDENCE
Cyclophosphamideifosfamide Myocarditis CHF 2517
Paclitaxeldocetaxel Hypotension hypertension bradycardia atrial and ventricular arrhythmia
05
Fluorouracil MI angina hypotension coronary vasospasm 16ndash68
Rituximab Hypotension hypertension arrhythmia 25
Arsenic trioxide QT prolongation tachycardia 8ndash55
Trastuzumab CHF 7ndash28
Thalidomide Pulmonary hypertension Unknown
Etoposide MI hypotension 1ndash2
Vinca alkaloids MI autonomic cardioneuropathy 25
Pentostatin MI CHF acute arrhythmia 3ndash10
Cytarabine Arrhythmia pericarditis CHF Unknown
Interferon (at high doses) Arrhythmia dilated cardio- myopathy ischemic heart disease
Unknown
Busulfan Endocardial fibrosis Unknown
Cisplatin Acute MI Unknown
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
5-FLUOROURACIL )5-FU( INCIDENCE 16ndash68 Onset
ndash in the first 72 hours of the initial treatment cycle
Risk factorsndash Infusional administrationndash concurrent radiotherapyndash pre-existing cardiac disease
Pathogenesisndash coronary spasm
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
5-FLUOROURACIL )5-FU(
Characteristics
bull The second most common bull Not dose related
bull Clinically ranges from angina pectoris within hours of a dose to myocardial infarction
bull Capecitabine (Xeloda) the oral prodrug of 5-FU is also reported to have similar cardiac toxic effects
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
5-FLUOROURACIL )5-FU( Prevention and management Careful clinical monitoring Administration of 5-FU should be stopped immediately in
patients who develop a cardiac event These patients should not be retreated with this agent The role of prophylactic calcium channel blockers and
nitrates remains unclear Most patients respond to conservative antianginal
therapy and supportive care
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
CYCLOPHOSPHAMIDE Incidence
bull 25bull The life-threatening incidence is 5 to 10 of patients
Pathogenesis ndash It causes cardiac necrosis may be related to acrolein ndash also cause ischemic cardiac toxicity
Risk factors ndash High dose regimens carry greater risk ie after the use of
very high does (120-140mgkg) in preparation for bone marrow transplant
ndash Prior treatment with anthracycline or mediastinal irradiation
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Manifestation Minor toxicities ndash Minor ECG changes bull ST-T wave segment changes bull Supraventricular arrhythmias ndash Pericarditis-with or without effusion Severe toxicities ndash ECG voltage loss ndash Progressive heart failure ndash Pericarditis with or without tamponade
NB Ifosfamide (Ifex) belongs to the same class of drugs and in one series is reported to have had significant cardiotoxicity in 17 of patients treated with the drug
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
CYCLOPHOSPHAMIDE Prevention and management There are no established guidelines Baseline MUGA scan or ECHO are done to measure left
ejection fraction prior to transplant (Exclusion criteria ndash EF lt 50)
Close clinical monitoring of patients for signs and symptoms of congestive heart failure
If suspect further therapy should be stopped and a complete evaluation including ECG and an echocardiogram performed to assess LVEF
These patients should be treated symptomatically for congestive heart failure
Repeat treatment with an alkylating agent can be instituted once LVEF returns to ge 50
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Vinca alkaloids bleomycin and cisplatin Pathogenesis
ndash Vasospasm in addition to electrolyte wasting with cisplatin
Manifestationndash MIndash Arrhythmia with cisplatin ndash Autonomic cardioneuropathy with Vinca alkaloids
ndash Raynaud phenomenon
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Taxanes Incidence 05 Pathogenesis
ndash It may be related to the cremaphor vehicle in paclitaxel
Manifestationsndash Hypotensionndash Hypertensionndash Atrial and ventricular arrhythmia sp Bradycardiandash Myocardial infarction
Taxanes interfere with the metabolism and excretion of anthracycline and potentiate its cardiotoxicity
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Taxanes Prevention and management No risk factors however patients with underlying
cardiac disease should be clinically monitored Asymptomatic bradycardiararr No any intervention
neither be stopped nor the dose reduced in these patients
Symptomatic cardiac dysfunction rarr supportive ttt Slow infusion of paclitaxel and doxorubicin or
increased time (24 h) between doxorubicin and paclitaxel treatments decreased cardiotoxicity
Newer paclitaxel formulations such as nanoparticle albumin-bound paclitaxel
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Cardiotoxicity Associated With Biologic
Agents
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Trastuzumab Incidence
bull 2 risk of developing cardiac dysfunction if used alone
bull Increased risk if given with doxorubicin andcyclophosphosphamide (16-27)bull Increased risk if given with paclitaxel (2-13) bull Manifestation Cardiomyopathy Arrythmias
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Trastuzumab )Herceptinreg(
bull Risk factors for the cardiomyopathy
1048766 If given with doxorubicin
1048766 If prior chest radiation therapy
1048766 If diabetes
1048766 If history heart valve disease
1048766 If history heart artery disease
bull In other words risk if prior heart disease
bull Not dose related
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Copyright copy2008 American Association for Cancer Research
Bird B RJ H et al Clin Cancer Res 20081414-24
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Type I (myocardial damage) Doxorubicin
May stabilize but underlying damage appears to be permanent and irreversible recurrence in months or years may be related to sequential cardiac stress
Cumulative dose related
Free radical formation oxidative stressdamage
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
High probability of recurrent dysfunction that is progressive may result in intractable heart failure and death
High
Type II (myocardial dysfunction) Trastuzumab
High likelihood of recovery
Not dose related
Blocked ErbB2 signaling
Decreased ejection fraction by ultrasound or nuclear determination global decrease in wall motion
Increasing evidence for the relative safety of rechallenge additional data needed
Low
Type Agent
Response to
Therapy
Dose
Mechanism
Cardiac testing
Effect of Rechallenge
Effect of late sequential
stress
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Algorithm for continuation and discontinuation of trastuzumab based on interval left ventricular ejection fraction (LVEF) assessments
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
RITUXIMAB Incidence 25 Include
ndash Reversible or transient infusion-related hypotensionndash Arrhythmiandash Acute myocardial infarction ventricular fibrillation
and cardiogenic shock Most of these reactions (80) occur during the
first infusion and may be associated with a cytokine-release phenomenon
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
RITUXIMAB
Prevention and management Discontinued in patients who develop significant
arrhythmia or other severe cardiotoxicity Careful monitoring during and after infusion is
warranted especially in patients with pre-existing cardiac disease
It is recommended that patients avoid taking antihypertensive medication the morning of rituximab infusion and delay taking these drugs until all transient cardiac side effects of rituximab have completely resolved
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Sunitinib
Sunitinib caused mitochondrial injuryRelease of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Imatinib Cardiac death myocardial infarction and
congestive heart failure Hypertension Fluid retention manifesting as pericardial effusion Tachycardia Hypotension Flushing
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Imatinib
Release of cytochrome C
Caspase activation ATP depletion
Apoptosis Necrosis
Myocyte lossLV
dysfunction
ER stress response JNK
BAX activation
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Nilotinib QT prolongation ( 21) sudden death (06 ) Nilotinib prolongs the QT interval in a concentration-
dependent manner Rare
ndash myocardial ischemia ndash atrial fibrillation ndash pericardial effusionndash Cardiomegalyndash bradycardia
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Dasatinib
Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib
arrhythmia and palpitations Severe pericardial effusions
QT prolongation
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Bevacizumab)Avastinreg(
Heart Attacks and Chemotherapy
bull May occur with bevacizumab (Avastinreg)
1048766 Antibody to VEGF (Vascular Endothelial Growth Factor) Thus blocks new blood vessel growth
Avastin can cause heart attacks angina CHF high blood pressure strokes and clots
Risk is 2 especially if prior heart disease
Risk is 14 if given together with doxorubicin
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Bevacizumab )Avastinreg(
bull Heart toxicity can manifest as
1048766 Decreased muscle function (EF)
1048766 Congestive heart failure
1048766 Rhythm problems
1048766 High blood levels of heart enzymes such as troponin T and troponin I
1048766 High blood levels of heart hormones such as BNP
1048766 Inflammation of the pericardium
1048766 Inflammation of the heart muscle
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
ARSENIC TRIOXIDE Arsenic trioxide is a novel agent currently used in
various hematologic malignancies Incidence 8-55 It is associated with prolongation of the QT interval and
potentially serious cardiac arrhythmia Cardiotoxicity associated with arsenic trioxide is usually
acute and occurs during or immediately after infusion Hypokalemia or hypomagnesemia predisposes patients
to the cardiotoxic effects of arsenic trioxide
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Prevention and management A baseline ECG should be done before starting therapy to
assess the rhythm pattern and QT interval This monitoring should be repeated weekly during induction
and biweekly during consolidation If the QT interval is gt 500 ms the patient should be
evaluated for potential risk versus benefit with further therapy
Prior to each infusion electrolytes should be checked and corrected if low
Recommended levels of potassium and magnesium are gt 4 mEqL and gt 18 mgdL respectively
Patients who develop cardiac symptoms should be hospitalized with close cardiac monitoring and correction of electrolytes
Arsenic trioxide can usually be restarted once the QTc interval is lt 460 ms
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
THALIDOMIDE Thalidomide is an immunomodulatory agent currently
used in the treatment of multiple myeloma and other malignancies
It is rarely associated with any cardiovascular side effects but recently pulmonary hypertension has occurred in a patient receiving thalidomide
Both symptoms and pulmonary pressure resolved after cessation of thalidomide
The exact etiology of this phenomenon remains unclear Patients typically complain of shortness of breath and dyspnea on exertion
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
THALIDOMIDE Prevention and management High-resolution computed tomography (CT)
and D-dimer should be performed to rule out pulmonary embolism
Diagnosis is made by echocardiogram with Doppler studies to assess pulmonary artery pressure
Further therapy with thalidomide should be stopped as this is a reversible phenomenon
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
MITOXANTRONE
Transient arrhythmias (7)
Cardiac ischemia (5)
Edema (10)
Hypertension (4) E
Congestive heart failure cardiomyopathy (26)
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
MITOXANTRONE
The recommended maximum cumulative dose of mitoxantrone is 140 mgm2
The cumulative dose is lower with prior anthracycline therapy
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Other drugs
Busulfan (Myleran)
Cardiac tamponade or endomyocardial fibrosis
Bleomycin
Pulmonary fibrosis
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Radiation Therapybull Factors that increase the risk of heart damage
1 1048766 Extent of the coronary arteries in the field
2 1048766 Total radiation dose
3 1048766 Radation dose per fraction
4 1048766 Anterior fields versus tangential fields
5 1048766 Patient age especially under 20 years
6 1048766 Concomitant doxorubicin
7 1048766 Usual heart risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Radiation Therapy
bull Coronary artery disease
1048766 Increased risk if combined with doxorubicin
bull Pericarditis acute or chronic
bull Pericarditis and myocarditis
bull Cardiomyopathy
bull Diastolic dysfunction
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors
Radiation Therapy Recommendations for Radiation Therapy
bull Use cardiac blocking during therapy
bull Limit the concomitant use of doxorubicin (although it can be used before or after)
bull Minimize all other atherosclerotic risk factors