Δημήτρης Φαρμάκης · 2018. 7. 5. · obesity valvularhd (mod./severe) combined...
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Ο ογκολογικός ασθενής και η καρδιά του
Δημήτρης Φαρμάκης
Αν. Καθηγητής, Πανεπιστήμιο Κύπρου
Καρδιακή Ανεπάρκεια & Καρδιο-Ογκολογία, ΠΓΝ «Αττικόν»
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Disclosures
• Consultation fees, speaker honoraria or travel grants from
Boehringer-Ingelheim, Daiichi-Sankyo, Menarini, Novartis,
Pfizer, Servier.
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Outline
• The burden
• The pathophysiology
• The spectrum
• The role of Cardiologist
• The open issues
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The burden
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Estimated and projected cancer survivors in USA
de Moor JS et al. Cancer Epidemiol Biomarkers Prev 2013
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Causes of death in cancer survivors
Ning et al. Cancer Res 2012
Causes of death in 1807 cancer survivors followed for 7 years
Cancer
51%Heart disease
33%
Other
16%
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Causes of death in breast cancer survivors
Patnaik et al, Breast Cancer Res 2011
Leading causes of death by time since breast cancer diagnosis
63,566 breast cancer women
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Childhood cancer survivors in UK
Skinner et al. Lancet Oncol 2006
Kroll et al. Cancer Stats Monograph 2004
• In 2000, 26000 childhood cancer survivors in UK
• Childhood cancer survival rates, 25% in 1960s vs. 75% in 1990s
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Mortality in childhood cancer survivors
• The Childhood Cancer Survivor Study
• 20,227 childhood cancer 5-year survivors, diagnosed 1970-
1986, up to 25 years follow-up
• Standardized mortality ratio (SMR):
– Overall mortality: 10.8 (10,3-11.3)
– Cardiac mortality: 8.2 (6.4-10.4)
Mertens et al, J Clin Oncol 2001
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The pathophysiology
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Farmakis et al. Eur J Heart Fail 2018
Determinants of cardiotoxicity in cancer
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1. Effects of cancer therapy
Lenneman and Sawyer, Circ Res 2016
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Main cardiotoxic agents
Ameri, Farmakis et al, Eur J Heart Fail 2018
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Molecular pathways of anthracycline
cardiotoxicity
Lenneman and Sawyer, Circ Res 2016
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Pathophysiology of anthracycline cardiotoxicity
Henriksen, Heart 2017
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Increased Top2β in peripheral blood in
anthracycline-sensitive patients
• Anthracycline-sensitive (n=21): low doxo dose (10% to 450 mg/m2 and preserved
LVEF)
Vejpongsa et al, Circulation 2013 (abstr)
0,4
24%
Anthra-resistant Anthra-sensitive
Top2β >0.5 ng/μg
• Top2β levels >0.5 ng/μg a risk factor
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Molecular pathways of ErbB2-targeted therapies
cardiotoxicity
Lenneman and Sawyer, Circ Res 2016
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ErbB2 is essential in the prevention of
dilated cardiomyopathy
• ErbB2-knock-out mice developed spontaneous dilated
cardiomyopathy
• Cardiomyocytes isolated from these mice were more
susceptible to anthracycline toxicity
Crone et al, Nat Med 2002
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Ewer and Ewer, Nat Rev Cardiol 2015
Anthracycline-trastuzumab synergy
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2. Effects of cancer
Farmakis et al, J Am Coll Cardiol 2014
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Cancer and heart failure interaction
Ameri, Farmakis et al, Eur J Heart Fail 2018
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Common risk factors in cancer and heart failure
Farmakis et al, Int J Cardiol 2016
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3. Effects of RF and CV disease
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Risk factors for cardiotoxicity
Farmakis et al, in press
Demographics Risk factors Heart disease Cancer therapy
Age 65 y
Diabetes Heart failure or LV
dysfunction
Prior antracyclines
Female gender
(anthracyclines)
Hypercho-
lesterolemia
CAD Prior chest
radiotherapy
Smoking Hypertensive HD
(LVH)
Combined
chemo/targeted
agents
Obesity Valvular HD
(mod./severe)
Combined chemo
and chest radiation
Sedentary life Cardiomyopathies Cumulative dose
(antrhacyclines)
Sign. arrhythmias
(AF, VT)
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The spectrum
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Myocardial dysfunction and heart failure:
Not just anthracyclines!
Farmakis et al, Eur J Heart Fail 2018
Class Drug Incidence
Anthacyclines Doxorubicin 3-48%
Alkylating agents Cyclophosphamide 7-28%
Antimicrotubule agents Docetaxel 2-13%
Monoclonal Ab Trastuzumab 1-20%
Tyrosine kinase inhibitors Sunitinib 3-19%
Proteasome inhibitors Carfilzomib 11-15%
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Cancer therapy cardiotoxicity:
Not just LV dysfunction!
Farmakis et al. (in press)
Class Drug
Arterial hypertension VEGF inh.
Myocardial ischemia Fluopyrimidines, cisplatin
Thromboembolism Cisplatin, VEGF inh.
QT prolongation Arsenic trioxide, lapatinib, vandetanib
Arrhythmias Alkylating agents, taxanes, anthracyclines
Myocarditis Check-point inhibitors
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Cardiovascular complications
in cancer
1. Myocardial dysfunction and heart failure
2. Coronary artery disease
3. Arrhythmias
4. Arterial hypertension
5. Valvular heart disease
6. Thromboembolic disease
7. Peripheral vascular disease and stroke
8. Pulmonary hypertension
9. Other: pericardial disease, ANS dysfunction
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The role of cardiologist:
In whom, when and how?
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In whom?
• Patients with a history of cardiotoxicity
• Patients with coexistent CV disease
• Patients with a constellation of CV risk factors
• Patients previously exposed to cardiotoxic therapies
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When?
• Before cancer therapy:
– Optimal treatment of CV disease and risk factors
– Primary prevention measures
• During cancer therapy:
– Close monitoring for early detection of cardiotoxicity
– Timely implementation of therapeutic measures
• After cancer therapy:
– Long-term surveillance
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How?
• Cardiovascular monitoring
• Prevention
• Treatment
• Long-term follow-up
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Cardiovascular monitoring
ESC 2016
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Cardinale et al, Circulation 2015
Echo monitoring for LVEF decline
• 2625 pts receiving anthracycline chemo (breast Ca or NHL)
• Close monitoring (3-monthy during chemo and 1st year, 6-monthly for 4
years, yearly afterwards)
• 9% LVEF decline (decrease >10% to
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Early detection of cardiotoxicity
Ewer and Ewer, Nat Rev Cardiol 2015
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Troponin predicts cardiac events and LVEF
decline
Cardinale et al, Circulation 2004
TnI measured soon after chemotherapy (early TnI) and 1 month later (late TnI).
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ΝT-proBNP predicts LVEF decline
Cardinale & Sandri, Prog Cardiovasc Dis 2010
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2D strain predicts LV dysfunction early
Stoodley et al, Eur J Echocard 2011
Florescu et al, J Am Soc Echocardiogr 2014
• Α decrease in longitudinal strain after the 3rd cycle of
epirubicin was the best predictor of cardiotoxicity
after treatment
• >15% reduction in global longitudinal strain
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2D strain predicts LV dysfunction early
• Global longitudinal strain >10-15% predicts future LVEF decline
Mougdil et al, Echocardiography 2018
Baseline 1 months 9 months
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Primary prevention
ESC 2016
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Dexrazoxane for primary prevention
• Meta-analysis, 10 RCTs, 1619 pts
• Reduction of heart failure by 70%
• No effect on tumor response rate, second malignancy or survival
• Inconclusive for adverse events
van Dalen et al, Cochrane Database Syst Rev. 2011
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Treatment
• Myocardial dysfunction/heart failure:
– LVEF decrease >10% and 10% but >50%: repeated LVEF in 3 w
• Coronary artery disease/events:
– Patients on pyrimidine analogues: close ECG monitoring for ischemia
– Discontinuation of chemotherapy if ischemia occurs; re-challenge only when
no alternatives, pretreatment with nitrates and/or CCB
• Arterial hypertension:
– Start antihypertensive agents (avoid non-dihydropyridine CCB)
– Reduce dose or stop VEGF inhibitors if BP not controlled; re-challenge once BP
controlled
• QT prolongation:
– Stop treatment if QTc >500 ms or QTc prolonged >60 ms or dysrhythmias
ESC 2016
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Cardinale et al, Circulation 2015
Effects of ACEi and BB on anthracycline-induced
cardiotoxicity
• 2625 pts receiving anthracycline chemo (breast Ca or NHL)
• Enalapril and carvedilol or bisoprolol:
• 82% LVEF recovery:
– 11% full recovery (pre-chemo value)
– 71% partial recovery (increase >5% and >50%)
• Mean time to LVEF recovery: 8 months
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Cardinale et al, JACC 2010
• 201 pts, LVEF 50% - 13% LVEF incr. >10% but
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ESC 2016
Long-term follow-up in cancer survivors
• Myocardial dysfunction: periodic screening (echo, biomarkers)
in patients treated with anthracyclines or with reversible LV
dysfunction during cancer therapy
• CAD: periodic screening in patients with mediastinal radiation,
starting 5 years post-treatment and at least every 5 years
thereafter
• Carotid artery disease: ultrasound scanning in patients with
previous neck irradiation
• Radiation-induced valvular heart disease: periodic screening
(echo) at 10 years post-radiation and every 5 years thereafter
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Τhe open issues
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Open issues
• Effectiveness of cardioactive agents in primary prevention
• Integration of biomarkers & sensitive echo techniques in
clinical practice
• Biomarker/echo-guided primary prevention
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Exercise for primary prevention
• Theoretical background
• Benefit proven in pre-clinical studies (rodent/murine models)
• Poor clinical evidence (observational studies, CRF as main outcome)
Chen et al, Am J Physiol Heart Circ Physiol 2017
Scott et al, Circulation 2018
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Trial Agent N Follow-up Endpoints
Kalay (2006) Carvedilol 12.5 50 6mo ↓ LVEF decline
↓ diastolic dysfunction
Bosch (2013)
OVERCOME
Carvedilol &
Enalapril
90 6mo ↓ LVEF decline
↓ Heat failure, death
Tashakori Behoshiti
(2016)
Carvedilol 6,25 70 During
chemo
No effect on LVEF
↓ LV strain decline
Avila (2018)
CECCY
Carvedilol 50 200 6mo No effect on LVEF
↓TnI increase
Guglin et al, Carvedilol CR or
lisinopril
470 24 monts ↓ LVEF decline only in
anthra-pretreated
Farmakis et al, in press
Main RCT on primary prevention:
Carvedilol
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Main RCT on primary prevention:
Other CV agents
Trial Agent N Follow-up Results
Cardinale (2006) Enalapril 114 12mo ↓ LVEF decline
↓ MACE
Pituskin (2015) Bisoprolol
Perindopril
99 12mo ↓ LVEF decline
Gulati (2015) Candesartan 120 12-16mo ↓ LVEF decline
Akpek (2015) Spironolactone 83 6mo ↓ LVEF decline
↓ TNI and BNP increase
Acar (2011) Atorvastatin 40 RCT/6mo ↓ LVEF decline
Farmakis et al, in press
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Ongoing trials
Meattini et al, Med Oncol 2017
Farmakis et al, in press
Trial Agent N Endpoints
SAFE Biosoprolol,
ramipril
480 Biomarkers, echo (GLS)
STOP Atorvastatin 90 CMR
McKennan Metformin 44 Echo (LVEF)
COG-ALTE1621 Carvedilol 250 Biomarkers, echo
TITAN Multidisciplinar
y care
Biomarkers, echo, MACE
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Biomarker-guided prevention
Enalapril in Tn elevation
• ICOS-ONE, open-label RCT
• 21 Italian hospitals, 273 pts
• 1st–line anthra
• Enalapril in all or in Tn ↑
• Mixed Tn assays (T/I, low/high sens.)
• Primary outcome, Tn elevation > ULN
• 23% vs. 26% (p=NS)
• LVEF decline only in 1%
Cardinale et al, Eur J Cancer 2018
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Antithrombotic therapy for AFib in cancer
Farmakis et al, J Am Coll Cardiol 2014
• Anticoagulation if CHA2DS2VASc >=2 and PTL >50,000/mm3
ESC 2016
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Cardiac journey of cancer patients
Cardinale et al, Curr Cardiol Rep 2016
??
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Thank you!
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