klinik und poliklinik für kinderchirurgie · 2017-06-06 · smith, l. a., v. r. cornelius, et al....
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Klinik und Poliklinik für Kinderchirurgie
THOMAS M. SUTER
KARDIOLOGIE UND KARDIO-ONKOLOGIE
UNIVERSITÄTSSPITAL BERN, SCHWEIZ
KARDIO-ONKOLOGIE
KARDIO-ONKOLOGIE [email protected]
ONCO-CARDIOLOGY
A cardiovascular sub-specialty focused on
identifying, preventing, and treating
cardiovascular complications of cancer therapy
www.cancerandtheheart.org
KARDIO-ONKOLOGIE [email protected]
CV SIDE EFFECTS OF MODERN CANCER THERAPY
„…you need to cure first…
…before you should be concerned about cardiotoxicity“
Emil J. Freireich, M.D., D.Sc. Oncologist
KARDIO-ONKOLOGIE [email protected]
Arrhythmia
QT-Prolong
AP / MICardiac Dysfunction
Cardiotoxicity
Thromboembolism
Hypertension
PAODPleural EffusionPulmonary
Hypertension
SYSTEMIC CANCER THERAPY RELATED CARDIOVASCULAR SIDE EFFECTS
KARDIO-ONKOLOGIE [email protected]
Arrhythmia
QT-Prolong
AP / MICardiac Dysfunction
Cardiotoxicity
Hypertension
PAODPleural EffusionPulmonary
Hypertension
Thromboembolism
SYSTEMIC CANCER THERAPY RELATED CARDIAC DYSFUNCTION/CARDIOMYOPATHY
KARDIO-ONKOLOGIE [email protected]
CARDIOVASCULAR SIDE EFFECTS OF CANCER TREATMENT
Cancer Therapy
Efficacy
Side Effects
Toxicity
KARDIO-ONKOLOGIE [email protected]
Suter, T. M. and M. S. Ewer, Eur Heart J 2013; 34(15): 1102-1111
KARDIO-ONKOLOGIE [email protected]
Modified; Hill JA, Olson EN-.N Engl J Med 2008;358:1370-80
THE HEART – A POSTMITOTIC, COMPLEX ORGAN
KARDIO-ONKOLOGIE [email protected]
INTRACELLULAR SIGNAL-TRANSDUCTION PATHWAYS MODULATING CARDIAC PROTEIN SYNTHESIS
Heineke J, Molkentin Nat Rev Mol Cell Biol 2006;7:589-600
Ras Inhib
TGF-b Inhib
Anti VEGF
Tyrosine Kinase Inh
EGFR Inhib
IGF 1 Inhib
Anti HER2
Raf Inhib
MEK Inhib
Farnesyl Transf Inhib
p38 Inhib
mTOR Inhib
HSP Inhib
Anti-Cyclin D1Anti HIF-1
HDAC Inhib
KARDIO-ONKOLOGIE [email protected]
WHAT IS CARDIOTOXICITY?
• Heart Failure • Cardiac Dysfunction
• Systolic Heart Failure (HFrEF)
asymptomatic
KARDIO-ONKOLOGIE [email protected]
SYSTEMIC THERAPY RELATED CARDIAC DYSFUNCTION / HEART FAILURE
Chemotherapeutics Cardiac Dysfunction Heart Failure
Anthracyclines
- Doxorubicin
- Epirubicin
2 – 12 %
4 – 15 %
Cyclophosphamide 1 %
Signaling Inhibitors
Trastuzumab 3-18 % 4 %
Lapatinib 10 % 2 %
Pertuzumab 3 – 18% 0 - 2% (9%)
Bevacizumab 3- 10 % 2-4 %
Sunitinib 8 -15 % 10 %
Sorafenib 1%
Pazopanib 7% 1%
Imatinib 2 % <1 %
Carfilzomib 19-25%
HE
R2
-In
hA
nti-V
EG
FB
cr-
Ab
l
Pro
t-
Inh
ib
KARDIO-ONKOLOGIE [email protected]
Anthracyclines (-like) Toxicity Intensifiers
Doxorubicin Cyclophosphamide
Indarubicin Mitamycin-C
Epirubicin Etoposide
Daunorubicin Vincristine
Bleomycin
Mitoxantrone Ifosfamide
Signaling Inhibitors
Trastuzumab
Pertuzumab
Lapatinib
Sunitinib
KARDIO-ONKOLOGIE [email protected]
days -weeks
1 y 2 y 3 y 4 y 5 y 6 y 7 y 8 y 9 y 10 y ...
ANTHRACYCLINE CARDIOTOXICITY – TIME COURSE
Early
Toxicity
Late Toxicity
Acute
Toxicity
Anthra
Heart Failure Treatment (ACE-I; BB)
KARDIO-ONKOLOGIE [email protected]
Heart Failure in RTCs
Smith, L. A., V. R. Cornelius, et al. (2010). BMC Cancer 10: 337
CARDIOTOXICITY OF ANTHRACYCLINES
0
10
20
30
40
50
60
70
80
90
100
0 100 200 300 400 500 600 700 800 900
Swain et al.
Von Hoff
CH
F (
%)
Doxorubicin Cumulative Dose (mg/m2)
Von Hoff D et al. Am J Med 1977;62:200-208
Swain S et al. Cancer 2003.Singal PK et al. NEJM 1998, 339, 900-5
• Cumulative dose of doxorubicin
• Combination therapy (CT and Sig Inhibitors)
• Prior/concomitant mediastinal radiotherapy
• Age
• Previous cardiac disease
• Hypertension
• Genetic predisposition
Risk Factors
KARDIO-ONKOLOGIE [email protected]
Normal
Myocyte
cytosol
extracellular
[Ca2+]i
Protein
Degradation
Protein
Synthesis
Myofibrillar
DisorganizationMyocyte
Necrosis
Myocyte
Apoptosis
[Ca2+]i [Ca2+]i
Protein
Degradation
Protein
Synthesis
Proteases Caspases
Sawyer DB, Suter TM: Circulation 2002Lim CC, Suter TM, Sawyer DB: J Biol Chem. 2004 Salvatorelli E, Minotti G: J Pharmacol Exp Ther 2013
Doxorubicin
KARDIO-ONKOLOGIE [email protected]
• Dose limitation
• Continuous infusion
• Liposomal delivery systems
• Less toxic anthracyclines
• Dexrazoxane
• ACE inhibition
CARDIOTOXICITY OF ANTHRACYCLINES- PREVENTION
KARDIO-ONKOLOGIE [email protected]
KARDIO-ONKOLOGIE [email protected]
de Azambuja, E., Suter T.M. et al J Clin Oncol. 2014 Jun 9
ANTI-HER2 CARDIOTOXICITY
KARDIO-ONKOLOGIE [email protected]
TRASTUZUMAB CARDIOTOXICITY - MECHANISMS
Strasser F, Suter TM.: NEJM 2001, 345(13): 996
HER2 in Human Heart
Force T , and Wang Y Circulation 2013;128:98-100
KARDIO-ONKOLOGIE [email protected]
PROGRESS IN CARDIO-ONCOLOGY
Slamon D. et al. N Engl J Med, 2001; 344 Piccart-Gebhart, M., et al. J Clin Oncol. 2015Romond EH et al. N Engl J Med 2005;353:1673-84
2001 Metastatic HER2 pos 2005 Adjuvant HER2 pos 2014 Adjuvant HER2 pos
0%
5%
10%
15%
20%
25%
30%
Metastatic HER2pos
HERA NSABP B-31 NCCTG N 9831 BCIRG006_Anthra
BCIRG 006_Taxo ALTTO L+T ALTTO T->L Trast
Severe Heart Failure
Card Dysfunction
KARDIO-ONKOLOGIE [email protected]
Prior RX
Risk Assessment
During Rx
Avoid Toxicity
Survivor
Surveillance
CV SIDE EFFECTS – PREVENTION/REDUCTION
KARDIO-ONKOLOGIE [email protected]
SCH-R. S. 14.07.1980
• 01.13 Mamma-Ca re pT1c,pN0(0/2),cM0,R0,G2
Ablatio re, LK-Entfernung
ER>90%, PR<1%, Hercep Test <10%,
«Luminal B, HER2-neg»
• 01.13 TTE normal
• 02.-05.13 EC x 4
• 06.13 Tamoxifen
- Dyspnoe – Spiral-Thorax-CT
- «Tamoxifen Hypersensivitätspneumonitis»
- Stopp Tamoxifen, Steroide
- Appetitlosigkeit, Dyspnoe, Abgeschlagenheit
KARDIO-ONKOLOGIE [email protected]
SCH-R. S. 14.07.1980
• 01.07.13 Spital Davos - ambulant
Progrediente Symptome
- CK 68, TnI 0.311 (<0.013), ASAT 122
• 03.07.13 Tachypoe, tachykard, hypoton
IMC Spital Davos
aBGA unter 8 l O2
- pH 7.2, pO2 78, pCO2 15.6 BE -19 Lact 9.1
- CK 824, TnI 2.32, ASAT 2943
KARDIO-ONKOLOGIE [email protected]
During Rx
Avoid Cardiotoxicity
Nature Medicine; 2011: 304–312
CARDIOTOXICITY – PREVENTION/REDUCTION
KARDIO-ONKOLOGIE [email protected]
0
10
20
30
40
50
60
Pre Pre 26.10.2015 23.12.2015 13.01.2016 17.02.2016
LVEF
LVEDD
O.S. 24.10.1952
A/C Ptx+Trast Trast
Heart Failure
ACE-Inhibitor
Beta-Blocker
Heart Failure
• Invasiv ductal Breast Cancer
• pT1c (16mm) N0(0/3)(sn)(i-)cM0
• Breast conserving surgery 08.11
–ER y1%, PR <1%, Ki-67 30-35%
HER-2/neu Score +++
KARDIO-ONKOLOGIE [email protected]
0
10
20
30
40
50
60
70
LV
EF
(%
) / LV
ED
D (
mm
)
LVEF
LVEDD
• Invasiv ductal Breast Cancer
• pT2 N0(0/5)(sn)(i-)M0, R0, G3
• Breast conserving surgery 08.11
–ER y1%, PR <1%, Ki-67 20%, p53-Expression <10%,
HER-2/neu 100%, Score ++
S.R. 19.11.1971
Epi/Endo Ptx+Trast Trast
Heart Failure
ACE-Inhibitor
KARDIO-ONKOLOGIE [email protected]
CARDIAC DYSFUNCTION / HEART FAILURE DURING AND AFTER
CANCER THERAPY
Suter, T. M. and M. S. Ewer, Eur Heart J 2013; 34(15): 1102-1111
• Anthracycline
• Risk Factors– Cumulative Dose
– Combination chemotherapy
– Prior/concomitant
mediastinal
radiotherapy
– Age
– Previous cardiac disease
– Hypertension
010203040506070
Pre 6
12
18
24
30
36
42
48
54
60
66
72
LV
EF
%
Months
Rx
010203040506070
Pre 6
12
18
24
30
36
42
48
54
60
66
72
LV
EF
(%
)
Months
Rx
• Signaling Inhibitors
• Risk Factors– Prior / concomitant anthracyclines
– Age > 50 y/o
– Previous cardiac disease
– Hypertension
– Higher BMI
KARDIO-ONKOLOGIE [email protected]
CARDIOVASCULAR SIDE EFFECTS OF RADIATION THERAPY
Ischemia
Cardiac Dysfunction
Valvular Disease Pericardial Disease
Conduction Disease
KARDIO-ONKOLOGIE [email protected]
THE HEART – A POSTMITOTIC, COMPLEX ORGAN
KARDIO-ONKOLOGIE [email protected]
Survivor
Surveillance
CARDIOTOXICITY – PREVENTION/REDUCTION
Childhood Cancer Survivors
• signs of cardiotoxicity
• within 10 years after therapy
Lipshultz SE et. al. Circulation. 2013;128(17):1927-95
Van der Pal HJ J Clin Oncol. 2012 May 1;30(13):1429-37
KARDIO-ONKOLOGIE [email protected]
Heart Failure
Patient
Oncology
Patient
Heart Failure
Patient
Oncology
Patient
KARDIO-ONKOLOGIE [email protected]
Prior RX
Risk Assessment
• Conventional RF
• Novel RF
• Rx Preexisting Dz
ROLE OF CARDIO-ONCOLOGIST
During Rx
Avoid Cardiotoxicity
Manage Side Effects
• Co-Medication
• Early Detection
• Risk Assessment
Survivor
Surveillance
• Early Detection
• Early Treatment
KARDIO-ONKOLOGIE [email protected]
CARDIAC MONITORING OF CANCER PATIENTS DURING
CANCER THERAPY
• «normal» LVEF ≥ 55%
• decrease in LVEF of >10 % points, to a value < 50%
• repeat study 3 weeks after baseline study
• LVEF with best method available (ideally 3DE)
• myocardial deformation using 2D speckle-tracking
• combination with biomarkers
KARDIO-ONKOLOGIE [email protected]
CARDIO-ONCOLOGY BERN UNIVERSITY HOSPITAL
Tel. +41 31 632-5173
Email [email protected]