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Therapy-Related Cardiac Toxicity in Cancer Patients. JEAN-BERNARD DURAND, M.D., FCCP, FACC ASSOCIATE PROFESSOR OF MEDICINE MEDICAL DIRECTOR CARDIOMYOPATHY SERVICES UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER HOUSTON, TEXAS. Jean-Bernard Durand, M.D. Presenter Disclosure Information. - PowerPoint PPT Presentation
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Therapy-Related Cardiac Toxicity in Cancer Patients
JEAN-BERNARD DURAND, M.D., FCCP, FACCASSOCIATE PROFESSOR OF MEDICINE
MEDICAL DIRECTOR CARDIOMYOPATHY SERVICESUNIVERSITY OF TEXAS
MD ANDERSON CANCER CENTERHOUSTON, TEXAS
I will not discuss off label use and/or investigational use in my presentation.
I have the following financial relationships to disclose:– Astellas– Employee of: University of Texas MD Anderson
Cancer Center
Jean-Bernard Durand, M.D.Presenter Disclosure Information
Overview• Cardiovascular disease is the number two killer
of cancer survivors• 108 million baby boomers will enter healthcare
industry by 2015• By 2015 over 15 Million U.S. cancer survivors
– Many definitions of a cancer survivor– Cardiologist viewpoint: survivorship starts at time of
diagnosis (Dr.Fitzhugh)
Overview
• Cancer treatment has shifted to targeted therapies, with more than 30 new agents in the past five years – Life-saving drugs and cardiology approach should
support use; not interrupt use– Limited randomized controlled trials on prevention of
cardiotoxicity – Treatment is based on prevention, early detection,
prevention of progression heart failure
Armstrong GT et al. JCO.2009;27:2328-2338
Late Mortality Among 5 Year Survivors of Childhood Cancer CCSS
N=20,483
• CAD or history of MI• Hypertension• Diabetes• Alcoholism• Cardiotoxic drugs• Inherited
cardiomyopathies• Sleep apnea
• Valvular heart disease • Congenital heart defects• Other:
– Obesity– Age– Reduced or falling vital
capacity– Smoking– High of low hematocrit
level
Risk Factors for Heart Failure
Dexrazoxane
Dexrazoxane
New Hypothesis
Doxorubicin-induced cardiotoxicity is mediated by Top2b
Two different Top2: a and b
Doxorubicin poisons both Top2a and Top2b.
Proliferating cells express Top2a.
However, the adult heart only expresses Top2b.
Top2bTop2b
15 mg/kg Doxorubicin IP Control
+/+ ∆/∆+/+∆/∆
Acute Model
Reactive Oxygen Species
Topoisomerase IIb
Top2b is required for doxorubicin-induced ROS production
?
Doxorubicin
Top2b deletion prevents doxorubicin-cardiotoxicity
Yeh et al Nature 2012
American Cancer Society
Cancer 2005; 104:2492-8
RPCT-Valsartan for Prevention of Cardiotoxicity
o Placebo
Valsartan
RPCT- Lipitor 40mg daily/Total dose doxo=251mg,one cycle per month X 6 monthsJACC Vol 58:2011
Therapies for Prevention of Cardiotoxicity with Anthracyclines
Comparison of LVEF at Baseline and After Chemotherapy
Kalay et al. JACC. Dec 2006. 48:2258-62Data expressed as mean values.
JACC Apr 9 2013
Overcome Trial
N=90
JACC Apr 9 2013
Overcome Trial
N=90
Journal of American College of Cardiology January 2010
Limited Time to Start Therapy
Journal of American College of Cardiology January 2010
Responders Have Less Cardiac Event Rates
703 patients (216 males) Age 47±12 years Treated with HDC Poor prognosis malignancies
TnI serum determination: Baseline = Before HDC Early = soon after HDC (0,12,24,36,72 hours) Late = 1 month after HDC Circulation 2004
♫ Follow-up = 48 months♫ MACE incidence
Cardiac Events3.5 Year Follow-up
Sudden deathCardiac deathAcute pulmonary edemaHeart failureAsymptomatic LVEF >25%Life-threatening arrhythmiasConduction disturbances requiring PM implantation
PersistentTnI +
NegativeTnI
TransientTnI +
Circulation 2004
1%
*= p<0.001 vs. TnI -
37% *
#= p<0.001 vs. TnI +-
84% * #
Positive predictive value = 84% Negative predictive value = 99%
=
=
=
High risk
Intermediate risk
Low risk
Persistent TnI+
Transient TnI+
Negative TnI
Cardiac Risk Stratification
Troponin I Early Positivity
Enalapril n = 56 pts
Controls n = 58 pts
physical examination, ECG, ECHO: b,1,3,6,12 months
started 1 month after HDC continued for 1 year
443 pts High-dose CT
TnI + = 114 pts (24%)
Secondary End-pointsFollow-up 12 months
Sudden death 0 (0%) 0 (0%) 0 (0%) NSCardiac death 2 (2%) 0 (0%) 2 (3%) NSAcute pulmonary edema 4 (2%) 0 (0%) 4 (3%) NSHeart failure 14 (12%) 0 (0%) 14 (22%) <0.001Life-threatening arrhythmias 11 (10%) 1 (2%) 10 (16%) 0.01
CUMULATIVE EVENTS 31 (28%) 1 (2%) 30 (52%) 0.001
Totaln=112 P
ACEI n=54
Controlsn=58
Cardinale et al. Circulation 2006
Cycle 1Baseline ECGEcho/Strain
TroponinBNP
Cycle 2BNP/Troponin
(-) proceed,(+) Echo(Strain),
Consider Ace/BB?
Continue Chemo
Cycle 3BNP/Troponin
(-) proceed,
(+) Echo(Strain), Consider Ace/BB?
Continue Chemo
Cycle 4BNP/Troponin
(-) proceed,
(+) Echo(strain), Consider Ace/BB?
Continue Chemo
Heart Failure Specialist Perspective Continuum of Cancer
Intervention
Lymphoma Patient-R-Chop
ECG HR<60 (Qtc)Any symptoms
Stop dox LVEF<40%
MUGA• Accurate for low
ejection fraction • Less accurate with
rhythm disorders• No information on
valvular disorders• Little information on
wall motion abnormalities
Echo• Valvular heart disease• Wall motion
abnormalities• Pulmonary pressures• Hemodynamics• Diastology• Strain
Echo Versus MUGA?
Class I Indications Assessment of LV Function
• Suspected cardiomyopathy or CHF• Edema with clinical signs of increased CVP• Dyspnea or clinical signs of heart disease• Unexplained hypotension• Exposure to cardiotoxic agents• “Pre-chemo”• Re-evaluation change in status or Rx
ACC/AHA/ASE Guidelines of Echo 2003
Cardiotoxicity occurs earlier than change in EF
3
2
1
0
Mackay — MDAH
Billingham — Stanford
200 –400 401 – 500 >500
Cumulative Doxorubicin Dose (mg/m2)
Doxorubicin was given IV every 3 to 4 weeks.Biopsy specimens were taken approximately 3 weeks following last therapy.
Mea
n B
iops
y G
rade
n=8n=18
n=22 n=8
n=3
n=7
Adapted from Ewer et al. J Clin Oncol 1984;2:112-117.
5% *
*Risk of CHF
Committee for Proporietary Medicinal Products . The European Agency for the Medicinal Products .London 17th Dec 1997.
http://www.emea.eu.int/pdfs/human/swp/098696en.pdf
Termination of T-wave; In the Eyes of the Beholder
Cancer patients: risks for prolonged QTc .
ECG Percent Reference
Prolonged QTc 10.6% Barbey et al 2003
Borderline or prolonged QTc
15% Vaterasian, et al. 2003
any ECG anomaly 36% Barbey et al 2003
• molecularly targeted agents with QTc• adjuvant regimens, long treatment periods• survival emphasis toxicity reduction
WHEN TO WORRY ABOUT QT?
• More than 25% prolongation of QTc interval from the baseline or a QTc interval longer than 500 ms increases the risk of precipitation of drug-induced torsade de pointes
• More than 90% of incidences of drug-induced torsade de pointes occur with QTc values of more than 500 ms
Bednar MM et al. Am. J. Cardiol 2002;89:1316–1319 Gowda RM et al. Int J Cardiol 2004;96:1-6
TREATMENT
• Discontinuation of the offending agent: Any offending agent should be withdrawn. Predisposing conditions such as hypokalemia, hypomagnesaemia, and bradycardia should be identified and corrected.
• (>90% of time, we just stop supportive cast of medications)
PROGNOSIS
• Because Long QT interval is primarily an electrical disorder, in the absence of structural heart disease and LV dysfunction, the long-term prognosis is good as long as the offending agents and risk factors are corrected and arrhythmia is controlled.
Things to Consider
• More than 500 known tyrosine kinases from Human Genome Project– Over 250 of these tyrosine kinases are cloned,
and expressed– 7 Tyrosine kinases are FDA approved– 4 Tyrosine kinases targeted (17 kinases in vivo)– How many kinases in the human genome are
cardiac specific?
Kinase-binding profiles of the ABL inhibitors imatinib (upper panel), dasatinib (middle panel), and bosutinib (bottom panel) across a set of protein kinases simultaneously identified from K562 cells. The bars indicate the IC50 values, defined as the concentration of drug at which half-maximal competition of kinobead binding is observed.
Nature Biotechnology 25(9)2007
Selective vs. Non-Selective Kinase Binding Profiles
Drug-Induced HF of FDA Approved Targeted Cancer Therapies
Sorafenib 2007 VEGF1,2,3/PDGF 1%
Dasatinib 2006 BCR-ABL/SRC C-Kit, PDGF
4%
Sunitinib 2006 VEGF/PDGF/ C-KIT
3-14%
Bevacizumab 2004 VEGF 2-14%
Trastuzumab 2000 ErbB-2/TKI 3-27%
Imatinib 2001 C-ABL, C-Kit 1%
Drug Approval Action CHF
FDA Approved Targeted Therapies
Sorafenib CMP Yes SHF
Dasatinib CMP Yes SHF
Sunitinib HTN/CMP Yes SHF/DHF
Bevacizumab HTN/CMP Yes SHF/DHF
Trastuzumab CMP Yes SHF
Imatinib CMP Yes SHF
Drug HTN/CMPResponds to
ACE/BB SHF/DHF
38
Hypertension is a Biomarker of Efficacy in Patients with Metastatic Renal Cell
Carcinoma Treated with Sunitinib
BI Rini,1 DP Cohen,2 DR Lu,2 I Chen,2 S Hariharan,3 RA Figlin,4
MS Baum,5 RJ Motzer5
1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Pfizer Oncology, 2La Jolla, CA, 3New York, NY;
4City of Hope National Medical Center, Duarte, CA; 5Memorial Sloan-Kettering Cancer Center, New York, NY, USA
39
Clinical Outcome by HTN StatusMax. SBP
≥140 mmHg (n=441)
Max. SBP <140 mmHg
(n=93) P-valueObjective response, n (%) 241 (54.6%) 9 (9.7%) <0.0001Progression-free survival, months 12.5 2.5 <0.0001Overall survival, months 30.5 7.8 <0.0001
Max. DBP ≥90 mmHg
(n=362)
Max. DBP <90 mmHg
(n=172) P-valueObjective response, n (%) 207 (57.2%) 43 (25.0%) <0.0001Progression-free survival, months 13.4 5.3 <0.0001Overall survival, months 32.1 15.0 <0.0001
40
Median OS by Use of Anti-HTN Agents, HTN-induced Dose Reductions and HTN Status as
Defined by Maximum SBP ≥140 mmHg on Sunitinib
1.00.90.80.70.60.50.40.30.20.10.0P
roba
bilit
y of
ove
rall
surv
ival
0 5 10 15 20 25 30 35 40 45 50Time (months)
Dose reduction onlyAnti-HTN drug onlyBothNeitherNo HTN
Powe, D. G. & Entschladen, F. Nature Reviews Clinical Oncology 8, 511-512 (2011)
Binding to specific adrenergic receptors, β‑blockers inhibit cancer cell migration and metastasis, suggesting a novel targeted therapeutic application in protecting against breast cancer disease progression
J Clin Oncol 29;2645-2652
Oncotarget 2010; 1:628-638
Baseline Hypertensive BC Patients Treated with Beta Blockers Live Longer
Heart Success
• Organizations for future:• Conquer, MD Anderson Cancer Center, 2001• Cardiology Oncology Partnership Vanderbilt
USA, 2004• International Society for Cardioncology, Milan,
Italy, 2009• Brazilian Cardiology Oncology, Sao Paulo,
Brazil, 2009• Canadian Cardioncology, 2010
Conclusions• Cardiologists and oncologists must collaborate
• Exciting new cancer therapies are being discovered, however, in order to maximize their potential, cardiac toxicities need to be identified and addressed upfront
• Although recent clinical experience has shown significant cardiotoxicity post-trial with cancer therapies, we have also seen resolution of toxicity using evidence-based cardiology guidelines (beta blockers need further study)
• More collaborative work with biomarkers/cardiac imaging for early detection and treatment
Patients receiving diuretics, ACE inhibitors, ± digoxin; follow-up 6 months; placebo (n=84), carvedilol (n=261).*Multicenter Oral Carvedilol Heart Failure Assessment.Adapted from Bristow MR et al. Circulation. 1996;94:2807–2816.
Carvedilol
Placebo0
1
2
3
4
5
6
7
8
LV
EF
(EF
units
)
Changes in LVEF
P<.001
‡
‡
‡
‡P<.05 vs placebo.
25 mg bid6.25 mg bid 12.5 mg bid
Carvedilol Dose-Response Trial (MOCHA*):Effect on Ejection Fraction and Mortality
