TherapyRelated Cardiac Toxicity in Cancer Patients JEANBERNARD DURAND
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 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
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
Late Mortality Among 5 Year Survivors of Childhood Cancer CCSS Armstrong GT et al. JCO. 2009; 27: 2328 -2338 N=20, 483
Risk Factors for Heart Failure • • • 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
Dexrazoxane
Two different Top 2: a and b Doxorubicin poisons both Top 2 a and Top 2 b. Proliferating cells express Top 2 a. However, the adult heart only expresses Top 2 b. New Hypothesis Doxorubicin-induced cardiotoxicity is mediated by Top 2 b
Acute Model Top 2 b +/+ ∆/∆ 15 mg/kg Doxorubicin IP ∆/∆ +/+ Control
Top 2 b is required for doxorubicin-induced ROS production Doxorubicin Topoisomerase IIb ? Reactive Oxygen Species
Top 2 b deletion prevents doxorubicin-cardiotoxicity Yeh et al Nature 2012
Therapies for Prevention of Cardiotoxicity with Anthracyclines RPCT-Valsartan for Prevention of Cardiotoxicity Cancer 2005; 104: 2492 -8 o Placebo Valsartan JACC Vol 58: 2011 RPCT- Lipitor 40 mg daily/Total dose doxo=251 mg, one cycle per month X 6 months
Comparison of LVEF at Baseline and After Chemotherapy Data expressed as mean values. Kalay et al. JACC. Dec 2006. 48: 2258 -62
Overcome Trial JACC Apr 9 2013 N=90
Overcome Trial JACC Apr 9 2013 N=90
Limited Time to Start Therapy Journal of American College of Cardiology January 2010
Responders Have Less Cardiac Event Rates Journal of American College of Cardiology January 2010
¬ 703 patients (216 males) ¬ Age 47± 12 years ¬ Treated with HDC ¬ Poor prognosis malignancies ♫ Follow-up = 48 months ♫ MACE incidence ü Tn. I serum determination: l Baseline = Before HDC l Early = soon after HDC (0, 12, 24, 36, 72 hours) l Late = 1 month after HDC Circulation 2004
Cardiac Events 3. 5 Year Follow-up Negative Tn. I Sudden death Cardiac death Acute pulmonary edema Heart failure Asymptomatic LVEF >25% Life-threatening arrhythmias Conduction disturbances requiring PM implantation *= p<0. 001 vs. Tn. I - #= p<0. 001 vs. Tn. I +- Transient Tn. I + Persistent Tn. I + 84% * # 37% * 1% Circulation 2004
Cardiac Risk Stratification Persistent Tn. I+ = Transient Tn. I+ = Negative Tn. I = Positive predictive value = 84% High risk Intermediate risk Low risk Negative predictive value = 99%
Troponin I Early Positivity 443 pts High-dose CT Tn. I + = 114 pts (24%) Tn. I + = Enalapril ü n = 56 pts ü started 1 month after HDC ü continued for 1 year Controls ü n = 58 pts ü physical examination, ECG, ECHO: b, 1, 3, 6, 12 months
Secondary End-points Follow-up 12 months Total n=112 Sudden death Cardiac death Acute pulmonary edema Heart failure Life-threatening arrhythmias CUMULATIVE EVENTS Cardinale et al. Circulation 2006 ACEI n=54 Controls n=58 P 0 (0%) NS 2 (2%) 0 (0%) 2 (3%) NS 4 (2%) 0 (0%) 4 (3%) NS 14 (12%) 0 (0%) 14 (22%) <0. 001 11 (10%) 1 (2%) 10 (16%) 0. 01 31 (28%) 1 (2%) 30 (52%) 0. 001
Heart Failure Specialist Perspective Continuum of Cancer Intervention Lymphoma Patient-R-Chop Cycle 3 BNP/Troponin Cycle 4 BNP/Troponin (-) proceed, (+) Echo(Strain), Consider Ace/BB? (+) Echo(strain), Consider Ace/BB? Continue Chemo Cycle 1 Cycle 2 Baseline ECG BNP/Troponin Echo/Strain Troponin BNP ECG HR<60 (Qtc) Any symptoms Continue Chemo Stop dox LVEF<40%
Echo Versus MUGA? Echo • Valvular heart disease • Wall motion abnormalities • Pulmonary pressures • Hemodynamics • Diastology • Strain MUGA • Accurate for low ejection fraction • Less accurate with rhythm disorders • No information on valvular disorders • Little information on wall motion abnormalities
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 Doxorubicin was given IV every 3 to 4 weeks. Biopsy specimens were taken approximately 3 weeks following last therapy. Mean Biopsy Grade 3 5% Mackay Billingham 2 n=7 — MDAH n=22 n=8 1 n=3 — Stanford n=8 n=18 * 0 *Risk of CHF 200 – 400 401 – 500 Cumulative Doxorubicin Dose (mg/m 2) Adapted from Ewer et al. J Clin Oncol 1984; 2: 112 -117. >500
Committee for Proporietary Medicinal Products. The European Agency for the Medicinal Products. London 17 th Dec 1997. http: //www. emea. eu. int/pdfs/human/swp/098696 en. 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?
Selective vs. Non-Selective Kinase Binding Profiles 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 K 562 cells. The bars indicate the IC 50 values, defined as the concentration of drug at which half-maximal competition of kinobead binding is observed. Nature Biotechnology 25(9)2007
Drug-Induced HF of FDA Approved Targeted Cancer Therapies Drug Approval Action CHF Sorafenib 2007 VEGF 1, 2, 3/PDGF 1% Dasatinib 2006 BCR-ABL/SRC 4% C-Kit, PDGF Sunitinib 2006 VEGF/PDGF/ C-KIT 3 -14% Bevacizumab 2004 VEGF 2 -14% Trastuzumab 2000 Erb. B-2/TKI 3 -27% Imatinib 2001 C-ABL, C-Kit 1%
FDA Approved Targeted Therapies Drug HTN/CMP Responds to ACE/BB SHF/DHF 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
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 Motzer 5 1 Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Pfizer Oncology, 2 La Jolla, CA, 3 New York, NY; 4 City of Hope National Medical Center, Duarte, CA; 5 Memorial Sloan-Kettering Cancer Center, New York, NY, USA 38
Clinical Outcome by HTN Status Objective response, n (%) Progression-free survival, months Overall survival, months Max. SBP ≥ 140 mm. Hg (n=441) Max. SBP <140 mm. Hg (n=93) P-value 241 (54. 6%) 9 (9. 7%) <0. 0001 12. 5 30. 5 2. 5 7. 8 <0. 0001 Max. DBP ≥ 90 mm. Hg (n=362) Max. DBP <90 mm. Hg (n=172) P-value 207 (57. 2%) 43 (25. 0%) <0. 0001 13. 4 5. 3 <0. 0001 32. 1 15. 0 <0. 0001 39
Probability of overall survival Median OS by Use of Anti-HTN Agents, HTNinduced Dose Reductions and HTN Status as Defined by Maximum SBP ≥ 140 mm. Hg on Sunitinib 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 Dose reduction only Anti-HTN drug only Both Neither No HTN 0 5 10 15 20 25 30 35 Time (months) 40 45 50 40
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 Powe, D. G. & Entschladen, F. Nature Reviews Clinical Oncology 8, 511 -512 (2011)
J Clin Oncol 29; 2645 -2652
Baseline Hypertensive BC Patients Treated with Beta Blockers Live Longer Oncotarget 2010; 1: 628 -638
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
Thank you! • Twitter Jean-Bernard Durand@oncocardiology jdurand@mdanderson. org
Carvedilol Dose-Response Trial (MOCHA*): Effect on Ejection Fraction and Mortality Changes in LVEF 8 01 . 0 P< 7 LVEF (EF units) ‡ ‡ 6 ‡ 5 4 3 2 1 0 Placebo 6. 25 mg bid 12. 5 mg bid 25 mg bid Carvedilol 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. ‡P<. 05 vs placebo.
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