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Therapy-Related Cardiac Toxicity in Cancer Patients

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.

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Therapy-Related Cardiac Toxicity in Cancer Patients

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  1. 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 CENTERHOUSTON, TEXAS

  2. 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

  3. 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)

  4. 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

  5. Late Mortality Among 5 Year Survivors of Childhood Cancer CCSS N=20,483 Armstrong GT et al. JCO.2009;27:2328-2338

  6. Risk Factors for Heart Failure • Valvular heart disease • Congenital heart defects • Other: • Obesity • Age • Reduced or falling vital capacity • Smoking • High of low hematocrit level • CAD or history of MI • Hypertension • Diabetes • Alcoholism • Cardiotoxic drugs • Inherited cardiomyopathies • Sleep apnea

  7. Dexrazoxane Dexrazoxane

  8. Two different Top2: a and b Doxorubicin poisons both Top2a and Top2b. Proliferating cells express Top2a. However, the adult heart only expresses Top2b. New Hypothesis Doxorubicin-induced cardiotoxicity is mediated by Top2b

  9. Acute Model Top2b Top2b ∆/∆ ∆/∆ +/+ +/+ Control 15 mg/kg Doxorubicin IP

  10. Top2b is required for doxorubicin-induced ROS production Doxorubicin Topoisomerase IIb ? Reactive Oxygen Species

  11. Top2b deletion prevents doxorubicin-cardiotoxicity Yeh et al Nature 2012

  12. American Cancer Society Therapies for Prevention of Cardiotoxicity with Anthracyclines RPCT-Valsartan for Prevention of Cardiotoxicity • Placebo • Valsartan Cancer 2005; 104:2492-8 JACC Vol 58:2011 RPCT- Lipitor 40mg daily/Total dose doxo=251mg,one cycle per month X 6 months

  13. Comparison of LVEF at Baseline and After Chemotherapy Data expressed as mean values. Kalay et al. JACC. Dec 2006. 48:2258-62

  14. Overcome Trial N=90 JACC Apr 9 2013

  15. Overcome Trial N=90 JACC Apr 9 2013

  16. Limited Time to Start Therapy Journal of American College of Cardiology January 2010

  17. Responders Have Less Cardiac Event Rates Journal of American College of Cardiology January 2010

  18. 703 patients (216 males) • Age 47±12 years • Treated with HDC • Poor prognosis malignancies • Follow-up = 48 months • MACE incidence • TnI serum determination: • Baseline = Before HDC • Early = soon after HDC (0,12,24,36,72 hours) • Late = 1 month after HDC Circulation 2004

  19. Cardiac Events 3.5 Year Follow-up Transient TnI + Negative TnI Persistent TnI + # * Sudden death Cardiac death Acute pulmonary edema Heart failure Asymptomatic LVEF >25% Life-threatening arrhythmias Conduction disturbances requiring PM implantation 84% * 37% 1% *= p<0.001 vs. TnI - #= p<0.001 vs. TnI +- Circulation 2004

  20. Cardiac Risk Stratification = High risk Persistent TnI+ = Intermediate risk Transient TnI+ = Negative TnI Low risk Positive predictive value = 84% Negative predictive value = 99%

  21. Troponin I Early Positivity 443 pts High-dose CT TnI + = 114 pts (24%) Controls Enalapril • n = 58 pts • n = 56 pts • started 1 month after HDC • continued for 1 year • physical examination, ECG, ECHO: b,1,3,6,12 months

  22. Secondary End-points Follow-up 12 months Total n=112 Controls n=58 ACEI n=54 P Sudden death 0 (0%) 0 (0%) 0 (0%) NS Cardiac death 2 (2%) 0 (0%) 2 (3%) NS Acute pulmonary edema 4 (2%) 0 (0%) 4 (3%) NS Heart failure 14 (12%) 0 (0%) 14 (22%) <0.001 Life-threatening arrhythmias 11 (10%) 1 (2%) 10 (16%) 0.01 CUMULATIVE EVENTS 31 (28%)1 (2%) 30(52%)0.001 Cardinale et al. Circulation 2006

  23. Heart Failure Specialist Perspective Continuum of Cancer Intervention Lymphoma Patient-R-Chop Cycle 3 BNP/Troponin (-) proceed, (+) Echo(Strain), Consider Ace/BB? Continue Chemo Cycle 4 BNP/Troponin (-) proceed, (+) Echo(strain), Consider Ace/BB? Continue Chemo Cycle 2 BNP/Troponin (-) proceed, (+) Echo(Strain), Consider Ace/BB? Continue Chemo Cycle 1 Baseline ECG Echo/Strain Troponin BNP ECG HR<60 (Qtc) Any symptoms Stop dox LVEF<40%

  24. 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

  25. 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

  26. 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. 3 n=7 Mackay — MDAH n=3 Billingham — Stanford 2 n=8 n=22 Mean Biopsy Grade n=8 n=18 1 5% * 0 200 – 400 >500 401 – 500 Cumulative Doxorubicin Dose (mg/m2) *Risk of CHF Adapted from Ewer et al. J Clin Oncol 1984;2:112-117.

  27. 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

  28. Termination of T-wave; In the Eyes of the Beholder

  29. Cancer patients: risks for prolonged QTc . • molecularly targeted agents with  QTc • adjuvant regimens, long treatment periods •  survival  emphasis toxicity reduction

  30. WHEN TO WORRY ABOUT QT? • More than 25% prolongation of QTc interval from the baseline or a QTc interval longer than 500 msincreases 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 GowdaRM et al. Int J Cardiol 2004;96:1-6

  31. 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)

  32. 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.

  33. 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?

  34. 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 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

  35. Drug-Induced HF of FDA Approved Targeted Cancer Therapies Approval Drug Action CHF

  36. FDA Approved Targeted Therapies Responds to ACE/BB HTN/CMP Drug SHF/DHF

  37. 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,4MS 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 38

  38. Clinical Outcome by HTN Status 39

  39. Median OS by Use of Anti-HTN Agents, HTN-induced Dose Reductions and HTN Status as Defined by Maximum SBP ≥140 mmHg on Sunitinib 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Probability of overall survival Dose reduction onlyAnti-HTN drug only BothNeitherNo HTN 0 5 10 15 20 25 30 35 40 45 50 Time (months) 40

  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)

  41. J Clin Oncol 29;2645-2652

  42. Baseline Hypertensive BC Patients Treated with Beta Blockers Live Longer Oncotarget 2010; 1:628-638

  43. 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

  44. 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

  45. Thank you! • Twitter Jean-Bernard Durand@oncocardiology jdurand@mdanderson.org

  46. 8 7 6 5 4 3 2 1 0 Carvedilol Dose-Response Trial (MOCHA*):Effect on Ejection Fraction and Mortality Changes in LVEF ‡ P<.001 ‡ ‡  LVEF (EF units) 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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