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Advanced HF 2014: Cardiac Toxicity in Cancer Patients

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Michel G. Khouri, MD
Assistant Professor of Medicine
Division of Cardiology
Duke University Medical Center

Published in: Education
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Advanced HF 2014: Cardiac Toxicity in Cancer Patients

  1. 1. Cardiac Toxicity in Cancer Patients Duke Heart Failure Symposium September 20, 2014 Michel G. Khouri, MD Assistant Professor of Medicine Division of Cardiology Duke University Medical Center
  2. 2. Disclosures • I do intend to discuss an off-label use of a product during this activity. • I have not had any relevant financial relations during the past 12 months to disclose
  3. 3. Cancer Therapy and the Heart Cardiac Toxicity I. Epidemiology II. Mechanisms of cardiac/cardiovascular injury III. Defining cardiac toxicity IV. Detection of cardiac toxicity V. Prevention/treatment of cardiac toxicity
  4. 4. Epidemiology of Cardiac Toxicity in Cancer • Cardio-toxic drug or treatment in expected long term survivors – Dose, location dependent • Many aspects of CV system may be affected • A range of severity (and reversibility?) – Subclinical – Symptomatic – Events • Multiple factors in play – Pre-existing CV risk factors/disease – Impaired CV reserve – Additive insults or ‘Multiple Hit’ • Serious implications – Limited access to life saving treatments – Long term reductions in quality/quantity of life
  5. 5. Why Worry About Cardiac Toxicity in Cancer? • Improved detection and therapy survival gains • Millions of cancer survivors in the US … and  ing • Acute toxicity can affect access to life saving drugs • Chronic toxicity can affect survival, morbidity and QOL CV Death Breast cancer Patnaik, et al. Breast Ca Res 2011 50 40 30 20 10 0 Years from diagnosis 1 2 3 4 5 6 7 8 9 10 11 12 Other causes % Mortality
  6. 6. Cancer Therapy Effects on CV System Arrhythmia Athero-inflammation Myocardium Skeletal muscle Vascular Pulmonary
  7. 7. Long-term Incidence of CV Disease Childhood Cancer Experience Anthracyclines Radiation Therapy Mulrooney, et al. BMJ 2009
  8. 8. Coronary Events in Breast Cancer Radiation Therapy Darby, et al. NEJM 2013
  9. 9. CV Toxicity of Chemo Agents Khouri, et al. Circulation 2012 Yeh, et al. Circulation 2009
  10. 10. Adapted from Protein Synthesis Suppression Khouri, et al. Circulation 2012 Yeh, et al. Clin Pharm Ther 2014 Direct Toxicity Anthracyclines Cardiomyocyte Death Myocardial Dysfunction Heart Failure DNA DSB’s Apoptosis Protein Synthesis Antioxidant Mechanisms Energy Metabolism Alteration Anthracycline – Topoisomerase 2β p53 Mitochondrial Dysfunction ROS Generation
  11. 11. Direct Toxicity Anti-HER2 Agents Adapted from Khouri, et al. Circulation 2012 Cardiac Stress Anthracyclines Ischemia Hypertension ↑Neuregulin-1 HER3/4 Protein Synthesis Protein Degradation Protein Hypertrophy Cell Survival HER2 (ErbB2) Trastuzumab Pertuzumab Lapatinib Myocardial Dysfunction / Heart Failure
  12. 12. Direct Toxicity Interplay of Anthracycline and Anti-HER2 Agents Adapted from Toccheti, et al. Eur J Heart Fail 2012
  13. 13. Direct Toxicity Angiogenesis (VSP) Inhibitors Adapted from Khouri, et al. Circulation 2012 Ischemia ↑VEGF Hypertension VEGFR (1/2/3) Sunitinib Sorafenib Pazopanib Axitinib Vandetanib Bevacizumab HIFα ↑PDGF PDGFR C-Kit Cell survival Vasodilation (NO production) Angiogenesis Prostaglandin production Hypertension Thromboembolism (VTE, ATE) Myocardial Dysfunction / Heart Failure
  14. 14. Forthcoming Challenges Cancer drug development Kinase inhibitors in clinical trials (2011) Clinical trial phase Small molecule kinase inhibitors Adapted from T. Force chemspot.com
  15. 15. The ‘multiple hit’ hypothesis Cytotoxic chemotherapy Signaling inhibitors Radiation Direct Effects ↓ Cardiovascular Reserve Indirect Effects Aging Other CV risk factors (HTN) Modifiable Lifestyle Risk Factors (deconditioning, obesity)  Baseline Cardiovascular Risk Factors Cancer Diagnosis Cardiotoxicity ( LVEF / HF) Adapted from Jones, et al. J Am Coll Cardiol 2007
  16. 16. CV late-effects in cancer Koelwyn, et al. J Clin Oncol, 2012 Running on empty Cancer Normal age-related decline
  17. 17. Cardio-Oncology • An emerging field to keep pace with the rapid evolution of cancer therapies and the incidence, magnitude and consequences of their CV side effects • Relevant to cancer survivorship: i. Early CV toxicities arising during treatment may interfere with completion of very therapies needed to enhance survivorship ii. CV issues arising after cancer therapy completion • New frontier in medicine – CV toxicities of novel targeted cancer therapies
  18. 18. What can we do about cardiac toxicity? Areas of Investigation / Improvement I. Defining cardiac toxicity II. Detection III. Prevention / Treatment
  19. 19. Defining Cardiac Toxicity Oncology Classification Severity Low High Grade 1 (mild) Grade 2 (moderate) Grade 3 (severe) Grade 4 (life-threatening) Grade 5 CTCAE, v4.03 Heart failure Asymptomatic with laboratory (e.g., BNP) or cardiac imaging abnormalities Symptoms with mild to moderate activity or exertion Severe with symptoms at rest or with minimal activity or exertion; Intervention indicated Life-threatening; Urgent intervention (e.g., continuous IV therapy or MCS) required Death CTCAE, v4.03 EF decline - Resting EF 50-40%; 10-19% ↓ from baseline Resting EF 39-20%; > 20% ↓ from baseline Resting EF < 20% - Cardiac Review and Evaluation Committee (CREC) Any of 4 criteria confirms cardiotoxicity: (1) Cardiomyopathy – reduced LVEF (global or more severe in the septum) (2) Symptoms of HF (3) Signs associated with HF (S3 gallop and / or tachycardia) (4) Decrease in LVEF from baseline ≥ 5% to < 55% with accompanying signs or symptoms of HF, or decline in LVEF ≥10% to < 55% without accompanying signs or symptoms of HF Drug continuation: LVEF criteria in clinical trials and practice (1) > 10% LVEF declines from baseline, to < 55%, (2) ≥ 10% LVEF decline from baseline, to < 50%, (3) ≥ 20% or > 15% LVEF decline from baseline, but remains ≥ 50%, or (4) Any LVEF decline to < 50% Khouri, et al. Circulation 2012
  20. 20. Defining Cardiac Toxicity Classification Severity Low High ACC/AHA heart failure stage Stage A Stage B Stage C Stage D At risk (e.g., patients receiving cardiotoxins) but without structural heart disease or symptoms Structural heart disease (hypertrophy, low EF, valve disease) but without signs or symptoms Structural heart disease with prior or current symptoms Refractory HF requiring specialized interventions NYHA symptom classification Grade I Grade II Grade III Grade IV No limitation of activity Mild limitation of activity Marked limitation of activity Confined to bed or chair Cardiology Khouri, et al. Circulation 2012
  21. 21. Defining Cardiac Toxicity Evolution of heart failure Yancy, et al. J Am Coll Cardiol, 2013
  22. 22. Detection of Cardiac Toxicity Desirable Features • Detects injury signal before LV impairment • Detects LV signal before symptoms • Highly predictive of clinically significant disease • Reproducible • Widely available • Noninvasive • Inexpensive • Actionable in guiding therapy
  23. 23. Detection New Approaches Diagnostic testing Emerging Biomarkers  Biochemical markers  Strain echo (tissue Doppler/speckle tracking)  Cardiac magnetic resonance imaging  Targeted nuclear cardiology  Functional capacity testing Surveillance Traditional Imaging  Echocardiography  Nuclear cardiology Diagnosis Guide treatment Baseline CV health & Risk factors Cancer Diagnosis Cytotoxic Therapy (“CV insult”) Cardiac toxicity (↓LVEF) (ACC/AHA Stage B) CV disease & Premature death Heart failure (ACC/AHA Stage C & D) Disease Progression Khouri, et al. Circulation 2012
  24. 24. LV Ejection Fraction 2D Echo 3D Echo
  25. 25. Myocardial Strain Speckle-tracking Strain Echocardiography Adapted from Stoylen; Gorcsan, et al. J Am Coll Cardiol 2011
  26. 26. Myocardial Strain Speckle-tracking Strain Echocardiography Thavendiranthan, et al. JACC 2014
  27. 27. LV Twist / Torsion Speckle-tracking Strain Echocardiography Adapted from Sengupta, et al. JACC Imaging 2008
  28. 28. Cardiac MRI Myocardial Strain (Tagging) Myocardial Fibrosis (T1 Mapping) LVEF/Volumes (Cine) Myocardial Ischemia (Perfusion) Adapted from Hundley, et al. J Cardiovasc MR 2013
  29. 29. Cardio-Pulmonary Exercise Testing (CPET) • Functional capacity related to mortality • Exercise capacity (METs) • Oxygen consumption (VO2peak; mL/kg/min)
  30. 30. Modalities of Cardiac Toxicity Detection Echocardiography RNA (MUGA) cMR Blood Biomarkers 2D 3D Strain Troponin Natriuretic peptides Target(s) LVEF; LV Vol LVEF; LV Vol Myocardial deformation LVEF; LV Vol LVEF; LV Vol; Myocardial damage/ deformation Myocardial injury Myocardial stretch/ stress Availability ++++ +++ +++ +++ + ++++ ++++ Cost Low Medium Medium Low Reproducibility ++ +++ +++ ++++ ++++ ++++ ++++ Cardiac structure Temporal resolution ++++ + +++ - - Spatial resolution ++ + +++ - - Myocardial function Systolic +++ +++(+) ++++ ++++ ++++ - - Diastolic ++++ + ++++ - ++ - - Tissue characterization + - - - ++++ - - Potential to detect Moderate- Low Low subclinical cardiac toxicity High Low Moderate High Unknown Khouri, et al. Circulation 2012
  31. 31. Early detection 3D vs. 2D Echo LVEF Walker, et al. J Clin Oncol 2010
  32. 32. Early detection Longitudinal Strain vs. 3D Echo LVEF Thavendiranthan, et al. JACC 2014
  33. 33. Early detection Biochemical markers - Troponin Cardinale, et al. Circulation 2004 (495) (145) (63)
  34. 34. Early detection Troponin vs. Other Blood-based Biomarkers Ky, et al. J Am Coll Cardiol 2013
  35. 35. Early detection Echo vs. Troponin • 81 breast cancer patients; HER2+ • Mean LVEF 64±5% → 59±6% (P < 0.0001) over 15 months • Cardiotoxicity (n = 26) defined by CREC criteria and heart failure (n = 5) • μs Troponin I and Echo longitudinal strain at anthracycline completion – Predicted subsequent development of cardiotoxicity • *Longitudinal strain only independent predictor of cardiotoxicity and LVEF <50% * Sawaya, et al. Circ Cardiovasc Imaging 2012
  36. 36. Controls Patients Early detection Cardiac MRI Chaosuwannakit, et al. J Clin Oncol 2010
  37. 37. Age-matched sedentary women Breast cancer Jones, et al. J Clin Oncol 2012 Early detection Cardiopulmonary Exercise Testing
  38. 38. Early detection Resting Indices of Cardiac Function Khouri, et al. Breast Ca Res Treat 2014
  39. 39. Early detection Exercise Indices of Cardiac Function Khouri, et al. Breast Ca Res Treat 2014
  40. 40. Prevention and Treatment Baseline CV health & Risk factors Cancer Diagnosis Cytotoxic Therapy (“CV insult”) Cardiac toxicity (↓LVEF) (ACC/AHA Stage B) CV disease & Premature death Heart failure (ACC/AHA Stage C & D) Diagnostic testing Disease Progression Emerging Biomarkers  Biochemical markers  Strain echo (tissue Doppler/speckle tracking)  Cardiac magnetic resonance imaging  Targeted nuclear cardiology  Functional capacity testing Surveillance Traditional Imaging  Echocardiography  Nuclear cardiology Diagnosis Guide treatment Prevention and Treatment Primordial prevention Primary prevention  ACE inhibitors  Beta blockers  Angiotensin Receptor Blockers  Statins  Exercise Secondary prevention Treatment Khouri, et al. Circulation 2012
  41. 41. Responders (%) (n = 130) (n = 71) Cardinale, et al. JACC 2010 For effective cardioprotection, timing is the key . . .
  42. 42. Primary Cardioprotection Assessment & Optimization of risk +/- extent of CV Disease Co-morbid conditions (CAD, HTN, HLP) Modifiable lifestyle risk factors (deconditioning, obesity) Primordial Prevention Treat all high cardiac risk patients Advantages Minimize screening Disadvantages Treatment despite: -Normal function -Low (~5%) overall incidence of overt HF Primary Prevention Screen for subclinical dysfunction (Imaging, blood biomarkers) Advantages Minimize unnecessary treatment Disadvantages Intensive / frequent screening Optimal screening method uncertain Potential delayed diagnosis / treatment Age Advantages Early intervention → Limit development of cardiotoxicity Disadvantages Duration of treatment uncertain
  43. 43. What is the optimal strategy? ACC/AHA Heart Failure guidelines (2013) Stage A: Recommendations (Class I, LOE C) Conditions that may lead to or contribute to HF, such as ... cardiotoxic agents, should be controlled or avoided. • “…it may be reasonable to evaluate those who are receiving (or who have received) cardiotoxic chemotherapy agents for LV dysfunction.” • “The use of advanced echocardiographic techniques or biomarkers to identify increased HF risk in those receiving may be useful ...” ESMO guidelines (2012) • Patients receiving anthracyclines and/or trastuzumab in the adjuvant setting should perform serial monitoring of cardiac function at baseline, 3, 6, and 9 months during treatment, and then at 12 and 18 months after the initiation of treatment. • Monitoring should be repeated during or following treatment as clinically indicated. Yancy, et al. Circulation 2013 Curigliano, et al. Ann Oncol 2012
  44. 44. Current Means of Cardioprotection • Cardio-active agents – ACE inhibitors – Angiotensin receptor blockers – Beta-blockers – Statins – Dexrazoxane* (Anthracyclines) • Exercise • Chemotherapy – Dose reduction – Dosing administration / formulation(e.g., liposomal DOX) – Alternative, less toxic agents (e.g., lapatinib) – Stop chemotherapy
  45. 45. Primordial Prevention Beta Blockers J Am Coll Cardiol 2006 Kaya, et al. Int J Cardiol 2013
  46. 46. Primordial Prevention ACE Inhibitors + Beta Blockers Bosch, et al. J Am Coll Cardiol 2013
  47. 47. Primordial Prevention Statins Statins p=0.03 Controls Seicean, et al. J Am Coll Cardiol 2013
  48. 48. Primordial Prevention Kalam, et al. Eur J Cancer 2013
  49. 49. Primordial Prevention Aerobic Exercise Anthracyclines Scott, et al. Circulation 2011 Anti-HER2 Agents Scott, et al. Oncologist 2013
  50. 50. Primary Prevention Troponin + ACE Inhibitors Cardinale, et al. Circulation 2006
  51. 51. Primary Prevention Strain + Beta Blockers Eur Heart J Img 2013
  52. 52. Ongoing Trials • MANTICORE 101-Breast – Bisoprolol, perindopril, or placebo on MRI indices of LV remodeling and serum biomarkers in 159 women with HER2+ early breast cancer • NCT01009918 – Carvedilol, lisinopril, or placebo on LVEF at 52 weeks in 468 women with HER2+ early breast cancer • PRADA (NCT01434134) – Metoprolol vs. placebo; Candesartan vs. placebo on LVEF by MRI in 120 breast cancer patients receiving anthracyclines or trastuzumab • NCT00806390 – Metoprolol vs. placebo on LVEF by MUGA in 188 breast cancer patients receiving anthracyclines or trastuzumab
  53. 53. Thank You

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