1. CARDIAC TOXICITY Prof. Maria PENCO Cardiologia UNIVERSITÀ DEGLI STUDI DELL’AQUILA SUPPORTIVE CARE IN ONCOLOGY Rome April 8, 2011

2.  In last 20 years life-expectancy for patients with cancer is steadily improving  There is a large group at risk of treatment-related complications CARDIOTOXICITY

3. CARDIOTOXICITY  Strong impact on quality of life and patient survival, regardless of the basic problem of cancer  Negative impact on the patient's cardiac prognosis  Significant limitation of therapeutic options

4. CARDIOTOXICITY  Incidence ranging from 5% to 65% of treated cases, in relation to the total dose of drugs administered and over the duration of follow-up considered  Drugs most frequently associated with cardiotoxicity are anthracyclines (doxorubicin, epirubicin), taxanes, alkylating agents and trastuzumab

5. CARDIOTOXICITY Systemic Therapy  Anthracyclines  Alkylanting Agents  Antimicrotubule Agents  Antimetabolities  Monoclonal Antibodies  Hormonal Agents

6. CARDIOTOXICITY  Acute or subacute Alteration of ventricular repolarization phase, duration of QT, arrhythmias, ischemia, acute heart failure, myocarditis-pericarditis-like syndrome  Chronic (early / late) Asymptomatic left ventricular dysfunction, systolic and/or diastolic dysfunction, severe form of dilated cardiomyopathy, cardiac death

7. CARDIOTOXICITY Pathogenesis Peroxidation of membranesDecrease of and influx of calciumGlutathione-peroxidase OXYGEN-FREE-RADICALS (iron-based stress oxidative) Mitochondrial dysfunctionDepletion of GATA-4 (persistence of 8-H Guanosine)

8. CARDIOTOXICITY  Formation of oxygen free radicals and calcium overload in myocytes  Deficiency of antioxidant systems, as catalase and superoxide dismutase  Possible immunological reaction induced by the drug Pathophysiological Mechanisms

9. B A C STAGE HIGH-RISK PATIENTS in the absence of heart disease PATIENTS WITH A HISTORY OF HEART FAILURE Hypertension, coronary artery disease, diabetes mellitus, previous treatment with cardiotoxic drugs, alcohol abuse, history of rheumatic fever, family history of cardiomyopathy. Left ventricular hypertrophy or fibrosis, dilatation of the left ventricle or reduced contractility, asymptomatic valvular heart disease, myocardial infarction Dyspnea or fatigue due mainly to left ventricular dysfunction. Asymptomatic patients treated for heart failure ACC/AHA Classification Heart Failure PATIENTS WITH CARDIAC DISEASE BUT WITHOUT SIGNS OR SYMPTOMS

10. SCREENING FOR CARDIOTOXICITY 1.Identify patients at high risk for developing cardiotoxicity 2.Diagnosis and treatment of left ventricular dysfunction to prevent progression to overt heart failure

11. Screening for cardiotoxicity Risk factors of chronic anthracycline cardiotoxicity -Total dose ( doxorubicin ˃ 450 mg/mq) -Pediatric o geriatric -Prior cardiotoxic treatments (chemotherapy and or radiotherapy) -Previous cardiac events -Presence of genetic cardiovascular risk -Body mass index ˃ 30 -Females

12. Cumulative Dose of Anthracyclines and Risk of Congestive Heart Failure

13. Risk factors for cardiovascular toxicity related to radiotherapy Screening for cardiotoxicity

14. CARDIOTOXICITY Monitoring of cardiac function during and after chemotherapy EARLY IDENTIFICATION EF EF EF > 10 percentage points, or if < 50% Discontinuation of treatment

15. CARDIOTOXICITY EARLY IDENTIFICATION Limits of the evaluation of EF Poor sensitivity and specificity in predicting the development of early cardiac dysfunction Identification of cardiac damage only when it has already had a functional impact risk of developing overt heart failure to less than 5% of treated patients

16. …AND EARLY DIAGNOSIS…?

17. Singal PK, NEJM 1998; 339: 990-905

18. Strategies for early detection of cancer treatment-induced cardiovascular toxicity

22. Changes in LVEF and timing of detection with several screening strategies during and after cancer treatment

23. NEW ECHO-TECHNOLOGIES PW-DMI Strain/S-Rate Strain-2D Quantitative evaluation of global and regional, radial and longitudinal, systolic and diastolic myocardial function

24. AuthorsType of populationNumber of patients TechniqueComments Tassan-Mangina SAggressive cancers20TDI of mitral ringDiastolic abnormalities appear earlier than changes in EF Mercuro GBreast cancer16Strain e strain rateEarlier reduction of strain e strain rate with respect to systolic and diastolic function Morandi PBreast cancer16TDIDiastolic abnormalities within the first 24 hours after the initial high dose of cyclophosphamide LITE study (Liposomal doxorubicin-Investigational chemotherapy-Tissue Doppler imaging Evaluation) C hanges in systolic and diastolic measures as primary endpoints for cardiotoxicity during anthracycline NEW ECHO-TECHNOLOGIES

26. Cardiac Troponin and Cardiotoxicity Dolci A, G Ital Card 2006;7 (9):604-11

27. BNP and Cardiotoxicity Dolci A, G Ital Card 2006;7 (9):604-11

28. Cardinale D, Circulation. 2004;109:2749-2754 Troponin I and Chemotherapy- Induced Cardiotoxicity 703 pts undergoing HDC regimens for different tumors

29. Cardinale D, Circulation. 2004;109:2749-2754 Troponin I and Chemotherapy- Induced Cardiotoxicity

30. NT-proBNP and Chemotherapy- Induced Cardiotoxicity Group A Group B Group C Sandri MT, Clin Chem 2005; 51: 1405-10 52 pts undergoing HDC regimens for different tumors

31. NT-proBNP and Chemotherapy- Induced Cardiotoxicity Group A Group B Group C Group B Group C Sandri MT, Clin Chem 2005; 51: 1405-10

32. NT-proBNP and Chemotherapy- Induced Cardiotoxicity Romano S, Eur Heart J 2009 abstr 72 ambulatory patients with breast cancer

33. NT-proBNP and Chemotherapy- Induced Cardiotoxicity M.Penco, C.Ficorella Eur Heart J 2009 abstr

34. NT-proBNP and Chemotherapy- Induced Cardiotoxicity M.Penco, C.Ficorella, Eur Heart J 2009 abstr

35. NT-proBNP and Chemotherapy- Induced Cardiotoxicity M.Penco, C.Ficorella Eur Heart J 2009 abstr EDV ESV Four patients with persistent NT-proBNP alterations reported symptoms (dyspnoea supra-ventricular arrhythmias)

36. NT-proBNP and Chemotherapy- Induced Cardiotoxicity M.Penco, C.Ficorella Eur Heart J 2009 abstr Serial evaluations of NT-pro-BNP may be a useful tool, more than c-TnI, in the early identification of patients at high risk of cardiotoxicity among those treated with not- high-dose anthracycline chemotherapy for breast cancer

37. SCREENING FOR CARDIOTOXICITY 1.Identify patients at high risk for developing cardiotoxicity 2.Diagnosis and treatment of left ventricular dysfunction in order to prevent progression to overt heart failure

38. CARDIOTOXICITY  Assessment of the therapeutic program / cardioprotective agents during chemotherapy  Planning for a closer monitoring of cardiac function  Early introduction of a cardiac preventive or supportive therapy EARLY IDENTIFICATION OF PATIENTS AT RISK

39. Strategies to Prevent Anthracycline Cardiotoxicity  Liposomal Formulation of Anthracyclines  Dexrazoxane  Sequential Use of Cardiotoxic Agents (?)

40. Pegylated Liposomal Formulation of Anthracyclines O’Brian M. et al. Ann Oncol 2004

41. Kalay N J Am Coll Cardiol 2006;48:2258–62 Baseline After chemoth 25 patients each in the carvedilol and control groups

42. Kalay N J Am Coll Cardiol 2006;48:2258–62

43. Cardinale D, Circulation. 2006;114:2474-2481 No TnI increase persistent TnI increase

44. Wells Q et al. Prog Cardiovasc Dis 2010;53:140-148

45. Cardiac dysfunction caused by Trastuzumab: ….these patients treated with beta-blockers and angiotensin-converting enzyme inhibitors on Trastuzumab discontinuation and fully recovered their LVEF, suggesting that the pathological changes induced by Trastuzumab are REVERSIBLE with medical therapy. Guarnieri V et al. JCO 2006

46. CONCLUSIONS Cardiotoxicity: beyond EF New echo-technologies can detect early abnormalities of ventricular function Promising results of biomarkers in the early identification of patients at risk of cardiotoxicity Further studies are needed in order to assess the reliability and sensitivity of monitoring strategies for early detection of cardiotoxicity

47. CONCLUSIONS II Screening Strategy First step: clinical screening and biormarkers to identify patients at higher risk Second step: confirm diagnosis by echocardiography for an appropriate decision- making