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CARDIAC TOXICITY

SUPPORTIVE CARE IN ONCOLOGY Rome April 8, 2011. CARDIAC TOXICITY. Prof. Maria PENCO Cardiologia UNIVERSITÀ DEGLI STUDI DELL’AQUILA. In last 20 years l ife-expectancy for patients with cancer is steadily improving There is a large group at risk of treatment-related complications.

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CARDIAC TOXICITY

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

  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 • Alterationofventricularrepolarizationphase, durationof QT, arrhythmias, ischemia, acute heartfailure, myocarditis-pericarditis-likesyndrome • Chronic (early / late) • Asymptomaticleftventriculardysfunction, systolic and/or diastolicdysfunction, severe formofdilatedcardiomyopathy, cardiacdeath

  7. CARDIOTOXICITY Pathogenesis Peroxidation of membranes Decrease of and influx of calcium Glutathione-peroxidase OXYGEN-FREE-RADICALS (iron-based stress oxidative) Mitochondrial dysfunction Depletion of GATA-4 (persistence of 8-H Guanosine)

  8. CARDIOTOXICITY PathophysiologicalMechanisms • 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

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

  10. SCREENING FOR CARDIOTOXICITY Identify patients at high risk for developing cardiotoxicity Diagnosis and treatment ofleftventriculardysfunctiontopreventprogressiontoovertheartfailure

  11. Screening for cardiotoxicity Risk factors of chronic anthracycline cardiotoxicity

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

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

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

  15. CARDIOTOXICITY EARLY IDENTIFICATION risk of developing overt heart failure to less than 5% of treated patients 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

  16. …AND EARLY DIAGNOSIS…?

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

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

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

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

  21. NEW ECHO-TECHNOLOGIES LITE study (Liposomaldoxorubicin-Investigationalchemotherapy-TissueDoppler imaging Evaluation) Changes in systolic and diastolic measures as primary endpoints for cardiotoxicity during anthracycline

  22. BIOMARKERS TROPONIN BNP

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

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

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

  26. Troponin I and Chemotherapy-InducedCardiotoxicity Cardinale D, Circulation. 2004;109:2749-2754

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

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

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

  30. NT-proBNP and Chemotherapy-InducedCardiotoxicity M.Penco, C.Ficorella Eur Heart J 2009 abstr

  31. NT-proBNP and Chemotherapy-InducedCardiotoxicity M.Penco, C.Ficorella, Eur Heart J 2009 abstr

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

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

  34. SCREENING FOR CARDIOTOXICITY Identify patients at high risk for developing cardiotoxicity Diagnosis and treatment ofleftventriculardysfunction in ordertopreventprogressiontoovertheartfailure

  35. CARDIOTOXICITY EARLY IDENTIFICATION OF PATIENTS AT RISK • 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

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

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

  38. 25 patients each in the carvedilol and control groups Baseline After chemoth Kalay N J Am Coll Cardiol 2006;48:2258–62

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

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

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

  42. 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

  43. 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

  44. 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

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