Anthracycline induced Cardiomyopathy AM Report December AM Report December

Chemotherapy and Cardiotoxicity Anthracyclines Herceptin Antimetabolites 5-fluorouracil - coronary vasospasm Fludarabine - high dose for BMT conditioning Vinca alkaloids - hypertension, myocardial ischemia Taxanes - conduction abnormalities Cyclophosphamide - cardiomyopathy Bleomycin - pericarditis Mitomycin C - heart failure Monoclonal antibodies Anthracyclines Herceptin Antimetabolites 5-fluorouracil - coronary vasospasm Fludarabine - high dose for BMT conditioning Vinca alkaloids - hypertension, myocardial ischemia Taxanes - conduction abnormalities Cyclophosphamide - cardiomyopathy Bleomycin - pericarditis Mitomycin C - heart failure Monoclonal antibodies

History of Anthracycline use Fermentation product of Streptomyces peucetius Daunomycin and doxorubicin devolped in 1960s Clinical Uses breast and esophageal carcinomas osteosarcoma, Kaposi's sarcoma and soft- tissue sarcomas Hodgkin's and non- Hodgkin's lymphomas Fermentation product of Streptomyces peucetius Daunomycin and doxorubicin devolped in 1960s Clinical Uses breast and esophageal carcinomas osteosarcoma, Kaposi's sarcoma and soft- tissue sarcomas Hodgkin's and non- Hodgkin's lymphomas Doxorubicin

Mechanism Therapuetic Intercalating between base pairs of the DNA/RNA Inhibits topoiosomerase II enzyme Cardiotoxicity Production of toxic oxygen ﾊ free radicals and an increase in oxidative stress Loss of myofibrils and the vacuolization of cytoplasm Therapuetic Intercalating between base pairs of the DNA/RNA Inhibits topoiosomerase II enzyme Cardiotoxicity Production of toxic oxygen ﾊ free radicals and an increase in oxidative stress Loss of myofibrils and the vacuolization of cytoplasm

Risk Factors - Cumulative dose

Risk Factors Age 70 years of age Previous/Concurrent Radiation Concomitant chemotherapy Herceptin and taxols Bone Marrow Transplant Cardiac Risk Factors Age 70 years of age Previous/Concurrent Radiation Concomitant chemotherapy Herceptin and taxols Bone Marrow Transplant Cardiac Risk Factors

Clinical Manifestations Acute - during infusion to 1 week Arrhythmias Ventricular dysfunction Pericarditis/myocarditis Early - < 1 year Dose-related cardomyopathy Late Acute - during infusion to 1 week Arrhythmias Ventricular dysfunction Pericarditis/myocarditis Early - < 1 year Dose-related cardomyopathy Late

Monitoring Serial noninvasive monitoring of LVEF Radionuclide angiography (MUGA) Echocardiography Exercise stress radionuclide ventriculography Biomarkers Serum troponins BNP/pro-BNP Endomyocardial Biopsy Serial noninvasive monitoring of LVEF Radionuclide angiography (MUGA) Echocardiography Exercise stress radionuclide ventriculography Biomarkers Serum troponins BNP/pro-BNP Endomyocardial Biopsy

Monitoring Normal EF Baseline (prior to 100 mg/m2) 2 nd study after 250 to 300 mg/m2 3 rd at mg/m2 Sequential studies prior to each additional dose EF 30-50% EF study prior to each dose EF < 30% - recommend against initiating Discontinue doxorubicin for decrease in EF >10% or absolute < 30% Normal EF Baseline (prior to 100 mg/m2) 2 nd study after 250 to 300 mg/m2 3 rd at mg/m2 Sequential studies prior to each additional dose EF 30-50% EF study prior to each dose EF < 30% - recommend against initiating Discontinue doxorubicin for decrease in EF >10% or absolute < 30%

Prevention Altering infusion protocol Alternate anthracycline derivatives Liposomal preparations Dexrazoxane - metal-chelating agent Beta-blockers ACE inhibitors Altering infusion protocol Alternate anthracycline derivatives Liposomal preparations Dexrazoxane - metal-chelating agent Beta-blockers ACE inhibitors

Prognosis and Treatment Prognosis Mortality rates of > 30% in early studies Treatment ACE inhibitors Traditional Heart failure Management Heart Transplant Prognosis Mortality rates of > 30% in early studies Treatment ACE inhibitors Traditional Heart failure Management Heart Transplant

Refrences Up-to-Date Cancer Medicine 6 CHEST February 1999 vol. 115 no Schwartz, RG, McKenzie, WB, Alexander, J, et al. Congestive heart failure and left ventricular dysfunction complication doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med 1987; 82:1109. Jannazzo A, Hoffman J, Lutz M. Monitoring of anthracycline-induced cardiotoxicity. Ann Pharmacother Jan;42(1): Appel JM, Nielsen D, Zerahn B, Jensen BV, Skagen K. Anthracycline-induced chronic cardiotoxicity and heart failure. Acta Oncol. 2007;46(5): Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med Sep 24;339(13): Up-to-Date Cancer Medicine 6 CHEST February 1999 vol. 115 no Schwartz, RG, McKenzie, WB, Alexander, J, et al. Congestive heart failure and left ventricular dysfunction complication doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med 1987; 82:1109. Jannazzo A, Hoffman J, Lutz M. Monitoring of anthracycline-induced cardiotoxicity. Ann Pharmacother Jan;42(1): Appel JM, Nielsen D, Zerahn B, Jensen BV, Skagen K. Anthracycline-induced chronic cardiotoxicity and heart failure. Acta Oncol. 2007;46(5): Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med Sep 24;339(13):900-5.