The use of dexrazoxane as a cardioprotectant in patients receiving epirubicin-based chemotherapy for metastatic breast cancer

Abstract

640 Background: The clinical utility of anthracyclines is limited by dose-related cardiotoxicity. Epirubicin, the 4’-epimer of doxorubicin, is reportedly less cardiotoxic than doxorubicin when administered at equimolar doses. However, the existence of cumulative dose-related cardiotoxicity of epirubucin is now clearly established. Dexrazoxane, a cardioprotective agent, has been shown to reduce the risk of anthracycline-associated cardiotoxicity. Methods: This multicenter, randomized, controlled study enrolled adult female subjects with advanced/metastatic breast cancer who had received prior anthracycline-based chemotherapy. Patients were randomized to receive anthracycline-based chemotherapy with or without dexrazoxane, (dose ratio for dexrazoxane:epirubicin = 10:1). Cardiac assessments were reviewed by an independent Adjudication Committee blinded to treatment arm. A reduction in left ventricular ejection fraction (LVEF) 10% measured by MUGA scan or 15% measured by echocardiography, or a reduction in absolute LVEF to a value below 45% was deemed to constitute a cardiac event. A sub-group analysis of patients treated with epirubicin alone (EPI, n=28) or epirubicin + dexrazoxane (DEX+EPI, n=29) was performed. Results: Median total cumulative doses of epirubicin (including pre-study exposure) were 742mg/M2 (range 375–1200) and 869mg/M2 (419–1188) respectively. Significantly fewer DEX+EPI patients developed a cardiac event (14%, 95% CI:4–32%) compared to the EPI group (43%, 95%CI:24–63%) (p=0.015, Pearson’s Chi Square test). Three patients in the EPI group developed congestive heart failure, (two NYHA grade III and one grade IV, total cumulative EPI doses 991, 952 and 610mg/M2 respectively). There were no cases of CHF in the DEX+EPI group, (p=NS). There was no significant difference in overall tumor response rates between the two groups; DEX+EPI 48% (95% CI 30–67%) vs EPI 25% (95%CI 11–43%), (p=0.054). Conclusions: This study confirms the cardiotoxicity of cumulative epirubicin-based chemotherapy. Dexrazoxane significantly reduces the risk of epirubicin-induced cardiotoxicity, both clinical and sub-clinical, without compromising tumor response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron Biopharmaceuticals Chiron Biopharmaceuticals