Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial

Abstract

Few prospective studies have assessed anthracycline-associated cardiotoxicity in patients with sarcoma. We evaluated cardiotoxicity in patients with soft-tissue sarcomas administered doxorubicin in the phase III ANNOUNCE trial (NCT02451943). Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) ≥50%. Patients could receive eight cycles of doxorubicin at 75 mg/m². The cardioprotectant, dexrazoxane, was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using Medical Dictionary for Regulatory Activities and graded using Common Terminology Criteria for Adverse Events 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to 10%. A total of 504 patients received ≥1 cycles of doxorubicin [median cumulative dose, 450.3 mg/m² (range, 72.3–634.0)]. Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was coadministered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving 2, 88.5% receiving 450–2, and 90% receiving ≥600 mg/m²) and did not affect treatment efficacy. LVEF deterioration was seen in 62 of 153 (40.5%) patients who received a cumulative dose 2, 82 of 159 patients (51.6%) who received 450–2, and 50 of 89 patients (56.2%) who received ≥600 mg/m². Grade ≥3 cardiac dysfunction occurred in 2% of patients at 2, 3% at 450–450 mg/m²), with a low rate of cardiotoxicities, in the context of dexrazoxane coadministration. See related commentary by Benjamin and Minotti, p. 3809