Anthracycline-induced cardiotoxicity in patients with early-stage breast cancer: the Canadian Cancer Trials Group (CCTG) MA.21 experience

Purpose Anthracyclines are frequently used in adjuvant treatment for early-stage breast cancer (ESBC). The purpose of this study was to evaluate cardiotoxic effects in the first five years after treatment with different anthracycline-based regimens. Methods CCTG MA.21 (NCT000142) was a phase III trial in ESBC that compared cyclophosphamide (75 mg/m(2)) orally for 14 days, epirubicin (60 mg/m(2)) and fluorouracil, IV days one and eight (CEF) for six cycles; dose-dense epirubicin (120 mg/m(2)) and cyclophosphamide, IV every 2 weeks for six cycles with concurrent G-CSF then paclitaxel every 2 weeks for four cycles (ddEC/T); doxorubicin (60 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every 3 weeks for four cycles then four cycles q3 weekly paclitaxel (175 mg/m(2)) (AC/T). Endpoints: LVEF decline; LV function changes (heart failure), or Grade 3-4 cardiac ischemia/infarction. A competing risk analysis was performed with endpoints of cardiotoxicity or recurrence in first 5 years after completion of chemotherapy. Results 2104 women were randomized. Compliance with cardiac LVEF assessments was 70% at 5 years in all arms. The 5-year cumulative risks of any cardiac event for CEF, ddECT, and AC/T were 22.3% (95%CI 18.9 to 25.7), 14.2% (95%CI 11.0 to 17.3), and 8.1% (95%CI 5.8 to 10.4), respectively,p < 0.0001. At 5 years, women in the ddEC/T and AC/T group had significantly lower risk of cardiotoxicity than those given CEF (HR 0.599 and 0.371, respectively). Most events were asymptomatic drop in LVEF. Conclusions Asymptomatic changes in LVEF accounted for most of the cardiotoxicity. The majority of cardiac events occurred in year one although occurrence of cardiotoxicity over time highlights the need for improved risk stratification to guide cardiac surveillance strategies.