Cardiac effects of high-dose epirubicin and cyclophosphamide in women with poor prognosis breast cancer

Purpose: To prospectively evaluate the long term cardiac effects of high-dose epirubicin and cyclophosphamide given to women with early stage, poor prognosis breast cancer. Patients and methods. Women with stage 2 breast cancer and 10+ nodes or 4+ nodes and estrogen receptor negative tumor, or stage 3 breast cancer received three cycles of epirubicin 200 mg/m(2) and cyclophosphamide 4 gm/m(2) with peripheral blood progenitor cell and filgrastim support. Treatment was given every 28 days (n = 79) or 21 days (n = 20). Fifty patients received radiotherapy to the chest wall or breast, 25 of to the left side. Patients were assessed clinically regularly during chemotherapy and at least three times yearly after completion of treatment. Cardiac left ventricular ejection fraction (LVEF) was assessed by radionuclide scan before therapy, after each cycle of chemotherapy, three months and six months after completion of chemotherapy, and yearly thereafter until relapse. Results. Ninety-nine women were treated, and 92 completed all three cycles of chemotherapy. The median age was 43 years (range 24 to 60 years). All patients were included in this analysis. The median relapse-free survival was 39 months (11 to 68 months). There was a significant fall in LVEF during chemotherapy. In general, there was no further deterioration in cardiac function from the third month after cessation of treat-ment, however there was substantial variation between individuals. 35 patients had at least one LVEF measure less than normal (<50%), but the LVEF returned to normal in 20 of these with further follow-up. Cardiac dysfunction was not increased in women who received radiotherapy and was not different between cohorts given chemotherapy every three or every four weeks. One patient died of acute myocardial necrosis following the third cycle of chemotherapy. Two patients developed clinical evidence of cardiac failure, and another had radiological signs but was asymptomatic. One woman died of progressive cardiac failure, one recovered clinically but also developed recurrent breast cancer, while the third recovered after commencement of medical therapy. Conclusions: During follow-up after high-dose epirubicin and cyclophosphamide as delivered in this study, the LVEF fell to below normal in approximately one third of patients. However, in over half of these patients the LVEF subsequently recovered to the normal range, and the incidence of clinically evident chronic cardiac failure was low. Further follow-up is required to assess the long-term safety. A randomized comparison with standard-dose anthracycline-based chemotherapy is needed to determine whether this regimen is associated with an increased risk of clinical cardiac toxicity.