Doubling epirubicin dose intensity (100 mg/m(2) versus 50 mg/m(2)) in the FEC regimen significantly increases response rates. An international randomised phase III study in metastatic breast cancer

Purpose: A phase III study was performed in patients with metastatic breast cancer (MBC) to evaluate the effect on response rate and survival of a doubling of the epirubicin dose intensity. Patients and methods: Four hundred fifty-six patients were randomised to receive either epirubicin 100 mg/m(2) or 50 mg/m(2) in combination with 5-FU (500 mg/m(2)) and cyclophosphamide (500 mg/m(2)) (FEC 100 vs. FEC 50) i.v., every 21 days for a maximum of six cycles (eight in case of CR). Results: Of 456 patients, 390 were evaluable for efficacy. Objective response (CR + PR) was seen in 57% (FEC 100) vs. 41% (FEC 50) of the evaluable patients (P = 0.003). The CR rate was higher in the FEC 100 arm (12% vs. 7%, P = 0.07). FEC 100 produced significantly higher response rates in patients with visceral localisation (50% vs. 34%, P = 0.011) and in patients with more than two metastatic organ sites (64% vs. 37%, P = 0.001). Median time to progression (7.6 vs. 7 months) and overall survival (18 months vs. 17 months) were similar. Myelosuppression was the principal toxic effect, with grade IV neutropenia observed in 57% of the patients treated with FEC 100 vs. 9% of those on FEC 50. Grade IV infection or febrile neutropenia were observed in 8% (FEC 100) vs. 0.4% (FEC 50), but the incidence of septic death was the same in the two arms (two patients each). Cardiac toxicity was similar in the two treatment groups, with 5% vs. 3% of the patients taken off study due to cardiac events, primarily due to a decline in LVEF. Only three patients (two in FEC 100) experienced congestive heart failure. Conclusion: This trial shows that FEC with epirubicin at 100 mg/m(2) can be administered for repeated cycles without bone marrow support with increased, though acceptable, toxicity and with a significant increase of antitumor effect (especially in visceral and/or high-burden disease), but no increased survival.