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Dose-Intensive Epirubicin-Based Chemotherapy Is Superior to an Intensive Intravenous Cyclophosphamide, Methotrexate, and Fluorouracil Regimen in Metastatic Breast Cancer: A Randomized Multinational Study

By Stephen P. Ackland, Antonio Anton, George Peter Breitbach, Elena Colajori, Jennifer M. Tursi, Carlos Delfino, Anna Efremidis, Adnan Ezzat, Alberto Fittipaldo, Kristo Kolaric, Massimo Lopez, Donatella Viaro, the HEPI 013 Study Group

From the Department of Medical Oncology, Newcastle Mater Misericordiae Hospital, Waratah, Australia.

Address reprint requests to Stephen Ackland, MD, Department of Medical Oncology, Newcastle Mater Misericordiae Hospital, Locked Bag 7, Hunter Region Mail Center, 2310 Australia; email: mdspa@ alinga.newcastle.edu.au.

PURPOSE: To determine the relative efficacy of a cyclophosphamide epirubicin and fluorouracil (CEF) regimen compared with an intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in metastatic breast cancer.

PATIENTS AND METHODS: Patients were randomized to receive either CEF (cyclophosphamide 400 mg/m² IV, epirubicin 50 mg/m² IV, and fluorouracil 500 mg/m² IV on days 1 and 8), or CMF (cyclophosphamide 500 mg/m² IV, methotrexate 40 mg/m² IV, and fluorouracil 600 mg/m² IV on days 1 and 8). Treatment was given in 3- to 4-week cycles for a total of six to nine cycles.

RESULTS: A total of 460 patients (223 CEF and 237 CMF) were randomized. Overall response rate was superior for CEF than CMF in all randomized patients (57% v 46%, respectively; P = .01) and in the assessable subset (66% v 52%, respectively; P = .005). With a median follow-up of more than 20 months, time to progression (TTP) was significantly longer with CEF than CMF (median 8.9 v 6.3 months, respectively; P = .0064), as was time to treatment failure (TTF) (median 6.2 v 5.0 months, respectively; P = .01). Significant survival differences were not observed between CEF and CMF (median 20.1 v 18.2 months, respectively; P = .23). Granulocytopenia and infections were similar in both arms. Grade 3/4 nausea/vomiting and alopecia were more frequent with CEF, whereas diarrhea was more frequent with CMF. Cardiac toxicity, primarily asymptomatic, required withdrawal from study of 15 patients on CEF (7%) and one patient on CMF.

CONCLUSION: This CEF regimen safely provides significantly better tumor control than CMF, manifest as a higher response rate, and longer TTP and TTF, but not survival, when used as first-line chemotherapy for metastatic breast cancer.

Deceased.

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