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Accelerated-Intensified Cyclophosphamide, Epirubicin, and Fluorouracil (CEF) Compared With Standard CEF in Metastatic Breast Cancer Patients: Results of a Multicenter, Randomized Phase III Study of the Italian Gruppo Oncologico Nord-Ouest–Mammella Inter Gruppo Group

From the Department of Medical Oncology, and Unit of Clinical Epidemiology and Trials, National Cancer Research Institute, Genoa; Oncologia Medica, E.O. Ospedali Galliera, Genoa; Divisione Ginecologia C, Ospedale S. Anna, Torino; U.O. Oncologia Medica, Ospedale G. Borea, Sanremo; Oncologia Medica, Azienda Ospedaliera 1, Sassari; U.O. Oncologia Medica, Ospedale S. Andrea, La Spezia; and Aventis Pharma SpA, Origgio, Italy.

Address reprint requests to Lucia Del Mastro, MD, Department of Medical Oncology, Istituto Nazionale per la Ricerca sul Cancro, L.go R. Benzi 10, 16132 Genoa, Italy; email: ldelmast{at}hp380.ist.unige.it

PURPOSE: To evaluate whether an accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) chemotherapy regimen with the support of granulocyte colony-stimulating factor (G-CSF) induces a higher activity and efficacy compared with standard CEF in metastatic breast cancer patients.

PATIENTS AND METHODS: Stage IV breast cancer patients were randomized to receive as first-line chemotherapy either standard CEF (cyclophosphamide 600 mg/m², epirubicin 60 mg/m², and fluorouracil 600 mg/m²) administered every 21 days (CEF21) or accelerated-intensified CEF (cyclophosphamide 1,000 mg/m², epirubicin 80 mg/m², and fluorouracil 600 mg/m²) administered every 14 days (HD-CEF14) with the support of G-CSF. Treatment was administered for eight cycles.

RESULTS: A total of 151 patients were randomized (74 patients on the CEF21 arm and 77 on the HD-CEF14 arm). In both arms, the median number of administered cycles was eight. The dose-intensity actually administered was 93% and 86% of that planned, in CEF21- and HD-CEF14–treated patients, respectively. Compared with the CEF21 arm, the dose-intensity increase in the HD-CEF14 arm was 80%. Both nonhematologic and hematologic toxicities were higher in the HD-CEF14 arm than in the CEF21 arm. During chemotherapy, four deaths occurred in the HD-CEF14 arm. No difference in overall response rate (complete plus partial responses) was observed: 49% and 51% in the CEF21 and HD-CEF14 arms, respectively (P = .94). A slightly non–statistically significant higher percentage of complete response was observed in the HD-CEF14 arm (20% v 15%). No difference in efficacy was observed. The median time to progression was 14.3 and 12.8 months in the CEF21 and HD-CEF14 arms, respectively (P = .69). Median overall survival was 32.7 and 27.2 months in the CEF21 and HD-CEF14 arms, respectively (P = .16).

CONCLUSION: In metastatic breast cancer patients, an 80% increase in dose-intensity of the CEF regimen, obtained by both acceleration and dose intensification, does not improve the activity and the efficacy compared with a standard dose-intensity CEF regimen.

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