Randomized trial of cyclophosphamide, methotrexate, and 5‐fluorouracil with or without estrogenic recruitment in women with metastatic breast cancer

Background. The fraction of breast cancer cells undergoing DNA synthesis at any one time is relatively low, which is problematic because most chemotherapeutic agents are most effective against dividing cells. Estrogens administered in vitro and in vivo can increase breast cancer cell proliferation. A randomized clinical trial was performed to determine if estrogenic recruitment could increase the effectiveness of combination chemotherapy. Methods. One hundred sixty‐five women were randomized, with two excluded from these analyses, to either an intravenous cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF) regimen alone (cyclophosphamide, 600 mg/m²; methotrexate, 40 mg/m²; 5‐fluorouracil, 600 mg/m²) or CMF preceded by 3 days of diethylstil‐bestrol (DES) at a dose of 1 mg orally per day. The planned cycle length was 3 weeks. Results. Objective responses were seen in 20 of 80 patients (25%) treated with CMF and 32 of 83 patients (39%) treated with DES‐CMF, and this difference almost achieved statistical significance (chi‐square, two‐sided P = 0.06). However, duration of response, time to disease progression, and survival time were similar for the two regimens. Conclusions. Estrogenic recruitment with DES as used in this study does not substantially increase the efficacy of a CMF regimen administered intravenously every 3 weeks.