ABSTRACT
In this trial, 133 women without prior chemotherapy for metastatic disease were randomly assigned to receive one of two different dose levels of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU)) administered intravenously every 3 weeks. On the high-dose arm, the prescribed doses were 600 mg/m2 of cyclophosphamide and 5-FU and 40 mg/m2 of methotrexate, with escalation if possible. Doses on the lower-dose arm were 300 mg/m2 of cyclophosphamide and 5-FU, respectively, and 20 mg/m2 of methotrexate without escalation. Patients who failed to respond to lower-dose CMF were crossed over to the higher-dose arm. Patients randomized to the higher-dose arm had longer survival (median survival 15.6 months versus 12.8 months) from initiation of chemotherapy (p 0.026 by log-rank test), but the effect of dose was of borderline significance (p 0.12) when adjusted using the Cox proportional hazard model for chance imbalance between the two arms in the time from first relapse to randomization. Response rates for patients with measurable disease were 30% (16 of 53) in the higher-dose arm and 11% (6 of 53) in the lower-dose arm. Only 1 of 37 patients responded on crossover from the lower-to the higherdose arm. Patients experienced more vomiting, myelosuppression, conjunctivitis, and alopecia when receiving higher doses of chemotherapy. Linear analogue self-assessment scales confirmed greater toxicity in the immediate post-treatment period, but also a trend to improvement in general health and in some disease-related indices in patients receiving higher-dose chemotherapy.
