ABSTRACT
This trial was designed following observations that many patients had difficulty tolerating and complying with 2 weeks of oral cyclophosphamide in the classic Bonadonna CMF regimen [6] which had become a standard schedule in both the advanced and adjuvant settings. Given that this schedule was selected more or less arbitrarily, this trial investigated whether an i.v. schedule, with all 3 drugs given day 1 (C 600 mg/m2, M 40 mg/m2, and F 600 mg/m2) and recycled every 3 weeks, would be better tolerated and equally efficacious. Both regimens were given as first-line CT until progressive disease (PD) or excessive toxicity. The design called for 137 eligible patients per arm (274 total) in order to demonstrate a 15% difference in response. Although 332 patients were randomized, only 233 patients were evaluable for response (78 were ineligible and further 21 not evaluable). Nevertheless, the response was significantly lower in the 3-week than in the classical regimen, 29% and 48%, respectively, p 0.003 (20.2% vs. 33.5% by intention to treat). Although duration of response in responding patients was similar, time to progression (TTP) (p 0.001) and OS (17 vs. 12 months, p 0.02) were longer in the classic CMF group. Hematologic toxicity necessitating dose reductions was higher in the classic group; however, only 11% and 8.5% of the patients in the classic and 3-week regimens, respectively, received less than 80% of the intended doses. Dose intensity of all 3 drugs was also higher in the classic regimen (C 2800 mg/m2 vs. 1800 mg/m2; M 160 mg/m2
vs. 120 mg/m2; F 2400 mg/m2 vs. 1800 mg/m2, after 2 CMF-classic and 3 CMF-3-weekly cycles, respectively), which is offered as the reason for the superior outcome in the former schedule.
