MITOXANTRONE DOSE AUGMENTATION UTILIZING FILGRASTIM SUPPORT IN COMBINATION WITH FIXED-DOSE 5-FLUOROURACIL AND LEUCOVORIN IN WOMEN WITH METASTATIC BREAST-CANCER

Based on reports of substantial antitumor efficacy of the combination of mitoxantrone (DHAD), 5-fluorouracil (FU) and leucovorin (LV), a cli nical trial was performed to attempt augmentation of the dose of DHAD with filgrastim support. The doses and schedules, all intravenous, wer e DHAD (total dose divided over days 1 and 2),level I:16 mg/m(2);II, 2 0 mg/m(2); III, 24 mg/m(2); IV, 32 mg/m(2); and LV, 300 mg, followed b y FU? 350 mg/m(2), on days 1-3. Filgrastim was given at 5 mu g/kg/day subcutaneously on days 4-13. The planned cycle length was 21 days, Thr ee or 4 patients were to be entered at each dose level and the maximum tolerated dose (MTD) was defined as the dose immediately below that w hich resulted in 2 patients with dose-limiting toxicity (DLT) in cycle 1. Once an apparent MTD was identified, an additional 6 patients were to be entered. Twenty patients (pts) were entered: level I: 3 pts; II : 3 pts;III: 10 pts;IV: 4 pts. The major toxicity was found to be cumu lative thrombocytopenia with platelet counts less than or equal to 20, 000/mu L occurring after cycle 1 at all levels beyond level I and five pts (25%) were removed from treatment solely because of platelet toxi city. Additional serious toxicities included grade 4 stomatitis in one patient (level IV) and cardiac toxicity in 2 patients with prior doxo rubicin exposure. Ten pts had measurable and 8 had evaluable disease, and in 17 pts assessed, 5 (29%) achieved an objective response. The re sponse rates in this study are lower than reported in the literature f or the combination of DHAD, 5FU, LV and this may be related to the fac t that only 40% of the patients were removed from protocol treatment b ecause of disease progression. On the basis of limited DHAD-dose augme ntation, toxicities observed, and modest response rate, the filgrastim -supported DHAD, 5FU, LV regimen as utilized in this study cannot be r ecommended for further development for treatment of women with metasta tic breast cancer.