Paclitaxel with mitoxantrone with or without 5-fluorouracil and high-dose leucovorin in the treatment of metastatic breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. We added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, 5-fluorouracil, and high-dose leucovorin. Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous infusion on day 1; mitoxantrone 10 mg/m2 by intravenous bolus on day 1; 5-fluorouracil 350 mg/m2 by intravenous bolus on days 1, 2, and 3; and leucovorin 300 mg intravenous over 30 to 60 minutes, immediately preceding 5-fluorouracil on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. Of 45 assessable patients, 23 (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. There were four treatment-related deaths, two sepsis, one congestive heart failure, and one sepsis and congestive heart failure, the last two after a large cumulative anthracycline dose. This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although how its activity compares with that of other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than had been anticipated based on previous results with the mitoxantrone/5-fluorouracil/high-dose leucovorin regimen or with single-agent paclitaxel administered at this dose and schedule. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with paclitaxel/doxorubicin combinations. We have embarked on a phase I/II trial of paclitaxel/mitoxantrone and have determined the maximum tolerated dose to be 200 mg/m2 and 10 mg/m2, respectively, without the use of cytokines. Fifteen patients have been treated at the maximum tolerated dose, and it is too early to assess results.