Phase I/II study with paclitaxel in combination with weekly high-dose 5-fluorouracil/folinic acid in the treatment of metastatic breast cancer: an interim analysis.

Phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/II trial in outpatients: high-dose 5-FU (24-hour infusion)/FA (2-hour infusion preceding 5-FU) is given for 6 weeks (days 1, 8, 15, 22, 29, and 36), with paclitaxel (3-hour infusion) administered on days 1 and 22; 2 weeks' rest follows. Folinic acid 500 mg/m2 was administered throughout; the respective 5-FU doses for dose levels 1 through 3 were 1.5, 1.8, and 2.0 g/m2 with paclitaxel 135 mg/m2. Dose level 4 (500 mg/m2 FA, 2.0 g/m2 5-FU, and 175 mg/m2 paclitaxel) was chosen for phase II evaluation. To date, 46 patients with bidimensionally measurable disease (four each at dose levels 1, 2, and 3, and 34 at dose level 4) have been entered. The 12 patients treated at dose levels 1 through 3 were titrated to level 4 doses when phase II began; 35 patients are evaluable for response. The median age is 46 years, and the median number of metastatic sites is 2.5. Fourteen patients had received adjuvant chemotherapy, nine chemotherapy for metastasis, and 23 chemotherapy both adjuvantly and for metastasis. Of 31 anthracycline-treated patients, 27 had anthracycline-resistant disease. No dose-limiting toxicity appeared until dose level 4, when grade 3 or 4 leukopenia and diarrhea occurred in 15 and eight, respectively, of 108 cycles. Mild to moderate mucositis, hand-foot syndrome, myalgia, and nausea/vomiting occurred in 20% to 40% of cycles. One (3%) of the 35 patients had a complete response, 18 (51%) had partial responses, 14 (40%) had stable disease, and two (6%) had disease progression. Eleven (55%) of 20 evaluable patients with anthracycline-resistant disease responded (95% confidence interval, 34% to 76%). Median time to maximum response was 2 months, and the remission duration was 8+ months. Median survival time has not been reached. Paclitaxel and weekly high-dose 5-FU/FA was well tolerated and highly effective, even in patients with anthracycline-resistant metastatic breast cancer. The regimen can be administered safely to outpatients.