Preclinical and clinical study results of the combination of paclitaxel and 5-fluorouracil/folinic acid in the treatment of metastatic breast cancer.

Results of phase II studies have demonstrated high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) when given to intensively pretreated patients with metastatic breast cancer. In a phase I/II study of outpatients, we have added paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in an attempt to improve the results. Patients were treated weekly for 6 weeks (days 1, 8, 15, 22, 29, and 36) with high-dose 5-FU 2.0 g/m2 by 24-hour infusion with FA 500 mg/m2 given as a 2-hour infusion prior to 5-FU. Paclitaxel 175 mg/m2 by 3-hour infusion was administered on days 1 and 22 prior to 5-FU/FA. Each cycle comprised 6 weeks followed by 2 weeks rest; the number of cycles depended on response and toxicity. To date, 40 patients have been entered into this trial during phase II. Pretreatment included adjuvant chemotherapy among 12 patients, prior chemotherapy for metastasis in nine patients, and both adjuvant therapy and treatment for metastasis in 19 patients. Of 24 anthracycline-pretreated patients, 20 had anthracycline-resistant disease. The observed toxicities were of mild to moderate intensity, especially with regard to myelosuppression. Thirty-four patients have been evaluable for response. Response rates included 3% complete response (one of 34 patients) and 50% partial response (17 of 34 patients) for an overall response rate of 53% (95% confidence interval, 37% to 69%). Additionally, 41% (14 of 34 patients) had stable disease and 6% had progressive disease (two of 34 patients). Among 20 anthracycline-resistant patients, 55% responded (11 of 20 patients). The median number of treatment cycles per patient was three (range, one to five); time to maximum response, 2 months (range, 1 to 5 months); and remission duration, 9 months (range, 2 to 17 months). Median time to progression was 10 months (range, 3 to 17 months). In conclusion, the combination of paclitaxel with weekly high-dose 5-FU/FA is well tolerated as second-line treatment of metastatic breast cancer, with high activity, even in patients with anthracycline-resistant disease. The regimen can be administered safely on an outpatient basis.