Weekly high-dose infusional 5-fluorouracil (HD-5-FU) combinations in the treatment of advanced breast cancer: results of phase I/II studies with weekly 24-hour infusion of HD-5-FU plus high-dose folinic acid (FA) alone and in combination with paclitaxel and cisplatin.

ABSTRACT

UNLABELLED Our Phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (HD5-FU/FA) in intensively pretreated metastatic breast cancer prompted addition of paclitaxel to this regimen in a phase I/II study in outpatients. TREATMENT Patients were treated with HD5-FU (24-hour infusion)/FA (2h infusion prior to FU) weekly for 6 weeks (d1, 8, 15, 22, 29, 36) and Paclitaxel (3-hour infusion) was administered additionally on day 1 and day 22, q day 50. During Phase I we chose the following dose levels (dl) Fixed doses of FA d11-4 500 mg/m2 followed by HDFU, 24-hour infusion d11 1.5, d12 1.8, d13 and d14 2.0 g/m2. .3-hour infusion of Paclitaxel on day 1 and day 22 d11 to d13 135. d14 175 mg/m2. D14 was chosen to be further evaluated during phase II. Results of an interim analysis were presented. PATIENT CHARACTERISTICS 46 patients entered this trial during phase II and had the following characteristics age 46 years (26 to 70) WHO performance status 0/1, metastatic disease sites 2.5(1 to 4). All patients had bidimensionally measurable disease. PRETREATMENT 9 patients had received adjuvant chemotherapy, 16 patients prior chemotherapy for metastasis, and 21 both adjuvantly and for metastasis. Of 29 anthracycline-pretreated patients, 25 had anthracycline-resistant disease. RESULTS: We observed the following results in 35 evaluable patients CR 3% (1/35), PR 51% (18/35), SD 40% (14/35). PD 6% (2/35). RR (Response rate) was 54%, 95% confidence interval 36 to 76%. The response concerning 20 patients with anthracycline resistant disease was RR 55% (11/20). Median number of treatment cycles per patient was 3 (1 to 5), time to maximum response 2 months (1 to 5), remission duration 8+ months (2 to 17). Median survival time is not yet reached. CONCLUSIONS: The combination of paclitaxel with weekly HDFU/FA is well tolerated in the second-line treatment of metastatic breast cancer and indicates high efficacy also in anthracycline-resistant disease. In an ongoing phase II study, we examine the addition of cisplatin to the regimen in the first-line treatment of metastatic breast cancer. Those trials confirm that infusional weekly HD-5-FU plus folinic acid is of considerable interest in the treatment of advanced breast cancer. Randomized studies are warranted.