Phase I-II study of vinorelbine in combination with 5-fluorouracil and folinic acid as first-line chemotherapy in metastatic breast cancer: A regimen with a low subjective toxic burden

Background: Vinorelbine, is an active drug in the treatment of metastatic breast cancer and has a favorable toxicity profile. Its combination with other effective and well-tolerated cytotoxics may thus be beneficial. We investigated the therapeutic effect of a combination of vinorelbine plus 5-fluorouracil and folinic acid as first-line treatment in patients with metastatic breast cancer. Patients and methods: Forty-five patients with advanced or metastatic breast cancer were enrolled in this phase I-II study and treated with 5-fluorouracil (350 mg/m² i.v. on day 1 to 3), folinic acid (100 mg/m² i.v. on day 1 to 3) and vinorelbine given on days 1 and 3 at the dose of 25 mg/m² (dose level 1), or 30 mg/m² (dose level 2). Therapy was given on an outpatient basis every three weeks. Results: Phase I: Dose limiting toxicity (DLT) occurred at the second dose level of vinorelbine (30 mg/m²), with two out of three patients developing severe constipation ('ileus-like syndrome' grade 4), and fever (grade 2). Consequently, the dose evaluated in the phase II study was 25 mg/m². Phase II: Objective responses were observed in 24 of 39 evaluable patients (95% confidence interval (95% CI), 47% to 77%). There were seven complete responses (18%), 17 partial responses (44%), and for nine patients (23%) disease was stable. Only six patients (15%) experienced disease progression. The median response duration was 10 months (range 6 to 24+) and the median time to progression was eight months (range 2 to 24+). Granulocytopenia was the most frequently observed side effect, with a grade 4 nadir being observed in 30 patients (77%), with four hospital admissions due to febrile neutropenia. Nausea, vomiting, and anorexia were mild to moderate and reported by less than half of the patients. Alopecia was moderate and occurred in about one-third of the patients. The other side effects were mild and easily manageable. Conclusions: This effective combination chemotherapy of vinorelbine, 5-fluorouracil and folinic acid is comparable to other first- line regimens in terms of efficacy, and is subjectively well tolerated, thus deserving a test in randomized trials in the advanced and adjuvant settings.