Ifosfamide given by continous-intravenous infusion in association with vinorelbine in patients with antracycline-resistant breast cancer: A phase I-II clinical trial.

Background; Vinorelbine (VNR) is highly active in metastatic breast cancer (MBC) and has shown an overall response rate of 40%-50% as first-line treatment. /;; vitro, a synergy has been observed between this drug and ifosfamide (IFX). In addition, the pharmacokinetics of IFX suggest that it may have greater activity when given by continuous-intravenous infusion (C.I.V.I.). The aim of this study was. therefore, to assess the antitumor efficacy and toxicity of the combination of bolus VNR and C.I.V.I. IFX as second-line therapy in anthracycline resistant breast cancer patients. Patients and methods: Forty-two patients with MBC who had already received anthracycline-based chemotherapy were treated with a regimen consisting of IFX, by C.I.V.I. for 72 hours and bolus VNR. The courses were repeated every three weeks for a maximum of eight cycles. Four dose intensification steps were planned: IFX, 1.5 g/m2 on days 1-3 + VNR, 30 mg/m2 on day 1 (six patients); IFX, 2 g/m2 on days 1-3 + VNR, 25 mg/m2 on day 1 (six patients); IFX, 1.8 mg/m2 on days 1-3 + VNR, 25 mg/m2 on days 1 and 8 (six patients); IFX, 2 g/m2 on days 1-3 + VNR, 25 mg/m2 on days 1 and 8 (24 patients). Sodium-2-mercaptoethane sulfonate (mesna) was associated with IFX at an infusion ratio of 1:1 and, once the infusion was completed, per os every four hours for three times. Results: All of the 42 patients entered were assessable for toxicity, and 41 of them for response. Neutropenia was the most frequently-occurring toxicity, but only five patients at the highest dose level (11.9%) presented grade 4, and none of those at the first three steps. Other significant toxic effects were mild (only grade I-II). The median relative dose intensity was 95% at the highest dose level and all of the treatments were administered on an out-patient basis. The overall response rate was 36.5% with a CR rate of 4.8% (two of 41 patients, all at the highest dose level) and a PR rate of 31.7% (13 of 41 patients). The median response duration was 7.0 months (range 2-13 months). Conclusions: The present phase I-II study shows that the IFX and VNR combination is an active and well-tolerated treatment in MBC and provides an alternative to taxanes for patients previously treated with anthracyclines.