Ifosfamide given by continuous-intravenous infusion in association with vinorelbine in patients with anthracycline-resistant metastatic breast cancer: A phase I-II clinical trial

Background: Vinorelbine (VNR) is highly active in metastatic breastcancer (MBC) and has shown an overall response rate of40%–50% as first-line treatment. In vitro, a synergy hasbeen observed between this drug and ifosfamide (IFX). In addition, thepharmacokinetics of IFX suggest that it may have greater activity when givenby continuous-intravenous infusion (C.I.V.I.). The aim of this study was.therefore. to assess the antitumor efficacy and toxicity of the combinationof bolus VNR and C.I.V.I. IFX as second-line therapy inanthracycline-resistant breast cancer patients.Patients and methods: Forty-two patients with MBC who had alreadyreceived anthracycline-based chemotherapy were treated with a regimenconsisting of IFX, by C.I.V.I. for 72 hours and bolus VNR. The courses wererepeated every three weeks for a maximum of eight cycles. Four doseintensification steps were planned: IFX, 1.5 g/m² on days1–3 + VNR, 30 mg/m² on day 1 (six patients); IFX, 2g/m² on days 1–3 + VNR, 25 mg/m² on day 1(six patients); IFX, 1.8 mg/m² on days 1–3 + VNR, 25mg/m² on days 1 and 8 (six patients); IFX, 2g/m² on days 1–3 + VNR, 25 mg/m² on days 1and 8 (24 patients). Sodium-2-mercaptoethane sulfonate (mesna) wasassociated with IFX at an infusion ratio of 1 : 1 and, once the infusion wascompleted, per os every four hours for three times.Results: All of the 42 patients entered were assessable for toxicity, and41 of them for response. Neutropenia was the most frequently-occurringtoxicity, but only five patients at the highest dose level (11.9%)presented grade 4, and none of those at the first three steps. Othersignificant toxic effects were mild (only grade I–II). The medianrelative dose intensity was 95% at the highest dose level and all ofthe treatments were administered on an out-patient basis. The overallresponse rate was 36.5% with a CR rate of 4.8% (two of 41patients, all at the highest dose level) and a PR rate of 31.7% (13of 41 patients). The median response duration was 7.0 months (range2–13 months).Conclusions: The present phase I–II study shows that the IFX and VNRcombination is an active and well-tolerated treatment in MBC and provides analternative to taxanes for patients previously treated with anthracyclines.