title: Ifosfamide given by continuous-intravenous infusion in association with vinorelbine in patients with anthracycline-resistant metastatic breast cancer: A phase I-II clinical trial.
abstract: 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. In 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.
  
  
  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/m(2) on days 1-3 + VNR, 30 mg/m(2) on day 1 (six patients); IFX, 2 g/m(2) on days 1-3 + VNR, 25 mg/m(2) on day 1 (six patients); IFX, 1.8 g/m(2) on days 1-3 + VNR, 25 mg/m(2) on days 1 and 8 (six patients); IFX, 2 g/m(2) on days 1-3 + VNR, 25 mg/m(2) 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 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.
authors.affiliation: National Research Council, Institute of Biomedical Technologies, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Campisi
authors.forename: A
authors.initials: A
authors.lastname: Fabi
authors.forename: P
authors.initials: P
authors.lastname: Papaldo
authors.forename: S
authors.initials: S
authors.lastname: Tomao
authors.forename: B
authors.initials: B
authors.lastname: Massidda
authors.forename: A
authors.initials: A
authors.lastname: Zappala
authors.forename: M T
authors.initials: MT
authors.lastname: Ionta
authors.forename: F
authors.initials: F
authors.lastname: Cognetti
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D007262:Infusions, Intravenous; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D000903:Antibiotics, Antineoplastic; D014747:Vinblastine; D000077235:Vinorelbine; D007069:Ifosfamide