PHASE-II STUDY OF CONTINUOUS-INFUSION HIGH-DOSE IFOSFAMIDE IN ADVANCED AND OR METASTATIC PRETREATED SOFT-TISSUE SARCOMAS/

Background. Ifosfamide has important activity in pretreated soft tissu e sarcomas (STS), and recent data support a clinically significant dos e-response relationship for this agent. Administration by continuous i nfusion and hematopoietic support have rendered dose intensification r egimens possible by reducing both hematologic and non-hematologic toxi cities. The optimal dose and schedule of ifosfamide when given at high doses remain to be defined. In a previous phase I study, we demonstra ted the feasibility of a continuous infusion (c.i.) high-dose ifosfami de (HDI) regimen in the ambulatory setting for patients with advanced solid tumors. The objective of the present phase II study was to asses s the antitumor activity and toxicity of such a schedule in patients w ith advanced pretreated STS. Patients and methods: Thirty-eight patien ts with advanced and/or metastatic STS, all pretreated with an anthrac ycline with or without standard-dose ifosfamide, were treated. Ifosfam ide was given by c.i. at a dose of 3.5 g/m(2)/day over four consecutiv e days, with equidose mesna uroprotection over five days. G-CSF was ad ded at a dose of 200 mu g/m(2)/day subcutaneously from day 6 to day 12 . Cycles were repeated every three weeks in the outpatient setting. Re sults: A total of 159 cycles of therapy were given (median 4 per patie nt, range 3-6). Treatment compliance was generally satisfactory. The m ajor toxicity was hematologic, with six febrile neutropenic episodes r equiring hospitalisation and parenteral antibiotics. Acute renal failu re occurred in one patient after three cycles of therapy; central nerv ous system toxicity was mild. An overall response rate of 39% was obse rved (95% confidence interval, 26% to 55%), with one complete and 14 p artial remissions. All but one of the responder patients had previousl y received standard-dose ifosfamide. The median response duration was nine months (range 5-21+ months), and the overall median survival rang ed from 6-30+ months (median 13 months). Conclusions: High-dose ifosfa mide is an active regimen in anthracycline-pretreated STS. Future clin ical trials should be aimed at evaluating the impact of different admi nistration schedules on clinical response and outcome. The potential r ole of HDI as front-line chemotherapy as well as in the adjuvant treat ment of STS needs to be investigated in randomized trials.