INCREASING 4'-EPIDOXORUBICIN AND FIXED IFOSFAMIDE DOSES PLUS GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IN ADVANCED SOFT-TISSUE SARCOMAS - A PILOT-STUDY

Purpose: To determine the maximum-tolerated dose (MTD) of 4'-epidoxoru bicin (EPI) in combination with full dose of ifosfamide (IFO) when gra nulocyte-macrophage colony-stimulating factor (GM CSF) was used, to es timate its clinical efficacy, and to evaluate the mobilization of hema topoietic progenitors. Patients and Methods: previously untreated adva nced patients were treated with fixed doses of IFO at 1.8 g/m(2)/d for 5 days and escalating doses of EPI. The starting dose level of EPI wa s 50 mg/m(2) bolus on days 1 and 2; subsequent levels were 60 mg/m(2) and 70 mg/ m(2) given on days 1 and 2. GM-CSF (5 mu g/kg/d) was admini stered from days +6 to +19. Clinical evaluation of response was perfor med after three consecutive cycles. Mobilization of hematopoietic prog enitors was evaluated as day 14 CFU-GM after the first cycle only. Res ults: Overall, six, 18, and 13 assessable patients were entered onto e ach EPI dose level, respectively. The first and the second EPI level w ere considered feasible. Conversely, at the third level, only six of 1 3 patients (46%) tolerated full EPI doses at the scheduled time. There fore, the dose-intensity of the three levels was 100%, 99.7%, and 86.1 %, respectively. Overall, 20 of 37 patients (54%1 obtained an objectiv e response. The response rates for the three EPI dose levels were sign ificantly different (17%, 53%, and 100%, respectively; test for trend, P < .001). Considering only lung metastases, the overall response rat e was 72% (20%, 66%, and 100% for the three EPI levels, respectively). The most relevant mobilization effect was obtained at the third EPI l evel, when both GM-CSF and IL-3 were used as in vitro-stimulating fact ors. Conclusion: The third EPI level (70 mg/m(2) on days 1 and 2) is t he MTD of this program, since it was administered, without dose reduct ion or treatment delay, for three consecutive cycles in less than half of the patients. Nevertheless, this level proved to be interesting wi th regard to response rate (13 of 13 objective responses) and in mobil ization of the hematopoietic progenitors. (C) 1997 by American Society of Clinical Oncology.