HIGH-DOSE IFOSFAMIDE - CIRCUMVENTION OF RESISTANCE TO STANDARD-DOSE IFOSFAMIDE IN ADVANCED SOFT-TISSUE SARCOMAS

Purpose: The study was designed to assess the toxicity activity of hig h-dose ifosfamide (HDI) administered by continuous infusion at a dose of 4 g/m(2)/d over 3 days every 4 weeks in adult patients with advance d soft tissue sarcomas (ASTS) pretreated with doxorubicin and/or a sta ndard-dose ifosfamide (SDI)-containing regimen. Patients and Methods: Between January 1991 and November 1993, 40 patients with progressive A STS were entered onto the study, Twenty-eight patients had been pretre ated with a multidrug regimen that contained SDI and were classified a s follows: SDI-refractory (n = 21), SDI-resistant (n = 2), and indeter minate SDI-sensitive (n = 5). Patients were treated until progression or major toxicity.Results: One hundred forty-seven cycles of HDI were administered. Neutropenia was dose-limiting, with 100% of patients exp eriencing grade 3 to 4 toxicity and 12 admissions for febrile neutrope nio (30% of patients). Neurotoxicity (17% of patients) was significant ly associated with acute renal failure (n = 4) (P < .001), grade 4 thr ombocytopenia (P < .01) and febrile neutropenia (P = .048). Chronic re nal toxicity (n = 4) was significantly associated with retroperitoneal masses and/or prior nephrectomy (P = .008). Partial responses (PRs) w ere observed in 12 of 36 assessable patients (33%) and eight patients (22%) experienced disease stabilization. All but one response occurred in patients pretreated with SDI, with five PRs among SDI-refractory p atients. Leiomyosarcomas appear resistant to HDI. The median response duration was 8 months (range, 6 to 13+) and the median overall surviva l time was 12 months. Conclusion: The activity of HDI in these pretrea ted ASTS patients and the apparent circumvention of SDI resistance sug gest a real dose-response relationship for ifosfamide and deserve furt her evaluation. Although toxic, this treatment appears feasible and ma nageable using routine clinical support. Since prophylaxis of ifosfami de-induced renal damage remains unknown, frequent monitoring of renal and tubular functions during therapy is highly recommended.