High-dose ifosfamide: Circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas

A. Le Cesne, E. Antoine, M. Spielmann, T. Le Chevalier, E. Brain, C. Toussaint, N. Janin, L. Kayitalire, F. Fontaine, J. Genin, D. Vanel, G. Contesso, T. Tursz

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Purpose: The study was designed to assess the toxicity and activity of high-dose ifosfamide (HDI) administered by continuous infusion at a dose of 4 g/m2/d over 3 days every 4 weeks in adult patients with advanced soft tissue sarcomas (ASTS) pretreated with doxorubicin and/or a standard-dose ifosfamide (SDI)-containing regimen. Patients and Methods: Between January 1991 and November 1993, 40 patients with progressive ASTS were entered onto the study. Twenty-eight patients had been pretreated with a multidrug regimen that contained SDI and were classified as follows: SDI-refractory (n = 21), SDI- resistant (n = 2), and indeterminate 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 experiencing grade 3 to 4 toxicity and 12 admissions for febrile neutropenia (30% of patients). Neurotoxicity (17% of patients) was significantly associated with acute renal failure (n = 4) (P <.001), grade 4 thrombocytopenia (P <.01) and febrile neutropenia (P= .048). Chronic renal toxicity (n = 4) was significantly associated with retroperitoneal masses and/or prior nephrectomy (P = .008). Partial responses (PRs) were 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 patients. Leiomyosarcomas appear resistant to HDI. The median response duration was 8 months (range, 6 to 13+) and the median overall survival time was 12 months. Conclusion: The activity of HDI in these pretreated ASTS patients and the apparent circumvention of SDI resistance suggest a real dose-response relationship for ifosfamide and deserve further evaluation. Although toxic, this treatment appears feasible and manageable using routine clinical support. Since prophylaxis of ifosfamide-induced renal damage remains unknown, frequent monitoring of renal and tubular functions during therapy is highly recommended.

Original languageEnglish
Pages (from-to)1600-1608
Number of pages9
JournalJournal of Clinical Oncology
Issue number7
Publication statusPublished - Jul 1995

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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