title: High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine B. Radiotherapy, Institut Gustave Roussy, Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Le Cesne
authors.forename: E
authors.initials: E
authors.lastname: Antoine
authors.forename: M
authors.initials: M
authors.lastname: Spielmann
authors.forename: T
authors.initials: T
authors.lastname: Le Chevalier
authors.forename: E
authors.initials: E
authors.lastname: Brain
authors.forename: C
authors.initials: C
authors.lastname: Toussaint
authors.forename: N
authors.initials: N
authors.lastname: Janin
authors.forename: L
authors.initials: L
authors.lastname: Kayitalire
authors.forename: F
authors.initials: F
authors.lastname: Fontaine
authors.forename: J
authors.initials: J
authors.lastname: Genin
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001927:Brain Diseases / Q000139:chemically induced; D003606:Dacarbazine / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004351:Drug Resistance; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage* / Q000009:adverse effects; D007668:Kidney / Q000187:drug effects; D008297:Male; D015080:Mesna / Q000008:administration & dosage; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced / Q000628:therapy; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D003606:Dacarbazine; D004317:Doxorubicin; D015080:Mesna; D007069:Ifosfamide