The German Society of Pediatric Oncology (GPO) has studied the efficacy of high-dose ifosfamide with mesna uroprotection in patients with Ewing's sarcoma. A phase II trial of ifosfamide (IFO) (2 g/m2 per day, days 1-5) in eight patients with recurrent evaluable disease resulted in three partial and two complete responses lasting from 3 to 12 months (median, 6 months). In a second phase II trial in 15 patients, the combination of IFO and cisplatin (20 mg/m2 per day, days 1-5) resulted in 7 partial and 2 complete responses lasting from 3 to 32 months (median, 6 months). Consequently, in 1985 IFO was incorporated into first-line chemotherapy for newly diagnosed patients (replacing cyclophosphamide) and given in combination with vincristine, actinomycin D, and adriamycin (VAIA) in patients considered to be at high risk for relapse. IFO was given at a dose of 3 g/m per day on days 1 and 2 as a 48-h continuous infusion, in combination with actinomycin D (0.5 mg/m2 per day on days 1-3) or Adriamycin (30 mg/m2 per day on days 1 and 2). The study was piloted from March to December 1985 and has been open since January 1986; 37 patients were entered during the pilot phase and 65 have been entered in the ongoing main trial since January 1986. At present, Kaplan-Meier disease-free survival projects that disease-free survival in patients with large primary tumors has improved compared with that reported for the previous CESS 81 trial. The toxicity of the VAIA regimen was comparable with that of the conventional vincristine, actinomycin D, cyclophosphamide, and adriamycin (VACA) regime used in the previous CESS 81 trial.