Phase II trial of first-line high-dose ifosfamide in advanced soft tissue sarcomas of the adult: A study of the Spanish Group for Research on Sarcomas (GEIS)

Background: The agent Ifosfamide (IFOS) is active against soft tissue sarcomas (STS), and patients who progress to IFOS at doses less than or equal to 10 g/m(2) show remissions when exposed to high-dose ifosfamide (HDI) (i.e., doses > 10 g/m(2)), which supports a dose-response relationship for this drug. Because of a lack of first-line studies in adult STS patients, we decided to test the activity and toxicity of HDI in a phase II trial. Patients and methods: Forty-eight patients were enrolled in the study IFOS was administered at a dose of 14 g/m(2) by continuous infusion over six days every four weeks. Granulocyte-macrophage colony-stimulating factor (GM-CSF) at 5 mu g/kg/day for 10 consecutive days was systematically administered after an episode of neutropenic fever or a delay in hematologic recovery. Patients were treated until progression or the occurrence of severe toxicity, and surgical rescue was attempted when possible. Results: Six pathology-established complete remissions and 11 partial remissions were observed in 45 assessable patients with a response rate of 37.7% (95% CI: 25.5%-50%). Grade 3-4 toxicity (% of cycles) was noted by hemoglobin (17%), leukocyte (75%), granulocyte (75%) and platelet (13%) counts in 158 evaluable cycles. GM-CSF was administered to 28 patients, and 25 suffered one or more episodes of neutropenic fever. Renal toxicity was mild and reversible with some degree of tubular and glomerular dysfunction detected in up to 60% of patients. Grade 3 CNS toxicity was observed in 32% of patients but only one required interruption of therapy. Sixty-four per cent of the patients had asthenia grade 2-3 and 20% were excluded from the study due to excessive toxicity. There was one treatment-related death. Conclusions: HDI is an active drug in first-line therapy against adult STS. Different administration schedules should be evaluated in an attempt to improve its therapeutic index.