Purpose: A phase I trial was performed to evaluate the feasibility of escalating the dose of etoposide in dose-intensive ifosfamide, carboplatin, and etoposide (ICE) with granulocyte-macrophage colony-stimulating factor (GM-CSF).
Patients and methods: Twenty-four patients were entered between November 1990 and November 1991. Patients received ifosfamide 5 g/m2 by continuous infusion over 48 hours, carboplatin 400 mg/m2 by intravenous bolus, and GM-CSF 5 micrograms/kg/d subcutaneously from day 4 until neutrophil recovery. The etoposide dose was escalated, with six patients receiving 300 mg/m2 total dose (level 1), six receiving 600 mg/m2 (level 2), three receiving 900 mg/m2 (level 3), and five receiving 1,200 mg/m2 (level 4). Level 4B consisted of three patients who received etoposide 1,200 mg/m2 and GM-CSF 10 micrograms/kg/d. Cycles were repeated every 21 days. The maximum-tolerated dose (MTD) was prospectively defined as the dose level at which the next higher level produced greater than 7 days of grade 4 myelosuppression in two or more of six patients.
Results: Twenty-three patients were assessable. The median duration of neutropenia was < or = 7 days on cycle 1 at all dose levels. The initial criteria for determination of the MTD was never achieved. However, seven of eight patients treated at levels 4 and 4B required hospitalization for neutropenic fever on cycle 1 of therapy, with three of four septic events occurring at these levels. Cumulative thrombocytopenia occurred at all dose levels, with > or = 50% of patients requiring platelet transfusions on cycle 3. This became the dose-limiting toxicity above level 3. The overall response rate was 48%, with 11 of 23 objective responses, including two complete responses (CRs). Seven of 11 (64%) patients with non-small-cell lung cancer (NSCLC) responded, including one CR. Two of four (50%) heavily pretreated non-Hodgkin's lymphoma (NHL) patients responded, with one CR.
Conclusion: The addition of GM-CSF to a dose-intensive ICE regimen permitted dose escalation of etoposide to 900 mg/m2, with cumulative thrombocytopenia as the dose-limiting toxicity. Carboplatin dosing by the area under the curve (AUC) may minimize thrombocytopenia. This appears to be an active regimen for patients with NSCLC and refractory NHL.