A phase I and II trial of dose-intensified cyclophosphamide and GM-CSF in pediatric malignant brain tumors

Purpose: Cyclophosphamide is commonly used in the treatment of children with malignant brain tumors. The purpose of this study was to develop a multicycle, high-dose intensity cyclophosphamide regimen with granulocyte-macrophage colony-stimulating factor (GM-CSF) and to assess its activity against malignant glioma and primitive neuroectodermal tumor (PNET). Methods:Twenty-three patients with brain tumors, including 15 with malignant glioma and six with PNET, were enrolled. Cyclophosphamide (1.8–2.25 g/m²/day for 2 days i.v.; total dose 3.6–4.5 g/m²) was administered and was followed by recombinant human GM-CSF (5 μg/kg/day s.c.) on days 3–11 or until the absolute granulocyte count reached 1.5 x 10⁹/L. Results: With a total of 83 cycles administered, the mean dose intensity of cyclophosphamide ranged from 1.5 g/m²/week through cycle 2 (22 patients) to 0.8 g/m²/week through cycle 8 (two patients). No activity was seen against malignant glioma, and five of six patients with PNET had partial responses. The mean duration of a neutrophil count of <0.5 x 10⁹/L was only 8 days; the platelet recovery was substantially longer. Fever during neutropenia occurred in 54 of 83 cycles. One patient died from transfusion-related graft-versus-host disease. Conclusions:A cyclophosphamide regimen equal to twice the dose intensity of that used in conventional therapy was administered. The regimen was active against PNET but inactive against malignant glioma.