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A phase I study of topotecan as a radiosensitizer for brainstem glioma of childhood: First report of the Children's Cancer Group-0952

University of Wisconsin, Madison, WI 53706 (S.N.S., M.P.M.); ImClone Systems Inc., Somerville, NJ 08876 (M.N.N.); Keck School of Medicine, University of Southern California, Los Angeles, CA 90089 (M.D.K.); Children's Hospital and Regional Medical Center, Seattle, WA 98105 (J.R.G.); and M. D. Anderson Cancer Center, Houston, TX 77030 (J.A.)

² Address correspondence and reprint requests to Minesh P. Mehta, M.D., Department of Human Oncology, University of Wisconsin Medical School, 600 Highland Avenue, K4/3, Madison, WI 53792.

Abstract

Our purpose was to establish the maximum tolerated dosage (MTD) of daily i.v. topotecan with conventionally fractionated radiotherapy (XRT) for patients with intrinsic pontine glioma of childhood. Topotecan was given as a 30-min i.v. infusion 30-60 min before each XRT treatment given daily for 33 days. Total XRT dose was 59.4 Gy. Dose escalation of topotecan was carried out using a standard phase I design. Dose limiting toxicity (DLT) was defined as an absolute neutrophil count (ANC) of <500/mm³ for >7 days; platelets of <50,000/mm³ for >7 days; >7 days platelet transfusions; fever and neutropenia (ANC <500/mm³ for >7 days); and/or any > grade 3 nonhematologic toxicity. In this multi-institutional phase I study, 17 patients <21 years with intrinsic pontine glioma were enrolled. Sixteen patients completed treatment. An ANC <500/mm³ for >7 days occurred in 2/5 patients at 0.50 mg/m² of topotecan, which was the DLT. The remaining 14 patients received topotecan without experiencing DLT. One patient at 0.40 mg/m² died of disease progression while on treatment. There were 6 other grade 4 hematologic events (5 ANCs <500/mm³, 1 hemoglobin <6. 5 g/dl) not meeting DLT criteria. No significant nonhematologic toxicities were seen. The actuarial median survival time is 15 months (95% confidence interval, 9.6-19 months); 1-year survival is 53%. DLT of daily topotecan with cranial XRT is grade 4 neutropenia for >7 days at 0.50 mg/m² x 33 (total dosage = 16.5 mg/m²); the recommended safe MTD of daily topotecan for further phase II testing is 0.40 mg/m² x 33 (total dosage = 13.2 mg/m²).

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