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Neuro-Oncology 2004 6(3):247-252; doi:10.1215/S1152851704000122
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© 2004 by the Society forNeuro-Oncology

Phase 1 study of 28-day, low-dose temozolomide and BCNU in the treatmentof malignant gliomas after radiation therapy

Jeffrey J. Raizer2, Mark G. Malkin, Martin Kleber and Lauren E. Abrey

Neurology Department, Northwestern Memorial Hospital,Chicago, IL 60611 (J.J.R.); Medical College ofWisconsin, Milwaukee, WI 53226 (M.G.M), MemorialSloan-Kettering Cancer Center, New York, NY 10021 (M.K., L.E.A);USA

2 Address correspondence to Jeffrey J. Raizer, Davee Department of Neurology,Abbott Hall, 710 North Lake Shore Drive, Room 1123, Chicago, IL 60611, USA(j-raizer{at}northwestern.edu).


  Abstract

We conducted a study to determine the dose-limiting toxicity of an extendeddosing schedule of temozolomide (TMZ) when used with a fixed dose of BCNU, or1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine), taking advantage of TMZ'sability to deplete O6-alkylguanine-DNA-alkyltransferaseand the synergistic activity of these two agents. Patients with malignantgliomas who had undergone radiation therapy were eligible. Patients weretreated with TMZ for 28 days, followed by a 28-day rest (1 cycle). The TMZ wasstarted at 50 mg/m2 and increased in 10-mg/m2increments; a fixed dose of BCNU (150 mg/m2) was given within 72 hof starting TMZ. A standard phase 1 dose-escalation scheme was used with 3patients per cohort. Fourteen glioblastoma patients and 10 anaplasticastrocytoma patients were treated. The dose-limiting toxicity wasmyelosuppression at 90 mg/m2 of TMZ. The total number of cyclesgiven was 73 (median number was 2). Six patients (25%) required a dosereduction in BCNU, and six were removed from study for hematologic toxicityafter cycle 1; three patients overlapped. The median time to progression andoverall survival were, respectively, 82 and 132 weeks for anaplasticastrocytomas and 14 and 69 weeks for glioblastomas. We conclude that thecombination of BCNU and the extended dosing schedule of TMZ is feasible andthat the maximal tolerated dose of a 28-day course of TMZ is 80mg/m2 when combined with a fixed dose of BCNU at 150mg/m2. This is the recommended dose for phase 2, butmyelosuppression after cycle 1 suggests that long-term treatment may bedifficult.

Received January 27, 2004; Accepted March 2, 2004


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