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


Authors: Raizer, J. J.; Malkin, M. G.; Kleber, M.; Abrey, L. E.
Article Title: Phase 1 study of 28-day, low-dose temozolomide and BCNU in the treatment of malignant gliomas after radiation therapy
Abstract: We conducted a study to determine the dose-limiting toxicity of an extended dosing schedule of temozolomide (TMZ) when used with a fixed dose of BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea (carmustine), taking advantage of TMZ's ability to deplete O6-alkylguanine- DNA-alkyltransferase and the synergistic activity of these two agents. Patients with malignant gliomas who had undergone radiation therapy were eligible. Patients were treated with TMZ for 28 days, followed by a 28-day rest (1 cycle). The TMZ was started at 50 mg/m2 and increased in 10-mg/m2 increments; a fixed dose of BCNU (150 mg/m2) was given within 72 h of starting TMZ. A standard phase 1 dose-escalation scheme was used with 3 patients per cohort. Fourteen glioblastoma patients and 10 anaplastic astrocytoma patients were treated. The dose-limiting toxicity was myelosuppression at 90 mg/m2 of TMZ. The total number of cycles given was 73 (median number was 2). Six patients (25%) required a dose reduction in BCNU, and six were removed from study for hematologic toxicity after cycle 1; three patients over-lapped. The median time to progression and overall survival were, respectively, 82 and 132 weeks for anaplastic astrocytomas and 14 and 69 weeks for glioblastomas. We conclude that the combination of BCNU and the extended dosing schedule of TMZ is feasible and that the maximal tolerated dose of a 28-day course of TMZ is 80 mg/m2 when combined with a fixed dose of BCNU at 150 mg/m2. This is the recommended dose for phase 2, but myelosuppression after cycle 1 suggests that long-term treatment may be difficult. Copyright © 2004 by the Society for Neuro-Oncology.
Keywords: adult; cancer survival; clinical article; controlled study; aged; middle aged; clinical trial; constipation; fatigue; neutropenia; cancer combination chemotherapy; diarrhea; drug dose reduction; drug potentiation; side effect; skin toxicity; liver dysfunction; cancer radiotherapy; temozolomide; glioma; brain neoplasms; dacarbazine; low drug dose; controlled clinical trial; drug eruption; infection; lung toxicity; pain; anemia; bone marrow suppression; bleeding; blood toxicity; leukopenia; neuropathy; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; dehydration; myalgia; drug administration schedule; radiotherapy; weight reduction; carmustine; coughing; dyspnea; hyperglycemia; pruritus; hyperkalemia; hypoalbuminemia; rigor; karnofsky performance status; cardiovascular disease; thrombosis; glioblastoma; muscle weakness; taste disorder; xerostomia; nausea and vomiting; antiemetic agent; seizure; anxiety; headache; maximum tolerated dose; phase 1 clinical trial; aphasia; drug dose regimen; dyspepsia; irritability; tremor; astrocytoma; visual disorder; amnesia; retinoic acid; hearing disorder; sore throat; weight gain; nystagmus; vertigo; face edema; pharyngitis; appetite disorder; common cold; consciousness disorder; stomach pain; otalgia; humans; human; male; female; article; 6 o alkylguanine dna alkyltransferase
Journal Title: Neuro-Oncology
Volume: 6
Issue: 3
ISSN: 1522-8517
Publisher: Oxford University Press  
Date Published: 2004-07-01
Start Page: 247
End Page: 252
Language: English
DOI: 10.1215/s1152851704000122
PROVIDER: scopus
PMCID: PMC1871994
PUBMED: 15279717
DOI/URL:
Notes: Neuro-Oncology -- Cited By (since 1996):25 -- Export Date: 16 June 2014 -- CODEN: NEURJ -- Source: Scopus
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MSK Authors
  1. Martin P Kleber
    1 Kleber
  2. Lauren E Abrey
    276 Abrey