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Phase II Study of Protracted Daily Temozolomide for Low-Grade Gliomas in Adults

Authors' Affiliations: ¹ Dana-Farber/Brigham and Women's Cancer Center, Center for Neuro-Oncology, Departments of ² Neurology, ³ Pathology, ⁴ Radiation Oncology, and ⁵ Neurosurgery, Brigham and Women's Hospital, ⁶ Harvard Medical School, ⁷ MGH Biostatistics Center, Massachusetts General Hospital, and ⁸ Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts; and ⁹ Neuro-Oncology Center, University of Virginia, Charlottesville, Virginia

Requests for reprints: Patrick Y. Wen, Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, 44 Binney Street, SW430D, Boston, MA 02115. Phone: 617-632-2166; Fax: 617-632-4773; E-mail: pwen{at}partners.org.

Purpose: Resistance to temozolomide chemotherapy is partly mediated by O⁶-methylguanine-DNA methlytransferase (MGMT). Protracted treatment with temozolomide potentially overcomes MGMT resistance and improves outcome. We conducted a phase II study of protracted daily temozolomide in adults with low-grade gliomas.

Experimental Design: Patients with newly diagnosed oligodendroglioma or oligoastrocytoma with a MIB-1 index of >5% or recurrent low-grade gliomas received temozolomide (75 mg/m²/day in 11-week cycles of 7 weeks on/4 weeks off). Treatment continued for a total of six cycles or until tumor progression or unacceptable toxicity. Primary end point was best overall response rate; secondary end points were progression-free survival, overall survival, and toxicity. We correlated response with MGMT promoter methylation and chromosome 1p/19q deletion status.

Results: Forty-four patients were treated (14 female, 30 male) with a median follow-up of 39.4 months. Median age was 43 years (range, 20-68 years) and median Karnofsky performance status was 90 (range, 70-100). The regimen was well tolerated. No patients had a complete response (0%), 9 had partial response (20%), 33 had stable disease (75%), and 2 had progressive disease (5%). A total of 21 patients eventually progressed with an overall median progression-free survival of 38 months. Patients with methylated MGMT promoter had a longer overall survival (P = 0.008). Deletion of either 1p or 19q chromosomes also predicted longer overall survival (hazard ratio, 0.17; 95% confidence interval, 0.03-0.93; log-rank P = 0.02).

Conclusions: A protracted course of daily temozolomide is a well-tolerated regimen and seems to produce effective tumor control. This compares favorably with historical data on the standard 5-day temozolomide regimen.