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

Abstract

Purpose: Resistance to temozolomide chemotherapy is partly mediated by O 6 -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-1index of >5% or recurrent low-grade gliomas received temozolomide (75 mg/m 2 /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.

Extracranial Skeletal Metastasis in Anaplastic Oligodendroglioma: Case Report and Review of the Literature

“…29 40 high levels of MGMT are thought to contribute to resistance to TMZ. 41 Levin et al. 34 reported that TMZ was active in patients with progressive oligodendrogliomas, and that the response to treatment was associated with 1p deletion and low MGMT protein expression.…”

Diagnostic Evaluation of Diffuse Gliomas

“…In glioblastomas, MGMT methylation status in addition as a marker of prolonged survival is a predictor to therapy response (Hegi et al, 2005). In oligodendroglial tumors there is a strong association between MGMT promoter methylation and 1p19q codeletion the latter also contributing to the improved survival of patients with MGMT methylation (Levin et al, 2006;Kesari et al, 2009). MGMT alone is useful as a prognostic marker but not useful to predict outcome of adjuvant treatment in oligodendrogliomas (van den Bent et al, 2009).…”

Evolvement of Molecular Biomarkers in Targeted Therapy of Malignant Gliomas

“…Kesari and colleagues conducted a phase II study of protracted daily TMZ (75 mg/m 2 /d for 49 consecutive days of each cycle, followed by 28 days off between cycles, until evidence of progression or unacceptable toxicity for a maximum of six cycles) in 44 patients with newly diagnosed low-grade glioma. After a median follow-up of 39.4 months, 21 patients progressed with an overall median progression-free survival of 38 months (Kesari et al, 2009). Patients with methylated MGMT promoter had a significantly longer overall survival (100% alive at analysis, versus 29 months with unmethylated promoter), as did patients with single or co-deleted 1p or 19q.…”