Adult Brain Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Management of Specific Tumor Types and Locations
O6-methylguanine-DNA methyltransferase (MGMT) promoter DNA methylation
A companion molecular, correlation subset study to the EORTC-NCIC trial provided strong evidence that epigenetic silencing of the MGMT DNA-repair gene by promoter DNA methylation was associated with increased OS in patients with newly diagnosed glioblastoma. MGMT promoter methylation was an independent favorable prognostic factor (P < .001 by the log-rank test; HR, 0.45; 95% CI, 0.32-0.61). The median OS for MGMT-methylated patients was 18.2 months (95% CI, 15.5-22.0), compared with 12.2 months (95% CI, 11.4-13.5) for MGMT-unmethylated patients.
MGMT DNA-repair activity has been proposed as a major mechanism of resistance to alkylating agents. Intracellular depletion of MGMT has been hypothesized to enhance treatment response, and protracted temozolomide schedules have been shown to deplete intracellular MGMT in peripheral blood mononuclear cells. To test whether protracted temozolomide enhances treatment response in patients with newly diagnosed glioblastoma, a multicenter, randomized, phase III trial conducted by the Radiation Therapy Oncology Group (RTOG), EORTC, and the North Central Cancer Therapy Group, RTOG 0525 (NCT00304031), compared standard adjuvant temozolomide treatment (days 1-5 of a 28-day cycle) with a dose-dense schedule (days 1-21 of a 28-day cycle). All patients were treated with surgery followed by radiation therapy and concurrent daily temozolomide. Patients were then randomly assigned to receive either standard adjuvant temozolomide or dose-dense temozolomide.[Level of evidence: 1iiA]
Among 833 randomly assigned patients, no statistically significant difference between standard and dose-dense temozolomide was observed for median OS (16.6 months for standard temozolomide vs. 14.9 months for dose-dense temozolomide; HR, 1.03; P = .63) or median progression-free survival (PFS) (5.5 vs. 6.7 months; HR, 0.87; P = .06). MGMT status was determined in 86% of randomly assigned patients, and no difference in efficacy was observed in either the MGMT-methylated or MGMT-unmethylated subsets. However, this study confirmed the strong prognostic effect of MGMT methylation because the median OS was 21.2 months (95% CI, 17.9-24.8) for methylated patients versus 14 months (95% CI, 12.9-14.7) (HR, 1.74; P < .001) for unmethylated patients.