No Benefit of Dose-Dense vs Standard Temozolomide in Newly Diagnosed Glioblastoma, MGMT Methylation Associated With Better Survival
Dose-dense temozolomide results in depletion of O6-methylguanine-DNA methyltransferase (MGMT)—a potential determinant of treatment response—in blood mononuclear cells and possibly in tumors. In a phase III trial (Radiation Therapy Oncology Group [RTOG] 0525) reported in the Journal of Clinical Oncology, Mark R. Gilbert, MD, of The University of Texas MD Anderson Cancer Center, and colleagues compared dose-dense and standard-dose temozolomide maintenance in patients with newly diagnosed glioblastoma multiforme. They found no difference in overall survival or progression-free survival between the two groups overall or according to MGMT methylation status. Among all patients, MGMT methylation was associated with improved survival.
Study Details
The phase III trial enrolled patients aged older than 18 years with performance score ≥ 60 and adequate tissue. After concurrent radiotherapy and temozolomide, 833 patients were randomly assigned to receive standard-dose (n = 411) or dose-dense (n = 422) maintenance temozolomide for 6 to 12 cycles. Standard treatment consisted of a starting dose of 150 mg/m2 for 5 consecutive days of a 28-day cycle and a dose increase for subsequent cycles to 200 mg/m2 in the absence of treatment-related adverse events greater than grade 2. Dose-dense treatment consisted of an initial dose of 75 mg/m2 for 21 consecutive days of a 28-day cycle and a dose increase for subsequent cycles to 100 mg/m2 in the absence of treatment-related adverse events greater than grade 2. The primary endpoint was overall survival. Secondary analyses evaluated the effects of MGMT status.
Patients in the standard-dose and dose-dense groups were well balanced for baseline characteristics; 73% and 74% were aged ≥ 50 years, 58% and 56% were male, 78% in both groups were white, 66% and 65% had Karnofsky performance status of 90 to 100, and 56% and 52% had total resection. MGMT status was methylated in 30% and 29%, unmethylated in 62% in both groups, and unknown in 8% and 9%.
No Difference in Survival
No statistically significant difference was observed between the standard-dose and dose-dense groups in median overall survival (16.6 vs 14.9 months, hazard ratio [HR] = 1.03, P = .63) or median progression-free survival (5.5 vs 6.7 months, HR = 0.87, P = .06). Efficacy did not differ by methylation status: Median overall survival was 23.5 vs 21.9 months and median progression-free survival was 8.8 vs 11.7 months among patients with methylated MGMT and 16.6 vs 15.4 months and 7.1 vs 8.2 months, respectively, among patients with unmethylated MGMT.
Among all patients, MGMT methylation vs unmethylated MGMT was associated with significantly improved overall survival (median, 21.2 vs 14 months, HR = 1.74, P < .001), progression-free survival (median, 8.7 vs 5.7 months, HR = 1.63, P < .001), and response (P = .012).
Toxicity
The dose-dense group had a greater incidence of grade 3 or worse toxicity (52% vs 34%, P < .001), primarily reflecting greater frequencies of lymphopenia (29% vs 15%) and fatigue (9% vs 3%). The dose-dense and standard-dose groups had similar frequencies of grade 3 or worse neutropenia (10% vs 7%) and thrombocytopenia (7% and 10%).
The investigators concluded, “This study did not demonstrate improved efficacy for dose-dense temozolomide for newly diagnosed [glioblastoma multiforme], regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.”
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