1. Dose-dense (DD) Temozolomide does not improve overall survival or progression-free survival in newly diagnosed glioblastoma.
2. O6methylguanine-DNA methyltransferase (MGMT) methylation status is predictive for treatment response.
Evidence rating level: 1 (Excellent)
Study rundown: Glioblastomas are malignancies of the central nervous system with extremely poor prognosis and median survival times of less than two years despite modern therapies. Currently, the standard regimen for newly diagnosed glioblastoma is radiotherapy with concomitant and adjuvant temozolomide. Efforts at improving treatment have involved identifying prognostic factors, including methylation of the MGMT gene, which encodes a DNA repair enzyme. Previous studies have also found that dose-dense (DD) temozolomide causes prolonged depletion of MGMT in blood mononuclear cells and possibly the tumor as well. The goal of this trial was to test whether DD temozolomide improved survival in patients with newly diagnosed glioblastoma. However, the investigators of this study found that there was no difference between DD or standard temozolamide. Nevertheless, they confirmed that MGMT methylation has prognostic significance. They also demonstrated the feasibility of large-scale accrual, prospective tumor collection, and molecular stratification for future studies.
These results are supported by the large number of patients enrolled and the randomized, controlled design of this study. Nevertheless, further investigation into the use of MGMT methylation status in guiding clinical management decision is called for.
In-Depth [randomized controlled trial]: The authors of this study enrolled a total of 833 patients, all older than 18 years with a Karnofsky performance score of >60. Clinical factors and tumor MGMT methylation status were determined, and patients were randomly assigned to either standard temozolomide therapy or DD temozolomide for 6 to 12 cycles. The primary outcome measured was overall survival and progression-free survival, and the impact of MGMT status was determined in analysis.
No statistically significant difference was found between the two treatment arms for median overall survival (16.6 vs. 14.9 months, respective, P = 0.63) or for median progression free survival (5.5 vs. 6.7 months, P = 0.06). MGMT methylation status did not affect efficacy, but was associated with improved overall survival (21.2 vs. 14 months, P < 0.001), progression free survival (8.7 vs. 5.7 months, P < 0.001) and response (P = 0.012).
By Monica Parks and Andrew Bishara
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