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MGMT promoter methylation is currently considered the main prognostic biomarker in glioblastoma, yet some concerns remain about its actual impact on outcome. The aim of the present study was to analyze literature data on this topic. Therefore, a systematic review and analysis of recently published glioblastoma cohorts examining the relationship between MGMT methylation and prognosis was performed. We found that only 19/28 studies (68%) confirmed the prognostic value of MGMT methylation and/or its role in predicting response to temozolomide. In these studies, however, the population showed significantly lower rates of unfavorable prognosticators as compared with studies where MGMT methylation was not prognostic/predictive. Moreover, studies demonstrating a better prognosis for MGMT methylated cases had significantly lower rates of deaths at 3 and 6 months. Multivariate analysis showed that the 3-month and 6-month deaths are significantly associated with the prognostic/predictive value of MGMT methylation, and that the percent of MGMT methylated tumors and of patients treated with alkylating drugs trend towards statistical significance if modeled with the 6-month but not with the 3-month mortality rate. These results suggest that the paucity of short-term survivors may represent a bias in studies focusing on MGMT methylation and prognosis, and that a temporal threshold may be necessary in order to demonstrate the clinical benefit of MGMT promoter methylation.
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