Abstract
Promoter status of O6-methylguanine-DNA methyltransferase (MGMT) has been widely established as a clinically relevant factor in glioblastoma (GBM) patients. However, in addition to varied therapy schedule, the prognosis of GBM patients is also affected by variations of age, race, primary or recurrent tumor. This study comprehensively investigated the association between MGMT promoter status and prognosis in overall GBM patients and in different GBM subtype including new diagnosed patients, recurrent patients and elderly patients. A comprehensive search was performed using PubMed, EMBASE, Cochrane databases to identify literatures (published from January 1, 2005 to April 1, 2017) that evaluated the associations between MGMT promoter methylation and prognosis of GBM patients. Totally, 66 studies including 7,886 patients met the inclusion criteria. Overall GBM patients with a methylated status of MGMT receiving temozolomide (TMZ)-containing treatment had better overall survival (OS) and progression-free survival (PFS) [OS: hazard ratio (HR) = 0.46, 95% confidence interval (CI): 0.41-0.52, p < 0.001, Bon = 0.017; PFS: HR = 0.48, 95% CI 0.40-0.57, p < 0.001, Bon = 0.014], but no significant advantage on OS or PFS in GBM patients with TMZ-free treatment was observed (OS: HR = 0.97, 95% CI 0.91-1.03, p = 0.08, Bon = 1; PFS: HR = 0.76, 95% CI 0.57-1.02, p = 0.068, Bon = 0.748). These different impacts of MGMT status on OS were similar in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM. Among patients receiving TMZ-free treatment, survival benefit in Asian patients was not observed anymore after Bonferroni correction (Asian OS: HR = 0.78, 95% CI 0.64-0.95, p = 0.02, Bon = 0.24, I2 = 0%; PFS: HR = 0.69, 95% CI 0.50-0.94, p = 0.02, Bon = 0.24). No benefit was observed in Caucasian receiving TMZ-free therapy regardless of Bonferroni adjustment. The meta-analysis highlights the universal predictive value of MGMT methylation in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM patients. For elderly methylated GBM patients, TMZ alone therapy might be a more suitable option than radiotherapy alone therapy. Future clinical trials should be designed in order to optimize therapeutics in different GBM subpopulation.
Highlights
Glioblastoma (GBM) is the most frequent primary malignant brain tumor with poor prognosis
We performed a systematic review to identify all related articles from PubMed, EMBASE and the Cochrane Library covering the association of methylguanine-DNA methyltransferase (MGMT) methylation with prognosis and data of hazard ratios (HRs) and 95% confidence intervals (CIs)
We evaluated the eligible studies only if all the following con ditions were met: [1] studies investigated the relation between MGMT promoter methylation and survival in GBM patients; [2] treatment schedules and testing methods were all included; [3] HR and 95% CI for overall survival (OS) and progressionfree survival (PFS) were available directly or cal culated using the Kaplan–Meier survival curves; and [4] specific drugs for chemotherapy were introduced
Summary
Glioblastoma (GBM) is the most frequent primary malignant brain tumor with poor prognosis. Status of MGMT promoter methylation is associated with tumor response to TMZ therapy [11, 12]. Results of European Organization for Research and Treatment of Cancer and National Cancer Institute of Canada trial indicated that MGMT promoter methylation was the strongest predictor for outcome and benefit from TMZ [2, 16]. This biomarker is currently used for clinical decision-making and stratifying or selecting GBM patients for clinical trials [17]. Methods: A comprehensive search was performed using PubMed, EMBASE, Cochrane databases to identify literatures (published from January 1, 2005 to April 1, 2017) that evaluated the associations between MGMT promoter methylation and prognosis of GBM patients
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