Abstract
Background and objective:
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.
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.
Results:
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.
Conclusion:
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.
Introduction
Glioblastoma (GBM) is the most frequent primary malignant brain tumor with poor prognosis. From 2005, radiotherapy combined with concomitant and adjuvant temozolomide (TMZ) after surgical maximal safe resection, namely STUPP treatment, has been widely used for newly diagnosed GBM patients less than 65 years old (1, 2). A phase III trial showed that tumor treatment fields, a novel cancer treatment modality, had similar efficacy as chemotherapy regimens in recurrent GBM (3). However, limited improvement of the overall survival (OS) has been achieved in patients with GBM (4, 5). Therefore, identification of biomarkers determining tumor response to treatment may help in developing targeted therapy or optimize patients’ management.
O-6-methylguanine-DNA methyltransferase (MGMT) is a ubiquitously expressed DNA repair enzyme. MGMT protein removes alkyl adducts at the O6 position of guanine, thereby neutralizing the cytotoxic effects of alkylating agents such as TMZ (6, 7). High MGMT expression in glioma cells is the predominant mechanism underlying tumor resistance to alkylating agents (8–10). Meanwhile, status of MGMT promoter methylation is associated with tumor response to TMZ therapy (11, 12). MGMT promoter methylation, resulting in transcriptional silencing, correlates well with improved survival in GBM patients exposed to alkylating agents’ treatment (13–15). 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). Accordingly, this biomarker is currently used for clinical decision-making and stratifying or selecting GBM patients for clinical trials (17).
Although MGMT promoter methylation has a strong influence on response to TMZ and clinical outcome in GBM patients, its prognostic value on GBM patients remains ambiguous. Some studies indicated that it was associated with better outcome in methylated patients receiving TMZ-containing therapy (18, 19). But some studies also showed that it conferred survival benefit in methylated patients receiving TMZ-free therapy (21, 22). So it is necessary to review whether the survival benefit from MGMT methylation is therapy dependent or independent, which will define MGMT promoter methylation as a predictive or prognostic biomarker. In addition to varied therapy schedules, the outcome and survival of GBM patients may be affected by other prognostic variables, including primary or recurrent tumor, age and race. Thus, we conducted a comprehensive and exact analysis on the association between MGMT promoter methylation and prognosis in overall GBM patients as well as in different GBM subpopulation, including newly diagnosed patients, recurrent patients, elderly patients and patients with different races. This meta-analysis will provide an updated and precise review on the clinical value of MGMT promoter methylation on progression-free survival (PFS) and OS in GBM patients.
Methods
Search Strategy
We performed a systematic review to identify all related articles from PubMed, EMBASE and the Cochrane Library covering the association of MGMT methylation with prognosis and data of hazard ratios (HRs) and 95% confidence intervals (CIs). The articles enrolled in analysis were published between January 1, 2005 and April 1, 2017. The following subject terms were used: (1) “Glioblastoma,” “GBM,” “High-Grade Glioma,” “Astrocytoma, Grade IV,” “Astrocytomas, Grade IV,” “Glioblastoma Multiform,” or “Glioblastomas”; (2) “MGMT” or “O-6-methylguanine-DNA methyltransferase.” The eligible studies were restricted to human beings.
Inclusion and Exclusion Criteria
We evaluated the eligible studies only if all the following conditions 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 OS and PFS were available directly or calculated using the Kaplan–Meier survival curves; and (4) specific drugs for chemotherapy were introduced.
Study Selection and Data Extraction
Study selection was independently performed by two authors and disagreements were resolved through discussion. The following data were extracted: the author’s name, country, publication year, number of patients, treatment detail, outcomes (including HRs and 95% CIs), the Cox regression model, and study design feature.
Quality Assessment
The bias risk in each study was independently assessed by two authors using a modified domain-based Newcastle-Ottawa Scale (NOS) for non-randomized studies. The assessment included selection bias, performance bias, detection bias, attrition bias and reporting bias. Important prognostic variables, including age, neurologic status, extent of resection, tumor location, primary or recurrent GBM and MGMT promoter status, were added into NOS according to the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) checklist for a tumor prognostic study (23, 24). The judgment criteria for the modified evaluation were explicitly described in Table S1 in Supplementary Material.
Statistical Analysis
The statistical analysis was performed by STATA 12.0 software. HR and 95% CI were directly extracted or calculated using the Kaplan–Meier survival curves or the methods reported by Tierney et al. (25). To evaluate the association of MGMT promoter methylation with OS and PFS, pooled HRs of methylated GBM patients were compared to those of unmethylated patients. Subgroup analysis was performed to evaluate whether methylated patients benefit from different therapies (TMZ-containing, TMZ-free alkylating agents, or radiotherapy alone). The statistical heterogeneity among studies was assessed by Q-test and I2 statistics (26). If there was no obvious heterogeneity, fixed-effect model was used to estimate the pooled HR (27); otherwise, random-effect model was used (28). Bonferroni method was used for multiple comparison adjustments. Publication bias was assessed by funnel plots and Egger’s test (29), and a trim and fill method was applied to estimate asymmetry in funnel plots (30). Sensitivity analysis by deleting each enrolled study in turn was conducted to assess overall robustness of the meta-analysis results.
Results
Characteristics of Studies
The flow chart of literature selection was presented in Figure 1. Totally, 3,181 articles were screened. Finally, a total of 7,886 patients in 66 studies (four articles comprising two individual trials were extracted as eight individual studies) were identified, including 7 randomized trials, 59 non-randomized trials. Of these 66 studies, 54 studies were related to TMZ-containing chemotherapy and 12 studies were related to TMZ-free treatment (4 studies of radiotherapy alone and 12 studies of TMZ-free alkylating agents chemotherapy). The characteristics of all studies are summarized in Table 1. Quality assessment showed no apparent variations among the studies in most domains of bias except for selection bias (see Table S1 in Supplementary Material).
Figure 1
Table 1
| Author | Country | Study type | Cox | Patients (N) | OS HR (95% CI) | Type of cancer | Treatment after resection | Race | Methylation assay method |
|---|---|---|---|---|---|---|---|---|---|
| Arita et al. (31) | Japan | Retrospective | Multivariate | 453 | 0.43 (0.33, 0.56) | GBM | RT + TMZ | Asian | Pyrosequencing |
| Arvold et al. (32) | America | Non-RCT | Univariate | 55 | 0.47 (0.27, 0.81) | GBM | RT + TMZ | Mixed race | NA |
| Azoulay et al. (33) | Canada | Non-RCT | Multivariate | 276 | 0.46 (0.33, 0.64) | GBM | RT + TMZ | Caucasian | NA |
| Brandes et al. (34) | Italy | Non-RCT | Multivariate | 119 | 0.66 (0.47, 0.94) | GBM | RT + TMZ | Caucasian | MSP |
| Brandes et al. (22) | Italy | Non-RCT | Univariate | 25 | 0.19 (0.04, 0.99) | Recurrent GBM | RT + FTM | Caucasian | MSP |
| Chen et al. (35) | China | Non-RCT | Multivariate | 128 | 0.65 (0.41, 1.01) | GBM | RT | Asian | NA |
| Clarke et al. (36) | America | RCT | Univariate | 85 | 0.42 (0.13, 1.39) | GBM | RT + TMZ | Mixed race | MSP |
| Cominelli et al. (37) | Italy | Non-RCT | Univariate | 70 | 0.12 (0.01, 0.98) | GBM | RT + TMZ | Caucasian | MSP |
| Etcheverry et al. (38) | Spain | Non-RCT | Multivariate | 399 | 0.33 (0.24, 0.46) | GBM | RT + TMZ | Caucasian | MSP and Pyrosequencing |
| Gallego Perez-Larraya et al. (39) | France | Non-RCT | Multivariate | 31 | 0.43 (0.20, 0.93) | GBM | TMZ | Caucasian | MSP |
| Gilbert et al. (40) | America | RCT | Univariate | 760 | 0.58 (0.48, 0.69) | GBM | RT + TMZ | Mixed race | MSP |
| Giordano et al. (41) | Germany | Non-RCT | Univariate | 65 | 1.31 (0.75, 2.28) | GBM | RT + TMZ + Celecoxid | Caucasian | NA |
| Glas et al. (42) | Switzerland | Non-RCT | Univariate | 23 | 0.43 (0.22, 0.76) | GBM | RT + TMZ + CCNU | Caucasian | MSP |
| Grossman et al. (43) | America | Non-RCT | Multivariate | 122 | 0.85 (0.56, 1.31) | GBM | RT + TMZ + BCNU | Mixed race | MSP |
| Gutenberg et al. (44) | Germany | Non-RCT | Univariate | 17 | 0.62 (0.43, 0.90) | Recurrent GBM | BCNU + TMZ | Caucasian | MSP |
| Gutenberg et al. (44) | Germany | Non-RCT | Univariate | 13 | 0.99 (0.94, 1.04) | GBM | BCNU | Caucasian | MSP |
| Han et al. (45) | China | Non-RCT | Multivariate | 152 | 0.66 (0.44, 0.98) | GBM | RT + TMZ | Asian | MSP |
| Jungk et al. (46) | Germany | Non-RCT | Multivariate | 63 | 0.89 (0.51, 1.53) | Recurrent GBM | RT + BCNU | Caucasian | MSP |
| Kerkhof et al. (47) | France | Non-RCT | Multivariate | 47 | 1.04 (0.84, 1.29) | GBM | RT + TMZ | Caucasian | NA |
| Kim et al. (48) | Korea | Non-RCT | Multivariate | 70 | 0.30 (0.14, 0.65) | GBM | RT + TMZ | Asian | NA |
| Kim et al. (49) | Korea | Non-RCT | Multivariate | 78 | 0.56 (0.40, 0.83) | GBM | RT + TMZ | Asian | MSP |
| Kreth et al. (50) | Germany | Non-RCT | Multivariate | 222 | 0.30 (0.22, 0.41) | GBM | RT + TMZ | Caucasian | MSP |
| Lai et al. (51) | America | Non-RCT | Multivariate | 70 | 0.49 (0.34, 0.71) | GBM | RT + TMZ + BEV | Mixed race | MSP |
| Lakomy et al. (52) | Czech Republic | Non-RCT | Univariate | 38 | 0.40 (0.21, 0.78) | GBM | RT + TMZ | Caucasian | MS-HRM |
| Lam and Chambers (53) | Canada | Non-RCT | Univariate | 101 | 0.64 (0.38, 1.08) | GBM | RT + TMZ | Caucasian | MSP |
| Lee et al. (54) | Korea | Non-RCT | Multivariate | 36 | 0.22 (0.04, 1.12) | GBM | RT + TMZ | Asian | MSP |
| Liu et al. (21) | China | Non-RCT | Multivariate | 137 | 0.88 (0.58, 1.26) | Recurrent GBM | BEV + FTM | Asian | MSP |
| Lombardi et al. (55) | Italy | Non-RCT | Multivariate | 151 | 0.2 (0.10, 0.50) | GBM | RT + TMZ | Caucasian | MSP |
| Lombardi et al. (56) | Italy | Non-RCT | Univariate | 34 | 0.80 (0.65, 0.97) | Recurrent GBM | TMZ + FTM | Caucasian | MSP |
| Ma et al. (57) | China | Non-RCT | Multivariate | 56 | 0.44 (0.19, 0.83) | GBM | RT + TMZ + ELE | Asian | MSP |
| Malmström et al. (58) | Europe (multicenter) | RCT | Univariate | 72 | 0.56 (0.34, 0.93) | GBM | TMZ | Caucasian | MSP |
| Malmström et al. (58) | Europe (multicenter) | RCT | Univariate | 131 | 0.97 (0.69, 1.38) | GBM | RT | Caucasian | MSP |
| Metellus et al. (59) | France | Non-RCT | Multivariate | 61 | 0.10 (0.02, 0.37) | GBM | RT + TMZ | Caucasian | MSP |
| Metellus et al. (60) | France | Non-RCT | Multivariate | 21 | 0.19 (0.06, 0.77) | Recurrent GBM | TMZ + BCNU | Caucasian | MSP |
| Minniti et al. (61) | Italy | Non-RCT | Multivariate | 243 | 0.30 (0.21, 0.42) | GBM | RT + TMZ | Caucasian | MSP |
| Minniti et al. (62) | Italy | Non-RCT | Multivariate | 83 | 0.41 (0.22, 0.75) | GBM | RT + TMZ | Caucasian | MSP |
| Minniti et al. (63) | Italy | Non-RCT | Multivariate | 36 | 0.40 (0.19, 0.94) | Recurrent GBM | RT + TMZ | Caucasian | MSP |
| Montano et al. (64) | Italy | Non-RCT | Multivariate | 73 | 0.72 (0.37, 1.37) | GBM | RT + TMZ | Caucasian | MSP |
| Motomura et al. (65) | Japan | Non-RCT | Multivariate | 68 | 0.38 (0.18, 0.83) | GBM | RT + TMZ + β-IFN | Asian | Pyrosequencing |
| Murat et al. (66) | Germany | Non-RCT | Multivariate | 42 | 0.06 (0.001, 0.20) | GBM | RT + TMZ | Caucasian | NA |
| Nguyen et al. (67) | America | Non-RCT | Multivariate | 303 | 0.39 (0.30, 0.52) | GBM | RT + TMZ + BEV | Mixed race | MSP |
| Niyazi et al. (68) | Germany | Non-RCT | Univariate | 30 | 0.28 (0.10, 0.77) | GBM | RT + TMZ | Caucasian | MSP |
| Park et al. (69) | Korea | Non-RCT | Multivariate | 48 | 0.81 (0.43, 1.52) | GBM | RT + ACNU + CDDP | Asian | MSP |
| Perry et al. (70) | Canada and Europe | RCT | Univariate | 281 | 0.93 (0.68, 1.21) | GBM | RT | Caucasian | MSP |
| Rosati et al. (71) | Italy | Non-RCT | Multivariate | 47 | 0.27 (0.12, 0.60) | GBM | RT + TMZ | Caucasian | MSP |
| Sana et al. (72) | Czech Republic | Non-RCT | Univariate | 58 | 0.51 (0.29, 0.91) | GBM | RT + TMZ | Caucasian | MS-HRM |
| Saraiva-Esperon et al. (73) | America | Non-RCT | Multivariate | 159 | 0.52 (0.36, 0.73) | GBM | RT + TMZ | Caucasian | MSP |
| Saraiva-Esperon et al. (73) | Australia | Non-RCT | Multivariate | 144 | 0.42 (0.28, 0.63) | GBM | RT + TMZ | Mixed race | Pyrosequencing |
| Schaich et al. (74) | Germany | Non-RCT | Multivariate | 61 | 0.88 (0.36, 2.15) | GBM | RT + TMZ | Caucasian | MSP |
| Schaub et al. (75) | Germany | Non-RCT | Univariate | 143 | 1.13 (0.77, 1.66) | Recurrent GBM | RT + BEV + CPT-11 | Caucasian | NA |
| Shenouda et al. (76) | Canada | Non-RCT | Univariate | 48 | 0.40 (0.19, 0.77) | GBM | RT + TMZ | Caucasian | NA |
| Soffietti et al. (77) | Italy | Non-RCT | Multivariate | 38 | 0.82 (0.38, 1.74) | Recurrent GBM | BEV + FTM | Caucasian | MSP |
| Stummer et al. (78) | Germany | Non-RCT | Univariate | 79 | 0.23 (0.10, 0.52) | GBM | RT + TMZ | Caucasian | MSP |
| Stupp et al. (79) | Europe(multicenter) | Non-RCT | Univariate | 55 | 0.44 (0.21, 0.91) | GBM | RT + TMZ + Cilengitide | Caucasian | MSP |
| Thon et al. (80) | Germany | Non-RCT | Multivariate | 56 | 0.31 (0.16, 0.58) | GBM | RT + TMZ (unresectable) | Caucasian | MSP |
| Vaios et al. (81) | America | Non-RCT | Multivariate | 86 | 0.11 (0.04, 0.26) | GBM | TMZ | Mixed race | NA |
| Van Mieghem et al. (82) | Belgium | Non-RCT | Multivariate | 112 | 0.70 (0.27, 1.8) | GBM | RT + TMZ | Caucasian | MSP |
| Wee et al. (83) | Korea | Non-RCT | Multivariate | 340 | 0.54 (0.41, 0.70) | GBM | RT + TMZ | Asian | MSP |
| Weller et al. (19) | Europe(multicenter) | Non-RCT | Univariate | 105 | 0.55 (0.44, 0.68) | Recurrent GBM | RT + TMZ | Caucasian | MSP |
| Wick et al. (84) | Europe(multicenter) | RCT | Univariate | 101 | 0.96 (0.56, 1.63) | GBM | RT | Caucasian | MSP |
| Wick et al. (84) | Europe(multicenter) | RCT | Univariate | 108 | 0.44 (0.27, 0.72) | GBM | TMZ | Caucasian | MSP |
| Yang et al. (85) | China | Non-RCT | Multivariate | 206 | 0.78 (0.57, 1.04) | GBM | RT + BCNU | Asian | MSP |
| Yang et al. (86) | China | Non-RCT | Multivariate | 238 | 0.59 (0.37, 0.95) | GBM | RT + TMZ | Asian | Pyrosequencing |
| Zhang et al. (87) | China | Non-RCT | Multivariate | 154 | 0.24 (0.15, 0.39) | GBM | RT + TMZ | Asian | NA |
| Author | Country | Study type | Cox | Patients (N) | OS HR (95% CI) | Type of cancer | Treatment after resection | Race | Testing methods |
| Lai et al. (51) | America | Non-RCT | Multivariate | 70 | 0.47 (0.32, 0.70) | GBM | RT + TMZ + BEV | Mixed race | MSP |
| Shenouda et al. (76) | Canada | Non-RCT | Univariate | 48 | 0.47 (0.22, 0.78) | GBM | RT + TMZ | Caucasian | NA |
| Soffietti et al. (77) | Italy | Non-RCT | Multivariate | 38 | 0.48 (0.21, 1.09) | Recurrent GBM | BEV + FTM | Caucasian | MSP |
| Stupp et al. (79) | Europe (multicenter) | Non-RCT | Univariate | 45 | 0.26 (0.13, 0.51) | GBM | RT + TMZ + Cilengitide | Caucasian | MSP |
| Arita et al. (31) | Japan | Non-RCT | Multivariate | 453 | 0.48 (0.37, 0.61) | GBM | RT + TMZ | Asian | Pyrosequencing |
| Lee et al. (54) | Korea | Non-RCT | Multivariate | 36 | 0.40 (0.15, 1.1) | GBM | RT + TMZ | Asian | MSP |
| Metellus et al. (59) | France | Non-RCT | Multivariate | 61 | 0.42 (0.21, 0.92) | GBM | RT + TMZ | Caucasian | MSP |
| Metellus et al. (60) | France | Non-RCT | Multivariate | 21 | 0.15 (0.08, 0.48) | Recurrent GBM | TMZ + BCNU | Caucasian | MSP |
| Minniti et al. (61) | Italy | Non-RCT | Multivariate | 243 | 0.29 (0.21, 0.40) | GBM | RT + TMZ | Caucasian | MSP |
| Minniti et al. (63) | Italy | Non-RCT | Multivariate | 36 | 0.38 (0.18, 0.79) | Recurrent GBM | RT + TMZ | Caucasian | MSP |
| Ohno et al. (88) | Japan | Non-RCT | Multivariate | 88 | 0.35 (0.21, 0.59) | GBM | RT + TMZ + ACNU | Asian | Pyrosequencing |
| Thon et al. (80) | Germany | Non-RCT | Multivariate | 56 | 0.32 (0.17, 0.59) | GBM | RT + TMZ | Caucasian | MSP |
| Weller et al. (19) | Europe (multicenter) | Non-RCT | Univariate | 105 | 0.57 (0.35, 0.90) | Recurrent GBM | RT + TMZ | Caucasian | MSP |
| Gilbert et al. (40) | America | RCT | Univariate | 760 | 0.61 (0.52, 0.73) | GBM | RT + TMZ | Mixed race | MSP |
| Cominelli et al. (37) | Italy | Non-RCT | Univariate | 70 | 0.29 (0.04, 2.24) | GBM | RT + TMZ | Caucasian | MSP |
| Giordano et al. (41) | Germany | Non-RCT | Univariate | 65 | 2.04 (1.04, 4.00) | GBM | RT + TMZ | Caucasian | NA |
| Gutenberg et al. (44) | Germany | Non-RCT | Univariate | 13 | 0.93 (0.70, 1.24) | GBM | BCNU | Caucasian | MSP |
| Gutenberg et al. (44) | Germany | Non-RCT | Univariate | 17 | 0.60 (0.33, 1.07) | Recurrent GBM | BCNU + TMZ | Caucasian | MSP |
| Kim et al. (89) | Korea | Non-RCT | Multivariate | 72 | 0.47 (0.27, 0.82) | Recurrent GBM | RT + TMZ | Asian | MSP |
| Kim et al. (49) | Korea | Non-RCT | Multivariate | 78 | 0.63 (0.46, 0.91) | GBM | RT + TMZ | Asian | MSP |
| Lakomy et al. (52) | Czech Republic | Non-RCT | Univariate | 38 | 0.48 (0.25, 0.92) | GBM | RT + TMZ | Caucasian | MS-HRM |
| Liu et al. (21) | China | Non-RCT | Multivariate | 137 | 0.69 (0.52, 0.97) | Recurrent GBM | BEV + FTM | Asian | MSP |
| Lombardi et al. (56) | Italy | Non-RCT | Univariate | 34 | 0.72 (0.59, 0.87) | Recurrent GBM | TMZ + FTM | Caucasian | MSP |
| Nguyen et al. (67) | America | Non-RCT | Multivariate | 303 | 0.43 (0.33, 0.57) | GBM | RT + TMZ + BEV | Mixed race | MSP |
| Sana et al. (72) | Czech Republic | Non-RCT | Univariate | 58 | 0.54 (0.23, 0.96) | GBM | RT + TMZ | Caucasian | MS-HRM |
Characteristics of included studies.
Studies enrolled for OS analysis. TMZ, temozolomide; RCT, randomized control trial; RT, radiotherapy; BCNU, carmustine; FTM; fotemustine; BEV, bevacizumab; CCNU, lomustine; ELE, β-element; ACNU, nimustine; CDDP, cisplatin; β-IFN, interferon-β; CPT-11, irinotecan; MSP, methylation-specific PCR; NA, not available.
Studies enrolled for PFS analysis. TMZ, temozolomide; RCT, randomized control trial. RT, radiotherapy; BCNU, carmustine; FTM; fotemustine; BEV, bevacizumab; ACNU, nimustine; MSP, methylation-specific PCR; NA, not available.
Association between MGMT Promoter Methylation and Survival in Overall GBM Patients
Sixty-four and 25 studies were included to describe the correlation of MGMT methylation status with OS and PFS in GBM patients, respectively. GBM patients with MGMT promoter methylation had significantly better OS and PFS than those with unmethylated status (OS: HR = 0.52, 95% CI 0.46–0.59, p < 0.001, I2 = 86.2%; PFS: HR = 0.51, 95% CI 0.43–0.59, p < 0.001, I2 = 70.2%; see Figure S1 in Supplementary Material), indicating the association between methylation and survival benefit in GBM patients. Next, subgroup analysis was conducted to evaluate whether methylated GBM patients could benefit from different therapies. The results of subgroup analysis were summarized in Table 2. Our analysis showed that, among patients exposed to TMZ-containing treatment, methylated patients had longer OS and PFS than unmethylated patients (OS: HR = 0.46, 95% CI 0.41–0.52, p < 0.001, Bon = 0.017, I2 = 70.9%, Figure 2; PFS: HR = 0.48, 95% CI 0.40–0.57, p < 0.001, Bon = 0.014, I2 = 67.4%, Figure 3). However, no significant OS benefit from TMZ-free treatment was observed in methylated patients by analysis of 12 studies (21, 35, 44, 58, 69, 70, 77, 84, 85) (HR = 0.97, 95% CI 0.91–1.03, p = 0.32, I2 = 2.9%, Figure 2). Further analysis showed that methylated patients derived no OS benefit from TMZ-free alkylating agents chemotherapy (HR = 0.97, 95% CI 0.93–1.03, p = 0.41, Bon = 1, I2 = 9.1%). Similarly, PFS was not significantly prolonged in methylated patients with TMZ-free alkylating agents chemotherapy (HR = 0.76, 95% CI 0.57–1.02, p = 0.40, Bon = 0.748, I2 = 40.8%, Figure 3). These results indicate that MGMT methylation is predictive for better response to TMZ therapy in GBM patients.
Table 2
| Variable | Subgroup | Treatment | Trial (N) | HR (95% CI) | P-value for HR | Bon | I2 | P-value (Egger’) |
|---|---|---|---|---|---|---|---|---|
| OS analysis (methylated vs. unmethylated) | ||||||||
| Overall | TMZ-containing | 52 | 0.46 (0.41–0.52) | <0.001 | 0.017 | 70.9% | 0.001 | |
| TMZ-free | 12 | 0.97 (0.91–1.03) | 0.32 | 1 | 2.90% | 0.053 | ||
| Race | Caucasian | TMZ-containing | 34 | 0.46 (0.39–0.55) | <0.001 | 0.017 | 75.5% | 0.003 |
| TMZ-free | 8 | 0.99 (0.94–1.04) | 0.71 | 1 | 0% | 0.27 | ||
| Asian | TMZ-containing | 10 | 0.48 (0.42–0.54) | <0.001 | 0.017 | 43.8% | 0.26 | |
| TMZ-free | 4 | 0.78 (0.64–0.95) | 0.015 | 0.24 | 0% | NA | ||
| Mixed race | TMZ-containing | 8 | 0.48 (0.38–0.62) | <0.001 | 0.017 | 67.7% | 0.302 | |
| TMZ- free | 0 | NA | NA | NA | NA | NA | ||
| Study type | non-RCT | TMZ-containing | 48 | 0.46 (0.40–0.52) | <0.001 | 0.017 | 72.9% | 0.001 |
| TMZ-free | 9 | 0.90 (0.78–1.03) | 0.13 | 1 | 26.3% | 0.033 | ||
| RCT | TMZ-containing | 4 | 0.56 (0.48–0.65) | <0.001 | 0.017 | 0% | NA | |
| TMZ-free | 3 | 1.02 (0.83–1.25) | 0.83 | 1 | 0% | NA | ||
| GBM Type | Newly diagnosed | TMZ-containing | 47 | 0.45 (0.40–0.52) | <0.001 | 0.017 | 69.80% | 0.007 |
| TMZ-free | 7 | 0.97 (0.90–1.04) | 0.374 | 1 | 5.6% | NA | ||
| Elderly | TMZ-containing | 8 | 0.46 (0.32–0.65) | <0.001 | 0.017 | 71% | 0.695 | |
| TMZ-free | 3 | 1.02 (0.83–1.25) | 0.83 | 1 | 0% | NA | ||
| Recurrent | TMZ-containing | 5 | 0.59 (0.44–0.78) | <0.001 | 0.017 | 65% | NA | |
| TMZ-free | 5 | 0.92 (0.70–1.19) | 0.52 | 1 | 16.40% | NA | ||
| PFS analysis (methylated vs. un-methylated) | ||||||||
| Overall | TMZ-containing | 22 | 0.48 (0.40–0.57) | <0.001 | 0.014 | 67.4% | 0.092 | |
| TMZ-free | 3 | 0.76 (0.57–1.02) | 0.068 | 0.748 | 40.8% | NA | ||
| Race | Caucasian | TMZ-containing | 14 | 0.46 (0.34–0.63) | <0.001 | 0.014 | 76.2% | 0.22 |
| TMZ-free | 2 | 0.75 (0.41–1.38) | 0.35 | 1 | 54.8% | NA | ||
| Asian | TMZ-containing | 5 | 0.49 (0.41–0.59) | <0.001 | 0.014 | 0% | NA | |
| TMZ-free | 1 | 0.69 (0.50–0.94) | 0.02 | 0.24 | NA | NA | ||
| Mixed race | TMZ-containing | 3 | 0.51 (0.40–0.65) | <0.001 | 0.014 | NA | NA | |
| TMZ-free | 0 | NA | NA | NA | NA | NA | ||
| Study type | non-RCT | TMZ-containing | 21 | 0.47 (0.39–0.56) | <0.001 | 0.014 | 67% | 0.19 |
| TMZ-free | 3 | 0.76 (0.57–1.02) | 0.07 | 0.7 | 40.8% | NA | ||
| RCT | TMZ-containing | 1 | 0.61 (0.52–0.73) | <0.001 | 0.014 | NA | NA | |
| TMZ-free | 0 | NA | NA | NA | NA | NA | ||
| GBM type | Newly diagnosed | TMZ-containing | 16 | 0.47 (0.39–0.57) | <0.001 | 0.014 | 66.1% | 0.44 |
| TMZ-free | 1 | 0.93 (0.70–1.24) | 0.62 | 1 | NA | NA | ||
| Elderly | TMZ-containing | 0 | NA | NA | NA | NA | NA | |
| TMZ-free | 0 | NA | NA | NA | NA | NA | ||
| Recurrent | TMZ-containing | 6 | 0.49 (0.34–0.70) | <0.001 | 0.014 | 66% | NA | |
| TMZ-free | 2 | 0.66 (0.49–0.88) | 0.005 | 0.065 | 0% | NA | ||
Summary of subgroup analysis.
HR, hazard ratio; CI, confidence interval; NA, not applicable; TMZ-containing treatment, TMZ-alone and combined radiotherapy/TMZ and combined radiotherapy/TMZ-containing chemotherapy; TMZ-free treatment, radiotherapy alone and combined radiotherapy/TMZ-free alkylation agents chemotherapy; Mixed race: patients in American studies; Bon, P for Step-down Bonferroni adjustment.
Figure 2
Figure 3
Association between MGMT Promoter Methylation and Survival in Newly Diagnosed GBM Subpopulation
There were 54 and 17 studies recruited to assess the impact of MGMT promoter methylation on OS and PFS in newly diagnosed GBM patients, respectively. MGMT promoter methylation in newly diagnosed GBM patients was also associated with improved OS and PFS (OS: HR = 0.49, 95% CI 0.43–0.57, p < 0.001, I2 = 87.7%; PFS: HR = 0.50, 95% CI 0.41–0.61, p < 0.001, I2 = 73.8%, Figure S2 in Supplementary Material). Subgroup analysis showed that methylated patients receiving TMZ-containing treatment had better OS and PFS than unmethylated patients (OS: HR = 0.45, 95% CI 0.40–0.52, p < 0.001, Bon = 0.017, I2 = 69.8%, Figure 4; PFS: HR = 0.47, 95% CI 0.39–0.57, p < 0.001, Bon = 0.014, I2 = 66.1%, Figure 5). No significant advantage on OS and PFS was observed in methylated patients receiving TMZ-free treatment (OS: HR = 0.97, 95% CI 0.90–1.04, p = 0.37, Bon = 1, I2 = 5.6%, Figure 4; PFS: HR = 0.93, 95% CI 0.70–1.24, p = 0.62, Bon = 1, Figure 5). These observations were similar to those in overall GBM patients, indicating that the beneficial effect of methylation on OS in newly diagnosed patients was also TMZ therapy-dependent.
Figure 4
Figure 5
Association between MGMT Promoter Methylation and Survival in Elderly GBM Subpopulation
Overall survival in elderly GBM patients was assessed on the basis of 11 studies comprising 1,321 patients. Among these studies, elderly was defined as 60 years or older (58), over 65 years old (32, 41, 55, 61, 70, 84), or 70 years or older (39, 62). A significant correlation between MGMT promoter methylation and better OS was observed in elderly GBM patients (HR = 0.58, 95% CI 0.40–0.82, p = 0.002, I2 = 83.4%, Figure S3 in Supplementary Material). A significant improvement on OS was also found in methylated elderly patients with TMZ-containing treatment compared to unmethylated patients with similar treatment (HR = 0.46, 95% CI 0.32–0.65, p < 0.001, Bon = 0.017, I2 = 71%, Figure 6). No significance benefit from TMZ-free treatment found in methylated elderly patients than unmethylated elderly patients (HR = 1.02, 95% CI 0.83–1.25, p = 0.83, Bon = 1, I2 = 0%, Figure 6).
Figure 6
The efficacy of TMZ-containing therapy versus radiotherapy in elderly patients was assessed according to three randomized controlled trials (58, 70, 84). Methylated elderly patients with TMZ-containing treatment had better OS than those with radiotherapy alone (HR = 0.55, 95% CI 0.44–0.68, p < 0.001; I2 = 0%, Figure 7). However, the benefit of TMZ-containing therapy was not observed in elderly patients with unmethylated status (HR = 0.97, 95% CI 0.68–1.38, p < 0.001, I2 = 72.8%, Figure 7). Elderly patients were often unable to tolerate multimodality therapy, so we further assess whether elderly patients with MGMT methylation could benefit from TMZ alone or radiotherapy alone therapy. Compared to unmethylated elderly patients, prolonged OS was observed in methylated elderly patients receiving TMZ alone therapy but not in those receiving radiotherapy alone (TMZ alone: HR = 0.48, 95% CI 0.35–0.66, p < 0.001, I2 = 0%; Radiotherapy alone: HR = 1.02, 95% CI 0.83–1.25, p = 0.83, I2 = 0%, Figure 8). These results indicated the strong correlation between MGMT methylation and better response to TMZ therapy in elderly GBM patients.
Figure 7
Figure 8
Association between MGMT Promoter Methylation and Survival in Recurrent GBM Subpopulation
Eleven studies were included to analyze the association between MGMT promoter methylation and survival in recurrent GBM patients (19, 21, 22, 44, 46, 56, 60, 63, 75, 77, 89). A significant improvement on OS and PFS was observed in methylated recurrent patients (OS: HR = 0.70, 95% CI 0.56–0.88, p < 0.001, I2 = 61.4%; PFS: HR = 0.54, 95% CI 0.42–0.70, p < 0.001, I2 = 54.8%, Figure S4 in Supplementary Material). Subgroup analysis showed TMZ-containing therapy conferred a survival benefit in methylated recurrent patients (OS: HR = 0.59, 95% CI 0.44–0.78, p < 0.001, Bon = 0.017, I2 = 65%, Figure 9; PFS: HR = 0.49, 95% CI 0.34–0.70, p = 0.001, Bon = 0.014, I2 = 66%, Figure 10). In contrast, TMZ-free therapy did not improve OS (HR = 0.92, 95% CI 0.70–1.19, p = 0.52, Bon = 1, I2 = 16.4%, Figure 9) or PFS (HR = 0.66, 95% CI 0.49–0.88, p = 0.005, Bon = 0.065, I2 = 0%, Figure 10) in methylated recurrent patients.
Figure 9
Figure 10
Association between MGMT Promoter Methylation and Survival in GBM Patients with Different Races
There were 42 studies for Caucasian (European, Canadian, Australian), 16 studies for Asian (Chinese, Japanese, Korean), and 8 studies for mixed race (American). Compared to unmethylated patients, both OS and PFS were improved in methylated patients (OS: Asian: HR = 0.54, 95% CI 0.44–0.65, p < 0.001, I2 = 61.1%; Caucasian: HR = 0.53, 95% CI 0.45–0.63, p < 0.001, I2 = 86.8%; Mixed race: HR = 0.48, 95% CI 0.38–0.62, p < 0.001, I2 = 67.7%; PFS: Asian: HR = 0.53, 95% CI 0.43–0.65, p < 0.001, I2 = 31.4%; Caucasian: HR = 0.49, 95% CI 0.37–0.65, p < 0.001, I2 = 77.8%; Mixed race: HR = 0.51, 95% CI 0.40–0.65, p < 0.001, I2 = 61%, Figure S5 in Supplementary Material). Among GBM patients with TMZ-containing treatment, MGMT methylation benefited to both Caucasian and Asian (Asian OS: HR = 0.48, 95% CI 0.42–0.54, p < 0.001, Bon = 0.017, I2 = 43.8%; PFS: HR = 0.49, 95% CI 0.41–0.59, p < 0.001, Bon = 0.014, I2 = 0%; Caucasian OS: HR = 0.46, 95% CI 0.39–0.55, p < 0.001, Bon = 0.017, I2 = 75.5%; PFS: HR = 0.46, 95% CI 0.34–0.63, p < 0.001, Bon = 0.014, I2 = 76.2%, Figure S6 in Supplementary Material). 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, Figure S6 in Supplementary Material). No benefit was observed in Caucasian receiving TMZ-free therapy regardless of Bonferroni adjustment. The impact of MGMT promoter methylation in mixed race was not evaluated since data in TMZ-free group was not available.
Publication Bias
Publication bias was evaluated by Egger’s test. Publication bias was observed in OS and PFS analysis in overall GBM patients (OS: p < 0.001; PFS: p = 0.04). More results were presented in Table 2. Therefore, we performed the trim and fill analysis to estimate the publication bias. However, those results remain unchanged after introducing the trim and fill method to correct the publication bias.
Sensitive Analysis
Sensitivity analysis was conducted by sequentially omitting individual studies to assess whether a single study might significantly affect the overall results. Sensitivity analysis showed one study (41) predominantly contributed to heterogeneity in elderly GBM subpopulation, especially in TMZ-containing group (Figure S7 in Supplementary Material). Further sensitivity analysis revealed that other results did not show any apparent variations in pooled HRs for OS or PFS, supporting the robustness of the primary findings.
Discussion
Although MGMT has been widely established as a clinically relevant biomarker in GBM patients, its clinical implication has not been definitely confirmed. A prognostic factor is a clinical or biologic characteristic that is objectively measured and provides information on likely outcome of the cancer disease independent of treatment, while a predictive factor is a clinical or biologic characteristic providing information on likely benefits from one specific treatment rather than another (90). Which one is more appropriate to describe the relationship between MGMT promoter methylation and GBM prognosis? Among overall GBM patients, MGMT methylation conferred a survival benefit to patients with TMZ-containing treatment, but not to those with TMZ-free treatment. It seems that MGMT methylation has a predictive value for GBM patients exposed to TMZ-containing treatment. However, considering the differentiation of prognostic variables among patients, including primary or recurrent GBM, age and race, the universality of predictive value of MGMT methylation in different GBM subgroups should be profoundly validated. Therefore, we further assess its clinical significance in newly diagnosed patients, recurrent patients, elderly patients, and Asian and Caucasian patients.
In newly diagnosed and recurrent GBM patients, MGMT methylation was associated with improved OS and PFS with TMZ-containing treatment, but not in those with TMZ-free treatment. Then MGMT methylation is predictive for a benefit from TMZ–containing chemotherapy in newly diagnosed and recurrent patients.
In elderly GBM patients, MGMT methylation also conferred an OS benefit in patients with TMZ-containing treatment, but not in those with TMZ-free treatment. Therefore, MGMT methylation in elderly patients is likely to have a similar predictive value as in newly diagnosed and recurrent GBM patients. Elderly GBM patients are often clinically unable to tolerate multimodality therapy, thus TMZ or radiotherapy alone is commonly used. This meta-analysis showed that elderly patients with methylated status exposed to TMZ alone had improved OS than those exposed to radiotherapy alone, while such difference was not observed in those with unmethylated status. Our results highlight that TMZ alone therapy might be a more effective option than radiotherapy alone therapy for elderly GBM patients with methylated MGMT status. But the optimal radiotherapy regimen for elderly and/or frail patients with newly diagnosed GBM remains to be defined (91). A recent study showed that short-course radiation (40 Gy in 15 fractions) plus TMZ conferred a survival advantage over radiotherapy alone in elderly patients (65 years of age or older) with newly diagnosed GBM, especially in those with methylated MGMT status (70). Due to the lack of a uniform definition for elderly, different cutoff age was employed in different studies. Patients aged more than 70 years were excluded from Stupp study (87). In this meta-analysis, patients aged 60 or more were enrolled for analysis. Our results showed that patients aged over 70 years with MGMT methylation also benefit from TMZ-containing therapy. The definition of cutoff age for the elderly are closely linked to prognosis, therapeutic goals, or patterns of care, so further research in this field should standardize the cutoff age for enrollment eligibility (92).
Another interesting issue is the clinical value of MGMT methylation in Asian and Caucasian patients. A previous study showed that MGMT methylation correlated with better OS and PFS in Caucasian patients and only better OS in Asian patients regardless of therapeutic intervention (93). But the benefit of different therapies in methylated patients was not investigated in the study. In our analysis, survival benefit in Asian patients with TMZ-free treatment was not observed anymore after Bonferroni adjustment. Bonferroni correction can avoid false positives, and then the risk of false negatives would be increased. So the finding in Asian patients should be cautiously interpreted. It must be noted that only four studies (519 patients) for OS and a single study (137 patients) for PFS were enrolled for this subgroup analysis. Therefore, our finding on patients with different races needs to be further verified by more clinical studies. Furthermore, recent studies also give a hint about the different regulation of MGMT methylation in different ethnic background. Single nucleotide polymorphisms (rs16906252) in MGMT promoter-enhancer is a key determinant in the acquisition of MGMT methylation (94). The genotype of rs16906252 varies among different ethnic groups (95), which may result in different MGMT methylation status. In addition to promoter methylation, other molecules are also involved in regulation of MGMT expression or function. For example, miR-181d can bind to the 3′untranslated region of MGMT transcripts, then decrease its mRNA stability and/or reduce protein translation (96). Further studies on ethnically genetic variations are necessary.
Due to the limited number of trials recruited for analysis, the presented information about PFS in patients with TMZ-free treatment, especially in newly diagnosed and recurrent subgroups, should be interpreted carefully. It should be acknowledged that we did not obtain any data of PFS in elderly patients exposed to TMZ-free treatment. Therefore, the predictive or prognostic value of this biomarker for PFS is far from identified in our analysis. In fact, clinical measurement of PFS may be a critical challenge in GBM trials. It is well known that GBM patients suffer inevitably recurrence despite integrated therapy (97). Pseudoprogression, also denoted as radiotherapy-introduced necrosis, exhibits contrast enhancement similar to early tumor progression on magnetic resonance imaging. Primary GBM patients receiving concurrent and adjuvant TMZ-based chemoradiotherapy have a high likelihood of developing pseudoprogression (98, 99), which occurs mainly within 3 months after completion of chemoradiotherapy. However, no technique has been proven to reliably differentiate between tumor recurrence and pseudoprogression. Additionally, both entities might coexist in the same patient at the same time in different areas of the tumor. The misdiagnosis of pseudoprogression as tumor recurrence may lead to a record of shorter PFS. Interestingly, MGMT promoter methylation was associated with a high incidence of pseudoprogression in newly diagnosed GBM patients undergoing TMZ-based chemoradiotherapy (100). In addition, GBM patients with the occurrence of pseudoprogression had a longer OS than those without pseudoprogression (98, 101), indicating that pseudoprogression may be a predictor for better response to therapy. Therefore, it is critically important to develop imaging techniques and biomarkers to discriminate pseudoprogression from early progression.
We also noticed the methodological diversity of measurement of MGMT promoter methylation. MGMT promoter methylation was detected by methylation-specific polymerase chain reaction (MSP), pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM) in 48, 6, and 2 studies, respectively. Additionally, various cutoff values for methylated positivity were used in these studies. However, there were few studies that have compared the merits and disadvantages of these MGMT testing methods (17). Further efforts should standardize the MGMT methylation testing methods and cutoff point.
Limitations of this study should be acknowledged. Firstly, heterogeneity existed in the pooled analysis for PFS and OS either in overall population or in subgroup analysis. Heterogeneity may result from different techniques of defining MGMT promoter status and varied therapy schedule. Different chemotherapy and radiotherapy schedules may influence the prognosis of GBM patients, thus analysis of the correlation between a single treatment schedule and MGMT promoter status was not conducted in this meta-analysis. Second, considering the scarce number of multivariate studies in some of subgroup analysis, univariate studies were also included in our analysis. We also performed analysis using only multivariate studies and similar findings were observed (Table S3 in Supplementary Material). Third, due to the limited number of original documents on PFS, there was not enough power to identify the impact of MGMT methylation on PFS, especially in patients receiving TMZ-free therapy. Fourth, quality assessment was performed by a modified domain-based NOS (102, 103), which was proposed as a potential helpful and practically method for assessment of tumor prognostic studies. However, this novel NOS has not been fully validated and results should be interpreted with caution. Fifth, Egger’s test showed that publication bias existed in pooled analysis for OS, but the trim and fill analysis upheld the reliability of our results.
In conclusion, our results highlight 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. This study may be helpful to optimize therapeutics in different GBM subpopulation.
Statements
Author contributions
Y-HZ and C-JC contributed to the conception of the experiments and manuscript preparation. Y-HZ, C-SX, X-TZ, J-LL, JL, and KL contributed to data research and review. Y-HZ and HW performed data analysis. Z-FW and Z-QL contributed to interpretation and discussion of the results.
Acknowledgments
This research was supported by grants from National Natural Science Foundation of China (no. 81573459). We acknowledge Dr. Yi Guo from Wuhan University for reviewing the statistical analysis in this manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewers CS, BW and handling Editor declared their shared affiliation.
Supplementary material
The Supplementary Material for this article can be found online at https://www.frontiersin.org/articles/10.3389/fneur.2018.00127/full#supplementary-material.
References
1
TrivediRNAlmeidaKHFornsaglioJLSchamusSSobolRW. The role of base excision repair in the sensitivity and resistance to temozolomide-mediated cell death. Cancer Res (2005) 65(14):6394–400.10.1158/0008-5472.can-05-0715
2
StuppRHegiMEMasonWPvan den BentMJTaphoornMJJanzerRCet alEffects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol (2009) 10(5):459–66.10.1016/s1470-2045(09)70025-7
3
StuppRWongETKannerAASteinbergDEngelhardHHeideckeVet alNovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer (2012) 48(14):2192–202.10.1016/j.ejca.2012.04.011
4
WenPYKesariS. Malignant gliomas in adults. N Engl J Med (2008) 359(5):492–507.10.1056/NEJMra0708126
5
LaperriereNWellerMStuppRPerryJRBrandesAAWickWet alOptimal management of elderly patients with glioblastoma. Cancer Treat Rev (2013) 39(4):350–7.10.1016/j.ctrv.2012.05.008
6
VlassenbroeckICalificeSDiserensACMigliavaccaEStraubJDi StefanoIet alValidation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. J Mol Diagn (2008) 10(4):332–7.10.2353/jmoldx.2008.070169
7
VlachostergiosPJHatzidakiEBefaniCDLiakosPPapandreouCN. Bortezomib overcomes MGMT-related resistance of glioblastoma cell lines to temozolomide in a schedule-dependent manner. Invest New Drugs (2013) 31(5):1169–81.10.1007/s10637-013-9968-1
8
HottaTSaitoYFujitaHMikamiTKurisuKKiyaKet alO6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications. J Neurooncol (1994) 21(2):135–40.10.1007/BF01052897
9
BelanichMPastorMRandallTGuerraDKibitelJAlasLet alRetrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine. Cancer Res (1996) 56(4):783–8.
10
JaeckleKAEyreHJTownsendJJSchulmanSKnudsonHMBelanichMet alCorrelation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study. J Clin Oncol (1998) 16(10):3310–5.10.1200/jco.1998.16.10.3310
11
NewlandsESStevensMFWedgeSRWheelhouseRTBrockC. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev (1997) 23(1):35–61.10.1016/S0305-7372(97)90019-0
12
StuppRGanderMLeyvrazSNewlandsE. Current and future developments in the use of temozolomide for the treatment of brain tumours. Lancet Oncol (2001) 2(9):552–60.10.1016/s1470-2045(01)00489-2
13
ChinotOLBarrieMFuentesSEudesNLancelotSMetellusPet alCorrelation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol (2007) 25(12):1470–5.10.1200/jco.2006.07.4807
14
EoliMMenghiFBruzzoneMGDe SimoneTVallettaLPolloBet alMethylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival. Clin Cancer Res (2007) 13(9):2606–13.10.1158/1078-0432.ccr-06-2184
15
HegiMELiuLHermanJGStuppRWickWWellerMet alCorrelation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol (2008) 26(25):4189–99.10.1200/jco.2007.11.5964
16
GorliaTvan den BentMJHegiMEMirimanoffROWellerMCairncrossJGet alNomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol (2008) 9(1):29–38.10.1016/s1470-2045(07)70384-4
17
WellerMStuppRReifenbergerGBrandesAAvan den BentMJWickWet alMGMT promoter methylation in malignant gliomas: ready for personalized medicine?Nat Rev Neurol (2010) 6(1):39–51.10.1038/nrneurol.2009.197
18
Lechapt-ZalcmanELevalletGDugueAEVitalADieboldMDMeneiPet alO(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide. Cancer (2012) 118(18):4545–54.10.1002/cncr.27441
19
WellerMTabatabaiGKästnerBFelsbergJSteinbachJPWickAet alMGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR trial. Clin Cancer Res (2015) 21(9):2057–64.10.1158/1078-0432.CCR-14-2737
20
DahlrotRHDowsettJFosmarkSMalmstromAHenrikssonRBoldtHet alPrognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression in glioblastoma excluding nontumour cells from the analysis. Neuropathol Appl Neurobiol (2018) 44(2):172–84.10.1111/nan.12415
21
LiuZZhangGZhuLWangJLiuDLianLet alRetrospective analysis of bevacizumab in combination with fotemustine in Chinese patients with recurrent glioblastoma multiforme. Biomed Res Int (2015) 2015:723612.10.1155/2015/723612
22
BrandesAAFinocchiaroGZagonelVReniMCasertaCFabiAet alAVAREG: a phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma. Neuro Oncol (2016) 18(9):1304–12.10.1093/neuonc/now035
23
HigginsJPGreenS. Cochrane Handbook for Systematic Reviews of Interventions. Chichester: John Wiley & Sons (2011).
24
AltmanDGMcShaneLMSauerbreiWTaubeSE. Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration. BMC Med (2012) 10(1):51.10.1186/1741-7015-10-51
25
TierneyJFStewartLAGhersiDBurdettSSydesMR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. (2007) 8:16.10.1186/1745-6215-8-16
26
HigginsJPThompsonSG. Quantifying heterogeneity in a meta-analysis. Stat Med (2002) 21(11):1539–58.10.1002/sim.1186
27
MantelNHaenszelW. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst (1959) 22(4):719–48.
28
DerSimonianRLairdN. Meta-analysis in clinical trials. Control Clin Trials (1986) 7:177–88.10.1016/0197-2456(86)90046-2
29
BeggCBMazumdarM. Operating characteristics of a rank correlation test for publication bias. Biometrics (1994) 50:1088–101.10.2307/2533446
30
DuvalSTweedieR. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics (2000) 56(2):455–63.10.1111/j.0006-341X.2000.00455.x
31
AritaHYamasakiKMatsushitaYNakamuraTShimokawaATakamiHet alA combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathol Commun (2016) 4(1):79.10.1186/s40478-016-0351-2
32
ArvoldNDTanguturiSKAizerAAWenPYReardonDALeeEQet alHypofractionated versus standard radiation therapy with or without temozolomide for older glioblastoma patients. Int J Radiat Oncol Biol Phys (2015) 92(2):384–9.10.1016/j.ijrobp.2015.01.017
33
AzoulayMSantosFSouhamiLPanet-RaymondVPetreccaKOwenSet alComparison of radiation regimens in the treatment of glioblastoma multiforme: results from a single institution. Radiat Oncol (2015) 10(1):106.10.1186/s13014-015-0396-6
34
BrandesAABartolottiMTosoniAPoggiRBartoliniSPaccapeloAet alPatient outcomes following second surgery for recurrent glioblastoma. Future Oncol (2016) 12(8):1039–44.10.2217/fon.16.9
35
ChenHLiXLiWZhengH. miR-130a can predict response to temozolomide in patients with glioblastoma multiforme, independently of O6-methylguanine-DNA methyltransferase. J Transl Med (2015) 13(1):1.10.1186/s12967-015-0435-y
36
ClarkeJLIwamotoFMSulJPanageasKLassmanABDeAngelisLMet alRandomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol (2009) 27(23):3861–7.10.1200/jco.2008.20.7944
37
CominelliMGrisantiSMazzoleniSBrancaCButtoloLFurlanDet alEGFR amplified and overexpressing glioblastomas and association with better response to adjuvant metronomic temozolomide. J Natl Cancer Inst (2015) 107(5):djv041.10.1093/jnci/djv041
38
EtcheverryAAubryMIdbaihAVauleonEMarieYMeneiPet alDGKI methylation status modulates the prognostic value of MGMT in glioblastoma patients treated with combined radio-chemotherapy with temozolomide. PLoS One (2014) 9(9):e104455.10.1371/journal.pone.0104455
39
Gallego Perez-LarrayaJDucrayFChinotOCatry-ThomasITaillandierLGuillamoJSet alTemozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial. J Clin Oncol (2011) 29(22):3050–5.10.1200/jco.2011.34.8086
40
GilbertMRWangMAldapeKDStuppRHegiMEJaeckleKAet alDose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol (2013) 31(32):4085–91.10.1200/JCO.2013.49.6968
41
WelzelGGehweilerJBrehmerSAppeltJUvon DeimlingASeiz-RosenhagenMet alMetronomic chemotherapy with daily low-dose temozolomide and celecoxib in elderly patients with newly diagnosed glioblastoma multiforme: a retrospective analysis. J Neurooncol (2015) 124(2):265–73.10.1007/s11060-015-1834-x
42
GlasMHappoldCRiegerJWiewrodtDBahrOSteinbachJPet alLong-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. J Clin Oncol (2009) 27(8):1257–61.10.1200/jco.2008.19.2195
43
GrossmanRBurgerPSoudryETylerBChaichanaKLWeingartJet alMGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel. J Clin Neurosci (2015) 22(12):1938–42.10.1016/j.jocn.2015.07.003
44
GutenbergABockHBrückWDoernerLMehdornHRoggendorfWet alMGMT promoter methylation status and prognosis of patients with primary or recurrent glioblastoma treated with carmustine wafers. Br J Neurosurg (2013) 27(6):772–8.10.3109/02688697.2013.791664
45
HanSLiuYLiQLiZHouHWuA. Pre-treatment neutrophil-to-lymphocyte ratio is associated with neutrophil and T-cell infiltration and predicts clinical outcome in patients with glioblastoma. BMC Cancer (2015) 15(1):617.10.1186/s12885-015-1629-7
46
JungkCChatziaslanidouDAhmadiRCapperDBermejoJLExnerJet alChemotherapy with BCNU in recurrent glioma: analysis of clinical outcome and side effects in chemotherapy-naive patients. BMC Cancer (2016) 16:81.10.1186/s12885-016-2131-6
47
KerkhofMDielemansJVan BreemenMZwinkelsHWalchenbachRTaphoornMet alEffect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro Oncol (2013) 80(7):961–7.10.1093/neuonc/not057
48
KimYHKimTJooJDHanJHKimYJKimIAet alSurvival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer (2015) 121(17):2926–32.10.1002/cncr.29439
49
KimYSKimSHChoJKimJWChangJHKimDSet alMGMT gene promoter methylation as a potent prognostic factor in glioblastoma treated with temozolomide-based chemoradiotherapy: a single-institution study. Int J Radiat Oncol Biol Phys (2012) 84(3):661–7.10.1016/j.ijrobp.2011.12.086
50
KrethFWThonNSimonMWestphalMSchackertGNikkhahGet alGross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann Oncol (2013) 24(12):3117–23.10.1093/annonc/mdt388
51
LaiATranANghiemphuPLPopeWBSolisOESelchMet alPhase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol (2011) 29(2):142–8.10.1200/jco.2010.30.2729
52
LakomyRSanaJHankeovaSFadrusPKrenLLzicarovaEet alMiR-195, miR-196b, miR-181c, miR-21 expression levels and O-6-methylguanine-DNA methyltransferase methylation status are associated with clinical outcome in glioblastoma patients. Cancer Sci (2011) 102(12):2186–90.10.1111/j.1349-7006.2011.02092.x
53
LamNChambersCR. Temozolomide plus radiotherapy for glioblastoma in a Canadian province: efficacy versus effectiveness and the impact of O6-methylguanine-DNA-methyltransferase promoter methylation. J Oncol Pharm Pract (2012) 18(2):229–38.10.1177/1078155211426198
54
LeeDSuhYLParkTIDoIGSeolHJNamDHet alPrognostic significance of tetraspanin CD151 in newly diagnosed glioblastomas. J Surg Oncol (2013) 107(6):646–52.10.1002/jso.23249
55
LombardiGPaceAPasqualettiFRizzatoSFaediMAnghileriEet alPredictors of survival and effect of short (40 Gy) or standard-course (60 Gy) irradiation plus concomitant temozolomide in elderly patients with glioblastoma: a multicenter retrospective study of AINO (Italian Association of Neuro-Oncology). J Neurooncol (2015) 125(2):359–67.10.1007/s11060-015-1923-x
56
LombardiGBelluLPambukuADella PuppaAFiducciaPFarinaMet alClinical outcome of an alternative fotemustine schedule in elderly patients with recurrent glioblastoma: a mono-institutional retrospective study. J Neurooncol (2016) 128(3):481–6.10.1007/s11060-016-2136-7
57
MaCZhouWYanZQuMBuX. β-elemene treatment of glioblastoma: a single-center retrospective study. Onco Targets Ther (2016) 9:7521–6.10.2147/OTT.S120854
58
MalmströmAGrønbergBHMarosiCStuppRFrappazDSchultzHet alTemozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol (2012) 13(9):916–26.10.1016/S1470-2045(12)70265-6
59
MetellusPNanni-MetellusIDelfinoCColinCTchogandjianACoulibalyBet alPrognostic impact of CD133 mRNA expression in 48 glioblastoma patients treated with concomitant radiochemotherapy: a prospective patient cohort at a single institution. Ann Surg Oncol (2011) 18(10):2937–45.10.1245/s10434-011-1703-6
60
MetellusPCoulibalyBNanniIFinaFEudesNGiorgiRet alPrognostic impact of O6-methylguanine-DNA methyltransferase silencing in patients with recurrent glioblastoma multiforme who undergo surgery and carmustine wafer implantation: a prospective patient cohort. Cancer (2009) 115(20):4783–94.10.1002/cncr.24546
61
MinnitiGScaringiCLanzettaGTerrenatoIEspositoVArcellaAet alStandard (60 Gy) or short-course (40 Gy) irradiation plus concomitant and adjuvant temozolomide for elderly patients with glioblastoma: a propensity-matched analysis. Int J Radiat Oncol Biol Phys (2015) 91(1):109–15.10.1016/j.ijrobp.2014.09.013
62
MinnitiGSalvatiMArcellaAButtarelliFD’EliaALanzettaGet alCorrelation between O6-methylguanine-DNA methyltransferase and survival in elderly patients with glioblastoma treated with radiotherapy plus concomitant and adjuvant temozolomide. J Neurooncol (2011) 102(2):311–6.10.1007/s11060-010-0324-4
63
MinnitiGArmosiniVSalvatiMLanzettaGCaporelloPMeiMet alFractionated stereotactic reirradiation and concurrent temozolomide in patients with recurrent glioblastoma. J Neurooncol (2011) 103(3):683–91.10.1007/s11060-010-0446-8
64
MontanoNCenciTMartiniMD’AlessandrisQGPelacchiFRicci-VitianiLet alExpression of EGFRvIII in glioblastoma: prognostic significance revisited. Neoplasia (2011) 13(12):1113–21.10.1593/neo.111338
65
MotomuraKNatsumeAKishidaYHigashiHKondoYNakasuYet alBenefits of interferon-beta and temozolomide combination therapy for newly diagnosed primary glioblastoma with the unmethylated MGMT promoter: a multicenter study. Cancer (2011) 117(8):1721–30.10.1002/cncr.25637
66
MuratAMigliavaccaEGorliaTLambivWLShayTHamouMFet alStem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol (2008) 26(18):3015–24.10.1200/JCO.2007.15.7164
67
NguyenHNLieALiTChowdhuryRLiuFOzerBet alHuman TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy. Neuro Oncol (2017) 19(3):394–404.10.1093/neuonc/now189
68
NiyaziMZehentmayrFNiemöllerOMEigenbrodSKretzschmarHOsthoffKSet alMiRNA expression patterns predict survival in glioblastoma. Radiat Oncol (2011) 6(1):153.10.1186/1748-717X-6-153
69
ParkCKParkSHLeeSHKimCYKimDWPaekSHet alMethylation status of the MGMT gene promoter fails to predict the clinical outcome of glioblastoma patients treated with ACNU plus cisplatin. Neuropathology (2009) 29(4):443–9.10.1111/j.1440-1789.2008.00998.x
70
PerryJRLaperriereNO’CallaghanCJBrandesAAMentenJPhillipsCet alShort-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med (2017) 376(11):1027–37.10.1056/NEJMoa1611977
71
RosatiAPolianiPLTodeschiniACominelliMMedicinaDCenzatoMet alGlutamine synthetase expression as a valuable marker of epilepsy and longer survival in newly diagnosed glioblastoma multiforme. Neuro Oncol (2013) 15(5):618–25.10.1093/neuonc/nos338
72
SanaJRadovaLLakomyRKrenLFadrusPSmrckaMet alRisk score based on microRNA expression signature is independent prognostic classifier of glioblastoma patients. Carcinogenesis (2014) 35(12):2756–62.10.1093/carcin/bgu212
73
Saraiva-EsperonURuibalAHerranzM. The contrasting epigenetic role of RUNX3 when compared with that of MGMT and TIMP3 in glioblastoma multiforme clinical outcomes. J Neurol Sci (2014) 347(1–2):325–31.10.1016/j.jns.2014.10.043
74
SchaichMKestelLPfirrmannMRobelKIllmerTKramerMet alA MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol (2009) 20(1):175–81.10.1093/annonc/mdn548
75
SchaubCTichyJSchaferNFranzKMackFMittelbronnMet alPrognostic factors in recurrent glioblastoma patients treated with bevacizumab. J Neurooncol (2016) 129(1):93–100.10.1007/s11060-016-2144-7
76
ShenoudaGSouhamiLPetreccaKOwenSPanet-RaymondVGuiotMCet alA phase 2 trial of neoadjuvant temozolomide followed by hypofractionated accelerated radiation therapy with concurrent and adjuvant temozolomide for patients with glioblastoma. Int J Radiat Oncol Biol Phys (2017) 97(3):487–94.10.1016/j.ijrobp.2016.11.006
77
SoffiettiRTrevisanEBerteroLCassoniPMorraIFabriniMGet alBevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology). J Neurooncol (2014) 116(3):533–41.10.1007/s11060-013-1317-x
78
StummerWMeinelTEweltCMartusPJakobsOFelsbergJet alProspective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery. J Neurooncol (2012) 108(1):89–97.10.1007/s11060-012-0798-3
79
StuppRHegiMENeynsBGoldbrunnerRSchlegelUClementPMet alPhase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol (2010) 28(16):2712–8.10.1200/jco.2009.26.6650
80
ThonNThorsteinsdottirJEigenbrodSSchüllerULutzJKrethSet alOutcome in unresectable glioblastoma: MGMT promoter methylation makes the difference. J Neurol (2017) 264(2):350–8.10.1007/s00415-016-8355-1
81
VaiosEJNahedBVMuzikanskyAFathiATDietrichJ. Bone marrow response as a potential biomarker of outcomes in glioblastoma patients. J Neurosurg (2016) 127(1):132–8.10.3171/2016.7.jns16609
82
Van MieghemEWozniakAGeussensYMentenJDe VleeschouwerSVan CalenberghFet alDefining pseudoprogression in glioblastoma multiforme. Eur J Neurol (2013) 20(10):1335–41.10.1111/ene.12192
83
WeeCWKimEKimNKimIAKimTMKimYJet alNovel recursive partitioning analysis classification for newly diagnosed glioblastoma: a multi-institutional study highlighting the MGMT promoter methylation and IDH1 gene mutation status. Radiother Oncol (2017) 123(1):106–11.10.1016/j.radonc.2017.02.014
84
WickWPlattenMMeisnerCFelsbergJTabatabaiGSimonMet alTemozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol (2012) 13(7):707–15.10.1016/s1470-2045(12)70164-x
85
YangMYuanYZhangHYanMWangSFengFet alPrognostic significance of CD147 in patients with glioblastoma. J Neurooncol (2013) 115(1):19–26.10.1007/s11060-013-1207-2
86
YangPZhangWWangYPengXChenBQiuXet alIDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry. Oncotarget (2015) 6(38):40896–906.10.18632/oncotarget.5683
87
ZhangXQSunSLamKFKiangMYPuKSHoSWet alA long non-coding RNA signature in glioblastoma multiforme predicts survival. Neurobiol Dis (2013) 58(10):123.10.1016/j.nbd.2013.05.011
88
OhnoMNaritaYMiyakitaYMatsushitaYAritaHYonezawaMet alGlioblastomas with IDH1/2 mutations have a short clinical history and have a favorable clinical outcome. Jpn J Clin Oncol (2016) 46(1):31–9.10.1093/jjco/hyv170
89
KimCKimHSShimWHChoiCGKimSJKimJH. Recurrent glioblastoma: combination of high cerebral blood flow with MGMT promoter methylation is associated with benefit from low-dose temozolomide rechallenge at first recurrence. Radiology (2017) 282(1):212–21.10.1148/radiol.2016152152
90
ItalianoA. Prognostic or predictive? It’s time to get back to definitions!J Clin Oncol (2011) 29(35):4718–4718.10.1200/JCO.2011.38.3729
91
RoaWKepkaLKumarNSinaikaVMatielloJLomidzeDet alInternational Atomic Energy Agency randomized phase III study of radiation therapy in elderly and/or frail patients with newly diagnosed glioblastoma multiforme. J Clin Oncol (2015) 33(35):4145–50.10.1200/JCO.2015.62.6606
92
JordanJTGerstnerERBatchelorTTCahillDPPlotkinSR. Glioblastoma care in the elderly. Cancer (2016) 122(2):189–97.10.1002/cncr.29742
93
YangHWeiDYangKTangWLuoYZhangJ. The prognosis of MGMT promoter methylation in glioblastoma patients of different race: a meta-analysis. Neurochem Res (2014) 39(12):2277–87.10.1007/s11064-014-1435-7
94
RapkinsRWWangFNguyenHNCloughesyTFLaiAHaWet alThe MGMT promoter SNP rs16906252 is a risk factor for MGMT methylation in glioblastoma and is predictive of response to temozolomide. Neuro Oncol (2015) 17(12):1589.10.1093/neuonc/nov064
95
ConsortiumEALekMKarczewskiKJMinikelEVSamochaKEBanksEet alAnalysis of protein-coding genetic variation in 60,706 humans. Nature (2016) 536(7616):285.10.1038/nature19057
96
ZhangWZhangJHoadleyKKushwahaDRamakrishnanVLiSet almiR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression. Neuro Oncol (2012) 14(6):712.10.1093/neuonc/nos089
97
National Comprehensive Cancer Network. NCCN Guidelines: Central Nervous System Cancers (Version 1.2012). The Category of Central Nervous System Cancers (2016). Available from: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp
98
BrandesAAFranceschiETosoniABlattVPessionATalliniGet alMGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol (2008) 26(13):2192–7.10.1200/JCO.2007.14.8163
99
JansenMYipSLouisDN. Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers. Lancet Neurol (2010) 9(7):717–26.10.1016/S1474-4422(10)70105-8
100
LiHLiJChengGZhangJLiX. IDH mutation and MGMT promoter methylation are associated with the pseudoprogression and improved prognosis of glioblastoma multiforme patients who have undergone concurrent and adjuvant temozolomide-based chemoradiotherapy. Clin Neurol Neurosurg (2016) 151:31–6.10.1016/j.clineuro.2016.10.004
101
TopkanETopukSOymakEParlakCPehlivanB. Pseudoprogression in patients with glioblastoma multiforme after concurrent radiotherapy and temozolomide. Am J Clin Oncol (2012) 35(3):284–9.10.1097/COC.0b013e318210f54a
102
YinA-AZhangL-HChengJ-XDongYLiuB-LHanNet alRadiotherapy plus concurrent or sequential temozolomide for glioblastoma in the elderly: a meta-analysis. PLoS One (2013) 8(9):e74242.10.1371/journal.pone.0074242
103
YinA-AZhangL-HChengJ-XDongYLiuB-LHanNet alThe predictive but not prognostic value of MGMT promoter methylation status in elderly glioblastoma patients: a meta-analysis. PLoS One (2014) 9(1):e85102.10.1371/journal.pone.0085102
Summary
Keywords
O6-methylguanine-DNA methyltransferase, methylation, glioblastoma, prognosis, temozolomide
Citation
Zhao Y-H, Wang Z-F, Cao C-J, Weng H, Xu C-S, Li K, Li J-L, Lan J, Zeng X-T and Li Z-Q (2018) The Clinical Significance of O6-Methylguanine-DNA Methyltransferase Promoter Methylation Status in Adult Patients With Glioblastoma: A Meta-analysis. Front. Neurol. 9:127. doi: 10.3389/fneur.2018.00127
Received
03 January 2018
Accepted
20 February 2018
Published
21 March 2018
Volume
9 - 2018
Edited by
Sandro M. Krieg, Technische Universität München, Germany
Reviewed by
Benedikt Wiestler, Technische Universität München, Germany; Christoph Straube, Technische Universität München, Germany; Brad E. Zacharia, Penn State Milton S. Hershey Medical Center, United States
Updates
Copyright
© 2018 Zhao, Wang, Cao, Weng, Xu, Li, Li, Lan, Zeng and Li.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhi-Qiang Li, lizhiqiang@whu.edu.cn
†These authors have contributed equally to this work.
Specialty section: This article was submitted to Neuro-Oncology and Neurosurgical Oncology, a section of the journal Frontiers in Neurology
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