***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: PURPOSE Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma ( GBM ) by increasing the therapeutic index , overcoming common mechanisms of temozolomide resistance , or both . The goal of this r and omized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM . PATIENTS AND METHODS Adult patients with newly diagnosed GBM were r and omly assigned to receive st and ard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense ( 150 mg/m(2 ) days 1 to 7 and 15 to 21 ) or metronomic ( 50 mg/m(2 ) continuous daily ) temozolomide . Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression . The primary end point was overall survival ( OS ) at 1 year . Tumor tissue was assayed to determine O(6)-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation status . RESULTS Eighty-five eligible patients were enrolled ; 42 were r and omly assigned to dose-dense and 43 to metronomic temozolomide . The 1-year survival rate was 80 % for the dose-dense arm and 69 % for the metronomic arm ; median OS was 17.1 months ( 95 % CI , 14.0 to 28.1 months ) and 15.1 months ( 95 % CI , 12.3 to 18.9 months ) , respectively . The most common toxicities were myelosuppression ( leukopenia , neutropenia , and thrombocytopenia ) and elevated liver enzymes . Pseudoprogression was observed in 37 % of assessable patients and may have had an impact on estimates of progression-free survival ( 6.6 months in the dose-dense arm and 5.0 months in the metronomic arm ) . CONCLUSION Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity . The dose-dense regimen appears promising , with 1-year survival of 80 % BACKGROUND A r and omised trial published by the European Organisation for Research and Treatment of Cancer ( EORTC ) and the National Cancer Institute of Canada ( NCIC ) Clinical Trials Group ( trial 26981 - 22981/CE.3 ) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival . We aim ed to undertake an exploratory sub analysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma , derive nomograms that predict an individual patient 's prognosis , and suggest stratification factors for future trials . METHODS Data from 573 patients with newly diagnosed glioblastoma who were r and omly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this sub analysis . Survival modelling was done in three patient population s : intention-to-treat population of all r and omised patients ( population 1 ) ; patients assigned temozolomide and radiotherapy ( population 2 , n=287 ) ; and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection ( population 3 , n=103 ) . Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation status . Nomograms were developed to predict an individual patient 's median and 2-year survival probabilities . No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new st and ard of care . FINDINGS Independent of the MGMT promoter methylation status , analysis in all r and omised patients ( population 1 ) identified combined treatment with temozolomide , more extensive tumour resection , younger age , Mini-Mental State Examination ( MMSE ) score of 27 or higher , and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome . In patients assigned temozolomide and radiotherapy ( population 2 ) , younger age , better performance status , more extensive tumour resection , and MMSE score of 27 or higher were associated with better survival . In patients who had tumours resected , who were assigned temozolomide and radiotherapy , and who had available MGMT promoter methylation status ( population 3 ) , methylated MGMT , better performance status , and MMSE score of 27 or higher were associated with improved survival . Nomograms were developed and are available at http://www.eortc.be/tools/g bmc alculator . INTERPRETATION MGMT promoter methylation status , age , performance status , extent of resection , and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma . Stratifying by MGMT promoter methylation status should be m and atory in all glioblastoma trials that use alkylating chemotherapy . Nomograms can be used to predict an individual patient 's prognosis , and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management PURPOSE This phase II trial was design ed to define the role of O(6)-benzylguanine ( O(6)-BG ) in restoring temozolomide sensitivity in patients with recurrent or progressive , temozolomide-resistant malignant glioma and to evaluate the safety of administering O(6)-BG in combination with temozolomide . PATIENTS AND METHODS Patients were accrued into two independent strata on the basis of histology : glioblastoma multiforme ( GBM ) and anaplastic glioma . Both temozolomide and O(6)-BG were administered on day 1 of a 28-day treatment cycle . Patients were administered a 1-hour O(6)-BG infusion at a dose of 120 mg/m(2 ) followed immediately by a 48-hour infusion at a dose of 30 mg/m(2)/d . Temozolomide was administered orally within 60 minutes of the end of the 1-hour O(6)-BG infusion at a dose of 472 mg/m(2 ) . The primary end point was objective response rate . Secondary end points included progression-free survival , overall survival , and safety . RESULTS Sixty-six of 67 patients who enrolled were treated with temozolomide and O(6)-BG . One of 34 patients ( 3 % ) with GBM ( 95 % CI , 0.1 % to 15 % ) and five of 32 assessable patients ( 16 % ) with anaplastic glioma ( 95 % CI , 5 % to 33 % ) were responders . The most commonly reported adverse events were grade 4 hematologic events experienced in 48 % of the patients . CONCLUSION O(6)-BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma , but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM Purpose : In the setting of a prospect i ve clinical trial , we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase ( MGMT ) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide .  Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy . Experimental Design : The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation .  The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR . Results : Inactivation of the MGMT gene by promoter methylation was associated with longer survival ( P = 0.0051 ; Log-rank test ) . At 18 months , survival was 62 % ( 16 of 26 ) for patients testing positive for a methylated MGMT promoter but reached only 8 % ( 1 of 12 ) in absence of methylation ( P = 0.002 ; Fisher ’s exact test ) . In the presence of other clinical ly relevant factors , methylation of the MGMT promoter remains the only significant predictor ( P = 0.017 ; Cox regression ) . Conclusions : This prospect i ve clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent .  The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implication s for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine , a noncytotoxic substrate of this enzyme Glioblastoma ( GBM ) is the most common and aggressive primary brain tumor . The identification of novel molecular prognostic markers of GBM has recently been an area of great interest in neuro-oncology . The methylation status of the MGMT gene promoter is currently a promising molecular prognostic marker , but some controversial data have precluded its clinical use . We analyzed MGMT methylation by methylation-specific PCR in 90 GBM patients from four Portuguese hospitals , uniformly treated with radiotherapy combined with concomitant and adjuvant temozolomide ( Stupp protocol ) .  The Kaplan-Meier method was used to construct survival curves , and the log-rank test and a Cox-regression model were used to analyze patient survival . The methylation status of MGMT was successfully determined in 89 % ( 80/90 ) of the tumors . The frequency of tumoral MGMT promoter methylation was 47.5 % . The median overall survivals ( OSs ) were 16 months ( 95 % CI 12.2 - 19.8 ) and 13 months ( 95 % CI 13.3 - 18.7 ) for patients whose tumors had a methylated or unmethylated MGMT , respectively . Univariate and multivariate analyses did not show any statistically significant association between MGMT methylation status and patient OS ( P=0.583 by the log-rank test ; P=0.617 by the Cox-regression test ) or progression-free survival ( P=0.775 by the log-rank test ; P=0.691 by the Cox-regression test ) . None of the patient clinical features were significantly correlated with survival . This is the first study to report the frequency of MGMT methylation among Portuguese GBM patients . Our data did not show statistically significant associations between MGMT promoter methylation and the outcome of GBM patients treated with temozolomide . Additional robust prospect i ve studies are warranted to clarify whether the MGMT status should be used in clinical decisions BACKGROUND In 2004 , a r and omised phase III trial by the European Organisation for Research and Treatment of Cancer ( EORTC ) and National Cancer Institute of Canada Clinical Trials Group ( NCIC ) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy .  We report the final results with a median follow-up of more than 5 years . METHODS Adult patients with newly diagnosed glioblastoma were r and omly assigned to receive either st and ard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide . The methylation status of the methyl-guanine methyl transferase gene , MGMT , was determined retrospectively from the tumour tissue of 206 patients . The primary endpoint was overall survival . Analyses were by intention to treat . This trial is registered with Clinical trials.gov , number NCT00006353 . FINDINGS Between Aug 17 , 2000 , and March 22 , 2002 , 573 patients were assigned to treatment . 278 ( 97 % ) of 286 patients in the radiotherapy alone group and 254 ( 89 % ) of 287 in the combined-treatment group died during 5 years of follow-up . Overall survival was 27.2 % ( 95 % CI 22.2 - 32.5 ) at 2 years , 16.0 % ( 12.0 - 20.6 ) at 3 years , 12.1 % ( 8.5 - 16.4 ) at 4 years , and 9.8 % ( 6.4 - 14.0 ) at 5 years with temozolomide , versus 10.9 % ( 7.6 - 14.8 ) , 4.4 % ( 2.4 - 7.2 ) , 3.0 % ( 1.4 - 5.7 ) , and 1.9 % ( 0.6 - 4.4 ) with radiotherapy alone ( hazard ratio 0.6 , 95 % CI 0.5 - 0.7 ; p<0.0001 ) . A benefit of combined therapy was recorded in all clinical prognostic subgroups , including patients aged 
    Output:
    
Epigenetic silencing of MGMT is associated with markedly improved survival in patients with HGG who receive adjuvant therapy .
MGMT silencing serves as a predictive marker , with the largest benefit seen in patients receiving CT as a component of adjuvant treatment , an intermediate benefit in patients receiving adjuvant RT , and no evidence to support benefit in those receiving surgery alone