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      Reoperation for Recurrent Glioblastoma and Its Association With Survival Benefit

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          Abstract

          BACKGROUND:

          Glioblastoma is the most common and aggressive primary brain tumor. Despite current treatment, recurrence is inevitable. There are no clear guidelines for treatment of recurrent glioblastoma.

          OBJECTIVE:

          To investigate factors at initial surgery predictive of reoperation, and the prognostic variables associated with survival, including reoperation for recurrence.

          METHODS:

          A retrospective cohort study was performed, including adult patients diagnosed with glioblastoma between January 2010 and December 2013. Student t test and Fisher exact test compared continuous and categorical variables between reoperation and nonreoperation groups. Univariable and Cox regression multivariable analysis was performed.

          RESULTS:

          In a cohort of 204 patients with de novo glioblastoma, 49 (24%) received reoperation at recurrence. The median overall survival in the reoperation group was 20.1 months compared with 9.0 months in the nonreoperation group (P =.001). Reoperation was associated with longer overall survival in our total population (hazard ratio, 0.646; 95% confidence interval, 0.543-0.922; P =.016) but subject to selection bias. Subgroup analyses excluding patients unlikely to be considered for reoperation suggested a much less significant effect of reoperation on survival, which warrants further study with larger cohorts. Factors at initial surgery predictive for reoperation were younger age, smaller tumor size, initial extent of resection ≥50%, shorter inpatient stay, and maximal initial adjuvant therapy. When unfavorable patient characteristics are excluded, reoperation is not an independent predictor of survival.

          CONCLUSION:

          Patients undergoing reoperation have favorable prognostic characteristics, which may be responsible for the survival difference observed. We recommend that a large clinical registry be developed to better aid consistent and homogenous data collection.

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          Most cited references41

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          Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

          Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.
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            Effects 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.

            In 2004, a randomised 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. Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard 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 Clinicaltrials.gov, number NCT00006353. 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 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.
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              MGMT gene silencing and benefit from temozolomide in glioblastoma.

              Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit. Copyright 2005 Massachusetts Medical Society.
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                Author and article information

                Journal
                Neurosurgery
                Ovid Technologies (Wolters Kluwer Health)
                0148-396X
                1524-4040
                November 2016
                November 01 2016
                July 06 2016
                November 2016
                November 01 2016
                July 06 2016
                : 79
                : 5
                : 678-689
                Affiliations
                [1 ]Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, Victoria, Australia;
                [2 ]The University of Notre Dame Australia, School of Medicine, Melbourne Clinical School, Werribee, Victoria;
                [3 ]The Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
                Article
                10.1227/NEU.0000000000001338
                27409404
                397996bc-0a3d-4613-bbef-f5c09fe1d695
                © 2016
                History

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