title: Outcome in unresectable glioblastoma: MGMT promoter methylation makes the difference.
abstract: In 2011, we reported a predominant prognostic/predictive role of MGMT promoter methylation status on progression-free survival (PFS) in unresectable glioblastoma patients undergoing upfront radiotherapy plus concomitant and maintenance temozolomide (RTX/TMZ → TMZ). We, here, present the final results of this prospective study focussing on the prognostic/predictive value of MGMT promoter methylation status for death risk stratification. Overall, 56 adult patients with unresectable, biopsy proven glioblastoma were prospectively assigned to upfront RTX/TMZ → TMZ treatment between March 2006 and August 2008. Last follow-up was performed in June 2016. MGMT promoter methylation was determined using methylation-specific PCR (MSP) and sodium bisulfite sequencing. Analyses were done by intention to treat. Prognostic factors were obtained from proportional hazard models. At the time of the final analysis 55 patients showed progressive disease and 53 patients had died. MGMT promoter was methylated (unmethylated) in 30 (26) patients. Methylation of the MGMT promoter was the strongest favorable predictor for overall survival (OS, median: 20.3 vs. 7.3 months, p < 0.001, HR 0.30, 95% CI 0.16-0.55), and PFS (median: 15.0 vs. 6.1 months, p < 0.001, HR 0.31, 95% CI 0.17-0.57) and was also associated with higher frequencies of treatment response and prolonged post-recurrence survival (PRS, median: 4.5 vs. 1.4 months, p < 0.002, HR 0.39, 95% CI 0.21-0.71). Knowledge of MGMT promoter methylation status is essential for patients' counseling, prognostic evaluation, and for the design of future trials dealing with unresectable glioblastomas.
authors.affiliation: Department of Neurosurgery, University of Munich LMU, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Thon
authors.affiliation: Department of Neurosurgery, University of Munich LMU, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany. jun.thorsteinsdottir@med.uni-muenchen.de.
authors.forename: Jun
authors.initials: J
authors.lastname: Thorsteinsdottir
authors.affiliation: Center for Neuropathology and Prion Research, University of Munich LMU, Feodor-Lynen-Str. 20, 81377, Munich, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Eigenbrod
authors.affiliation: Center for Neuropathology and Prion Research, University of Munich LMU, Feodor-Lynen-Str. 20, 81377, Munich, Germany.|Research Institute Children's Cancer Center, Hamburg, Germany.|Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20264, Hamburg, Germany.|Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20264 Hamburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.affiliation: Department of Neuroradiology, University of Munich LMU, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany.|Department of Neuroradiology, Klinikum Ingolstadt, Krumenauerstraße 25, 85049, Ingolstadt, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Lutz
authors.affiliation: Department of Anaesthesiology, University of Munich LMU, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Kreth
authors.affiliation: Department of Radiation Oncology, University of Munich LMU, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
authors.affiliation: Department of Neurosurgery, University of Munich LMU, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Jörg-Christian
authors.initials: JC
authors.lastname: Tonn
authors.affiliation: Department of Radiation Oncology, University of Munich LMU, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Niyazi
authors.affiliation: Department of Neurosurgery, University of Munich LMU, Campus Grosshadern, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Friedrich Wilhelm
authors.initials: FW
authors.lastname: Kreth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001706:Biopsy; D016543:Central Nervous System Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D059248:Chemoradiotherapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D016879:Salvage Therapy; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: Biopsy; Extent of resection; Glioblastoma; MGMT; Outcome; Prognostic factors