Outcome in unresectable glioblastoma: MGMT promoter methylation makes the difference

• Published in: Journal of neurology Vol. 264; no. 2; pp. 350 - 358
• Main Authors: Thon, Niklas, Thorsteinsdottir, Jun, Eigenbrod, Sabina, Schüller, Ulrich, Lutz, Jürgen, Kreth, Simone, Belka, Claus, Tonn, Jörg-Christian, Niyazi, Maximilian, Kreth, Friedrich Wilhelm
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2017; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating - therapeutic use; Biopsy; Cancer therapies; Central Nervous System Neoplasms - diagnosis; Central Nervous System Neoplasms - drug therapy; Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - radiotherapy; Chemoradiotherapy; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; DNA Methylation; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; Drug Resistance, Neoplasm - genetics; Female; Follow-Up Studies; Glioblastoma - diagnosis; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - radiotherapy; Humans; Interdisciplinary aspects; Longitudinal Studies; Male; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; Neurology; Neuropathology; Neuroradiology; Neurosciences; Oncology; Original Communication; Prognosis; Promoter Regions, Genetic; Prospective Studies; Radiation therapy; Salvage Therapy; Temozolomide; Tumor Suppressor Proteins - genetics; Tumors; Young Adult; Germany; Extent of resection; Biopsy; Outcome; Prognostic factors; Glioblastoma; MGMT
• ISSN: 0340-5354; 1432-1459
• DOI: 10.1007/s00415-016-8355-1

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.