title: MGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel.
abstract: We examined the relationship between the O(6)-methylguanine-methyltransferase (MGMT) methylation status and clinical outcomes in newly diagnosed glioblastoma multiforme (GBM) patients who were treated with Gliadel wafers (Eisai, Tokyo, Japan). MGMT promoter methylation has been associated with increased survival among patients with GBM who are treated with various alkylating agents. MGMT promoter methylation, in DNA from 122 of 160 newly diagnosed GBM patients treated with Gliadel, was determined by a quantitative methylation-specific polymerase chain reaction, and was correlated with overall survival (OS) and recurrence-free survival (RFS). The MGMT promoter was methylated in 40 (32.7%) of 122 patients. The median OS was 13.5 months (95% confidence interval [CI] 11.0-14.5) and RFS was 9.4 months (95% CI 7.8-10.2). After adjusting for age, Karnofsky performance score, extent of resection, temozolomide (TMZ) and radiation therapy (RT), the newly diagnosed GBM patients with MGMT methylation had a 15% reduced mortality risk, compared to patients with unmethylated MGMT (hazard ratio 0.85; 95% CI 0.56-1.31; p=0.46). The patients aged over 70 years with MGMT methylation had a significantly longer median OS of 13.5 months, compared to 7.6 months in patients with unmethylated MGMT (p=0.027). A significant difference was also found in older patients, with a median RFS of 13.1 versus 7.6 months for methylated and unmethylated MGMT groups, respectively (p=0.01). Methylation of the MGMT promoter in newly diagnosed GBM patients treated with Gliadel, RT and TMZ, was associated with significantly improved OS compared to the unmethylated population. In elderly patients, methylation of the MGMT promoter was associated with significantly better OS and RFS.
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Grossman
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Burger
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Ethan
authors.initials: E
authors.lastname: Soudry
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States. Electronic address: btyler@jhmi.edu.
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Kaisorn L
authors.initials: KL
authors.lastname: Chaichana
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Jon
authors.initials: J
authors.lastname: Weingart
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Olivi
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Gallia
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Quiñones-Hinojosa
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Xiaobu
authors.initials: X
authors.lastname: Ye
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States.
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics* / Q000628:therapy; D002330:Carmustine / Q000008:administration & dosage; D059248:Chemoradiotherapy; D019175:DNA Methylation / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003652:Decanoic Acids / Q000008:administration & dosage; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000628:therapy; D006801:Humans; D007564:Japan; D017567:Karnofsky Performance Status; D008297:Male; D008875:Middle Aged; D011091:Polyesters / Q000008:administration & dosage; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D003652:Decanoic Acids; D011091:Polyesters; D025521:Tumor Suppressor Proteins; C574855:carmustine, poliferprosan 20 drug combination; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D002330:Carmustine; D000077204:Temozolomide
keywords: Gliadel; Glioblastoma multiforme; MGMT; Methylation; Outcome; Survival