Prognostic significance of O6-methylguanine-DNA methyltransferase protein expression in patients with recurrent glioblastoma treated with temozolomide.
BACKGROUND
Temozolomide (TMZ) is active against newly diagnosed glioblastoma (GBM), and O(6)-methylguanine-DNA methyltransferase (MGMT) is implicated in resistance to TMZ and nitrosoureas. We evaluated the efficacy and safety of the standard 5-day TMZ regimen in patients with recurrent GBM after initial therapy including nitrosourea-based chemotherapy, in conjunction with an analysis of the prognostic value of MGMT protein expression regarding response to TMZ and survival.


METHODS
From September 2003 to January 2007, 30 patients having recurrent GBM received 150-200 mg/m(2)/day of TMZ for five consecutive days every 28 days. Tumor tissue from 19 patients was analysed for MGMT protein expression using western blotting, and 17 of them were assessable for a response.


RESULTS
The overall response rate was 23.5% (one complete response and three partial responses). Six patients had stable disease (35.3%). Median progression-free survival (PFS) time was 2.2 months, and median overall survival (OS) time was 9.9 months from the initiation of TMZ therapy. Patients with low MGMT protein expression had a significantly improved PFS (P = 0.016) and OS (P = 0.019) compared to those with high expression. Both low MGMT expression (P = 0.040) and re-resection at relapse (P = 0.014) persisted as significant independent favorable prognostic factors for OS. The most common grade 3 and 4 hematological toxicity was lymphopenia (22.2%).


CONCLUSIONS
The standard 5-day TMZ regimen resulted in moderate antitumor activity with an acceptable safety profile in patients with nitrosourea-pretreated recurrent GBM, and protein expression of MGMT is an important prognostic factor for patients treated with TMZ even after recurrence.
D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D016543:Central Nervous System Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000201:enzymology; D002648:Child; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000737:chemistry* / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009607:Nitrosourea Compounds / Q000008:administration & dosage; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis*; D011237:Predictive Value of Tests; D011379:Prognosis; D000077204:Temozolomide; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D009607:Nitrosourea Compounds; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide