Japanese Journal of Clinical Oncology Advance Access originally published online on December 21, 2007
Japanese Journal of Clinical Oncology 2007 37(12):897-906; doi:10.1093/jjco/hym132
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© 2007 Foundation for Promotion of Cancer Research
Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Protein Expression in Patients with Recurrent Glioblastoma Treated with Temozolomide
1 Department of Neurosurgery, Kyorin University School of Medicine, Tokyo
2 Department of Neuro-Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama
3 Brainpier Minamiohta, Ibaragi, Japan
For reprints and all correspondence: Motoo Nagane, Department of Neurosurgery, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. E-mail: nagane-nsu{at}umin.ac.jp
Received August 8, 2007; accepted September 10, 2007
Background: Temozolomide (TMZ) is active against newly diagnosed glioblastoma (GBM), and O6-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/m2/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.
Key Words: glioblastoma • temozolomide • O6-methylguanine-DNA methyltransferase • western blot • recurrence
Abbreviations: MST, medial survival time; GBM, glioblastoma multiforme; TMZ, temozolomide; EORTC, European Organisation for Research and Treatment of Cancer; NCIC, National Cancer Institute of Canada; RT, radiotherapy; MGMT, O6-methylguanine-DNA methyltransferase; PCR, polymerase-chain reaction; MSP, methylation-specific PCR; IHC, immunohistochemistry; KPS, Karnofsky performace status; MRI, magnetic resonance imaging; PFS, progression-free survival; OS, overall survival; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
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