Clinical StudyMGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel☆
Introduction
Glioblastoma multiforme (GBM) is the most common primary brain tumor, with a median survival of less than 2 years [1]. To date, only two alkylating agents have been shown to be consistently associated with prolonged survival: temozolomide (TMZ) and locally delivered Gliadel wafers (Eisai, Tokyo, Japan) [1], [2], [3].
Gliadel wafers are intracranially implanted and locally deliver carmustine (1,3-bis[2-chloroethyl]-1; nitrosourea [BCNU]) at the site of tumor resection, allowing for a higher concentration of local chemotherapeutic dose while minimizing systemic adverse effects [2], [3], [4]. These wafers provide a controlled release form of local chemotherapy over approximately 3 weeks [4], [5].
Methylation of the O6-methylguanine-methyltransferase (MGMT) promoter in gliomas has been found to be an important predictor of tumor responsiveness after several cytotoxic regimens [1], including BCNU treatment [6]. Expression of the DNA repair protein, MGMT, results in GBM resistance to alkylating agents. Alkylating agents cause cell death by binding to DNA, most commonly to the O6 position of guanine, and forming cross links between adjacent DNA strands. This cross linking of double stranded DNA is inhibited by the cellular DNA repair protein MGMT.
In this study, through a unique analysis of 122 patients with newly diagnosed GBM who had enough tumor tissue for MGMT analysis and were treated with Gliadel, we retrospectively examined the association between the MGMT promoter methylation status and overall survival (OS) and recurrence-free survival (RFS).
Section snippets
Patients and tumor specimens
We retrospectively reviewed 160 patients with newly diagnosed GBM, who received Gliadel after their tumor resections at Johns Hopkins Hospital in Baltimore, Maryland, USA, between July 1997 and December 2006. Of these patients, only 122 had stored tumor samples that were available for MGMT analysis; 38 (24%) did not have enough tumor tissue. The clinical, radiological and hospital courses of these patients were retrospectively reviewed. Age, sex, Karnofsky performance score (KPS) at time of
Patient population
At the Johns Hopkins Hospital between 1997 and 2006, 600 patients with newly diagnosed GBM underwent craniotomies. Of these patients, 185 received Gliadel (30.8%) after their tumor resections. Methylation-specific PCR was performed for 122 of the 160 patients (76%), because 38 did not have sufficient paraffin embedded tumor tissue for MGMT analysis. The patient characteristics and treatment details are shown in Table 2. The clinical course of 40 patients who had MGMT promoter methylation was
Discussion
We investigated the significance of MGMT methylation status in a series of 122 patients with newly diagnosed GBM, who underwent surgical resection and implantation of Gliadel wafers. The results of our series show a reduction in the hazard of death for patients who had MGMT methylation compared to those with unmethylated MGMT. Interestingly, this effect was much more profound in the patients who were aged >70 years at GBM diagnosis. The elderly patients with methylated MGMT had significantly
Conclusion
Our results show a reduction in the hazard of death for patients with methylated MGMT compared to unmethylated. This effect was more profound in the elderly (>70 years old). MGMT methylation showed a significantly better OS and RFS compared to unmethylated MGMT. These results may support Gliadel use in this subpopulation, since accumulating data indicate that with increasing age, the benefit of adding an alkylating agent such as TMZ to RT decreases, and may be less well tolerated. Gliadel, as
Conflicts of Interest/Disclosures
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
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This work was supported in part by grants from American Physicians Fellowship (APF) for Medicine in Israel (Rachel Grossman).