MGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel

doi:10.1016/j.jocn.2015.07.003

Journal of Clinical Neuroscience

Volume 22, Issue 12, December 2015, Pages 1938-1942

https://doi.org/10.1016/j.jocn.2015.07.003 Get rights and content

Abstract

We examined the relationship between the O⁶-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.

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.

References (18)

H. Brem et al.
Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group
Lancet
(1995)
W. Wick et al.
Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial
Lancet Oncol
(2012)
A. Malmstrom et al.
Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial
Lancet Oncol
(2012)
M.E. Hegi et al.
MGMT gene silencing and benefit from temozolomide in glioblastoma
N Engl J Med
(2005)
M. Westphal et al.
A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma
Neuro Oncol
(2003)
A.B. Fleming et al.
Pharmacokinetics of the carmustine implant
Clin Pharmacokinet
(2002)
L.K. Fung et al.
Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain
Cancer Res
(1998)
M. Esteller et al.
Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents
N Engl J Med
(2000)
G.E. Dinse et al.
Nonparametric estimation of lifetime and disease onset distributions from incomplete observations
Biometrics
(1982)

There are more references available in the full text version of this article.

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^☆: This work was supported in part by grants from American Physicians Fellowship (APF) for Medicine in Israel (Rachel Grossman).

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Clinical StudyMGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel☆

Abstract

Introduction

Section snippets

Patients and tumor specimens

Patient population

Discussion

Conclusion

Conflicts of Interest/Disclosures

Lancet

Lancet Oncol

Lancet Oncol

MGMT gene silencing and benefit from temozolomide in glioblastoma

N Engl J Med

A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma

Neuro Oncol

Pharmacokinetics of the carmustine implant

Clin Pharmacokinet

Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain

Cancer Res

Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents

N Engl J Med

Nonparametric estimation of lifetime and disease onset distributions from incomplete observations

Biometrics

Clinical Study
MGMT inactivation and clinical response in newly diagnosed GBM patients treated with Gliadel☆