Abstract
Prolonged exposure to temozolomide (TMZ) could improve clinical outcomes in recurrent glioblastoma multiforme (GBM) patients. We previously developed a dose-dense regimen of TMZ in a phase II study (180 mg/m2 from days 1 to 5 every two weeks). A retrospective analysis of patients with macroscopic residual GBM treated with “post-induction” dose-dense TMZ was conducted, adding an explorative subgroup analyses among patients with different O6-methylguanine DNA methyltransferase (MGMT) expressions (negative vs positive, < vs ≥ of 50 % of cells stained, < vs ≥ 70% of cells stained). Thirty-six patients were evaluated; after a median follow-up of 36 weeks, median Progression Free Survival (PFS) and median Overall Survival (OS) were 19 and 34 weeks, respectively. MGMT expression (70% cut-off) and sex were confirmed as independent predictors for disease control rate (DCR) at multivariate analysis. At univariate analysis ECOG-PS, Sex (female), extensive tumor resection was shown to be related to a longer PFS, while MGMT expression (cut-off 70%) to a shorter PFS. Multivariate analysis with Cox hazard regression confirmed only ECOG-PS as an independent predictor for PFS. ECOG-PS showed to be significant related to a longer OS. Our analysis showed that dose-dense TMZ regimens are still an option for patients with recurrent GBM, but should be used for re-challenge treatments. MGMT immunohistochemistry high expression might be used as a “surrogate” negative predictor for DCR for dd-TMZ treatments.
Highlights
The current standard of care for patients with newly diagnosed glioblastoma multiforme (GBM) is maximum safe surgical resection followed by concomitant temozolomide (TMZ) and radiation therapy (RT), and adjuvant TMZ (5/28 day cycle), based on the results of the Stupp clinical trial [1]
Methylation of the promoter region of the methylguanine DNA methyltransferase (MGMT) gene cause silencing of MGMT enzyme expression and has been associated with a statistically significant improvement in progression free survival (PFS) and overall survival (OS) in patients receiving combined radiotherapy and TMZ regimen [4]
In order to evaluate the feasibility of an alternative dd-TMZ regimen, we previously developed a phase II study, with a dose-finding initial cohort, in patients with high grade gliomas (World Health Organization grade 3 and 4) [16]; our clinical experience with “dose-dense” dd-TMZ involved 70 patients until December 2016
Summary
The current standard of care for patients with newly diagnosed glioblastoma multiforme (GBM) is maximum safe surgical resection followed by concomitant temozolomide (TMZ) and radiation therapy (RT), and adjuvant TMZ (5/28 day cycle), based on the results of the Stupp clinical trial [1]. O6-methylguanine DNA methyltransferase (MGMT) is a DNA repair enzyme that has been established as a major mechanism of resistance to alkylating agents, such as TMZ [3] It transfers methyl adducts from the O6 position of guanine residue to its cysteine, in its active enzymatic domain, but this action in turn leads to inactivation and consumption of MGMT itself, and subsequent degradation; high MGMT expression levels in cells may confer resistance to TMZ. Methylation of the promoter region of the MGMT gene cause silencing of MGMT enzyme expression and has been associated with a statistically significant improvement in progression free survival (PFS) and overall survival (OS) in patients receiving combined radiotherapy and TMZ regimen [4] These findings suggest that modulation of MGMT enzymatic activity may increase sensitivity and response to TMZ regimens; a prolonged exposure to alkylating agents has been shown to deplete intracellular MGMT in peripheral blood mononuclear cells [5]
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