Characterizing benefit from temozolomide in MGMT promoter unmethylated and methylated glioblastoma: a systematic review and meta-analysis

Abstract

Background The current standard of care for the management of patients with newly diagnosed glioblastoma (GBM) includes maximal safe resection followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). While it is well established that TMZ has better efficacy in patients with MGMT promoter methylation, it remains an area of debate whether TMZ should be omitted when treating GBM patients with unmethylated MGMT. Methods We conducted a systematic review and meta-analysis to provide separate estimates of median overall survival (OS) and progression-free survival (PFS) for patients with methylated and unmethylated GBM treated with RT with or without TMZ. We searched multiple databases from inception to January 13, 2020. Results The median OS for patients with unmethylated GBM treated with RT/TMZ pooled from 5 phase III studies (N = 655) was 14.11 months (95% confidence interval [CI], 13.18–15.04) with a median PFS of 4.99 months (95% CI, 4.25–5.72). In contrast, the median OS for patients with methylated GBM pooled from 6 studies (N = 753) was 24.59 months (95% CI, 22.19–26.99) with a median PFS pooled from 7 studies (N = 805) of 9.51 months (95% CI, 7.41–11.61). There is a paucity of prospective data pertaining to OS/PFS in unmethylated patients treated with RT only and therefore a direct comparison was not possible. Conclusions This meta-analysis provides estimates of survival for patients with MGMT methylated or unmethylated GBM treated with RT/TMZ. Further research is needed to delineate whether TMZ should be withheld for patients with unmethylated GBM outside of the setting of clinical trials.

A Root in Synapsis and the Other One in the Gut Microbiome-Brain Axis: Are the Two Poles of Ketogenic Diet Enough to Challenge Glioblastoma?

“…A recent meta-analysis confirms initial data and found a median overall survival (OS) of about 14 months as compares to 24 for patients with unmethylated and methylated GBM, respectively. Progression-free survival (PFS) was almost doubled in methylated (10 months) compared to unmethylated patients (about 5 months) (2). However, the irrefutable value of MGMT promoter methylation as a prognostic and predictive marker has not therapeutic reverse: lack of methylation does not translate into changes in therapeutic algorithms to date.…”

Effect of Cold Atmospheric Plasma on Epigenetic Changes, DNA Damage, and Possibilities for Its Use in Synergistic Cancer Therapy

“…Although glioblastomas generally have high expression of this gene which makes them largely resistant to the effect of TMZ, some of these cell lines have reduced gene expression. This is usually due to promoter methylation, and these have notably higher sensitivity to TMZ [200]. However, CAP application enhanced this cytotoxic effect, even in cell lines with highly expressed MGMT [201], and this cytotoxic effect was comparable with that in cell lines with methylated MGMT.…”

A Key Pathway to Cancer Resilience: The Role of Autophagy in Glioblastomas

“…Promoter methylation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene is a prognostic marker in patients with glioma because MGMT methylation leads to better response to alkylating agents, such as TMZ (198). Indeed, patients harboring MGMT-methylated GBMs had a 10-month and 4month higher median overall and PFS, respectively, compared with MGMT-non-methylated patients (199). Interestingly, two different groups showed that MGMT-methylated gliomas presented a lower autophagy risk score compared with MGMTnon-methylated patients (136,137).…”