Ep-GBM is a newly classified histological subtype of GBM included in the 2016 WHO Classification of Tumors of the Central Nervous System[6]. Currently, there is a scarcity of studies focusing on the clinical and pathological characteristics, as well as treatment outcomes related to Ep-GBM subtypes, especially regarding treatment options after Ep-GBM recurrence. Therefore, this study is unique and aims to provide more specific information on the prognosis and therapeutic choices for these cancers.
The mean age of the 58 patients diagnosed histologically with Ep-GBM was 37.6 ± 16.3 years (range: 5–70 years). This was consistent with the findings of Suxia et al.[7]. However, it is worth noting that Andrey et al.[5] reported a lower median age of 25 years for Ep-GBM patients, attributed to the large proportion of juvenile patients in their study (approximately 52%). In our study, only eight patients were under 18 years of age. The median age at diagnosis for all patients in the trial was 39.3 years, indicating a significantly younger population than conventional GBM, which typically have a median age at diagnosis of 65 years[8].
We found that majority of Ep-GBM tumors occurred in the supratentorial cerebral cortical areas, specifically in the temporal and frontal lobes, which supports the results reported by Khanna et al.[9]. However, a smaller number of tumors were also found in unconventional locations, such as the thalamus, corpus callosum, and cerebellar hemispheres. Additionally, we identified 20 patients with large tumors affecting multiple lobes of the brain. According to a report, Ep-GBM accounts for approximately 3% of all GBM cases [10]. The results of our study aligns with these findings, as we observed that Ep-GBMs constituted 4.5% of all cases of glioblastomas during the same period.
In our study, 58 patients had a median survival time of 29.1 months. Similarly, Chatterjee et al.[11] conducted a study where they reported a median survival time of 25.5 months among 24 patients diagnosed with Ep-GBM. However, Wang et al.[7] reported a significantly lower median survival time of only 10.6 months for Ep-GBM. These differences in the survival outcomes could be attributed to the treatment approach employed in their study. Specifically, Wang et al. found that 48.4% of patients received simultaneous chemoradiotherapy, compared with that of 67.2% in our study. Additionally, the absence of a defined treatment regimen for post-tumor recurrence in their study could also contribute to the disparity in survival times.
The primary objective of GBM surgery is to achieve maximum safe resection. A meta-analysis conducted by Brown et al.[12] revealed that GTR significantly improved OS and PFS in patients with GBM compared with PR. Similarly, in a study conducted by Lu et al.[3], patients with Ep-GBM who underwent GTR had longer PFS and OS than those who underwent PR. However, a study conducted by Ansari et al.[13] failed to establish a correlation between GTR and survival outcomes. In our study, we found that patients who underwent GTR demonstrated a significantly longer median PFS than those who underwent PR (P = 0.021). Additionally, the median OS in the GTR group was 31.2 months, which was 13.2 months higher than the median OS in the PR group (18.0 months). Although the difference was not significant (P = 0.139), GTR tended to improve the OS. Notably, our study identified five patients who achieved an OS exceeding 65 months. This favorable outcome was strongly correlated with the attainment of GTR during their initial surgical procedure, highlighting the potential for long-term survival in patients who underwent GTR.
Radiotherapy has been recognized as a crucial tool for GBM treatment because of its ability to enhance the local control and OS of tumors[14]. Sun et al.[15] reported prolonged survival after radiation therapy. However, contrasting findings have been reported by Wang et al.[7], suggesting that radiotherapy does not significantly affect the prognosis. In our study, we found that patients who received radiotherapy experienced a significant extension in median OS compared to those who did not. Currently, the treatment approach for Ep-GBMs is closely aligned with that for conventional GBM. The standard treatment for GBM typically involves maximal surgical resection followed by radiotherapy in combination with TMZ. In our study, we noted an increase in the median PFS among patients who received the standard treatment regimen compared with those who underwent surgical treatment alone. However, none of these differences was significant (P = 0.233), which could potentially be attributed to our study’s limited sample size. Additionally, we found a correlation between an increased number of cycles of adjuvant chemotherapy with TMZ and improved PFS and OS.
Our study revealed a substantial recurrence rate of 67.2% among patients diagnosed with Ep-GBM, indicating a high likelihood of recurrence in this subtype. These findings highlight the importance of understanding and addressing challenges associated with the treatment of recurrent Ep-GBM. However, there is limited literature on the treatment of this specific subtype in its recurrent state. Therefore, further research is required to identify more effective treatment options. Our study findings suggest that patients who underwent reoperation showed trends towards improved survival compared with patients who did not undergo reoperation. with a median survival of 24.5 months vs 5.2 months (P = 0.001). These results align with those of previous research, supporting the potential benefits of reoperation in managing recurrent GBM[16]. It is worth mentioning that among patients with recurrent Ep-GBM, five experienced relapse after their second surgery and subsequently underwent a third surgery. Notably, the average survival time for these patients was 67.2 months, ranging from 32.2 months to 89.0 months. These findings suggest that similar to conventional GBM cases, reoperation is equally relevant and applicable in the management of recurrent Ep-GBM, offering a potential avenue for improved outcomes and extended survival.
Re-irradiation has been shown to be a feasible and effective treatment option for recurrent gliomas, as supported by published evidence[17]. The study suggested that combining reoperation, chemotherapy, or re-irradiation as treatment modalities leads to a substantial improvement in survival compared to using individual treatments alone[18]. Our study focused on recurrent Ep-GBM and found that the combination of re-irradiation and reoperation resulted in a significant increase in patient survival. The median survival time was 28.6 months, compared to 9.2 months with reoperation alone. This difference was statistically significant (P = 0.007).
BRAF is a critical regulator of the MAPK signaling pathway and plays significant roles in cell differentiation, proliferation, migration, and pro-tumorigenic activity. Its importance has led to its recognition as a promising molecular target for precision medicine and development of new therapeutic approaches. Among BRAF mutations, V600E is most frequently observed in gliomas[19]. Reports indicate that approximately 50% of Ep-GBM cases exhibit BRAF-V600E mutations, whereas conventional glioblastomas rarely show BRAF-V600E mutations[20, 21]. In our investigation, we observed BRAF-V600E mutant protein expression in 56.1% of cases. Previous studies have shown that gliomas with BRAF-V600E mutation have better prognoses than those without this mutation[22, 23]. In our study, patients with the BRAF-V600E mutation had a median survival time of 31.2 months, slightly longer than Ep-GBM patients without the BRAF-V600E mutation (24.8 months). However, this difference was not significant in our analysis (P = 0.927).
Vemurafenib has been approved for treating malignant melanoma, papillary thyroid carcinoma, and lung cancer. Strong clinical responses have been demonstrated in these settings, effectively reducing tumor development and progression caused by the BRAF-V600E mutation[24, 25]. The clinical efficacy of vemurafenib in the treatment of Ep-GBM has been active investigation[26–29]. According to Nakagomi et al.[30], vemurafenib, a BRAF-V600E inhibitor, has shown remarkable efficacy in reducing tumor cell survival and suppressing the phosphorylation of crucial intracellular signaling proteins. In our trial, 6 patients were treated with vemurafenib. 2 patients received it after the initial surgery, and 4 patients received it after recurrence. 1 patient's prognosis was not assessed. In our study, the remaining patients exhibited either steady or partial remission. Research[31] has demonstrated that the combination of BRAF and MEK inhibitors effectively inhibits tumor growth by dual-targeted activation of the MAPK pathway. This finding is supported by several recent clinical studies that established combination therapy with MEK inhibitors as a recognized therapeutic strategy for treating Ep-GBM[32, 33]. In our study, 1 patient developed resistance to vemurafenib after one year of treatment. To address this issue, the patient underwent a third surgery and received simultaneous chemoradiotherapy (60 Gy/30 fractions, TMZ 75 mg/m2) with BRAF-MEK inhibitors. Consequently, the patient experienced an additional 8 months survival benefit.
Methylation status of the MGMT promoter is an important prognostic factor in GBM[34]. However, few studies have investigated the methylation status of the MGMT promoter in Ep-GBM. In our study, we found a MGMT promoter methylation positivity rate of 56.9%, whereas Wang et al. [7] reported a rate of 45.4% in their study. GBM patients with a methylated MGMT promoter experience therapeutic benefits from TMZ, whereas those without the promoter do not show such advantages[35]. In contrast, we did not observe a significant effect of MGMT promoter methylation on PFS or OS. Similar findings were reported by Sun et al. [15]. These results may be attributed to the limited sample sizes analyzed in both studies. Further large-scale case studies are necessary to elucidate the underlying reasons.