According to our study, the overall survival (OS) was 24.33 ± 2.34 months, and the progression-free survival (PFS) was 13.21 ± 1.35 months. The 2-year OS and PFS rates were 44.6% and 17.6%, respectively. Roger Stupp and colleagues' study on 573 patients divided into two groups, one group received concurrent chemoradiotherapy (CRT) and the other received radiotherapy (RT) alone post-operative. The results showed that the 2-year OS was 26.5% in the group undergoing standard protocol, compared to 10.4% in the RT-only group9. The median OS in the two groups was 14.6 months and 12.1 months, respectively3,10. A study in the Czech Republic on 155 patients treated from January 2014 to December 2017 with the Stupp protocol showed median PFS and OS of 6.7 and 16 months, respectively, with a 2-year OS of 30.7%11. This study compared to a previous group of patients showed that the Stupp protocol increased OS by 2 months (16 months compared to 13.8 months). Our OS and PFS are higher than those of the patient groups in other studies because we selected patients who completed the full concurrent CRT protocol (60 Gy) after surgery. Patients who were not suitable for concurrent CRT or received hypofraction RT were excluded from our study12,13.
The pecentages of patients who underwent total resection, partial resection, and tumor biopsy were 43.75%, 31.25%, and 25%, respectively. Among them, 7 out of 64 patients (10.94%) were assessed by the surgeon as having a higher level of resection compared to MRI images. When comparing the extent of resection and survival, we observed a significant impact on 2-year OS, and 2-year PFS with longer survival in group with total resection/ partial resection versus tumor biopsy group (p = 0.008 and 0.033, respectively). The findings of our study are consistent with previous researchs, such as Nader Sanai's research on 500 newly diagnosed GBM patients who underwent surgery in San Francisco from 1997 to 2009, which showed a significant correlation between the extent of resection and OS (p < 0.0001); OS increased significantly when 78% of the tumor was resected, and even further when 95–100% was resected14. Thibault Smets and colleague’s study on immediate postoperative MRI (≤ 2 hours) and early postoperative MRI (within 24–48 hours) indicated that small nodular and streaky enhancement patterns were associated with early postoperative recurrence, reducing OS by 2.5 times (125 vs. 51 months) and PFS by 4 times (61 vs. 15 weeks)15. Additionally, areas of later recurrence often had higher relative cerebral blood volume (rCBV) compared to other regions. Similarly, Francisco Revilla-Pacheco's meta-analysis highlighted the association between GTR and OS with a rate of 1.25 (p < 0.01), supporting the standpoint that maximal tumor resection improves OS in GBM patients16.
Ajay Chaurasia et al reported 163 adult GBMs, 15.3% of enrolled GBMs demonstrated loss of ATRX expression (ATRX-), 10.4% expressed an aberrant IDH1 R132H protein (IDH1+), and 48.4% exhibited p53 overexpression (p53+)4. In the case of single protein expression, the patients with each IDH1+, or ATRX-, or p53- GBMs showed better survival than patients with counterparts protein expressed GBMs. In the case of double protein pairs, the patients with ATRX-/p53-, ATRX-/IDH1+, and IDH1+/p53- GBMs revealed better survival than the patients with GBMs with the remained pairs. The patients with ATRX-/IDH+/p53- (comprised only 2.5%) has best OS and PFS (47.9 and 47.9 months), and the lowest OS and PFS group was ATRX+/P53+/IDH1- combination (17.8 and 14.5 months, respectively). According to A. Jani et al. (2015), a study on 95 patients with GBM treated with radiotherapy from 2005 to 2014 showed that 6.3% of patients had IDH1 mutation and 67.4% had unmethylated MGMT. The results indicated that OS for the IDH + and IDH- groups was 114 and 20.9 months, respectively (p = 0.024). No difference in OS was observed concerning the MGMT status6. Regarding the Ki67 proliferation index, Daniele Armocida et al. studied 127 patients with IDH wildtype, revealing that tumor volumes greater than 45 cm³ had higher Ki67 expression. Multivariate analysis indicated that a Ki67 index greater than 20% predicted reduced PFS17. However, some other studies did not establish a relationship between Ki67 and OS in IDH wildtype patients5, suggesting that high Ki67 expression should not be overinterpreted for prognosis in clinical practice.
This analyse revealed the percentages of ATRX-, IDH+, and p53- patients were 23.44%, 18.75%, and 23.44%, respectively. Univariate analysis of these molecular markers and survival showed that a Ki67 proliferation index ≤ 15% was associated with improved 2-year OS (82.4% vs. 48.5%, p = 0.03). There was also a trend towards improved OS and PFS in the ATRX-, IDH+, and p53- groups, although this was not reach statistical significance, most likely due to the limited number of patients in our investigation. Additionally, due to insurance issues in Viet Nam, there was a significantly low number of patients who underwent testing for MGMT, preventing an analysis of survival based on MGMT status. In conclusion, it can be recommended that comprehensive molecular marker analysis on tumor tissue is essential for patient prognosis. All GBM patients should be analyzed for IDH, ATRX, p53, Ki67, and MGMT markers.
Our examination indicated the majority of patients (64.06%) began RT 4–8 weeks postoperative. The 2-year OS rates for the groups starting RT before and after 8 weeks were 47.3% and 20%, respectively (p = 0.02). However, there was no statistical difference in 2-year PFS between the two groups (p = 0.4). Buszek SM et al reported 45,942 GBM patients from 2004 to 2015, the highest OS was observed in the group starting RT from 4.1 to 6 months post-surgery (15.2 months), followed by the group starting RT after 8 weeks (14.6 months), the group starting RT 6.1 to 8 weeks (14.4 months), and the lowest OS in the group starting RT within 4 weeks (13.9 months)(p < 0.0001)18. Notably, in the group undergoing total tumor resection, delaying RT beyond 8 weeks reduced OS (16.9 months compared to 15.2 months). This reduction in OS can be attributed to tumor regrowth during the extended period before starting chemoradiotherapy, increasing the radiotherapy volume, which consequently reduced OS to a level similar to that of the partial resection group19. Based on these findings, we recommend starting CRT within 4–8 weeks postoperative. Collaboration between surgeons and radiotherapists is essential to evaluate patients postoperative and prepare an appropriate interdisciplinary treatment plan, includes procedures of patient transfer, reassessment, imaging consultation, pathology and IHC review, and radiotherapy planning.
Approximately two-thirds of patients in this study experienced treatment interruptions, with an interruption time per patient of 9 ± 5 days. Of these interruptions, 56% were attributed to holidays, nearly 19% were due to COVID-19 (timing of research from 2020 to 2022 is outbreak time of the COVID-19 pandemic), and the remaining interruptions were caused by machine breakdowns, patient non-compliance,...However, when analyzing the relationship between interruption duration and radiation therapy duration with survival, we observed a trend towards reduced 2-year OS and PFS with prolonged treatment time, though the analysis was not statistically significant. The Royal College of Radiologists recommended on management of unscheduled treatment interruptions in radiotherapy, rapidly progressing tumors are likely to have affected treatment outcomes if there are treatment interruptions, based on the principle of repopulation in radiobiology, even in cases where there is no direct evidence. GBMs are very fast-growing tumours, and there is evidence that delay in starting therapy affects outcome. However, there is still no report of breaks in treatment on outcome, possibly due to the complexities of neural cell repair.
The propotion of FIF and VMAT/IMRT technique were nearly equivalent. However, in clinical practice, patients with tumors near critical organs such as the brainstem, optic chiasm, and hippocampus were prioritized for dose-modulated techniques to reduce radiation exposure to these organs. Analysis of survival did not demonstrate a correlation between radiotherapy technique and OS or PFS. Furthermore, due to the short survival time, progression or local recurrence disease, most patients may have died before clinically manifesting any side effects from radiation therapy. The majority of patients (82.81%) were planned according to EORTC guidelines (single-phase). There was no significantly difference in 2-year OS and PFS between the two groups. Although no direct comparison studies between contouring methods, both approaches have been implemented in CENTRIC and RTOG 0525 studies with no differences in OS or PFS outcomes20. Additionally, some retrospective studies comparing patients treated according to RTOG and EORTC guidelines showed that larger PTV volumes did not reduce local or distant recurrence. Currently, at our hospital, we establish radiotherapy volumes according to single-phase EORTC guidelines by fusing postoperative MRI scans with CT-simmulation data using post-contrast T1 fusion.
The analysis of the association between the size of the tumor before surgery and the volume of the gross tumor for radiation therapy planning did not show any correlation with survival. The use of Dexamethasone during CRT treatment appears to be associated with OS (p = 0.04), but not with PFS (p = 0.258). Early disease progression after chemoradiotherapy (equivalent to not receiving Temolozomide treatment) was a prognostic factor closely associated to a 2-year OS rate of 24% compared to 49.7% (p = 0.007), as well as a 2-year PFS rate of 0% compared to 19.9% (p = 0.000).
Currently, the effectiveness of treatment options after disease progression or recurrence has not seen significant advancements8. The choice of approach is determined by the specific location, size, and timing of the recurrence, with surgery or stereotactic radiosurgery being prioritized for small recurrences. In VNCH, daily Temozolomide (50mg/m2) combined with Bevacizumab was the preferred regimen (45.5%, 20/44 patients); then daily Temozolomide (20.5%, 9/44 patients) and surgery (16%, 7/44 patients). Treatment must consider the preservation of neurological function and the patient's ability to perform daily activities. According to Stupp et al., among patients with recurrence or progression, 23% underwent re-surgery3, 72% of patients in the radiotherapy-only group and 58% in the chemoradiotherapy group received salvage chemotherapy (mainly TMZ). Bevacizumab showed effectiveness in increasing PFS but did not result in improved OS21,22.
This study has some limitations. Firstly, this was a retrospective study at a single center, small size may not represent for all GBMs. Secondly, due to technique, we haven’t perform completed pathology and molecular exammination, such as MGMT, IDH2,… for all patients, so that the relating of them with OS cann’t be analysed. Thirdly, it is worth noting that all of our patients were administered a dosage of 60Gy of radiation therapy, resulting in greater OS and PFS rates compared to earlier studies conducted on GBM. However, our study provided a perspective in homogenerous patient group and this remains an encouraging result for such a difficult and unfavorable prognosis as those with GBMs.