Evaluating treatment outcome of Glioblastoma with Stupp’s regimen: an experienced in single Institute

Introduction

According to the Global Cancer Observatory (GLOBOCAN) 2020 data, there are approximately 308,102 new cases of central nervous system tumors worldwide, ranking 20^th globally, with 251,329 deaths ranking 13^th in mortality. In Vietnam, there were approximately 3,102 new cases, ranking 15th, with over 2,600 deaths, ranking 11^th in mortality and accounting for 2.1% of cancer patient deaths (1). Glioblastoma (GBM) accounts for 15.6% of all brain tumors and approximately 45% of primary malignant brain tumors (2). Despite intensive multimodal treatment consisting of maximal safe resection followed by combined chemoradiotherapy (Stupp’s regimen), GBMs still have a high rate of recurrence and poor prognosis, with overall survival (OS) of 27.2%, 16%, 12.1% and 9.8% at 2, 3, 4, and 5 years, respectively (3). However, only around 44–50% of patients are able to receive the complete conventional treatment, and only one-fourth of those who start treatment are able to successfully finish the six cycles of adjuvant temozolomide (TMZ).

GBMs can have aberrant expression of different growth-control genes and their proteins, including impaired alpha thalassemia/mental retardation syndrome X-linked (ATRX) expression (ATRX⁻), p53 overexpression (p53⁺), and mutant IDH1 (H09) expression (IDH1⁺). Prior research has demonstrated a correlation between these pathological variables and survival (4-6). These pathological characteristics are necessary for all new glioma not only to classification but also prognostic.

We focused on completed irradiation group to analyze survival and some prognostic factors. Real-world evidence data are an increasingly important supplement to clinical and translational research. Our analyses of current real-world patients treated outside controlled clinical trials may provide valuable information in clinical and survival for proper powering in future clinical trials. We present this article in accordance with the STROBE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-103/rc).

Methods

Study design and patients

Patients diagnosed with histologically confirmed GBM by pathology and immunohistochemistry (IHC) according to the World Health Organization Central Nervous System (WHO CNS) 2016 classification, who received treatment with irradiation and TMZ at Vietnam National Cancer Hospital (VNCH) from January 2020 to September 2022, have been collected. Patients with insufficient medical data, exposure to hyperfractionated radiotherapy (RT), or incomplete 60-Gy treatment course were excluded. All patients who fully met criteria would be selected to this cross-sectional study.

Treatment

RT was performed in all patients within the study cohorts. RT planning was based on computed tomography (CT) simulation with thermomask, and contouring with fusion with postoperative magnetic resonance imaging (MRI). Both standards of care approaches in target volume definitions were employed in patients eligible for treatment: Radiation Therapy Oncology Group (RTOG) and European Organization for Research and Treatment of Cancer (EORTC) approach. RTOG contouring approach [RTOG 0525, 0825, 0913, Avastin in Glioblastoma (AVAglio) trial]: gross tumor volume (GTV) 2= MRI T1 (surgical cavity + enhanced post-contrast), GTV1 = MRI fluid-attenuated inversion recovery (signal enhancement area), clinical tumor volume (CTV) 46= GTV1 + 1–2 cm, adjusted according to anatomical barriers (ventricles, falx cerebri, tentorium cerebelli, skull), CTV 60= GTV2 + 1–2 cm, adjusted according to anatomical structures. EORTC single-phase contouring approach (EORTC 22981/22961, EORTC 26981/22981, AVAglio): GTV = MRI T1 (surgical cavity + enhanced post-contrast), CTV 60= GTV1 + 1–2 cm, adjusted according to anatomical barriers (ventricles, falx cerebri, tentorium cerebelli, skull), planning treatment volume (PTV) = CTV + 0.5 cm. RT was prepared employing planning system Monaco (Elekta systems, Stockholm, Sweden) and performed on linear accelerator Elekta such as VersaHD, Synergy and Infinity.

Concurrent chemoradiotherapy (CCRT) and adjuvant chemotherapy were prescribed according to the original Stupp protocol. TMZ (75 mg/m²) was administered on days 1 through 42 with concomitant RT (60 Gy). After 4 weeks, treatment follows by the administration of TMZ alone (150–200 mg/m²) on days 1–5 in six consecutive 4-week cycles or until the disease progression. The prophylaxis against Pneumocystis jirovecii pneumonia was at the discretion of the treating physician. The indication for dexamethasone was based on patients’ clinical symptoms such as headache, nausea, vomiting, and other symptoms postoperatively or during the RT course, with a dose of 4 to 16 mg per day (with or without 20% mannitol).

Outcome and assessments

Response was evaluated one month after RT and every three cycles of chemotherapy, using contrast MRI and clinical practice, according to Response Assessment in Neuro-Oncology (RANO) criteria for high-grade glioma (7). Treatment choices after progression or recurrent diseases are determined based on clinical status, size, location of tumor on MRI, previous treatment and multidisciplinary collaboration. These options may include a second surgery, reirradiation, and re-treatment with medications such as TMZ, nitrosoureas or bevacizumab (8).

The following data were collected: basic patients’ characteristics (age, gender, signs and symptoms, tumor location, number and size of tumors, pathology features: Ki-67, ATRX, p53, IDH1); time to RT, time of RT interruptions, dexamethasone in RT, RT technique, contour based, RT volume, OS, progressive-free survival (PFS), using SPSS software package (version 22).

Statistical analysis

SPSS software package (version 22) was used for statistical analysis. Time-to-event data were estimated by Kaplan-Meier method, and compared using log-rank test between groups. Univariable Cox regression analyses were used to determine the associated factors of PFS and OS. For all analyses, one-sided P value <0.05 was considered statistically significant.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by VNCH Review Board (No. 701/QĐ-BVK-2022). Patients’ informed consent was waived due to the retrospective nature of the study.

Results

A total of 64 GBM patients completed the CCRT phase in VNCH from 1/2020 to 9/2022. The median age was 50±14 years, 59.4% were older than 50 years, and there was a slightly higher number of male (male/female =5/3). Most patients had good general condition, with 81% of patients demonstrating a Karnofsky Performance Status score of 80 to 100 before radiation therapy. The patients usually complain of headache (75%), hemiplegia (23.4%), and other problems (seizure, dementia, aphasia, vomiting). Other characteristics are summarized in Table 1.

Fifty-nine/64 (92.2%) patients were started RT within 8 weeks from surgery. More than half of patients (67.2%) had RT interruptions (median 9±5 days) due to coronavirus disease 2019 (COVID-19), holidays, machine issues, etc. The utilization rate of volumetric-modulated arc therapy/intensity-modulated radiation therapy (VMAT/IMRT) techniques is equal to field-and-field (FIF) technique. More details about the patients’ treatment are summarized in Table 2.

About survival, median OS was 21.91 months, with a 2-year OS of 44.6%. Median PFS was 9.39 months, with a 2-year PFS of 16.7% (Figure 1).

Figure 1 Overall survival and progression-free survival (Kaplan-Meier survival analysis). (A) Progression-free survival. (B) Overall survival. CI, confidence interval.

Univariable analysis (Cox regression analysis) of prognostic factors for 2-year OS and PFS is summarized in Figure 2. Better OS was observed in female patients (P=0.02), gross tumor resection/subtotal tumor resection (GTR/STR) (P=0.008), time to start RT within 8 weeks postoperatively (P=0.03), no progression disease after CCRT (P=0.007), no dexamethasone required (P=0.04). About PFS, some factors, such as younger age ≤40 years (P=0.01), GTR/STR (P=0.03), and no progression disease after CCRT (P<0.001), were associated with significantly better survival.

Figure 2 Univariable analysis for overall survival and progression-free survival. (A) Univariable analysis for progression-free survival. (B) Univariable analysis for overall survival. CCRT, concurrent chemoradiotherapy; EORTC, European Organization for Research and Treatment of Cancer; FIF, field-in-field; GTR/STR, gross total resection/subtotal resection; GTV, gross tumor volume; PD, progressive disease; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group; VMAT/IMRT, volumetric-modulated arc therapy/intensity-modulated radiation therapy.

The pathology results revealed that the percentages of ATRX⁻, IDH⁺, and p53⁻ patients were 23.44%, 18.75%, and 23.44%, respectively. There was also a trend towards improved OS and PFS in the ATRX⁻, IDH⁺, and p53⁻ groups, although this was not reach statistical significance (Table 3).

Regarding the Ki-67 proliferation index, 51/64 patients (79.7%) was assessed by IHC techniques, and 100% was positive. Among them, 17 patients had Ki-67 ≤15% and exhibited a 2-year OS rate of 82.4%; 34 patients had Ki-67 >15%, with a 2-year OS rate of 48.5% (P=0.03). No significant difference in PFS was observed at the 15% Ki-67 cutoff level (Figure 3).

Figure 3 Ki-67 expression and survival (Kaplan-Meier survival analysis). (A) Ki-67 expression and PFS. (B) Ki-67 expression and OS. CI, confidence interval; PFS, progression-free survival, OS, overall survival.

Discussion

According to our study, the median OS was 21.91 months, and PFS was 9.39 months. The 2-year OS and PFS rates were 44.6% and 16.7%, respectively. Roger Stupp and colleagues’ study divided 573 patients into two groups: one group received CCRT and the other received RT alone post-operative. The results showed that the 2-year OS rate was 26.5% in the group undergoing standard protocol, compared to 10.4% in the RT-only group (9). The median OS in the two groups was 14.6 and 12.1 months, respectively (3,10). A study in the Czech Republic on 155 patients who received treatment with the Stupp protocol from January 2014 to December 2017 showed median PFS and OS of 6.7 and 16 months, respectively, with a 2-year OS rate of 30.7% (11). Compared to a previous group of patients, this study showed that the Stupp protocol increased OS by 2 months (16 months compared to 13.8 months). Our OS and PFS were higher than those reported in other studies because we selected patients who completed the full CCRT protocol (60 Gy) after surgery. Patients who were not suitable for CCRT or received hypofractionated RT were excluded from our study (12,13). The patients who didn’t completed the CCRT course showed a very dismal prognosis, which means the tumor was resistant to the treatment. Besides, in our clinical practice, patients who got the hypofractionated RT usually were elderly or poorly status people; all of these factors were predictor of decreased survival in GBM. In this context, we analyzed patients who completed the full CCRT protocol and evaluated other factors influencing OS and PFS.

The percentages 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 0.03, respectively). The findings of our study are consistent with previous researches, 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 resected (14). 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 patients (16).

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 either IDH1⁺, ATRX⁻, or p53⁻ GBMs showed better survival than patients with GBMs expressing counterpart protein. 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 the best OS and PFS (47.9 and 47.9 months), and the lowest OS and PFS group was the ATRX⁺/P53⁺/IDH1⁻ combination (17.8 and 14.5 months, respectively). According to Jani et al. [2015], a study on 95 patients with GBM treated with RT from 2005 to 2014 showed that 6.3% of patients had IDH1 mutation and 67.4% had unmethylated methylguanine-DNA methyltransferase (MGMT). The results indicated that OS for the IDH1⁺ and IDH1⁻ groups was 114 and 20.9 months, respectively (P=0.024). No difference in OS was observed concerning the MGMT status (6).

Regarding the Ki-67 proliferation index, in our study, 51/64 patients (79.7%) was assessed by IHC techniques, and 51/51 patients (100%) was positive. Among them, 17 patients with Ki-67 ≤15% had a 2-year OS rate of 82.4%, and 34 patients with Ki-67 >15% had a 2-year OS rate of 48.5% (P=0.03). The Ki-67 represents the percentage of cells that express Ki-67, and in GBM it is usually tied to the histological grade as a proliferative index. It has been revealed that the overexpression of Ki-67 is corelated with a poorer prognosis and PFS regardless of its cutoff value, and it could be a predictive marker even a criterion to stratify high-risk GBM. Armocida et al. studied 127 patients with IDH wildtype, revealing that tumor volumes greater than 45 cm³ had higher Ki-67 expression; multivariate analysis indicated that a Ki-67 index greater than 20% predicted reduced PFS (17). Dumke et al. confirmed Ki-67 labeling index ≤20% as an independent prognostic factor for prolonged PFS and OS (18). In 2023, Tini et al. also concluded that Ki-67/MIB-1-LI expression <15% significantly correlated with a longer OS (median survival 40 vs. 11 months), independent of other characteristics in IDH wildtype GBM. This study also revealed the patients with methylated MGMT Ki-67 <15% had longest OS (41 months) (19). However, unlike other authors, Wong et al. demonstrated Ki-67 <22% appears to predict poorer survival in GBM (5-year survival of 5% vs. 30%) (20). Other study did not establish a relationship between Ki-67 and OS in IDH wildtype patients suggesting that high Ki-67 expression should not be overinterpreted for prognosis in clinical practice (5). Although most studies concluded that Ki-67 can be important biomarker for proliferation and survival in GBM (17-19), its role as a prognostic factor is debated and the cutoff value was still unclear.

This analysis revealed that the percentages of ATRX⁻, IDH1⁺, and p53⁻ patients were 23.44%, 18.75%, and 23.44%, respectively. There was also a trend towards improved OS and PFS in the ATRX⁻, IDH1⁺, and p53⁻ groups, although this did not reach statistical significance, most likely due to the limited number of patients in our investigation. Additionally, due to insurance issues in Vietnam, there was a significantly lower 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 IDH1, ATRX, p53, Ki-67, and MGMT markers.

Our examination indicated that 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=0.03). However, there was no statistical difference in 2-year PFS between the two groups (P=0.41). Buszek et al. reported 45,942 GBM patients from 2004 to 2015, with the highest OS being 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), and the group starting RT from 6.1 to 8 weeks (14.4 months). The lowest OS was observed in the group starting RT within 4 weeks (13.9 months) (P<0.0001) (21). 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 group (22). Based on these findings, we recommend starting CCRT 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 RT 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, among others. 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 management of unscheduled treatment interruptions in RT. 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 tumors, and there is evidence that delay in starting therapy affects outcome. However, there is still no report of the effect of breaks in treatment on outcome, possibly due to the complexities of neural cell repair.

The proportion 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 RT 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 the EORTC guidelines (single-phase). There was no significant 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 outcomes (23). 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 (11,24). Currently, at VNCH, we establish RT volumes according to single-phase EORTC guidelines by fusing postoperative MRI scans with CT-simulation 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=0.26). Early disease progression after chemoradiotherapy (equivalent to not receiving TMZ 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<0.001).

Currently, the effectiveness of treatment options after disease progression or recurrence has not seen significant advancements (8). 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 TMZ (50 mg/m²) combined with Bevacizumab was the preferred regimen (45.5%, 20/44 patients); then daily TMZ (20.5%, 9/44 patients) and surgery (16%, 7/44 patients). Treatment must consider the preservation of neurological function and the patients’ ability to perform daily activities. According to Stupp et al., among patients with recurrence or progression, 23% underwent re-surgery (3), 72% of patients in the RT-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 OS (25,26).

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 technical limitations, we haven’t performed completed pathology and molecular examination, such as MGMT methylation, and IDH2, for all patients; therefore, their associations with OS could not be analyzed, which may impact our analysis from missing data. Thirdly, it is worth noting that all of our patients were administered a dosage of 60 Gy of radiation therapy, resulting in greater OS and PFS rates compared to earlier studies conducted on GBM.

However, our study provided a perspective in homogeneous and this remains an encouraging result for such a difficult and unfavorable prognosis as those with GBMs. Besides, some factors related to survival should be noticed in clinical practice, discussing about prognostic and therapeutics with patient and family.

Conclusions

Multidisciplinary collaboration, as well as improvements in diagnosis and customized treatment strategies, are critical in the treatment of GBM patients. In actual life, completing the entire Stupp’s program significantly improves GBM survival. Several characteristics, such as being female, younger age, extent of resection, Ki-67 levels >15%, duration from surgery to RT <8 weeks and absence progression disease following CCRT had improved survival.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-103/rc

Data Sharing Statement: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-103/dss

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-103/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-103/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Vietnam National Cancer Hospital Review Board (No. 701/QĐ-BVK-2022). Informed consent of patients was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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