Abstract
Objectives
To determine survival and investigate associated prognostic factors in glioblastoma multiforme (GBM) patients receiving adjuvant therapy.
Materials and Methods
The study population comprised patients with isocitrate dehydrogenase wild-type GBM who were enrolled between 1 September 2022 and 1 March 2024. The primary endpoint was overall survival (OS), while the secondary endpoint was progression-free survival. Comparisons between groups were conducted using the log-rank test, and multivariate analyses were performed using Cox regression.
Results
A total of 67 patients were evaluated. The median OS of patients was 19.3 months [95% confidence interval (CI) 15.1 to not reached (NR)]. A total of 60 patients (89.1%) underwent adjuvant treatment. The median OS was 31.1 months (95% CI 19.3 to NR) for patients treated within the first four weeks, 15.7 months (95% CI 15.1 to NR) for those treated within four to six weeks, and 11.3 months (95% CI 9.8 to NR) for those treated after six weeks.
Conclusion
The observed survival rate in our study was comparable to that reported in clinical trials. However, the survival rate was significantly lower in patients who received treatment at a later stage. Therefore, further studies with larger patient populations are recommended to ensure that the guidelines more accurately reflect the timing of adjuvant therapy in GBM patients.
Introduction
Glioblastoma multiforme (GBM) represents the most prevalent primary central nervous system (CNS) tumor (1). In accordance with the 2021 World Health Organization (WHO) Classification of CNS tumors, GBM is characterised as isocitrate dehydrogenase (IDH)-wild-type (2, 3). The median survival time for this aggressive tumor, with a median age of onset of approximately 60 years, is currently 12 to 15 months, and the 5-year survival rate is 6% (4).
The current gold standard treatment for GBM, a tumor with an adverse prognosis, comprises maximal safe resection and subsequent adjuvant therapy. This consists of temozolomide (TMZ), concurrent chemoradiotherapy (CRT), and six months of maintenance TMZ (5). The Stupp protocol has been demonstrated to enhance overall survival (OS) in patients under 70 with favorable performance status. The treatment regimen entails the concurrent administration of 75 mg/m²/day TMZ in 2 Gy fractions, with a total dose of 60 Gy, followed by six cycles of TMZ monotherapy (6). The long-term results of the trial demonstrated that survival in the TMZ arm remained superior to radiotherapy (RT) alone at both two-year (27% vs. 11%) and five-year (10% vs. 2%) follow-up points (7). In patients of an advanced age and/or with a markedly poor performance status, a supportive care approach may be considered the most appropriate course of action (8).
A number of studies have been conducted in order to ascertain the optimal timing for the commencement of adjuvant treatment in patients with various types of cancer. In patients with non-small cell lung cancer who are to receive adjuvant treatment following a curative resection, commencing treatment after a period of six weeks has been demonstrated to result in a reduction in disease-free survival (9). A study of 24,843 patients who had undergone surgery for breast cancer revealed that those who received adjuvant therapy 91 days or more after surgery exhibited a diminished OS rate [hazard ratio (HR): 1.34, 95% confidence interval (CI): 1.15-1.57] (10).
Despite adjuvant treatment currently being the standard of care, there is no consensus regarding the optimal timing for initiating treatment. The objective of this study was to ascertain the OS of patients diagnosed with GBM who received adjuvant treatment at our center and to evaluate the relationship between treatment approach, clinical characteristics, and time of treatment initiation and survival.
Materials and Methods
The present study is a retrospective cohort study that encompasses patients diagnosed with GBM at our medical center between 1 September 2022 and 1 March 2024. Patients diagnosed with an International Classification of Diseases 10th Revision code C71 (malignant neoplasm of the brain), histologically confirmed (biopsy or resection) GBM IDH-wild-type, CNS WHO grade 4, aged 18 years or older, with no previous chemotherapy or cranial RT, and no active infection, were identified through medical records as meeting the requisite criteria. Patients who did not fulfill the requisite criteria were excluded from the study.
The demographic information of the patients, including diagnosis dates and treatment initiation dates, as well as details of the treatment methods employed (surgery, chemotherapy, RT), the time elapsed between diagnosis and treatment initiation, and survival data (survival time and date of death), were defined. Additionally, data on recurrence and other treatment processes were also determined. The time to diagnosis was defined as the initial pathology date at which the primary brain tumor was identified. The early treatment group was defined as comprising those patients who commenced treatment within the first four weeks of diagnosis, while the delayed treatment group was defined as comprising those patients who commenced treatment six weeks or more after diagnosis (Figure 1).
OS defined as the time elapsed between diagnosis and death or the date of the last visit-served as the primary endpoint in this analysis. The secondary endpoint, progression-free survival (PFS), was operationalized as the time elapsed between the commencement of treatment and the date of the initial observational assessment of relapse, or death/last visit, whichever occurred first.
The time elapsed between surgical intervention and the commencement of CRT was examined as both a continuous variable and a categorical one, based on three defined time intervals. The intervals were defined as follows: less than four weeks, four to six weeks, and greater than six weeks. This study was approved by the Scientific Research Evaluation and Ethics Committee of Etlik City Hospital (decision no.: AEŞH-BADEK-2024-758, date: 02.10.2024).
Statistical Analysis
In order to facilitate the analysis and presentation of the data, quantitative variables were expressed as means, with accompanying ranges. Similarly, categorical variables were described in terms of percentage frequency distributions. Kaplan-Meier survival curves were employed to estimate survival outcomes. Subsequently, intergroup comparisons were conducted utilising log-rank tests. A Cox regression analysis was employed to conduct multiple analyses. A two-tailed p-value of less than 0.05 was considered statistically significant. The statistical analyses were conducted using the BlueSky Statistics version 10.3.2 software.
Results
The mean age of the 67 patients included in the study was 60 years (range: 42-86 years). Upon analysis of the age distribution, it was observed that approximately half of the patients were under the age of 60. Of the total number of patients, 31 (46.2%) were male. Upon diagnosis, 61.2% of patients exhibited an Eastern Cooperative Oncology Group score of 0 to 1. Among the patients included in the study, 38 (56%) had pre-existing comorbidities. The most prevalent comorbidity was hypertension. A summary of the patient and tumor characteristics is presented in Table 1.
All patients included in the study underwent surgical intervention. A total resection was performed in 41 patients, representing 61.1% of the total number of patients included in the study. Over 90% of the patients were eligible for adjuvant treatment. Of the seven patients who were not eligible for adjuvant treatment, three were excluded due to age and performance status, two patients succumbed to postoperative complications, and two patients refused treatment. Of the total number of patients, 58 (86.5%) received and completed adjuvant. Two patients received only RT due to thrombocytopenia, which precluded the use of chemotherapy. The mean time to commencement of adjuvant treatment was 30 days (range 15-119 days). All patients received the standard doses of RT. During the follow-up period, 22 patients (32.8%) experienced recurrence. The estimated median PFS was 5.3 months (95% CI 3.6 to 12.6) (Figure 2a). During the follow-up period of 9.1 months, 21 patients succumbed to their disease. The estimated OS was 19.3 months (95% CI 15.1 to NR) (Figure 2b) (Table 2).
The Kaplan-Meier curves for PFS and OS were analysed according to the timing of adjuvant treatment initiation among patients. The median PFS was 7.0 months (95% CI 4.4 to NR) for 24 patients (35.8%) who commenced treatment within four weeks, 5.3 months (95% CI 3.5 to NR) for 21 patients (31.3%) who initiated treatment between four and six weeks, and 3.6 months (95% CI 2.8 to NR) for 13 patients (19.4%) who started treatment after six weeks. No statistically significant difference in PFS was observed between treatment groups (p=0.18) (Figure 3a).
The median OS was 31.1 months (95% CI 19.3 to NR) for patients whose treatment was initiated within the first four weeks, 15.7 months (95% CI 15.1 to NR) for patients whose treatment commenced between four and six weeks, and 11.3 months (95% CI 9.8 to NR) for patients whose treatment began after six weeks. The OS time between the groups was statistically significant (p=0.04) (Figure 3b).
The effects of demographic and therapeutic characteristics on PFS were analysed and performance status at diagnosis (p=0.04) and intraoperative resection (total/subtotal) status (p=0.01) were statistically significant in univariate analyses. The only significant effect in multivariate analyses was intraoperative resection (p=0.03) (Table 3).
Univariate and multivariate analyses of OS revealed that performance status (p=0.001), gender (p=0.03) and time of chemotherapy initiation (p=0.03) had a statistically significant effect in univariate analysis. In multivariate analysis, the only significant effect was chemotherapy initiation time (p=0.01) (Table 4). When evaluated as post hoc analysis, a statistically significant difference was seen in all 3 groups 4 weeks/4-6 weeks, 4 weeks/6 weeks later, 4-6 weeks/6 weeks later (p<0.05).
Discussion
Several factors contribute to the poor prognosis of GBM and its resistance to current therapies. The heterogeneity of GBM, the pro-tumorigenic role of the tumor microenvironment, the blood-brain barrier as a barrier to systemic treatment, and the low immunogenicity of GBM, which prevents a strong immunological response, are all factors that contribute to the poor prognosis of GBM and its resistance to current therapies (11). Furthermore, studies have demonstrated that patient characteristics (age, comorbidity, performance status), as well as surgical and adjuvant treatment-related factors (total resection, subtotal resection/biopsy), can influence OS (12-14). The tumor- and patient-related analyses, as well as the survival analyses, of our study, are in accordance with the findings of the existing literature on the subject.
The hypothesis that the growth rate of a tumor slows down with increasing tumor size may prove useful as a general rule for all tumors and may also assist in determining the optimal time to commence treatment for GBM (15). Given that radiosensitivity is inversely proportional to tumor growth rate, the commencement of RT at a later stage may result in a reduction in its efficacy (16). Nevertheless, an alternative perspective posits that hypoxia and edema in the vicinity of the surgical site in the immediate postoperative period may result in a reduction in radiosensitivity (17). In fact, the studies conducted support both of these perspectives.
A study conducted in 2007 investigated the efficacy of RT in the early postoperative period. The findings indicated that, contrary to the delay observed at the time of presentation to the RT department, the delay at the time of surgery was associated with a reduction in survival (17). It is important to acknowledge that this study was conducted prior to the establishment of TMZ concurrent RT as the standard treatment. However, a recent retrospective study involving a substantial patient cohort demonstrated that adjuvant treatment initiated within the initial 35 days following total resection was associated with enhanced survival outcomes (18). However, the same improvement was not observed in residual tumors in this study. In a further large patient cohort, the early implementation of the Stupp protocol in patients with high-grade glioma was associated with a notable reduction in survival rates (19). In a separate study, a minimum interval of six weeks between surgery and CRT was associated with superior OS and PFS in patients with GBM (20). Some studies have reached the conclusion that the timing of the initiation of adjuvant treatment has no prognostic significance (21, 22). The findings of our study indicate that the initiation of treatment within the first four weeks had a significant positive effect on OS.
While there is a paucity of evidence regarding the optimal timing of treatment initiation, existing studies have yielded conflicting results. Notably, only a handful of investigations have focused on O6-methylguanine (O6-MeG)-DNA methyltransferase (MGMT) promoter methylation, which is regarded as a potential predictor of TMZ efficacy. In a study comprising a limited number of patients, univariate regression analysis demonstrated that although MGMT methylation exhibited a borderline significant correlation with OS across the entire population (p=0.048), the initiation of RT within 24 days had a detrimental impact (23). In a separate investigation, MGMT was accessible in approximately half of the patients, and the period of adjuvant therapy exceeding six weeks was linked to diminished survival (24). It was not possible to analyse MGMT in the context of this study. Nevertheless, in the entire cohort of patients, the commencement of treatment after six weeks, irrespective of MGMT methylation status, was associated with a poorer prognosis.
In a 2016 systematic review and meta-analysis of 19 retrospective studies examining the relationship between RT treatment delay and OS in GBM patients, no statistically significant association was identified (HR: 0.98; 95% CI: 0.90-1.08; p=0.70) (25). It is important to note that the study also examined the current standard pretreatment time. The findings of our study indicate that early treatment initiation is a statistically significant predictor of OS, as demonstrated by both univariate and multivariate analyses.
Study Limitations
The study is limited by the absence of investigation into the role of promoter methylation in the pathology slides, the relatively brief follow-up period, and the lack of detail regarding the treatment options employed in the event of recurrence. Furthermore, the lack of information regarding the rationale for the prolonged adjuvant treatment process (e.g., infection or post-operative complications) represents a significant limitation of the study. Nevertheless, it is evident that this study, conducted in a recently established center and clinic, is of significant value and will inform future prospective studies.
Conclusion
A review of the literature and existing guidelines reveals a lack of consensus regarding the optimal timing for initiating adjuvant treatment in patients with GBM. The present study offers significant insights into the subject matter, given the characteristics of the patient population and the results obtained. Further prospective, multicenter studies with larger patient populations are required.
