Browse the corpus

Early Initiation of Radiation Therapy Improves Survival in Elderly Patients With Glioblastoma. BACKGROUND AND OBJECTIVES: To study the impact of early initiation of radiation therapy (RT) in elderly patients with newly diagnosed glioblastoma. METHODS: A total of 56 elderly patients (aged 65 and older) diagnosed with isocitrate dehydrogenase (IDH)-wildtype glioblastoma were analyzed from a prospective registry from 2020 to 2024. Survival analysis was conducted to evaluate the impact of timing of RT initiation after surgical resection on survival outcomes. A specific cutoff point for RT initiation was evaluated using the log-rank test, with P -values adjustment for multiple comparisons using the false discovery rate approach. Kaplan-Meier curves were used to illustrate survival distributions. Associations of various risk factors with survival were initially examined through univariate Cox regression models, followed by multivariate analysis to assess the combined effects of these factors. The results were reported as hazard ratios with 95% CIs. RESULTS: Elderly patients with glioblastoma who underwent initiation of RT < 20 days from date of surgery demonstrated improved overall survival (OS) ( P = .0460) and progression-free survival (PFS) ( P = .0075) in our cohort. Multivariate analysis demonstrated that adjuvant temozolomide significantly affected both OS ( P = .0038) and PFS ( P = .0133). Conventionally fractionated RT consisting of 60 Gy in 30 fractions demonstrated significantly improved PFS ( P = .0164) in patients who underwent early initiation of RT (<20 days). By contrast, hypofractionated RT delivering 40 Gy in 15 fractions did not show significantly improved PFS ( P = .0509) in patients who underwent early initiation of RT (<20 days). CONCLUSION: Early initiation of RT in elderly patients with newly diagnosed glioblastoma improves both OS and progression-free survival. Timing of RT is particularly of significance in this patient population who may not be optimal candidates for systemic chemotherapy.

This retrospective cohort study was conducted using data extracted from a prospective patient registry. The study population consisted of 56 elderly patients, defined as those aged 65 years and older, with a new diagnosis of isocitrate dehydrogenase (IDH)-wildtype glioblastoma who underwent surgical resection followed by RT. Treatment modalities for these patients were categorized into 2 primary RT fractionation schemes: hypofractionated RT, 40 Gy in 15 fractions, or conventionally fractionated RT, 60 Gy in 30 fractions. The distribution of treatment types among the elderly patients revealed that 26 received conventionally fractionated RT, while 30 were treated with hypofractionated RT. Patient demographics, clinical characteristics, surgical details, RT initiation dates, and follow-up outcomes were obtained from the registry. The primary end points of the study were OS and progression-free survival (PFS). OS was defined as the time from surgery to death from any cause, and PFS was defined as the time from surgery to disease progression or death, whichever occurred first.

tiation dates, and follow-up outcomes were obtained from the registry. The primary end points of the study were OS and progression-free survival (PFS). OS was defined as the time from surgery to death from any cause, and PFS was defined as the time from surgery to disease progression or death, whichever occurred first. Survival analysis was performed to assess the impact of the timing of RT initiation on OS and PFS. Patients were categorized based on the number of days from surgery to the start of RT, with specific cutoff points evaluated to determine their impact on survival outcomes. Cutoff points for RT initiation were investigated and Kaplan-Meier survival curves generated to illustrate survival distributions. The log-rank test, adjusted for multiple comparisons using the Benjamini-Hochberg False Discovery Rate method, assessed significance in survival differences between groups, with a P-value threshold of less than 0.05. The relationship between overall survival and the timing of RT initiation, alongside other clinical variables, was assessed using univariate Cox regression analyses. The clinical variables considered included the extent of surgical resection, concurrent temozolomide, 06-methylguanine-DNA methyltransferase promoter methylation status, and adjuvant temozolomide, which were confirmed at baseline. Subsequently, a multivariate Cox regression analysis was conducted to evaluate the combined impact of these variables on survival outcomes. To assess the effect of several prognostic variables, including performance status, adjuvant temozolomide, preoperative tumor volume, and brainstem/basal ganglia involvement, on overall survival within early and late RT groups, a Cox regression analysis incorporating an interaction term was performed. The results are reported as hazard ratios (HRs) with accompanying 95% confidence intervals (CIs).

us, adjuvant temozolomide, preoperative tumor volume, and brainstem/basal ganglia involvement, on overall survival within early and late RT groups, a Cox regression analysis incorporating an interaction term was performed. The results are reported as hazard ratios (HRs) with accompanying 95% confidence intervals (CIs). 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 have been appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) as well as the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The study was approved by the institutional review board (EDR-103707). The IRB has agreed that individual consent is not needed.

Survival analysis was performed to assess the impact of the timing of RT initiation on OS and PFS. Patients were categorized based on the number of days from surgery to the start of RT, with specific cutoff points evaluated to determine their impact on survival outcomes. Cutoff points for RT initiation were investigated and Kaplan-Meier survival curves generated to illustrate survival distributions. The log-rank test, adjusted for multiple comparisons using the Benjamini-Hochberg False Discovery Rate method, assessed significance in survival differences between groups, with a P-value threshold of less than 0.05. The relationship between overall survival and the timing of RT initiation, alongside other clinical variables, was assessed using univariate Cox regression analyses. The clinical variables considered included the extent of surgical resection, concurrent temozolomide, 06-methylguanine-DNA methyltransferase promoter methylation status, and adjuvant temozolomide, which were confirmed at baseline. Subsequently, a multivariate Cox regression analysis was conducted to evaluate the combined impact of these variables on survival outcomes. To assess the effect of several prognostic variables, including performance status, adjuvant temozolomide, preoperative tumor volume, and brainstem/basal ganglia involvement, on overall survival within early and late RT groups, a Cox regression analysis incorporating an interaction term was performed. The results are reported as hazard ratios (HRs) with accompanying 95% confidence intervals (CIs).

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 have been appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) as well as the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. The study was approved by the institutional review board (EDR-103707). The IRB has agreed that individual consent is not needed.

Patient demographics are presented in Table 1. Patients who initiated RT < 20 days after surgery demonstrated significantly higher OS than patients who received RT ≥ 20 days (P = .0460). In addition, patients who initiated RT < 20 days after surgery had significantly improved progression-free survival than patients who underwent RT ≥ 20 days postoperatively (P = .0075). These results are illustrated in Figures 1 and 2, respectively. There was no observed disease progression in our study before the initiation of radiotherapy in the cohort of patients treated beyond 20 days from surgery. The impact of fractionation of RT (hypofractionation vs conventional fractionation) on PFS among patients who underwent early initiation of RT (<20 days) is shown in Figure 3 (P = .0509) and Figure 4 (P = .0164), respectively. Patients Characteristics ECOG, Eastern Cooperative Oncology Group; GTR, gross total resection; KPS, Karnofsky Performance Status; MGMT, 06-methylguanine-DNA methyltransferase; RT, radiation therapy; STR, subtotal resection. P-values are from Student t-test or χ2 test. Impact of early initiation of radiation therapy < 20 days on overall survival. OS, overall survival. Impact of early initiation of radiation therapy < 20 days on progression-free survival. PFS, progression-free survival. Progression-free survival of hypofractionated radiation therapy < 20 days vs ≥ 20 days after surgery. PFS, progression-free survival. Progression-free survival of conventionally fractionated radiation therapy < 20 days vs ≥ 20 days after surgery. PFS, progression-free survival.

Impact of early initiation of radiation therapy < 20 days on progression-free survival. PFS, progression-free survival. Progression-free survival of hypofractionated radiation therapy < 20 days vs ≥ 20 days after surgery. PFS, progression-free survival. Progression-free survival of conventionally fractionated radiation therapy < 20 days vs ≥ 20 days after surgery. PFS, progression-free survival. In the univariate Cox regression analysis, delayed initiation of RT was significantly associated with worse overall survival (HR = 2.04, 95% CI: 1.07-3.9, P = .0312) from Figure 5 and worse progression-free survival (HR = 2.83, 95% CI: 1.48-5.41, P = .0017) from Figure 6. However, in the multivariate model adjusting for other variables including performance status (Karnofsky Performance Status [KPS] score), adjuvant temozolomide, the association between RT timing and overall survival or progression-free survival was no longer statistically significant (P = .2962 and P = .0670, respectively, Tables 2 and 3). Univariate analysis of treatment characteristics with overall survival. HR, hazard ratio; MGMT, 06-methylguanine-DNA methyltransferase; OS, overall survival. Univariate analysis of treatment characteristics with progression-free survival. HR, hazard ratio; MGMT, 06-methylguanine-DNA methyltransferase; PFS, progression-free survival. Multivariate Analysis of Treatment Characteristics With Overall Survival GTR, gross total resection; HR, hazard ratio; KPS, Karnofsky Performance Status; MGMT, 06-methylguanine-DNA methyltransferase; RT, radiation therapy; STR, subtotal resection.

Univariate analysis of treatment characteristics with progression-free survival. HR, hazard ratio; MGMT, 06-methylguanine-DNA methyltransferase; PFS, progression-free survival. Multivariate Analysis of Treatment Characteristics With Overall Survival GTR, gross total resection; HR, hazard ratio; KPS, Karnofsky Performance Status; MGMT, 06-methylguanine-DNA methyltransferase; RT, radiation therapy; STR, subtotal resection. Multivariate Analysis of Treatment Characteristics With Progression-Free Survival GTR, gross total resection; HR, hazard ratio; KPS, Karnofsky Performance Status; MGMT, 06-methylguanine-DNA methyltransferase; RT, radiation therapy; STR, subtotal resection. We further included an interaction term between RT timing and performance status in the Cox regression model to evaluate potential effect modification. However, the interaction term was not statistically significant (P = .927, Supplemental Digital Content 1 [http://links.lww.com/NEU/F46]) nor were the main effects of RT timing or performance status. These results suggest that the association between RT initiation and overall survival does not differ significantly by performance status.

action term was not statistically significant (P = .927, Supplemental Digital Content 1 [http://links.lww.com/NEU/F46]) nor were the main effects of RT timing or performance status. These results suggest that the association between RT initiation and overall survival does not differ significantly by performance status. In addition, univariate analysis demonstrated that both concurrent temozolomide and adjuvant temozolomide were significantly associated with improved overall survival (P = .0012 and P = .0001, Figure 5). Multivariate analysis confirmed that adjuvant temozolomide significantly affected overall survival (P = .0127, Table 2). Similarly, in both the univariate analysis and multivariate analysis for PFS, the adjuvant temozolomide was significantly associated with the PFS (P = .0127 and P = .0133, respectively, Figure 6 and Table 3). The results of Cox regression model indicated that the adjuvant temozolomide, preoperative tumor volume, and brainstem or basal ganglia involvement did not significantly affect overall survival across the early or late RT groups (P = .1533, P = .4368, and P = .9163, respectively, Supplemental Digital Content 2 [http://links.lww.com/NEU/F47], Supplemental Digital Content 3 [http://links.lww.com/NEU/F48], and Supplemental Digital Content 4 [http://links.lww.com/NEU/F49]).

t significantly affect overall survival across the early or late RT groups (P = .1533, P = .4368, and P = .9163, respectively, Supplemental Digital Content 2 [http://links.lww.com/NEU/F47], Supplemental Digital Content 3 [http://links.lww.com/NEU/F48], and Supplemental Digital Content 4 [http://links.lww.com/NEU/F49]). A subgroup analysis has been performed to check the effect of timing of RT in different groups. It showed that there are significant differences of overall survival between the early and late RT group in the high preoperative midline shift, high postoperative midline shift, low preoperative edema, bilateral involvement (no) groups, and tumor volume (Supplemental Digital Content 5 [http://links.lww.com/NEU/F50], Supplemental Digital Content 6 [http://links.lww.com/NEU/F51], Supplemental Digital Content 7 [http://links.lww.com/NEU/F52], Supplemental Digital Content 8 [http://links.lww.com/NEU/F53], Supplemental Digital Content 9 [http://links.lww.com/NEU/F54], Supplemental Digital Content 10 [http://links.lww.com/NEU/F55], and Supplemental Digital Content 11 [http://links.lww.com/NEU/F56]).

Elderly patients with newly diagnosed glioblastoma present a unique challenge for management due to their functional deficits, multiple medical comorbidities, and vulnerability to treatment-related toxicity.10 Optimizing treatment outcomes in this patient population entails maximizing the therapeutic benefit of RT. There is a paucity of data regarding outcomes of elderly patients with newly diagnosed glioblastoma and the impact of timing to RT from surgery. The impact of RT timing on glioblastoma outcomes has demonstrated varying results in the literature.11,12 The bulk of the current data demonstrates a survival detriment with delaying RT postsurgery.7,13-16 These findings have molded the current National Comprehensive Cancer Network17 recommendation that an RT initiation within 4 to 8 weeks after resection is associated with better overall survival than an RT delay of >8 weeks for patients with newly diagnosed glioblastoma. The optimal timing of RT from surgery before this 8-week cutoff is unknown, particularly in elderly patients with glioblastoma. Adeberg et al18 investigated favorable glioblastoma patients and demonstrated initiating RT sooner than 24 days after surgery has a negative impact on progression and survival. This is contrary to our findings demonstrating initiation of RT ≤ 20 days from date of surgery demonstrated improved OS. This discrepancy could be due to the authors investigating a favorable patient cohort with a median KPS of 90 who were optimal candidates for systemic therapy as opposed to our elderly patient cohort with a median KPS of 70.

indings demonstrating initiation of RT ≤ 20 days from date of surgery demonstrated improved OS. This discrepancy could be due to the authors investigating a favorable patient cohort with a median KPS of 90 who were optimal candidates for systemic therapy as opposed to our elderly patient cohort with a median KPS of 70. Elderly patients with poorer performance status with newly diagnosed glioblastoma are often times suboptimal candidates for adjuvant temozolomide after RT.19 Our elderly patient cohort had only 26 patients (46%) receiving adjuvant chemotherapy, underscoring the impact of early initiation of RT in a patient population who are not uniformly receiving systemic therapy. Furthermore, our previous work demonstrated that high or low performance status in elderly patients with glioblastoma multiforme (GBM) did not affect patient outcomes in this population regardless of RT fractionation.20 This study emphasizes the need to tailor adjuvant therapy on a case-by-case basis to maximize patient outcomes. Our work underscores the survival benefits of initiating treatment with chemotherapy in addition to RT in elderly patients with GBM, demonstrated by Perry et al.21

population regardless of RT fractionation.20 This study emphasizes the need to tailor adjuvant therapy on a case-by-case basis to maximize patient outcomes. Our work underscores the survival benefits of initiating treatment with chemotherapy in addition to RT in elderly patients with GBM, demonstrated by Perry et al.21 Previous literature has demonstrated that aggressive management with surgical resection should be considered in elderly patients with glioblastoma, even those with relatively poor performance status.22 Perioperative complications in elderly patients and surgically acquired neurological deficits could affect patients' inpatient rehabilitation progress and recover.23 Our results highlight that potential delays to initiation of RT could affect survival outcomes in elderly patients with glioblastoma. Furthermore, our results demonstrate that these improved survival outcomes are observed after adjustment for multiple prognostic variables.

patient rehabilitation progress and recover.23 Our results highlight that potential delays to initiation of RT could affect survival outcomes in elderly patients with glioblastoma. Furthermore, our results demonstrate that these improved survival outcomes are observed after adjustment for multiple prognostic variables. Our multivariate analysis demonstrates that the impact of early RT in elderly patients with GBM is not independent of other clinical factors. The lack of significant main or interaction effects suggests that the observed difference in univariate analysis is confounded by other clinical variables, including performance status and adjuvant therapy. Elderly patients with GBM who are poor performers are particularly affected by the logistics of daily RT which both conventionally and hypofractionated RT regimens require.24 We postulate that these bedridden and dependent elderly GBM patients have functional limitations which potentially delayed their initiation to RT. We summarized the experiences of our practice regarding timing of RT from surgery in elderly patients diagnosed with GBM. Our outcomes are prone to bias, particularly regarding our patient population treatment experiences and the retrospective nature of this study. Regardless, our treatment decision making and management approach is reflective of challenges encountered nationwide by practitioners and is highly relevant to neurosurgery and neuro-oncology.

Our multivariate analysis demonstrates that the impact of early RT in elderly patients with GBM is not independent of other clinical factors. The lack of significant main or interaction effects suggests that the observed difference in univariate analysis is confounded by other clinical variables, including performance status and adjuvant therapy. Elderly patients with GBM who are poor performers are particularly affected by the logistics of daily RT which both conventionally and hypofractionated RT regimens require.24 We postulate that these bedridden and dependent elderly GBM patients have functional limitations which potentially delayed their initiation to RT. We summarized the experiences of our practice regarding timing of RT from surgery in elderly patients diagnosed with GBM. Our outcomes are prone to bias, particularly regarding our patient population treatment experiences and the retrospective nature of this study. Regardless, our treatment decision making and management approach is reflective of challenges encountered nationwide by practitioners and is highly relevant to neurosurgery and neuro-oncology.

Early initiation of RT in elderly patients with newly diagnosed glioblastoma improves both overall survival and progression-free survival. The significant positive association between early initiation of RT and survival outcomes was retained after accounting for potential confounding factors. Timing of RT is particularly of significance in this patient population who may not be optimal candidates for systemic chemotherapy. Our as-yet-unpublished experience of survival outcomes across glioblastoma in all age groups will shed further insight on the impact of timing of RT from surgery. A prospective randomized trial designed to evaluate the impact of timing of RT or concurrent chemoradiation is paramount to optimize outcomes in this vulnerable patient population.