Glioblastoma IDH-wildtype (GBM) is the most common primary malignant brain tumor in adults, carrying a median overall survival (OS) of 9 months [1]. Current standard-of-care consists of maximal safe resection followed by postoperative radiation therapy, chemotherapy, and potentially tumor treating fields [2, 3]. The median age at diagnosis is 65 years, and incidence increases with age, peaking between 70 and 74 years [1].

Reduced tolerance for aggressive therapy in elderly patients with GBM may influence treatment decisions [4, 5, 6, 7, 8]. The ANOCEF trial represents the only prospective randomized study comparing resection with biopsy in elderly GBM patients [9]. While OS did not differ between groups (9.37 months for resection vs. 8.96 months for biopsy), extent of resection (EOR) was associated with improved progression-free survival and quality of life. Most retrospective studies outlined in Supplemental Table 1 demonstrate that resection is associated with a significant OS benefit compared to biopsy in elderly GBM patients (median OS 6–15 months for resection, 3–8 months for biopsy). Additionally, higher baseline functional status, receipt of adjuvant radiation and temozolomide (TMZ), and O6-Methylguanine-DNA Methyltransferase (MGMT) methylation have been associated with greater OS. However, all retrospective studies are limited by selection bias; patients with higher baseline functional are more likely to undergo resection, whereas frailer patients are preferentially treated with biopsy and supportive care [10, 11].

Several gaps remain in the literature. First, the majority of studies have a liberal definition of “elderly,” meaning patients older than 65. There are significant increasing risks with age in elderly GBM patients, particularly in octogenarians [12, 13, 14, 15, 16, 17], and also tumor and non-tumor intrinsic factors which impact the aggressiveness of the disease [18, 19]. Among the studies that analyzed the oldest-old octogenarian population, all find that resection and adjuvant chemoradiation results in better survival outcomes in carefully selected patients [11, 13, 17]. However, the heterogeneity in adjuvant therapy regimen [13] and lack of tumor molecular data including isocitrate dehydrogenase (IDH) and MGMT status [11, 17] in these studies, which are now recognized as critical biomarkers, complicates interpretation. More studies need to explore outcomes in these particularly vulnerable populations.

In addition, functional outcomes following surgery in elderly GBM patients remain poorly characterized. Of the studies that have examined postoperative function, results are conflicting. Klingenschmid and colleagues reported that biopsy and resection patients had similarly good functional outcomes (median KPS 90) three to six months postoperatively [20]. In contrast, Fogg and others observed functional decline in 88% of patients three months after surgery (median biopsy KPS 50, median resection KPS 60) [13]. Whether such discrepancies reflect differences in patient selection, surgical technique, or institutional protocols remain unclear.

To address these gaps, we conducted a single-surgeon, single-center retrospective cohort study of elderly patients who underwent surgery for newly diagnosed GBM between 2016 and 2024. We hypothesized that resection would be associated with greater OS compared to biopsy in elderly patients, and that this benefit would be modulated by tumor molecular features and adjuvant therapy. We further aimed to determine whether this survival advantage persists in octogenarians. Finally, we aimed to characterize long-term survivors in our cohort to identify features associated with exceptional outcomes.

We present a single-surgeon, single-center comparison of resection versus biopsy for elderly patients with GBM, demonstrating that maximal safe resection is associated with improved OS across the entire cohort and among octogenarians. This association remained robust after adjusting for MGMT methylation, receipt of adjuvant therapy, and preoperative ASA score.

Our findings add to the growing body of evidence supporting that maximal safe surgical resection and adjuvant management of GBM in elderly patients improve survival outcomes [4, 5, 22, 28, 30]. Notably, our series represents one of the largest single-center cohorts of elderly GBM patients undergoing resection, with uniform surgical technique and postoperative management, thereby minimizing inter-surgeon variability and institutional bias. Prior studies have suggested a benefit of resection but were often limited by heterogeneity in surgical approaches and adjuvant protocols [4, 9, 11, 13, 24, 26, 27, 29] or incomplete molecular profiling, with many lacking MGMT or IDH data [5, 14, 11, 17, 22, 23, 26, 29]. By incorporating molecular markers and adjuvant treatment data into multivariate models within a uniform setting, our study confirms that the survival benefit of resection persists even after accounting for these variables.

To address selection bias, we reviewed patients with good preoperative functional status (ECOG 0–1). Within this subgroup, resection remained associated with improved OS on univariate analysis; however, after multivariate adjustment, the independent effect of resection was no longer statistically significant, whereas MGMT methylation status and receipt of adjuvant therapy remained strong predictors of outcome. Although this analysis should be interpreted cautiously given retrospective ECOG assignment and the small number of biopsy patients with good baseline functional status, it suggests that the observed survival advantage is not solely attributable to preferential selection of healthier patients for resection but rather reflects the combined benefit of resection followed by comprehensive adjuvant therapy in appropriately selected patients.

Stratified analyses of the overall cohort demonstrated a survival benefit of resection irrespective of MGMT methylation status. In contrast, within the octogenarian subgroup, a significant survival advantage was observed only in patients with MGMT-methylated tumors, suggesting that in particularly vulnerable populations, tumor biology may exert a greater influence on the therapeutic value of resection [19]. Although limited by sample size, this is, to our knowledge, the first study to examine the effect of EOR stratified by MGMT status in octogenarians, and it highlights the need for further investigations in larger cohorts.

We also found that the survival advantage associated with resection in the overall cohort was evident only when followed by adjuvant therapy. These findings align with prior reports suggesting that the benefit of surgical cytoreduction is maximized when integrated with comprehensive multimodal therapy. For example, Niare et al. reported a median OS of 17.5 months among octogenarians treated with resection followed by the Stupp protocol, compared with 9.5 months among all resected patients [11]. Our findings also contextualize the ANOCEF trial, which reported no OS difference between resection and biopsy in elderly patients [9]. In that study, patients enrolled before 2017 received radiotherapy alone, whereas those enrolled later received combined chemoradiotherapy, introducing temporal confounding that may have attenuated any survival advantage of resection – consistent with our observation that surgical benefit is most apparent when both radiation and TMZ are delivered.

A major contribution of this study is the assessment of post-operative functional trajectories. We report serial ECOG performance status at 3, 6, and 12 months. Our data challenge concerns that aggressive resection results in prolonged survival at the cost of debilitating functional decline. Among resection patients, the majority maintained functional independence, with ECOG 0–1 in 65.3% at 3 months, 69.4% at 6 months, and 70.0% at 1 year. Similar proportions were observed in octogenarians, indicating that advanced age alone does not preclude favorable functional outcomes. These findings contrast with those of Fogg et al. [13], who reported functional decline in 88% of octogenarians at 3 months, but are more consistent with Klingenschmid et al. [20], who reported preserved function at 3–6 months with median KPS of 90 in both groups. Our analysis of long-term survivors further supports functionally meaningful survival: eight of nine patients surviving beyond two years, including two octogenarians, maintained ECOG 1–2 at one year, underwent resection, completed full adjuvant therapy, and had excellent baseline functional status. Collectively, these data suggest that, in carefully selected elderly patients, resection can extend quality survival.

This study’s retrospective, single-center design limits generalizability. Although the single-surgeon approach reduces technical variability, it may not reflect outcomes across different surgical practices. The modest sample size, particularly among octogenarians, restricts statistical power for subgroup and interaction analyses. Selection bias remains possible, as patients with poorer preoperative health or functional status were more likely to undergo biopsy, and although we adjusted for ASA score, residual confounding cannot be excluded. Finally, the results can only be interpreted as associative and not causative.

Future studies with larger sample sizes can validate these findings across more heterogeneous populations. Integration of molecular and genomic profiling may further refine patient selection [28]. Prospective studies incorporating patient-reported outcomes and longitudinal functional trajectories will be essential to balance OS against quality-of-life considerations. Overall, our work supports that maximally safe resection ought to be considered as a component of a multi-modal treatment plan for GBM in elderly patients.