Repeat resection for recurrent glioblastoma – Does timing matter?

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Obada T. Alhalabi, Kirill Mironov, Khurshed Nabiev, Johanna Krämer, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8490591/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Feb, 2026 Read the published version in Journal of Neuro-Oncology → Version 1 posted 12 You are reading this latest preprint version Abstract Background The optimal timing of repeat surgical resection in patients with recurrent IDH-wildtype glioblastoma (rGB) remains unclear. We aimed to characterize temporal patterns between radiological suspicion of recurrence and repeat resection and to evaluate the impact of early versus delayed surgery on the extent of resection (EOR), functional outcomes, adjuvant therapy, and survival. Methods We retrospectively analyzed a consecutive cohort of 150 patients who underwent resection for histopathologically confirmed rGB between 2015 and 2023 at a single tertiary care center. All patients had available pre- and early postoperative MRI and underwent surgery under intraoperative MRI guidance. Assessment of contrast-enhancing preoperative and residual tumor volumes (RTV) was performed using semi-automated segmentation. Based on the mean time between suspicion of recurrence and repeat resection (54 days), patients were stratified into early (≤ 54 days) and late (> 54 days) surgery. EOR was classified according to RANO Resect criteria and a 0.175-ml RTV threshold. Functional outcomes, postoperative treatment, as well as progression-free survival (PFS), and overall survival (OS) after repeat resection were compared between groups. Results Median time from suspicion of recurrence to repeat resection was 18 days, with 75% of patients undergoing reoperation within 6 weeks. Early (n = 120) and late (n = 30) surgery groups showed comparable baseline demographics, performance status, tumor eloquence, and preoperative neurological deficits. Preoperative tumor volumes were significantly smaller in the early surgery group (12.7 vs. 25.9 ml, p = 0.002). Late surgery was associated with a trend toward higher RTV and lower rates of gross total resection, though without statistical significance. Rates of transient and permanent postoperative neurological deficits were low (15% and 2%) and did not differ between groups. Adjuvant treatment patterns differed, with early surgery patients more frequently receiving CCNU-based chemotherapy, while late surgery patients more often received no further treatment. Median OS (14.3 vs. 12.4 months) and PFS (4 months in both groups) after repeat resection were not significantly different between early and late surgery groups. Conclusion Most repeat resections for rGB are performed shortly after radiological suspicion of recurrence. While delayed surgery is associated with larger tumor volumes and a trend toward less favorable EOR and adjuvant treatment options, timing of surgery alone was not independently associated with functional outcomes or survival. These findings support individualized decision-making for repeat resection based on clinical and radiological factors rather than timing alone. Recurrent glioblastoma repeat resection volumetric analysis pseudo-progression timing of surgery Figures Figure 1 Introduction Glioblastoma (GB) is an aggressive systemic brain disease characterized by therapy-resistance and poor prognosis [ 1 , 2 ]. Indeed, the current median overall survival (OS) of patients with GB, isocitrate dehydrogenase (IDH) wildtype is around 15 months [ 3 , 4 ]. Despite multimodal therapy, tumor recurrence is almost inevitable, with no consensus on the standard-of-care at relapse [ 5 ]. Many trials involving systemic therapy for recurrent GB (rGB) have failed in the past [ 6 , 7 ]. At the same time, several studies have shown the clinical benefit of repeat resection for selected patients dependent on tumor location and functional status [ 8 – 10 ]. The importance of maximizing the extent of resection (EOR) during repeat resection has been well established [ 11 – 14 ]. The median survival after surgery for rGB is reported to be at 12 to 18 months [ 15 – 17 ]. This is achieved under a reasonable rate of non-resolving post-operative neurological deterioration of about 8% in previous cohorts [ 9 , 14 , 18 – 21 ]. Reflecting the challenges in the assessment of treatment response, up to 40% of GB patients receiving chemoradiotherapy develop increased contrast enhancement (CE) on magnetic resonance imaging (MRI) during treatment that subsequently stabilizes or even spontaneously regresses [ 22 , 23 ]. This pseudo-progression occurs at 3 to 6 months after initial therapy [ 24 , 25 ] and can be associated with clinical deterioration [ 26 ]. It is unknown how long such imaging changes can be tolerated before therapy for recurrence should be initiated and once initiated, how treatment response should be assessed before repeat resection is triggered in selected patients. In newly diagnosed glioblastoma, previous studies reported no adverse sequelae in patients who underwent surgery within one month of tumor suspicion [ 27 , 28 ]. Therapeutic decision-making at recurrence remains highly heterogeneous. Some patients undergo upfront repeat resection, whereas others are managed with a watch-and-wait strategy or receive salvage systemic treatment or radiotherapy. In the latter group, treatment responses are variable, with some patients showing no benefit and experiencing early progression, while others achieve initial disease control followed by delayed progression. Consequently, the optimal timing of repeat resection for recurrent glioblastoma (rGB) remains uncertain. In particular, it is unclear whether a watch-and-wait strategy allows tumors to progress to a size or location that limits resectability, increases surgical risk, or adversely affects neurological outcomes and survival. Therefore, this study aimed to evaluate whether delayed repeat resection is associated with a higher risk of postoperative deficits, or differences in oncological outcomes compared with earlier repeat resection at GB recurrence. Methods Study population This study analyzed a consecutive cohort of patients with repeat resection for local recurrence of a previously resected IDH-wildtype glioblastoma (as per WHO 2021 classification [ 29 ]) treated between 2015 and 2023 at the Department of Neurosurgery, University Hospital Heidelberg that was retrospectively identified from our institutional database. Only patients with histopathologically diagnosed GB recurrence were included, while histopathologically confirmed radiation-induced necroses were excluded. Inclusion required the availability of preoperative MRI (3 Tesla; Siemens Magnetom Verio™, Prisma™, or Skyra™) and early postoperative MRI (epMRI) acquired within 48 hours after surgery using comparable scanner specifications (Siemens, 3 Tesla). Radiological evaluation of tumor recurrence followed the RANO (Response Assessment in Neuro-Oncology) criteria [ 13 ]. Eligibility for repeat resection at our center required sufficient performance status, surgically accessible tumor location, and multidisciplinary consensus that repeat resection was clinically appropriate. All patients underwent tumor resection with intraoperative MRI (1.5T Siemens Espree). Tumor volumetry Volumetric analysis of CE tumor volumes on preoperative and postoperative post-contrast T1-weighted MR was performed by semi-automated segmentation using the Brainlab™ software SmartBrush version 4.5 (Brainlab, Germany). The RANO Resect criteria were utilized to classify patients into RANO classes 1 to 3 [ 13 ] or the 0.175 ml threshold introduced by Stummer et al. [ 30 ]. Tumors with anatomical localization within motor, sensory, language and visual cortical and subcortical areas as described by Chang et al[ 31 ], were defined as “eloquent”, in addition to deep-seated lesions (thalamic, basal ganglia). Study endpoints Patients were followed until death or loss to follow-up (censored on the day of last follow-up), with survival after repeat resection defined as the interval from the date of suspicion of recurrence to death from any cause or censorship. Progression-free survival 2 (PFS-2) was defined as the interval between repeat resection and the next radiological progression. ‘Transient’ postoperative neurological deficits were defined as deficits resolving within 30 days, which otherwise are termed ‘permanent’. Statistical analysis Statistical analyses were performed using GraphPad PRISM (Version 10, GraphPad Software, Inc., La Jolla, USA). Continuous variables were reported as means ± standard deviation (SD) and/or median and interquartile range (IQR). Categorial variables were presented as numbers and percentages and compared using Chi-Square and Fisher’s exact test. Ethics Approval The Ethics Committee at the University of Heidelberg approved this retrospective analysis under S-455/2023 which has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments and for which patient consent was not required. Results Time-course patterns of recurrence and subsequent repeat resection This cohort of 150 GB patients with radiological suspicion of tumor recurrence experienced a heterogeneous management that, in this cohort, always led to repeat resection. While upfront repeat resection was performed in just over half of cases (80 patients, 53%), salvage non-surgical therapy, including chemotherapy, immune therapy and/or radiotherapy, was recommended by the multidisciplinary tumor board (TB) in 44 patients (29%). A watch-and-wait strategy was pursued in 20 patients (13%) when pseudo-progression could not be ruled out. In a minority of cases, patient preference led to deferral of the otherwise recommended repeat resection (6 patients, 4%; Table 1 ). Table 1 Time course until repeat resection at suspicion of recurrence of GB. a Because patients received combination therapies, the subtotal exceeds 44. b Suspicion of radiation necrosis. Fate of patients with suspected tumor recurrence n = 150 (%) Decision for upfront repeat resection 80 (53) Deferred Resection: Combination of systemic/radiotherapy CCNU/VP-16 = Lomustine/Etoposide VXM01 plus avelumab Parvovirus Temozolomide Bevacizumab Irradiation Other 44 (29) a 19 8 7 4 4 5 3 Deferred Resection: Watch-and-wait b 20 (13) Deferred Resection: Patient preference 6 (4) All patients ultimately underwent repeat resection, with the interval between radiological suspicion of tumor recurrence and surgery varying widely, ranging from 3 to 799 days (≈ 26.6 months), with a median of 18 days and a mean of 54 days (SD = 80.4). Analysis of the cumulative interval distribution (Fig. 1 A) revealed that 50% of repeat surgeries occurred within 18 days, and 75% occurred within 42 days (6 weeks) of suspicion of recurrence. For stratification purposes of what is regarded as an ‘early’ or ‘late’ surgery at suspicion of recurrence, we utilized the mean interval of 54 days as the threshold to distinguish early (≤ 54 days, n = 120) from late (> 54 days, n = 30) repeat resection. Overall, the mean interval between initial resection and repeat resection was 430 (SD = 365) days. Comparison of clinical characteristics between early and late repeat resection patients The early and late surgery groups demonstrated comparable baseline demographics. Age distribution was similar between early (mean 59.2 ± 9.73 years) and late (mean 55.4 ± 12.2 years) groups (p = 0.123, Welch’s test, Fig. 1 B). Sex distribution showed a male predominance in both groups (early: 65% male; late: 53% male), with no statistically significant difference (p = 0.237, Chi-squared test). Tumor localization patterns were largely similar, with temporal location being most common in both early (44%) and late (33%) groups, followed by frontal location (28% and 30%, respectively). However, a notable exception was observed in insular tumors, which were significantly overrepresented in the late surgery group (0% vs 10%, p = 0.0074, Chi-Squared test). Tumor lateralization (right vs left) did not differ significantly between groups (p = 0.288, Chi-squared test). Karnofsky Performance Status (KPS) as a surrogate for preoperative functional status showed a non-significant higher score in the early group (median KPS 90) compared to the late group (median KPS 80, p = 0.085, Mann-Whitney test). The frequency of focal neurological deficits (FNDs) before repeat resection was similar (early: 59%; late: 60%; p = 0.9338, Chi-square test). Moreover, tumor eloquence was comparable between groups (early: 45%; late: 47%; p = 0.8697, Chi-square test) and consequently the application of intraoperative neuromonitoring (IONM) and awake craniotomy (early: 9%; late: 13%; p = 0.759, Chi-square test). Notably, preoperative CE tumor volumes were significantly lower in the early group (mean 12.7 ± 14.9 ml) compared with the late group (mean 25.86 ± 19.8 ml; p = 0.0016, Welch’s t-test, Fig. 1 C). Differences in extent of resection and functional outcomes between early and late repeat resection patients Interestingly, a subtle difference in post-operative RTV was noticed between the early and the late surgery groups (mean early group = 0.53 ± 1.50 vs late group = 1.58 ± 2.93), without reaching statistical significance (p = 0.066, Welch’s t-test, Table 2 ). Because a T1-CE RTV mean of > 1ml would have an implication for the RANO resect classification, we classified patients according to RANO resect criteria (RANO 1 and 2 vs RANO 3) based on RTV accordingly, revealing a non-significant overrepresentation of RANO 3 resections in the late surgery group (27% vs 73% RANO 1 and 2) compared to the early group (13% vs 87% RANO 1 and 2, p = 0.0541, Chi-square test). When stratifying by gross total resection (GTR) versus subtotal resection (STR) using the 0.175 ml threshold set by Stummer et al. [ 30 ], the late group also demonstrated a non-significantly lower proportion of GTR (RTV < 0.175 ml, 57% vs 73% in the early group, p = 0.093, Chi-square test), suggesting that delayed recurrences may not have achieved the desired EOR. Regarding functional outcomes, post-operative KPS at discharge was consistent across both groups (median KPS 80 for both; p = 0.228, Mann-Whitney test). Corroborating this, we examined the rate of transient and permanent post-operative neurological deterioration and found non-significant differences in rates of transient deficits between the early and late groups (17% vs 7% p = 0.249, Chi-square test) and permanent deficits (1.7% vs 3%, p = 0.491, Chi-square test), indicating that the timing of repeat resection did not substantially affect the risk of neurosurgical morbidity. The overall rate of post-operative transient and permanent deterioration in this cohort was 15% and 2%, respectively. Comparison of post-surgery therapies and survival outcomes between early and late repeat resection patients The MGMT promoter methylation status showed similar distribution between early and late surgery groups: Approximately half the patients had non-methylated MGMT status in both groups (early: 51%; late: 57%), with methylated status present in approximately 30% of each group (p = 0.9118, Chi-square test). After repeat resection, adjuvant treatment patterns revealed several significant differences between groups. CCNU/VP-16 combination therapy was significantly more common in the early surgery group (53% vs 43%, p = 0.0224, Chi-square test), probably due to such options regarded as redundant in patients of the late group previously exposed to this regimen. Accordingly, patients in the late surgery group were significantly more likely to receive no adjuvant treatment following reoperation (33% vs 16%, p = 0.0299). Postoperative radiotherapy was administered in 26 patients (17%), including 19 patients in the early group (16%) and 7 patients in the late group (23%), with no significant difference between groups (p = 0.332, Chi-square test). Other treatment modalities, including temozolomide and bevacizumab, showed no significant differences between groups. Survival analysis revealed no significant difference in overall survival from suspicion of recurrence to death or censorship between early (12.4) and late groups (14.3 months, p = 0.218, Logrank (Mantel-Cox) test, Fig. 1 F, patients censored = 10). Analysis of PFS-2 similarly showed no significant difference between groups, with a median PFS-2 of 4 months in both groups (p = 0.372, Logrank (Mantel-Cox) test, Fig. 1 F). Altogether, these data indicate that EOR and adjuvant treatment strategies might vary depending on the timepoint of surgery but did not significantly impact overall survival or progression-free survival after repeat resection. Discussion While there is increasing evidence supporting the significance of repeat resection in the multimodal treatment of rGB, the optimal timing for surgery remains unclear. In this cohort, tumors resected at later time points approximately two months after radiological suspicion of recurrence were significantly larger at the preoperative stage than tumors resected at earlier time-points. Despite this, only subtle, non-significant differences in the EOR were observed between both groups, with a trend toward higher RTVs and hence lower rates of GTR in the late surgery group. However, these differences did not translate into measurable differences in overall or progression-free survival after repeat resection. Importantly, a longer interval between radiological suspicion of recurrence and repeat resection was not associated with an increased risk of neither transient nor permanent postoperative neurological deterioration. Beyond previous studies showing that early recurrence and hence a short time-span between primary and repeat resection in GB is associated with poor prognosis [ 32 ], there is yet no understanding of how differences in patient management upon suspicion of tumor recurrence can influence or are influenced by surgical decision-making. For example, it is conceivable that while localization of non-eloquent brain regions showed no difference between the early and late repeat resection cohort, a notable exception was observed in insular tumors, which were significantly overrepresented in the late group (10% vs 0%). This reflects surgery-reluctant decision-making when anatomically challenging regions are involved to avoid the eventuality of neurosurgical morbidity, with eloquent location known to be associated with reduced survival in rGB [ 33 , 34 ]. These findings highlight the considerable heterogeneity and uncertainty that characterize clinical decision-making in patients with suspected recurrent glioblastoma. While upfront repeat resection was pursued in just over half of cases, a substantial proportion of patients were initially managed with non-surgical treatment or close radiological follow-up, which also reflects the challenge of distinguishing true tumor recurrence from treatment-related changes [ 35 , 36 ]. This intermediate clinical state—where surgery is deferred to allow for assessment of response to systemic therapy or to monitor disease evolution—represents a quite occasional but rather poorly defined scenario in routine practice. Like studies on primary GB, differences in tumor volume between early and late repeat resection groups demonstrate volumetric tumor growth during extended observation intervals [ 27 , 28 ]. The diverse distribution of the “time-to-surgery” intervals indicates that while most patients underwent early repeat resection, a distinct subset experienced prolonged disease control before requiring repeat surgical intervention [ 33 , 37 ]. But what defines a “delayed” surgery in the context of recurrent GB? Given the highly skewed distribution of the interval between radiological suspicion of recurrence and repeat resection, the mean interval of 54 days was not intended to represent an optimal or biologically meaningful cut-off. Rather, it was used as a pragmatic threshold to distinguish patients undergoing repeat resection within a relatively short interval from those experiencing clearly prolonged decision pathways, often involving salvage therapy, surveillance, or deferred surgery. Future studies using time-to-surgery as a continuous variable or employing time-dependent modeling will be required to further refine the relationship between surgical timing and outcome. In our study, patients with rGB conferred a median survival after repeat resection of 12 months in the early group and 14 months in the late group without significant differences, possibly owing to an overall low sample number. This is consistent with survival outcomes reported in previous trials focusing on GB patients with 1st repeat resection, which range at around one year [ 9 , 11 ]. In addition, PFS is known to correlate with response to treatment and in-turn to correlate with survival [ 38 ]. Indeed, there were no differences pertaining to PFS-2 between early and late repeat resection patients in this study. A potential advantage of ‘early’ repeat resection lies in the opportunity to obtain tumor tissue for molecularly-guided treatment [ 15 , 39 – 44 ], enabling personalized therapeutic approaches [ 45 , 46 ], like mTOR-targeted therapy [ 47 , 48 ]. Such strategies are more likely to be implemented at an earlier disease stage, when patients are less heavily pretreated and therefore more amenable to therapy. This concept is supported by the observed differences in post-resection adjuvant therapy patterns between groups in our study. Notably, patients undergoing early repeat resection more frequently received chemotherapy (CCNU/VP-16) compared with those in the late group. This may reflect a greater availability of effective systemic treatment options in earlier disease stages, whereas similar regimens may be regarded as redundant or less synergistic in patients who have already been exposed to different lines of therapy. In line with this interpretation, patients in the late surgery group were significantly more likely to receive no adjuvant treatment following reoperation, suggesting a narrowing of therapeutic options and potentially diminished treatment tolerance at later time points. Together, these findings underscore the potential role of early surgical intervention not only in effective cytoreduction but also as a facilitator of subsequent, more active adjuvant treatment strategies. An additional advantage of early repeat resection is increased diagnostic certainty, since tissue sampling usually allows reliable exclusion of radiation necrosis. At present, no imaging modality can fully replace histological confirmation, and advanced techniques such as PET imaging were not routinely used in our cohort [ 49 ]. Even though we selected patients with confirmed histopathological diagnosis of rGB, advances in artificial intelligence enabling pixel-level analysis and the integration of multi-sequence and multi-modality data show considerable promise for distinguishing treatment-related effects from recurrent tumor and may render the research question at hand redundant in the future [ 50 ], which would help improve patient stratification for individualizing decision-making. The overall rate of transient and permanent postoperative neurological deficits in our cohort was 15% and 2% respectively, with no significant difference observed between the early and late surgery groups. This is lower than what was reported in the literature for similar cohorts (surgical complication rates 8% to 30%) [ 9 , 51 , 52 ] and challenges the notion that patients with recurrent glioblastoma are at a higher risk of surgical and neurological complications [ 53 ]. This study has several limitations, especially given the retrospective study design. This study does not address whether salvage therapy prior to a later resection affects tumor growth to off-set a potential benefit of an otherwise early surgery. We also acknowledge that this approach results in a smaller and more heterogeneous delayed-surgery subgroup and may limit statistical power; however, it reflects the inherent heterogeneity of recurrent glioblastoma management and allows clinically interpretable group comparisons aligned with routine practice. However, this study was conceived to examine the effect of multi-disciplinary decision-making on the longitudinal neurosurgical management of patients with recurrent glioblastoma rather than to explore differences between different therapies. Also, different patterns of recurrence were not taken into consideration, as this might have influenced the rationale of surgery to prolong survival or alleviate symptoms through cytoreduction [ 54 ]. This study also does not examine the effect of these interventions on the quality of life or the cognitive performance of affected patients, especially since higher disease burden and cognitive impairment are known to reduce patient survival in glioblastoma [ 55 , 56 ]. Nevertheless, these findings suggest that while deferred surgery may risk continued tumor growth, a carefully selected watch-and-wait or pre-surgical salvage therapy does not compromise functional safety or oncological outcomes in patients undergoing repeat resection for recurrent glioblastoma. Conclusion Tumor resection of recurrent glioblastoma beyond two months after radiological suspicion of recurrence was associated with only subtle, non-significant differences in the EOR compared to resection early time point, without a statistically significant difference in progression-free and overall survival after repeat resection. Importantly, delaying surgery was not associated with an increased risk of postoperative neurological deterioration. These findings suggest that delaying repeat surgery for selected patients could be justified, especially if pseudoprogression cannot be ruled out or systemic salvage therapy has not been assessed for efficacy in individual patients. Declarations FUNDING: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. CONFLICTS OF INTEREST: The authors have no further relevant financial or non-financial interests to disclose. AUTHOR CONTRIBUTION: Study concept and design: CJ, OTH. Data collection and analysis: OTH, KM, KN, JK, NG, HO, SJ, CJ. Data interpretation: OTH, CJ. Writing the manuscript: OTH, CJ. Reviewing and editing: CJ, OTH, AU, SMK. Supervision: CJ, all authors approved the final version of the submitted manuscript. DATA AVAILABILITY: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. ETHICS APPROVAL : The committee of ethical practice at the University of Heidelberg approved the protocol of this retrospective analysis under S-455/2023 which has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments and for which patient consent was not required. 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10:55:40","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":209787,"visible":true,"origin":"","legend":"","description":"","filename":"a16456be54424cf5b7cdef6fcc8ccdc41structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8490591/v1/85b4262648ff2c6404aefde2.xml"},{"id":99793110,"identity":"441e19a6-cf62-49c7-859d-c9810230d875","added_by":"auto","created_at":"2026-01-08 13:31:02","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":222362,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8490591/v1/6c68aed0e5b5c3474b0ef082.html"},{"id":99603078,"identity":"c2934585-b925-4d61-bd8f-d79b16c843cf","added_by":"auto","created_at":"2026-01-06 10:55:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1957633,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime to repeat resection in patients with recurrent glioblastoma and comparison of clinical, radiological, and outcome parameters between early and late repeat resection groups\u003c/strong\u003e. A: Distribution of time from recurrence to repeat resection for the entire cohort (n = 150) demonstrates marked variability, with a mean interval of 54 days. B: Age at repeat resection was comparable between patients undergoing early (n = 120) and late (n = 30) repeat resection, with no statistically significant difference observed (ns, Welch’s test). C: Preoperative contrast-enhancing tumor volume on T1-weighted MRI differed between early and late repeat resection groups (p= 0.0016, Welch’s test). D: New postoperative neurological deficits after repeat resection were infrequent and did not differ significantly between early and late groups, including transient deficits (p= 0.2492, Chi-Square test) and permanent deficits (p = 0.4906, Fisher’s exact test). E: The extent of resection assessed on early postoperative MRI showed no statistically significant difference between early and late repeat resection when categorized according to RANO criteria (p= 0.0541, Chi-Square test) or when stratified by residual contrast-enhancing tumor volume using a cutoff of 0.175 ml (p= 0.0925, Chi-Square test). F: Overall survival after suspicion of recurrence did not differ significantly between early (median 12.4 months) and late (median 14.3 months) repeat resection groups (log-rank p= 0.218, Logrank (Mantel-Cox) test, censored patients= 10: Early group: 7, late 3). G: Progression-free survival after repeat resection was similar between early and late groups (median 4 months in both), with no significant difference observed (log-rank p= 0.3735, Logrank (Mantel-Cox) test)).\u003c/p\u003e","description":"","filename":"TimingFigure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8490591/v1/2ab8562ec3428e1e6a5366a0.jpg"},{"id":103765885,"identity":"3c59b2ec-84ec-4665-b44e-c60b5875cbe7","added_by":"auto","created_at":"2026-03-02 16:10:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2777513,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8490591/v1/f0e07654-455d-457b-91cf-e73334e3821b.pdf"},{"id":99603076,"identity":"c645ab0a-17fc-4161-a272-d882c4c9553d","added_by":"auto","created_at":"2026-01-06 10:55:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18515,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8490591/v1/e193c1d99eab14063ae5725f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Repeat resection for recurrent glioblastoma – Does timing matter?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlioblastoma (GB) is an aggressive systemic brain disease characterized by therapy-resistance and poor prognosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Indeed, the current median overall survival (OS) of patients with GB, isocitrate dehydrogenase (IDH) wildtype is around 15 months [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Despite multimodal therapy, tumor recurrence is almost inevitable, with no consensus on the standard-of-care at relapse [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Many trials involving systemic therapy for recurrent GB (rGB) have failed in the past [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. At the same time, several studies have shown the clinical benefit of repeat resection for selected patients dependent on tumor location and functional status [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe importance of maximizing the extent of resection (EOR) during repeat resection has been well established [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The median survival after surgery for rGB is reported to be at 12 to 18 months [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This is achieved under a reasonable rate of non-resolving post-operative neurological deterioration of about 8% in previous cohorts [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eReflecting the challenges in the assessment of treatment response, up to 40% of GB patients receiving chemoradiotherapy develop increased contrast enhancement (CE) on magnetic resonance imaging (MRI) during treatment that subsequently stabilizes or even spontaneously regresses [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. This pseudo-progression occurs at 3 to 6 months after initial therapy [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and can be associated with clinical deterioration [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. It is unknown how long such imaging changes can be tolerated before therapy for recurrence should be initiated and once initiated, how treatment response should be assessed before repeat resection is triggered in selected patients. In newly diagnosed glioblastoma, previous studies reported no adverse sequelae in patients who underwent surgery within one month of tumor suspicion [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherapeutic decision-making at recurrence remains highly heterogeneous. Some patients undergo upfront repeat resection, whereas others are managed with a watch-and-wait strategy or receive salvage systemic treatment or radiotherapy. In the latter group, treatment responses are variable, with some patients showing no benefit and experiencing early progression, while others achieve initial disease control followed by delayed progression. Consequently, the optimal timing of repeat resection for recurrent glioblastoma (rGB) remains uncertain.\u003c/p\u003e \u003cp\u003eIn particular, it is unclear whether a watch-and-wait strategy allows tumors to progress to a size or location that limits resectability, increases surgical risk, or adversely affects neurological outcomes and survival. Therefore, this study aimed to evaluate whether delayed repeat resection is associated with a higher risk of postoperative deficits, or differences in oncological outcomes compared with earlier repeat resection at GB recurrence.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis study analyzed a consecutive cohort of patients with repeat resection for local recurrence of a previously resected IDH-wildtype glioblastoma (as per WHO 2021 classification [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]) treated between 2015 and 2023 at the Department of Neurosurgery, University Hospital Heidelberg that was retrospectively identified from our institutional database. Only patients with histopathologically diagnosed GB recurrence were included, while histopathologically confirmed radiation-induced necroses were excluded. Inclusion required the availability of preoperative MRI (3 Tesla; Siemens Magnetom Verio\u0026trade;, Prisma\u0026trade;, or Skyra\u0026trade;) and early postoperative MRI (epMRI) acquired within 48 hours after surgery using comparable scanner specifications (Siemens, 3 Tesla). Radiological evaluation of tumor recurrence followed the RANO (Response Assessment in Neuro-Oncology) criteria [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Eligibility for repeat resection at our center required sufficient performance status, surgically accessible tumor location, and multidisciplinary consensus that repeat resection was clinically appropriate. All patients underwent tumor resection with intraoperative MRI (1.5T Siemens Espree).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTumor volumetry\u003c/h3\u003e\n\u003cp\u003eVolumetric analysis of CE tumor volumes on preoperative and postoperative post-contrast T1-weighted MR was performed by semi-automated segmentation using the Brainlab\u0026trade; software SmartBrush version 4.5 (Brainlab, Germany). The RANO Resect criteria were utilized to classify patients into RANO classes 1 to 3 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] or the 0.175 ml threshold introduced by Stummer et al. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Tumors with anatomical localization within motor, sensory, language and visual cortical and subcortical areas as described by Chang et al[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], were defined as \u0026ldquo;eloquent\u0026rdquo;, in addition to deep-seated lesions (thalamic, basal ganglia).\u003c/p\u003e\n\u003ch3\u003eStudy endpoints\u003c/h3\u003e\n\u003cp\u003ePatients were followed until death or loss to follow-up (censored on the day of last follow-up), with survival after repeat resection defined as the interval from the date of suspicion of recurrence to death from any cause or censorship. Progression-free survival 2 (PFS-2) was defined as the interval between repeat resection and the next radiological progression. \u0026lsquo;Transient\u0026rsquo; postoperative neurological deficits were defined as deficits resolving within 30 days, which otherwise are termed \u0026lsquo;permanent\u0026rsquo;.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using GraphPad PRISM (Version 10, GraphPad Software, Inc., La Jolla, USA). Continuous variables were reported as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and/or median and interquartile range (IQR). Categorial variables were presented as numbers and percentages and compared using Chi-Square and Fisher\u0026rsquo;s exact test.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics Approval\u003c/h3\u003e\n\u003cp\u003e The Ethics Committee at the University of Heidelberg approved this retrospective analysis under S-455/2023 which has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments and for which patient consent was not required.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eTime-course patterns of recurrence and subsequent repeat resection\u003c/h2\u003e \u003cp\u003eThis cohort of 150 GB patients with radiological suspicion of tumor recurrence experienced a heterogeneous management that, in this cohort, always led to repeat resection. While upfront repeat resection was performed in just over half of cases (80 patients, 53%), salvage non-surgical therapy, including chemotherapy, immune therapy and/or radiotherapy, was recommended by the multidisciplinary tumor board (TB) in 44 patients (29%). A watch-and-wait strategy was pursued in 20 patients (13%) when pseudo-progression could not be ruled out. In a minority of cases, patient preference led to deferral of the otherwise recommended repeat resection (6 patients, 4%; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eTime course until repeat resection at suspicion of recurrence of GB.\u003c/b\u003e \u003csup\u003ea\u003c/sup\u003eBecause patients received combination therapies, the subtotal exceeds 44. \u003csup\u003eb\u003c/sup\u003eSuspicion of radiation necrosis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFate of patients with suspected tumor recurrence\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;150 (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecision for upfront repeat resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (53)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeferred Resection: Combination of systemic/radiotherapy\u003c/p\u003e \u003cp\u003eCCNU/VP-16\u0026thinsp;=\u0026thinsp;Lomustine/Etoposide\u003c/p\u003e \u003cp\u003eVXM01 plus avelumab\u003c/p\u003e \u003cp\u003eParvovirus\u003c/p\u003e \u003cp\u003eTemozolomide\u003c/p\u003e \u003cp\u003eBevacizumab\u003c/p\u003e \u003cp\u003eIrradiation\u003c/p\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (29)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e19\u003c/p\u003e \u003cp\u003e8\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeferred Resection: Watch-and-wait \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeferred Resection: Patient preference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAll patients ultimately underwent repeat resection, with the interval between radiological suspicion of tumor recurrence and surgery varying widely, ranging from 3 to 799 days (\u0026asymp;\u0026thinsp;26.6 months), with a median of 18 days and a mean of 54 days (SD\u0026thinsp;=\u0026thinsp;80.4). Analysis of the cumulative interval distribution (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA) revealed that 50% of repeat surgeries occurred within 18 days, and 75% occurred within 42 days (6 weeks) of suspicion of recurrence. For stratification purposes of what is regarded as an \u0026lsquo;early\u0026rsquo; or \u0026lsquo;late\u0026rsquo; surgery at suspicion of recurrence, we utilized the mean interval of 54 days as the threshold to distinguish early (\u0026le;\u0026thinsp;54 days, n\u0026thinsp;=\u0026thinsp;120) from late (\u0026gt;\u0026thinsp;54 days, n\u0026thinsp;=\u0026thinsp;30) repeat resection. Overall, the mean interval between initial resection and repeat resection was 430 (SD\u0026thinsp;=\u0026thinsp;365) days.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eComparison of clinical characteristics between early and late repeat resection patients\u003c/h3\u003e\n\u003cp\u003eThe early and late surgery groups demonstrated comparable baseline demographics. Age distribution was similar between early (mean 59.2\u0026thinsp;\u0026plusmn;\u0026thinsp;9.73 years) and late (mean 55.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.2 years) groups (p\u0026thinsp;=\u0026thinsp;0.123, Welch\u0026rsquo;s test, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Sex distribution showed a male predominance in both groups (early: 65% male; late: 53% male), with no statistically significant difference (p\u0026thinsp;=\u0026thinsp;0.237, Chi-squared test). Tumor localization patterns were largely similar, with temporal location being most common in both early (44%) and late (33%) groups, followed by frontal location (28% and 30%, respectively). However, a notable exception was observed in insular tumors, which were significantly overrepresented in the late surgery group (0% vs 10%, p\u0026thinsp;=\u0026thinsp;0.0074, Chi-Squared test). Tumor lateralization (right vs left) did not differ significantly between groups (p\u0026thinsp;=\u0026thinsp;0.288, Chi-squared test). Karnofsky Performance Status (KPS) as a surrogate for preoperative functional status showed a non-significant higher score in the early group (median KPS 90) compared to the late group (median KPS 80, p\u0026thinsp;=\u0026thinsp;0.085, Mann-Whitney test). The frequency of focal neurological deficits (FNDs) before repeat resection was similar (early: 59%; late: 60%; p\u0026thinsp;=\u0026thinsp;0.9338, Chi-square test). Moreover, tumor eloquence was comparable between groups (early: 45%; late: 47%; p\u0026thinsp;=\u0026thinsp;0.8697, Chi-square test) and consequently the application of intraoperative neuromonitoring (IONM) and awake craniotomy (early: 9%; late: 13%; p\u0026thinsp;=\u0026thinsp;0.759, Chi-square test). Notably, preoperative CE tumor volumes were significantly lower in the early group (mean 12.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.9 ml) compared with the late group (mean 25.86\u0026thinsp;\u0026plusmn;\u0026thinsp;19.8 ml; p\u0026thinsp;=\u0026thinsp;0.0016, Welch\u0026rsquo;s t-test, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eDifferences in extent of resection and functional outcomes between early and late repeat resection patients\u003c/h2\u003e \u003cp\u003eInterestingly, a subtle difference in post-operative RTV was noticed between the early and the late surgery groups (mean early group\u0026thinsp;=\u0026thinsp;0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50 vs late group\u0026thinsp;=\u0026thinsp;1.58\u0026thinsp;\u0026plusmn;\u0026thinsp;2.93), without reaching statistical significance (p\u0026thinsp;=\u0026thinsp;0.066, Welch\u0026rsquo;s t-test, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Because a T1-CE RTV mean of \u0026gt;\u0026thinsp;1ml would have an implication for the RANO resect classification, we classified patients according to RANO resect criteria (RANO 1 and 2 vs RANO 3) based on RTV accordingly, revealing a non-significant overrepresentation of RANO 3 resections in the late surgery group (27% vs 73% RANO 1 and 2) compared to the early group (13% vs 87% RANO 1 and 2, p\u0026thinsp;=\u0026thinsp;0.0541, Chi-square test). When stratifying by gross total resection (GTR) versus subtotal resection (STR) using the 0.175 ml threshold set by Stummer et al. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], the late group also demonstrated a non-significantly lower proportion of GTR (RTV\u0026thinsp;\u0026lt;\u0026thinsp;0.175 ml, 57% vs 73% in the early group, p\u0026thinsp;=\u0026thinsp;0.093, Chi-square test), suggesting that delayed recurrences may not have achieved the desired EOR. Regarding functional outcomes, post-operative KPS at discharge was consistent across both groups (median KPS 80 for both; p\u0026thinsp;=\u0026thinsp;0.228, Mann-Whitney test). Corroborating this, we examined the rate of transient and permanent post-operative neurological deterioration and found non-significant differences in rates of transient deficits between the early and late groups (17% vs 7% p\u0026thinsp;=\u0026thinsp;0.249, Chi-square test) and permanent deficits (1.7% vs 3%, p\u0026thinsp;=\u0026thinsp;0.491, Chi-square test), indicating that the timing of repeat resection did not substantially affect the risk of neurosurgical morbidity. The overall rate of post-operative transient and permanent deterioration in this cohort was 15% and 2%, respectively.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch2\u003eComparison of post-surgery therapies and survival outcomes between early and late repeat resection patients\u003c/h2\u003e\n\u003cp\u003eThe MGMT promoter methylation status showed similar distribution between early and late surgery groups: Approximately half the patients had non-methylated MGMT status in both groups (early: 51%; late: 57%), with methylated status present in approximately 30% of each group (p\u0026thinsp;=\u0026thinsp;0.9118, Chi-square test). After repeat resection, adjuvant treatment patterns revealed several significant differences between groups. CCNU/VP-16 combination therapy was significantly more common in the early surgery group (53% vs 43%, p\u0026thinsp;=\u0026thinsp;0.0224, Chi-square test), probably due to such options regarded as redundant in patients of the late group previously exposed to this regimen. Accordingly, patients in the late surgery group were significantly more likely to receive no adjuvant treatment following reoperation (33% vs 16%, p\u0026thinsp;=\u0026thinsp;0.0299). Postoperative radiotherapy was administered in 26 patients (17%), including 19 patients in the early group (16%) and 7 patients in the late group (23%), with no significant difference between groups (p\u0026thinsp;=\u0026thinsp;0.332, Chi-square test). Other treatment modalities, including temozolomide and bevacizumab, showed no significant differences between groups. Survival analysis revealed no significant difference in overall survival from suspicion of recurrence to death or censorship between early (12.4) and late groups (14.3 months, p\u0026thinsp;=\u0026thinsp;0.218, Logrank (Mantel-Cox) test, Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eF, patients censored\u0026thinsp;=\u0026thinsp;10). Analysis of PFS-2 similarly showed no significant difference between groups, with a median PFS-2 of 4 months in both groups (p\u0026thinsp;=\u0026thinsp;0.372, Logrank (Mantel-Cox) test, Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eF). Altogether, these data indicate that EOR and adjuvant treatment strategies might vary depending on the timepoint of surgery but did not significantly impact overall survival or progression-free survival after repeat resection.\u003c/p\u003e\n"},{"header":"Discussion","content":"\u003cp\u003eWhile there is increasing evidence supporting the significance of repeat resection in the multimodal treatment of rGB, the optimal timing for surgery remains unclear. In this cohort, tumors resected at later time points approximately two months after radiological suspicion of recurrence were significantly larger at the preoperative stage than tumors resected at earlier time-points. Despite this, only subtle, non-significant differences in the EOR were observed between both groups, with a trend toward higher RTVs and hence lower rates of GTR in the late surgery group. However, these differences did not translate into measurable differences in overall or progression-free survival after repeat resection. Importantly, a longer interval between radiological suspicion of recurrence and repeat resection was not associated with an increased risk of neither transient nor permanent postoperative neurological deterioration.\u003c/p\u003e \u003cp\u003eBeyond previous studies showing that early recurrence and hence a short time-span between primary and repeat resection in GB is associated with poor prognosis [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], there is yet no understanding of how differences in patient management upon suspicion of tumor recurrence can influence or are influenced by surgical decision-making. For example, it is conceivable that while localization of non-eloquent brain regions showed no difference between the early and late repeat resection cohort, a notable exception was observed in insular tumors, which were significantly overrepresented in the late group (10% vs 0%). This reflects surgery-reluctant decision-making when anatomically challenging regions are involved to avoid the eventuality of neurosurgical morbidity, with eloquent location known to be associated with reduced survival in rGB [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThese findings highlight the considerable heterogeneity and uncertainty that characterize clinical decision-making in patients with suspected recurrent glioblastoma. While upfront repeat resection was pursued in just over half of cases, a substantial proportion of patients were initially managed with non-surgical treatment or close radiological follow-up, which also reflects the challenge of distinguishing true tumor recurrence from treatment-related changes [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. This intermediate clinical state\u0026mdash;where surgery is deferred to allow for assessment of response to systemic therapy or to monitor disease evolution\u0026mdash;represents a quite occasional but rather poorly defined scenario in routine practice.\u003c/p\u003e \u003cp\u003eLike studies on primary GB, differences in tumor volume between early and late repeat resection groups demonstrate volumetric tumor growth during extended observation intervals [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The diverse distribution of the \u0026ldquo;time-to-surgery\u0026rdquo; intervals indicates that while most patients underwent early repeat resection, a distinct subset experienced prolonged disease control before requiring repeat surgical intervention [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBut what defines a \u0026ldquo;delayed\u0026rdquo; surgery in the context of recurrent GB? Given the highly skewed distribution of the interval between radiological suspicion of recurrence and repeat resection, the mean interval of 54 days was not intended to represent an optimal or biologically meaningful cut-off. Rather, it was used as a pragmatic threshold to distinguish patients undergoing repeat resection within a relatively short interval from those experiencing clearly prolonged decision pathways, often involving salvage therapy, surveillance, or deferred surgery. Future studies using time-to-surgery as a continuous variable or employing time-dependent modeling will be required to further refine the relationship between surgical timing and outcome.\u003c/p\u003e \u003cp\u003eIn our study, patients with rGB conferred a median survival after repeat resection of 12 months in the early group and 14 months in the late group without significant differences, possibly owing to an overall low sample number. This is consistent with survival outcomes reported in previous trials focusing on GB patients with 1st repeat resection, which range at around one year [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, PFS is known to correlate with response to treatment and in-turn to correlate with survival [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Indeed, there were no differences pertaining to PFS-2 between early and late repeat resection patients in this study.\u003c/p\u003e \u003cp\u003eA potential advantage of \u0026lsquo;early\u0026rsquo; repeat resection lies in the opportunity to obtain tumor tissue for molecularly-guided treatment [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan additionalcitationids=\"CR40 CR41 CR42 CR43\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], enabling personalized therapeutic approaches [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], like mTOR-targeted therapy [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Such strategies are more likely to be implemented at an earlier disease stage, when patients are less heavily pretreated and therefore more amenable to therapy. This concept is supported by the observed differences in post-resection adjuvant therapy patterns between groups in our study. Notably, patients undergoing early repeat resection more frequently received chemotherapy (CCNU/VP-16) compared with those in the late group. This may reflect a greater availability of effective systemic treatment options in earlier disease stages, whereas similar regimens may be regarded as redundant or less synergistic in patients who have already been exposed to different lines of therapy. In line with this interpretation, patients in the late surgery group were significantly more likely to receive no adjuvant treatment following reoperation, suggesting a narrowing of therapeutic options and potentially diminished treatment tolerance at later time points. Together, these findings underscore the potential role of early surgical intervention not only in effective cytoreduction but also as a facilitator of subsequent, more active adjuvant treatment strategies.\u003c/p\u003e \u003cp\u003eAn additional advantage of early repeat resection is increased diagnostic certainty, since tissue sampling usually allows reliable exclusion of radiation necrosis. At present, no imaging modality can fully replace histological confirmation, and advanced techniques such as PET imaging were not routinely used in our cohort [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Even though we selected patients with confirmed histopathological diagnosis of rGB, advances in artificial intelligence enabling pixel-level analysis and the integration of multi-sequence and multi-modality data show considerable promise for distinguishing treatment-related effects from recurrent tumor and may render the research question at hand redundant in the future [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], which would help improve patient stratification for individualizing decision-making.\u003c/p\u003e \u003cp\u003eThe overall rate of transient and permanent postoperative neurological deficits in our cohort was 15% and 2% respectively, with no significant difference observed between the early and late surgery groups. This is lower than what was reported in the literature for similar cohorts (surgical complication rates 8% to 30%) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] and challenges the notion that patients with recurrent glioblastoma are at a higher risk of surgical and neurological complications [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study has several limitations, especially given the retrospective study design. This study does not address whether salvage therapy prior to a later resection affects tumor growth to off-set a potential benefit of an otherwise early surgery. We also acknowledge that this approach results in a smaller and more heterogeneous delayed-surgery subgroup and may limit statistical power; however, it reflects the inherent heterogeneity of recurrent glioblastoma management and allows clinically interpretable group comparisons aligned with routine practice. However, this study was conceived to examine the effect of multi-disciplinary decision-making on the longitudinal neurosurgical management of patients with recurrent glioblastoma rather than to explore differences between different therapies. Also, different patterns of recurrence were not taken into consideration, as this might have influenced the rationale of surgery to prolong survival or alleviate symptoms through cytoreduction [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. This study also does not examine the effect of these interventions on the quality of life or the cognitive performance of affected patients, especially since higher disease burden and cognitive impairment are known to reduce patient survival in glioblastoma [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNevertheless, these findings suggest that while deferred surgery may risk continued tumor growth, a carefully selected watch-and-wait or pre-surgical salvage therapy does not compromise functional safety or oncological outcomes in patients undergoing repeat resection for recurrent glioblastoma.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTumor resection of recurrent glioblastoma beyond two months after radiological suspicion of recurrence was associated with only subtle, non-significant differences in the EOR compared to resection early time point, without a statistically significant difference in progression-free and overall survival after repeat resection. Importantly, delaying surgery was not associated with an increased risk of postoperative neurological deterioration. These findings suggest that delaying repeat surgery for selected patients could be justified, especially if pseudoprogression cannot be ruled out or systemic salvage therapy has not been assessed for efficacy in individual patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFUNDING:\u003c/strong\u003e The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICTS OF INTEREST: \u003c/strong\u003eThe authors have no further relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTION: \u003c/strong\u003eStudy concept and design: CJ, OTH. Data collection and analysis: OTH, KM, KN, JK, NG, HO, SJ, CJ. Data interpretation: OTH, CJ. Writing the manuscript: OTH, CJ. Reviewing and editing: CJ, OTH, AU, SMK. Supervision: CJ, all authors approved the final version of the submitted manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY: \u003c/strong\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL\u003c/strong\u003e: The committee of ethical practice at the University of Heidelberg approved the protocol of this retrospective analysis under S-455/2023 which has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments and for which patient consent was not required.\u003cbr\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. 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Cochrane Database Syst Rev 8:Cd013047. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/14651858.CD013047.pub2\u003c/span\u003e\u003cspan address=\"10.1002/14651858.CD013047.pub2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 2","content":"\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Recurrent glioblastoma, repeat resection, volumetric analysis, pseudo-progression, timing of surgery","lastPublishedDoi":"10.21203/rs.3.rs-8490591/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8490591/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe optimal timing of repeat surgical resection in patients with recurrent IDH-wildtype glioblastoma (rGB) remains unclear. We aimed to characterize temporal patterns between radiological suspicion of recurrence and repeat resection and to evaluate the impact of early versus delayed surgery on the extent of resection (EOR), functional outcomes, adjuvant therapy, and survival.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e We retrospectively analyzed a consecutive cohort of 150 patients who underwent resection for histopathologically confirmed rGB between 2015 and 2023 at a single tertiary care center. All patients had available pre- and early postoperative MRI and underwent surgery under intraoperative MRI guidance. Assessment of contrast-enhancing preoperative and residual tumor volumes (RTV) was performed using semi-automated segmentation. Based on the mean time between suspicion of recurrence and repeat resection (54 days), patients were stratified into early (\u0026le;\u0026thinsp;54 days) and late (\u0026gt;\u0026thinsp;54 days) surgery. EOR was classified according to RANO Resect criteria and a 0.175-ml RTV threshold. Functional outcomes, postoperative treatment, as well as progression-free survival (PFS), and overall survival (OS) after repeat resection were compared between groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMedian time from suspicion of recurrence to repeat resection was 18 days, with 75% of patients undergoing reoperation within 6 weeks. Early (n\u0026thinsp;=\u0026thinsp;120) and late (n\u0026thinsp;=\u0026thinsp;30) surgery groups showed comparable baseline demographics, performance status, tumor eloquence, and preoperative neurological deficits. Preoperative tumor volumes were significantly smaller in the early surgery group (12.7 vs. 25.9 ml, p\u0026thinsp;=\u0026thinsp;0.002). Late surgery was associated with a trend toward higher RTV and lower rates of gross total resection, though without statistical significance. Rates of transient and permanent postoperative neurological deficits were low (15% and 2%) and did not differ between groups. Adjuvant treatment patterns differed, with early surgery patients more frequently receiving CCNU-based chemotherapy, while late surgery patients more often received no further treatment. Median OS (14.3 vs. 12.4 months) and PFS (4 months in both groups) after repeat resection were not significantly different between early and late surgery groups.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eMost repeat resections for rGB are performed shortly after radiological suspicion of recurrence. While delayed surgery is associated with larger tumor volumes and a trend toward less favorable EOR and adjuvant treatment options, timing of surgery alone was not independently associated with functional outcomes or survival. These findings support individualized decision-making for repeat resection based on clinical and radiological factors rather than timing alone.\u003c/p\u003e","manuscriptTitle":"Repeat resection for recurrent glioblastoma – Does timing matter?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-06 10:55:35","doi":"10.21203/rs.3.rs-8490591/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-19T00:01:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-17T10:57:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-12T11:05:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-11T05:54:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8878499278945127300379701065137936509","date":"2026-01-07T03:15:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223401127636924210463000211559226997395","date":"2026-01-04T19:36:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238976851009815636205989190948197371873","date":"2026-01-02T21:52:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"94309203399622556845578467347303536720","date":"2026-01-02T17:15:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-02T13:45:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-02T08:31:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-02T08:29:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2025-12-31T14:34:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8fbab702-d0c4-4d91-b49b-7c90e8320a6c","owner":[],"postedDate":"January 6th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:08:07+00:00","versionOfRecord":{"articleIdentity":"rs-8490591","link":"https://doi.org/10.1007/s11060-026-05477-8","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2026-02-24 15:58:32","publishedOnDateReadable":"February 24th, 2026"},"versionCreatedAt":"2026-01-06 10:55:35","video":"","vorDoi":"10.1007/s11060-026-05477-8","vorDoiUrl":"https://doi.org/10.1007/s11060-026-05477-8","workflowStages":[]},"version":"v1","identity":"rs-8490591","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8490591","identity":"rs-8490591","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}