Impact of Carmustine wafer implantation in epileptic seizures of newly diagnosed glioblastomas, IDH-wildtype in adults

Impact of Carmustine wafer implantation in epileptic seizures of newly diagnosed glioblastomas, IDH-wildtype in adults | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Impact of Carmustine wafer implantation in epileptic seizures of newly diagnosed glioblastomas, IDH-wildtype in adults Alexandre ROUX, Angela ELIA, Camille NADLER, Benoit HUDELIST, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8523222/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Feb, 2026 Read the published version in Journal of Neuro-Oncology → Version 1 posted 14 You are reading this latest preprint version Abstract Purpose. The impact of Carmustine wafer implantation on epileptic seizure control in adult patients with newly diagnosed supratentorial glioblastoma, IDH- wildtype, remains unclear. We assessed whether Carmustine wafer implantation influences postoperative seizure control. Methods. We conducted an observational, retrospective, single-centre cohort study at a tertiary neurosurgical oncology center between January 2006 and December 2024. We included adults treated with surgical resection for a newly diagnosed supratentorial glioblastoma, IDH -wildtype with or without Carmustine wafer implantation in the early postoperative period and during the first six months of adjuvant oncological treatment. Results. 676 patients who benefited from a first-line surgical resection with (n = 257) or without (n = 419) Carmustine wafer implantation were included. Epilepsy at diagnosis was present in 244 patients (36.1%), with no difference in prevalence (35.8% vs. 36.3%, p = 0.483) or in preoperative seizure control (96.1% vs. 92.1%, p = 0.070) between groups. Uncontrolled seizures occurred in 17.6% (n = 43/244) of patients in the early postoperative period and in 18.6% (n = 41/221) of patients during the first six months of adjuvant oncological treatment. In multivariable analysis, preoperative uncontrolled seizures (adjusted Odds Ratio 76.9, 95%CI 34.5-187.7, p < 0.001) was independently associated with uncontrolled seizure in the early postoperative period, while Carmustine wafer implantation was not (aOR 0.78, 95%CI 0.36–1.60, p = 0.496). Similarly, a history of epilepsy at diagnosis (aOR 2.38, 95%CI 1.43–3.98, p < 0.001), but not Carmustine wafer implantation (aOR 0.92, 95%CI 0.55–1.54, p = 0.761), predicted uncontrolled seizures during the first six months of adjuvant oncological treatment. Conclusion. Carmustine wafer implantation does not impact the risk of uncontrolled epileptic seizures in the postoperative and adjuvant oncological treatment periods. No specific adaptation of antiseizure medication is required following Carmustine wafer implantation for newly diagnosed supratentorial glioblastoma, IDH- wildtype patients. Figures Figure 1 Introduction Glioblastoma, isocitrate dehydrogenase (IDH) wildtype (World Health Organization (WHO) grade 4) is the most common aggressive primary brain tumour in adults [ 1 ] associated with a dismal prognosis despite multimodal treatment strategies. The extent of surgical resection remains a cornerstone of management, aiming for maximal safe removal of the contrast-enhancing tumor and beyond [ 2 – 4 ]. To further improve local control, biodegradable wafers impregnated with the cytotoxic agent Carmustine (1,3-bis(2-chloreoethyl)-1-nitrosourea, BCNU) can be implanted along the resection cavity walls [ 5 , 6 ]. Several studies have suggested that Carmustine wafer implantation combined with surgical resection - regardless of the surgical ventricular opening [ 7 ] - improves survival in newly diagnosed glioblastomas [ 6 , 8 ], when used in association with the current standard radiochemotherapy protocol [ 9 – 15 ]. As a practical consequence, Carmustine wafer implantation is currently indicated worldwide [ 16 – 19 ] in cases where ≥ 90% of resection of the contrast-enhancing part of the tumour is achievable, in order to improve survival outcomes [ 12 , 13 , 17 – 19 ]. In glioblastoma patients, epileptic seizures are common, often drug-resistant, and tend to worsen with tumor progression despite oncological treatment and long-term antiseizure medications [ 20 ]. While the extent of resection has been linked to seizure control after first-line oncological treatments, the impact of Carmustine wafer implantation on epileptic seizure prevalence and control remains unclear [ 5 , 6 , 10 – 12 , 19 , 21 – 25 ]. Theoretically, local delivery of chemotherapy could either exacerbate seizures due to chemotoxicity or reduce them through enhanced tumor suppression. However, existing data are conflicting and primarily derived from heterogeneous cohorts, often including both newly diagnosed and recurrent gliomas, or predating the current molecular classification of glioblastoma[ 12 , 13 , 17 – 19 ]. To date, no study has specifically evaluated the impact of Carmustine wafer implantation on postoperative epileptic seizure control in adults with newly diagnosed glioblastoma, IDH- wildtype. Addressing this knowledge gap is critical for optimizing postoperative care, particularly regarding antiseizure medication strategies. This study aims to assess the influence of Carmustine wafer implantation on epileptic seizure control in this population, providing evidence-based guidance for clinicians. Methods Study design We conducted an observational, retrospective, single-centre cohort study at a tertiary surgical neuro-oncological centre between January 2006 and December 2024 during the era of the standard radiochemotherapy protocol [ 26 , 27 ]. The manuscript was prepared in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Participants Eligibility criteria were: 1) age ≥ 18 years; 2) histomolecular diagnosis of glioblastoma, IDH -wildtype according to the 2021 WHO classification [ 1 ]; 3) supratentorial location, 4) surgical resection with or without Carmustine wafer implantation as first-line treatment; 5) availability of pre- and postoperative MRIs; and 6) availability of preoperative data and postoperative follow-up including epileptic status until the first six months of adjuvant oncological treatment. The decision to implant Carmustine wafers was made intraoperatively by the treating neurosurgeon based on guidelines from the French Neurosurgical Society [ 19 ]: 1) preoperative feasibility of a subtotal, total or supratotal resection of the contrast enhanced mass; 2) informed consent; and 3) intraoperative extemporaneous histopathological diagnosis of high-grade glioma. Data collection Data were systematically retrieved from medical records using a predefined protocol. Clinical variables collected at diagnosis included: sex, age and, Karnofsky Performance Status (KPS) score, presenting symptom, neurological or neurocognitive deficit, signs of raised intracranial pressure, epileptic seizure status (presence, type, frequency, and control) and antiseizure medication (drug type, monotherapy/polytherapy). Seizure control during tumor evolution was documented from seizure diaries and clinical reports, including patient and caregiver accounts. Preoperative MRI characteristics included: tumor location, cortical or ventricular involvement, and tumor volume (cm 3 ), quantified by segmentation of postcontrast T1-weighted sequences. Treatment-related variables included: extent of surgical resection assessed on early postoperative contrast-enhanced T1-weighted MRI (within 48h) and classified as partial (< 90% resection of enhancing tumour ), subtotal (≥ 90% resection of enhancing tumour) or total [ 28 ], adverse postoperative events within 30 days (hematoma requiring surgical evacuation, new neurological deficit, postoperative seizures, wound-healing defect, cerebrospinal fluid leak, hydrocephalus, infection, and systemic thromboembolic complications), time from surgery to radiotherapy, completion of the standard radiochemotherapy protocol, and KPS score at the end of first-line treatment. Epilepsy assessment Tumor-related epilepsy was defined according to the International League Against Epilepsy, as ≥ 1 unprovoked epileptic seizure with the presence of an enduring alteration in the brain (i.e. the glioblastoma, IDH -wildtype) [ 29 ]. Seizure occurrence and control were assessed at the following time points: 1) at diagnosis (from first symptom to surgery), 2) in the early postoperative period (from the day of surgery until one month postoperative), 3) during the oncological treatment in the absence of progression (within the first six months of adjuvant oncological treatment). At each interval, seizure control was defined as complete seizure freedom (including focal signs without impaired awareness) with or without antiseizure medication, corresponding to class 1 of the International League Against Epilepsy Outcome Scale. Patients experiencing at least one seizure while on antiseizure medication were classified as having an uncontrolled epilepsy. Statistical analyses Univariate analyses were performed to identify factors associated with tumor-related epilepsy and seizure control, using chi-square or Fisher’s exact tests for categorical variables, and unpaired t-tests or Mann–Whitney rank-sum test for continuous variables, as appropriate. Variables with p < 0.100 in unadjusted analysis were entered into backward stepwise logistic regression models. Final model retained predictors significant at p < 0.050. Missing data were treated as a separate category to maintain sample size stability. Statistical analyses were performed using JMP software (Version 18.2.2; SAS Institute Inc, Cary, NC). Ethics approval All methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by the human research institutional review board (IRB00011687 – Collège de Neurochirurgie). The study received required authorizations (IRB#1:2025/30) from the IRB00011687 – Collège de Neurochirurgie. Informed consent was obtained from all subjects and/or their legal guardian(s), according to French legislation (observational retrospective study). Data Availability Statement Data not provided in the article may be shared (anonymized) at the reasonable request of any qualified investigator for purposes of replicating procedures and results. Results Clinical, imaging, and treatment-related characteristics During the study period, 1324 patients were treated for a newly diagnosed supratentorial glioblastoma, IDH -wildtype. We excluded 609 patients (46.0%) treated with biopsy only, 18 patients (1.4%) with diffuse astrocytic glioma, IDH- wildtype, with molecular features of glioblastoma, WHO grade IV [ 30 ] and 21 patients (1.4%) without epileptic status data available. A total of 676 patients undergoing first-line surgical resection were included: 257 patients (38.0%) with Carmustine wafer implantation (mean 8.0 ± 2.0 wafers; range, 4–16) and 419 patients (62.0%) without. Study flowchart is presented in Fig. 1. Baseline characteristics are detailed in Table 1 . At diagnosis, 244 patients (36.1%) presented with epilepsy. Preoperative epileptic seizure prevalence did not differ between patients with (n = 92/257, 35.8%) and without (n = 152/419, 36.3%) Carmustine wafer implantation (p = 0.483). Preoperative seizure control did not differ between patients with (n = 247/257, 96.1%) and without (n = 386/419, 92.1%) Carmustine wafer implantation (p = 0.070). Epileptic seizures in the early postoperative period Early postoperative epileptic control status was available for all 676 patients. Among them, 244/676 patients (36.1%) had a history of epilepsy at diagnosis, 201/244 (82.4%) achieved seizure control in the early postoperative period and 43/244 (17.6%) had uncontrolled seizures. In the 432/676 (63.9%) patients without epilepsy at diagnosis, 414/432 (95.8%), achieved seizure control in the early postoperative period and 18/432 (4.2%) had uncontrolled seizures. Finally, 61/676 patients (9.0%) had uncontrolled seizures in the early postoperative period. Uncontrolled seizures during the early postoperative period did not differ between patients with (n = 17/257, 6.6%) and without (n = 44/419, 10.5%) Carmustine wafer implantation (p = 0.098). Risk factors of uncontrolled epileptic seizures in the early postoperative period are detailed in Table 2 . In multivariable analysis, preoperative uncontrolled seizure (aOR 76.9, 95%CI 34.5-187.7, p < 0.001) was independently associated with uncontrolled seizure in the early postoperative period. Carmustine wafer implantation was not significantly associated with uncontrolled seizures during this period (aOR 0.78, 95%CI 0.36–1.60, p = 0.496). Epileptic seizures during first-line oncological treatment Seizure status during the first six months of adjuvant oncological treatment was available for 599 alive patients; 77 patients died within this interval. Among them, 221/599 patients (36.9%) had a history of epilepsy at diagnosis, and 180/221 (81.4%) achieved seizure control during the first six months of adjuvant oncological treatment; 41/221 (18.6%) had uncontrolled seizures. In the 378/599 (63.1%) patients without epilepsy at diagnosis, 346/378 (91.5%), achieved seizure control during the first six months of adjuvant oncological treatment and 32/378 (8.5%) had uncontrolled seizures. Overall, 73/599 patients (12.2%) experienced epileptic seizures during the first six months of adjuvant oncological treatment: 32 (43.8%) were new-onset seizures in patients without preoperative epilepsy, and 41 (56.2%) occurred in patients with previously controlled seizures. Among the 548 alive patients with early postoperative epileptic seizure control, 64/548 (11.7%) developed uncontrolled seizures during the first six months of adjuvant oncological treatment. Uncontrolled seizures during the first six months of adjuvant oncological treatment did not differ between patients with (n = 26/224, 11.6%) and without (n = 47/375, 12.5%) Carmustine wafer implantation (p = 0.797). Risk factors of uncontrolled epileptic seizures during the first six months of adjuvant oncological treatment are detailed in Table 3 . In multivariable analysis, a history of epileptic seizure at diagnosis (aOR 2.38, 95%CI 1.43–3.98, p < 0.001) was independently associated with uncontrolled epileptic seizures during the first six months of adjuvant oncological treatment. Carmustine wafer implantation was not significantly associated with uncontrolled seizures during this period (aOR 0.92, 95%CI 0.55–1.54, p = 0.761). Discussion Key results In this retrospective, single centre study, we evaluated the impact of Carmustine wafer implantation on epileptic seizure control during surgical resection of newly diagnosed glioblastomas, IDH -wildtype in adults. Our findings indicate that Carmustine wafer implantation: 1) did not worsen the early postoperative epileptic seizure control; 2) did not worsen seizure control during the first six months of adjuvant oncological treatment; and 3) did not improve epileptic seizure control in either the early postoperative period or during the first six-postoperative months of adjuvant oncological treatment. Furthermore, we identified preoperative uncontrolled seizures as an independent predictor of uncontrolled seizures in the early postoperative period, and epileptic seizure at diagnosis as independent predictor of uncontrolled seizures during the first six months of adjuvant oncological treatment. Interpretation We recently investigated the natural history of epileptic seizures in adult patients with glioblastomas, IDH- wildtype[ 20 ]. In a large cohort of 1,006 patients, the cumulative incidence of tumor-related epilepsy increased substantially over the disease course, rising from 26.6% at diagnosis to 51.8% at the end of life. Similarly, uncontrolled epileptic seizures increased from 20.1% at diagnosis to 41.1% at the end of life. Importantly, a greater extent of surgical resection was associated with improved seizure control. In addition, data from resections of temporal glioblastomas further suggest that, when feasible, supratotal resection may confer additional seizure benefit compared with standard gross total resection [ 31 ]. However, compared with lower-grade IDH- mutant diffuse gliomas, glioblastomas, IDH -wildtype exhibit lower intrinsic epileptogenicity, which likely attenuates the potential benefits of tumor-directed therapies on epileptic seizure outcomes [ 32 , 33 ]. Thus, while the antiepileptic effect of resection is less pronounced in glioblastomas than in lower-grade diffuse gliomas, surgical extent remains a key determinant of seizure control[ 20 ]. Radiotherapy exerts a dual effect on seizure dynamics. During treatment, approximately 40–45% of patients with high-grade gliomas experience transient worsening [ 34 ], likely due to treatment-related edema and neuronal irritation. In contrast, long-term epileptic seizure reduction is frequently observed following radiotherapy, with one study reporting significant improvement in nearly three-quarters of diffuse glioma patients [ 35 ]. This suggests that radiotherapy may modulate epileptogenesis primarily through tumor control, although robust evidence specific to glioblastoma, IDH -wildtype remains scarce. Temozolomide appears to play a modest role in epileptic seizure control. In a randomized trial in elderly glioblastoma patients, seizure incidence did not differ significantly between radiotherapy alone and radiochemotherapy (24% vs. 30%), though a trend toward delayed seizure onset was noted [ 36 ]. This suggests that the antiepileptic effect of Temozolomide is poor in glioblastoma, IDH -wildtype. Given the potential influence of oncological treatments on epileptic seizure control, we assessed for the first time the natural history of epileptic seizures in homogeneous cohort of patients with a glioblastoma, IDH -wildtype treated with surgical resection and Carmustine wafer implantation. Previous studies evaluating the safety of Carmustine wafer implantation as a first-line therapy consistently reported no significant increase in early postoperative seizures [ 10 – 13 , 22 – 24 ], while two studies suggested an increased epileptic seizure risk in recurrent glioblastomas [ 25 , 37 ]. Across several prospective and retrospective studies, findings regarding postoperative epileptic seizure prevalence have been variable. Valtonen et al. in 1997 reported no difference in early postoperative seizures incidence between high-grade glioma patients receiving Carmustine wafers and placebo (19% vs 13%) [ 23 ]. Westphal et al. in 2003, in a randomized, double-blind trial of 240 patients, observed a slightly lower early seizure incidence in the wafer implantation group (33.3% vs 37.5%), raising the possibility of a modest antiepileptic effect [ 6 ]. Sabel and Giese in 2008, reviewed 29 studies in both first-line and recurrent settings, reporting epileptic seizure rates ranging from 19% to 33%, with higher rates in recurrent cases but no consistent difference compared with controls [ 38 ]. Notably, these early investigations predated the era of the standard radiochemotherapy protocol [ 26 ]. In the standard radiochemotherapy era, larger retrospective cohorts have confirmed the absence of a clear association between Carmustine wafer implantation and epileptic seizure risk. Attenello et al. in 2008, reported comparable 3-month epileptic seizure rates in 1013 craniotomies, including 288 with Carmustine wafer implantation (14.6% vs. 15.7%) [ 10 ]. Menei et al. in 2010, observed early postoperative epileptic seizure rates at 4.8% in newly-diagnosed cases and at 10% in recurrent cases across 163 patients receiving Carmustine wafer implantation [ 11 ]. Dixit et al. in 2011, described postoperative epileptic seizure rates of 5–16% in patients receiving Carmustine wafer implantation with radiochemotherapy, comparable to rates from radiotherapy-only series [ 22 ]. Duntze et al. in 2013, found a low epileptic seizure incidence of 3.3% in a prospective multicenter cohort of 92 patients [ 24 ], while Aoki et al. in 2014, found a 25% rate in a phase I/II trial of 16 patients, consistent with outcomes in patients not receiving Carmustine wafer implantation [ 21 ]. Larger retrospective series further reinforced these observations. Pallud et al. in 2015, in 787 patients (354 with Carmustine wafer implantation), found no significant increase in early postoperative epileptic seizures [ 12 ]. Bettag et al. in 2021, reported a 13% incidence of early postoperative epileptic seizure in 54 patients, with no association with intraoperative ventricular opening [ 39 ]. Taken together, these data suggest that Carmustine wafer implantation does not substantially modify seizure incidence in high-grade glioma patients. However, most series combined grade III and grade IV gliomas and predated the 2016 WHO classification, which distinguished IDH- mutant astrocytomas from IDH- wildtype glioblastoma [ 40 ]. Since glioblastoma, IDH- wildtype is intrinsically less epileptogenic than astrocytomas, IDH- mutant, grade 4, historical epileptic seizure data must be interpreted cautiously in this molecularly defined subgroup. Our study provides the first dedicated, longitudinal assessment of the impact of Carmustine wafer implantation on epileptic seizure outcomes in a large, homogeneous cohort of adults with newly diagnosed glioblastoma, IDH- wildtype, treated in the current radiochemotherapy era. By addressing a critical knowledge gap, we offer robust evidence that Carmustine wafer implantation neither exacerbates nor improves postoperative seizure control, thereby informing clinical decision-making regarding antiseizure medication management. These findings are particularly relevant given the paucity of data specific to this molecularly defined glioblastoma subtype, which is known for its distinct biological behavior and lower intrinsic epileptogenicity compared to lower-grade diffuse gliomas. Carmustine wafers can be safely integrated into the standard oncological protocol without necessitating adjustments to antiseizure medication strategies. Furthermore, by highlighting preoperative seizure control as a key predictor of postoperative outcomes, we underscore the importance of individualized epilepsy management in glioblastoma patients. Generalizability This study represents the largest and most contemporary single-center analysis focusing on the impact of Carmustine wafer implantation on epileptic seizure outcomes in adults with newly diagnosed glioblastoma, IDH- wildtype. By restricting our cohort to this molecularly defined subtype and standardizing treatment protocols according to current guidelines, we minimize confounding variables related to histomolecular heterogeneity and evolving therapeutic standards. Our findings are directly applicable to real-world neurosurgical oncology practice, where Carmustine wafers could be used as an adjunct to maximal safe resection and standard radiochemotherapy. The homogeneity of our population, reflecting modern diagnostic criteria and treatment paradigms, strengthens the external validity of our conclusions, particularly for centers adopting similar management strategies. These results suggest not to modify the usual antiseizure medication after Carmustine wafer implantation. Limitations The present results should be interpreted with caution given the retrospective, single-centre, and observational study design. First, Carmustine wafer implantation was not randomly assigned but determined intraoperatively by the neurosurgeon, introducing a potential selection bias. Carmustine wafers use may have been influenced by unmeasured confounders such as tumor location, intraoperative findings, or neurosurgeon preference. Second, key molecular markers were not systematically collected including the MGMT promoter methylation status (non-routinely assessed for clinical purposes according to Association of French-speaking Neuro-oncologists guidelines), which could influence both tumor behavior and seizure outcomes. Third, the diagnosis and characterization of epileptic seizures relied solely on clinical documentation, without the systematic use of electroencephalography monitoring. This approach is prone to recall, recognition, and reporting biases, potentially leading to underestimation or misclassification of seizure events. Additionally, the absence of quantitative data on seizure frequency over time and the lack of analysis of steroid use, which may independently affect seizure control, further constrain the robustness of our findings. Finally, we acknowledge that subjective biases in patient and physician reporting, as well as variations in documentation practices, may have influenced the assessment of epilepsy and seizure control. To address these limitations, future prospective, multicenter studies incorporating standardized EEG monitoring, detailed molecular profiling, and rigorous seizure assessment are warranted to better define the impact of Carmustine wafer implantation on postoperative epileptic seizure control. Conclusion In this large, homogenous cohort of adults with glioblastoma, IDH- wildtype, Carmustine wafer implantation does not appear to influence postoperative epileptic seizure risk. From a clinical perspective, these findings simplify postoperative management by obviating the need for adjusting antiseizure medication solely based on Carmustine wafer implantation. Finally, this study underscores the importance of individualized epilepsy management in glioblastoma patients, where seizure control remains a pivotal criterion for health-related quality of life alongside oncological efficacy. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Alexandre Roux and Johan Pallud. The first draft of the manuscript was written by Alexandre Roux and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgements Alexandre Roux would like to thank the Nuovo - Soldati Foundation for Cancer Research , the Servier Institute, the Ligue contre le Cancer and the association: Des Etoiles Dans La Mer – Vaincre le cancer du cerveau for their support. Alexandre Roux and Johan Pallud would like to thank Frédéric Dhermain for his help in retrieving follow-up data. 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J Neurooncol 152:339–346. https://doi.org/10.1007/s11060-021-03705-x Avila EK, Tobochnik S, Inati SK et al (2024) Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management. Neuro-Oncol 26:7–24. https://doi.org/10.1093/neuonc/noad154 Rossi J, Cavallieri F, Bassi MC et al (2024) To be or not to be: The dilemma over the prognostic role of epilepsy at presentation in patients with glioblastoma - a systematic review and meta-analysis. BMC Cancer 24:1488. https://doi.org/10.1186/s12885-024-13249-8 Rades D, Witteler J, Trillenberg P et al (2022) Increasing Seizure Activity During Radiation Treatment for High-grade Gliomas - Final Results of a Prospective Interventional Study. Vivo Athens Greece 36:2308–2313. https://doi.org/10.21873/invivo.12961 Rudà R, Magliola U, Bertero L et al (2013) Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study. Neuro-Oncol 15:1739–1749. https://doi.org/10.1093/neuonc/not109 Climans SA, Brandes AA, Cairncross JG et al (2020) Temozolomide and seizure outcomes in a randomized clinical trial of elderly glioblastoma patients. J Neurooncol 149:65–71. https://doi.org/10.1007/s11060-020-03573-x De Bonis P, Anile C, Pompucci A et al (2012) Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. Acta Neurochir (Wien) 154:1371–1378. https://doi.org/10.1007/s00701-012-1413-2 Sabel M, Giese A (2008) Safety profile of carmustine wafers in malignant glioma: a review of controlled trials and a decade of clinical experience. Curr Med Res Opin 24:3239–3257. https://doi.org/10.1185/03007990802508180 Bettag C, Hussein A, Sachkova A et al (2021) Implantation of Carmustine wafers after resection of malignant glioma with and without opening of the ventricular system. J Neurooncol 153:519–525. https://doi.org/10.1007/s11060-021-03792-w Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol (Berl) 131:803–820. https://doi.org/10.1007/s00401-016-1545-1 Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Table3.docx Cite Share Download PDF Status: Published Journal Publication published 04 Feb, 2026 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 22 Jan, 2026 Reviews received at journal 22 Jan, 2026 Reviews received at journal 22 Jan, 2026 Reviews received at journal 17 Jan, 2026 Reviewers agreed at journal 12 Jan, 2026 Reviewers agreed at journal 12 Jan, 2026 Reviewers agreed at journal 10 Jan, 2026 Reviews received at journal 10 Jan, 2026 Reviewers agreed at journal 10 Jan, 2026 Reviewers agreed at journal 09 Jan, 2026 Reviewers invited by journal 08 Jan, 2026 Editor assigned by journal 08 Jan, 2026 Submission checks completed at journal 08 Jan, 2026 First submitted to journal 05 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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08:32:25","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":34595,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8523222/v1/966460ec26f40467e8af493b.docx"},{"id":100025526,"identity":"2f263c43-f6d7-4f5f-8c64-d2f55db9a2db","added_by":"auto","created_at":"2026-01-12 08:32:25","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":34111,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8523222/v1/1af1aaf0cb3e164a0bd8b7eb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of Carmustine wafer implantation in epileptic seizures of newly diagnosed glioblastomas, IDH-wildtype in adults","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlioblastoma, \u003cem\u003eisocitrate dehydrogenase (IDH)\u003c/em\u003e wildtype (World Health Organization (WHO) grade 4) is the most common aggressive primary brain tumour in adults [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] associated with a dismal prognosis despite multimodal treatment strategies. The extent of surgical resection remains a cornerstone of management, aiming for maximal safe removal of the contrast-enhancing tumor and beyond [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To further improve local control, biodegradable wafers impregnated with the cytotoxic agent Carmustine (1,3-bis(2-chloreoethyl)-1-nitrosourea, BCNU) can be implanted along the resection cavity walls [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Several studies have suggested that Carmustine wafer implantation combined with surgical resection - regardless of the surgical ventricular opening [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] - improves survival in newly diagnosed glioblastomas [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], when used in association with the current standard radiochemotherapy protocol [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. As a practical consequence, Carmustine wafer implantation is currently indicated worldwide [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] in cases where \u0026ge;\u0026thinsp;90% of resection of the contrast-enhancing part of the tumour is achievable, in order to improve survival outcomes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn glioblastoma patients, epileptic seizures are common, often drug-resistant, and tend to worsen with tumor progression despite oncological treatment and long-term antiseizure medications [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. While the extent of resection has been linked to seizure control after first-line oncological treatments, the impact of Carmustine wafer implantation on epileptic seizure prevalence and control remains unclear [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22 CR23 CR24\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Theoretically, local delivery of chemotherapy could either exacerbate seizures due to chemotoxicity or reduce them through enhanced tumor suppression. However, existing data are conflicting and primarily derived from heterogeneous cohorts, often including both newly diagnosed and recurrent gliomas, or predating the current molecular classification of glioblastoma[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, no study has specifically evaluated the impact of Carmustine wafer implantation on postoperative epileptic seizure control in adults with newly diagnosed glioblastoma, \u003cem\u003eIDH-\u003c/em\u003ewildtype. Addressing this knowledge gap is critical for optimizing postoperative care, particularly regarding antiseizure medication strategies. This study aims to assess the influence of Carmustine wafer implantation on epileptic seizure control in this population, providing evidence-based guidance for clinicians.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eWe conducted an observational, retrospective, single-centre cohort study at a tertiary surgical neuro-oncological centre between January 2006 and December 2024 during the era of the standard radiochemotherapy protocol [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The manuscript was prepared in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eEligibility criteria were: 1) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; 2) histomolecular diagnosis of glioblastoma, \u003cem\u003eIDH\u003c/em\u003e-wildtype according to the 2021 WHO classification [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]; 3) supratentorial location, 4) surgical resection with or without Carmustine wafer implantation as first-line treatment; 5) availability of pre- and postoperative MRIs; and 6) availability of preoperative data and postoperative follow-up including epileptic status until the first six months of adjuvant oncological treatment.\u003c/p\u003e \u003cp\u003eThe decision to implant Carmustine wafers was made intraoperatively by the treating neurosurgeon based on guidelines from the French Neurosurgical Society [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]: 1) preoperative feasibility of a subtotal, total or supratotal resection of the contrast enhanced mass; 2) informed consent; and 3) intraoperative extemporaneous histopathological diagnosis of high-grade glioma.\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eData were systematically retrieved from medical records using a predefined protocol. Clinical variables collected at diagnosis included: sex, age and, Karnofsky Performance Status (KPS) score, presenting symptom, neurological or neurocognitive deficit, signs of raised intracranial pressure, epileptic seizure status (presence, type, frequency, and control) and antiseizure medication (drug type, monotherapy/polytherapy). Seizure control during tumor evolution was documented from seizure diaries and clinical reports, including patient and caregiver accounts.\u003c/p\u003e \u003cp\u003ePreoperative MRI characteristics included: tumor location, cortical or ventricular involvement, and tumor volume (cm\u003csup\u003e3\u003c/sup\u003e), quantified by segmentation of postcontrast T1-weighted sequences. Treatment-related variables included: extent of surgical resection assessed on early postoperative contrast-enhanced T1-weighted MRI (within 48h) and classified as partial (\u0026lt;\u0026thinsp;90% resection of enhancing tumour ), subtotal (\u0026ge;\u0026thinsp;90% resection of enhancing tumour) or total [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], adverse postoperative events within 30 days (hematoma requiring surgical evacuation, new neurological deficit, postoperative seizures, wound-healing defect, cerebrospinal fluid leak, hydrocephalus, infection, and systemic thromboembolic complications), time from surgery to radiotherapy, completion of the standard radiochemotherapy protocol, and KPS score at the end of first-line treatment.\u003c/p\u003e\n\u003ch3\u003eEpilepsy assessment\u003c/h3\u003e\n\u003cp\u003eTumor-related epilepsy was defined according to the International League Against Epilepsy, as \u0026ge;\u0026thinsp;1 unprovoked epileptic seizure with the presence of an enduring alteration in the brain (i.e. the glioblastoma, \u003cem\u003eIDH\u003c/em\u003e-wildtype) [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Seizure occurrence and control were assessed at the following time points: 1) at diagnosis (from first symptom to surgery), 2) in the early postoperative period (from the day of surgery until one month postoperative), 3) during the oncological treatment in the absence of progression (within the first six months of adjuvant oncological treatment).\u003c/p\u003e \u003cp\u003eAt each interval, seizure control was defined as complete seizure freedom (including focal signs without impaired awareness) with or without antiseizure medication, corresponding to class 1 of the International League Against Epilepsy Outcome Scale. Patients experiencing at least one seizure while on antiseizure medication were classified as having an uncontrolled epilepsy.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eUnivariate analyses were performed to identify factors associated with tumor-related epilepsy and seizure control, using chi-square or Fisher\u0026rsquo;s exact tests for categorical variables, and unpaired t-tests or Mann\u0026ndash;Whitney rank-sum test for continuous variables, as appropriate. Variables with p\u0026thinsp;\u0026lt;\u0026thinsp;0.100 in unadjusted analysis were entered into backward stepwise logistic regression models. Final model retained predictors significant at p\u0026thinsp;\u0026lt;\u0026thinsp;0.050. Missing data were treated as a separate category to maintain sample size stability.\u003c/p\u003e \u003cp\u003eStatistical analyses were performed using JMP software (Version 18.2.2; SAS Institute Inc, Cary, NC).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003e All methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by the human research institutional review board (IRB00011687 \u0026ndash; Coll\u0026egrave;ge de Neurochirurgie). The study received required authorizations (IRB#1:2025/30) from the IRB00011687 \u0026ndash; Coll\u0026egrave;ge de Neurochirurgie. Informed consent was obtained from all subjects and/or their legal guardian(s), according to French legislation (observational retrospective study).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Availability Statement\u003c/h3\u003e\n\u003cp\u003eData not provided in the article may be shared (anonymized) at the reasonable request of any qualified investigator for purposes of replicating procedures and results.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eClinical, imaging, and treatment-related characteristics\u003c/h2\u003e \u003cp\u003eDuring the study period, 1324 patients were treated for a newly diagnosed supratentorial glioblastoma, \u003cem\u003eIDH\u003c/em\u003e-wildtype. We excluded 609 patients (46.0%) treated with biopsy only, 18 patients (1.4%) with diffuse astrocytic glioma, \u003cem\u003eIDH-\u003c/em\u003ewildtype, with molecular features of glioblastoma, WHO grade IV [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and 21 patients (1.4%) without epileptic status data available. A total of 676 patients undergoing first-line surgical resection were included: 257 patients (38.0%) with Carmustine wafer implantation (mean 8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0 wafers; range, 4\u0026ndash;16) and 419 patients (62.0%) without. Study flowchart is presented in Fig.\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eBaseline characteristics are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. At diagnosis, 244 patients (36.1%) presented with epilepsy. Preoperative epileptic seizure prevalence did not differ between patients with (n\u0026thinsp;=\u0026thinsp;92/257, 35.8%) and without (n\u0026thinsp;=\u0026thinsp;152/419, 36.3%) Carmustine wafer implantation (p\u0026thinsp;=\u0026thinsp;0.483). Preoperative seizure control did not differ between patients with (n\u0026thinsp;=\u0026thinsp;247/257, 96.1%) and without (n\u0026thinsp;=\u0026thinsp;386/419, 92.1%) Carmustine wafer implantation (p\u0026thinsp;=\u0026thinsp;0.070).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eEpileptic seizures in the early postoperative period\u003c/h2\u003e \u003cp\u003eEarly postoperative epileptic control status was available for all 676 patients. Among them, 244/676 patients (36.1%) had a history of epilepsy at diagnosis, 201/244 (82.4%) achieved seizure control in the early postoperative period and 43/244 (17.6%) had uncontrolled seizures.\u003c/p\u003e \u003cp\u003eIn the 432/676 (63.9%) patients without epilepsy at diagnosis, 414/432 (95.8%), achieved seizure control in the early postoperative period and 18/432 (4.2%) had uncontrolled seizures. Finally, 61/676 patients (9.0%) had uncontrolled seizures in the early postoperative period.\u003c/p\u003e \u003cp\u003eUncontrolled seizures during the early postoperative period did not differ between patients with (n\u0026thinsp;=\u0026thinsp;17/257, 6.6%) and without (n\u0026thinsp;=\u0026thinsp;44/419, 10.5%) Carmustine wafer implantation (p\u0026thinsp;=\u0026thinsp;0.098).\u003c/p\u003e \u003cp\u003eRisk factors of uncontrolled epileptic seizures in the early postoperative period are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In multivariable analysis, preoperative uncontrolled seizure (aOR 76.9, 95%CI 34.5-187.7, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was independently associated with uncontrolled seizure in the early postoperative period. Carmustine wafer implantation was not significantly associated with uncontrolled seizures during this period (aOR 0.78, 95%CI 0.36\u0026ndash;1.60, p\u0026thinsp;=\u0026thinsp;0.496).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eEpileptic seizures during first-line oncological treatment\u003c/h2\u003e \u003cp\u003eSeizure status during the first six months of adjuvant oncological treatment was available for 599 alive patients; 77 patients died within this interval. Among them, 221/599 patients (36.9%) had a history of epilepsy at diagnosis, and 180/221 (81.4%) achieved seizure control during the first six months of adjuvant oncological treatment; 41/221 (18.6%) had uncontrolled seizures. In the 378/599 (63.1%) patients without epilepsy at diagnosis, 346/378 (91.5%), achieved seizure control during the first six months of adjuvant oncological treatment and 32/378 (8.5%) had uncontrolled seizures. Overall, 73/599 patients (12.2%) experienced epileptic seizures during the first six months of adjuvant oncological treatment: 32 (43.8%) were new-onset seizures in patients without preoperative epilepsy, and 41 (56.2%) occurred in patients with previously controlled seizures. Among the 548 alive patients with early postoperative epileptic seizure control, 64/548 (11.7%) developed uncontrolled seizures during the first six months of adjuvant oncological treatment. Uncontrolled seizures during the first six months of adjuvant oncological treatment did not differ between patients with (n\u0026thinsp;=\u0026thinsp;26/224, 11.6%) and without (n\u0026thinsp;=\u0026thinsp;47/375, 12.5%) Carmustine wafer implantation (p\u0026thinsp;=\u0026thinsp;0.797).\u003c/p\u003e \u003cp\u003eRisk factors of uncontrolled epileptic seizures during the first six months of adjuvant oncological treatment are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. In multivariable analysis, a history of epileptic seizure at diagnosis (aOR 2.38, 95%CI 1.43\u0026ndash;3.98, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) was independently associated with uncontrolled epileptic seizures during the first six months of adjuvant oncological treatment. Carmustine wafer implantation was not significantly associated with uncontrolled seizures during this period (aOR 0.92, 95%CI 0.55\u0026ndash;1.54, p\u0026thinsp;=\u0026thinsp;0.761).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eKey results\u003c/h2\u003e \u003cp\u003eIn this retrospective, single centre study, we evaluated the impact of Carmustine wafer implantation on epileptic seizure control during surgical resection of newly diagnosed glioblastomas, \u003cem\u003eIDH\u003c/em\u003e-wildtype in adults. Our findings indicate that Carmustine wafer implantation: 1) did not worsen the early postoperative epileptic seizure control; 2) did not worsen seizure control during the first six months of adjuvant oncological treatment; and 3) did not improve epileptic seizure control in either the early postoperative period or during the first six-postoperative months of adjuvant oncological treatment. Furthermore, we identified preoperative uncontrolled seizures as an independent predictor of uncontrolled seizures in the early postoperative period, and epileptic seizure at diagnosis as independent predictor of uncontrolled seizures during the first six months of adjuvant oncological treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eInterpretation\u003c/h2\u003e \u003cp\u003eWe recently investigated the natural history of epileptic seizures in adult patients with glioblastomas, \u003cem\u003eIDH-\u003c/em\u003ewildtype[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In a large cohort of 1,006 patients, the cumulative incidence of tumor-related epilepsy increased substantially over the disease course, rising from 26.6% at diagnosis to 51.8% at the end of life. Similarly, uncontrolled epileptic seizures increased from 20.1% at diagnosis to 41.1% at the end of life. Importantly, a greater extent of surgical resection was associated with improved seizure control. In addition, data from resections of temporal glioblastomas further suggest that, when feasible, supratotal resection may confer additional seizure benefit compared with standard gross total resection [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. However, compared with lower-grade \u003cem\u003eIDH-\u003c/em\u003emutant diffuse gliomas, glioblastomas, \u003cem\u003eIDH\u003c/em\u003e-wildtype exhibit lower intrinsic epileptogenicity, which likely attenuates the potential benefits of tumor-directed therapies on epileptic seizure outcomes [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Thus, while the antiepileptic effect of resection is less pronounced in glioblastomas than in lower-grade diffuse gliomas, surgical extent remains a key determinant of seizure control[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Radiotherapy exerts a dual effect on seizure dynamics. During treatment, approximately 40\u0026ndash;45% of patients with high-grade gliomas experience transient worsening [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], likely due to treatment-related edema and neuronal irritation. In contrast, long-term epileptic seizure reduction is frequently observed following radiotherapy, with one study reporting significant improvement in nearly three-quarters of diffuse glioma patients [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. This suggests that radiotherapy may modulate epileptogenesis primarily through tumor control, although robust evidence specific to glioblastoma, \u003cem\u003eIDH\u003c/em\u003e-wildtype remains scarce. Temozolomide appears to play a modest role in epileptic seizure control. In a randomized trial in elderly glioblastoma patients, seizure incidence did not differ significantly between radiotherapy alone and radiochemotherapy (24% vs. 30%), though a trend toward delayed seizure onset was noted [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. This suggests that the antiepileptic effect of Temozolomide is poor in glioblastoma, \u003cem\u003eIDH\u003c/em\u003e-wildtype.\u003c/p\u003e \u003cp\u003eGiven the potential influence of oncological treatments on epileptic seizure control, we assessed for the first time the natural history of epileptic seizures in homogeneous cohort of patients with a glioblastoma, \u003cem\u003eIDH\u003c/em\u003e-wildtype treated with surgical resection and Carmustine wafer implantation. Previous studies evaluating the safety of Carmustine wafer implantation as a first-line therapy consistently reported no significant increase in early postoperative seizures [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], while two studies suggested an increased epileptic seizure risk in recurrent glioblastomas [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Across several prospective and retrospective studies, findings regarding postoperative epileptic seizure prevalence have been variable. Valtonen et al. in 1997 reported no difference in early postoperative seizures incidence between high-grade glioma patients receiving Carmustine wafers and placebo (19% vs 13%) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Westphal et al. in 2003, in a randomized, double-blind trial of 240 patients, observed a slightly lower early seizure incidence in the wafer implantation group (33.3% vs 37.5%), raising the possibility of a modest antiepileptic effect [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Sabel and Giese in 2008, reviewed 29 studies in both first-line and recurrent settings, reporting epileptic seizure rates ranging from 19% to 33%, with higher rates in recurrent cases but no consistent difference compared with controls [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Notably, these early investigations predated the era of the standard radiochemotherapy protocol [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the standard radiochemotherapy era, larger retrospective cohorts have confirmed the absence of a clear association between Carmustine wafer implantation and epileptic seizure risk. Attenello et al. in 2008, reported comparable 3-month epileptic seizure rates in 1013 craniotomies, including 288 with Carmustine wafer implantation (14.6% vs. 15.7%) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Menei et al. in 2010, observed early postoperative epileptic seizure rates at 4.8% in newly-diagnosed cases and at 10% in recurrent cases across 163 patients receiving Carmustine wafer implantation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Dixit et al. in 2011, described postoperative epileptic seizure rates of 5\u0026ndash;16% in patients receiving Carmustine wafer implantation with radiochemotherapy, comparable to rates from radiotherapy-only series [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Duntze et al. in 2013, found a low epileptic seizure incidence of 3.3% in a prospective multicenter cohort of 92 patients [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], while Aoki et al. in 2014, found a 25% rate in a phase I/II trial of 16 patients, consistent with outcomes in patients not receiving Carmustine wafer implantation [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Larger retrospective series further reinforced these observations. Pallud et al. in 2015, in 787 patients (354 with Carmustine wafer implantation), found no significant increase in early postoperative epileptic seizures [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Bettag et al. in 2021, reported a 13% incidence of early postoperative epileptic seizure in 54 patients, with no association with intraoperative ventricular opening [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Taken together, these data suggest that Carmustine wafer implantation does not substantially modify seizure incidence in high-grade glioma patients. However, most series combined grade III and grade IV gliomas and predated the 2016 WHO classification, which distinguished \u003cem\u003eIDH-\u003c/em\u003emutant astrocytomas from \u003cem\u003eIDH-\u003c/em\u003ewildtype glioblastoma [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Since glioblastoma, \u003cem\u003eIDH-\u003c/em\u003ewildtype is intrinsically less epileptogenic than astrocytomas, \u003cem\u003eIDH-\u003c/em\u003emutant, grade 4, historical epileptic seizure data must be interpreted cautiously in this molecularly defined subgroup.\u003c/p\u003e \u003cp\u003eOur study provides the first dedicated, longitudinal assessment of the impact of Carmustine wafer implantation on epileptic seizure outcomes in a large, homogeneous cohort of adults with newly diagnosed glioblastoma, \u003cem\u003eIDH-\u003c/em\u003ewildtype, treated in the current radiochemotherapy era. By addressing a critical knowledge gap, we offer robust evidence that Carmustine wafer implantation neither exacerbates nor improves postoperative seizure control, thereby informing clinical decision-making regarding antiseizure medication management. These findings are particularly relevant given the paucity of data specific to this molecularly defined glioblastoma subtype, which is known for its distinct biological behavior and lower intrinsic epileptogenicity compared to lower-grade diffuse gliomas. Carmustine wafers can be safely integrated into the standard oncological protocol without necessitating adjustments to antiseizure medication strategies. Furthermore, by highlighting preoperative seizure control as a key predictor of postoperative outcomes, we underscore the importance of individualized epilepsy management in glioblastoma patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eGeneralizability\u003c/h2\u003e \u003cp\u003eThis study represents the largest and most contemporary single-center analysis focusing on the impact of Carmustine wafer implantation on epileptic seizure outcomes in adults with newly diagnosed glioblastoma, \u003cem\u003eIDH-\u003c/em\u003ewildtype. By restricting our cohort to this molecularly defined subtype and standardizing treatment protocols according to current guidelines, we minimize confounding variables related to histomolecular heterogeneity and evolving therapeutic standards. Our findings are directly applicable to real-world neurosurgical oncology practice, where Carmustine wafers could be used as an adjunct to maximal safe resection and standard radiochemotherapy. The homogeneity of our population, reflecting modern diagnostic criteria and treatment paradigms, strengthens the external validity of our conclusions, particularly for centers adopting similar management strategies. These results suggest not to modify the usual antiseizure medication after Carmustine wafer implantation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThe present results should be interpreted with caution given the retrospective, single-centre, and observational study design. First, Carmustine wafer implantation was not randomly assigned but determined intraoperatively by the neurosurgeon, introducing a potential selection bias. Carmustine wafers use may have been influenced by unmeasured confounders such as tumor location, intraoperative findings, or neurosurgeon preference. Second, key molecular markers were not systematically collected including the \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status (non-routinely assessed for clinical purposes according to Association of French-speaking Neuro-oncologists guidelines), which could influence both tumor behavior and seizure outcomes. Third, the diagnosis and characterization of epileptic seizures relied solely on clinical documentation, without the systematic use of electroencephalography monitoring. This approach is prone to recall, recognition, and reporting biases, potentially leading to underestimation or misclassification of seizure events. Additionally, the absence of quantitative data on seizure frequency over time and the lack of analysis of steroid use, which may independently affect seizure control, further constrain the robustness of our findings. Finally, we acknowledge that subjective biases in patient and physician reporting, as well as variations in documentation practices, may have influenced the assessment of epilepsy and seizure control. To address these limitations, future prospective, multicenter studies incorporating standardized EEG monitoring, detailed molecular profiling, and rigorous seizure assessment are warranted to better define the impact of Carmustine wafer implantation on postoperative epileptic seizure control.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this large, homogenous cohort of adults with glioblastoma, \u003cem\u003eIDH-\u003c/em\u003ewildtype, Carmustine wafer implantation does not appear to influence postoperative epileptic seizure risk. From a clinical perspective, these findings simplify postoperative management by obviating the need for adjusting antiseizure medication solely based on Carmustine wafer implantation. Finally, this study underscores the importance of individualized epilepsy management in glioblastoma patients, where seizure control remains a pivotal criterion for health-related quality of life alongside oncological efficacy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Alexandre Roux and Johan Pallud. The first draft of the manuscript was written by Alexandre Roux and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlexandre Roux would \u003cem\u003elike to thank the\u003c/em\u003e \u003cem\u003eNuovo\u003c/em\u003e-\u003cem\u003eSoldati Foundation\u003c/em\u003e \u003cem\u003efor\u003c/em\u003e \u003cem\u003eCancer Research\u003c/em\u003e, the \u003cem\u003eServier Institute,\u0026nbsp;\u003c/em\u003ethe\u003cem\u003e\u0026nbsp;Ligue contre le Cancer\u0026nbsp;\u003c/em\u003eand the association:\u003cem\u003e\u0026nbsp;Des Etoiles Dans La Mer – Vaincre le cancer du cerveau\u0026nbsp;\u003c/em\u003efor their support. Alexandre Roux and Johan Pallud would like to thank Frédéric Dhermain for his help in retrieving follow-up data.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLouis DN, Perry A, Wesseling P et al (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-Oncol 23:1231\u0026ndash;1251. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/neuonc/noab106\u003c/span\u003e\u003cspan address=\"10.1093/neuonc/noab106\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarschnia P, Gerritsen JKW, Teske N et al (2024) The oncological role of resection in newly diagnosed diffuse adult-type glioma defined by the WHO 2021 classification: a Review by the RANO resect group. 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J Neurooncol 153:519\u0026ndash;525. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11060-021-03792-w\u003c/span\u003e\u003cspan address=\"10.1007/s11060-021-03792-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLouis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol (Berl) 131:803\u0026ndash;820. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00401-016-1545-1\u003c/span\u003e\u003cspan address=\"10.1007/s00401-016-1545-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are 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":"","lastPublishedDoi":"10.21203/rs.3.rs-8523222/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8523222/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose.\u003c/strong\u003e The impact of Carmustine wafer implantation on epileptic seizure control in adult patients with newly diagnosed supratentorial glioblastoma, \u003cem\u003eIDH-\u003c/em\u003ewildtype, remains unclear. We assessed whether Carmustine wafer implantation influences postoperative seizure control.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods.\u003c/strong\u003e We conducted an observational, retrospective, single-centre cohort study at a tertiary neurosurgical oncology center between January 2006 and December 2024. We included adults treated with surgical resection for a newly diagnosed supratentorial glioblastoma, \u003cem\u003eIDH\u003c/em\u003e-wildtype with or without Carmustine wafer implantation in the early postoperative period and during the first six months of adjuvant oncological treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults.\u003c/strong\u003e 676 patients who benefited from a first-line surgical resection with (n = 257) or without (n = 419) Carmustine wafer implantation were included. Epilepsy at diagnosis was present in 244 patients (36.1%), with no difference in prevalence (35.8% vs. 36.3%, p = 0.483) or in preoperative seizure control (96.1% vs. 92.1%, p = 0.070) between groups. Uncontrolled seizures occurred in 17.6% (n = 43/244) of patients in the early postoperative period and in 18.6% (n = 41/221) of patients during the first six months of adjuvant oncological treatment. In multivariable analysis, preoperative uncontrolled seizures (adjusted Odds Ratio 76.9, 95%CI 34.5-187.7, p \u0026lt; 0.001) was independently associated with uncontrolled seizure in the early postoperative period, while Carmustine wafer implantation was not (aOR 0.78, 95%CI 0.36–1.60, p = 0.496). Similarly, a history of epilepsy at diagnosis (aOR 2.38, 95%CI 1.43–3.98, p \u0026lt; 0.001), but not Carmustine wafer implantation (aOR 0.92, 95%CI 0.55–1.54, p = 0.761), predicted uncontrolled seizures during the first six months of adjuvant oncological treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion.\u003c/strong\u003e Carmustine wafer implantation does not impact the risk of uncontrolled epileptic seizures in the postoperative and adjuvant oncological treatment periods. No specific adaptation of antiseizure medication is required following Carmustine wafer implantation for newly diagnosed supratentorial glioblastoma, \u003cem\u003eIDH-\u003c/em\u003ewildtype patients.\u003c/p\u003e","manuscriptTitle":"Impact of Carmustine wafer implantation in epileptic seizures of newly diagnosed glioblastomas, IDH-wildtype in adults","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 08:32:21","doi":"10.21203/rs.3.rs-8523222/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-22T11:45:01+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-22T11:18:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-22T11:02:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-17T15:05:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"176776208554058667754806501107203191212","date":"2026-01-12T11:32:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"269789003232682040145343557917732947753","date":"2026-01-12T10:16:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"266477904831136393854566439077505883153","date":"2026-01-10T14:37:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-10T11:19:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"46255419807810608489311185981881725168","date":"2026-01-10T11:02:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"94309203399622556845578467347303536720","date":"2026-01-09T12:06:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-08T11:12:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-08T08:45:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-08T08:42:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2026-01-05T15:53:39+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":"13b188c5-6c4b-47c4-a94e-a39ae2d02e2d","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:03:18+00:00","versionOfRecord":{"articleIdentity":"rs-8523222","link":"https://doi.org/10.1007/s11060-026-05452-3","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2026-02-04 15:59:41","publishedOnDateReadable":"February 4th, 2026"},"versionCreatedAt":"2026-01-12 08:32:21","video":"","vorDoi":"10.1007/s11060-026-05452-3","vorDoiUrl":"https://doi.org/10.1007/s11060-026-05452-3","workflowStages":[]},"version":"v1","identity":"rs-8523222","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8523222","identity":"rs-8523222","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}