Sektionstage Herbst 2023 der Deutschen Gesellschaft für Neurochirurgie

PD Dr. med.

PD Dr.

Prof. Dr.

Multimodal treatment of Glioblastoma with multiple lesions – A multi-center retrospective analysis

Abstract-Text Objective: The presence of multiple localizations in Glioblastoma is rare and associated with perceived poor prognosis. The presence of a visible connection between enhancing lesions on magnetic resonance imaging (MRI) is defined as multifocal (MF), the absence of a dissemination pathway as multi-centric (MC). The aim of this study is to evaluate the impact of a multimodal treatment on overall survival (OS) in the treatment of Glioblastoma with multiple localizations. Methods: Data acquisition was conducted as a retrospective analysis. Patients presenting with IDH-wildtype Glioblastoma (CNS WHO Grad 4) with multiple localizations were included in our study. Demographic data included tumor size, Karnofsky Performance Score (KPS) before and after surgery. EOR was measured using fluid-attenuated inversion recovery (FLAIR) and contrast-enhanced T1-weighted MRI and classified in concordance with the RANO resection group. Adjuvant treatment including radiation and chemo therapy were analyzed. Results: A total of 423 patients with newly diagnosed glioblastoma (CNS WHO grade 4) were included. 119 patients (median age 62 years (18–84 years; 48.7% females). 62 (38.5%) patients presented with MC lesions, 57 (61.5%) with MF. The median did not differ between both groups (age: p=0.56). Median KPS on admission was similar across both subtypes (MF: 70 (40-100), MC: 70 (40-100)). The median OS (MC: 441.6 days, SE: 53.2; MF: 391.2 days, SE: 81.3) did not differ among MC and MF glioblastoma. GTR was achieved in 37.8% (MC)/36.1% (MF), STR in 40% (MC)/22% (MF), PR in 13% (MC)/8.3% (MF) and biopsy was performed in 9.2% (MC)/33.6% (MF). In MF glioblastoma GTR (461 days, 95CI 224-724; p=0.0001) and STR (317.5 days, 95CI 149-783; p=0.0001) significantly increased the median OS compared to PR (334 days, 95CI 57-370) and biopsy (51 days, 95CI 38-105). Likewise, OS was increased after GTR (490 days, 95CI 195-827; p=0.0272) and STR (416.5 days, 95CI 179-677; p=0.0272) in MC glioblastoma. Overall, resection significantly increase OS (510±69.5 days) in patients with Glioblastoma with multiple localizations compared to biopsy (76±37.24 days) alone. Post-operative KPS did not decrease in patients undergoing resection, compared to biopsy alone. Using multivariate logistic regression analysis, EOR and chemotherapy were significant and independent predictors of OS. Under multimodal treatment, OS of patients with multiple lesions compared to those with singular lesions (p=0.4). Conclusion: The presented data suggests that glioblastoma with multiple lesions treated with multimodal therapy have a similar clinical course compared to those with singular lesions. Resection positively influence OS. These results advocate a more aggressive stance towards surgical treatment of these tumors with particular poor prognosis even if GTR is not within reach prior to resection.

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Prof. Dr. Dr.

Evaluating the impact and perception of clinical guidelines in neurooncology: A nationwide survey

Abstract-Text Introduction: Medical guidelines in the realm of neurooncology are essential instruments, bridging the gap between groundbreaking research and pragmatic clinical practice. These guidelines, by standardizing care, foster a shared understanding among medical practitioners. However, neurooncology, with its multifaceted nature of neurological malignancies and a constant influx of novel therapeutic modalities, presents unique challenges. Specifically, the introduction of Tumor Treating Fields (TTFields) into the clinical setting and its subsequent recognition in guidelines have drawn notable attention. This study delves into the perceptions surrounding neurooncology guidelines and the receptivity towards new therapies like TTFields. Methods: A comprehensive survey was designed to evaluate perceptions and challenges related to clinical guidelines, especially in glioblastoma management. The survey was disseminated to members of the Neuroonkologische Arbeitsgemeinschaft (NOA) and gathered data on demographics, perceptions of guidelines, challenges, comparisons with other information sources, and specific queries about TTFields. Results: Of the 92 responses, 87 were analyzed, representing a 24.7% response rate with respect to the NOA membership. Most respondents were from the neurosurgery specialty (66.7%) practicing in university hospitals (70.1%). A significant 81.6% strongly agreed that guidelines aim to enhance treatment quality. However, 32.2% felt that guidelines limited therapeutic freedom. Additionally, 77% viewed guidelines as an objective knowledge summary. Notably, while 78.2% were aware of TTFields' absence in the latest DGN glioblastoma guideline, 71.3% were informed of its Category 1 recommendation in the NCCN guideline. Conclusions: The findings underscore the critical role of guidelines in neurooncology clinical decision-making. There is a substantial trust in these guidelines, emphasizing their importance in guiding clinical decisions. However, the latent incorporation of novel therapies, such as TTFields, into guidelines indicates a need for more dynamic updates. Concurrently, the integration of experiential knowledge from alternative information sources remains indispensable. This intricate balance underscores the necessity for guidelines to be both evidence-based and agile, facilitating optimal patient care in the realm of neurooncology.

Leben mit (kindlichem) Hirntumor

Prof. Dr. med.

Prof. Dr. med

PD Dr.med. Dr.med.habil. 

Prof. Dr med.

Frequency and type of adjuvant therapy and adherence to current guidelines in patients with grade 2 and 3 glioma

Abstract-Text Background: Recent evidence based guidelines for grade 2 and 3 gliomas recommend adjuvant treatment after surgery in the majority of cases. However, individual treatment decisions may differ significantly from the recommendations. Therefore, we aimed to evaluate the current postoperative management in Germany based on multicenter registry data from representative certified neurooncological centers. Methods: We analyzed data from the prospective, ongoing, multicenter registry study on Clinical Outcome in Patients with Low Grade Gliomas (The LOG-Glio-Project) on adjuvant therapy for adult patients with diffuse grade 2 and 3 gliomas from November 2015 to December 2022 from 12 centers. Inclusion criteria were IDH-mutant gliomas and complete follow-up data on adjuvant treatment after at least 3 months and reported tumor review board decision. Deviation between EANO 2017 or 2021 guidelines and intended therapy based on board decisions and actual therapy was tested with the paired sample sign test. Multivariate logistic regression was performed to identify factors associated with wait-and-scan follow-up. Results: We analyzed 140 patients, 116 (83%) had a grade 2 lesion and 75 (54%) of patients were diagnosed with astrocytoma and 65 (46%) with oligodendroglioma. Paired sample sign test showed a deviance between guidelines and therapy in 53% of all patients (p&lt;0.001). 79% of patients had at least one unfavorable prognostic factor (age 40 years or older, residual tumor, neurological deficit, grade 3 tumor), yet 35% of the high-risk subgroup were followed by wait-and-scan. In patients who should receive adjuvant treatment according to guidelines, low tumor burden (p=0.02); HR 4.9), but not young age or absence of neurological deficit, was associated with wait-and-scan follow-up. Patients with grade 3 glioma were treated with radiotherapy (RT) and chemotherapy (83%) or RT alone (17%). For oligodendrogliomas, 8% of patients were treated with RT followed by temozolomide, 3% each received temozolomide or PCV alone, 37% were treated with RT and sequential PCV therapy, 12% received RT alone while all others were followed by wait-and-scan. Conclusions: This multicenter study demonstrates that despite clear guidelines, treatment of low-grade gliomas still remains an individual decision. Further evidence is needed to support the low adherence to current guidelines for adjuvant treatment.

Frau

Prognostic impact of extended resections in IDH mutant lower-grade diffuse glioma: Results from a volumetric analysis

Abstract-Text Objective: In diffuse glioma, the prognostic impact of resection is still a matter of debate. The outcome benefit of extended resections may be influenced by the tumor"s molecular phenotype. Also, many studies lack objective quantitative assessment of residual tumor volume (RTV). We aimed at analyzing the prognostic benefit of surgery in a molecularly defined cohort of IDH mutant (IDHmut) diffuse astrocytoma and oligodendroglioma WHO grade 2 and 3 ("lower-grade"). Methods: Patients treated at our department were identified retrospectively for whom molecular work-up classified tumors unambiguously as IDHmut diffuse lower-grade glioma and volumetric analysis of RTV was possible. Patient-, tumor- and treatment-related factors including pre- and post-operative MR FLAIR tumor volumes were correlated with progression-free (PFS) and overall (OS) survival by univariate and multivariate analysis. Confounders of resectability were analyzed by multiple linear regression. Results: 206 patients treated over one decade fulfilled inclusion criteria. Mean age was 40.37 (+/-11.38) years. 105 patients suffered from IDHmut astrocytoma WHO grade 2 (n=48) and 3 (n=57) and 101 patients from oligodendroglioma WHO grade 2 (n=61) and 3 (n=40). 185 patients (89.8%) underwent resection as opposed to biopsy. This was associated with prolonged PFS and OS in astrocytoma (p=0.007; p=0.038) and WHO grade 2 tumors (p=0.012; p&lt;0.0001). Adjuvant treatment was administered in 36% and 97% of WHO grade 2 and 3 patients, respectively. In patients undergoing resection, median pre- and post-op tumor volumes did not differ between tumor subtypes but were significantly larger in WHO grade 3 than 2 tumors (pre: 71.3 vs. 28.8 cm3; post: 7.78 vs. 1.98 cm3). Median RTV was 4.6 cm3 in all IDHmut lower-grade gliomas. There was a stepwise improvement of outcome with decreasing RTV (PFS: p=0.0003; OS: p=0.0004; data given for quartiles), with the strongest effect observed for patients with no RTV (median PFS: undefined vs. 58 months; p=0.007). In multivariate analysis, RTV independently predicted OS (p=0.001; HR 1.012) but not PFS. Resectability was only influenced by pre-op FLAIR tumor volume (p&lt;0.0001). Conclusion: In molecularly defined IDHmut lower-grade glioma, a continuous association of RTV and patient outcome was observed, even at the highest levels of resection. This finding was more pronounced in astrocytoma. Thus, a maximal resection should be strived for whenever safely achievable.

Regorafenib- as a feasible treatment option depending on EGFRvIII mutation?

Abstract-Text Background: Recurrent glioblastoma has a devastating prognosis and limited treatment options. Evidence beyond second line therapy remains scarce. Since the REGMOA trial, Regorafenib has been introduced as a new treatment for recurrent glioblastoma. The aim of this study is to investigate the impact of EGFRvIII mutation on improved therapy response to regorafenib as a third line salvage therapy in recurrent glioblastoma. Methods: Data collection was performed as a single-center retrospective analysis. From January 1st, 2016, to December 31th, 2022 patients with recurrent IDH wild-type glioblastoma (CNS WHO grade 4) had received alkylating chemotherapy as first-line therapy, were reviewed. Inclusion criteria were histological diagnosis, gross total resection in the primary and recurrent situation, prior first-line therapy according to STUPP protocol or CeTeG and Eastern Cooperative Oncology Group (ECOG) performance status score £2. Overall survival after first- and second-line therapy was assessed. Therapeutic effect was evaluated according to Response Assessment in Neuro-Oncology (RANO) criteria. National Cancer Institute-Common Terminology Criteria Adverse Events version 4.0 (NCI-CTCAE 5.0) was used to evaluate adverse events. Additionally, the expression of the EGFR mutant, EGFRvIII, has been determined by our neuropathological institute. Results: A total of 96 patients (42.7% females) with a median age of 56 y (range 30-86 y) were enrolled in the study. MGMT promotor methylation was found in 43 (44.8%) patients. 19 patients (42.1% female) received Regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle as 3rd line therapy during the course of treatment. The median overall survival for all patients was 420 d (95% CI 363.0-506.0). Those who received Regorafenib as salvage therapy had a significantly longer OS (895 d, 95% CI 471.0-813.0) (p=0.021). Patients with recurrent glioblastoma who received second-line therapy with CCNU as salvage therapy, had significantly shorter median OS (376 d, 95% CI 330.0-441.0) than those who were switched to regorafenib after second progression. Adverse effects of any CTCAE grade were noted in 10 patients (52.6%), with 5 patients (26.3%) presenting with CTCAE °III-IV reactions. No death was considered to be drug-related. Noteworthy, patients, who received regorafenib and showed a strong EGFRvIII expression (26 %) had a significantly longer median overall survival than patients with a weak EGFRvIII expression (74 %) (1029 d versus 617 d). Conclusion: Median OS was significantly longer in patients who received Regorafenib as 3rd line chemotherapy after disease progression. Strikingly, strong EGFRvIII expression was associated with a significantly longer OS in these patients and might represent a positive predictor for therapy response to Regorafenib in recurrent glioblastoma.

Dr. med.

Real world experience with TTFields in glioma patients with emphasis on therapy compliance

Abstract-Text Objective Tumor Treating Fields (TTF) therapy has emerged as a significant adjunctive component in the treatment of high-grade tumors following its validation in the EF-14 trial in 2017. The incorporation of TTF therapy, alongside cyclic temozolomide (TMZ) therapy, has demonstrated enhanced outcomes in terms of PFS and OS when the usage exceeds 18 hours per day (75% compliance rate). Post-hoc analysis of the EF-14 trial has demonstrated that compliance rates exceeding 90% are associated with an additional benefit. Given the cost-intensive nature and significant constraints associated with the therapy, our objective is to generate real-world data on compliance through a retrospective analysis at a high-throughput academic center. Methods In this single institutional retrospective cohort study, we analysed usage data of 113 patients (2015-2022, provided by Novocure®). Clinical data were collected from our medical reports. Results are presented as mean values +/- standard deviation. Survival was assessed with the Log-rank test, and regression models were used to identify therapy compliance predictors. A p-value &lt; 0.05 was considered to be statistically significant. Results Mean age was 49.6y and mean preoperative Karnofsky Index 80-90. Most of the patients (75.2%) initiated therapy concurrently with 1st-line treatment, of whom 27.6% started TTFields concomitant to the first cycle of temozolomide. 15.2% started TTFields in the 2nd-line and 9.5% in the 3rd-line setting. 8 patients discontinued TTFields treatment within the first 2 months not reaching an average compliance rate of 50% and were consequently excluded from further compliance analysis. Across the study cohort, the average duration of therapy was 9.3 months with an average of 44.4 days of breaks observed. The median compliance rate was 65.5% (SD 17.6%). Compliance was highest during the first 3 cycles, with rates of 77.7%, 72.3%, and 71.6%, respectively. Linear regression analysis did not identify any predictors of compliance, including age at surgery, timing of therapy, duration of therapy, gender, and preoperative Karnofsky Index. Conclusion This high volume, real-world data reveals that the compliance rate falls short on the intended 75%. These findings highlight the importance of monitoring and promoting adherence to TTFields therapy to maximize its potential benefits in the management of high-grade gliomas. Further, strategies are warranted to expedite the start of therapy and improve long-term adherence.

Re-Resection for recurrent glioblastoma – Does timing matter?

Abstract-Text Objective: Surgery for recurrent glioblastoma (GBM) could prolong patient survival. However, the impact of the timepoint of re-resection on post-surgical progression-free survival (PFS-2) and neurological deterioration remains unclear. Methods: Patients receiving undergoing first re-resection for recurrent GBM IDH-wildtype were analyzed retrospectively. Post-surgical neurological deterioration and progression-free survival of patients undergoing early surgery (within 3 weeks) after suspected recurrence were compared to those receiving surgery at a later time point. In addition, patients receiving re-resection for early (within the first year) vs. late tumor recurrence were also compared. Results: 66 consecutive patients undergoing first re-resection for recurrent GBM in the years 2019 and 2020 were analyzed (mean age: 59 years; 41 males and 25 female). A gross total resection (GTR) had been achieved in 58 patients (88%) at first diagnosis and was achieved in 59 patients (89%) in repeat surgery. Intraoperative MRI guided resection was performed in 59 cases and 5-ALA was applied in 7 cases. The median time interval between first and second resection was 341 days (IQR 194 days) while the median time interval between suspected tumor recurrence and re-resection was d 20 days (IQR 32 days). Surgery was delayed beyond 3 weeks after suspected recurrence in 24 cases (mean time 11 in the "early" vs 187 days in the "late" group, p&lt;0.001) due to salvage chemotherapy/targeted therapy in 13 (54%) cases and initial suspicion of pseudo-progression 11 cases (46%). Compared to patients receiving "early" repeat surgery, this delay was not associated with a higher rate of direct post-operative (7/27 vs 6/24 patients, p=0.934) or permanent (2/27 vs 4/24 patients, p=0.473) neurological deterioration (overall transient deterioration rate= 9%). Median PFS-2 (after repeat surgery) was 211 days in the whole study cohort and did not significantly differ between early and late surgery after suspicion of tumor recurrence (208 in the late vs 238 days in the early group, p=0.644). Across all variables, there were no notable differences in patients with early or late tumor recurrence. Conclusion: Early surgery for suspected recurrent GBM does not seem to be associated with a lower neurological deterioration rate or prolonged survival compared to surgery at a later timepoint. In general, satisfactory rates of postoperative neurological deficits and PFS in this contemporary cohort of patients with repeat surgery for recurrent GBM should be noted.

Antikonvulsive Therapie des IDH-Wildtyp Glioblastom basierend auf DNA Methylierungsklassen

Abstract-Text Objective: Seizures occur in one-third of glioblastoma patients, and in another third, seizures develop during the disease. Nevertheless, the choice of antiseizure medication (ASM) remains challenging, and many patients need an increasement of initial dosage or a polytherapy to achieve seizure control. Here, we investigated the efficacy of levetiracetam to achieve seizure control and define therapeutic targets in RTK I, RTK II, and MES glioblastoma. Methods: We studied 163 patients with IDH-wildtype glioblastoma and DNA methylation was analyzed using the Illumina EPIC array. Differential methylation analysis was performed, examining differentially methylated CpG sites of genes that are therapeutic targets of the most clinically relevant ASM. To further identify RNA expression of these genes, we queried the TCGA database to identify tumors for which DNA methylation and RNA expression were available and vertically integrated both. Results: Preoperative seizures were observed in 54 (33.1%) patients. Of these, 45 (83.3%) patients were treated with levetiracetam achieving seizure freedom in 51.1%. Subdivision into methylation subclasses revealed seizure freedom in 100% (5/5) of RTK I (Figure 1B) and 75.0% (9/12) of MES tumors. In RTK II, only 36.7% (11/30) were seizure-free. Additionally, the average daily dose of levetiracetam decreased in patients with RTK I and MES tumors during follow-up, whereas in RTK II tumors, the dose was increased. We analyzed target receptor genes of levetiracetam (SV2A), perampanel (GRIA), and benzodiazepines (GABRR). RNA expression revealed enrichment of SV2A in RTK I and MES but not RTK II tumors. However, SV2B and SV2C genes were upregulated in RTK II, highlighting its epileptogenic potential. Among the differentially methylated CpG sites of the SV2A gene, significant hypomethylation was observed in RTK I and MES subclasses, whereas RTK II subclass was significantly hypermethylated. Further analysis revealed gene enrichment of GRIA1, GRIA2, and GRIA3 in the RTK II subclass. These results obtained from RNA expression were reflected in methylation profiling, with CpG sites of GRIA genes significantly hypomethylated in the RTK I and RTK II subclasses. Conclusion: Our study provides evidence for DNA methylation-based anticonvulsant treatment in glioblastoma patients. According to our findings, levetiracetam achieves satisfactory seizure-free rates in RTK I and MES tumors, whereas perampanel may be the optimal ASM choice in RTK II tumors.

Neuroonkologie
Klinische Studien: Gliome

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Programm

NeuroonkologieKlinische Studien: Gliome

Termin

Vorsitzende

Programm

Neuroonkologie
Klinische Studien: Gliome