Oral anticancer agents (OAAs) are commonly prescribed for patients with primary brain tumors, but adherence can be challenging due to cognitive impairment and discontinuous treatment schedules. This subgroup analysis of the randomized phase 3 CAPRI trial evaluated the impact of a nurse navigator-led intervention combined with a digital platform (web portal and mobile app) versus standard care in patients with primary brain tumors treated with OAAs. The primary endpoint was Relative Dose Intensity (RDI), with secondary endpoints including adherence, toxicity, healthcare utilization, and patient-reported experience. Fifty-one patients were included between October 2016 and May 2019, 63% of whom had glioblastoma. Twenty-six patients received the intervention. RDI was significantly higher in the intervention group compared to the control group (105% ± 12 vs. 97.6% ± 13, p = 0.04). The intervention also resulted in fewer emergency room visits, reduced hospitalizations, greater use of supportive care services, and improved patient-reported experience (all p < 0.05). Remote monitoring allowed early corticosteroid adjustments in cases suggestive of intracranial hypertension, helping to prevent hospitalizations. No significant differences were observed in treatment-related toxicity. These findings suggest that a nurse navigator-led digital intervention can improve care continuity and outcomes in this population and merit further investigation.

PURPOSE:Prognosis in low-grade gliomas (LGGs) remains highly variable, and treatment-related late toxicity is a concern. This trial was comparing single-modality therapies in patients who often survive for years or decades and investigating differential responses according to molecular markers. METHODS:Four hundred seventy-eight patients with clinical high-risk LGG (WHO grade 2) were randomly assigned to standard radiotherapy (RT; 28 × 1.8 Gy) or dose-dense temozolomide (TMZ; 75 mg/m2 once daily × 21/28 days, up to 12 cycles). RESULTS:There was no significant difference in progression-free survival or overall survival (OS) between study arms. Analyzable tumor tissue in 73% (351/478) of patients allowed for post hoc reclassification according to the 2021 WHO pathologic criteria. In astrocytoma, IDHmt/1p/19q noncodeleted (n = 178), median OS was similar, 6.6-6.7 years irrespective of arm (0.67-1.44, P = .93). In oligodendroglioma, IDHmt/1p/19q codeleted (n = 109), median OS was 12.9 years (9.4-not reached) with RT and 14.9 years (10.1-number of events not reached) with TMZ (hazard ratio [HR], 0.88 [0.52-1.49], P = .63). In 64 tumors without isocitrate dehydrogenase (IDH) mutations, survival favored the TMZ arm: OS 2.5 (1.8-3.3) versus 4.7 (2.2-7.2) years (HR, 0.47 [0.27-0.82], P = .0068). Patients age 40 years and older fared better than patients younger than 40 years, challenging the current notion of age alone as a negative prognostic factor. CONCLUSION:The assigned initial treatment modality did not affect progression-free survival or OS, regardless of the molecular subtype. Combined-modality therapy was not tested in this trial but has since become a standard of care for IDH-mutant astrocytoma. With emerging novel therapeutic options, rational treatment strategies tailored at the individual clinical and pathologic recurrence risk profiles will be needed. The validity of an age cutoff as prognostic factor is challenged when tumors are molecularly classified.

BACKGROUND:The CATNON trial investigated the benefit of the addition of concurrent or adjuvant temozolomide to radiotherapy in individuals with anaplastic astrocytoma. We report the long-term follow-up of the study focusing on the individuals with isocitrate dehydrogenase (IDH) mutated (IDHmt) tumours. METHODS:This randomised, open-label, phase 3 study in 137 institutions across Australia, Europe, and North America included participants aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions), radiotherapy with concurrent oral temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Participants were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. The eighth amendment of the study protocol (June 27, 2011) incorporated analysis of IDH mutational status into the study. We report the intention-to-treat analysis and the exploratory analysis within the population of participants with astrocytoma with an IDH mutation. As the safety data have been published previously, no safety data are reported. This trial is registered with ClinicalTrials.gov, NCT00626990, and is completed. FINDINGS:Between Dec 4, 2007, and Sept 11, 2015, 1407 participants were registered and 751 participants were randomly allocated, 444 of whom were diagnosed with an IDHmt tumour. After a median follow-up for overall survival of 10·9 years (IQR 9·5-12·7), in the intention-to-treat population, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (hazard ratio [HR] 0·65 [95% CI 0·54-0·77]), but concurrent did not compared with no concurrent temozolomide (HR 0·91 [0·76-1·08]). In univariable analysis of the participants with an IDHmt tumour, concurrent temozolomide had no statistically significant effect on overall survival (median 9·7 years [8·2-12·5] vs 7·2 years [6·2-9·4]; HR 0·81 [0·63-1·04]), but median overall survival was 12·5 years (95% CI 9·4-15·0) with adjuvant temozolomide compared with 6·0 years (5·1-7·2) with no adjuvant temozolomide (HR 0·54 [0·42-0·69]). No benefit of temozolomide, neither concurrent nor adjuvant, was observed in participants with IDH wild-type tumours. Methylation-based subtyping and several DNA alterations (eg, amplification of PDGFRA and CDK4, homozygous deletion of CDKN2A, and total copy number variation) were associated with worse outcome, none of which was predictive for benefit to temozolomide. INTERPRETATION:Long-term follow-up confirms that radiotherapy followed by 12 cycles of adjuvant temozolomide without concurrent temozolomide during radiotherapy improves survival for individuals with aggressive IDHmt astrocytoma. FUNDING:MSD.

BACKGROUND:Effective radiotherapy requires balancing target coverage with sparing of organs at risk. We developed a fully automated, Python-based pipeline to integrate white matter tracts (WMTs) into stereotactic brain radiotherapy (SBRT) planning. METHODS:The pipeline uses a probabilistic atlas of 52 WMTs and includes image pre-processing, affine and non-linear registration to a standardized space, and dose mapping into the atlas framework. Various interpolation techniques were assessed to optimize dose-mapping accuracy. Robustness was assessed through sensitivity analyses of four interpolation methods for affine and non-linear transformations, resulting in 16 combinations, and local perturbations of registration fields. Prospective validation was performed in nine patients with pre-treatment diffusion MRI (GE 3T, 64 directions, b = 1000, 2 mm isotropic, 4'30 acquisition), where atlas-based WMTs were compared with individual tractography using TractSeg and DeepWMA. RESULTS:Applied to 108 patients, the pipeline achieved precise spatial registration, with B-spline interpolation providing the most consistent dose mapping. Sensitivity analyses showed negligible effects of interpolation or perturbations on the mean and minimum doses to WMTs, while the maximum dose in tracts located adjacent to the planning target volume was more sensitive, with rare deviations up to ∼1 Gy. In prospective validation, median Dice coefficients across all evaluated WMTs were 0.49 (range 0.00-0.66) for TractSeg versus DeepWMA, 0.45 (0.02-0.68) for TractSeg versus the atlas, and 0.31 (0.00-0.55) for DeepWMA versus the atlas. Despite modest Dice values, as consistently reported in tractography benchmarks, the atlas-based pipeline performed within the same range of variability as that observed between two widely used tractography methods, supporting its validity for clinical application. CONCLUSIONS:This pipeline enables robust and reproducible integration of WMTs into SBRT planning, validated against tractography and applicable when diffusion MRI is unavailable. It provides a foundation for establishing tract-specific dose constraints, advancing neurocognitive-sparing SBRT.

Hypo-fractionated stereotactic radiotherapy (HFSRT) may enhance anti-PDL1 immunotherapy efficacy in recurrent glioblastoma by promoting immunogenic cell death. After establishing the safety of HFSRT combined with Durvalumab in a phase I trial, we present the results of the randomized phase II STERIMGLI trial (NCT02866747). Eligible patients with recurrent glioblastoma (WHO 2016 classification) and tumor volume ≤35 mm were randomized 1:2 to receive HFSRT alone (24 Gy in 3 fractions over 5 days, Arm A) or the same HFSRT plus Durvalumab 1500 mg on day 5, then every 4 weeks until progression or 12 months (Arm B). The primary endpoint was overall survival (OS) from randomization. With 100 patients and 77 events, the study had 85% power to detect an HR of 0.57 (one-sided, 10%-level test). Between February 2018 and April 2023, 102 patients (median age 61.5 years old, range [26-87]) were randomized (n=34 and 68 in Arm A and B). Baseline characteristics were balanced, except for more prior targeted therapy in Arm B (22.1% vs 2.9%) and more IDH-mutated in Arm A (15.6% vs 6.1%). Treatment was well tolerated, 12.4% of patients experienced grade 3 treatment-related adverse events (no grade 4 or 5). After a median follow-up of 34.1 months, 78 deaths were reported, median OS was 13.3 months in Arm A vs, 16.1 months in Arm B (Hazard Ratio (HR)=0.77, 80%CI = [0.56;1.06], one-sided p=0.146). In multivariate analysis, adjusted HR for prognostic factors was 0.41 (80%CI = [0.28;0.60]). Among patients with IDH-wildtype glioblastoma (WHO 2021), median OS was 10.9 vs, 16.1 months (HR=0.54, 80%CI=[0.39;0.76], one-sided p=0.010). The median intracranial progression-free interval assessed by investigators with RANO criteria was 2.3 vs, 3.5 months (HR=0.91, 80%CI=[0.68;1.23], one-sided p=0.349). Re-irradiation with HFSRT (24 Gy/3 fractions) combined with Durvalumab is safe and improves overall survival in patients with recurrent glioblastoma.

PURPOSE:The multicentre randomised phase III trial EORTC-1709-BTG/CCTG CE.8 (MIRAGE) (NCT03345095) analysed the addition of the proteasome inhibitor marizomib to temozolomide-based chemoradiotherapy with 60 Gy in 30 fractions in patients with newly diagnosed glioblastoma. Here, we analysed the benchmark case procedure for delineation and planning radiotherapy quality assurance (RTQA) that was performed before patient inclusion. MATERIALS AND METHODS:Prior to trial activation, all participating centers were required to submit a benchmark case for radiotherapy volume delineation and planning. Submissions were prospectively reviewed by the RTQA team, and in cases of unacceptable variations, centers were required to revise and resubmit the same case until protocol compliance was achieved. Structure sets and dose distributions of the same benchmark patient submitted by participating centres were analysed. We determined the rate and causes of variations of glioblastoma target volumes (TV) and organs at risk (OAR) from the protocol-specified delineation guidelines. Delineation interobserver variability before and after RTQA review were quantified using the Dice similarity coefficient (DSC) with respect to ground truth contours at first and final submission of the benchmark case. The influence of reducing delineation interobserver variability on dose parameters of ground truth structures was determined. RESULTS:The delineations by 88 institutes were judged by RTQA reviewers to contain "unacceptable" variations in 80 % (n = 70) of the cases. TV contours were more frequently deemed unacceptable than organs at risk (72 % vs 55 %). After RTQA review, the mean DSC significantly improved for TV (GTV: 0.77 vs 0.82, p = 0.002; CTV: 0.85 vs 0.88, p < 0.0001; PTV: 0.85 vs 0.88, p < 0.0001), brainstem (0.87 vs 0.88, p = 0.007), cochlea (0.58 vs 0.62, p = 0.004) and optic nerve (0.65 vs 0.67, p = 0.0005), indicating reduced interobserver variability. The delineation adjustments after RTQA review resulted in a significant increase of the mean CTV D98% (+2.2 Gy, +4%, p = 0.005), indicating an improved target coverage. Doses to organs at risk did not change significantly but still met predefined constraints. CONCLUSIONS:Variations in the delineation of target volumes and organs at risk were frequently judged as "unacceptable" during the RTQA review process. Besides a significant increase of CTV coverage, the impact of variations on organ at risk dosimetry was minor, suggesting a potentially negligible effect on toxicity outcomes. Quantitative metrics to assess delineation variations should be explored to improve the RTQA process in clinical trials and routine practice, aiming to flag delineation variations that confer an effect on tumour control or toxicity.

Background and Purpose: Although reirradiation of glioblastoma has a long history of clinical practice, guidance on how to perform it in the context of recent technological advances, modern imaging modalities or systemic therapy is scarce. This joint ESTRO/EANO guideline aims to collect the existing evidence to produce recommendations for safe reirradiation of glioblastoma. Methods: The basis of this ESTRO/EANO clinical practice guideline are nine key questions (KQ) which were formulated by a consortium of radiation-oncologists, radiologists, medical oncologists, neurooncologists, medical physicists and radiation therapists. A systematic review was conducted and the KQ were addressed based on this evidence and expert opinion to draft recommendations and statements which were then voted on in a modified DELPHI process. Results: The DELPHI consensus process resulted in 18 recommendations and nine statements of which all achieved group consensus. Thirteen (48%) were based on available prospective evidence and 14 (52%) on expert opinion. Level of evidence did not exceed "moderate", reflecting the scarcity of prospective randomized evidence for most aspects of reirradiation. Consensus recommendations and statements reflected aspects of patient se- lection, imaging for recurrence assessment, target volume delineation, treatment planning, combined modality treatment, and follow-up. Conclusions: Currently, based on the ESTRO/EANO consensus, reirradiation may be considered in selected pa- tients with glioblastoma. GTV definition is based on T1-weighted MR-sequences, while a GTV to CTV margin is not mandatory. A PTV margin of maximum 3 mm is recommended based on the individual mask system and IGRT procedures. A biological effective dose greater than 36 Gy in 2 Gy fractions is recommended. A careful assessment of prognostic factors on survival such as age, interval from initial radiation, large treatment volumes, poor KPS, and poor neurologic/neurocognitive status is essential for making a clinical recommendation.

The management of brain metastases is challenging and should ideally be coordinated through a multidisciplinary approach. Stereotactic radiosurgery (SRS) has been the cornerstone of management for most patients with oligometastatic central nervous system involvement (one to four brain metastases), and several technological and therapeutic advances over the past decade have broadened the indications for SRS to include polymetastatic central nervous system involvement (>4 brain metastases), preoperative application and fractionated SRS, as well as combinatorial approaches with targeted therapy and immune-checkpoint inhibitors. For example, improved imaging and frameless head-immobilization technologies have facilitated fractionated SRS for large brain metastases or postsurgical cavities, or lesions in proximity to organs at risk. However, these opportunities come with new challenges and questions, including the implications of tumour histology as well as the role and sequencing of concurrent systemic treatments. In this Review, we discuss these advances and associated challenges in the context of ongoing clinical trials, with insights from a global group of experts, including recommendations for current clinical practice and future investigations. The updates provided herein are meaningful for all practitioners in clinical oncology. Stereotactic radiosurgery (SRS) has been established as a key therapeutic modality for the management of brain metastases. In this Review, an international group of experts discuss the expanding opportunities for SRS, including application for larger brain metastases and cumulative intracranial tumour volumes, fractionated delivery, neoadjuvant use and combinatorial approaches with modern systemic therapy, as well as associated challenges and remaining questions.

Purpose This guideline will discuss radiotherapeutic management of IDH-mutant grade 2 and grade 3 diffuse glioma, using the latest 2021 WHO (5th) classification of brain tumours focusing on: imaging modalities, tumour volume delineation, irradiation dose and fractionation. Methods The ESTRO Guidelines Committee, CNS subgroup, nominated 15 European experts who identified questions for this guideline. Four working groups were established addressing specific questions concerning imaging, target volume delineation, radiation techniques and fractionation. A literature search was performed, and available literature was discussed. A modified two-step Delphi process was used with majority voting resulted in a decision or highlighting areas of uncertainty. Results Key issues identified and discussed included imaging needed to define target definition, target delineation and the size of margins, and technical aspects of treatment including different planning techniques such as proton therapy. Conclusions The GTV should include any residual tumour volume after surgery, as well as the resection cavity. Enhancing lesions on T1 imaging should be included if they are indicative of residual tumour. In grade 2 tumours, T2/FLAIR abnormalities should be included in the GTV. In grade 3 tumours, T2/FLAIR abnormalities should also be included, except areas that are considered to be oedema which should be omitted from the GTV. A GTV to CTV expansion of 10 mm is recommended in grade 2 tumours and 15 mm in grade 3 tumours. A treatment dose of 50.4 Gy in 28 fractions is recommended in grade 2 tumours and 59.4 Gy in 33 fractions in grade 3 tumours. Radiation techniques with IMRT are the preferred approach.

PURPOSE Patients with IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma (O3 IDHmt/Codel ) benefit from adding alkylating agent chemotherapy to radiotherapy (RT). However, the optimal chemotherapy regimen between procarbazine, 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and vincristine (PCV) and temozolomide (TMZ) remains unclear given the lack of randomized trial data comparing both regimens. METHODS The objective was to assess the overall survival (OS) and progression-free survival (PFS) associated with first-line PCV/RT versus TMZ/RT in patients newly diagnosed with O3 IDHmt/Codel . We included patients with histologically proven O3 IDHmt/Codel (according to WHO criteria) from the French national prospective cohort Prise en charge des OLigodendrogliomes Anaplasiques (POLA). All tumors underwent central pathologic review. OS and PFS from surgery were estimated using the Kaplan-Meier method and Cox regression model. RESULTS 305 newly diagnosed patients with O3 IDHmt/Codel treated with RT and chemotherapy between 2008 and 2022 were included, of which 67.9% of patients (n = 207) were treated with PCV/RT and 32.1% with TMZ/RT (n = 98). The median follow-up was 78.4 months (IQR, 44.3-102.7). The median OS was not reached (95% CI, Not reached [NR] to NR) in the PCV/RT group and was 140 months (95% CI, 110 to NR) in the TMZ/RT group (log-rank P = .0033). On univariable analysis, there was a significant difference in favor of PCV/RT in both 5-year (PCV/RT: 89%, 95% CI, 85 to 94; TMZ/RT: 75%, 95% CI, 66 to 84) and 10-year OS (PCV/RT: 72%, 95% CI, 61 to 85; TMZ/RT: 60%, 95% CI, 49 to 73), which was confirmed using the multivariable Cox model adjusted for age, type of surgery, gender, Eastern Cooperative Oncology Group performance status, and CDKN2A homozygous deletion (hazard ratio, 0.53 for PCV/RT, 95% CI, 0.30 to 0.92, P = .025). CONCLUSION In patients with newly diagnosed O3 IDHmt/Codel from the POLA cohort, first-line PCV/RT was associated with better OS outcomes compared with TMZ/RT. Our data suggest that the improved safety profile associated with TMZ comes at the cost of inferior efficacy in this population. Further investigation using prospective randomized studies is warranted.

Abstract BACKGROUND Predicting progression-free survival (PFS) in glioblastoma (GB) is crucial for post-surgery treatment decisions. Detecting post-operative volumes via pre-radiotherapy (preRT) MRI, combined with clinical and molecular data, improves prognosis. A decision tree model using these features provides valuable insights into PFS when aligned with the new RANO resection categories. MATERIAL AND METHODS We analyzed retrospective data from 205 GB treated by STUPP protocol across three French centers (2009-2021) as part of the AIDREAM project. Data included clinical and anatomopathological information. Advanced automated segmentation of tumor subregions on preRT MRI was used, subsequently revalidated by experts, and a detailed brain atlas to refine lesion site. A survival analysis was performed using Kaplan-Meier with log-rank tests to compare survival distributions according to clinical data, surgical extension and the 4 RANO volume subcategories. A conventional univariate and multivariate Cox proportional HR analysis based on clinical/anatomopathological data and residual non-contrast-enhanced (nonCE) and contrast-enhanced (CE) volumes on pre-RT MRI was also conducted. The SurvivalTree algorithm, chosen for its capability to handle survival data and missing values, was applied in two experimental setups: one using only clinical data and another using combined clinical and volumetric data. Variables included age, sex, KPS, surgical extension, MGMT, tumor site and nonCE, CE, tumor bed and postoperative changes volumes. In our 5-fold cross-validation process, we individually assessed the importance of each feature in every fold through permutations. This approach enabled us to evaluate the consistency and dependability of feature importance across various data subsets. We then calculated the mean importance of each feature over all folds. RESULTS Median PFS was 8 months (1-62) and median OS was 18 months (2- 93). Based on the log-rank test, it was shown that extensive surgical resection and lower RANO categories improved PFS, with significant p-values. MGMT status correlated strongly with longer PFS (p < 0.001). Univariate analysis highlighted significant predictors including nonCE (p=0.002) and CE volume (p=0.017), while multivariate analysis confirmed only the significance of nonCE volume (HR 1.011, 95% CI 1.005-1.018, p < 0.001). The decision tree model’s performance increased with volumetric data, from a mean C-index of 0.546 ± 0.057 to 0.576 ± 0.066, identifying CE and nonCE volumes and MGMT status as key predictive factors. CONCLUSION Integrating surgical, volumetric, and molecular data into a decision tree model could effectively enhance the prediction of PFS in glioblastoma. Expanding the study to the entire AIDREAM cohort of 733 patients will validate the robustness of the model and its clinical utility for personalized treatment strategies.