This study presents the development of a glossary designed to harmonize terminology, foster consensus and support the successful implementation of the Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) guidelines. SISAQOL-IMI consortium representatives from 41 international organisations were invited to participate in the development of the glossary. From 2021 to 2024, the glossary was developed through iterative processes, guided by consortium members input and formally updated twice yearly. A template with categories for term, acronym, topic, scientific definition, plain language definition, examples and references/sources was applied and were accessible for input throughout the process. As project documents such as draft guideline recommendations were updated, new terms for the glossary were identified. Definition of terms were primarily sought from a predefined hierarchical list of references and acknowledged resources, such as existing glossaries, prior to seeking other references. Patient representatives and patient advocates from The Workgroup of European Cancer Patient Advocacy Networks contributed to plain language definitions. The glossary development resulted in 227 terms with scientific and plain language definitions, which are integrated into the online SISAQOL-IMI guidelines. During the initial development phase, of 205 terms, the project’s work package teams agreed on 166 (81

INTRODUCTION:Chemical exchange saturation transfer (CEST) has been demonstrated to provide a noninvasive opportunity to image gliomas. Preclinical ultrahigh-field MRI studies have shown the value of the 2 ppm pool; however, in vivo studies in glioma patients are currently lacking. This study aimed to explore the 7 T MRI CEST contrast of the 2 ppm in gliomas and the tumor's different components. METHODS:Twenty-one glioma patients treated at two tertiary referral centers for brain tumors in the Netherlands were scanned. Regions of interest were defined as contrast-enhancing (CE-lesion), nonenhancing (NE-lesion) tumor, and the contralateral normal-appearing white matter (CL NAWM). Magnetization transfer ratio asymmetry (MTRasym), Lorentzian difference (LD), spillover and magnetization transfer-corrected inverse difference (REX), and relaxation-compensated (AREX) were calculated for all regions of interest. RESULTS:The 2 ppm CEST pool signal between tumor regions and normal-appearing tissue was found to be significantly different for all four CEST quantification methods (MTRasym p = 0.001; LD p < 0.001; REX p = 0.008; AREX p = 0.001). The CE and NE lesions showed significantly different 2 ppm pool CEST MTRasym (p = 0.034) and LD (p = 0.052). Significantly different 2 ppm CEST REX (p = 0.005) and AREX (p = 0.001) were found between the CL NAWM and the NE lesions. CONCLUSIONS:CEST 2 ppm pool contrast was distinctive between normal-appearing white matter, enhancing and nonenhancing tumor lesions, independently of the metric used. These findings suggest that the CEST pool at 2 ppm provides a valuable noninvasive contrast for imaging gliomas.

Glioblastoma is the most common type of malignant primary brain tumor and a major cause of morbidity and mortality. In 2021, the World Health Organization updated the classification of Central Nervous System (CNS) tumors to restrict glioblastomas to isocitrate dehydrogenase-wildtype (IDHwt) tumors, improving understanding of the prognosis and optimal therapy for these tumors. This revision also enables more homogeneous populations of patients to be enrolled in clinical trials, facilitating the evaluation of novel therapies. In this updated consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of patients with glioblastoma is discussed. In addition, novel therapies such as immunotherapies, viral therapies, targeted molecular therapies, theranostics, and antibody-drug conjugates will be reviewed, as well as the current challenges and future directions for research.

BACKGROUND AND OBJECTIVES:The aim of this study was to evaluate the long-term results of seizure recurrence after antiseizure medication (ASM) withdrawal vs continuation in patients with diffuse glioma, grades 2 and 3. METHODS:A prospective multicenter observational study was conducted, and patients were recruited from January 2014 until May 2016 from 3 neuro-oncology outpatient clinics in the Netherlands. The main inclusion criteria were as follows: history of ≥1 seizure, for which ASM was started; clinically and radiologically stable disease for ≥12 months; and seizure freedom for ≥12 months from the date of last antitumor treatment or seizure freedom for ≥24 months from the last seizure if seizures occurred after the last antitumor treatment. The primary outcome was time to recurrent seizure. A competing risk model was used to estimate cumulative incidences of recurrent seizure for ASM groups (i.e., ASM withdrawal vs ASM continuation) with death as the competing event. The proportional hazard assumption was violated for the ASM group; therefore, 2 Cox models were constructed for different time intervals (<48 months and ≥48 months since study inclusion). RESULTS:A total of 71 patients were included (39 men [55%] and 58 older than 40 years [82%]); 46 patients with glioma (65%) were in the ASM withdrawal group and 25 (35%) in the ASM continuation group. The cumulative incidence of a recurrent seizure at 48 and 96 months was 48% (95% CI 33%-61%) and 66% (95% CI 48%-78%) for the ASM withdrawal group vs 28% (95% CI 12%-46%) and 52% (95% CI 31%-70%) for the ASM continuation group. The risk of a recurrent seizure differed in the 2 time intervals between the ASM continuation group (reference) and the ASM withdrawal group (cause-specific adjusted hazard ratio [aHR] 2.32 [95% CI 0.93-5.81], p = 0.071, during <48 months, and cause-specific aHR 0.73 [95% CI 0.21-2.49], p = 0.611, during ≥48 months since study inclusion). DISCUSSION:Risk of recurrent seizure when withdrawing ASM was not statistically significantly higher in patients continuing ASM. However, a clinically relevant higher percentage of patients had a recurrent seizure in the ASM withdrawal group compared with the ASM continuation group. The lack of a statistical difference may be explained by the small sample size. Larger studies are needed to confirm these findings. Our results suggest that ASM withdrawal should be initiated cautiously and only when necessary. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that withdrawal of ASM does not significantly increase the risk of recurrent seizures in patients with glioma with stable disease and no seizures for >1 year. Confidence intervals do not exclude a clinically important increased risk of seizures.

Supplementary Figure 3: Characteristics of RTK1 tumors in comparison to RTK2 and MES. A Distribution of MGMT promotor methylation in main glioblastoma methylation subgroups. Classifier assignment is based on the v12.5 version (n = 295). Mutational profiles in B RTK1 tumors (n = 89), C RTK2 tumors (n = 140) and D MES tumors (n = 66).

Supplementary Table 1: Representativeness of study participants.

Purpose Interpretation of changes on the individual level is often based on minimally important differences (MIDs) developed on the group level. We investigated the impact of applying different group-level MIDs (anchor-based and 10-point MIDs) to determine health-related quality of life (HRQoL) changes in glioma patients. We further explored directions and magnitudes of these changes and their relationship to response formats and types of scale. Methods We included 92 glioma patients at least 18 years old from a previously conducted randomized prospective study. We calculated changes in HRQoL (EORTC QLQ-C30 and QLQ-BN20) at individual levels over a two-week period and used anchor-based and 10-point MIDs to estimate if change is clinically meaningful; thereafter, we explored the direction and magnitude of changes. Results Between 8.8% and 66.3% of the patients had actual changes in estimated scales. While 16.3%-60.9% and 8.8%-59.8% of the patients changed to a clinically relevant extent using anchor-based and 10-point MIDs in any scale, respectively. Changes were mostly in the functional than symptom scales and mostly minor, i.e., changes between ‘not at all’ and ‘a little’ or ‘a little’ and ‘quite a bit.’ Conclusion 10-point compared to anchor-based MIDs underestimates clinically relevant changes. Therefore, the application of different MIDs to the same research question can lead to diverse result interpretations. As most changes were minor, it could be argued if these reflect actual relevant changes for an individual or that the current response scale lacks sufficient differentiating ability, warranting further research over the best method to evaluate individual-level changes.

ABSTRACT Gliomas are highly heterogeneous and often include a nonenhancing component that is hyperintense on T 2 weighted MRI. This can often not be distinguished from secondary gliosis and surrounding edema. We hypothesized that the extent of these T 2 hyperintense areas can more accurately be determined on high‐quality 7 T MRI scans. We investigated the extension, volume, and complexity (shape) of T 2 hyperintense areas in patients with glioma on high‐quality 7 T MRI scans compared to clinical MRI scans. T 2 hyperintense areas of 28 patients were visually compared and manually segmented on 7 T MRI and corresponding clinical (1.5 T/3 T) MRI scans, and the volume and shape markers were calculated and subsequently compared between scans. We showed extension of the T 2 hyperintense areas via the corpus callosum to the opposite hemisphere in four patients on the 7 T scans that was not visible on the clinical scan. Furthermore, we found a significantly larger volume of the T 2 hyperintense areas on the 7 T scans compared with the clinical scans (7 T scans: 28 mL [12.5–59.1]; clinical scans: 11.9 mL [11.8–56.6]; p = 0.01). We also found a higher complexity of the T 2 hyperintense areas on the 7 T scans compared with the clinical scans (convexity, solidity, concavity index and fractal dimension [ p < 0.001]). Our study suggests that high‐quality 7 T MRI scans may show more detail on the exact extension, size, and complexity of the T 2 hyperintense areas in patients with a glioma. This information could aid in more accurate planning of treatment, such as surgery and radiotherapy.

Background:There is mounting evidence for surgery as an effective treatment in selected patients with non-hydrocephalic symptomatic pineal cyst (nhSPC) syndrome. We present the first prospective cohort study of surgical PC resection to treat nhSPC syndrome. Methods:CamProS-PC is an observational, single-centre, prospective cohort study. Patients were eligible if aged >18 years, PC size >10 mm, had severe symptoms refractory to medical treatment, without ventriculomegaly. Patient-reported data were collected preoperatively, and 3 and 12 months postoperatively. MR imaging was performed before and 12 months after surgery. The primary outcome was improvement in Role Functioning (RF) at 12 months. Secondary outcomes were changes in other domains of Health-Related Quality of Life (HRQoL) and symptoms at 3 and 12 months, and safety of the intervention. CamProS-PC is registered (ISRCTN51545574) and has been completed. Findings:Between January 2019 and May 2023, 122 consecutive patients were screened and 40 were recruited and underwent PC resection. No loss of follow-up occurred. Mean age was 38 [SD 28-49] with 80% (32/40) females. At baseline, all patients reported headaches, 95% (38/40) dizziness, and 98% (39/40) reported impairment of vision, 98% (38/40) sleep, 90% (36/40) concentration, 88% (35/40) memory, 68% (27/40) speech, and 60% (24/40) hearing. At 12 months postoperatively, HRQoL was improved across all functional scales: RF mean difference 46 [SD 11-80, p < 0.0001] points, Physical 22 [SD -1 to 45, p < 0.0001], Emotional 35 [SD -2 to 71, p < 0.0001], Cognitive 38 [SD 3-73, p < 0.0001], and Social 50 [SD 14-87, p < 0.0001]. Global Health Status improved by 32 [SD 4-61, p < 0.0001] points. Symptoms improved overall in 95% (38/40) of patients. Most benefits were already seen at 3 months. Complications occurred in 23% (9/40) of patients; one was permanent (diplopia). All patients were alive at last follow-up. Interpretation:CamProS-PC demonstrated significant benefit to HRQoL and symptoms one year after PC resection with overall acceptable safety profile. Funding:Department of Clinical Neuroscience, University of Cambridge.

The development of the first European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group (QLG) health-related quality of life (HRQoL) questionnaires contributed to the systematic uptake of HRQoL as an endpoint in cancer clinical trials, and to the measurement of HRQoL for individual assessment in routine care. Following a modular approach, these patient-reported outcome (PRO) measures (PROMs) ensure that both generic and disease-specific issues are assessed, enabling comparison of PROs across groups and studies. The application of a comprehensive and continually refined methodology for developing and updating these PROMs has been crucial in supporting their psychometric and cross-cultural validity, and their continued implementation in clinical research. However, the advancement of measurement science, the more widespread implementation of PROMs, and the significant evolution of anti-cancer therapies over the last decades have highlighted the need to adopt more flexible approaches to PRO assessment to ensure that PROMs remain relevant and fit-for-purpose. The QLG has responded to this call by implementing more tailored PRO measurement approaches through the development and release of the computerised adaptive test (CAT) version of the EORTC QLQ-C30 (i.e., the EORTC CAT Core) and the EORTC Item Library. The EORTC Item Library is an interactive online platform that allows for the creation of customised questionnaires (item lists) from the pool of available items derived from established EORTC QLG PROMs. The aim of this article is to describe the current EORTC QLG approach to PRO measurement in oncology, covering important historical developments and best practice recommendations.

BACKGROUND:Instruments to assess patient-reported outcomes (PRO) should generate high-quality evidence. Reliable PRO evidence is essential to policymakers, in conjunction with outcomes such as survival and radiological response, to understand the net clinical benefit of antitumor treatments. This study aimed to establish the content validity of 215 identified PRO measures used in patients with brain tumors. METHODS:A survey (n = 148 items) was developed reflecting aspects of the WHO International Classification of Functioning, Disability, and Health (ICF) framework. Patients with brain tumors, their proxies, and healthcare professionals (HCPs) were asked to rate each survey item on relevance. An item was considered a relevant issue if ≥25% of the patients or proxies or ≥50% of the HCPs considered that item to be an issue. Next, all items in the identified PRO measures were linked to ICF and relevant items in the survey, and the percentage of content coverage was calculated. RESULTS:In total, 114 patients, 71 proxies, and 65 HCPs from different countries completed the survey. Fifty-six of 148 (37.8%) items in the survey were considered relevant. The most important aspects mentioned by both patients and proxies were difficulty concentrating, difficulty remembering, multitasking, and handling stress. Depending on the definition, between 35% and 49% of PRO measures were considered to have sufficient content validity (≥80% coverage). CONCLUSION:The content validity was insufficient in more than half of the identified PRO measures, particularly multidimensional measures. Future research should investigate whether different approaches to PRO assessment better meet the needs of all stakeholders.

Standardising the implementation of patient-reported outcomes (PROs) in clinical trials is crucial for evaluating the benefits and risks of cancer treatments. The Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) has developed 146 consensus-based recommendations for designing, analysing, interpreting, and presenting PROs in cancer clinical trials. This initiative, undertaken from 2021 to 2025, involved experts, including statisticians, PRO measurement experts, clinicians, and patient representatives from 41 organisations representing regulatory agencies, academia, the pharmaceutical industry, health-technology assessment bodies, and patient advocates. SISAQOL-IMI provides guidance on the implementation of PROs in randomised controlled trials and single-arm trials, terminology, definitions and the selection of PRO score interpretation thresholds, and for visualising PRO results for different audiences. To facilitate the implementation of these standards, in addition to this Policy Review, four key outputs are available: an interactive table, a guidebook, plain language materials, and a glossary.

Purpose The rate of missing data on patient-reported health-related quality of life (HRQOL) in brain tumor clinical trials is particularly high over time. One solution to this issue is the use of proxy (i.e., partner, relative, informal caregiver) ratings in lieu of patient-reported outcomes (PROs). In this study we investigated patient–proxy agreement on HRQOL outcomes in high-grade glioma (HGG) patients. Methods Generic and disease-specific HRQOL were assessed using the EORTC QLQ-C30 and QLQ-BN20 in a sample of 501 patient–proxy dyads participating in EORTC trials 26101 and 26091. Patients were classified as impaired or intact, based on their neurocognitive performance. The level of patient–proxy agreement was measured using Lin’s concordance correlation coefficient (CCC) and the Bland–Altman limit of agreement. The Wilcoxon signed-rank test was used to evaluate differences between patients’ and proxies’ HRQOL. Results Patient–proxy agreement in all HGG patients ( N = 501) ranged from 0.082 to 0.460. Only 18.8% of all patients were neurocognitively intact. Lin’s CCC ranged from 0.088 to 0.455 in cognitively impaired patients and their proxies and from 0.027 to 0.538 in cognitively intact patients and their proxies. Conclusion While patient–proxy agreement on health-related quality of life outcomes is somewhat higher in cognitively intact patients, agreement in high-grade glioma patients is low in general. In light of these findings, we suggest to cautiously consider the use of proxy’s evaluation in lieu of patient-reported outcomes, regardless of patient’s neurocognitive status.

Background: Glioblastoma is an incurable form of brain cancer with a median overall survival of 1.5 years. Despite its progressive nature and high symptom burden, palliative care is not consistently integrated in routine glioblastoma care. Early integration of palliative care better addresses the needs of patients and caregivers, improves quality of life, and reduces inappropriate care in the end-of-life phase. This study aims to design an integrated care pathway to support the early integration of palliative care for patients with glioblastoma. Methods: We used a design thinking approach, engaging stakeholders from neuro-oncology, specialist palliative care, primary care, district nursing, healthcare administration, health insurance, health economics, and patient advocacy. The process consisted of thirteen informal interviews (with healthcare professionals, patients, and caregivers), six expert meetings, and two workshops. Results: First, we mapped existing routine glioblastoma care and identified perceived barriers to early palliative care integration, including variations in advance care planning (ACP) timing, clinicians’ hesitation, unclear referral criteria to specialist palliative care, suboptimal care coordination, and limited experience with glioblastoma in the primary care setting. Second, iterative prototyping led to the development of a care pathway with key components: initiation of ACP by the lead clinician within six weeks of diagnosis, integrated multidisciplinary team meetings for complex cases, ongoing coordination, clear referral triggers for specialist palliative care, and structured caregiver care. Conclusions: The co-designed pathway provides a feasible model for integrating early palliative care into routine care for patients with glioblastoma. Future steps include implementation and evaluation of the care pathway and development of a payment model.

Supplementary Table 2: Characteristics of patients with RTK1 tumors compared to RTK2 and MES according to classifier version v12.5. P-value was calculated for comparison between RTK1 and both other groups (RTK2 and MES) combined. NA, not available.

Background:Core Outcome Sets (COS) define the minimum outcomes that should be measured and reported in all clinical trials for a specific health condition or health area. The aim was to develop 2 COS for intracranial meningioma to be used in future clinical studies: COSMIC: Intervention for effectiveness trials and COSMIC: Observation for studies of incidental/untreated meningioma. Methods:A study advisory group was formed with representation from international stakeholder groups: EORTC BTG, ICOM, EANO, SNO, RANO-PRO, BNOS, SBNS, BIMS, TBTC, International Brain Tumour Alliance, and Brainstrust. Outcomes of potential relevance to key stakeholders were identified and rationalized to populate 2 eDelphi surveys. Participants were recruited internationally and asked to rate each outcome on its importance for inclusion in the COS. The 2 final COS were ratified through 2, one-day, online consensus meetings. Results:The COSMIC: Intervention eDelphi survey contained 25 items and was completed by 199 participants. Following the consensus meeting, 15 outcomes were included. The COSMIC: Observation eDelphi survey contained 17 items and was completed by 129 participants. Sixteen outcomes were included. Eight core outcomes were common to both COS; tumor growth, physical, emotional, and neurocognitive functioning, overall quality of life, progression-free survival, meningioma-specific mortality and overall survival. Role and social functioning were core outcomes in COSMIC: Observation but not COSMIC: Intervention. Conclusions:Uptake of these COS in relevant future meningioma clinical studies will ensure that stakeholder-determined, critically important outcomes are consistently measured and reported across similar clinical studies.

Supplementary Figure 1: Overview of the clinical trial and biomarker analysis. Out of 596 patients in the EORTC-26101 trial, patient tumor tissue to perform DNA methylation (Meth) and NGS sequencing analysis was available from 380 patients (63.8%). Of these, 99 patients treated with lomustine and 189 patients treated with lomustine and bevacizumab were eligible to detect biomarkers for bevacizumab response.

Background:A pooled data analysis by Quinten et al. (2009) found three European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) health-related quality of life (HRQoL) scales to be prognostic for survival: physical functioning, pain and appetite loss. This study aims to replicate these findings in an independent data set comprising a broader cancer population. Methods:Data were obtained from 46 clinical trials across three cancer research networks conducted between 1996 and 2013 that assessed HRQoL using the EORTC QLQ-C30. A stratified Cox proportional hazards model was employed to assess the prognostic significance of baseline QLQ-C30 scale scores on overall survival, adjusting for socio-demographic and clinical variables. Stepwise model selection was done at 5% significance level. Model stability and prognostic accuracy were evaluated via bootstrapping and the C index respectively. Findings:Data from 16,210 patients reporting HRQoL at baseline, spanning 17 cancer types, was used. The stratified multivariable model confirmed that better physical functioning (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.93-0.96), lower pain (HR, 1.02; 95% CI, 1.01-1.03), and appetite loss (HR, 1.04; 95% CI, 1.03-1.05) were significantly associated with survival. Additionally, global health status/QoL, dyspnoea, emotional and cognitive functioning were found to be prognostic for survival. This final model, encompassing sociodemographic, clinical, and HRQoL variables, achieved a corrected C index of 0.74, marking a 48% enhancement in discriminatory ability. Bootstrap evaluation indicated no major instability issues. Interpretation:These results support previous findings that baseline physical functioning, pain, and appetite loss scores, along with four other scales from the EORTC QLQ-C30, predict survival in cancer patients. Funding:EORTC Quality of Life Group.

Supplementary Figure 6: Overall Survival according to PTEN mutation status in the group of IDH-wildtype glioblastomas (n = 362).

Supplementary Figure 4: Multivariate analysis. Baselines were MGMT = “methylated” and Classifier = “GBM MES”. Classifier assignment is based on the v12.5 version (n = 380).