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Cancer-related cognitive impairment (CRCI) is a broad term encompassing subtle cognitive problems to more severe impairment. CRCI severity is influenced by host, disease, and treatment factors and affects patients prior to, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a Clinical Trial Planning Meeting (CTPM) to review the state of the science on CRCI and to develop both Phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system (CNS) disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of CRCI, members of the SxQOL SC, patient advocates, representatives from all seven NCI Community Oncology Research Program (NCORP) Research Bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacologic and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three CTPM working groups (longitudinal studies and pharmacologic and behavioral intervention trials) convened for one year to discuss and report on top priorities and to design studies. The CTPM experts concluded sufficient data exist to advance Phase II/Phase III trials utilizing selected pharmacologic and behavioral interventions for the treatment of CRCI in the non-CNS setting with recommendations included herein., (© The Author(s) 2024. Published by Oxford University Press.)

Background: EuroQoL EQ-5D-5L is a commonly used measure of health-related quality of life in clinical trials given the use of its index score as a measure of health utilities. It is unclear whether EQ-5D-5L is sensitive to changes in neurocognitive function and progression that occur following brain radiation. This study sought to evaluate the sensitivity of EQ-5D-5L in reflecting these changes., Methods: A secondary analysis of NRG Oncology CC001 was performed. Mean EQ-5D-5L index and visual analog scale (VAS) score changes from baseline between groups of patients stratified by neurocognitive function and intracranial progression status were assessed. MD Anderson Symptom Inventory for brain tumor (MDASI-BT) symptom and interference items were also analyzed between groups., Results: EQ-5D-5L mean index and VAS score changes between patients who had cognitive failure and those who had preserved cognition showed no statistically significant differences at any timepoint. In contrast, VAS changes at 4 months (1.61 vs -5.13, P = .05) and 6 months (8.17 vs -0.14, P = .04) were significantly improved in the patients who survived without intracranial progression. MDASI-BT cognitive factor scores were improved in the cohort of patients with preserved neurocognitive function at 2 months (1.68 vs 2.08, P = .05) and 4 months (1.35 vs 1.83, P = .04). MDASI-BT symptom interference was significantly associated with intracranial progression at 4 months, but not with neurocognitive status., Conclusion: EQ-5D-5L index and VAS scores were not sensitive to neurocognitive changes that patients experienced, but VAS scores were sensitive to progression. This study challenges the routine use of EQ-5D as a quality of life metric in brain metastases clinical trials that are focused on preventing neurocognitive dysfunction., Trial Registration: NCT# 02360215., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Hippocampal avoidant whole brain radiotherapy (HA-WBRT) is the standard of care for patients needing WBRT for brain metastases. This study, using existing data from NRG Oncology CC001 including baseline tumor characteristics and patient-reported MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) scores, sought to identify subgroups of patients that demonstrate differential neuroprotective treatment response to HA-WBRT., Methods: An exploratory analysis of NRG CC001, a phase 3 trial in which 518 patients were randomly assigned to WBRT plus memantine or HA-WBRT plus memantine, was performed. Rates of neurocognitive function failure (NCFF) were estimated between subgroups and stratified by arm. Covariate and subgroup interaction with differential treatment response were calculated., Results: The benefit of HA-WBRT on decreasing NCFF was seen in patients living ≥ 4 months (HR 0.75, 95% CI: 0.58-0.97, P = .03), whereas patients living < 4 months derived no significant neurocognitive benefit. A significant association between baseline MDASI-BT cognitive factor and treatment response (interaction P = .03) was identified. Patients with lower MDASI-BT scores (less patient-reported cognitive impairment) derived significantly greater benefit (HR = 0.64, 95% CI: 0.48-0.85, P = .002) compared to those with highest MDASI-BT scores (HR = 1.24, 95% CI: 0.76-2.04, P = .39). Tumor histology also had a significant interaction (P = .01) with treatment response. Primary lung histology patients derived cognitive failure risk reduction (HR = 0.58, 95% CI: 0.43-0.77, P = .0007) from HA-WBRT, in contrast to nonlung primary histology patients (HR = 1.15, 95% CI: 0.78-1.50, P = .48)., Conclusions: Differential neuroprotective response to HA-WBRT was identified in this analysis. Patients surviving ≥ 4 months derived benefit from HA-WBRT. There is evidence of heterogeneity of treatment effect for patients with less severe patient-reported cognitive impairment at baseline and those with primary lung histology., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: A significant unmet need exists for the treatment of glioblastoma, IDH- wildtype (GBM). Preclinical work shows that acetazolamide sensitizes GBM to temozolomide (TMZ) by overcoming TMZ resistance due to BCL-3-dependent upregulation of carbonic anhydrase. Acetazolamide is Food and Drug Administration-approved for the treatment of altitude sickness. Drug repurposing enables the application of drugs to diseases beyond initial indications. This multi-institutional, open-label, phase I trial examined a combination of acetazolamide and TMZ in patients with MGMT promoter-methylated high-grade glioma., Methods: A total of 24 patients (GBM, IDH -wildtype = 22; Grade 4 astrocytoma, IDH -mutant = 1; Grade 3 astrocytoma, IDH -mutant = 1) were accrued over 17 months. All patients received oral acetazolamide (250 mg BID for 7 days increased to 500 mg BID for Days 8-21 of each 28-day cycle) during the adjuvant phase of TMZ for up to 6 cycles., Results: No patient had a dose-limiting toxicity. Adverse events were consistent with known sequelae of acetazolamide and TMZ. In the 23 WHO Grade 4 patients, the median overall survival (OS) was 30.1 months and the median progression-free survival was 16.0 months. The 2-year OS was 60.9%. In total 37% of the study population had high BCL-3 staining and trended toward shorter OS (17.2 months vs N.R., P  = .06)., Conclusions: The addition of acetazolamide is safe and tolerable in GBM patients receiving standard TMZ. Survival results compare favorably to historical data from randomized trials in patients with MGMT promoter - methylated GBM and support examination of acetazolamide in a randomized trial. BCL-3 expression is a potential biomarker for prognosis in GBM or for patients more likely to benefit from TMZ., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Global incidence for brain tumors varies substantially without explanation. Studies correlating radon exposure and incidence are inconclusive. Particulate pollution has been linked to increased tumor incidence. Particulates may disrupt the blood-brain barrier allowing intracranial exposure to oncogenic radon. We investigated the relationship between exposure to residential radon, particulate pollution, and brain tumor incidence in the United States (US)., Methods: County-level median radon testing results and annual air quality index values were obtained and divided into tertiles. Counties without both values were excluded. Four groups of counties were generated: high particulate/high radon (high/high), high/low, low/high, and low/low. Using incidence data from the Central Brain Tumor Registry of the US (provided by CDC's National Program of Cancer Registries and NCI's SEER), annual age-adjusted incidence rates (AAAIRs) by group were generated by behavior. Incidence rate ratios were calculated to examine for significant differences (α = .05). Poisson regression accounting for possible confounders was conducted., Results: Counties with available data included 83% of the US population. High/high exposure was significantly associated with increased AAAIR of all non-malignant tumors (up to 26% higher, including most meningiomas) even after accounting for potential confounders. An increased AAAIR was noted for all malignant tumors (up to 10% higher), including glioblastoma, but was negated after accounting for demographic/socioeconomic differences., Conclusions: We present the first report suggesting increased non-malignant brain tumor incidence in regions with high particulate and radon exposure. These findings provide insight into unexplained variation in tumor incidence. Future studies are needed to validate these findings in other populations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: CNS myeloma is a rare manifestation of multiple myeloma and is often associated with a dismal prognosis; however, cases are increasing in frequency as overall survival improves for MM. There is currently no standardized treatment for CNS myeloma; however, different chemotherapy and radiotherapy regimens have been described., Methods: We had previously reported on the efficacy of proton-based craniospinal irradiation in a patient with CNS myeloma; here we present a patient with a history of extramedullary plasmacytoma, 10 years in remission status post standard systemic chemotherapy, with biopsy-proven CNS myeloma successfully treated with systemic chemotherapy as a first-line treatment., Results: The patient achieved clinical and radiographic remission on 2 separate occasions with systemic chemotherapy alone., Conclusions: This case demonstrates that systemically administered agents may have activity in CNS myeloma. Further investigations are necessary to establish the optimal combination of agents and treatment schedules., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

As novel systemic therapies yield improved survival in metastatic cancer patients, the frequency of brain metastases continues to increase. Over the years, management strategies have continued to evolve. Historically, stereotactic radiosurgery has been used as a boost to whole-brain radiotherapy (WBRT) but is increasingly being used as a replacement for WBRT. Given its capacity to treat both macro- and micro-metastases in the brain, WBRT has been an important management strategy for years, and recent research has identified technologic and pharmacologic approaches to delivering WBRT more safely. In this review, we outline the current landscape of radiotherapeutic treatment options and discuss approaches to integrating radiotherapy advances in the contemporary management of brain metastases., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

The incidence of brain metastasis is increasing as improvements in systemic therapy lead to increased survival. This provides new and challenging clinical decisions for patients who are trying to balance the risk of recurrence or progression with treatment-related side effects, and it requires appropriate management strategies from multidisciplinary teams. Improvements in prognostic assessment and systemic therapy with increasing activity in the brain allow for individualized care to better guide the use of local therapies and/or systemic therapy. Here, we review the current landscape of brain-directed therapy for the treatment of brain metastasis in the context of recent improved systemic treatment options. We also discuss emerging treatment strategies including targeted therapies for patients with actionable mutations, immunotherapy, modern whole-brain radiation therapy, radiosurgery, surgery, and clinical trials., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Survivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent X-ray radiotherapy (XRT) versus proton radiotherapy (PRT)., Methods: Pediatric patients who underwent either XRT or PRT and received posttreatment age-appropriate neuropsychological evaluation-including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning-were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time., Results: Between 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%), or posterior fossa (53.6%) compartments received radiation and had posttreatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated SES and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs 2.6 y, P < 0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (β = 10.6, P = 0.048) and processing speed (β = 14.4, P = 0.007) relative to XRT, with trend toward higher verbal IQ (β = 9.9, P = 0.06) and general adaptive functioning (β = 11.4, P = 0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ (P = 0.01) and IQ (P = 0.04) following PRT, with trend toward improved processing speed (P = 0.09)., Conclusions: PRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Gliomas represent a broad spectrum of disease with life-expectancy outcomes ranging from months to decades. As our understanding of the molecular profiles of gliomas expands rapidly, practitioners are now better able to identify patients with favorable versus nonfavorable prognoses. Radiation therapy plays a key role in glioma treatment, improving disease control and oftentimes survival. However, for survivors, either long-term or short-term, radiation-induced cognitive impairments may negatively impact their quality of life. For patients with both favorable and unfavorable prognoses, intensity modulated proton therapy (IMPT) may offer significant, yet unproven benefits. IMPT is the newest and most advanced proton delivery technique, one with substantial benefits compared with historical proton techniques. IMPT allows practitioners to maximize the physical benefits of protons, increasing normal tissue sparing and reducing the potential for adverse effects. For more aggressive tumors, the dose conformality and normal tissue sparing afforded by IMPT may also allow for dose escalation to target volumes. However, in order to truly maximize the clinical potential of IMPT, the field of radiation oncology must not only implement the most advanced technologies, but also understand and capitalize on the unique biologic aspects of proton therapy., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)