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The 2016 and 2021 World Health Organization 2021 Classification of central nervous system tumors have resulted in a major improvement in the classification of isocitrate dehydrogenase (IDH)-mutant gliomas. With more effective treatments many patients experience prolonged survival. However, treatment guidelines are often still based on information from historical series comprising both patients with IDH wild-type and IDH-mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological, and molecular factors associated with the outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with IDH-mutant grades 2 and 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize the overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.

BackgroundStandard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier.MethodsEuropean Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors.ResultsThe trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm.ConclusionsAdding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.

INTRODUCTION: A greater extent of resection of the contrast-enhancing (CE) tumour part has been associated with improved outcomes in glioblastoma. Recent results suggest that resection of the non-contrast-enhancing (NCE) part might yield even better survival outcomes (supramaximal resection, SMR). Therefore, this study evaluates the efficacy and safety of SMR with and without mapping techniques in high-grade glioma (HGG) patients in terms of survival, functional, neurological, cognitive and quality of life outcomes. Furthermore, it evaluates which patients benefit the most from SMR, and how they could be identified preoperatively. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of observational nature. Consecutive glioblastoma patients will be operated with SMR or maximal resection at a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months postoperatively. Secondary endpoints are (1) residual CE and NCE tumour volume on postoperative T1-contrast and FLAIR (Fluid-attenuated inversion recovery) MRI scans; (2) progression-free survival; (3) receipt of adjuvant therapy with chemotherapy and radiotherapy; and (4) quality of life at 6 weeks, 3 months and 6 months postoperatively. The total duration of the study is 5 years. Patient inclusion is 4 years, follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media.

BACKGROUND: Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a low-grade appearance on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement. METHODS: The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement. RESULTS: Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller postoperative tumor volumes were associated with more favorable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had a more favorable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables. CONCLUSIONS: The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favorable outcome.

Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, how to define those regions on the basis of preoperative imaging, and the optimal sample volume. Practical recommendations for tissue sampling are given for people with low-grade and high-grade gliomas, as well as for people with newly diagnosed and recurrent disease. Sampling of liquid biopsies is also addressed. A standardised workflow for subsequent handling of the resected tissue is proposed to avoid information loss due to decreasing tissue quality or insufficient clinical information. The recommendations offer a framework for prospective biobanking studies.

BACKGROUND: The value of re-resection in recurrent glioblastoma remains controversial as a randomized trial that specifies intentional incomplete resection cannot be justified ethically. Here, we aimed to (1) explore the prognostic role of extent of re-resection using the previously proposed Response Assessment in Neuro-Oncology (RANO) classification (based upon residual contrast-enhancing (CE) and non-CE tumor), and to (2) define factors consolidating the surgical effects on outcome. METHODS: The RANO resect group retrospectively compiled an 8-center cohort of patients with first recurrence from previously resected glioblastomas. The associations of re-resection and other clinical factors with outcome were analyzed. Propensity score-matched analyses were constructed to minimize confounding effects when comparing the different RANO classes. RESULTS: We studied 681 patients with first recurrence of Isocitrate Dehydrogenase (IDH) wild-type glioblastomas, including 310 patients who underwent re-resection. Re-resection was associated with prolonged survival even when stratifying for molecular and clinical confounders on multivariate analysis; ≤1 cm3 residual CE tumor was associated with longer survival than non-surgical management. Accordingly, maximal resection (class 2) had superior survival compared to submaximal resection (class 3). Administration of (radio-)chemotherapy in the absence of postoperative deficits augmented the survival associations of smaller residual CE tumors. Conversely, supramaximal resection of non-CE tumor (class 1) was not associated with prolonged survival but was frequently accompanied by postoperative deficits. The prognostic role of residual CE tumor was confirmed in propensity score analyses. CONCLUSIONS: The RANO resect classification serves to stratify patients with re-resection of glioblastoma. Complete resection according to RANO resect classes 1 and 2 is prognostic.

BackgroundIsocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas.MethodsIn a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed.ResultsA total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P

Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials.

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P < .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P < .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P < .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P < .01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.

BackgroundTerminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit.MethodsThe international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected.ResultsWe collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with "maximal CE resection" (class 2) had superior outcome compared to patients with "submaximal CE resection" (class 3) or "biopsy" (class 4). Extensive resection of non-CE tumor (≤5 cm3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 ("supramaximal CE resection"). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers.ConclusionsThe proposed "RANO categories for extent of resection in glioblastoma" are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such "supramaximal CE resection."

BackgroundTo assess whether artificial intelligence (AI)-based decision support allows more reproducible and standardized assessment of treatment response on MRI in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden using the Response Assessment in Neuro-Oncology (RANO) criteria.MethodsA series of 30 patients (15 lower-grade gliomas, 15 glioblastoma) with availability of consecutive MRI scans was selected. The time to progression (TTP) on MRI was separately evaluated for each patient by 15 investigators over two rounds. In the first round the TTP was evaluated based on the RANO criteria, whereas in the second round the TTP was evaluated by incorporating additional information from AI-enhanced MRI sequences depicting the longitudinal changes in tumor volumes. The agreement of the TTP measurements between investigators was evaluated using concordance correlation coefficients (CCC) with confidence intervals (CI) and P-values obtained using bootstrap resampling.ResultsThe CCC of TTP-measurements between investigators was 0.77 (95% CI = 0.69,0.88) with RANO alone and increased to 0.91 (95% CI = 0.82,0.95) with AI-based decision support (P = .005). This effect was significantly greater (P = .008) for patients with lower-grade gliomas (CCC = 0.70 [95% CI = 0.56,0.85] without vs. 0.90 [95% CI = 0.76,0.95] with AI-based decision support) as compared to glioblastoma (CCC = 0.83 [95% CI = 0.75,0.92] without vs. 0.86 [95% CI = 0.78,0.93] with AI-based decision support). Investigators with less years of experience judged the AI-based decision as more helpful (P = .02).ConclusionsAI-based decision support has the potential to yield more reproducible and standardized assessment of treatment response in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden, particularly in patients with lower-grade gliomas. A fully-functional version of this AI-based processing pipeline is provided as open-source (https://github.com/NeuroAI-HD/HD-GLIO-XNAT).

Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.

Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for "response" and ultimately lead to identification of effective treatments.

BackgroundThere is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring.MethodsThe RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, that is circulating tumor DNA, circulating tumor cells, and extracellular vesicles in blood and CSF.ResultsctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA, and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict the outcome.ConclusionsThere is a need for standardization of biofluid collection, choice of an analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice.

Context.—The diagnosis and clinical management of patients with diffuse gliomas (DGs) have evolved rapidly over the past decade with the emergence of molecular biomarkers that are used to classify, stratify risk, and predict treatment response for optimal clinical care.Objective.—To develop evidence-based recommendations for informing molecular biomarker testing for pediatric and adult patients with DGs and provide guidance for appropriate laboratory test and biomarker selection for optimal diagnosis, risk stratification, and prediction.Design.—The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. A systematic review of literature was conducted to address the overarching question, "What ancillary tests are needed to classify DGs and sufficiently inform the clinical management of patients?" Recommendations were derived from quality of evidence, open comment feedback, and expert panel consensus.Results.—Thirteen recommendations and 3 good practice statements were established to guide pathologists and treating physicians on the most appropriate methods and molecular biomarkers to include in laboratory testing to inform clinical management of patients with DGs.Conclusions.—Evidence-based incorporation of laboratory results from molecular biomarker testing into integrated diagnoses of DGs provides reproducible and clinically meaningful information for patient management.

Mutations in isocitrate dehydrogenase (IDH) 1 or IDH2 occur in most of the adult low-grade gliomas and, less commonly, in cholangiocarcinoma, chondrosarcoma, acute myeloid leukemia, and other human malignancies. Cancer-associated mutations alter the function of the enzyme, resulting in production of R(-)-2-hydroxyglutarate and broad epigenetic dysregulation. Small molecule IDH inhibitors have received regulatory approval for the treatment of IDH mutant (mIDH) leukemia and are under development for the treatment of mIDH solid tumors. This article provides a current view of mIDH adult astrocytic and oligodendroglial tumors, including their clinical presentation and treatment, and discusses novel approaches and challenges toward improving the treatment of these tumors.

BackgroundThe Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.MethodsA systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living [(I)ADL] or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.ResultsA total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORTC QLQ-C30 and QLQ-BN20 (n = 286 and n = 247), and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).ConclusionMany different PRO measures assessing symptoms, (I)ADL or HRQoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their scales/items exhibit good content validity and other measurement properties for use in brain tumor patients.

Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.

Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been expended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients who receive subtherapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements and determining intratumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood-brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this paper, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0-like ("window of opportunity") studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include (i) only patients in whom a resection of the tumor is planned, (ii) use of clinical doses of an investigational agent, (iii) tissue sampling from enhancing and non-enhancing portions of the tumor, and (iv) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40-50 ms at 1.5 T, 20-35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The "minimum standard" recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)-prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An "ideal" protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.