Radiotherapeutic advances in the management of glioblastoma.

Glioblastoma remains a fatal diagnosis despite continuous efforts to improve upon the current standard backbone management paradigm of surgery, radiation therapy, systemic therapy and Tumor Treating Fields. Radiation therapy (RT) plays a pivotal role, with progress recently achieved in multiple key areas of research. The evolving landscape of dose and fractionation schedules and dose escalation options for different patient populations is explored, offering opportunities to better tailor treatment to a patient's overall status and preferences; novel efforts to modify treatment volumes are presented, such as utilizing state-of-the-art MRI-based linear accelerators to deliver adaptive therapy, hoping to reduce normal tissue exposure and treatment-related toxicity; specialized MR techniques and functional imaging using novel PET agents are described, providing improved treatment accuracy and the opportunity to target areas at risk of disease relapse; finally, the role of particle therapy and new altered dose-rate photon and proton therapy techniques in the treatment paradigm of glioblastoma is detailed, aiming to improve tumor control and patient outcome by exploiting novel radiobiological pathways. Improvements in each of these aforementioned areas are needed to make the critical necessary progress and allow for new approaches combining different advanced treatment modalities. This plethora of multiple new treatment options currently under investigation provides hope for a new outlook for patients with glioblastoma in the near future.

Surgically targeted radiation therapy versus stereotactic radiation therapy: A dosimetric comparison for brain metastasis resection cavities.

PURPOSE: Surgically targeted radiation therapy (STaRT) with Cesium-131 seeds embedded in a collagen tile is a promising treatment for recurrent brain metastasis. In this study, the biological effective doses (BED) for normal and target tissues from STaRT plans were compared with those of external beam radiotherapy (EBRT) modalities. METHODS: Nine patients (n = 9) with 12 resection cavities (RCs) who underwent STaRT (cumulative physical dose of 60 Gy to a depth of 5 mm from the RC edge) were replanned with CyberKnifeⓇ (CK), Gamma KnifeⓇ (GK), and intensity modulated proton therapy (IMPT) using an SRT approach (30 Gy in 5 fractions). Statistical significance comparing D95% and D90% in BED10Gy (BED10Gy95% and BED10Gy90%) and to RC + 0 to + 5 mm expansion margins, and parameters associated with radiation necrosis risk (V83Gy, V103Gy, V123Gy and V243Gy) to the normal brain were evaluated by a Wilcoxon-signed rank test. RESULTS: For RC + 0 mm, median BED10Gy 90% for STaRT (90.1 Gy10, range: 64.1-140.9 Gy10) was significantly higher than CK (74.3 Gy10, range:59.3-80.4 Gy10, p = 0.04), GK (69.4 Gy10, range: 59.8-77.1 Gy10, p = 0.005), and IMPT (49.3 Gy10, range: 49.0-49.7 Gy10, p = 0.003), respectively. However, for the RC + 5 mm, the median BED10Gy 90% for STaRT (34.1 Gy10, range: 22.2-59.7 Gy10) was significantly lower than CK (44.3 Gy10, range: 37.8-52.4 Gy10), and IMPT (46.6 Gy10, range: 45.1-48.5 Gy10), respectively, but not significantly different from GK (34.1 Gy10, range: 22.8-47.0 Gy10). The median V243Gy was significantly higher in CK (11.7 cc, range: 4.7-20.1 cc), GK(6.2 cc, range: 2.3-11.9 cc) and IMPT (19.9 cc, range: 11.1-36.6 cc) compared to STaRT (1.1 cc, range: 0.0-7.8 cc) (p < 0.01). CONCLUSIONS: This comparative analysis suggests a STaRT approach may treat recurrent brain tumors effectively via delivery of higher radiation doses with equivalent or greater BED up to at least 3 mm from the RC edge as compared to EBRT approaches.

Comparative evaluation of the diagnostic and prognostic performance of CNSide™ versus standard cytology for leptomeningeal disease.

Background: This retrospective study compares the real-world performance of cerebrospinal fluid (CSF) CNSide™ versus cytology in leptomeningeal disease (LMD). Methods: Consecutive patients with suspected LMD who underwent lumbar punctures for CSF cytology and CNSide™ from January 2020 to December 2022 were reviewed. LMD was classified by EANO criteria. Descriptive statistics, confusion matrix, Kaplan-Meier curves, and Cox proportional regression were used. Results: Median age for 87 evaluable patients was 63 years (range: 23-93); 82 (94%) met EANO criteria for possible/probable/confirmed LMD (EANO/LMD). The commonest primary cancers were breast (36,44.0%) and lung (34,41.5%). Primary lung harbored actionable mutations in 18 (53.0%); primary breast expressed hormone receptors in 27 (75%), and HER2 amplification in 8 (22%). Uncontrolled systemic disease was detected in 35 (40%), while 25 (46%) received systemic therapy with medium/high CNS penetrance at LMD diagnosis. The median time from initial cancer to LMD diagnosis was 31 months (range: 13-73). LMD was confirmed by CSF cytology in 23/82 (28%), all identified by CNSide™. CNSide™ identified 13 additional cases (36/82, 43.9%), increasing diagnostic yield by 56.5%. Median overall survival (mOS) was 31 weeks (95%CI: 21-43), significantly worse for CNSide™ positive versus negative: 4.0 versus 16.0 weeks, respectively (HR = 0.50, P = .010). While survival since LMD diagnosis did not differ by histology, time to LMD diagnosis from initial cancer diagnosis was longer for breast (48.5 months, IQR: 30.0-87.5) versus lung (8 months, IQR:0.5-16.0) cohorts. mOS was longer for patients eligible for intrathecal chemotherapy (HR: 0.189, 95%CI: 0.053-0.672, P = .010). Conclusions: This retrospective, real-world analysis of CNSide™ showed increased sensitivity versus cytology and provided clinically relevant molecular CSF analyses.

Stereotactic Body Radiation Therapy Versus Conventional Radiation Therapy for Painful Spinal Metastases: A Comparative Analysis of Randomized Trials and Practical Considerations.

PURPOSE: Recent randomized trials have compared the efficacy and safety of stereotactic body radiation therapy (SBRT) with those of standard conventional external beam radiation therapy (cEBRT) for the treatment of painful spinal metastases. We conducted a composite analysis of these trials in order to inform current practice using pooled outcomes. METHODS AND MATERIALS: Data from each randomized trial were abstracted from the final publications with biologically effective doses (BEDs) recalculated for SBRT and cEBRT. Primary outcome measures were overall pain response (OR) and complete pain response (CR) rates at 1, 3, and 6 months and rates of vertebral compression fracture. Random effects models were used to estimate primary outcome measures, and meta-regression assessed the effect of BED. RESULTS: Four prospective randomized clinical trials published between 2018 and 2024 were included, with a total of 686 patients (383 and 303 in the SBRT and cEBRT groups, respectively). Dose and fraction (fx) number ranged from 24 Gy/1 fx to 48.5 Gy/10 fx for the SBRT group (median BED using an α-to-ß ratio of 10, 50 Gy) and from 8 Gy/1 fx to 30 Gy/10 fx for the cEBRT group (median BED using an α-to-ß ratio of 10, 28 Gy). The 1-, 3-, and 6-month OR rates for SBRT and cEBRT were similar: 53.6%, 52.4%, and 58.8% versus 48.4%, 47.9%, and 43.8%, respectively (p > .05). The 3-month CR rate was significantly higher for SBRT than for cEBRT (31.9% vs 14.8%; risk ratio, 2.26; 95% CI, 1.48-3.45; p < .001), but not the 6-month rate (34.4% vs 16.3%; risk ratio, 1.83; 95% CI, 0.74-4.53; p = .194). Vertebral compression fracture rates were similar at 17.3% and 18.4% for SBRT and cEBRT, respectively. No significant dose-dependent effect was observed with increasing BED for any efficacy or safety outcomes. CONCLUSIONS: OR rates are similar, but CR rates appear higher with SBRT than with cEBRT, yet no dose-dependent effects were identified despite approximately 1.8 × BED dose with SBRT.

Case report: Intrafraction dose-guided tracking for gastrointestinal organ-at-risk isotoxicity delivery on an MR-guided radiotherapy system.

In the current era of high-precision radiation therapy, real-time magnetic resonance (MR)-guided tracking of the tumor and organs at risk (OARs) is a novel approach that enables accurate and safe delivery of high-dose radiation. Organ tracking provides a general sense of the need for daily online adaptation but lacks precise information regarding exact dosimetry. To overcome this limitation, we developed the methodology for monitoring intrafraction motion with real-time MR-guided isodose line-based tracking of an OAR in combination with anatomic tumor-based tracking and reported the first case treated with this approach. An isolated para-aortic (PA) nodal recurrence from carcinosarcoma of the endometrium was treated with an ablative dose of 50 Gy in five fractions using MR-guided radiotherapy (MRgRT). This report demonstrates the feasibility, workflow, dosimetric constraints, and treatment paradigm for real-time isodose line-based OAR tracking and gating to enable an isotoxicity delivery approach. This innovative treatment strategy effectively tracked the intrafraction motion of both the target and OAR independently and enhanced the accuracy of structure localization in time and space with a more precise dosimetric evaluation.

Multidisciplinary Management of Isocitrate Dehydrogenase-Mutated Gliomas in a Contemporary Molecularly Defined Era.

Mutations in isocitrate dehydrogenase (IDH) genes, an early step in the ontogeny of lower-grade gliomas, induce global epigenetic changes characterized by a hypermethylation phenotype and are critical to tumor classification, treatment decision making, and estimation of patient prognosis. The introduction of IDH inhibitors to block the oncogenic neomorphic function of the mutated protein has resulted in new therapeutic options for these patients. To appreciate the implications of these recent IDH inhibitor results, it is important to juxtapose historical outcomes with chemoradiotherapy. Herein, we rationally evaluate recent IDH inhibitor data within historical precedents to guide contemporary decisions regarding the role of observation, maximal safe resection, adjuvant therapies, and the import of patient and tumor variables. The biological underpinnings of the IDH pathway and the mechanisms, impact, and limitations of IDH inhibitors, the actual magnitude of tumor regression and patient benefit, and emergence of resistance pathways are presented to guide future trial development. Management in the current, molecularly defined era will require careful patient selection and risk factor assessment, followed by an open dialog about the results of studies such as INDIGO, as well as mature data from legacy trials, and a discussion about risk-versus-benefit for the choice of treatment, with multidisciplinary decision making as an absolute prerequisite.

Radiotherapy Plan Quality Assurance in NRG Oncology Trials for Brain and Head/Neck Cancers: An AI-Enhanced Knowledge-Based Approach.

The quality of radiation therapy (RT) treatment plans directly affects the outcomes of clinical trials. KBP solutions have been utilized in RT plan quality assurance (QA). In this study, we evaluated the quality of RT plans for brain and head/neck cancers enrolled in multi-institutional clinical trials utilizing a KBP approach. The evaluation was conducted on 203 glioblastoma (GBM) patients enrolled in NRG-BN001 and 70 nasopharyngeal carcinoma (NPC) patients enrolled in NRG-HN001. For each trial, fifty high-quality photon plans were utilized to build a KBP photon model. A KBP proton model was generated using intensity-modulated proton therapy (IMPT) plans generated on 50 patients originally treated with photon RT. These models were then applied to generate KBP plans for the remaining patients, which were compared against the submitted plans for quality evaluation, including in terms of protocol compliance, target coverage, and organ-at-risk (OAR) doses. RT plans generated by the KBP models were demonstrated to have superior quality compared to the submitted plans. KBP IMPT plans can decrease the variation of proton plan quality and could possibly be used as a tool for developing improved plans in the future. Additionally, the KBP tool proved to be an effective instrument for RT plan QA in multi-center clinical trials.

A Neuroradiologist's Guide to Operationalizing the Response Assessment in Neuro-Oncology (RANO) Criteria Version 2.0 for Gliomas in Adults.

Radiographic assessment plays a crucial role in the management of patients with central nervous system (CNS) tumors, aiding in treatment planning and evaluation of therapeutic efficacy by quantifying response. Recently, an updated version of the Response Assessment in Neuro-Oncology (RANO) criteria (RANO 2.0) was developed to improve upon prior criteria and provide an updated, standardized framework for assessing treatment response in clinical trials for gliomas in adults. This article provides an overview of significant updates to the criteria including (1) the use of a unified set of criteria for high and low grade gliomas in adults; (2) the use of the post-radiotherapy MRI scan as the baseline for evaluation in newly diagnosed high-grade gliomas; (3) the option for the trial to mandate a confirmation scan to more reliably distinguish pseudoprogression from tumor progression; (4) the option of using volumetric tumor measurements; and (5) the removal of subjective non-enhancing tumor evaluations in predominantly enhancing gliomas (except for specific therapeutic modalities). Step-by-step pragmatic guidance is hereby provided for the neuroradiologist and imaging core lab involved in operationalization and technical execution of RANO 2.0 in clinical trials, including the display of representative cases and in-depth discussion of challenging scenarios.

NRG-BN002: Phase I study of ipilimumab, nivolumab, and the combination in patients with newly diagnosed glioblastoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have efficacy in several solid tumors but limited efficacy in glioblastoma (GBM). This study evaluated the safety of anti-CTLA-4 and anti-PD-1 ICIs alone or in combination in newly diagnosed GBM after completion of standard radiochemotherapy with the subsequent intent to test combinatorial ICIs in this setting. METHODS: The primary endpoint was dose-limiting toxicity (DLT) for adults with unifocal, supratentorial newly diagnosed GBM after resection and chemoradiation. Ipilimumab and nivolumab were tested separately and in combination with a planned expansion cohort dependent upon DLT results. RESULTS: Thirty-two patients were enrolled at 9 institutions: 6 to each DLT assessment cohort and 14 to the expansion cohort. Median age: 55 years, 67.7% male, 83.9% White. Treatment was well tolerated with 16% Grade 4 events; the combination did not have unexpectedly increased toxicity, with no Grade 5 events. One DLT was seen in each single-agent treatment; none were observed in the combination, leading to expanded accrual of the combined treatment. The median follow-up was 19.6 months. For all patients receiving combination treatment, median overall survival (OS) and progression-free survival (PFS) were 20.7 and 16.1 months, respectively. CONCLUSIONS: IPI and NIVO are safe and tolerable with toxicities similar to those noted with other cancers when given in combination with adjuvant temozolomide for newly diagnosed GBM. Combination IPI + NIVO is not substantially more toxic than single agents. These results support a subsequent efficacy trial to test the combination of ICIs in Phase II/III for patients with newly diagnosed GBM. CLINICALTRIALS.GOV REGISTRATION: NCT02311920.

Quality assurance of an established online adaptive radiotherapy program: patch and software upgrade.

Introduction: The ability to dynamically adjust target contours, derived Boolean structures, and ultimately, the optimized fluence is the end goal of online adaptive radiotherapy (ART). The purpose of this work is to describe the necessary tests to perform after a software patch installation and/or upgrade for an established online ART program. Methods: A patch upgrade on a low-field MR Linac system was evaluated for post-software upgrade quality assurance (QA) with current infrastructure of ART workflow on (1) the treatment planning system (TPS) during the initial planning stage and (2) the treatment delivery system (TDS), which is a TPS integrated into the delivery console for online ART planning. Online ART QA procedures recommended for post-software upgrade include: (1) user interface (UI) configuration; (2) TPS beam model consistency; (3) segmentation consistency; (4) dose calculation consistency; (5) optimizer robustness consistency; (6) CT density table consistency; and (7) end-to-end absolute ART dose and predicted dose measured including interruption testing. Differences of calculated doses were evaluated through DVH and/or 3D gamma comparisons. The measured dose was assessed using an MR-compatible A26 ionization chamber in a motion phantom. Segmentation differences were assessed through absolute volume and visual inspection. Results: (1) No UI configuration discrepancies were observed. (2) Dose differences on TPS pre-/post-software upgrade were within 1% for DVH metrics. (3) Differences in segmentation when observed were small in general, with the largest change noted for small-volume regions of interest (ROIs) due to partial volume impact. (4) Agreement between TPS and TDS calculated doses was 99.9% using a 2%/2-mm gamma criteria. (5) Comparison between TPS and online ART plans for a given patient plan showed agreement within 2% for targets and 0.6 cc for organs at risk. (6) Relative electron densities demonstrated comparable agreement between TPS and TDS. (7) ART absolute and predicted measured end-to-end doses were within 1% of calculated TDS. Discussion: An online ART QA program for post-software upgrade has been developed and implemented on an MR Linac system. Testing mechanics and their respective baselines may vary across institutions, but all necessary components for a post-software upgrade QA have been outlined and detailed. These outlined tests were demonstrated feasible for a low-field MR Linac system; however, the scope of this work may be applied and adapted more broadly to other online ART platforms.

Comparative evaluation of outcomes amongst different radiosurgery management paradigms for patients with large brain metastasis.

INTRODUCTION: This study compares four management paradigms for large brain metastasis (LMB): fractionated SRS (FSRS), staged SRS (SSRS), resection and postoperative-FSRS (postop-FSRS) or preoperative-SRS (preop-SRS). METHODS: Patients with LBM (≥ 2 cm) between July 2017 and January 2022 at a single tertiary institution were evaluated. Primary endpoints were local failure (LF), radiation necrosis (RN), leptomeningeal disease (LMD), a composite of these variables, and distant intracranial failure (DIF). Gray's test compared cumulative incidence, treating death as a competing risk with a random survival forests (RSF) machine-learning model also used to evaluate the data. RESULTS: 183 patients were treated to 234 LBMs: 31.6% for postop-FSRS, 28.2% for SSRS, 20.1% for FSRS, and 20.1% for preop-SRS. The overall 1-year composite endpoint rates were comparable (21 vs 20%) between nonoperative and operative strategies, but 1-year RN rate was 8 vs 4% (p = 0.012), 1-year overall survival (OS) was 48 vs. 69% (p = 0.001), and 1-year LMD rate was 5 vs 10% (p = 0.052). There were differences in the 1-year RN rates (7% FSRS, 3% postop-FSRS, 5% preop-SRS, 10% SSRS, p = 0.037). With RSF analysis, the out-of-bag error rate for the composite endpoint was 47%, with identified top-risk factors including widespread extracranial disease, > 5 total lesions, and breast cancer histology. CONCLUSION: This is the first study to conduct a head-to-head retrospective comparison of four SRS methods, addressing the lack of randomized data in LBM literature amongst treatment paradigms. Despite patient characteristic trends, no significant differences were found in LF, composite endpoint, and DIF rates between non-operative and operative approaches.

The IDH paradox: Meta-analysis of alkylating chemotherapy in IDH-wild type and -mutant lower grade gliomas.

BACKGROUND: IDH-wild type (-wt) status is a prerequisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low-grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower-grade gliomas is unclear. METHODS: We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grades 2-3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling. RESULTS: We identified 6 trials with 1204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95% CI: 0.62-0.97], P = .03) but not OS (HR:0.87 [95% CI: 0.64-1.18], P = .17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95% CI: 0.42-0.64], P < .001) and PFS (HR = 0.47 [95% CI: 0.39-0.57], P < .001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion. CONCLUSIONS: Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower-grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy.

An Update on H3K27M-altered Diffuse Midline Glioma: Diagnostic and Therapeutic Challenges in Clinical Practice.

H3K27-altered diffuse midline glioma (DMG H3K27-altered) is a relatively newly-designated WHO entity which primarily affects the midline structures of the central nervous system (CNS), including the brainstem (predominantly pontine region), thalamus, midbrain, or spinal cord, and primarily affects children and young adults. Despite the proximity of these tumors to eloquent areas in the CNS, novel stereotactic approaches have facilitated the ability to obtain tissue diagnoses without significant morbidity, providing molecular diagnostic information in more than half of patients. Conventionally fractionated radiation therapy to a total dose of 54-60 Gy in 27-30 fractions and 24 Gy in 12 fractions play a crucial role in the definitive treatment of these tumors in the primary and salvage settings, respectively. Hypofractionated regimens may allow for accelerated treatment courses in selected patients without jeopardizing disease control or survival. The decision to add concurrent or adjuvant systemic therapy mainly relies on the physicians' experience without solid evidence in the literature in favor of any particular regimen. Recently, novel agents, such as ONC201 have demonstrated promising oncologic outcomes in progressive/recurrent tumors and are currently under investigation in ongoing randomized trials. Given the scarcity of data and well-established guidelines due to the rare nature of the disease, we provide a contemporary overview on the molecular underpinnings of this disease entity, describe the role of radiotherapy and systemic therapy, and present practice management principles based on the published literature.

DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology.

DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.

How proton therapy fits into the management of adult intracranial tumors.

Intracranial tumors include a challenging array of primary and secondary parenchymal and extra-axial tumors which cause neurologic morbidity consequential to location, disease extent, and proximity to critical neurologic structures. Radiotherapy can be used in the definitive, adjuvant, or salvage setting either with curative or palliative intent. Proton therapy (PT) is a promising advance due to dosimetric advantages compared to conventional photon radiotherapy with regards to normal tissue sparing, as well as distinct physical properties, which yield radiobiologic benefits. In this review, the principles of efficacy and safety of PT for a variety of intracranial tumors are discussed, drawing upon case series, retrospective and prospective cohort studies, and randomized clinical trials. This manuscript explores the potential advantages of PT, including reduced acute and late treatment-related side effects and improved quality of life. The objective is to provide a comprehensive review of the current evidence and clinical outcomes of PT. Given the lack of consensus and directives for its utilization in patients with intracranial tumors, we aim to provide a guide for its judicious use in clinical practice.

Clinical application of an institutional fractionated stereotactic radiosurgery (FSRS) program for brain metastases delivered with MRIdianⓇ BrainTx™.

Single-fraction stereotactic radiosurgery (SRS) or fractionated SRS (FSRS) are well established strategies for patients with limited brain metastases. A broad spectrum of modern dedicated platforms are currently available for delivering intracranial SRS/FSRS; however, SRS/FSRS delivered using traditional CT-based platforms relies on the need for diagnostic MR images to be coregistered to planning CT scans for target volume delineation. Additionally, the on-board image guidance on traditional platforms yields limited inter-fraction and intra-fraction real-time visualization of the tumor at the time of treatment delivery. MR Linacs are capable of obtaining treatment planning MR and on-table MR sequences to enable visualization of the targets and organs-at-risk and may subsequently help identify anatomical changes prior to treatment that may invoke the need for on table treatment adaptation. Recently, an MR-guided intracranial package (MRIdian A3i BrainTxTM) was released for intracranial treatment with the ability to perform high-resolution MR sequences using a dedicated brain coil and cranial immobilization system. The objective of this report is to provide, through the experience of our first patient treated, a comprehensive overview of the clinical application of our institutional program for FSRS adaptive delivery using MRIdian's A3i BrainTx system-highlights include reviewing the imaging sequence selection, workflow demonstration, and details in its delivery feasibility in clinical practice, and dosimetric outcomes.

Proton Therapy: Current Status and Controversies.

Expert commentary on the evolving role of proton therapy, discussing the current status and controversies of proton therapy in the modern era.

ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.

PURPOSE: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. METHODS: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. RESULTS: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. CONCLUSION: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.