BACKGROUND:Classical leptomeningeal disease (cLMD) impacts the entire craniospinal axis, but isolated parenchymal metastases sometimes display focal leptomeningeal extension (fLME) without diffuse LMD elsewhere. We assessed whether patients with fLME can be managed with stereotactic radiation (SRS/SRT) as opposed to whole brain/craniospinal radiation without excess development of marginal recurrences or subsequent cLMD. METHODS:We identified 796 patients with 2,354 newly-diagnosed brain metastases (BrM) without cLMD at diagnosis managed at a tertiary center between 2007 and 2022. Each metastasis was assessed for fLME, defined as isolated leptomeningeal extension of an intact BrM without cytologic or radiographic evidence of cLMD. Multivariable Fine and Gray's models were constructed for the primary outcomes of local recurrence and cLMD development. RESULTS:Among 796 patients, 138 (17.3%) displayed evidence of fLME, corresponding to 185 of 2,354 (7.9%) BrM. Patients with versus without fLME did not display excess local recurrences (1-year rate: 4.5% vs. 8.2%, respectively, P = .14; multivariable HR 0.56 [95% CI 0.30-1.07], P = .08), including in lesions managed with SRS/SRT (1-year rate: 4.4% vs. 4.9%, respectively; P = .63; multivariable HR 1.21 [95% CI 0.58-2.50], P = .61). The presence of fLME was not a significant predictor of subsequent cLMD (1-year rate: 5.2% vs. 5.2%, P = .99; multivariable HR 0.87 [95% CI 0.44-1.71], P = .68), including following treatment with SRS/SRT (1-year rate: 6.2% vs. 4.1%, P = .83; multivariable HR 0.92 [95% CI 0.36-2.39], P = .87). CONCLUSIONS:We describe a novel entity, fLME, which displays patterns of intracranial failure similar to parenchymal BrM. Stereotactic approaches may be viable in this population.

2011 Background: Radiation therapy forms the mainstay of management for patients with brain metastases. Published randomized trials have found improved quality of life with stereotactic radiation (SRS/SRT) over whole brain radiation (WBRT) in patients with ≤ 4 brain metastases; comparative trials in patients with >4 brain metastases are lacking. In addition, prior randomized trials have demonstrated the superiority of hippocampal avoidance WBRT (HA-WBRT) over traditional WBRT, but no study has compared SRS/SRT to HA-WBRT. Accordingly, we conducted a multicenter, phase 3 randomized trial comparing SRS/SRT to HA-WBRT in patients with 5-20 brain metastases. Methods: Eligible patients were age 18-80 with 5-20 brain metastases secondary to a solid primary other than small cell lung cancer, were naïve to prior brain-directed radiation, and lacked leptomeningeal disease. The primary endpoint was the average of patient-reported symptom severity and interference over the first six months post-baseline relative to baseline, using the MD Anderson Symptom Inventory–Brain Tumor (MDASI-BT) module, a validated instrument assessing 22 symptoms and 6 interference measures integral to quality of life, each scored 0-10 with higher scores indicating greater symptomatology/interference in function. The target effect size was a symptom severity of 0.70, corresponding to 50% of the observed difference between patients with a good (90-100) versus poor (≤80) Karnofsky performance status; with 80% power and a two-sided alpha of 0.05, 196 patients were required. Results: Between 4/2017-5/2024, 196 patients enrolled, 98 in each arm. The median number of brain metastases was 14 (IQR 11-18); 25% of patients underwent prior neurosurgical resection. Baseline mean MDASI-BT symptom severity scores were 2.2 (SRS/SRT arm) and 1.9 (HA-WBRT arm), p=0.20; respective interference scores were 3.5 and 3.2 (p=0.40). The average of weighted post-baseline severity and interference scores relative to baseline indicated lower symptomatology/inference in the SRS/SRT arm, meeting the primary endpoint of the study (difference between SRS/SRT and HA-WBRT: -1.06, p<0.001). Averaged post-baseline symptom severity scores minus baseline were -0.03 and 0.59 in the SRS/SRT and HA-WBRT arms, respectively (difference -0.62, with lower symptom severity in the SRS/SRT arm, p<0.001); respective interference estimates were -0.62 and 0.89 (difference -1.50, with lower interference in the SRS/SRT arm, p<0.001). Median survival was 8.3 and 8.5 months in the SRS/SRT and HA-WBRT arms, respectively (p=0.30). Conclusions: This phase 3 randomized trial indicates that patients with 5-20 brain metastases experience fewer symptoms and less interference in function after SRS/SRT as opposed to HA-WBRT, without compromise of survival, supporting SRS/SRT as the standard of care in this population. Clinical trial information: NCT03075072 .

PURPOSE:Stereotactic radiation (SRS/SRT) as opposed to whole-brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases given the relatively favorable toxicity profile associated with stereotactic treatment. However, in patients with small cell lung cancer (SCLC), WBRT remains standard because of a lack of prospective data supporting SRS/SRT and concerns related to intracranial progression and neurologic death when WBRT is omitted. We conducted a single-arm, multicenter, phase II trial of SRS/SRT in patients with SCLC and 1-10 brain metastases to assess neurologic death rates relative to historical controls managed with WBRT (ClinicalTrials.gov identifier: NCT03391362). METHODS:Patients were eligible if they had SCLC or an extrathoracic small cell primary and 1-10 brain metastases. Previous brain-directed radiation including prophylactic cranial irradiation was not permitted. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression or systemic symptoms of a life-threatening nature. Close imaging-based surveillance of the brain post-SRS/SRT was used. RESULTS:Between February 2018 and April 2023, 100 patients were enrolled. The median number of brain metastases was 2 (IQR, 1-4; range, 1-10). The median overall survival was 10.2 months; only 22% of patients required salvage WBRT. In total, 20 neurologic deaths were observed, relative to 64 non-neurologic deaths. The neurologic death rate at 1 year was 11.0% (95% CI, 5.8 to 18.1); the historical rate in patients managed with WBRT was 17.5%. CONCLUSION:Our prospective, multi-institutional study demonstrated low rates of neurologic death when SRS/SRT as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases who are surveilled closely post-treatment, supporting the utility of stereotactic approaches in this population.

BACKGROUND:Master clinical trial protocol structures offer administrative, procedural, and statistical advantages but have not been applied in assessing new radiotherapy devices. Herein, we report on a pooled analysis from a first-of-kind master trial evaluating stereotactic MRI-guided adaptive radiotherapy (SMART). METHODS:Subjects were enrolled in a prospective master protocol evaluating SMART for multiple oncologic indications. CTCAE v5 toxicities, patient-reported outcome measures (PROMs), and treatment efficiency metrics were assessed across the entire cohort and in anatomic subsets. RESULTS:One hundred and ninety three subjects were enrolled into 20 sub-protocols for different SMART indications. Data were analyzed from the first 161 subjects. The median time from subprotocol amendment submission to activation was 70.5 days (range: 63-93). All completed phase I sub-protocols (n = 9) met the primary endpoints of safety and feasibility. The risk of grade 3+ toxicity was 1.9% (95% CI 0.4% to 5.3%), 7.1% (95% CI 0.9% to 23.5%), 1.8% (95% CI 0.05% to 9.6%) and 0% (95% CI 0.0% to 4.7%) in the overall cohort and thoracic, abdominal and pelvic subsets, respectively. PROMs (PROMIS-10) during and after SMART were unchanged from baseline in all subsets. SMART delivery efficiency improved over the study period (first vs. final 3 months: 78.5 vs. 48.2 minutes, P < .001). Adaptive planning performed for 771 fractions resulted in clinically significant plan improvements in 93.0% of fractions (52.7% for organ-at-risk sparing, 20.5% for target coverage, and 19.8% for both). CONCLUSIONS:SMART is feasible and safe for multiple thoracic, abdominal and pelvic radiotherapy indications. The master protocol platform offers an adaptable approach for assessment of new oncologic treatment technologies applicable to multiple indications. CLINICAL TRIAL:NCT04115254.

Introduction and background: While recurrent glioblastoma patients are often treated with re-irradiation, there is limited data on the use of re-irradiation in the setting of bevacizumab (BEV), temozolomide (TMZ) re-challenge, or immune checkpoint inhibition (ICI). We describe target delineation in patients with prior anti-angiogenic therapy, assess safety and efficacy of re-irradiation, and evaluate patterns of recurrence.Materials and methods: Patients with a histologically confirmed diagnosis of glioblastoma treated at a single institution between 2013 and 2021 with re-irradiation were included. Tumor, treatment and clinical data were collected. Logistic and Cox regression analysis were used for statistical analysis.Results: One hundred and seventeen recurrent glioblastoma patients were identified, receiving 129 courses of reirradiation. In 66 % (85/129) of cases, patients had prior BEV. In the 80 patients (62 %) with available reirradiation plans, 20 (25 %) had all T2/FLAIR abnormality included in the gross tumor volume (GTV). Median overall survival (OS) for the cohort was 7.3 months, and median progression-free survival (PFS) was 3.6 months. Acute CTCAE grade >= 3 toxicity occurred in 8 % of cases.Concurrent use of TMZ or ICI was not associated with improved OS nor PFS. On multivariable analysis, higher KPS was significantly associated with longer OS (p < 0.01). On subgroup analysis, patients with prior BEV had significantly more marginal recurrences than those without (26 % vs. 13 %, p < 0.01). Conclusion: Re-irradiation can be safely employed in recurrent glioblastoma patients. Marginal recurrence was more frequent in patients with prior BEV, suggesting a need to consider more inclusive treatment volumes incorporating T2/FLAIR abnormality.

Background/Purpose: Central/ultra-central thoracic tumors are challenging to treat with stereotactic radiotherapy due potential high-grade toxicity. Stereotactic MR-guided adaptive radiation therapy (SMART) may improve the therapeutic window through motion control with breath-hold gating and real-time MR-imaging as well as the option for daily online adaptive replanning to account for changes in target and/or organ-at-risk (OAR) location. Materials/Methods: 26 central (19 ultra-central) thoracic oligoprogressive/oligometastatic tumors treated with isotoxic (OAR constraints-driven) 5-fraction SMART (median 50 Gy, range 35-60) between 10/2019-10/2022 were reviewed. Central tumor was defined as tumor within or touching 2 cm around proximal tracheobronchial tree (PBT) or adjacent to mediastinal/pericardial pleura. Ultra-central was defined as tumor abutting the PBT, esophagus, or great vessel. Hard OAR constraints observed were <= 0.03 cc for PBT V40, great vessel V52.5, and esophagus V35. Local failure was defined as tumor progression/recurrence within the planning target volume. Results: Tumor abutted the PBT in 31 %, esophagus in 31 %, great vessel in 65 %, and heart in 42 % of cases. 96 % of fractions were treated with reoptimized plan, necessary to meet OAR constraints (80 %) and/or target coverage (20 %). Median follow-up was 19 months (27 months among surviving patients). Local control (LC) was 96 % at 1-year and 90 % at 2-years (total 2/26 local failure). 23 % had G2 acute toxicities (esophagitis, dysphagia, anorexia, nausea) and one (4 %) had G3 acute radiation dermatitis. There were no G4-5 acute toxicities. There was no symptomatic pneumonitis and no G2 + late toxicities. Conclusion: Isotoxic 5-fraction SMART resulted in high rates of LC and minimal toxicity. This approach may widen the therapeutic window for high-risk oligoprogressive/oligometastatic thoracic tumors.

Objective.We aim to: (1) quantify the benefits of lung sparing using non-adaptive magnetic resonance guided stereotactic body radiotherapy (MRgSBRT) with advanced motion management for peripheral lung cancers compared to conventional x-ray guided SBRT (ConvSBRT); (2) establish a practical decision-making guidance metric to assist a clinician in selecting the appropriate treatment modality.Approach.Eleven patients with peripheral lung cancer who underwent breath-hold, gated MRgSBRT on an MR-guided linear accelerator (MR linac) were studied. Four-dimensional computed tomography (4DCT)-based retrospective planning using an internal target volume (ITV) was performed to simulate ConvSBRT, which were evaluated against the original MRgSBRT plans. Metrics analyzed included planning target volume (PTV) coverage, various lung metrics and the generalized equivalent unform dose (gEUD). A dosimetric predictor for achievable lung metrics was derived to assist future patient triage across modalities.Main results.PTV coverage was high (median V100% > 98%) and comparable for both modalities. MRgSBRT had significantly lower lung doses as measured by V20 (median 3.2% versus 4.2%), mean lung dose (median 3.3 Gy versus 3.8 Gy) and gEUD. Breath-hold, gated MRgSBRT resulted in an average reduction of 47% in PTV volume and an average increase of 19% in lung volume. Strong correlation existed between lung metrics and the ratio of PTV to lung volumes (RPTV/Lungs) for both modalities, indicating that RPTV/Lungsmay serve as a good predictor for achievable lung metrics without the need for pre-planning. A threshold value of RPTV/Lungs< 0.035 is suggested to achieve V20 < 10% using ConvSBRT. MRgSBRT should otherwise be considered if the threshold cannot be met.Significance.The benefits of lung sparing using MRgSBRT were quantified for peripheral lung tumors; RPTV/Lungswas found to be an effective predictor for achievable lung metrics across modalities. RPTV/Lungscan assist a clinician in selecting the appropriate modality without the need for labor-intensive pre-planning, which has significant practical benefit for a busy clinic.

The aim of this review was to highlight why the use of master protocols trial design is particularly useful for radiotherapy intervention trials where complex setup pathways (including quality assurance, user training, and integrating multiple modalities of treatment) may hinder clinical advances.We carried out a systematic review according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, reviewing the findings using a landscape analysis. Results were summarized descriptively, reporting on trial characteristics highlighting the benefits, limitations, and challenges of developing and implementing radiotherapy master protocols, with three case studies selected to explore these issues in more detail.Twelve studies were suitable for inclusion (4 platform trials, 3 umbrella trials, and 5 basket trials), evaluating a mix of solid tumor sites in both curative and palliative settings. The interventions were categorized into 1) novel agent and radiotherapy combinations; 2) radiotherapy dose personalization; and 3) device evaluation, with a case study provided for each intervention. Benefits of master protocol trials for radiotherapy intervention include protocol efficiency for implementation of novel radiotherapy techniques; accelerating the evaluation of novel agent drug and radiotherapy combinations; and more efficient translational research opportunities, leading to cost savings and research efficiency to improve patient outcomes.Master protocols offer an innovative platform under which multiple clinical questions can be addressed within a single trial. Due to the complexity of radiotherapy trial setup, cost and research efficiency savings may be more apparent than in systemic treatment trials. Use of this research approach may be the change needed to push forward oncological innovation within radiation oncology.

Purpose/Objective(s) Classical leptomeningeal disease (cLMD) has historically been considered a global phenomenon impacting the entire craniospinal axis, but isolated parenchymal metastases sometimes display focal leptomeningeal extension into the surrounding leptomeninges without diffuse LMD elsewhere. Descriptions of this phenomenon are lacking, and the optimal management of such patients remains unclear. We hypothesized that, in order to spare such patients the deleterious outcomes of whole brain radiation (WBRT), patients with focal LMD (fLMD) could be successfully managed with stereotactic radiation (SRS/SRT) without excess development of adverse sequelae such marginal recurrences or subsequent cLMD. Materials/Methods We identified 796 patients with 2,354 newly-diagnosed brain metastases (BrM) secondary to a solid tumor primary without cLMD at diagnosis managed at a tertiary cancer center between 2007-2022. Each metastasis was assessed for fLMD, which was defined as isolated focal leptomeningeal extension of an intact brain metastasis or single, isolated focal leptomeningeal enhancement without cytologic or radiographic evidence of cLMD (enhancement of cranial nerves or multifocal involvement of subarachnoid spaces including the cerebellar folia and supratentorial sulci). Multivariable Fine and Gray's models were constructed for the primary outcomes of local recurrence and development of cLMD. Results Among 796 patients, 138 (17.3%) displayed evidence of fLMD, corresponding to 185 of 2,354 (7.9%) BrM. Patients with versus without fLMD were not more likely to display distant intracranial failures post-initial treatment (56.8% vs. 58.3% at 1 year, respectively, p=0.78) or local recurrence (4.4% vs. 8.2% at 1 year, respectively, p=0.14), including in lesions managed with SRS/SRT (1-year local recurrence: 4.4% vs. 4.9%, respectively; p=0.63). On a per-patient level, the presence of fLMD was not a significant predictor of development of cLMD (1-year rate: 5.2% vs 5.2%, HR: 0.99 [0.52-1.89], p=0.97). Conclusion We describe a novel pattern of LMD that has not been well-characterized in prior literature; fLMD appears to be a distinct oncologic entity whose pattern of intracranial failure resembles that of parenchymal BrM. Nationally, it may be that patients with fLMD are managed as having cLMD with routine use of WBRT. Our study suggests that despite the presence of enhancing disease in the leptomeningeal space, stereotactic approaches may be viable in this population given the lack of detectable excess risk of local recurrence or development of cLMD.

2011 Background: Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. As a result, radiation doses and fractionation schemes are prescribed with a “one-size-fits-all” approach. We sought to develop a DNA-based signature of radiation-based efficacy among patients with BrM, utilizing readily testable genes, to identify subpopulations at greater vs. lesser risk of recurrence. Methods: We retrospectively identified 570 patients with 1,487 distinct BrM managed with whole-brain (WBRT) or stereotactic radiation therapy (SRS/SRT) at a tertiary cancer center (2013-2020) for whom next-generation sequencing panel data (OncoPanel, 239 genes) were available on at least one tumor specimen. Local recurrence was assessed in a manner consistent with Response Assessment in Neuro-Oncology – Brain Metastases guidelines (i.e., radiographic enlargement of >20% in maximal cross-sectional diameter). Enlarging lesions managed with salvage treatment prior to >20% enlargement were considered to have recurred on the date of salvage therapy. Fine/Gray’s competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with vs. without somatic alterations of likely biological significance across 84 OncoPanel genes with a mutational frequency >0.5%. Genes with a q-value<0.10 were utilized to develop a numeric “Brain-Radiation Prediction Score” (“Brain-RPS”) to quantify local recurrence risk. Results: Genomic alterations of potential biological relevance in 11 ( ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, MDM4) and two genes ( FBXW 7 and AURKA) were associated with a decreased or increased risk of local recurrence, respectively (q-value<0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level RPS. On multivariable Fine/Gray’s competing risks regression, RPS [1.66 (1.44-1.92, p<0.001)], metastasis-associated edema [1.89 (1.38-2.59), p<0.001] and receipt of WBRT without SRS/SRT or neurosurgical resection [2.73 (1.78-4.20), p<0.001] were independent predictors of local failure. Conclusions: We developed a genomic score that can be calculated from an extracranial or intracranial site to quantify local recurrence risk following brain-directed radiation. Prior attempts to develop a biomarker-based radiation response signature have not been BrM-specific and have primarily relied on RNA-based measures of radiosensitivity, limiting their utility in clinical practice. To our knowledge, this represents the first study to systemically correlate DNA-based alterations with radiation-based outcomes among patients with BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genomic personalization of radiation treatment among patients with BrM.

Utilizing a targeted panel of genes with a known role in cancer pathogenesis, we identified genomic alterations in three genes as being predictive of LMD development. If validated in independent datasets, development of clinical trials exploring inhibition of pathways affected by these genomic alterations may be warranted with the goal of LMD prevention and targeted treatment among particularly high-risk cohorts. To our knowledge, this represents the first study to identify potentially actionable alterations as predictive of leptomeningeal disease development among patients with brain metastases.

PURPOSE The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid–dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS Patients with newly diagnosed O 6 -methylguanine–DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780 ). RESULTS Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit ( P > .05). CONCLUSION The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

Abstract BACKGROUND Leveraging external data has the potential to increase efficiency and precision of drug development in glioblastoma by complementing or replacing data from in-trial controls. We used an external control arm (ECA) to re-analyze data of the abemaciclib, neratinib and CC-115 arms of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. METHODS INSIGhT (NCT02977780) is an ongoing phase 2 adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma with a shared control arm of patients receiving radiation therapy with concurrent and maintenance temozolomide. The initial experimental arms (abemaciclib, neratinib, CC-115) have not shown a survival benefit relative to the shared control arm. We re-analyzed the experimental arm data and replaced the shared control arm with an ECA. The ECA was developed from a collection of trial datasets and real-world data available through the Glioblastoma External (GBM-X) Data Platform (). Propensity score matching was used to adjust for possible differences between pretreatment covariates (age, sex, resection, KPS) in the ECA and shared control arm. Cox proportional hazards models were used to estimate treatment effects. RESULTS On INSIGhT, patients were randomized to abemaciclib (n = 74), neratinib (n = 80), and CC-115 (n = 12). There were 687 unmethylated MGMT patients in the GBM-X ECA. After propensity score matching, there was no significant treatment effect associated with abemaciclib (HR 1.091, 95%CI:0.834-1.433, p = 0.536), neratinib (HR = 1.043, 95%CI:0.787-1.383, p = 0.770), or CC-115 (HR 1.088, 95%CI:0.834-1.433, p = 0.794) compared to the ECA. CONCLUSION In comparison to an ECA, there was no significant survival benefit with abemaciclib, neratinib and CC-115. Treatment effects estimates were similar to the primary analyses based on the original shared control arm of INSIGhT. The use of external control arms in early phase testing of new therapies is supported by our findings and could significantly reduce costs and time to conduct trials in newly diagnosed glioblastoma.

Background Recent data have found an overall survival benefit from prostate-directed radiotherapy in patients with low-volume metastatic prostate cancer. Prostate SBRT is an attractive treatment in this setting and may be optimised with MR-guided adaptive treatment. Here, we share our institutional experience delivering stereotactic MR-guided adaptive prostate SBRT (SMART) for patients with low-volume metastatic disease. Methods We reviewed patients with low-volume metastatic disease who received prostate SMART from October 2019 to December 2021 on a 0.35T MR-Linac. The cohort included 14 patients. Genitourinary (GU) and gastrointestinal (GI) toxicities were assessed using CTCAE v 5.0. Progression was defined as a change in systemic or hormonal therapy regimen as a result of PSA rise or disease progression. Results The median follow-up time was 29 months. Seven patients had hormone sensitive prostate cancer and 7 had castrate resistant prostate cancer (CRPC). 13 patients received 36.25 Gy in 5 fractions and one patient received 33 Gy in 5 fractions. At the time of last follow-up, 11 patients had not experienced progression and three patients, all with CRPC, had experienced progression. No patients developed local progression in the prostate after SMART. One patient experienced acute grade 2 urinary toxicity (7%) and no patients experienced acute grade 2 GI toxicity (0%). No grade 3 + acute toxicities were observed. Conclusions Prostate SMART was found to be well tolerated and all patients had local control of disease within the prostate at the time of last follow-up. Prostate SMART may represent a low-risk and well-tolerated approach for delivering prostate-directed radiotherapy for patients with limited metastatic disease.

PURPOSE The Response Assessment in Neuro-Oncology (RANO) criteria are widely used in high-grade glioma clinical trials. We compared the RANO criteria with updated modifications (modified RANO [mRANO] and immunotherapy RANO [iRANO] criteria) in patients with newly diagnosed glioblastoma (nGBM) and recurrent GBM (rGBM) to evaluate the performance of each set of criteria and inform the development of the planned RANO 2.0 update. MATERIALS AND METHODS Evaluation of tumor measurements and fluid-attenuated inversion recovery (FLAIR) sequences were performed by blinded readers to determine disease progression using RANO, mRANO, iRANO, and other response assessment criteria. Spearman's correlations between progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS Five hundred twenty-six nGBM and 580 rGBM cases were included. Spearman's correlations were similar between RANO and mRANO (0.69 [95% CI, 0.62 to 0.75] v 0.67 [95% CI, 0.60 to 0.73]) in nGBM and rGBM (0.48 [95% CI, 0.40 to 0.55] v 0.50 [95% CI, 0.42 to 0.57]). In nGBM, requirement of a confirmation scan within 12 weeks of completion of radiotherapy to determine progression was associated with improved correlations. Use of the postradiation magnetic resonance imaging (MRI) as baseline scan was associated with improved correlation compared with use of the pre-radiation MRI (0.67 [95% CI, 0.60 to 0.73] v 0.53 [95% CI, 0.42 to 0.62]). Evaluation of FLAIR sequences did not improve the correlation. Among patients who received immunotherapy, Spearman's correlations were similar among RANO, mRANO, and iRANO. CONCLUSION RANO and mRANO demonstrated similar correlations between PFS and OS. Confirmation scans were only beneficial in nGBM within 12 weeks of completion of radiotherapy, and there was a trend in favor of the use of postradiation MRI as the baseline scan in nGBM. Evaluation of FLAIR can be omitted. The iRANO criteria did not add significant benefit in patients who received immune checkpoint inhibitors.

Stereotactic magnetic resonance (MR)-guided adaptive radiotherapy (SMART) for renal cell carcinoma may result in more precise treatment delivery through the capabilities for improved image quality, daily adaptive planning, and accounting for respiratory motion during treatment with real-time MR tracking. In this study, we aimed to characterize the safety and feasibility of SMART for localized kidney cancer. Twenty patients with localized kidney cancer (ten treated in a prospective phase 1 trial and ten in the supplemental cohort) were treated to 40 Gy in five fractions on a 0.35 T MR-guided linear accelerator with daily adaptive planning and a cine MR-guided inspiratory breath hold technique. The median follow-up time was 17 mo (interquartile range: 13-20 months). A single patient developed local failure at 30 mo. No grade ≥3 adverse events were reported. The mean decrease in estimated glomerular filtration rate was -1.8 ml/min/1.73 m2 (95% confidence interval or CI [-6.6 to 3.1 ml/min/1.73 m2]), and the mean decrease in tumor diameter was -0.20 cm (95% CI [-0.6 to 0.2 cm]) at the last follow-up. Anterior location and overlap of the 25 or 28 Gy isodose line with gastrointestinal organs at risk were predictive of the benefit from online adaptive planning. Kidney SMART is feasible and, at the early time point evaluated in this study, was well tolerated with minimal decline in renal function. More studies are warranted to further evaluate the safety and efficacy of this technique. PATIENT SUMMARY: For patients with localized renal cell carcinoma who are not surgical candidates, stereotactic magnetic resonance--guided adaptive radiotherapy is a feasible and safe noninvasive treatment option that results in minimal impact on kidney function.

Abstract BACKGROUND Glioblastoma (GBM) is the most common malignant primary nervous system tumor and remains incurable with a poor prognosis despite current therapy. The standard for monitoring response to treatment, as defined by the Response Assessment in Neuro-Oncology (RANO) criteria, relies on a bidimensional (2D) measurement product of T1-gadolinium enhancing disease. However, due to the variability of bidimensional tumor characterization, there is considerable interest in volumetric segmentation to assess tumor burden, which could be implemented using machine learning models offering workflow automatization. METHODS In this study, we evaluate a commercially available automated tumor segmentation tool and correlate its volumetric output to the manual assessment of bidimensional 2D enhancing tumor burden by experts. MRI examinations during systemic treatment for two retrospective cohorts of patients with either newly diagnosed (nGBM) or recurrent GBM (rGBM) were assessed. The 2D diameter product in cm^2 of enhancing tumor was determined by blinded readers and volumetric segmentations in cm^3 were automatically generated. Spearman's correlation between the manual 2D and automated volume measurements was calculated for each cohort. RESULTS 315 patients with nGBM, and 482 with rGBM were evaluated, comprising 3073 total brain MRIs in the nGBM cohort and 2439 MRIs in the rGBM cohort. Spearman's correlation between the manual 2D and automated volumetric measurements was 0.7463 (0.730, 0.762) in the nGBM cohort and 0.8598 (0.849, 0.870) in the rGBM cohort. CONCLUSION Automated segmentation tools have the potential to revolutionize radiology workflows and increase sensitivity to subtle changes on imaging. However, the differential performance of this volumetric assessment confirms the need for further refinement and customization of such automated tools to account for tumor- and patient-specific factors.

Introduction Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. Methods Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. Results OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). Conclusions After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

BACKGROUND:Glioblastomas comprise heterogeneous cell populations with dynamic, bidirectional plasticity between treatment-resistant stem-like and treatment-sensitive differentiated states, with treatment influencing this process. However, current treatment protocols do not account for this plasticity. Previously, we generated a mathematical model based on preclinical experiments to describe this process and optimize a radiation therapy fractionation schedule that substantially increased survival relative to standard fractionation in a murine glioblastoma model. METHODS:We developed statistical models to predict the survival benefit of interventions to glioblastoma patients based on the corresponding survival benefit in the mouse model used in our preclinical study. We applied our mathematical model of glioblastoma radiation response to optimize a radiation therapy fractionation schedule for patients undergoing re-irradiation for glioblastoma and developed a first-in-human trial (NCT03557372) to assess the feasibility and safety of administering our schedule. RESULTS:Our statistical modeling predicted that the hazard ratio when comparing our novel radiation schedule with a standard schedule would be 0.74. Our mathematical modeling suggested that a practical, near-optimal schedule for re-irradiation of recurrent glioblastoma patients was 3.96 Gy × 7 (1 fraction/day) followed by 1.0 Gy × 9 (3 fractions/day). Our optimized schedule was successfully administered to 14/14 (100%) patients. CONCLUSIONS:A novel radiation therapy schedule based on mathematical modeling of cell-state plasticity is feasible and safe to administer to glioblastoma patients.