Background Patients with locally advanced non-small-cell lung cancer (NSCLC) who undergo concurrent chemotherapy and radiotherapy often experience synergistic toxicity, and local regional control rates remain poor. We assessed the activity and safety outcomes of primary tumour stereotactic body radiotherapy (SBRT) followed by conventional chemoradiotherapy to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced NSCLC. Methods In this multicentre, single-arm, phase 2 trial, patients aged 18 years and older were enrolled at eight regional cancer centres in North Carolina and South Carolina, USA. Patients were eligible if they had stage II-III, unresectable, locally advanced NSCLC (any histology), with peripheral or central primary tumours that were 7 cm or smaller, excluding central tumours within 2 cm of involved nodal disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients who had previously received systemic therapy or radiotherapy were excluded. Participants received SBRT to the primary tumour (50-54 Gy in three to five fractions) followed by standard radiotherapy (planned up to 60 Gy in 30 2 Gy fractions) to the involved lymph nodes with concurrent platinum doublet chemotherapy (either paclitaxel 50 mg/m2 intravenously plus carboplatin area under the curve mg/mL per min every 7 days for a total of six 1-week cycles or etoposide 50 mg/m2 intravenously on days 1-5 and days 29-33 plus cisplatin 50 mg/m2 intravenously on days 1, 8, 29, and 36 for two cycles of 4 weeks). An amendment to the protocol (Dec 11, 2017) permitted the administration of consolidation durvalumab at the discretion of the treating investigator. An additional protocol amendment on Jan 13, 2021, directed patients without disease progression after chemoradiotherapy to receive consolidation durvalumab (10 mg/kg intravenously on day 1 and day 15 of a 4-week cycle for up to 12 cycles or 1500 mg intravenously on day 1 of a 4-week cycle for up to 12 cycles). The primary endpoint was 1-year progression-free survival (per Response Evaluation Criteria in Solid Tumours version 1.1), assessed in all participants who received at least one fraction of SBRT and had radiological follow-up data up to 1 year. A 1-year progression-free survival rate of greater than 60% was required to reject the null hypothesis and show significant improvement in 1-year progression-free survival. One-sided exact binomial tests were used to compare the primary endpoint versus the historical control 1-year progression-free survival rate used to determine the sample size. Safety was assessed in all patients who received at least one fraction of SBRT. This study is registered with ClinicalTrials.gov, NCT03141359, and is closed to accrual. Findings Between May 11, 2017, and June 27, 2022, 61 patients were enrolled and received at least one dose of fractionated SBRT, of whom 59 were evaluable for the primary endpoint. Median age was 67 years (IQR 61-72), 28 (46%) of 61 were female, 33 (54%) were male, 51 (84%) were White, seven (11%) were Black, and three (5%) were of other or unknown race. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. As of data cutoff (July 12, 2023), median follow-up was 295 months (IQR 149-471). 1-year progression-free survival was 627% (90% CI 512-732; one-sided p=039, compared with the historical control rate), with 37 of 59 evaluable participants progression free and alive 1 year after enrolment (n=14 progressed, n=8 died). The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (nine [15%] of 61 patients), decreased white blood cell count (five [8%]), and anaemia (four [7%]). Treatment-related serious adverse events occurred in 11 (18%) of 61 patients, which included lung infection (three [5%]), pneumonitis (two [3%]), decreased neutrophil count (two [3%]), febrile neutropenia (two [3%]), and dyspnoea, hypoxia, respiratory failure, sinus tachycardia, bronchial infection, and acute kidney injury (each in one [2%] patient). Treatment-related deaths occurred in four (7%) of 61 patients (one each of respiratory failure, respiratory failure and dyspnoea, lung infection, and pneumonitis). Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Purpose: Single fraction preoperative stereotactic radiosurgery (SRS) has historically used a 10% to 20% dose reduction standard dosing. However, the effects of this dose reduction are not well characterized. The goal of this study was to compare outcomes and toxicity of standard dose (SD) with reduced dose (RD) single fraction preoperative SRS. Methods and Materials: Patients with brain metastases from solid cancers, of which at least 1 lesion measuring ≤ 4 cm was treated with single fraction preoperative SRS and underwent planned resection were included from the Preoperative Radiosurgery for Brain Metastases (PROPS-BM international multicenter combined prospective and retrospective registries from 8 institutions. SD was a priori defined as ≥20 Gy for lesions ≤2 cm, ≥17 Gy for >2 to 3 cm, and ≥14 Gy for >3 to 4 cm based on institutional dosing practices. Multivariable and propensity score matched analyses were performed. Results: The cohort consisted of 307 patients with 307 preoperative SRS treated index lesions. SD was used in 124 patients (40%) and RD was used in 183 patients (60%). Median dose for lesions 0 to 2 cm (n = 73), >2 to 3 cm (n = 152), and >3 to 4 cm (n = 82) was 20, 18, and 15 Gy in the SD cohort and 16, 15, and 13 Gy in the RD cohort, respectively. There was no difference in 2-year cavity local recurrence (LR, 16% vs 15%, P = .69), adverse radiation effect (ARE, 8% vs 6%, P = .77), meningeal disease (2% vs 8%, P = .07), composite endpoint of cavity LR, ARE, or nodular meningeal disease (23% vs 22%, P = .86), or overall survival (49% vs 36%, P = .15). Results were similar within each specific lesion diameter subgroup and within the propensity score matched cohorts (n = 168). Conclusions: Both SD and RD single fraction preoperative SRS demonstrate excellent rates of cavity LR and ARE. Cavity LR risk increased with larger lesion size, regardless of SRS dose category. There does not seem to be an advantage in efficacy or toxicity for RD over SD single fraction preoperative SRS. Additional studies are warranted to optimize preoperative SRS dose and fractionation.

Enhancing the efficacy of immunotherapy in brain metastases (BrM) requires an improved understanding of the immune composition of BrM and how this is affected by radiation and dexamethasone. Our two-arm pilot study (NCT04895592) allocated 26 patients with BrM to either low (Arm A) or high (Arm B) dose peri-operative dexamethasone followed by pre-operative stereotactic radiosurgery (pSRS) and resection (n= 13 per arm). The primary endpoint, a safety analysis at 4 months, was met. The secondary clinical endpoints of overall survival, distant brain failure, leptomeningeal disease and local recurrence at 12-months were 66%, 37.3%, 6%, and 0% respectively and were not significantly different between arms (p= 0.7739, p= 0.3884, p= 0.3469). Immunological data from two large retrospective BrM datasets and confirmed by correlates from both arms of this pSRS prospective trial revealed that BrM CD8 T cells were composed of predominantly PD1+ TCF1+ stem-like and PD1+ TCF1-TIM3+ effector-like cells. Clustering of TCF1+ CD8 T cells with antigen presenting cells in immune niches was prognostic for local control, even without pSRS. Following pSRS, CD8 T cell and immune niche density were transiently reduced compared to untreated BrM, followed by a rebound 6+ days post pSRS with an increased frequency of TCF1- effector-like cells. In sum, pSRS is safe and therapeutically beneficial, and these data provide a framework for how pSRS may be leveraged to maximize intracranial CD8 T cell responses. Radiation and steroid dosing can affect the immune composition of brain metastasis (BM). The authors have designed a pilot study of pre-operative stereotactic radiosurgery with low or high dose of peri-operative dexamethasone for resectable brain metastases, here reporting clinical outcomes and characterization of intratumor TCF1+ CD8+ stem-like T cell immune niches in the brain.

Background: These are the efficacy and toxicity outcomes of a prospective phase II trial of primary tumor stereotactic body radiation (SBRT) followed by conventional chemoradiation to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced non-small cell lung cancer (LA NSCLC). Methods: Eligible patients included stages II-III LA NSCLC with peripheral primary tumors ≤7 cm or centrally-based tumors with ≥2 cm separation from involved nodal disease. Patients received SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by standard radiation (60 Gy in 30 fractions) to the involved lymph nodes with concurrent platinum-doublet chemotherapy. Trial amendment allowed patients without disease progression after chemoradiation to receive consolidation durvalumab. The primary endpoint was 1-year progression-free survival (PFS). Frequencies and proportions were used for reporting this primary endpoint, adverse events, and patterns of failure. Time to event endpoints, including PFS and overall survival (OS), were estimated using Kaplan Meier (KM) methods. Findings: 61 patients across 8 centers were enrolled, including 59 evaluable for the primary objective, with a median follow-up of 48.1 months. Overall grade 3 or higher toxicity related to SBRT and/or mediastinal radiation was 13·1%, with three patients (5%) developing grade 3 pneumonitis. KM-estimated PFS at 1-year for all patients was 62.8%, median PFS was 25·3 months (95% CI: 11·5, 54·1), and median OS was 47·1 months. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. The KM-estimated 1-year PFS for patients who received durvalumab was 69·6%. Interpretation: SBRT to the primary tumor followed by conventional chemoradiation to the involved lymph nodes and consolidation immunotherapy was well tolerated and showed improved 1-year PFS compared to prior conventional chemoradiation trials for inoperable LA NSCLC. These findings serve as the basis for the randomized phase III study NRG Oncology LU008 (NCT05624996).Trial Registration: The trial is registered with ClinicalTrials.gov, NCT03141359.Funding: This research was supported by AstraZeneca and Atrium Health Levine Cancer.Declaration of Interest: The authors have no potential competing interests to report.Ethical Approval: This was an open-label, single-arm, phase II study approved by our Institutional Review Board and monitored by our institutional data and safety monitoring committee. All participants provided written informed consent to participate. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice at eight different centers within North and South Carolina all within the Levine Cancer Institute Atrium Health network. The trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice and approved by the IRB of the Levine Cancer Institute Atrium Health network (IRB approval number Pro00021247).

The CD8+ T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1+ TCF1+ stem-like CD8+ T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS's impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8+ T cells at 3 days. However, CD8+ T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1+ stem-like population.

PURPOSE:Preoperative radiosurgery (SRS) is a feasible alternative to postoperative SRS, with potential benefits in adverse radiation effect (ARE) and leptomeningeal disease (LMD) relapse. However, previous studies are limited by small patient numbers and single-institution designs. Our aim was to evaluate preoperative SRS outcomes and prognostic factors from a large multicenter cohort (Preoperative Radiosurgery for Brain Metastases [PROPS-BM]).METHODS AND MATERIALS:Patients with brain metastases (BM) from solid cancers who had at least 1 lesion treated with preoperative SRS and underwent a planned resection were included from 5 institutions. SRS to synchronous intact BM was allowed. Radiographic meningeal disease (MD) was categorized as either nodular or classical "sugarcoating" (cLMD).RESULTS:The cohort included 242 patients with 253 index lesions. Most patients (62.4%) had a single BM, 93.7% underwent gross total resection, and 98.8% were treated with a single fraction to a median dose of 15 Gray to a median gross tumor volume of 9.9 cc. Cavity local recurrence (LR) rates at 1 and 2 years were 15% and 17.9%, respectively. Subtotal resection (STR) was a strong independent predictor of LR (hazard ratio, 9.1; P < .001). One and 2-year rates of MD were 6.1% and 7.6% and of any grade ARE were 4.7% and 6.8% , respectively. The median overall survival (OS) duration was 16.9 months and the 2-year OS rate was 38.4%. The majority of MD was cLMD (13 of 19 patients with MD; 68.4%). Of 242 patients, 10 (4.1%) experienced grade ≥3 postoperative surgical complications.CONCLUSIONS:To our knowledge, this multicenter study represents the largest cohort treated with preoperative SRS. The favorable outcomes previously demonstrated in single-institution studies, particularly the low rates of MD and ARE, are confirmed in this expanded multicenter analysis, without evidence of an excessive postoperative surgical complication risk. STR, though infrequent, is associated with significantly worse cavity LR. A randomized trial between preoperative and postoperative SRS is warranted and is currently being designed.

Importance:Preoperative stereotactic radiosurgery (SRS) has been demonstrated as a feasible alternative to postoperative SRS for resectable brain metastases (BMs) with potential benefits in adverse radiation effects (AREs) and meningeal disease (MD). However, mature large-cohort multicenter data are lacking.Objective:To evaluate preoperative SRS outcomes and prognostic factors from a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM).Design, Setting, and Participants:This multicenter cohort study included patients with BMs from solid cancers, of which at least 1 lesion received preoperative SRS and a planned resection, from 8 institutions. Radiosurgery to synchronous intact BMs was allowed. Exclusion criteria included prior or planned whole-brain radiotherapy and no cranial imaging follow-up. Patients were treated between 2005 and 2021, with most treated between 2017 and 2021.Exposures:Preoperative SRS to a median dose to 15 Gy in 1 fraction or 24 Gy in 3 fractions delivered at a median (IQR) of 2 (1-4) days before resection.Main Outcomes and Measures:The primary end points were cavity local recurrence (LR), MD, ARE, overall survival (OS), and multivariable analysis of prognostic factors associated with these outcomes.Results:The study cohort included 404 patients (214 women [53%]; median [IQR] age, 60.6 [54.0-69.6] years) with 416 resected index lesions. The 2-year cavity LR rate was 13.7%. Systemic disease status, extent of resection, SRS fractionation, type of surgery (piecemeal vs en bloc), and primary tumor type were associated with cavity LR risk. The 2-year MD rate was 5.8%, with extent of resection, primary tumor type, and posterior fossa location being associated with MD risk. The 2-year any-grade ARE rate was 7.4%, with target margin expansion greater than 1 mm and melanoma primary being associated with ARE risk. Median OS was 17.2 months (95% CI, 14.1-21.3 months), with systemic disease status, extent of resection, and primary tumor type being the strongest prognostic factors associated with OS.Conclusions and Relevance:In this cohort study, the rates of cavity LR, ARE, and MD after preoperative SRS were found to be notably low. Several tumor and treatment factors were identified that are associated with risk of cavity LR, ARE, MD, and OS after treatment with preoperative SRS. A phase 3 randomized clinical trial of preoperative vs postoperative SRS (NRG BN012) has began enrolling (NCT05438212).

PURPOSE:Stereotactic body radiation therapy (SBRT) has been used with high effectiveness in early-stage non-small cell lung cancer (NSCLC) but has not been studied extensively in locally advanced NSCLC. We conducted a phase 2 study delivering SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes for patients with node-positive locally advanced NSCLC. This manuscript serves as both a guide to planning techniques used on this trial and the subsequent phase 3 study, NRG Oncology LU-008, and to report patient dosimetry and toxicity results. METHODS AND MATERIALS:We initiated a phase 2 multicenter single arm study evaluating SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by conventionally fractionated chemoradiation to 60 Gy in 2 Gy fractions with doublet chemotherapy to the involved lymph nodes for patients with stage III or unresectable stage II NSCLC. Patients eligible for adjuvant immunotherapy received up to 12 months of durvalumab. We report a detailed guide for the entire treatment process from computed tomography simulation through treatment planning and delivery. The dosimetric outcomes from the 60 patients who completed therapy on study are reported both for target coverage and normal structure doses. We also report correlation between radiation-related toxicities and dosimetric parameters. RESULTS:Sixty patients were enrolled between 2017 and 2022. Planning techniques used were primarily volumetric modulated arc therapy for SBRT to the primary tumor and conventionally fractionated radiation to the involved nodes, with a minority of cases using dynamic conformal arc technique or static dynamic multileaf collimator intensity modulated radiation therapy. Grade 2 or higher pneumonitis was associated with lung dose V5 Gy > 70% and grade 2 or higher pulmonary toxicity was associated with lung dose V10 Gy > 50%. Only 3 patients (5%) experienced grade 3 or higher pneumonitis. Grade 2 or higher esophagitis was associated with esophageal doses, including mean dose > 20 Gy, V60 Gy > 7%, and D1cc > 55 Gy. Only 1 patient (1.7%) experienced grade 3 esophagitis. CONCLUSIONS:SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes is feasible with planning techniques as described. Radiation-related toxicity on this phase 2 study was low. This manuscript serves as a guideline for the recently activated NRG Oncology LU-008 phase 3 trial evaluating this experimental regimen.

Background While tumor infiltrating T-cells have a prognostic benefit in many tumor types1-8, the prognostic role of infiltrating immune cells is in patients with brain metastases (BrM) is poorly understood. While patients with 1-2 BrM are treated with resection and stereotactic radiosurgery (SRS), intracranial failure is common, and prognostic biomarkers are needed. Our group recently reported the T-cell response in renal tumors is beneficial for patient outcomes. This response is supported by TCF1+ stem-like CD8 T-cells residing in dense regions of closely clustered antigen presenting cells within the tumor known as the immune niche.9 Notably, these stem-like T cells are critical for a robust anti-PD-1 response. Here, we wished to determine whether: 1) TCF1+ stem-like CD8 T-cells are present, residing in immune niches, in BrM?, (2) the density of these niches is associated with patient outcomes? and (3) stem-like CD8 T-cells and immune niches persist following SRS? Methods Tumor tissue was collected from 146 patients with BrM undergoing surgery at two clinical centers. Samples were analyzed by flow cytometry, single cell RNA sequencing, and immunofluorescence. Imaging data was analyzed using custom quantitative pipelines. Together, this allowed for evaluation of the BrM immune microenvironment at baseline or following pre-operative SRS. Results We describe the presence of TCF1+ stem-like CD8 T-cells in BrM (figure 1A-B), regardless of histology, these stem-like cells reside in dense, antigen-presenting immune niches (figure 1C-D). We find that higher density of these immune niches in BrM correlates with improved local control of BrM (figure 1E). Pre-operative SRS did not decrease immune niche density (figure 1F-G), nor significantly alter the stem-like signature of this population of T-cells. Finally, we also find that a longer time from SRS to resection may lead to increased CD8+ T-cell density in BrM (figure 1H). Conclusions We have shown that stem-like T-cells are present in BrM in immune niches. The density of this intratumoral immune organization is associated with improved patient outcomes regardless of primary tumor origin. These findings recapitulate the previously reported phenomena of immune organization in tumor tissue, underscoring the trans-tumor/trans-tissue importance of this biology in the anti-tumor immune response. Finally, this niche is maintained following SRS suggesting it is a relatively radioresistant compartment. This has significant implications for combinatorial strategies of immunotherapy and SRS for BrM. Acknowledgements We would like to acknowledge NCI grant 1-F30-CA-243250 (to C.S. Jansen), the Yerkes NHP Genomics Core which is supported in part by NIH P51 OD011132, the Emory Flow Cytometry Core supported by the National Center for Georgia Clinical & Translational Science Alliance of the National Institutes of Health under award number UL1TR002378, the Intramural Research Program of the NIH, National Cancer Institute and the Emory University Integrated Cellular Imaging Microscopy Core of the Winship Cancer Institute of Emory University and NIH/NCI under award number 2P30CA138292-04. References Azimi F, et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 2012;30(21):2678–83. Epub 2012/06/20. doi: 10.1200/jco.2011.37.8539. PubMed PMID: 22711850. Galon J, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4. Epub 2006/09/30. doi: 10.1126/science.1129139. PubMed PMID:17008531. Mlecnik B, et al. Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity. 2016;44(3):698–711. Epub 2016/03/18. doi: 10.1016/j.immuni.2016.02.025. PubMed PMID: 26982367. Mlecnik B, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011;29(6):610–8. Epub 2011/01/20. doi:10.1200/JCO.2010.30.5425. PubMed PMID: 21245428. Pagès F, et al. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 2009;29:1093. doi:10.1038/onc.2009.416. Peranzoni E, et al. Macrophages impede CD8 T-cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proceedings of the National Academy of Sciences of the United States of America 2018;115(17):E4041–E50. Epub 2018/04/11. doi: 10.1073/pnas.1720948115. PubMed PMID: 29632196. Savas P, et al. Single-cell profiling of breast cancer T-cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med. 2018;24(7):986–93. Epub 2018/06/27. doi: 10.1038/s41591-018-0078-7. PubMed PMID: 29942092. Tosolini M, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011;71(4):1263–71. Epub 2011/02/10. doi: 10.1158/0008-5472.Can-10-2907. PubMed PMID: 21303976. Jansen CS, et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T-cells. Nature. 2019;576(7787):465–70. doi: 10.1038/s41586-019-1836-5. Ethics Approval Samples are collected under an approved IRB protocol (00001896). Consent All patients provided informed consent.

Stereotactic radiosurgery (SRS) is the delivery of a high dose ionizing radiation in a highly conformal manner, which allows for significant sparing of nearby healthy tissues. It is typically delivered in 1–5 sessions and has demonstrated safety and efficacy across multiple intracranial neoplasms and functional disorders. In the setting of brain metastases, postoperative and definitive SRS has demonstrated favorable rates of tumor control and improved cognitive preservation compared to conventional whole brain radiation therapy. However, the risk of local failure and treatment-related complications (e.g. radiation necrosis) markedly increases with larger postoperative treatment volumes. Additionally, the risk of leptomeningeal disease is significantly higher in patients treated with postoperative SRS. In the setting of high grade glioma, preclinical reports have suggested that preoperative SRS may enhance anti-tumor immunity as compared to postoperative radiotherapy. In addition to potentially permitting smaller target volumes, tissue analysis may permit characterization of DNA repair pathways and tumor microenvironment changes in response to SRS, which may be used to further tailor therapy and identify novel therapeutic targets. Building on the work from preoperative SRS for brain metastases and preclinical work for high grade gliomas, further exploration of this treatment paradigm in the latter is warranted. Presently, there are prospective early phase clinical trials underway investigating the role of preoperative SRS in the management of high grade gliomas. In the forthcoming sections, we review the biologic rationale for preoperative SRS, as well as pertinent preclinical and clinical data, including ongoing and planned prospective clinical trials.

PURPOSE:Volumetric modulated arc therapy (VMAT) craniospinal irradiation (CSI) has been shown to have significant dosimetric advantages compared to 3-dimensional conformal therapy but is a technically complex process. We sought to develop a guide for all aspects of the VMAT CSI process and report patient dosimetry results. METHODS AND MATERIALS:We initiated VMAT CSI in 2017 and have regularly revised our standard operating procedure for this process since then. Herein, we report a detailed template for the entire VMAT CSI process from initial patient setup and immobilization at time of computed tomography (CT) simulation to contouring and treatment planning, quality assurance, and therapy delivery. The records of 12 patients who were treated with VMAT CSI were also retrospectively reviewed. RESULTS:Patient age ranged from 2 to 59 years with 5 pediatric patients (age <18 years), 5 young adults (age 18-35 years), and 2 older adults (age >35 years). The majority of patients (67%) had medulloblastoma. CSI dose ranged from 21.6 to 36 Gy, with a median of 36 Gy. The median CSI planning target volume was 2383 cc with a median V95% of 99.8% and median 0.03 cc hotspot of 112.5%. The average V107% was 7.4% and the average conformality index was 1.01. CONCLUSIONS:VMAT CSI has potentially significant dosimetric and acute toxicity advantages compared to 3-dimensional conformal. However, proper procedures need to be in place throughout the process in order to be able to realize these potential advantages. We herein describe our detailed standard operating procedure for VMAT CSI. Recognizing the scarcity of proton beam centers in many areas, VMAT CSI represents a feasible treatment with more widespread availability.

PurposeThis guideline provides updated evidence-based recommendations addressing recent developments in the management of patients with brain metastases, including advanced radiation therapy techniques such as stereotactic radiosurgery (SRS) and hippocampal avoidance whole brain radiation therapy and the emergence of systemic therapies with central nervous system activity.MethodsThe American Society for Radiation Oncology convened a task force to address 4 key questions focused on the radiotherapeutic management of intact and resected brain metastases from nonhematologic solid tumors. The guideline is based on a systematic review provided by the Agency for Healthcare Research and Quality. Recommendations were created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength.ResultsStrong recommendations are made for SRS for patients with limited brain metastases and Eastern Cooperative Oncology Group performance status 0 to 2. Multidisciplinary discussion with neurosurgery is conditionally recommended to consider surgical resection for all tumors causing mass effect and/or that are greater than 4 cm. For patients with symptomatic brain metastases, upfront local therapy is strongly recommended. For patients with asymptomatic brain metastases eligible for central nervous system–active systemic therapy, multidisciplinary and patient-centered decision-making to determine whether local therapy may be safely deferred is conditionally recommended. For patients with resected brain metastases, SRS is strongly recommended to improve local control. For patients with favorable prognosis and brain metastases receiving whole brain radiation therapy, hippocampal avoidance and memantine are strongly recommended. For patients with poor prognosis, early introduction of palliative care for symptom management and caregiver support are strongly recommended.ConclusionsThe task force has proposed recommendations to inform best clinical practices on the use of radiation therapy for brain metastases with strong emphasis on multidisciplinary care.

PURPOSE American Society of Radiation Oncology (ASTRO) has developed a guideline on appropriate radiation therapy for brain metastases. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS “Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline”2 was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations. RESULTS The ASCO Endorsement Panel determined that the recommendations from the ASTRO guideline, published May 6, 2022, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorses “Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline.”2 RECOMMENDATIONS Within the guideline, stereotactic radiosurgery (SRS) is recommended for patients with Eastern Cooperative Oncology Group performance status of 0-2 and up to four intact brain metastases, and conditionally recommended for patients with up to 10 intact brain metastases. The guideline provides detailed dosing and fractionation recommendations on the basis of the size of the metastases. For patients with resected brain metastases, radiation therapy (SRS or whole-brain radiation therapy [WBRT]) is recommended to improve intracranial disease control; if there are limited additional brain metastases, SRS is recommended over WBRT. For patients with favorable prognosis and brain metastases ineligible for surgery and/or SRS, WBRT is recommended with hippocampal avoidance where possible and the addition of memantine is recommended. For patients with brain metastases, limiting the single-fraction V12Gy to brain tissue to ≤ 10 cm3 is conditionally recommended. Additional information is available at www.asco.org/neurooncology-guidelines.

Purpose/Objective(s) Preoperative (preop) stereotactic radiosurgery (SRS) is a feasible alternative to postoperative (postop) SRS with potential benefits in adverse radiation effect (ARE) and meningeal disease (MD) compared to postop SRS. The goal of this study was to determine risk factors for progression and toxicity after preop SRS in an expanded multicenter cohort. Materials/Methods Patients with brain metastases (BM) from solid cancers, of which at least 1 lesion was treated with preop SRS and underwent planned resection were included from 6 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included classically radiosensitive or non-solid cancers and prior or planned whole brain radiotherapy (WBRT). SRS dose, fractionation, and interval between preop SRS and surgery was per individual institutional protocol. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Radiographic MD was categorized as nodular (nMD) or classical "sugarcoating" (cMD). Results The cohort consisted of 378 patients with 389 preop SRS treated index lesions. Most patients (61.1%) had a single BM, underwent gross total resection (GTR, 95.4%), and had non-small cell lung (NSCLC, 47.9%), breast (16.1%), or melanoma (11.4%) cancer. Median dose was 15 Gy in 1 fraction to a median gross tumor volume (GTV) of 10.1 cc. Median interval between preop SRS and surgery was 2 days. Median cranial imaging follow-up interval was 9.5 months overall and 17.5 months for alive patients. The 2-year cavity local recurrence (LR) rate was 14.5%. Multivariable analysis (MVA) for LR demonstrated subtotal resection (STR, vs. GTR), single fraction SRS (vs. fractionated), larger GTV, gastrointestinal (GI) primary (vs. NSCLC), active systemic disease, and piecemeal resection (vs. en bloc) to be associated with higher risk of LR. Of note, interval between preop SRS and surgery was not significant. The 2-year any grade ARE rate was 7.7%. MVA for ARE demonstrated only larger planning target volume (PTV) margin expansion as associated with higher risk of ARE. The 2-year rate of MD was 5.6%. Most MD (76%) was classical type, with the remainder being nodular type. MVA for MD demonstrated STR (vs. GTR) and breast or melanoma histology (vs. NSCLC) as associated with higher risk of MD. Of note, posterior fossa location and type of surgical resection were not significant. Conclusion Preop SRS demonstrates overall excellent rates of cavity LR, ARE, and MD in this expanded multicenter cohort study. We have identified several tumor and treatment factors that are significantly associated with risk of cavity LR, ARE, and MD after treatment with preop SRS. Minimizing likelihood of STR and treating with fractionated preop SRS for larger higher risk tumors may lead to improved outcomes. A randomized trial of preop versus postop SRS is currently being designed (NRG BN012).

SGRT provides a reliable technique for BH SBRT treatments of the lung. Minimal target displacements on mid treatment BH CBCT were observed. Higher 4D ROM on free breathing scans correlated with larger displacements in tumor position utilizing this technique.

Purpose To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. Methods ASCO convened an Expert Panel and conducted a systematic review of the literature. Results Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. Recommendations Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non–small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy. Additional information is available at www.asco.org/neurooncology-guidelines.

PURPOSE:Postoperative stereotactic radiosurgery (SRS) is associated with up to 30% risk of subsequent leptomeningeal disease (LMD). Radiographic patterns of LMD (classical sugarcoating [cLMD] vs. nodular [nLMD]) in this setting has been shown to be prognostic. However, the association of these findings with neurologic death (ND) is not well described.METHODS AND MATERIALS:The records for patients with brain metastases who underwent surgical resection and adjunctive SRS to 1 lesion (SRS to other intact lesions was allowed) and subsequently developed LMD were combined from 7 tertiary care centers. Salvage radiation therapy (RT) for LMD was categorized according to use of whole-brain versus focal cranial RT.RESULTS:The study cohort included 125 patients with known cause of death. The ND rate in these patients was 79%, and the rate in patients who underwent LMD salvage treatment (n = 107) was 76%. Univariate logistic regression demonstrated radiographic pattern of LMD (cLMD vs. nLMD, odds ratio: 2.9; P = .04) and second LMD failure after salvage treatment (odds ratio: 3.9; P = .02) as significantly associated with ND. The ND rate was 86% for cLMD versus 68% for nLMD. Whole-brain RT was used in 95% of patients with cLMD and 52% with nLMD. In the nLMD cohort (n = 58), there was no difference in ND rate based on type of salvage RT (whole-brain RT: 67% vs. focal cranial RT: 68%, P = .92).CONCLUSIONS:LMD after surgery and SRS for brain metastases is a clinically significant event with high rates of ND. Classical LMD pattern (vs. nodular) and second LMD failure after salvage treatment were significantly associated with a higher risk of ND. Patients with nLMD treated with salvage focal cranial RT did not have higher ND rates compared with WBRT. Methods to decrease LMD and the subsequent high risk of ND in this setting warrant further investigation.

Abstract BACKGROUND Preoperative single fraction radiosurgery (SRS) and postoperative fractionated SRS delivered over 3–5 fractions have been shown to have favorable outcomes compared to postoperative single fraction SRS for resected brain metastases. No study has directly compared these 2 treatment approaches. METHODS Records for patients with resected brain metastases treated with either single fraction preoperative SRS or fractionated (3-5 fractions) postoperative SRS were reviewed. Preoperative SRS was 10-20% dose reduced compared to standard and surgery generally followed within 48 hours. Eligibility criteria included solid tumor metastases, 1 brain metastasis resected, and no previous cranial RT. Fine-Gray and Cox multivariable (MVA) and propensity score matched (PSM) analyses were used. RESULTS A total of 330 patients (137 preoperative; 193 postoperative) were included. Median dose was 15 Gy in 1 fraction and 24 Gy in 3 fractions, respectively. In MVA, preoperative SRS was significantly associated with higher risk of cavity local recurrence (LR, hazard ratio (HR) 2.04, p=0.002) and lower risk of leptomeningeal disease (LMD, HR 0.41, p=0.05). There was no difference in adverse radiation effect (ARE) or overall survival (OS) between groups. In the PSM analysis (65 matched pairs), 1-year outcomes for preoperative vs. postoperative SRS were as follows - cavity LR: 22.9% vs. 3.1%, p< 0.001, LMD: 4.2% vs. 15.5%, p=0.04, ARE: 3.2% vs. 7.9%, p=0.73, composite endpoint (cavity LR, symptomatic ARE, or LMD): 27.6% vs. 20.1%, p=0.33, OS: 56.3% vs. 62.3%, p=0.8. CONCLUSIONS Preoperative single fraction SRS and postoperative fractionated (3-5 fractions) SRS demonstrate distinct patterns of failure. Compared to postoperative SRS, preoperative SRS was associated with increased risk of cavity LR and lower risk of LMD in both multivariable and PSM analyses. There was no difference in risk of ARE or OS. Methods to reduce preoperative SRS cavity LR, such as with higher dose fractionated regimens, should be considered.