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Purpose Achieving competency as educators is increasingly recognized as a critical part of residents’ training in graduate medical education across specialties. In addition to teaching medical students, radiation oncology residents often play a vital role in peer and interprofessional education. We conducted a survey to identify the needs of radiation oncology residents for developing skills in teaching. Methods and Materials An anonymous, web-based survey was developed and distributed to resident physicians at US radiation oncology programs. Analyses describe respondent demographics, experiences with teaching, and interest in various aspects of a formal “residents-as-teachers” curriculum. Results There were 171 completed survey responses (27.5% response rate). A total of 146 residents (85.4%) reported receiving no formal training in teaching before residency, and 121 (70.8%) reported no formal training during residency. Residents who had formal training in teaching were significantly more likely to be “quite” or “extremely” confident about teaching compared with residents who had no prior formal training (76.0% vs 51.4%; P = .022). Residents most commonly taught other residents and medical students (163 [95.3%] and 160 [93.6%] respondents, respectively). The most common settings for teaching were one-on-one teaching (164 respondents [95.9%]), small-group lectures (135 respondents [78.9%]), and intradepartmental lectures (136 respondents [79.5%]). In response to open-ended questions regarding desired teaching opportunities and domains for teaching development, many residents expressed a lack of confidence in teaching and were interested in improvement across many aspects of teaching. Conclusions Radiation oncology residents are expected and desire to teach in a multitude of settings across a wide variety of audiences. However, a significant proportion of radiation oncology residents lack formal training and rarely receive feedback for their teaching skills. The results of this national survey support the development of a residents-as-teachers curriculum for radiation oncology residents that would address the needs for and significant interest in this area.

BACKGROUND Disparity in mental health care among cancer patients remains understudied. METHODS A large, retrospective, single tertiary-care institution cohort study was conducted based on deidentified electronic health record data of 54,852 adult cancer patients without prior mental health diagnosis (MHD) diagnosed at the University of California, San Francisco between January 2012 and September 2019. The exposure of interest was early-onset MHD with or without psychotropic medication (PM) within 12 months of cancer diagnosis and primary outcome was all-cause mortality. RESULTS There were 8.2% of patients who received a new MHD at a median of 197 days (interquartile range, 61-553) after incident cancer diagnosis; 31.0% received a PM prescription; and 3.7% a mental health-related visit (MHRV). There were 62.6% of patients who were non-Hispanic White (NHW), 10.8% were Asian, 9.8% were Hispanic, and 3.8% were Black. Compared with NHWs, minority cancer patients had reduced adjusted odds of MHDs, PM prescriptions, and MHRVs, particularly for generalized anxiety (Asian odds ratio [OR], 0.66, 95% CI, 0.55-0.78; Black OR, 0.60, 95% CI, 0.45-0.79; Hispanic OR, 0.72, 95% CI, 0.61-0.85) and selective serotonin-reuptake inhibitors (Asian OR, 0.43, 95% CI, 0.37-0.50; Black OR, 0.51, 95% CI, 0.40-0.61; Hispanic OR, 0.79, 95% CI, 0.70-0.89). New early MHD with PM was associated with elevated all-cause mortality (12-24 months: hazard ratio [HR], 1.43, 95% CI, 1.25-1.64) that waned by 24 to 36 months (HR, 1.18, 95% CI, 0.95-1.45). CONCLUSIONS New mental health diagnosis with PM was a marker of early mortality among cancer patients. Minority cancer patients were less likely to receive documentation of MHDs or treatment, which may represent missed opportunities to identify and treat cancer-related mental health conditions.

Understanding the molecular landscape and microenvironment of melanoma brain metastases is critical to devise improved treatments. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular correlates of clinical outcome. 84 consecutive patients who underwent surgical resection at a single institution with a histo-pathologically confirmed diagnosis of melanoma brain metastasis were retrospectively identified. In 60 patients (71%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay. Single nuclear RNA sequencing using the 10x platform was performed on n=6 samples from treatment naïve patients. Overall survival (OS) and CNS progression free survival (CNS PFS) from time of brain metastasis diagnosis were estimated using the Kaplan-Meier method. The median patient age was 62 years old (range: 25-78 years), and the median clinical follow up was 17 months. A total of 33 patients (39%) had BRAFV600E melanoma brain metastases. Multivariate analysis incorporating age, performance status, and extracranial disease revealed BRAF status was an independent prognostic factor for OS (p< 0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was TERT promoter mutation (n=44; 73%). With regard to TCGA molecular melanoma subgroups, NRAS mutant (n=22; 37%) brain metastases were most common followed by BRAF mutant (n=20; 33%), NF1 mutant (n=11; 18%), and triple wildtype (n=7; 12%). Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by TERT status but demonstrated worse overall survival in the BRAF mutant molecular group (p< 0.01, log-rank test). Single nuclear sequencing of 36,115 nuclei across 6 samples revealed BRAF wildtype tumors exhibit greater infiltrating immune cell populations including microglia and T cell subtypes. Future work will require integration of these findings with different systemic therapy regimens and across larger, prospective, multi-institutional cohorts.

INTRODUCTION Predictors of postoperative leptomeningeal disease (LMD) after resection of brain metastases (BMs) are not well defined. OBJECTIVE This study examined rates and predictors of LMD, including subtypes, in patients who underwent resection of a BM followed by postoperative radiation.Method: A retrospective, single-center study was conducted examining overall LMD, classical LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression and a Cox proportional hazards analyses were performed to identify risk factors associated with LMD. Random forest models were constructed to predict LMD and differentiate cLMD versus nLMD. Accuracy and the area under the receiver operating characteristic curve (AUROC) were calculated to evaluate the models.Result: Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD with 19(8.8%) cLMD cases and 28(12.9%) nLMD cases . Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from LMD diagnosis compared to nLMD (2.4 vs 6.9 mo, Log-rank p=0.02), and treatment of LMD was associated with improved survival for both cLMD and nLMD subtypes. Multivariate Cox hazard analysis identified cerebellar/insular/occipital location (HR 3.25, 95% CI 1.73-6.11, p=0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27-4.88, p=0.008), and ventricle contact (HR 2.82, 95% CI 1.5-5.3, p=0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an AUROC of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. Both regression analysis and random forest analysis identified postoperative systemic therapy exposure as the main factor differentiating cLMD from nLMD development. CONCLUSION Tumor location, absence of extracranial disease at the time of surgery, contact with a ventricle, and increased tumor volume are associated with LMD. Classical LMD is associated with worse prognosis compared to nLMD.

Purpose/objective(s) Management of progressive brain tumors following high dose radiotherapy is controversial. In select cases, surgical resection can provide rapid relief of regional mass effect and edema, and highly focal adjuvant re-irradiation can be administered in the form of brachytherapy. Permanent low-dose rate cesium-131 brachytherapy may offer dosimetric and radiobiologic advantages over other isotopes. The purpose of this study was to examine the safety and efficacy of intracranial cesium-131 brachytherapy after surgical resection in a heavily pre-treated patient cohort. Materials/methods A retrospective chart review was conducted of all patients treated with intraoperative intracranial cesium-131 brachytherapy from an institutional database. Treatment consisted of maximal safe resection followed by implantation of suture-stranded cesium-131 seeds, maintaining approximately 10mm spacing between seeds, with a planned target dose of 80 Gy to 5mm depth. Local failure was defined as recurrence in or contacting the resection cavity after salvage resection and brachytherapy. Regional failure was defined as recurrence within 10mm of the resection cavity. Recurrence was defined as a new lesion or growth of ≥25% in any axial dimension on interval MRI. Toxicity was collected based on CTCAE 4.0. Results A total of 35 patients with a median imaging follow up of 17.0 months (interquartile range [IQR] 9.7-25.9) underwent 41 consecutive cesium-131 implants between 2016 and 2020. 20 patients (59%; N = 22 implants) were treated for recurrent brain metastasis, 12 patients (34%; N = 16 implants) were treated for recurrent atypical (N = 8) or anaplastic meningioma (N = 4), and 3 patients (9%) were treated for recurrent glioma (N = 2) or hemangiopericytoma (N = 1). A majority of lesions had received prior surgery (N = 28, 66.7%, range 0-3 prior surgeries) and 34 patients had received prior high dose radiation. 34 of 41 (82.9%) tumors had received prior radiosurgery, and 12 (29.2%) had undergone prior external beam radiation (range 50-60 Gy). 17 of 41 lesions (41.5%) had radiologic evidence of adverse radiation/treatment effect (ARE) prior to salvage therapy. Median tumor size was 3.0cm (IQR 2.3-3.7). Overall actuarial local/loco-regional control at 1-year was 91.6%/84.7% (89.8%/88.9% for metastases and 100%/82.5% for meningiomas). Crude loco-regional control was 86.3% for metastases, 75% for meningiomas, and 66.7% for other lesions. Symptomatic ARE following treatment was observed in 9.8% (N = 4) resection cavities. The surgical complication rate was 14.6% (N = 6 total, N = 3 [7.3%] grade 3-5) including 1 peri-operative death. Conclusion Cesium-131 brachytherapy in this heavily pre-treated cohort resulted in good local control and an acceptable rate of symptomatic adverse radiation effect and toxicity and may be a reasonable treatment option for this select population. Author disclosure W.C. Chen: None. M. Lafreniere: None. C. Phuong: None. M. Lometti: None. O. Morin: None. B.P. Ziemer: None. H. Vasudevan: Research Grant; Children's Tumor Foundation. Patent/License Fees/Copyright; Genentech, Eli Lilly. S. Hervey-Jumper: None. P.V. Theodosopoulos: None. S. Magill: None. S.E. Fogh: Independent Contractor; Accuray. J.L. Nakamura: None. L. Boreta: None. P.K. Sneed: None. M.W. McDermott: Chair; Miami Baptist. D. Raleigh: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.

PURPOSE/OBJECTIVE(S) Previous studies have characterized dose gradient patterns for various hypo-fractionated brain radiosurgery (hSRS) treatment platforms. The Gamma Knife Icon (GKI) has consistently exhibited either superior or non-inferior peripheral dose fall-off and normal brain sparing characteristics when compared to other Linac-based hSRS treatment platforms. Given the prevalence of Linac-based treatments, identifying planning techniques to optimize treatment parameters is desirable. In this study, we investigated a novel Linac-based treatment approach that aimed to create the sharpest dose fall-off for hSRS of large brain lesions. MATERIALS/METHODS A cohort of patient cases (n = 10) with single brain lesions (volume 27.6+/-8.1 mL, range 20.-42.1 mL) treated with GKI at our institution were selected as sample test cases for our study. A non-coplanar unconstrained VMAT (NCU-VMAT) treatment planning approach was developed, and its script was implemented on a commercial treatment planning system for clinical Linac treatment equipped with the latest high-definition multi-leaf collimators (MLCs). Treatment plans produced via the NCU-VMAT approach were then compared against further optimized treatment plans from GKI, as well as conventional coplanar and non-coplanar VMAT treatment planning approaches. The comparison was carried out using DVH-derived parameters including target volume coverage, target dose conformity, modified dose fall-off index defined as the volume of 50% prescribed target dose divided by the target volume (PIV50). RESULTS For each case studied, NCU-VMAT achieved practically identical target coverage (0.98 ± 0.01) and Paddick dose conformity index (0.87 ± 0.02) compared to optimized GKI treatments. The mean PIV50 values were 2.99 ± 0.14, 3.77 ± 0.22, and 3.36 ± 0.19 for optimized GKI, conventional coplanar, and non-coplanar VMAT treatment plans, respectively. These results were in excellent agreement with previously published studies. However, the NCU-VMAT technique yielded a mean PIV50 of 2.41 ± 0.07. This represents an improvement of approximately 40% (P < 0.001, paired two-tailed Student t-test) over all existing approaches including GKI. Further analyses revealed that PIV50 of NCU-VMAT approached the theoretical minimum for all the studied cases. CONCLUSION Our results demonstrate that in treatment of large brain tumors, a treatment planning approach using Bremsstrahlung x-ray based Linacs can achieve superior dose fall-off for intracranial hSRS compared to GKI. We dispel the myth that physical characteristics of Cobalt γ-rays are needed to create the sharpest dose fall-off. Given the prevalence of Linac-based treatments compared to GKI, we present a novel optimized planning technique that achieves a new benchmark of sharpest dose fall-off. AUTHOR DISCLOSURE T. Nano: None. O. Morin: None. B.P. Ziemer: None. D. Raleigh: None. L. Boreta: None. J.L. Nakamura: None. S.E. Fogh: Independent Contractor; Accuray. P.K. Sneed: None. S. Hervey-Jumper: None. P.V. Theodosopoulos: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.L. Ma: Patent/License Fees/Copyright; University of California Regents.

Purpose/Objective(s) To report our initial clinical implementation of a hypofractionated brain radiosurgery (hSRS) approach via packing hundreds of isocenters for treatment of a large target with a substantial GTV expansion in order to reduce dose hot spots in eloquent brain. Materials/Methods A high-density isocenter packing (HDIP) technique similar to “onion peeling” was developed for hSRS, where a large target volume of 14.1 cc was sequentially shrunk or “peeled” by a margin of 2 to 4-mm depending on its size. The isocenters were densely packed inside each layer or each “peel” of the target, especially within the GTV-to-PTV margin. Once packed, the isocenter location, shapes and weights of the beams were inversely optimized and manually adjusted to achieve an optimal dose distribution. This technique was clinically implemented on a frameless SRS unit for the purpose of expediting the workflow in treating brain lesions with GTV-to-PTV expansion of at least 5 mm. Results HDIP enabled the target dose to be prescribed to the 80-90% isodose line (normalized to the dose maximum), thus reducing dose hot spots greater than 120% of prescription dose inside the GTV expansion volume comprised mostly of normal brain tissue. Compared to the conventional approach of using only 1/3 to 1/4 as many isocenters, HDIP achieved identical dose coverage (> 98%), dose conformality ( 0.01 min to enable clinical implementation. This strategy negligibly impacted the total treatment time of 20-30 min of a typical HDIP treatment with a dose rate of 2.0 Gy/min of our LGKI unit. Conclusion HDIP is technically feasible and successfully implemented for the first time at our institution, enabling us to expedite the hSRS workflow to care for patients with targets in eloquent brain requiring substantial GTV-to-CTV/PTV margin expansion. Author Disclosure N. Cho: Employee; Thermo Fisher Scientific. D. Raleigh: None. B.P. Ziemer: None. T. Nano: None. P.V. Theodosopoulos: None. P.K. Sneed: None. L. Boreta: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.L. Ma: Patent/License Fees/Copyright; University of California Regents.

PURPOSE: The purpose of this study is to describe outcomes after pediatric radiosurgery for malignant CNS lesions. METHODS: Retrospective chart review was performed for 31 pediatric patients treated at a single institution with Gamma Knife stereotactic radiosurgery (SRS) for primary or metastatic CNS malignancies between 2000-2020. RESULTS: 25 patients were treated with SRS for focal recurrences of primary CNS malignancies, 1 patient was treated in the adjuvant setting after initial resection, and 5 patients were treated for brain metastases. Primary CNS histologies included ependymoma (n=14), glioma (n=4), medulloblastoma (n=2), and meningioma (n=2). 65% were WHO grade 3 or 4. 71% of patients had received a prior course of involved-field external beam radiation to the brain to a median dose of 59.4 Gy in 33 fractions. Median age at SRS was 14 years (range 4-21). Radiosurgery was predominantly performed in a single fraction to a median dose of 17 Gy to a total of 42 targets among 29 patients. Two patients underwent fractionated radiosurgery to 30 Gy in 5 fractions for larger lesions. Median follow up after SRS was 44 months. 7 patients (23%) had no evidence of disease after SRS at a median follow up of 39 months. 6 patients (19%) developed local recurrence at the site of their treated lesion at a median of 13 months after SRS. 20 patients (65%) developed recurrent disease in the CNS outside of the radiosurgery field at a median of 11 months after SRS. 4 patients developed toxicity from SRS related to radiation treatment effect, all of which occurred within 1 year of SRS. CONCLUSIONS: SRS for malignant CNS lesions in the pediatric population provides effective local control and is well-tolerated. However, there remains a substantial risk of distant CNS failures given the nature of recurrent or metastatic disease in these patients.

PURPOSE/OBJECTIVE(S) Patients with large brain metastases may receive fractionated stereotactic radiosurgery (FSRS) if they are not surgical candidates yet still pursuing cancer-directed therapy. FSRS with limited margins can allow for optimal sparing of uninvolved regional brain tissue. However, due to required treatment planning process, there is often elapsed time between MRI brain and treatment start which may contribute to marginal misses. Growth rates of large brain metastases and implications for optimal margin to account for growth rate and time interval between planning MRI and FSRS are incompletely characterized. MATERIALS/METHODS Patients treated at a single institution from 2018-2020 who received frameless FSRS on a Cobalt-60 treatment unit for large (> 2cm diameter) brain metastases were identified. Patients with a prior diagnostic brain MRI scan with technically similar parameters to a second MRI obtained for treatment planning were included. Resection cavities and lesions undergoing re-treatment after prior SRS were excluded. Brain metastasis volumes were obtained by contouring on both diagnostic and planning MRIs. Patient characteristics and treatment details were also collected. Analysis was conducted using paired Student's t test and Pearson's R and growth rate was determined using a linear model. RESULTS Thirty-six patients with 54 brain metastases met inclusion criteria. The most common primary cancer sites were lung (36%), colorectal (14%), and skin (14%), and most common histologies were adenocarcinoma (53%) and melanoma (17%). Nearly half (47%) of patients were on systemic therapy at the time of FSRS and the majority (85%) received steroids prior to starting FSRS. Treatment dose ranged from 24-32.5 Gy in 3-5 fractions, with median of 30 Gy in 5 fractions with zero margin. Median time from diagnostic to planning MRI was 15 days (IQR: 11-21) and planning MRI to FSRS was 1 day (IQR 1-3). The median size of included brain metastases on planning MRI was 7.38cc (IQR: 5.09-11.55) compared to 6.03cc (IQR: 3.87-8.95) on prior diagnostic MRI (P 90% of lesions over 3, 7, 10, and 14 days between planning and treatment, respectively. CONCLUSION In the absence of expedited planning, FSRT for intact large brain metastases with limited margins may result in geometric under treatment. An adaptive margin strategy based upon initial tumor size, and time between planning imaging and treatment delivery may be afforded to maintain ideal conformity, properly targeting a growing target lesion while maximally sparing uninvolved regional brain. AUTHOR DISCLOSURE J. Chew: None. S. Sinha: None. S.J. Liu: None. S.E. Fogh: Independent Contractor; Accuray. L. Boreta: None. D. Raleigh: None. L. Ma: Patent/License Fees/Copyright; University of California Regents. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.

Purpose/Objective(s) Unchecked growth of brainstem metastases (BSM) can lead to acute morbidity and death. Stereotactic radiosurgery (SRS) remains the only local therapy for BSM, but the safety and efficacy of this approach are not fully understood, partly because BSM patients are excluded from many clinical trials. The aim of this study was to perform a systematic review and comparative meta-analysis of studies of SRS for BSM in the context of prospective trials of SRS or molecular/targeted therapy for non-brainstem brain metastases (BM). Materials/Methods A comprehensive search of the PubMed and Embase databases was performed on 12/6/19 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to identify relevant studies of SRS for BSM, and prospective trials of SRS or molecular/targeted therapy for BM. Outcomes included 1-year local control (LC), objective response rate (ORR, defined as partial or complete response), 1-year overall survival (OS), neurologic death rate, and CTCAE 4.0 grade 3-5 adverse events. Pooled binomial proportions were estimated using a random effects model. Study heterogeneity was assessed using I2 and τ using the maximum likelihood method and the Wald test. Results A total of 32 retrospective studies with a study level median follow up of 8.5 months (interquartile range [IQR] 5.7-11.0) were identified comprising 1446 patients undergoing SRS for 1590 B.M.. Median BSM volume was 0.40cm3 (study level IQR 0.20-1.05cm3), and SRS treatments were delivered using fixed-frame radiosurgery (73.8%, median dose 16 Gy, range 6-30 Gy, median isodose 50%), linear accelerator (17.2%, median dose 13.7 Gy, range 11.1-39.0 Gy in 1-13 fractions, median isodose 85%), or robotic-arm radiosurgery (9%, median 17.5 Gy, range 16-24 in 1-5 fractions, median isodose 80%). Pooled 1-year LC was 86% (95% CI 83-88%, I2 = 38%), 1-year OS was 33% (30-37%, I2 = 35%), and the rate of grade 3-5 toxicity was 2.4% (1.5-3.7%, I2 = 33%). On univariate meta-regression, melanoma histology (coefficient 4.26, QM = 4.15, P = 0.042) and prior or concurrent WBRT (coefficient 1.62, QM = 3.98, P = 0.046) were associated with higher grade 3-5 toxicity from SRS for BSM. Deaths from BSM progression after SRS were rare (2.7%), and the neurologic death rate in BSM patients (24%, 19-31%, I2 = 62%) was not statistically different from the neurologic death rate in BM patients who were treated on prospective SRS trials (21%, 13-32%, I2 = 90%, N = 6 trials, Q = 0.36, P = 0.55). The pooled rate of ORR of 59% (47-71%, I2 = 88%) for SRS of BSM compared favorably to the wide range of intracranial ORR reported for molecular therapies (17-56%). Conclusion SRS for BSM is safe and effective, and the potential for acute morbidity or death from growth of untreated BSM is significant. The data here suggest SRS for BSM should be considered upon or prior to clinical trial enrollment of molecular/targeted therapy for BM. Author Disclosure W.C. Chen: None. U. Baal: None. J.D. Baal: None. J. Pai: None. H. Vasudevan: Research Grant; Children's Tumor Foundation. Patent/License Fees/Copyright; Genentech, Eli Lilly. L. Boreta: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.D. Raleigh: None.

Purpose/Objective(s) The 2019 coronavirus pandemic (COVID-19) had a broad impact on the care of cancer patients, including the rapid adoption of telehealth video visits. On March 15, 2020, our institutional leadership recommended transition to video visits, which posed a risk of altering patients’ access to care. We assessed the impact of this rapid transition on demographic patterns in an urban academic radiation oncology department. Materials/Methods Consultation and follow-up visits from the pre-COVID-19 period (January 1, 2019 to March 14, 2020) and COVID-19 period (March 15, 2020 to August 31, 2020) in a single radiation oncology department were identified. Demographics and appointment data were abstracted from the institutional electronic health record. Time trends and patient and visit characteristics were compared across the pre-COVID-19 and COVID-19 periods. Results During the study period, 9,450 consult and follow-up visits were performed pre-COVID-19 and 3,298 visits in the COVID-19 period. The proportion of video visits increased markedly in the transition period, from 0.6% of all visits in the week of March 2, 2020, to 87% in the week of March 23, 2020. In-person visits decreased from 98% to 3%. Among all visits (in-person and telehealth), those during the COVID-19 period were less likely to be new consultations (43.1% from 60.1%; P < 0.001). There was a small and significant increase in the proportion of visits with patients who: identified as white (61.8% from 58.4%, P = 0.019), spoke English as their primary language (91.3% from 89.4%, P = 0.002), and had commercial insurance (34.1% from 32.0%; P = 0.009). Conclusion The overall COVID-19 clinic population retained demographic features similar to the pre-COVID-19 population despite a very rapid near-complete transition to telehealth. Nonetheless, the telehealth-predominant COVID-19 period had slightly increased visits with patients who were white or primarily English speaking or had commercial insurance. Strategies for ensuring telehealth is accessible to diverse populations should be a priority as telemedicine is integrated into long-term clinical operations.

Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non–small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

BACKGROUND Clinical biomarkers for identifying patients at risk for recurrence after resection of meningioma are lacking and are needed for guiding adjuvant therapy. The aim of this study was to identify a prognostic gene expression signature for meningioma. METHODS Targeted gene expression analysis was performed on a discovery dataset of 96 meningiomas with suitable tissue identified from a retrospective institutional biorepository. Recurrence was dichotomized based on the median time to local recurrence (TTR). With median follow-up of 6.4 years, the discovery dataset was enriched for clinical endpoints of local recurrence (58%), mortality (42%), and disease-specific mortality (49% of deaths). A 266 gene expression panel was used to interrogate the discovery dataset, and a prognostic gene signature and risk score was generated using prediction analysis for microarrays (PAM) and elastic net regression. The risk score was validated using gene expression data (GSE58037) from 56 meningiomas resected at an independent institution (20% local recurrence, 18% mortality, median follow-up 5.4 years). RESULTS A 36-gene signature was identified achieving an AUC of 0.86 for TTR faster than the median in the discovery cohort. A risk score between 0 and 1 based on this signature was strongly associated with shorter TTR (F-test, P< 0.0001), and on multivariate Cox regression (MVA), was independently associated with recurrence (RR 1.56 per 0.1 increase, 95% CI 1.30–1.90, P< 0.0001) and mortality (RR 1.32 per 0.1 increase, 1.07–1.64, P=0.01) after adjusting for WHO grade, age, extent of resection, and sex. Similarly, in the validation dataset, the gene risk score was correlated with shorter TTR (P=0.002) and associated with mortality on MVA (RR 1.86 per 0.1 increase, 1.19–2.88, P=0.005) after adjustment for WHO grade. CONCLUSIONS The prognostic meningioma gene expression risk score presented here could be useful in identifying patients at higher risk of progression after resection.

IMPORTANCE: Owing to the proximity to critical neurologic structures, treatment options for brainstem metastases (BSM) are limited, and BSM growth can cause acute morbidity or death. Stereotactic radiosurgery (SRS) is the only local therapy for BSM, but efficacy and safety of this approach are incompletely understood because patients with BSM are excluded from most clinical trials. OBJECTIVE: To perform a systematic review and comparative meta-analysis of SRS studies for BSM in the context of prospective trials of SRS or molecular therapy for nonbrainstem brain metastases (BM). DATA SOURCES: A comprehensive search of Pubmed/MEDLINE and Embase was performed on December 6, 2019. STUDY SELECTION: English-language studies of SRS for BSM with at least 10 patients and reporting 1 or more outcomes of interest were included. Duplicate studies or studies with overlapping data sets were excluded. Studies were independently evaluated by 2 reviewers, and discrepancies were resolved by consensus. A total of 32 retrospective studies published between 1999 and 2019 were included in the analysis. DATA EXTRACTION AND SYNTHESIS: Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed to identify studies. Study quality was assessed using Methodological Index for Non-Randomized Studies criteria. Fixed and random-effects meta-analyses and meta-regressions were performed for the outcomes of interest. MAIN OUTCOMES AND MEASURES: Primary study outcomes included 1-year and 2-year local control and overall survival, objective response rate, symptom response rate, neurological death rate, and rate of grade 3 to 5 toxic effects as described in Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The 32 retrospective studies included in the analysis comprised 1446 patients with 1590 BSM that were treated with SRS (median [range] dose, 16 [11-39] Gy; median [range] fractions, 1 [1-13]). Local control at 1 year was 86% (95% CI, 83%-88%; I(2) = 38%) in 1410 patients across 31 studies, objective response rate was 59% (95% CI, 47%-71%; I(2) = 88%) in 642 patients across 17 studies, and symptom improvement was 55% (95% CI, 47%-63%; I(2) = 41%) in 323 patients across 13 studies. Deaths from BSM progression after SRS were rare (19 of 703 [2.7%] deaths across 19 studies), and the neurologic death rate in patients with BSM (24%; 95% CI, 19%-31%; I(2) = 62%) was equivalent to the neurologic death rate in patients with BM who were treated on prospective trials. The rate of treatment-related grade 3 to 5 toxic effects was 2.4% (95% CI, 1.5%-3.7%; I(2) = 33%) in 1421 patients across 31 studies. These results compared favorably to trials of targeted or immunotherapy for BM, which had a wide objective response rate range from 17% to 56%. CONCLUSIONS AND RELEVANCE: Results of this systematic review and meta-analysis show that SRS for BSM was associated with effectiveness and safety and was comparable to SRS for nonbrainstem BM, suggesting that patients with BSM should be eligible for clinical trials of SRS. In this analysis, patients treated with SRS for BSM rarely died from BSM progression and often experienced symptomatic improvement. Given the apparent safety and efficacy of SRS for BSM in the context of acute morbidity or death from BSM growth, consideration of SRS at the time of enrollment on emerging trials of targeted therapy for BM should be considered.

Brain metastases are the most common intracranial neoplasm yet clinical outcomes remain poor. The purpose of this study was to evaluate the efficacy of multimodal therapy comprising surgery followed by focal radiation, and/or systemic therapy and elucidate clinically significant biomarkers for resected melanoma brain metastases. Forty consecutive patients with newly diagnosed melanoma brain metastases who underwent surgical resection and targeted mutational analysis at UCSF between 2011 and 2020 were identified. Demographic, clinical, and outcome data were extracted from the medical record and institutional cancer registry. Surgical cavity local recurrence free survival (LRFS), intracranial progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The median age of patients in this cohort was 58 years (range: 27-75 years) with median MRI follow up of 13.15 months. Twenty patients (50%) were treated with concurrent stereotactic radiation (1-5 fractions) and systemic therapy while 16 patients (40%) were treated with systemic therapy only. Mutational testing demonstrated the most common pathogenic variant was BRAF V600E, found in 16 patients (40%), while the remaining 24 patients (60%) did not harbor this mutation. Microsatellite instability (MSI) estimation was available for 8 patients (20%), all of which were found to be MSI low ( Citation Format: Harish N. Vasudevan, Matthew S. Susko, Lijun Ma, Jean L. Nakamura, David R. Raleigh, Lauren Boreta, Shannon Fogh, Philip V. Theodosopoulos, Michael W. McDermott, Katy K. Tsai, Penny K. Sneed, Steve E. Braunstein. Mutational status and clinical outcomes following systemic therapy and focal radiation for melanoma brain metastases [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-073.

OBJECTIVES Brain metastases are a common sequelae of advanced melanoma, and can lead to significant morbidity and mortality. Systemic therapy, inclusive of BRAF/MEK inhibitors and immunotherapy, are increasingly being utilized for metastatic melanoma brain metastases. This study sought to evaluate the clinical outcomes of resected melanoma brain metastases treated with systemic therapy, with or without focal radiotherapy. METHODS Patients at a single institution who underwent resection of a melanoma brain metastasis were retrospectively identified and reviewed. Patients were required to have received immunotherapy or BRAF/MEK inhibitors in the 3-month perioperative time period. This cohort was then analyzed by receipt of focal radiotherapy, including SRS and brachytherapy, for resection cavity failure, distant CNS progression, and adverse radiation effect, using the Kaplan Meier method. RESULTS From 2011-2020, 43 resections for melanoma brain metastases were performed, of which 29 patients and 37 resection cavities met criteria for analysis. Median MRI follow up was 15 months (IQR: 6-38). Twenty-two (59%) lesions were treated with focal radiotherapy and systemic therapy, and 15 (41%) were treated with systemic therapy alone. 12-month freedom from local recurrence was 64.8% (95% CI: 42.1-99.8%) for systemic therapy alone, and 93.3% (95% CI: 81.5-100%) for focal radiotherapy with systemic therapy (p=0.01). 12-month CNS progression free survival was 35.7% (95% CI: 17.7-72.1%) for systemic therapy alone, and 31.8% (95% CI: 17.3-58.7%) for focal radiotherapy (p=0.51). UVA demonstrated focal radiotherapy (HR: 0.10; 95% CI: 0.01-0.85; p=0.04) was the only significant factor associated with reduction of risk for surgical cavity recurrence. CONCLUSIONS Use of focal radiotherapy with systemic therapy for resected melanoma brain metastases significantly reduced surgical cavity recurrence compared to systemic therapy alone. Focal radiotherapy did not delay initiation of systemic therapy and should be the preferred treatment option for optimal local control of the surgical cavity in melanoma brain metastases.

2041 Background: Cancer patients are at increased risk of mental and emotional distress. The aim of this study is to investigate risk factors and timing of mental health disorder (MHD) onset following a cancer diagnosis, and evaluate its impact on emergency visits. Methods: All patients with a new onset diagnosis of malignancy ( ICD-10 codes C00-C97, with conversion of ICD-9 codes) were identified from an institutional de-identified electronic health data warehouse. Demographic data, Charlson comorbidity index excluding cancer, mortality, and time to onset of a new MHD diagnosis ( ICD-10 codes F00-F99) and emergency visits were extracted and used to calculate rates and Cox-model hazard ratios. A predictive logistic model of MHD was tested on an internal hold-out sample (25%). Results: A total of 110,306 patients with 338,208 person-years of follow up were identified with a new diagnosis of cancer from February 1980 to July 2019, of which 95,474 (86.5%) had no prior diagnosis of MHD. Actuarial rates of new MHD among previously MHD-free patients were 8.1% at 6 months, and 14.1% and 20.8% at 2 and 5 years. Median time to onset of MHD was fastest among head and neck cancer (57 days, HR 2.32 [2.1-2.6]), urinary organ cancer (94 days, HR 2.21 [2.0-2.4]), and lung and thoracic cancers (99 days, HR 2.47 [2.2-2.7]), compared to skin neoplasms (987 days, HR 1.0). Median time to onset was less than one year for all malignancies except for skin neoplasms and male genital cancers (840 days). Male sex, older age, Charlson score, divorce or legal separation, self-identification of a gender-neutral partner, African American or American Indian race, Hispanic ethnicity, current or former smoking status, and self-identification as Christian were associated with higher risk of MHD onset, while married status and native Hawaiian or Pacific Islander race were protective. A logistic model predicted new MHD with an AUROC of 0.72. Onset of new MHD was associated with greater rates of emergency visit (HR 1.92 [1.8-2.0], adjusted for cancer type and Charlson score), and patients with new MHD who experienced an emergency visit had a mean of 3.75+/-0.03 (SEM) total emergency visits versus 2.65+/-0.02 (p < 0.0001). Finally, onset of new MHD was associated with greater mortality even after adjusting for age, Charlson score and cancer type (HR 1.29, [1.23-1.35]). Conclusions: Onset of new mental health diagnosis after a cancer diagnosis was correlated with greater rates of emergency visits and mortality. Cancer patients with risk factors identified here may benefit from increased social and mental health support.

Glioblastomas are aggressive brain tumors that frequently recur in the subventricular zone (SVZ) despite maximal treatment. The purpose of this study was to evaluate imaging patterns of subventricular progression and impact of recurrent subventricular tumor involvement and radiation dose to patient outcome. Retrospective review of 50 patients diagnosed with glioblastoma and treated with surgery, radiation, and concurrent temozolomide from January 2012 to June 2013 was performed. Tumors were classified based on location, size, and cortical and subventricular zone involvement. Survival was compared based on recurrence type, distance from the initial enhancing tumor (local ≤ 2 cm, distant > 2 cm), and the radiation dose at the recurrence site. Progression of enhancing subventricular tumor was common at both local (58%) and distant (42%) sites. Median survival was better after local SVZ recurrence than distant SVZ recurrence (8.7 vs. 4.3 months, p = 0.04). Radiation doses at local SVZ recurrence sites recurrence averaged 57.0 ± 4.0 Gy compared to 44.7 ± 6.7 Gy at distant SVZ recurrence sites (p = 0.008). Distant subventricular progression at a site receiving ≤ 45 Gy predicted worse subsequent survival (p = 0.05). Glioblastomas frequently recurred in the subventricular zone, and patient survival was worse when enhancing tumor occurred at sites that received lower radiation doses. This recurrent disease may represent disease undertreated at the time of diagnosis, and further study is needed to determine if improved treatment strategies, such as including the subventricular zone in radiation fields, could improve clinical outcomes.

This chapter will discuss radiation therapy for multiple myeloma and solitary plasmacytoma.

113 Background: Whole brain radiation (WBRT) is standard therapy used for palliation of brain metastases (BM). SRS is also used as primary treatment in patients with multiple BM, with WBRT reserved for salvage. We sought to describe WBRT practice patterns at a tertiary cancer center with a high-volume radiosurgical practice, and hypothesized that patients treated with WBRT at our institution had limited survival. Methods: Retrospective chart review was performed for patients treated with WBRT for BM from January 2013-Jan 2019. Patients with complete records were included in the analysis. Mann-Whitney U and chi-squared tests were for comparison of clinical factors. Results: Data for 100 patients receiving WBRT were available for analysis. Patients had NSCLC (32%) breast cancer (30%) and melanoma (9%). Median age was 52 (IQR 23). 43% of patients had SRS prior to WBRT, and 41% had 2+ SRS treatments prior to WBRT. 44% of patients had WBRT only. Median survival from diagnosis of BM was 9.3 months (IQR 17.9) and median survival from WBRT was 2.7 months (IQR 11.3). 35% of patients died within 30 days of WBRT, and 3% of patients died on treatment. 77% of patients had uncontrolled extracranial metastases and 43% of patients had imaging evidence of leptomeningeal disease (LMD). Of those with documented cause of death, 65% of patients with LMD died of neurologic causes, compared with 22% of those without LMD (p < 0.001). Patients with KPS < 70 had median survival of 2 months after WBRT, compared with 3.7 months in those with KPS > 70. Patients treated with WBRT alone and those treated with salvage WBRT after SRS had median survival after WBRT of 2.1 months, however median survival from time of brain met diagnosis was 3.3 months in those treated with WBRT alone, versus 12.8 months in those treated with salvage WBRT (p < 0.0001). Conclusions: This study reveals the poor prognosis of patients requiring WBRT at a tertiary cancer center. 35% patients died within 30 days of WBRT, in contrast to a prior study demonstrating 10% 30-day mortality after SRS, owing to differences in patient selection. The potential for poor outcome should be discussed with patients during shared-decision making, balancing toxicity or futility with potential benefits of treatment.

93 Background: Approximately half of patients undergoing radiotherapy (RT) do so with palliative intent. Urgent indications for RT may include neurologic compromise, pain, or bleeding. While some practices have a dedicated palliative RT team, the majority utilize an “on-call” system with a rotating outpatient radiation oncologist. We report our experience with a dedicated nurse practitioner (NP) to assist with palliative RT workflow, with the goal of expediting patient care. Methods: 226 inpatients treated with RT to a site of metastatic disease from May 2012 to May 2018 were included. Since August 2017, an NP has helped expedite emergent RT referrals. Mann-Whitney U tests were used to compare days between steps in the treatment planning process before and after integration of an NP. Results: The median age at RT was 60 years (IQR 49–69). The most common primary sites were lung (26%) and breast (12%). The most common indication for RT was symptomatic brain metastases (SBM, 33% of patients), followed by pain (27%) and spinal cord compression or cauda equina syndrome (SCC) (21%). The median time from referral (defined as initial contact by the primary team) to consultation was one day (IQR 0-2), and from referral to RT was four days (IQR 2-6). Median time from referral to RT was shorter for SCC (two days, IQR 1-4.5) and SBM (three days, IQR 1–6), than pain (five days, IQR 2–8) (p = 0.001 and p = 0.015, respectively). 68% of patients with SCC (32/47) and 35% of patients with SBM (26/74) started RT within one day of consultation. With an NP, patients were more likely to undergo simulation (sim) the same day as consultation (74% vs. 58%, p = 0.03). Same day sim was more common in patients with neurologic deficits (SCC+SBM) than those without (87% vs. 62%, p = 0.02). In those with neurologic deficits, time from consultation to sim decreased from 0.85 to 0.23 days (p = 0.04) and time from sim to RT decreased from 2.7 to 1.8 days (approaching significance, p = 0.06). In patients treated for pain, time from consultation to RT was reduced from 6.3 to 2.1 days (p = 0.02). Conclusions: For practices without a dedicated palliative RT team, involvement of an NP can improve workflow and expedite urgent RT. Further research is needed to rigorously explore quality improvement in the delivery of palliative RT.

246 Background: In patients with advanced prostate cancer (PCa), urinary obstruction (UO) can lead to urinary retention requiring indwelling or suprapubic catheterization, which negatively impacts quality of life. Palliative options for UO from advanced PCa include surgical and medical treatment. Surgical intervention, including prostatectomy, pelvic exenteration and TURP, may confer undue risk to patients with advanced disease. Medical palliation may require months to take effect. Stereotactic Body Radiotherapy (SBRT) is a non-invasive technique that delivers high-dose and highly conformal radiation in ≤5 fractions, often used to treat PCa and metastatic disease. Here, we reviewed the utility of SBRT to treat UO from advanced PCa. Methods: A retrospective review of patients undergoing SBRT for UO was completed at a single institution between 2011 and 2017. Stage, PSA at diagnosis and time of treatment were recorded. Assessment of urinary function by IPSS/SHIM and documentation of catheterization were reviewed at consultation andsubsequent follow-up. Results: A total of 3 patients were treated with SBRT to the prostate for the palliation of urinary obstruction. Patient ages were 67, 57 and 52 years, and all had high risk, stage IV disease, Gleason 4+4 or 4+5, T3 or T4, with regional nodal, bony or visceral metastases. All patients required indwelling catheterization for an average 4 months prior to SBRT. Two patients were treated with whole pelvis irradiation after SBRT. In those who received subsequent pelvic irradiation, the SBRT doses to the prostate were 19 Gy in 2 fractions. The patient treated with SBRT monotherapy received 38 Gy in 4 fractions. Catheters were successfully removed in all 3 patients, one at the completion of radiation, and the others within 4 weeks of completion. With follow-up ranging from 1.2 to 6 years, no patients required re-catheterization, and there were no reports of grade ≥3 acute or long-term toxicity. Conclusions: SBRT is an effective treatment to palliate UO from locally advanced PCa, leading to removal of urinary catheters and presumed improved in quality of life. Further investigation is required to establish the optimal dose and fractionation of palliative SBRT for UO from PCa.