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OBJECTIVE Immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are commonly used in the systemic management of non–small cell lung cancer (NSCLC) brain metastases (BMs). However, optimizing control of NSCLC BM with stereotactic radiosurgery (SRS) and various systemic therapies remains an area of investigation. METHODS Between 2016 and 2019, the authors identified 171 NSCLC BM patients with 646 BMs treated with single-fraction SRS within 3 months of receiving treatment with ICIs (n = 56; 33%), EGFR-TKI (n = 30; 18%), chemotherapy and ICIs (n = 23; 14%), or standard chemotherapy alone (n = 62; 36%). Time-to-event analysis was conducted, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival from SRS. RESULTS The median follow-up from BM diagnosis was 8.9 months (range 0.3–127 months). The 12-month Kaplan-Meier DIC rates were 37%, 53%, 41%, and 21% (p = 0.047) for the ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy-alone groups, respectively. On multivariate analysis, DIC was improved with EGFR-TKI (HR 0.4, 95% CI 0.3–0.8, p = 0.005) compared with conventional chemotherapy and treatment with SRS before systemic therapy (HR 0.5, 95% CI 0.3–0.9, p = 0.03) compared with after; and LC was improved with SRS before (HR 0.4, 95% CI 0.2–0.9, p = 0.03) or concurrently (HR 0.3, 95% CI 0.1–0.6, p = 0.003) compared with after. No differences in radionecrosis were noted by timing or type of systemic therapy. CONCLUSIONS The authors’ analysis showed significant differences in DIC based on receipt of systemic therapy and treatment with SRS before systemic therapy improved DIC. Prospective evaluation of the potential synergism between systemic therapy and SRS in NSCLC BM management is warranted.

Background: Breast cancer patients with brain metastases have a high unmet clinical need and improved management strategies are needed. There has been interest in studying CDK 4/6 inhibitors in the management of breast cancer brain metastases. A phase II study has shown abemaciclib to have activity in the management of hormone receptor (HR)+/HER2- brain metastases. Pre-clinical data suggests a potential synergy with CDK inhibitors and radiation therapy. Stereotactic radiosurgery (SRS) is a cornerstone in the management of limited brain metastases. We hypothesize treatment with abemaciclib and SRS will be safe and improve intracranial progression free survival (PFS) compared to abemaciclib alone. Trial Design: The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of abemaciclib and endocrine therapy with SRS among patients with HR+/HER2- metastatic breast cancer brain metastases. Treatment will be initiated with one week of abemaciclib followed by stereotactic radiation to sites of brain metastases or post-operative cavities with continued abemaciclib. Safety will be monitored initially by a 3+3 design. If unexpected neurologic toxicities are noted, the dose of radiation therapy will be reduced. This will be followed by a phase II study to evaluate intracranial PFS. Eligibility: Eligible patients include those that are HR+/HER2-, ≥18, ECOG ≤2 with ≤15 breast cancer brain metastases with measurable disease per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Specific Aims: The primary objective of the phase I study is to evaluate the safety and feasibility of abemaciclib and SRS to sites of brain metastases in the management of HR+/HER2- metastatic breast cancer with brain metastases. The primary objective of the phase II portion is to determine PFS intracranially. Secondary objectives include evaluation of extracranial PFS, local and distant intracranial control, and overall survival. Statistical Methods: Safety and feasibility will be monitored in the phase I study using a 3 + 3 design followed by a phase II study to assess intracranial PFS. The phase II study is designed as a single-arm, two-stage trial using the Restricted-Kwak-and-Jung’s method. In the first stage, a total of 21 patients will be enrolled. If pre-specified endpoints are met, an additional 10 patients will be enrolled in the second stage. Patient Accrual: A total of up to 31 patients will be enrolled inclusive of patients in the phase I portion treated at the recommended phase II dose. Clinical trial information: NCT04923542. Citation Format: Kamran A. Ahmed, Youngchul Kim, Michelle DeJesus, Sasha J. Beyer, Nicole O. Williams, Joshua Palmer, Kristina D. Woodhouse, Rashmi K. Murthy, Jing Li, Avan J. Armaghani, John A. Arrington, Ricardo L. Costa, Brian J. Czerniecki, Arnold B. Etame, Peter A. Forsyth, Hung T. Khong, Daniel E. Oliver, Marilin Rosa, Solmaz Sahebjam, Hatem H. Soliman, Aixa E. Soyano, Michael A. Vogelbaum, Michael Yu, Hyo S. Han. Phase I/II study of stereotactic radiation and abemaciclib in the management of hormone receptor positive HER2 negative breast cancer brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-09-01.

This study assessed the presentation and institutional outcomes treating brain metastases (BM) of breast cancer (BC), non-small cell lung cancer (NSCLC), and melanoma origin. Patients with brain metastases treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan–Meier method. A total of 959 patients were identified including melanoma (31%), NSCLC (51%), and BC (18%). Patients with BC were younger at BM diagnosis (median age: 57) than NSCLC (65) and melanoma patients (62, p

Summary Background Despite advances in cancer genomics, radiotherapy is still prescribed on the basis of an empirical one-size-fits-all paradigm. Previously, we proposed a novel algorithm using the genomic-adjusted radiation dose (GARD) model to personalise prescription of radiation dose on the basis of the biological effect of a given physical dose of radiation, calculated using individual tumour genomics. We hypothesise that GARD will reveal interpatient heterogeneity associated with opportunities to improve outcomes compared with physical dose of radiotherapy alone. We aimed to test this hypothesis and investigate the GARD-based radiotherapy dosing paradigm. Methods We did a pooled, pan-cancer analysis of 11 previously published clinical cohorts of unique patients with seven different types of cancer, which are all available cohorts with the data required to calculate GARD, together with clinical outcome. The included cancers were breast cancer, head and neck cancer, non-small-cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. Our dataset comprised 1615 unique patients, of whom 1298 (982 with radiotherapy, 316 without radiotherapy) were assessed for time to first recurrence and 677 patients (424 with radiotherapy and 253 without radiotherapy) were assessed for overall survival. We analysed two clinical outcomes of interest: time to first recurrence and overall survival. We used Cox regression, stratified by cohort, to test the association between GARD and outcome with separate models using dose of radiation and sham-GARD (ie, patients treated without radiotherapy, but modelled as having a standard-of-care dose of radiotherapy) for comparison. We did interaction tests between GARD and treatment (with or without radiotherapy) using the Wald statistic. Findings Pooled analysis of all available data showed that GARD as a continuous variable is associated with time to first recurrence (hazard ratio [HR] 0·98 [95% CI 0·97–0·99]; p=0·0017) and overall survival (0·97 [0·95–0·99]; p=0·0007). The interaction test showed the effect of GARD on overall survival depends on whether or not that patient received radiotherapy (Wald statistic p=0·011). The interaction test for GARD and radiotherapy was not significant for time to first recurrence (Wald statistic p=0·22). The HR for physical dose of radiation was 0·99 (95% CI 0·97–1·01; p=0·53) for time to first recurrence and 1·00 (0·96–1·04; p=0·95) for overall survival. The HR for sham-GARD was 1·00 (0·97–1·03; p=1·00) for time to first recurrence and 1·00 (0·98–1·02; p=0·87) for overall survival. Interpretation The biological effect of radiotherapy, as quantified by GARD, is significantly associated with time to first recurrence and overall survival for patients with cancer treated with radiation. It is predictive of radiotherapy benefit, and physical dose of radiation is not. We propose integration of genomics into radiation dosing decisions, using a GARD-based framework, as the new paradigm for personalising radiotherapy prescription dose. Funding None. Video Abstract Download : Download video (123MB) YouTube URL: https://youtu.be/gvyiNOPJ-14

BackgroundLittle is known about the safety and efficacy of concurrent capecitabine and stereotactic radiotherapy in the setting of breast cancer brain metastases (BCBM).MethodsTwenty-three patients with BCBM underwent 31 stereotactic sessions to 90 lesions from 2005 to 2019 with receipt of capecitabine. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of stereotactic radiation. Imaging was independently reviewed by a neuro-radiologist.ResultsMedian follow-up from stereotactic radiation was 9.2 months. Receptor types of patients treated included triple negative (n = 7), hormone receptor (HR)+/HER2- (n = 7), HR+/HER2+ (n = 6), and HR−/HER2+ (n = 3). Fourteen patients had stage IV disease prior to BCBM diagnosis. The median number of brain metastases treated per patient was 3 (1 to 12). The median dose of stereotactic radiosurgery (SRS) was 21 Gy (range: 15–24 Gy) treated in a single fraction and for lesions treated with fractionated stereotactic radiation therapy (FSRT) 25 Gy (24–30 Gy) in a median of 5 fractions (range: 3–5). Of the 31 stereotactic sessions, 71% occurred within 1 month of capecitabine. No increased toxicity was noted in our series with no cases of radionecrosis. The 1-year OS, LC, and DIC were 46, 88, and 30%, respectively.ConclusionsIn our single institution experience, we demonstrate stereotactic radiation and capecitabine to be a safe treatment for patients with BCBM with adequate LC. Further study is needed to determine the potential synergy between stereotactic radiation and capecitabine in the management of BCBM.

We investigated the prognostic ability of tumor subtype for patients with breast cancer brain metastases (BCBM) treated with stereotactic radiation (SRT). This is a retrospective review of 181 patients who underwent SRT to 664 BCBM from 2004 to 2019. Patients were stratified by subtype: hormone receptor (HR)-positive, HER2-negative (HR+/HER2−), HR-positive, HER2-positive (HR+/HER2+), HR-negative, HER2-positive (HR−/HER2+), and triple negative (TN). The Kaplan–Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of SRT. Multivariate analysis (MVA) was conducted using the Cox proportional hazards model. Median follow up from SRT was 11.4 months. Of the 181 patients, 47 (26%) were HR+/HER2+, 30 (17%) were HR−/HER2+, 60 (33%) were HR+/HER2−, and 44 (24%) were TN. Of the 664 BCBMs, 534 (80%) received single fraction stereotactic radiosurgery (SRS) with a median dose of 21 Gy (range 12–24 Gy), and 130 (20%) received fractionated stereotactic radiation therapy (FSRT), with a median dose of 25 Gy (range 12.5–35 Gy) delivered in 3 to 5 fractions. One-year LC was 90%. Two-year DIC was 35%, 23%, 27%, and 16% (log rank, p = 0.0003) and 2-year OS was 54%, 47%, 24%, and 12% (log rank, p

Background: Advances in imaging and systemic therapy have improved the survival for patients with breast cancer brain metastases (BCBM). However, an improved understanding of patients with long-term survival after stereotactic radiation (SRT) for BCBM is warranted and could allow for better prognostication and personalized treatment. Methods: This is a single institution retrospective review of 188 patients who underwent SRT sessions to 685 BCBM from August 2004 to June 2020. Patients who were lost to follow up within 2 years after SRT were excluded. Patients were stratified into 2 groups: those with overall survival (OS) from SRT less than 2 years (short-term survival, STS) and those with OS from SRT of at least 2 years (long-term survival, LTS). Patient, tumor, and treatment characteristics were compared between the 2 groups via the student t-test and Chi-square testing as appropriate. The Kaplan-Meier (KM) method was used to calculate OS, local control (LC), and distant intracranial control (DIC) from the date of SRT. The reverse KM method was used to estimate follow-up from SRT. Results: The median follow up from BCBM diagnosis was 52.8 months (95% CI: 40.5-75.2 months). Of the 685 treated BCBMs, 552 (81%) received stereotactic radiosurgery (SRS) to a median dose of 21 Gy (12-24 Gy) and 133 received fractionated stereotactic radiation therapy (FSRT) to a median dose of 25 Gy (20-35 Gy) in 3-5 fractions. The 2-year LC, DIC, and OS was 78.4%, 26.5%, and 38.3%, respectively. The 5-year OS was 19%. There were 72 patients (38%) in the LTS group and 116 patients (62%) in the STS group. The LTS group had lower rates of invasive lobular carcinoma (0% vs 6%, p=0.001) and higher rate of HER2+ disease (61% vs 30%, p< 0.001). The LTS group had lower rates of concurrent extracranial metastasis (74% vs 89%, p=0.008) and lung metastasis (33% vs 53%, p=0.009), though there were no differences in the rates of bone or liver metastasis. The LTS group had less BCBM at the time of SRT (mean 1.9 vs 2.5, p=0.013) and more often received SRT to a single BCBM (65% vs 42%, p=0.002). There were no significant differences in age or performance status between the groups. Conclusion: Prognosis for patients with BCBM is heterogeneous, as a minority of patients have prolonged OS after SRT. These patients more often have limited BCBM, HER2+ disease, and a lower extracranial disease burden. Citation Format: Joseph D. Tang, Matthew N. Mills, Chetna Thawani, Daniel E. Oliver, Aixa Soyano, Arnold Etame, Hsiang-Hsuan Michael Yu, Nam Tran, Michael A. Vogelbaum, Peter A. Forsyth, Brian J. Czerniecki, Hatem H. Soliman, Hyo S. Han, Kamran A. Ahmed. Characteristics of Long-Term Survival in Breast Cancer Brain Metastasis after Stereotactic Radiation [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-06.

Whole brain radiotherapy with hippocampal avoidance (HA-WBRT) is a technique utilized to treat metastatic brain disease while preserving memory and neurocognitive function. We hypothesized that the treatment planning and delivery of HA-WBRT plans is feasible with an MRI-guided linear accelerator (linac) and compared plan results with clinical non-MRI-guided C-Arm linac plans.Twelve HA-WBRT patients treated on a non-MRI-guided C-Arm linac were selected for retrospective analysis. Treatment plans were developed using a 0.35T MRI-guided linac system for comparison to clinical plans. Treatment planning goals were defined as provided in the Phase II Trial NRG CC001. MRI-guided radiotherapy (MRgRT) treatment plans were developed by a dosimetrist and compared with clinical plans. quality assurance (QA) plans were generated and delivered on the MRI-guided linac to a cylindrical diode detector array. Planning target volume (PTV) coverage was normalized to ∼95% to provide a control point for comparison of dose to the organs at risk.MRgRT plans were deliverable and met all clinical goals. Mean values demonstrated that the clinical plans were less heterogeneous than MRgRT plans with mean PTV V37.5 Gy of 0.00% and 0.03% (p = 0.013), respectively. Average hippocampi maximum doses were 14.19 ± 1.29 Gy and 15.00 ± 1.51 Gy, respectively. The gamma analysis comparing planned and measured doses resulted in a mean of 99.9% ± 0.12% of passing points (3%/2mm criteria). MRgRT plans had an average of 38.33 beams with average total delivery time and beam-on time of 13.7 (11.2-17.5) min and 4.1 (3.2-5.4) min, respectively. Clinical plan delivery times ranged from 3 to 7 min depending on the number of noncoplanar arcs. Planning time between the clinical and MRgRT plans was comparable.This study demonstrates that HA-WBRT can be treated using an MRI-guided linear accelerator with comparable treatment plan quality and delivery accuracy.

OBJECTIVES The brain is a rare site for sarcoma metastases. Sarcoma's radioresistance also makes standard whole-brain radiotherapy less appealing. We hypothesize that stereotactic radiation techniques (stereotactic radiosurgery [SRS]/stereotactic fractionated radiotherapy [FSRT]) may provide effective local control. MATERIALS AND METHODS This single-institution retrospective analysis evaluated our experience with linear acceleator-based SRS/FSRT for sarcoma brain metastases. Time to event analysis was estimated via Kaplan-Meier. Univariable/multivariable Cox regression analyses followed to assess the impact of patient and disease characteristics on outcomes. RESULTS Between 2003 and 2018, 24 patients were treated with 34 courses of SRS/FSRT to 58 discrete lesions. The median age at first treatment was 57 years (range: 25 to 87 y). Majority of patients had concurrent lung metastases (n=21; 88%), diagnosed spindle cell sarcoma (n=15; 25%) or leiomyosarcoma (n=12; 21%) histology, and were treated with either SRS (n=43; median dose=19 Gy, range: 15 to 24 Gy) or FSRT (n=17; 3/5 fractions, median dose=25 Gy, range: 25 to 35 Gy). With a median follow-up after brain metastasis of 7.3 months, the 6 month/12 month local control, distant brain control, and overall survival of 89%/89%, 59%/34%, and 50%/38%, respectively. All local failures were of primary spindle cell histology (P

This study assessed the presentation and institutional outcomes treating brain metastases (BM) of breast cancer (BC), non-small cell lung cancer (NSCLC), and melanoma origin.Patients with brain metastases treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan-Meier method.A total of 959 patients were identified including melanoma (31%), NSCLC (51%), and BC (18%). Patients with BC were younger at BM diagnosis (median age: 57) than NSCLC (65) and melanoma patients (62, p 0.0001). Breast cancer patients were more likely to present with at least 5 BM (27%) than NSCLC (14%) and melanoma (13%), leptomeningeal disease (23%, 6%, and 6%, p = 0.0004) and receive whole brain radiation therapy (WBRT) (58%, 37%, and 22%, p 0.0001). There were no differences in surgical resection (24%, 24%, and 29%, p = 0.166). Median OS was shorter for BC patients (9.9, 10.3, and 13.7 months, p = 0.0006).Breast cancer patients were more likely to be younger, present with advanced disease, require WBRT, and have poorer OS than NSCLC and melanoma patients. Further investigation is needed to determine which BC patients are at sufficient risk for brain MRI screening.

Background Chordomas and chondrosarcomas are a rare but challenging subset of tumors to treat; however, previous studies have shown benefits from proton therapy, which are thought to be primarily driven by prescription conformality permitting homogeneous tumor dosing and the allowance of higher doses. No retrospective studies to date have directly compared the outcomes of conventional and particle therapy or examined the role of high doses (specifically ≥70 Gy) in definitive radiotherapy (DRT) or perioperative radiotherapy (PRT) for both types of malignancies. Methods A total of 863 patients with chondrosarcoma and 715 patients with chordoma treated with nonpalliative proton or conventional radiation therapy with a dose range of 20 to 80 Gy and at least 15 months of follow-up were identified from the National Cancer Data Base for the years 2003-2014. The primary endpoint of overall survival (OS) was evaluated, and clinical features, including age, sex, grade, clinical stage, and Charlson-Deyo comorbidity index, were compared. Results Patients receiving DRT were older and had more advanced disease. In DRT for chondrosarcoma, a high dose (40.6% vs 16.9%; P = .006) and proton therapy (75.0% vs 19.1%; P = .046) were associated with improved OS at 5 years in a multivariate analysis. In DRT for chordoma, proton therapy was associated with improved OS at 5 years in a multivariate analysis (100% vs 34.1%; P = .031), and a high dose for chordoma was significant for improved OS in a univariate analysis with both DRT (79.0% vs 54.1%; P = .027) and PRT (83.3% vs 77.4%; P = .007). Conclusions In the largest retrospective series to date, dose escalation and proton radiotherapy were associated with improved OS in patients with chondrosarcoma and chordoma despite limited follow-up and access to particle therapy.

Purpose/Objective(s) Patients with high-grade gliomas (HGG) progress despite multimodality therapy. Hypofractionated stereotactic re-irradiation therapy (HFSRT) has been used with promising efficacy as a salvage treatment in the setting of recurrent HGG (rHGG). We recently completed a phase I study combining HFSRT with concurrent pembrolizumab and bevacizumab (Bev) for patients with rHGG (NCT02313272). The main objective of this study is to identify patterns of failure in the above regimen. Materials/Methods Data from 32 patients enrolled in the phase I trial from June 2015 to January 2018 were reviewed. Patient characteristics, time to progression, and treatment outcomes were evaluated. Brain MRIs were taken at baseline, and every 6 to 8 weeks until progression. T1 post-contrast and T2- FLAIR images at baseline and at progression were imported into commercial software and the extent of hyperintensity was contoured by a single physician and reviewed by a second physician. An automated algorithm was used to compare the volumetric similarities between the pre- and post-treatment structures. This algorithm used Dice similarity coefficient (DSC), a statistical validating index for evaluating reproducibility and spatial overlap accuracy in the MRI image segmentation. A DSC value of 0.3 or greater indicated significant spatial overlap accuracy. Pearson's single and two-tailed tests were used to identify correlation between time to progression and volumetric parameters. Results The median age of patients at re-irradiation was 56 years (22-68).24 patients had Bev naive tumor. The median radiation dose was 35 Gy in 5 fractions (25-40). The median progression free survival was 7.92 months (95% CI:6.31-12.45). A total of 22 (68%) patients with radiological progression were included for this analysis. Considerable similarities were observed (11/22) between the pretreatment T2- FLAIR and the post-treatment T1 contrast: with a median DSC of 0.31(range 0.05-0.6) and pre-treatment T2-FLAIR and post-treatment T2-FLAIR; DSC 0.66 (range 0.15-0.7). The median DSC value comparing pre- and post-treatment T1 contrast volumes were 0.24 (range 0-0.5). These findings suggest that recurrence or progression occurred in the pretreatment T2-FLAIR region outside the pre-treatment post-contrast T1 region. A positive correlation between time to progression with maximum dose received by pre-treatment (P = 0.02) and post-treatment T2-FLAIR (P = 0.02) volumes was observed. Conclusion Our analysis of a prospective trial of HSFRT with concurrent pembrolizumab and bevacizumab showed recurrences occurred outside the radiation field (i.e., region of T1post contrast abnormality). Recurrences predominantly occurred in the pre-treatment T2-FLAIR region. Including T2-FLAIR region in the pre-treatment GTV contours may be needed in achieving optimal local control. Author Disclosure R. Padmanabhan: None. G.G. Zhang: None. D.E. Oliver: None. J. Graham: None. D. Grass: None. S. Sahebjam: Research Grant; Merck, Bristol Myers Squibb and Brooklyn Immuno Therapeutics. Advisory Board; Merck, Boehringer Ingelheim. Travel Expenses; Eli Lilly. H.M. Yu: Honoraria; UpToDate. Speaker's Bureau; BrainLab. Advisory Board; Novocure, AbbVie.

PURPOSE/OBJECTIVE(S) Recurrent high-grade glioma (rHGG) continues to cause increased morbidity and mortality. To date, salvage therapy for rHGG remains ineffective, even with novel immune checkpoint blockade approaches. Here we evaluate molecular factors that may influence outcomes in rHGG patients treated with HFSRT and immunotherapy. MATERIALS/METHODS This retrospective analysis identified 76 continuous rHGG patients treated with HFSRT and PD-1 inhibitors on or off trial protocol with > 3 months of follow-up from 2010 to 2020. Clinical characteristics, treatment, outcomes, and available molecular alterations in IDH1 (n = 74), PTEN (n = 54), EGFRvIII (n = 64) or amplification (n = 56), CDKN2A (n = 42), TERT (n = 42) and MGMT promoter methylation (n = 69) were collected. Time to recurrence (TTR) and overall survival (OS) were estimated from the end of HFSRT with univariable (UVA) Kaplan-Meier methods compared via log-rank test as well as Cox regression analyses. RESULTS The median age at HFSRT was 55 years (range: 22-83) with a KPS of 80 (range: 50-100). The majority (63%) of patients were male, 35% had > 2 recurrences of HGG before HFSRT and 55% underwent salvage surgery. A total of 11 patients (15%) received bevacizumab (Bev) prior to HFSRT. The median HFSRT dose was 35 Gy (range: 30-40 Gy) given in 5-10 fractions. Sixty-six (87%) patients were treated with concurrent HFSRT and Bev followed by immunotherapy. At a median follow-up from HFSRT of 13.8 months (range: 8.7-18.9), 55 (72%) patients relapsed with a median TTR of 6.94 months (5.0-8.87) and OS of 10.1 months (7.4-12.9); this included Bev-naive and -resistant patients. Bev vs no Bev with HFSRT improved TTR (13.7 vs 6.3 months, P < 0.001), though Bev with HFSRT was not associated with improved OS. Of interest, no Bev prior to HFSRT improved OS from HFSRT (12.0 vs 8.4 months, P = 0.01). No molecular factors were associated with TTR after HFSRT, though IDH1-mut (P = 0.001) and wild-type PTEN (P = 0.02) and EGFR (P = 0.02) were related with prolonged OS. Similarly, mutations in TERT were associated with inferior OS (26.7 vs 60.7 months, P < 0.001). MGMT methylation status was not associated with TTR of OS. CONCLUSION Salvage treatments for rHGG remain a challenge. This study provides further insight into prognostic molecular determinants in the setting of HFSRT, PD-1 blockade and Bev. AUTHOR DISCLOSURE E. Guvenli: None. D. Grass: None. D.E. Oliver: None. A.B. Etame: None. N. Tran: None. R.J. Macaulay: None. P. Forsyth: Research Grant; NIH/NCI, CDMRP, Department of Defense, Pfizer, State of Florida - Bankhead Coley, Moffitt Center of Excellence Celgene project, NIH/NCI. Honoraria; BTG, NIH, Ziopharm, Tocagen, NCRI. Consultant; AbbVie, Inc, Ziopharm, Novellus, NCI Neuro-Oncology Branch Peer Review, Physical Sciences Oncology Network, Tocagen. Advisory Boar. S. Sahebjam: Research Grant; Merck, Bristol Myers Squibb, Brooklyn Immunotherapeutics. Advisory Board; Merck, Boehringer Ingelheim. Travel Expenses; Eli Lilly. H.M. Yu: Honoraria; UpToDate. Speaker's Bureau; BrainLab. Advisory Board; Novocure, AbbVie.

Purpose/Objective(s) To monitor intrafraction motion during spine stereotactic radiosurgery (SRS) treatment delivery with readily available device, we implemented triggered kV imaging using the on-board imager of the medical linear accelerator advanced imaging package. Materials/Methods Triggered kV imaging technique was clinically implemented and applied to 32 spine SBS patients (75 fx, 20 T-spine tumors, 12 L-spine tumors) during VMAT delivery. Currently available trigger options in the medical linear accelerator software package are MU, gantry angle, time, and respiratory gating. Time trigger was selected to acquire kV images every 15 seconds, in an effort to balance temporal resolution with reasonable time for image evaluation. Upon each image acquisition, a 2D projection of the 3D image-guided radiotherapy (IGRT) structures was automatically calculated and updated at arbitrary angles as a qualitative visual guide for patient alignment during treatment delivery. For IGRT structures, patient anatomy (vertebra and spinous process) and orthopedic hardware if present were contoured, with a 1 mm expansion. As the technique depends on visual inspection, decisions could vary depending on interobserver variability. Therefore, a survey of 10 trained physicists (4) and physicians (6) was conducted to evaluate efficiency and accuracy of clinical decision with kV images collected using an anthropomorphic phantom with different CT slice thicknesses and shifts introduced. The survey consisted of 192 sample images. The participants were asked to determine if a shift requiring intervention was observed. Average time per decision was recorded. Results The robustness of our current patient immobilization system was validated in our clinical implementation. Based on visual inspection of projected IGRT contours on planar kV images, appreciable movement was detected in only one fraction (1.3%). However, in this instance, motion was well beyond PTV/PRV margins (2.4 mm) and treatment was stopped to take a CBCT and correct the displacement, which otherwise would have not been detected. From the survey, the average time spent per decision was 7.5 seconds. In all shift directions, detectability was proportional to the shift size and superior detectability was observed with contours drawn using CT images with 1 mm slice thickness. Shifts smaller than 1 mm are less noticeable (12.6%) compared to 2 mm shifts (42.6%). Participant detection capability was dependent on the level of training. Conclusion This approach provides an effective, non-invasive intrafraction motion monitoring solution, using the built in triggered-imaging technique of the medical linear accelerator. One of the benefits this technique offers is that it can serve as a quality assurance approach to verify adequacy of a patient immobilization system. An important limitation is that the monitoring result is qualitative and depends on observer visual detection capability. Enhanced precision and utility could be achieved if an automated quantitative evaluation feature is implemented. Author Disclosure J. Koo: None. L.Nardella: None. M.Degnan: None. J.Andreozzi: None. H.M. Yu: Honoraria; UpToDate. Speaker's Bureau; BrainLab. Advisory Board; Novocure, AbbVie. J.A.Penagaricano: None. P.A. Johnstone: None. D.E. Oliver: None. K.A. Ahmed: Research Grant; Bristol-Myers Squibb, Genentech. S.Rosenburg: Consulting; Novocure. E.J.Wuthrick: Research Grant; BMS. Honoraria; Regeneron/Sanofi, Varian. Consultant; Regeneron/Sanofi, Varian. R. Diaz: Honoraria; Zeiss; Global Health Outreach. V.Feygelman: None. E.G. Moros: Research Grant; Varian Medical Systems. Promote research in the AAPM; American Association of Physicists in Medicine. Promoting research in the AAPM; American Association of Physicists in Medicine. G.Redler: None.

Purpose/Objective(s) Whole brain radiotherapy with hippocampal avoidance (HA-WBRT) is a technique utilized to treat extensive metastatic brain disease while preserving memory and neurocognitive function. We hypothesized that the treatment planning and delivery of HA-WBRT plans is feasible with an MRI-guided linear accelerator (Linac) and compared plan results with clinical non-MRI-guided C-Arm Linac plans. Materials/Methods Twelve patients treated with HA-WBRT plans on a non-MRI-guided C-Arm Linac were selected for retrospective analysis. Treatment plans were developed for comparison using a 0.35T MRI-guided Linac. Hippocampi were contoured by the physician on a T1 MRI image fused to a planning CT image with a 5mm expansion to the hippocampi for the avoidance structure. The PTV was expanded from the CTV excluding the hippocampal avoidance structure. Treatment planning goals were defined as provided in the Phase II Trial NRG CC001. MRI-guided treatment (MRgRT) plans were developed by a dosimetrist and compared with clinical plans. QA plans were developed and a subset were delivered on the MRI-guided Linac and measured with a cylindrical diode detector array. PTV coverage was normalized to ∼95% to provide a control point for comparison of dose to the organs at risk. Results MRgRT plans were deliverable and met all clinical goals. Mean values demonstrated that the clinical plans were cooler than MRgRT plans with mean V37.5 of 0.00% and 0.66%, respectively. Average hippocampi maximum doses were 14.20 ± 2.04 Gy and 14.33 ± 1.19 Gy for clinical vs MRgRT plans, respectively. Average hippocampi D100% were 8.63 ± 0.52 Gy and 7.87 ± 0.23 Gy, respectively. Average maximum doses to 0.03 cc of optic structures were 30.93 ± 1.10 Gy and 31.78 ± 0.66 Gy, respectively. The gamma analysis comparing planned and measured doses resulted in a mean of 99.9% ± 0.14% of passing points (3%/2mm criteria). MRgRT plans had an average of 38.33 beams with total delivery time ranging from 10.7-15.7 minutes and 4.03 minutes for total beam on time. Clinical plans had average delivery times of 3-7 minutes depending on the number of coplanar arcs. Conclusion This study demonstrates that HA-WBRT can be treated using an MRI-guided linear accelerator with comparable treatment plan quality and delivery accuracy. Given the equitable dosimetric outcomes to traditional CT based plans, the use of MRgRT for hippocampal sparing whole brain radiotherapy opens the possibility of radiomic analysis and potential adaptive treatments (i.e., boost) to lesions based on disease response.

We investigated the prognostic ability of tumor subtype for patients with breast cancer brain metastases (BCBM) treated with stereotactic radiation (SRT).This is a retrospective review of 181 patients who underwent SRT to 664 BCBM from 2004 to 2019. Patients were stratified by subtype: hormone receptor (HR)-positive, HER2-negative (HR+/HER2-), HR-positive, HER2-positive (HR+/HER2+), HR-negative, HER2-positive (HR-/HER2+), and triple negative (TN). The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), and distant intracranial control (DIC) from the date of SRT. Multivariate analysis (MVA) was conducted using the Cox proportional hazards model.Median follow up from SRT was 11.4 months. Of the 181 patients, 47 (26%) were HR+/HER2+, 30 (17%) were HR-/HER2+, 60 (33%) were HR+/HER2-, and 44 (24%) were TN. Of the 664 BCBMs, 534 (80%) received single fraction stereotactic radiosurgery (SRS) with a median dose of 21 Gy (range 12-24 Gy), and 130 (20%) received fractionated stereotactic radiation therapy (FSRT), with a median dose of 25 Gy (range 12.5-35 Gy) delivered in 3 to 5 fractions. One-year LC was 90%. Two-year DIC was 35%, 23%, 27%, and 16% (log rank, p = 0.0003) and 2-year OS was 54%, 47%, 24%, and 12% (log rank, p 0.0001) for HR+/HER2+, HR-/HER2+, HR+/HER2-, and TN subtypes, respectively. On MVA, the TN subtype predicted for inferior DIC (HR 1.62, 95% CI 1.00-2.60, p = 0.049). The modified breast-Graded Prognostic Assessment (GPA) significantly predicted DIC and OS (both p 0.001).Subtype is prognostic for OS and DIC for patients with BCBM treated with SRT.

Spinal metastasis incidence is increasing due to improved systemic therapies combined with sensitive diagnostic imaging modalities in oncologic management. In the majority of cases, spinal metastasis represents either isolated metastases or oligometastatic disease, and local control can translate into improved survival. Image-guided spinal stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) exploits precise localization to safely deliver dose-escalated ablative radiation doses providing excellent local control. This chapter reviews and highlights the management algorithm, patient selection, contouring guidelines, and toxicity associated with spinal SRS/SBRT.

OBJECTIVE Tumor-associated microglia and macrophages (TAMs) influence brain tumor biology and promote tumor-proliferating phenotype. Studies have shown these cell types predict outcomes in various tumor sites with limited evidence in high-grade gliomas (HGG). In this study, we assessed the presence of immune cell infiltrate (ICI) and overall survival (OS) in HGGs. METHODS A total of 97 consecutively treated patients with primary HGG with complete gene expression profiling were identified from our IRB-approved institutional tissue biorepository. Patients underwent primary surgical resection between 02/2004 and 03/2011. Gene expression levels were assessed by Affymetrix Hu-RSTA assays (Affymetrix; Santa Clara, CA). CIBERSORT estimated the presence of ICI via gene expression deconvolution. Tumor characteristics and the presence of 22 individual ICI subtypes were assessed with respect to OS. Time-to-event analyses were performed with Kaplan-Meier estimates and compared via log-rank test. Associations between the ICI and outcomes were explored using Cox-regression. P< 0.05 (two-tailed) was considered statistically significant. RESULTS Median follow-up from primary surgical resection was 12.8 months (range: 0.1-162.8), and median age was 58 years (20-85). Most patients were male (n=63; 65%) and had grade 4 tumors (n=71; 73%). OS differed by grade with 24-month actuarial OS rates of 81% and 34% (P< 0.0001) for grade 3 and 4 gliomas, respectively. The presence of M0 (HR 2.2; 95% CI 1.4-3.6; P=0.001), M1 (HR 1.8; 95%CI 1.1-2.9; P=0.01), and M2 macrophages (HR 1.9; 95%CI 1.2-3.2; P=0.007) predicted OS. No other ICI subtypes were predictive of OS. The presence of M0- and M2-polarized macrophages were more common in grade 4 compared to grade 3 gliomas 46% vs. 11% (P=0.002) and 69% vs. 31% (P=0.0007), respectively. CONCLUSION The increased presence of non-polarized or M2 TAMs within the glioma microenvironment was significantly associated with OS in HGG. Their presence may serve as unique stratification and a potential therapeutic target.

Objectives The role of local disease control in the oligometastatic setting is evolving. Stereotactic body radiation therapy (SBRT) is a noninvasive treatment option for oligometastases; however, using ablative radiation doses for adrenal metastases raises concern given the proximity to radiosensitive organs. Novel treatment techniques may allow for selective dose escalation to improve local control (LC) while minimizing dose to nearby critical structures. Materials and methods We retrospectively reviewed patients with adrenal oligometastases treated with SBRT from 2013 to 2018. LC, disease-free survival, and overall survival were estimated using Kaplan-Meier methods. Predictors of outcomes were evaluated by log-rank and Cox proportional hazard analyses. Results We identified 45 adrenal oligometastases in 41 patients treated with SBRT. The median age at treatment was 67 years (range, 40 to 80). The most common primary histologies were non-small cell lung cancer (51%), renal cell carcinoma (24%), and small cell lung cancer (10%). The median prescription dose was 50 Gy (range, 25 to 60 Gy), with 30 (67%) lesions receiving ≥50 Gy and 14 (31%) receiving 60 Gy. In total, 26 (58%) lesions received a simultaneous-integrated boost. Of the 42 treatment simulations, 26 (62%) were supine, 5 (12%) prone, and 11 (26%) in the left lateral decubitus position. At a median follow-up of 10.5 months, there were 3 local failures with a 12-month LC rate of 96%. Conclusions Adrenal SBRT for oligometastatic disease is a feasible, noninvasive option with excellent LC and minimal toxicity. Lesions in close proximity to radiosensitive organs may benefit from dynamic patient positioning and selective simultaneous-integrated boost techniques to allow for dose escalation, while also limiting toxicity risks.

Triple negative breast cancer (TNBC) is an aggressive disease, but recent studies have identified heterogeneity in patient outcomes. However, the utility of histologic subtyping in TNBC has not yet been well-characterised. This study utilises data from the National Cancer Center Database (NCDB) to complete the largest series to date investigating the prognostic importance of histology within TNBC.A total of 729,920 patients (pts) with invasive ductal carcinoma (IDC), metaplastic breast carcinoma (MBC), medullary breast carcinoma (MedBC), adenoid cystic carcinoma (ACC), invasive lobular carcinoma (ILC) or apocrine breast carcinoma (ABC) treated between 2004 and 2012 were identified in the NCDB. Of these, 89,222 pts with TNBC that received surgery were analysed. Kaplan-Meier analysis, log-rank testing and multivariate Cox proportional hazards regression were utilised with overall survival (OS) as the primary outcome.MBC (74.1%), MedBC (60.6%), ACC (75.7%), ABC (50.1%) and ILC (1.8%) had significantly different proportions of triple negativity when compared to IDC (14.0%, p 0.001). TNBC predicted an inferior OS in IDC (p 0.001) and ILC (p 0.001). Lumpectomy and radiation (RT) were more common in MedBC (51.7%) and ACC (51.5%) and less common in MBC (33.1%) and ILC (25.4%), when compared to IDC (42.5%, p 0.001). TNBC patients with MBC (HR 1.39, p 0.001), MedBC (HR 0.42, p 0.001) and ACC (HR 0.32, p = 0.003) differed significantly in OS when compared to IDC.Our results indicate that histologic heterogeneity in TNBC significantly informs patient outcomes and thus, has the potential to aid in the development of optimum personalised treatments.

Purpose/Objective(s) Glioblastoma (GBM) is characterized with poor survival and local control outcomes despite attempts at dose escalation. Fractional equivalent dosing (FED) does not account for intratumor heterogeneity or development of resistance during treatment. We develop and validate a mathematical model to investigate the impact of ramping up radiation dose (RUD) during treatment. Materials/Methods A mathematical simulation of radiation treatment (mRT) was developed with the following parameters: 1. One billion starting cells 2. 72 hour doubling time 3. Intratumor heterogeneity: Ten distinct subpopulations for each patient that represent a normal distribution of their RSIab value (a previously described genomic model for estimating alpha and beta values based on gene expression) 4. Treatments simulated 5 days of RT with 2 day break 5. Cell death dictated by RSIab parameters and the LQ equation 1. LQ equation = SF = e^(-a*d-b*d^2) 6. Cells that survive are only allowed to double 7. If subpopulation reaches mRT output is surviving fraction at the end of the treatment. A simulation cohort of 40 GBM patients with available genomic information and RSIab was used to simulate the dynamics of FED (60 Gy in 30 fractions) vs. RUD (60 Gy in 30 fractions with an average of 2 Gy/fx qday increment of 0.1 Gy with a range of 0.5-3.5 Gy). A separate validation cohort derived from EORTC26951 high grade glioma trial with available RSIab and clinical endpoints were put into mRT for validation after locking down model parameters. The clinical end point was overall survival. Wilcoxon signed-rank test was used in the simulation cohort between FED vs RUD. In the validation cohort, univariate analysis of the SF for each patient was conducted using log-rank Kaplan-Meier curves with median dichotomization. Multivariate cox-regression analysis of SF was performed with SF and age as continuous variables and PCV as a categorical variable. Results The simulation cohort demonstrates a significant decrease in average alpha/beta ratio in the cohort with respective subpopulations during FED (a/b ratio of 7.95, 4.53, 3.07, and 1.608 after the 0th, 5th, 10th, and 30th fraction, respectively). This is contrast with RUD dosing that shows a less dramatic decrease as dose ramps up (a/b ratio of 7.95, 5.91, 3.93, and 1.94 for the 0th, 5th, 10th, and 30th fraction, respectively). The median SF at the end of treatment between FED (1%) vs. RUD (0.51%) after 60 Gy in 30 fractions had statistically significant difference (P = 0.02). In the validation cohort, the output of SF was statistically significant for overall survival on univariate (P = 0.001) and multivariate analysis (HR: 1.03-4.33 P = 0.041). Conclusion This work demonstrates RUD is superior to FED when considering intratumor heterogeneity in radiation treatment of Glioblastoma because it accounts for the selection of lower alpha/beta subpopulations. Author Disclosure A. Subramanian: None. C. Li: None. D.E. Oliver: None. J.G. Scott: None. J.F. Torres-Roca: None. J. Peacock: None.

Purpose/Objective(s) GBM is a heterogenous tumor with diverse co-existing cell types. However, very little is known of the recurrent GBM (rGBM) microenvironment, and how immune cell infiltrates (ICI) may predict outcome. CIBERSORT provides an estimate of ICI via a gene expression deconvolution algorithm. We have previously validated the radiosensitivity index (RSI) as a measure of overall survival (OS) in primary GBM treated with radiotherapy (RT). In this novel study, we analyzed the presence of ICI, RSI, neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte (PLR) ratios with respect to outcomes in previously treated rGBMs. Materials/Methods From IRB-approved institutional tissue biorepository, we identified patients treated between 2004 – 2012, with rGBM who underwent re-excision and had complete gene expression profiling. Patients with prior low-grade glioma (secondary GBM) were excluded. Gene expression levels were assessed by Affymetrix Hu-RSTA assays. RSI was calculated using the previously published rank-based algorithm. For ICI, the presence and high expression (75%) were used to assess relationships with OS and progression free survival (PFS). For NLR, 2.4 was used based on published data in primary GBM. The 75% of PLR was assessed. Time-to-event analyses were performed with Kaplan-Meier estimates and compared via log-rank test. Associations of factors and outcomes were explored using Cox-regression. Results A total of 42 rGBM patients were identified, of which 40 (95%) were treated previously by adjuvant RT. Median follow-up from initial GBM diagnosis was 25 (range, 6-119) months and 8 (1-63) months from rGBM re-excision. All patients underwent surgery, 4 (9.5%) received re-irradiation, and 22 (50%) received further treatment under clinical trial. Median PFS was 2.5 (1-18) months after re-excision. Current smoking status (P = 0.04), KPS 50 years (P = 0.01) were poor prognostic factors for OS. Treatment under clinical trial did not affect OS (P = 0.2) or PFS (P = 0.6). Four patients were treated with RT following re-excision. As expected, since RSI is predictive of outcome in RT treated patients, RSI was not predictive of PFS (P = 0.9) or OS (P = 0.6) in the cohort. Among ICI, lack of monocytes (P = 0.05) and presence of resting NK-cells (P = 0.01) adversely affected OS. In addition, high expression (³75%) of neutrophils (P = 0.01) and helper T-cells (P = 0.01) adversely affected OS. No other ICI subtypes were predictive of OS or PFS. Patients with pre-surgery NLR > 2.4 (P = 0.03) and high PLR > 240 (P = 0.04) had significantly worse OS. On multivariate analysis, helper T-cells (HR 0.99; 95% CI 0.98-0.99; P = 0.03), neutrophils (HR 0.43; 95% CI 0.21-0.91; P = 0.02), NLR (HR 0.33; 95% CI 0.11-0.96; P = 0.04) and PLR (HR 0.46; 95% CI 0.21-1.0; P = 0.05) remained significant for OS. Conclusion Immune activation in previously treated rGBM may have a role in tumor biology affecting survival. The knowledge of ICI and NLR/PLR may serve as a unique risk-stratification and guide clinical decisions.

Purpose/Objective(s) Immune checkpoint inhibitors (ICI) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have shown responses in the management of non-small cell lung cancer (NSCLC) brain metastases (BM). However, optimizing control with stereotactic radiosurgery (SRS) and various systemic therapies in the management of NSCLC BM remains an area of investigation. We evaluated clinical outcomes in NSCLC BM treated with SRS and ICI, EGFR-TKI, ICI and chemotherapy, compared to conventional chemotherapy. Materials/Methods A total of 174 NSCLC BM patients, treated between 2015 and 2019, to a total of 660 intact (non-operative) BM over 239 single-fraction SRS sessions within 3 months of receiving ICI (n = 58; 33%), EGFR-TKI (n = 30; 17%), chemotherapy and ICI (n = 22; 13%) or standard chemotherapy (n = 64; 37%) were identified. Time-to-event analysis was conducted with the Kaplan-Meier method, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival (OS) from SRS. Cox proportional hazards model was utilized for multivariate analysis (MVA) to identify correlations of clinical variables with outcomes. Results Median follow-up from BM diagnosis was 8.9 months (0.26-126.5 months) and 7.3 months from SRS (2.5-17.6 months). No significant differences in age (P = 0.55), gender (P = 0.49), treated gross tumor volume (P = 0.31), presence of systemic metastasis (P = 0.1), SRS dose (P = 0.61), or KPS (0.35) were noted between treatment groups. The 12-month DIC was 35%, 53%, 41%, and 20% (P = 0.02) for ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy alone groups, respectively. No differences were noted in LC (P = 0.1) and OS (P = 0.5) between treatment groups. Upon MVA, factors found to be significant for improved DIC included treatment with EGFR-TKI therapy compared to conventional chemotherapy (HR 0.4; 95% CI 0.25-0.76; P = 0.04) and treatment with SRS before systemic therapy (HR 0.6; 95% CI 0.3-0.9; P = 0.03). Factors found to be significant for improved LC on MVA included treatment with SRS before (HR 0.4; 95% CI 0.2-0.9; P = 0.03) or concurrent (HR 0.3; 95% CI 0.1-0.6; P = 0.003) compared to following receipt of systemic therapy. Rates of radiation necrosis (RN) did not differ between treatment groups and were 6% (n = 12), 5% (n = 12), 3% (n = 3), 3% (n = 3), for ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy alone groups, respectively, P = 0.43. In addition, no differences were noted in RN between timing of SRS and receipt of systemic therapy, (P = 0.81). Conclusion In our analysis of NSCLC BM patients treated with single session SRS alongside systemic therapy, we found significant differences in DIC based on receipt of systemic therapy. In addition, treatment with SRS before or concurrent with systemic therapy improved control rates. No differences in RN were noted between treatment groups or by timing of SRS and systemic therapy. Prospective evaluation of the potential synergistic effect between systemic therapy and SRS in NSCLC BM management is warranted. Author Disclosure A.E. Dohm: None. J. Tang: None. M.N. Mills: None. B.A. Perez: Research Grant; BMS.T.J. Robinson: None. B. Creelan: Research Grant; NGenomics Laboratories, Adaptive Biotechnologies Corp. Consultant; Xilio Inc, E.R. Squibb LLC, F. Hoffmann-La Roche AG, AstraZeneca plc, AbbVie, KSQ Therapeutics Inc, GlaxoSmithKline plc, Gilead Sciences Inc, Celgene corp. Speaker's Bureau; AstraZeneca plc, ARIAD Pharmaceuticals, Hoffmann-La Roche AG.J. Gray: None. A.B. Etame: None. M. Vogelbaum: Honoraria; Celgene, Tocagen. Stock Options; Infuseon Therapeutics. Royalty; Infuseon Therapeutics. P. Forsyth: Research Grant; Pfizer, Celgene. Advisory Board; Novocure, BTG, Inovio, AbbVie, Ziopharm, Tocagen, Pfizer. H.M. Yu: Honoraria; UpToDate. Speaker's Bureau; BrainLab. Advisory Board; Novocure, AbbVie. D.E. Oliver: None. K.A. Ahmed: Research Grant; Bristol-Myers Squibb, Genentech.

2033 Background: As systemic therapy improves; the prevalence of brain metastases is increasing. Screening brain MRIs are currently recommended for all stage ≥ II non-small cell lung cancer (NSCLC) and stage IIIB–IV melanoma patients, but only when neurologic symptoms arise in stage IV or recurrent breast cancer (BC) patients. This study assessed the presentation and institutional outcomes treating brain metastases (BM) of BC, NSCLC, and melanoma origin. Methods: Patients with BM treated between 2014 and 2019 with primary melanoma, NSCLC, and BC were identified. Characteristics of initial BM diagnoses were retrieved from clinical chart review. Kruskal-Wallis and Pearson’s chi-square tests were used to test differences between groups. Overall survival (OS) was calculated from dates of initial BM diagnosis using the Kaplan–Meier method. Results: A total of 959 patients were identified (BC 18%, NSCLC 51%, melanoma 31%). BC patients were younger at initial presentation (BC median age: 57, NSCLC 65, melanoma 62, p< 0.0001). At BM diagnosis, BC patients were more likely to have concurrent systemic metastasis (BC 77%, NSCLC 42%, melanoma 69%, p< 0.0001), at least 5 BM (BC 27%, NSCLC 14%, melanoma 13%, p= 0.0004), and leptomeningeal disease (BC 23%, NSCLC 6%, melanoma 6%, p< 0.0001). Patients with BC were significantly more likely to receive whole brain radiation therapy (WBRT) (BC 58%, NSCLC 37%, melanoma 22%, p< 0.0001) and less likely to receive stereotactic radiation (BC 26%, NSCLC 48%, melanoma 58%, p< 0.0001) following initial BM diagnosis. There were no significant differences in surgical resection between cancer types (BC 24%, NSCLC 24%, melanoma 29%, p =0.166). Median OS was shorter for BC (BC 9.9 months, NSCLC 10.3 months, melanoma 13.7 months, p= 0.0006) following BM diagnosis. Conclusions: Our institutional analysis found BC patients were more likely to be younger, present with more advanced brain disease, require WBRT, and have poorer OS than NSCLC and melanoma patients following initial brain metastasis diagnosis. This may be due in part to a lack of brain MRI screening recommendations in BC. Further investigation is needed to determine which BC patients are at sufficient risk to warrant brain MRI screening.

Metastases (BM) carries the risk of hemorrhaging lesions and can be effectively treated using stereotactic radiotherapy (SRT). Nivolumab is a recently approved immunotherapy for stage IV RCC. We evaluate whether patients with RCC BM treated with SRT overlapping with nivolumab have altered clinical and BM outcomes. METHODS: 38 consecutive patients were identified in our retrospective database from 1/2011 to 6/2018. Analyses were performed on a per-lesional basis (n=170), per-treatment session basis (n=79), and per-patient basis (n=38). Patients who received nivolumab within 6 months of SRT were considered to have overlapping treatments. ROC curve, chi-squared, Kaplan-Meier, log-rank, and Cox regression model were employed for statistical analyses. RESULTS: A total of 7 (18.4%) patients received overlapping treatments for 64 (37.6%) eligible lesions. Median follow-up was 15.4 months and median overall survival from first BM treatment was 14.8 months (0.5 – 98.4). Median time to subsequent distant brain and non-brain failures were 3.4 and 2.2 months, respectively. Median time to local failure was 20.2 months (two lesions). There were 11 hemorrhagic toxicities (7 in the nivolumab group) and 17 radionecrosis toxicities (4 in the nivolumab group) with no significant difference amongst the groups. Lesions receiving nivolumab within 6 months of SRT did not exhibit a higher rate of toxicity (p=0.521) but had a shortened time to hemorrhage (p< 0.001). Patients who received SRT > 1 month after nivolumab had a prolonged time to subsequent distant brain failure (median 11.1 months) than patients who received SRT > 1 month before (median 3.1 months) or within 1 month (median 1.6 months) of nivolumab, p=0.014. CONCLUSIONS: Overlapping nivolumab with SRT is safe with no increased risk of hemorrhagic lesions. An optimal treatment sequence of nivolumab administration followed by SRT prolongs the time to subsequent BM and warrants further investigation.

Cyclin-dependent kinase (CDK) 4/6 inhibitors are becoming increasingly utilized in the setting of advanced, hormone receptor (HR+) positive breast cancer. Pre-clinical data suggests a potential synergy between radiation therapy (RT) and CDK4/6 inhibitors. We assessed clinical outcomes of patients treated at our institution with the use of CDK4/6 inhibitors and stereotactic radiation in the management of HR+ breast brain metastases. A retrospective analysis of patients who received stereotactic radiotherapy for HR+ brain metastases within 6 months of CDK4/6 inhibitor administration was performed. The primary endpoint was neurotoxicity during or after stereotactic radiation. Secondary endpoints were local brain control, distant brain control, and overall survival (OS). A total of 42 lesions treated with stereotactic radiation in 15 patients were identified. Patients received either palbociclib (n = 10; 67%) or abemaciclib (n = 5; 33%). RT was delivered concurrently, before, or after CDK4/6 inhibitors in 18 (43%), 9 (21%), and 15 (36%) lesions, respectively. Median follow-up following stereotactic radiation was 9 months. Two lesions (5%) developed radionecrosis, both of which received four prior RT courses to the affected lesion prior to onset of radionecrosis and subsequently managed with steroids and bevacizumab. Six- and 12-month local control of treated lesions was 88% and 88%, while 6- and 12-month distant brain control was 61% and 39%, respectively. Median OS was 36.7 months from the date of brain metastases diagnosis. Stereotactic radiation to breast brain metastases was well tolerated alongside CDK4/6 inhibitors. Compared to historical data, brain metastases control rates are similar whereas survival appears prolonged.

Current standard radiotherapy doses have been derived from empiric methods rather than a scientific framework. Subclinical nodal dosing remains relatively uniform across most disease sites, despite heterogeneity in patient and tumor biology. It is now clear that there are subsets of patients who will benefit from genomically-informed radiotherapy planning, and there are increasing efforts toward prescribing radiation dose to match the radiosensitivity of the tumor. By using novel genomic biomarkers to personalize delivery of radiotherapy, there is an opportunity to improve loco-regional control and cure rates. We survey the current landscape of personalized radiation oncology across commonly treated disease sites.

Purpose: To monitor intrafraction motion during spine stereotactic body radiotherapy(SBRT) treatment delivery with readily available technology, we implemented triggered kV imaging using the on-board imager(OBI) of a modern medical linear accelerator with an advanced imaging package. Methods: Triggered kV imaging for intrafraction motion management was tested with an anthropomorphic phantom and simulated spine SBRT treatments to the thoracic and lumbar spine. The vertebral bodies and spinous processes were contoured as the image guided radiotherapy(IGRT) structures specific to this technique. Upon each triggered kV image acquisition, 2D projections of the IGRT structures were automatically calculated and updated at arbitrary angles for display on the kV images. Various shifts/rotations were introduced in x, y, z, pitch, and yaw. Gantry-angle-based triggering was set to acquire kV images every 45°. A group of physicists/physicians(n = 10) participated in a survey to evaluate clinical efficiency and accuracy of clinical decisions on images containing various phantom shifts. This method was implemented clinically for treatment of 42 patients(94 fractions) with 15 second time-based triggering. Result: Phantom images revealed that IGRT structure accuracy and therefore utility of projected contours during triggered imaging improved with smaller CT slice thickness. Contouring vertebra superior and inferior to the treatment site was necessary to detect clinically relevant phantom rotation. From the survey, detectability was proportional to the shift size in all shift directions and inversely related to the CT slice thickness. Clinical implementation helped evaluate robustness of patient immobilization. Based on visual inspection of projected IGRT contours on planar kV images, appreciable intrafraction motion was detected in eleven fractions(11.7%). Discussion: Feasibility of triggered imaging for spine SBRT intrafraction motion management has been demonstrated in phantom experiments and implementation for patient treatments. This technique allows efficient, non-invasive monitoring of patient position using the OBI and patient anatomy as a direct visual guide.

Background: Patients with extensive-stage small cell lung cancer (ES-SCLC) often develop brain metastases. There is significant controversy regarding the benefit of prophylactic cranial irradiation (PCI) for patients with ES-SCLC. Our objective is to identify ES-SCLC patients who might be most likely to benefit from PCI. Methods: We retrospectively reviewed 173 patients with ES-SCLC treated between 2010–2015. Of these, 117 patients were initially diagnosed without brain metastases and received systemic chemotherapy. Following exclusion of patients who received PCI and less than 2 cycles of platinum doublet therapy, 93 patients remained. Patient records were reviewed for clinical and radiographic features previously identified as relevant risk factors. Primary outcome was brain metastasis-free survival (BMFS). Kaplan-Meier analysis, log-rank tests and Cox multivariate models were used to compare outcomes. Results: Median follow-up was 10.7 months (range, 3–58 months). Thirty-eight (40.9%) patients developed brain metastases. Three or more metastatic sites was associated with inferior BMFS on univariable (1-year estimate 43.8% vs . 61.3%; P=0.020) and multivariable (MVA) analysis [hazard ratio (HR) 2.33, 95% CI: 1.08–5.01; P=0.03). Conclusions: Our results suggest that extracranial metastatic burden is associated with an increased risk for brain metastases in patients with ES-SCLC. As there is no clear standard regarding delivery of PCI in this patient population, utilizing the number of metastatic disease sites as a clinical indicator may help to improve selection of patients who benefit from PCI.

Guidelines regarding specific resection margins for primary Merkel cell carcinoma (MCC) are not well established. The current National Comprehensive Cancer Network (NCCN) guidelines recommend 1- to 2-cm resection margins. This study aimed to determine the impact of margin width on local recurrence (LR), disease-specific survival (DSS), overall survival (OS), and type of wound closure. All patients who underwent resection of primary MCC at a single institution from 2000 to 2015 were reviewed. Patient demographics, clinicopathologic characteristics, treatments, and outcomes were reviewed. A total of 240 patients underwent resection of primary MCC with resection margin width identified in the operative report. The median age was 76 years, and 65.8% of the patients were men. Of the 240 patients, 85 (35.4%) had head and neck primaries, 140 (58.3%) had extremity primaries, and 15 (6.3%) had trunk primaries. In terms of margins, 69 patients (28.8%) had a margin of 1 cm, 36 patients (15%) had a margin of 1.1–1.9 cm, and 135 patients (56.2%) had a margin of 2 cm or more. The median follow-up period was 21 months. The LR rate was 2.9% for a margin of 1 cm, 2.8% for a margin of 1.1–1.9 cm, and 5.2% for a margin of 2 cm or more (p = 0.80). The 5-year OS was 63.6% for a margin of 1 cm, 59.7% for a margin of 1.1–1.9, and 70.7% for a margin of 2 cm or more (p = 0.66). The 5-year DSS was 80.3% for a margin of 1 cm, 66.2% for a margin of 1.1–1.9 cm, and 91.8% for a margin of 2 cm or more (p = 0.28). For wound closure, 43.5, 50, and 65.9% of the patients respectively required a flap or graft with a margin of 1, 1.1–1.9, and 2 cm or more (p = 0.006). A 1-cm resection margins did not increase the risk of LR. Margin width did not make a significant difference in DSS or OS. Larger resection margins increase the need for a graft or flap closure.

BACKGROUND. Approximately 30% of patients with clinically localized Merkel cell carcinoma (MCC) show nodal involvement on sentinel lymph node biopsy (SLNB). Optimal management of SLNB-positive disease has not been defined. This study compared outcomes after completion lymphadenectomy (CLND), radiation, and combined CLND plus radiation after a positive SLNB. METHODS. All patients treated at a single institution for SLNB-positive MCC (1998–2015) were retrospectively evaluated, with examination of patient demographics, clinicopathologic characteristics, outcomes, and regional toxicity. RESULTS. The study identified 71 evaluable patients with SLNB-positive disease. The median age of these patients was 76 years, and 76.1% were men. Of the 71 patients, 11 (15.5%) underwent CLND, 40 (56.3%) received radiation, and 20 (28.2%) underwent CLND plus postoperative radiation. Lymphovascular invasion was significantly more common in the radiation-alone cohort (p = 0.04). For the three cohorts, the median percentages of nodal involvement were respectively 2, 10, and 30% (p = 0.06). After a median follow-up period of 22.3 months, four patients had recurrence in their regional nodal basin (3 radiation-alone patients and 1 CLND + radiation patient). The three cohorts did not differ significantly in the development of distant metastases (p = 0.68) or overall survival (p = 0.72). Six patients experienced surgical-site infections (2 CLND and 4 CLND + radiation patients), and three patients experienced symptomatic lymphedema (1 CLND patient and 2 CLND + radiation patients). CONCLUSIONS. Regional failure was infrequent (≤ 10%) regardless of treatment, and morbidity appeared to be low with all approaches. Given that multiple treatment approaches can be successful in treating micrometastatic MCC, future efforts should be directed at refining criteria for allocating patients to a specific method, or possibly no further nodal basin treatment, in an effort to maximize regional control at the lowest cost and morbidity.

Radiation therapy (RT) plays a prominent role in the treatment of many cancers. With increasing use of RT and high overall survival rates, the risks associated with RT must be carefully considered. Of these risks, the cardiovascular and autonomic toxicities have been of significant concern. In fact, cardiovascular disease is the leading cause of nonmalignancy-related death in cancer survivors. The manifestations of radiation induced cardiac injury include the acute toxicities of myopericarditis and late toxicities including constrictive pericarditis, restrictive cardiomyopathy, coronary artery disease, valvular heart disease, heart failure, and conduction abnormalities. Neck and cranial RT have also been associated with significant long-term toxicities including accelerated occlusive carotid artery disease, autonomic dysfunction due to baroreceptor damage, and development of metabolic syndromes due to damage to the hypothalamic-pituitary axis. The clinical manifestations of radiation induced disease may not present until several years following the delivery of radiation. We review the adverse effects of RT on these organ systems and discuss risk reduction strategies that may effectively mitigate some of these adverse outcomes.

The National Comprehensive Cancer Network (NCCN) 2014 guidelines are unclear about the role of radiotherapy in the management of desmoplastic melanoma. The guidelines specify that radiotherapy can be 'considered' for select patients with desmoplastic melanoma with narrow surgical margins. Patient selection criteria, including margins, are not well defined, causing considerable differences in practice patterns across the country. There are also several conflicting reports about the role of radiotherapy in improving postsurgical outcomes when other adverse pathological risks factors, such as increased Clark level, head and neck involvement, perineural invasion, positive margins, or recurrent disease, are also present. Recent data provide further clarification and insights into the role of radiotherapy. Thus, in light of the NCCN guidelines and the recently published series, we critically review the role of radiotherapy for desmoplastic melanoma. In our review, we highlight the published risk factors that predict for increased risk of recurrence after surgery. We also provide a comparison of surgical and radiation outcomes data, and then address areas for further research.

The aim of this study was to compare outcomes of postoperative whole brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) alone in patients with resected brain metastases (BM). We reviewed records of patients who underwent surgical resection of BM followed by WBRT or SRS alone between 2003 and 2013. Local control (LC) of the treated resected cavity, distant brain control (DBC), leptomeningeal disease (LMD), overall survival (OS), and radiographic leukoencephalopathy rates were estimated by the Kaplan-Meier method. One-hundred thirty-two patients underwent surgical resection for 141 intracranial metastases: 36 (27 %) patients received adjuvant WBRT and 96 (73 %) received SRS alone to the resection cavity. One-year OS (56 vs. 55 %, p = 0.64) and LC (83 vs. 74 %, p = 0.31) were similar between patients receiving WBRT and SRS. After controlling for number of BM, WBRT was associated with higher 1-year DBC compared with SRS (70 vs. 48 %, p = 0.03); single metastasis and WBRT were the only significant predictors for reduced distant brain recurrence in multi-variate analysis. Freedom from LMD was higher with WBRT at 18 months (87 vs. 69 %, p = 0.045), while incidence of radiographic leukoencephalopathy was higher with WBRT at 12 months (47 vs. 7 %, p = 0.001). One-year freedom from WBRT in the SRS alone group was 86 %. Compared with WBRT for patients with resected BM, SRS alone demonstrated similar LC, higher rates of LMD and inferior DBC, after controlling for the number of BM. However, OS was similar between groups. The results of ongoing clinical trials are needed to confirm these findings.

447 Background: The role and associated risks of stereotactic body radiotherapy (SBRT) for adrenal metastases remain unclear. We report our single institution experience and report novel techniques to selectively dose-escalate treatment while concurrently minimizing dose to nearby critical structures. Methods: We retrospectively reviewed patients with evidence of metastatic adrenal disease originating from any primary histology treated with SBRT from 2013 to 2018. The primary endpoint was local control (LC). Secondary endpoints were disease-free survival (DFS), overall survival (OS), and treatment-related toxicity. LC, DFS, and OS were calculated with Kaplan-Meier analysis. Univariable and multivariable analysis were performed with long-rank and Cox proportional analysis. Results: A total of 45 adrenal metastases in 41 patients received SBRT. The median age was 67 years (range 40-80). The most common primary histologies were non-small cell lung cancer (51%), renal cell carcinoma (24%), and small cell lung cancer (10%). The median gross internal and planned target volumes were 21.23cc (range, 3.1–124.7cc) and 31.68cc (range, 5.2–175.9cc), respectively. The median dose administered was 50 Gy with 30 (67%) lesions receiving ≥50 Gy and 14 (31%) receiving 60 Gy. Twenty-six (58%) lesions were selectively dose-painted. Of the 42 simulations, 26 (62%) were treated supine, 5 (12%) prone, and 11 (26%) in the left lateral decubitus position. At a median follow-up of 10.5 months, there were 3 local recurrences (LR). 12-month LC rate was 96% with a median LC of 35 months. All three LR were in the metachronous, oligometastatic patients. One patient developed a hypertensive crisis which required intravenous antihypertensives. Conclusions: Adrenal SBRT for oligometastatic disease is a reasonable, noninvasive option with excellent LC and minimal toxicity. Lesions in close proximity to radiosensitive organs may benefit from techniques, such as dynamic patient positioning and selective dose-painting, for further dose-escalation to optimize LC rates while simultaneously limiting associated toxicity risks.