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External beam radiation therapy (EBRT) dose escalation has been tested in multiple prospective trials. However, the impact on patient reported outcomes (PROs) associated with higher doses of EBRT remain poorly understood. We sought to assess the differences in PROs between men treated with a dose of 70.2 Gy versus 79.2 Gy of EBRT for prostate cancer.The phase 3 clinical trial RTOG 0126 randomized 1532 patients with prostate cancer between March 2002 and August 2008 to 79.2 Gy over 44 fractions versus 70.2 Gy over 39 fractions. Eligible patients participated in the PRO data collection. PROs completed included the International Index of Erectile Function Questionnaire (IIEF), Functional Alterations due to Changes in Elimination (FACE), and the Spitzer Quality of Life Index (SQLI). The timepoints for the IIEF were collected pre-entry and at 6, 12, and 24 months. The FACE and SQLI were collected pre-entry and at 3, 6, 12, 18, and 24 months. The impact of EBRT dose to normal structures (penile bulb, rectum, and bladder) on PROs was also examined. Mixed effects models were used to analyze trends across time.In total, 1144 patients completed baseline IIEF forms and of these, 56%, 64%, and 61% completed the IIEF at 6, 12, and 24 months, respectively; 1123 patients completed the FACE score at baseline and 50%, 61%, 73%, 61%, and 65% completed all 15 items for the FACE metric at timepoints of 3, 6, 12, 18, and 24 months, respectively. Erectile dysfunction at 12 months based on the single question was not significantly different between arms (38.1% for the standard dose radiation therapy arm vs 49.7% for the dose escalated radiation therapy arm; P = .051). Treatment arm (70.2 vs 79.2) had no significant impact on any PRO metrics measured across all collected domains. Comprehensive dosimetric analyses are presented and reveal multiple significant differences to regional organs at risk.Compliance with PRO data collection was lower than anticipated in this phase 3 trial. Examining the available data, dose escalated EBRT did not appear to be associated with any detriment to PROs across numerous prospectively collected domains. These data, notwithstanding limitations, add to our understanding of the implications of EBRT dose escalation in prostate cancer. Furthermore, these results illustrate challenges associated with PRO data collection.

PURPOSE: To report the long-term outcomes of the RTOG 0424 study of a high-risk, low-grade glioma population treated with concurrent and adjuvant temozolomide (TMZ) and radiation therapy (RT). METHODS AND MATERIALS: For this single-arm, phase 2 study, patients with low-grade gliomas with ≥3 risk factors (age ≥40 years, astrocytoma, bihemispheric tumor, size ≥6 cm, or preoperative neurologic function status >1) received RT (54 Gy in 30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The initial primary endpoint P was overall survival (OS) at 3 years after registration. Secondary endpoints included progression-free survival (PFS) and the association of survival outcomes with methylation status. The initial 3-year report of this study was published in 2015. RESULTS: The study accrued 136 patients, of whom 129 were analyzable. The median follow-up for surviving patients was 9.0 years. The 3-year OS was 73.5% (95% confidence interval, 65.8%−81.1%), numerically superior to the 3-year OS historical control of 54% (P < .001). The median survival time was 8.2 years (95% confidence interval, 5.6–9.1). Five- and 10-year OS rates were 60.9% and 34.6%, respectively, and 5- and 10-year PFS rates were 46.8% and 25.5%, respectively. CONCLUSIONS: The long-term results confirmed the findings from the initial report for efficacy, suggesting OS and PFS outcomes with the RT-TMZ regimen exceeded historical control groups treated with radiation alone. Toxicity was acceptable.

BACKGROUND: Phase 2 cooperative group meningioma trial assessing the safety and efficacy of risk-adaptive management strategies. This is the initial analysis of the high-risk cohort. METHODS AND MATERIALS: High-risk patients were those with a new or recurrent World Health Organization (WHO) grade III meningioma of any resection extent, recurrent WHO grade II of any resection extent, or new WHO grade II after subtotal resection. Patients received intensity-modulated radiotherapy (IMRT) using a simultaneous integrated boost technique (60 Gy high dose and 54 Gy low dose in 30 fractions). Three-year progression-free survival (PFS) was the primary endpoint. Adverse events (AEs) were scored per NCI Common Terminology Criteria for Adverse Events version 3. RESULTS: Of 57 enrolled patients, 53 received protocol treatment. Median follow-up was 4.0 years (4.8 years for living patients). Two patients withdrew without progression before year 3; for the remaining 51 patients, 3-year PFS was 58.8%. Among all 53 protocol-treated patients, 3-year PFS was 59.2%. Three-year local control was 68.9%, and overall survival was 78.6%. Of 51 patients, 1 patient (1.9%) experienced a late grade-5 necrosis-related AE. All other acute (23 of 53 patients) and late (21 of 51 patients) AEs were grades 1 to 3. CONCLUSIONS: Patients with high-risk meningioma treated with IMRT (60 Gy/30) experienced 3-year PFS of 58.8%. Combined acute and late AEs were limited to grades 1 to 3, except for a single necrosis-related grade 5 event. These results support postoperative IMRT for high-risk meningioma and invite ongoing investigations to improve outcomes further. © 2019 Elsevier Inc. All rights reserved.

Black men in the United States suffer significantly higher incidence of and mortality from prostate cancer (PCa) than non-Black men. The cause of this disparity is multifactorial, though inequitable access to curative radiation modalities, including low-dose-rate (LDR) brachytherapy, may contribute. Despite this, there are few analyses evaluating the potential of different radiation therapies to mitigate outcome disparities. Therefore, we examined the clinical outcomes of Black and non-Black patients treated with definitive LDR brachytherapy for prostate cancer.Data were collected for all patients treated with definitive LDR brachytherapy between 2005 and 2018 on a retrospective IRB-approved protocol. Pearson Chi-Squared analysis was used to assess demographic and cancer differences between Black and non-Black cohorts. Freedom from biochemical failure (FFBF) was calculated using Kaplan-Meier analysis. Univariate and multivariate analyses were used to identify factors predictive of biochemical failure.One hundred and sixty-seven patients were included in the analysis (Black: n=81 [48.5%]) with a median follow-up of 88.4 months. Black patients were from lower income communities (P0.01), had greater social vulnerability (P0.01), and had a longer interval between diagnosis and treatment (P = 0.011). Overall cumulative FFBF was 92.3% (95% CI: 87.8% - 96.8%) at 5 years and 87.7% (95% CI: 82.0% - 93.4%) at 7 years. There was no significant difference in FFBF in Black and non-Black patients (P = 0.114) and Black race was not independently predictive of failure (HR 1.51 [95% CI: 0.56 - 4.01]; P = 0.42). Overall survival was comparable between racial groups (P = 0.972). Only nadir PSA was significantly associated with biochemical failure on MVA (HR = 3.57 [95% CI: 02.44 - 5.22]; P0.001).Black men treated with LDR brachytherapy achieved similar FFBF to their non-Black counterparts despite poorer socioeconomic status. This suggests that PCa treatment with brachytherapy may eliminate some disparities clinical outcomes.

Our ability to prognosticate the clinical course of patients with cancer has historically been limited to clinical, histopathological, and radiographic features. It has long been clear however, that these data alone do not adequately capture the heterogeneity and breadth of disease trajectories experienced by patients. The advent of efficient genomic sequencing has led to a revolution in cancer care as we try to understand and personalize treatment specific to patient clinico-genomic phenotypes. Within prostate cancer, emerging evidence suggests that tumor genomics (e.g., DNA, RNA, and epigenetics) can be utilized to inform clinical decision making. In addition to providing discriminatory information about prognosis, it is likely tumor genomics also hold a key in predicting response to oncologic therapies which could be used to further tailor treatment recommendations. Herein we review select literature surrounding the use of tumor genomics within the management of prostate cancer, specifically leaning toward analytically validated and clinically tested genomic biomarkers utilized in radiotherapy and/or adjunctive therapies given with radiotherapy.

BACKGROUND Proton therapy (PRT) is increasingly utilized for pediatric brain tumors to reduce radiation associated treatment effects, but there is a lack of data evaluating PRT in pediatric high-grade glioma (pHGG). The purpose of this analysis is to report patterns of care and clinical outcomes for pHGG patients treated with PRT and enrolled in the prospective Pediatric Proton/Photon Consortium Registry (PPCR). METHODS Fifty-five pHGG participants treated with PRT were enrolled in the PPCR between Jan 2013 and Aug 2020. Progression free (PFS) and overall survival (OS) rates were calculated according to the Kaplan-Meier method. Univariate analyses were performed using Cox proportional hazards model with Firth’s penalization. RESULTS Among 49 patients with complete data, the median age was 12, the majority of patients were male (29), white (35), and non-Hispanic/Latino (41). Histology was grade IV (37), grade III (10) or HGG not specified (8). Resection was gross-total (24), near-total (4), or sub-total/biopsy (17). Six patients received prior RT. The median RT dose was 57.6 Gy (RBE) starting a median of 33.5 days after surgery. 39 patients received chemotherapy. The most common acute treatment toxicities were alopecia (36), fatigue (34), radiation dermatitis (22), nausea/vomiting (19), and headache (19). Median follow-up was 3.14 years (95% CI 1.62-3.97). At 3 years, PFS (95% CI) was 35.5% (20.8-50.6%) and OS was 55.6% (38-70%). Median PFS and OS are 1.6 (1.2-3.1) and 3.6 (1.6-NA) years, respectively. Higher radiation dose was associated with greater PFS (HR 0.97 (0.94-1.01), p=0.059) and OS (HR 0.95 (0.93-0.99), p=0.006). Patients ≤ 3 years at diagnosis (n=8) had 3-year PFS/OS of 72.9%/87.5% vs. 27.8%/49.4% for older patients (p=0.068/0.089, respectively). CONCLUSION These are the first published data with PRT for pHGG. Clinical outcomes are comparable to historical data with photon therapy. Additional analysis of treatment associated toxicity and patient quality-of-life are warranted.

199 Background: Contained within the spectrum of metastatic cancer is an oligometastatic state where metastases are limited in number. Recent prospective data have shown that metastasis directed therapy (MDT) can alter the natural history of oligometastatic disease. In hormone-sensitive prostate cancer (HSPC), the positive clinical effect of MDT has been observed by the phase II STOMP and ORIOLE trials. Circulating tumor cells (CTCs) are a likely origin of the formation of macroscopic metastases. CTCs thus may provide an approach for identifying subgroups of patients with oligometastatic HSPC (oligoHSPC) that would benefit most from MDT. Our main goal was to evaluate the association between presence of CTCs at baseline or day 180 with clinical outcomes in the ORIOLE trial. Methods: ORIOLE was a phase II trial randomizing men with recurrent oligoHSPC with 1-3 metastases to observation (Obs) versus stereotactic ablative radiotherapy (SABR) MDT. Blood samples were prospectively collected at baseline and day 180. Progression-free survival (PFS) was a composite endpoint including any of the following: a PSA rise of at least 2 ng/dL and 25% above nadir; radiologic progression by CT, MRI or bone scan (RECIST v1.1); symptomatic progression of disease; initiation of ADT; or death. Patient blood samples were shipped for analysis on Epic Sciences liquid biopsy platform (Epic Sciences, San Diego, CA). Machine learning algorithms identified CTCs and characterized androgen receptor (AR) expression. Comparisons of patient and tumor characteristics between the groups were performed by two-sample t-tests. Survival curves were generated using the Kaplan-Meier method and p-values were calculated using log-rank test. Analysis was performed using SPSS version 28. Results: A total of 82 samples were collected: 70 from the SABR arm (35 baseline and 35 on day 180) and 12 Obs (7 baseline and 5 on day 180). CTCs were detected in 30/42 samples at baseline (71%, AR+= 7) and in 26/40 samples on day 180 (65%, AR+= 9). In the SABR group there was no difference between CTC+ versus CTC- and AR + versus AR- groups for PSA evaluated at baseline, day 90 or day 180 or Gleason score. With a median follow-up of 41.7 months, PFS was significantly lower in the patients with AR+ versus AR- CTCs at baseline in the SABR arm (p = 0.011, mean PFS: AR+ = 9.3 months, AR- = 27.1 months). The mean biochemical failure-free survival was AR+= 12.9 versus AR-= 29.2 months (p = 0.058). Conclusions: Our preliminary results demonstrate an association between AR+ CTCs at baseline and Day 180 with clinical outcomes following SABR MDT in oligoHSPC. This is the first report examining baseline and dynamic presence of CTCs in oligoHSPC treated from a prospective randomized trial of SABR. Longer follow-up, further analysis and a greater number of patients are needed for a more comprehensive conclusion.

TPS275 Background: It is now recognized that some patients with “oligo,” or few sites of metastases, may have the potential to completely eradicate their disease with aggressive local therapy. There are recent encouraging randomized prospective data for total consolidation of macroscopic metastases through treatment intensification involving metastasis-directed therapy (MDT). Hypotheses include that radiation to primary prostate tumor and metastatic sites affects the natural history of metastasis by virtue of radiation effects on cancer cell autonomous pathways and tumor microenvironment/normal tissue pathways. This study aims to evaluate the utility of the addition of MDT to the evolving standard of care treatment for de novo low volume metastatic prostate cancer (PCa) patients. This study will evaluate the efficacy of best systemic therapy (BST) and primary prostate radiation (XRT) versus BST, XRT and stereotactic ablative radiation therapy (SABR) MDT. Discovery correlatives associated with clinical outcome will be assessed by collection of including, but not limited to: circulating tumor cells, immunologic biomarkers, microbiota and radiomics. Methods: This study is a multi-site, non-blinded, randomized Phase II trial in patients with oligometastatic PCa. Men with de novo histologically confirmed (at any site) oligometastatic PCa (75.6 Gy to the prostate. BST will allow standard and intensified androgen blockade. The trial will evaluate the addition of SABR MDT and explore several translational and imaging correlatives. Subjects who meet eligibility criteria and qualify for enrollment will be stratified according to: (i) hormonal therapy vs intensified hormonal therapy; (ii) XRT vs XRT + primary prostate boost, and (iii) absence vs presence of bone metastasis. This study has been approved and began accrual on October 3rd, 2022, the Clinicaltrials.gov. Identifier: NCT05223803. We assume an accrual time of 24 months, with 24 months of additional follow-up time, and will randomize a total of 122 patients (61 patients in each arm). The primary endpoint with be to assess 2-year failure-free survival (FFS). Secondary endpoints will include toxicity, quality of life (QoL), time to locoregional progression, time to distant progression, time to new metastasis, radiographic progression-free survival, and duration of response. Clinical trial information: NCT05223803 .

Craniospinal irradiation (CSI) is commonly used for pediatric brain tumors with a propensity for spread in craniospinal fluid, principally medulloblastoma. Evolving technology has led to the use of highly conformal radiation therapy (RT) techniques for CSI, including proton therapy. Target delineation and plan coverage are critical for CSI, but there is ongoing controversy and variability in these realms, with little available data on practice patterns. We sought to characterize proton CSI practice patterns in the United States by examining CSI plans in the Pediatric Proton/Photon Consortium Registry (PPCR).PPCR was queried for data on proton CSI patients from 2015 to early 2020. Each plan was manually reviewed, determining patient position; prescription dose; and coverage of optic nerves, vertebral bodies, spinal nerve roots, sacral nerves, and cranial foramina, among other variables. Two radiation oncologists blinded to clinical data and treating institution assessed coverage at the 95% prescription isodose line and per published European Society for Paediatric Oncology guidelines. Variability in coverage was assessed with nonparametric tests and univariate and multivariate logistic regression.PPCR supplied data for 450 patients, 384 of whom had an evaluable portion of a CSI plan. Most patients (90.3%) were supine. Optic nerves were fully covered in 48.2%; sacral nerves in 87.7%; cranial foramina in 69.3%; and spinal nerves in 95.6%. Vertebral body (VB) sparing was used in 18.6% of skeletally immature cases, increasing over time (P.001). Coverage in all categories was significantly different among treating institutions, on univariate and multivariate analyses. Cribriform plate deficits were rare, with marginal misses of the foramen ovale (17.4%) and frontal lobe (12%) most common.We found consistent variation based on treating institution in proton CSI practices including optic nerve, VB, sacral nerve, cranial, and spinal nerve coverage. These data may serve as a baseline quantification of current proton CSI practices in the United States as they continue to evolve.

PURPOSE/OBJECTIVE(S): Management of localized high-risk prostate cancer remains challenging. At our institution we performed a prospective Phase II study of 2 years of androgen deprivation therapy (ADT), pelvic radiation, Cesium (Cs)-131 brachytherapy boost, and adjuvant docetaxel in high risk, localized prostate cancer with a primary endpoint of 3-year disease-free survival. MATERIALS/METHODS: Acute/chronic hematologic, gastrointestinal (GI) and genitourinary (GU) toxicities were scored based on the CTCAE v3.0/RTOG-EORTC criteria, respectively. Actuarial biochemical recurrence free survival (bRFS), bRFSdisease free survival (DFS) and overall survival (OS) were calculated. Patients had a median age of 62 years (range 45–82), median Gleason score 8 (74% Gleason 8–10), median PSA of 11.2 (range 2.8–96), and 47% cT2-T3a stage disease. Androgen deprivation was given for two years, 45 Gy whole-pelvis IMRT was followed by an 85 Gy Cs-131 boost to the prostate gland, and adjuvant docetaxel was given for 4 cycles. RESULTS: Thirty eight patients enrolled from 2006–2014, with 82% completing protocol specified treatment, and 84.2% completing 4 cycles of docetaxel. Median follow-up for the entire and alive cohorts were 44 months and 58 months (range 3.4–118), respectively. Acute grade ≥ 2 GI and GU toxicity rates were 18.4% and 23.7%, respectively. Chronic grade ≥ 2 GI and GU toxicity rates were 2.6% and 2.6%, respectively. Twelve patients (31.6%) developed grade 4 hematologic toxicity, with no grade 5 toxicity. The 5-year DFS, bRFS and OS rates were 74.1%, 86.0% and 80.0%, respectively. CONCLUSION: This aggressive pilot multi-modal approach appears to be safe and well-tolerated, providing disease control in a significant proportion of patients with particularly high risk prostate cancer.

Rhabdomyosarcoma (RMS) is an aggressive soft tissue sarcoma originating from skeletal muscle in children and adolescent young adults. Despite multi-modal aggressive therapies, relapsed, refractory or metastatic rhabdomyosarcoma remains a lethal disease with no significant improvement in outcome over decades of clinical trials. Therefore novel therapies are needed. FGFR4 is a developmentally regulated cell surface receptor tyrosine kinase that is overexpressed in RMS when compared with normal tissues, and mutationally activated in about 7.5% of RMS. Recently we showed that PAX3-FOXO1 establishes a super-enhancer in the FGFR4 genomic locus driving its high expression in fusion positive RMS. CAR T-cell therapy is effective in treating refractory and relapsed B-cell leukemia and lymphoma, with three CARs targeting CD19 approved by the FDA. Multiple CART trials are currently underway for solid tumors. Since FGFR4 is a cell surface protein, we hypothesized that FGFR4 will provide a rational target for immunotherapy in RMS. We confirmed by immunohistochemistry staining, western analysis, and Meso Scale Discovery that FGFR4 protein is highly differentially expressed in RMS samples. We developed a murine anti-FGFR4 antibody, 3A11, by immunizing mouse with FGFR4-IG fusion protein. 3A11 showed high affinity and specificity of binding to FGFR4. We then developed a second-generation CAR using the VL and VH domain of 3A11 antibody and found that the scFvFc retained its specificity and high affinity at nanomolar range. Human T cells transduced with 3A11 CAR construct were found to be highly potent at inducing IFN-γ, TNF-α, IL-2 and cytotoxicity when the FGFR4-CART was co-cultured with RMS cells, but not with RMS cells with FGFR4 knocked out or FGFR4 negative cells. 3A11 CART incubated with human primary cells obtained from liver, kidney, heart, and pancreas, did not elicit a cytokine response, indicating a low potential for “on-target off-tumor” toxicity. In vivo testing also found that 3A11 CART eliminated RMS cells in both murine xenograft metastatic and localized subcutaneous models. Therefore we have developed a CART targeting FGFR4 that shows high potency for treating RMS. A phase 1 FGFR4-CART clinical trial is planned for children and adolescent young adults with relapsed/refractory rhabdomyosarcoma. Citation Format: Adam Tai Chi Cheuk, Meijie Tian, Nityashree Shivaprasad, Steven Highfill, David Milewski, G Tom Brown, Peter Azorsa, Dina Schneider, Berkley Gryder, Jun S Wei, Young Kwok Song, Hsien-Chao Chou, Jerry Wu, Joon-Yong Chung, Brian Belyea, Corinne Linardic, Stephen M Hewitt, Boro Dropulic, Rimas Orentas, Javed Khan. Potent antitumor activity of a FGFR4 CAR-T in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB213.

TPS4615 Background: While a standard approach to muscle-invasive bladder cancer (MIBC) management involves neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC), up to 50% of pts recur with metastatic disease. Moreover, removal of the bladder has a significant impact on pts’ quality of life. Pathologic downstaging to non-muscle-invasive disease (5 cm by cystoscopic assessment, and Bacillus Calmette-Guérin (BCG)-refractory disease (beyond standard induction and maintenance) are not allowed. Intravesical chemotherapy is allowed. Pts must be eligible for cisplatin chemotherapy. Eligible pts will receive either standard dose or dose dense gemcitabine and cisplatin chemotherapy (investigator’s choice) with simultaneous genetic sequencing of pre-treatment transurethral resection specimens. Pts whose tumors contain deleterious alterations in any 1 of 9 pre-selected DDR genes ( ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, RAD51C, ATM, ATR, and FANCC) and who exhibit T1 disease after NAC will undergo RC or chemoradiation therapy (investigator/patient choice). The primary endpoint is 3-year event-free survival in DDR-altered pts who undergo bladder sparing, defined as the proportion of pts without BCG-unresponsive non-muscle invasive recurrences, any >T2 recurrences, or any metastatic recurrences. Secondary endpoints include clinical response rate (

PURPOSE/OBJECTIVE(S) Craniospinal irradiation (CSI) is commonly used for pediatric brain tumors with propensity for spread in the CSF, principally medulloblastoma. Evolving technology has led to the use of highly conformal radiotherapy (RT) techniques for CSI, including proton therapy. Target delineation and plan coverage are therefore critical for CSI, but there is ongoing controversy and variability in these realms, with little available data on practice patterns. We sought to characterize proton CSI practice patterns in the US by examining CSI plans in the Pediatric Proton Consortium Registry (PPCR). MATERIALS/METHODS We queried the PPCR for all proton CSI data from 2015-2020. Each plan was manually reviewed for: prescription dose; coverage of optic nerves, vertebral bodies, lateral spinal nerve roots, and sacral nerves; esophageal mean and max doses; and lens max doses. Coverage was assessed at the 95% prescription isodose line. We determined the rate of vertebral body sparing (VBS), as defined by SIOP guidelines, in skeletally immature patients (boys < 16y, girls < 14y). RESULTS PPCR supplied data for 451 patients; 317 had complete RT data (208 males and 109 females). Medulloblastoma was the most common diagnosis (217), followed by germ cell (32). The median age was 8.8y (IQR 5.8 - 12.4). The median CSI dose was 23.4 Gy (range 10.8 - 45 Gy). Most patients were treated prone (95.6%). Optic nerves were covered completely in 152 cases (47.9%). The average max dose to lenses was 79.1% of prescription (22.6 Gy) vs. 38.2% (10.6 Gy) depending on optic coverage (P < 0.01). Four plans (1.3%) failed to cover the lateral spinal nerve roots. Thirty-nine cases (12.3%) did not completely cover sacral nerves. VBs were spared in 87 cases (27.4%), and covered fully in 138 (43.5%). The remaining 92 plans (29.0%) covered the anterior VBs to a lower dose or utilized anterior avoidance (intermediate sparing). Of 277 plans for skeletally immature patients, 52 (18.8%) were VBS. Both VBS and intermediate sparing significantly reduced mean and max esophageal doses compared to full coverage (P < 0.01). VBS rates by institution (n = 13) varied significantly, from 0 to 71.4%. Rates also increased over time (5.8% in 2015-16; 36.8% in 2017-20). CONCLUSION There is significant variability in proton CSI practices nationally, with regard to optic nerve, sacral nerve, and VB coverage. VBS was associated with reduced esophageal doses, and this CSI technique has been correlated in clinical studies to reduced GI and hematologic toxicity. There is growing evidence that VBS may not result in clinically significant growth abnormality, and an ongoing phase II trial is studying this. As evidence evolves, the promulgation of clear guidelines is recommended to optimize and standardize target delineation and planning of CSI.

Purpose/Objectives To compare the dose escalation potential of stereotactic body proton therapy (SBPT) versus stereotactic body photon therapy (SBXT) using high-dose rate prostate brachytherapy (HDR-B) dose-prescription metrics. Patients and Methods Twenty-five patients previously treated with radiation for prostate cancer were identified and stratified by prostate size (≤ 50cc; n = 13, > 50cc; n = 12). Initial CT simulation scans were re-planned using SBXT and SBPT modalities using a prescription dose of 19Gy in 2 fractions. Target coverage goals were designed to mimic the dose distributions of HDR-B and maximized to the upper limit constraint for the rectum and urethra. Dosimetric parameters between SBPT and SBXT were compared using the signed-rank test and again after stratification for prostate size (≤ 50cm3 and >50cm3) using the Wilcoxon rank test. Results Prostate volume receiving 100% of the dose (V100) was significantly greater for SBXT (99%) versus SBPT (96%) (P ≤ 0.01), whereas the median V125 (82% vs. 73%, P < 0.01) and V200 (12% vs. 2%, P < 0.01) was significantly greater for SBPT compared to SBXT. Median V150 was 49% for both cohorts (P = 0.92). V125 and V200 were significantly correlated with prostate size. For prostates > 50cm3, V200 was significantly greater with SBPT compared to SBXT (14.5% vs. 1%, P = 0.005), but not for prostates 50cm3 (9% vs 4%, P = 0.11). Median dose to 2cm3 of the bladder neck was significantly lower with SBPT versus SBXT (9.6 Gy vs. 14 Gy, P < 0.01). Conclusion SBPT and SBXT can be used to simulate an HDR-B boost for locally advanced prostate cancer. SBPT demonstrated greater dose escalation potential than SBXT. These results are relevant for future trial design, particularly in patients with high risk prostate cancer who are not amenable to brachytherapy.

Purpose There is limited information on the use of data visualization tools for health services research applications. We provide a proof-of-concept application that focuses on claims-based measures of palliative radiation therapy. We investigate whether a guided, data-driven investigation contributes information for subsequent statistical analysis and algorithm development. Methods This retrospective cohort study used linked registry and claims data on men who were diagnosed with stage IV M0 or stage IV M1b prostate cancer between 2005 and 2009, with associated claims from 2005 through 2010, and receiving radiation therapy. Preprocessing of data was accomplished by using EventFlow software to investigate longitudinal patterns in claims for radiation therapy in the 13 months after cancer diagnosis. Guided by results from EventFlow, we developed descriptive statistics to investigate the length of radiation therapy, use of bone metastasis coding, and mortality between M1b and M0 patients. Results A total of 1,151 patients met the inclusion criteria. Taking advantage of the novel aggregation capability of EventFlow, we observed differences in the length of radiation therapy and the use of bone metastasis coding between men with (M1b) and without (M0) a diagnosis of bone metastasis. Seventy-nine percent of M1b patients received radiation for a duration ≤ 4 weeks, which suggested palliative radiation (to the bone). Seventy-six percent of M0 patients received radiation for ≥ 6 weeks, which suggested radiation to the prostate. Mortality was higher among those who received a shorter duration of radiation therapy compared with those who received a longer duration of therapy. Conclusion Use of EventFlow, followed by statistical analysis of the linked registry and claims data, identified useful components of a claims-based measure of radiation to the bone.

Purpose of review The overview summarizes recent developments in radiation oncology for high risk and recurrent prostate cancer. Recent findings A number of well known phase III prostate hypofractionated radiation therapy (HFxRT) trials were finally published with long-term follow-ups. These trials demonstrate patterns of equivalent tumor control with several showing worse toxicity rates. The ASCENDE-RT randomized trial demonstrated the superiority of brachytherapy boost in intermediate and high-risk prostate cancer. Important randomized trials show a clear benefit to androgen deprivation therapy (ADT) in both intermediate-risk prostate cancer and postprostatectomy patients with rising PSA. Finally, the first randomized trial of metastasis-directed therapy showed a delay in time to ADT and biochemical failures in oligometastatic prostate cancer. Summary The use of brachytherapy boost in high-risk disease and ADT in locally recurrent cancer after prostatectomy are practice changing given the magnitude of benefit seen in the randomized trials. The benefit of metastasis-directed therapy in oligometastatic prostate cancer must be validated in a larger randomized trial. However, hypofractionated radiation therapy requires further long-term follow-up so that late toxicity risk can be accurately assessed before it becomes a standard of care in prostate cancer.

Purpose/objective(s) Although proton beam therapy (PBT) results in decreased dose to non-target tissue compared to modern photon therapy, there are concerns of rare CNS injury occurring following PBT due in part to RBE/LET uncertainties. Such uncertainties can be further exacerbated when delivering PBT using pencil beam scanning (PBS) technology. The primary objective of this study was to report the incidence of CNS toxicities in a large cohort of adult brain tumor patients treated with PBS at a single academic proton center. We hypothesized that PBS can be safely delivered for treatment of CNS tumors. Materials/methods A single-institution retrospective IRB-approved analysis was conducted of all patients with CNS tumors treated with PBT at our institution between February 2016 and April 2020. Patients were excluded if follow up was less than one month. Kaplan-Meier estimates of treatment toxicities were calculated, accounting for death and local recurrence as competing risks. Multivariate analysis (MVA) was performed using the Cox proportional hazard model to determine risk factors associated with symptomatic toxicity. Results A total of 283 consecutive patients with CNS toxicities (116 [41%] males, 167 [59%] females) completed a course of definitive-intent PBT; 116 patients had meningiomas/pituitary adenomas, 92 patients had gliomas/GBM, and 75 patients had other histologies (chordoma, paraganglioma, ependymoma, medulloblastoma, pineal tumor). Median age was 52 years old (range 18-91). Median dose of PBT was 51.3 Gy (RBE = 1.1, [range 20.4 - 78.8 Gy RBE]). Median dose per fraction was 1.8 Gy/fx (range 1.1-3.8 Gy/fx). Sixty patients [21%] had received some form of prior intracranial RT. Concurrent systemic therapy was delivered in 49 patients [17%]. Median follow-up time was 20 months. The 2-year incidence of symptomatic-treatment toxicity was 8.7%. Symptomatic radiation necrosis occurred in 13 patients including optic neuritis [N = 2], seizure [N = 3], neurologic deficit [N = 9], stroke [N = 1] and brainstem necrosis [N = 2]. Two patients had symptoms with no radiation-related imaging changes including stroke [N = 1] and seizure [N = 1]. MVA identified prior intracranial irradiation (HR 3.901, 95% CI 1.42, 10.73, P = 0.008) and increasing EQD2 of proton radiation (HR 1.077 per Gray, 95% CI 1.00, 1.15, P = 0.036) as predictive factors for increased incidence of adverse events including symptomatic toxicity and asymptomatic radiation necrosis. No PBT treatment planning parameters were found to correlate with toxicity risk. Conclusion This is the largest series to date reporting outcomes for patients with CNS tumors treated with pencil beam scanning PBT. Our analysis indicates that pencil beam scanning PBT in this setting is well-tolerated with a toxicity profile similar to modern photon therapy. Future studies correlating toxicity-risk with LET are warranted. Author disclosure B. Savla: None. G.S. Alexander: None. K. Sun: None. S.M. Bentzen: Travel Expenses; University of Copenhagen. S. Mossahebi: None. Y. Kwok: None. W.F. Regine: None. M.V. Mishra: Employee; Orthofix. Research Grant; ASTRO, Keep Punching. Advisory Board; Patient Centers Outcomes Research Institute (PCORI. Travel Expenses; Patient Centers Outcomes Research Institute (PCORI.

Purpose/Objective(s) Prostatectomy (RP) is a treatment (tx) option even for high-risk prostate cancer (PC) per the NCCN guidelines. We report the long-term follow-up of a pilot clinical trial using an aggressive multimodal approach integrating chemo-hormone tx, prostatectomy (RP) and adjuvant radiation (RT) in men with high/very high-risk PC. Materials/Methods Preoperative tx entailed 6 months (mo) of chemo-hormones consisting of LHRH agonist (6 mo) integrated with adriamycin (A) and docetaxel (T). Two dose levels of A and T were incorporated with LHRH agonist tx: a higher dose (HD) of A (50mg/m2) and T (70mg/m2), and a lower dose (LD) of A (15mg/m2) and T (30mg/m2). HD chemo was given on 2 separate occasions (3 days post LHRH injection) in an effort to take advantage of the expected testosterone surge that occurs 3-5 days post LHRH agonist tx, while LD chemotherapy was given at other time points during the 6-month neoadjuvant period. This was followed by RP. The median post-op RT dose was 70.2 Gy (whole pelvis, with cone downs; range: 64.8-70.2) via 3D-CRT/IMRT. Three patients did not undergo RP after neoadjuvant chemo-hormone tx and went on to receive definitive RT (75.6 Gy). The overall survival (OS), disease-free survival (DFS), freedom from PSA failure (bNED, PSA > 0.2), and late GI/GU toxicity rates were calculated using the Kaplan-Meier method. Results A total of 22 men were enrolled from 2002-2006. Median pre-tx age, PSA and Gleason score were 61 years (range, 43-70), 24.1 ng/ml (range, 1.6-168.3) and 7 (range, 6-10), respectively. A total of 77% of patients received all therapy as planned. Median follow-up for the entire cohort and those alive were 10.9 years (range, 3.4-18.4) and 16.8 years (range, 15-18.4), respectively. The 15-year OS, DFS and bNED rates were 31.2%, 22.7% and 46.2%, respectively. Six patients (27%) never achieved PSA Conclusion Despite an aggressive multimodal regimen that incorporated chemo-hormones, RP and adjuvant RT for high/very high-risk prostate cancer, the 15-year bNED rate was only 46.5%. Therefore, the role of RP and neoadjuvant chemo-hormone therapy remains questionable among high-risk patients in light of superior long-term outcomes demonstrated in trials like ASCENDE-RT that incorporated brachytherapy boost with RT and androgen deprivation.

PURPOSE/OBJECTIVE(S) Daily anesthesia is commonly used for pediatric patients undergoing radiation therapy. However, general anesthesia increases the short- and long-term risks of treatment, is emotionally difficult for patients and families, and requires greater personnel and facility resources. Strategies for mitigating use of anesthesia is of increasing interest. Prior reports of anesthesia use rates are from single institutions, the largest involving 779 patients. In this study, we used a large multi-institution cohort to characterize anesthesia use in pediatric patients undergoing proton therapy. MATERIALS/METHODS We reviewed prospectively-collected data on pediatric patients treated with proton therapy for whom anesthesia data is available in the Pediatric Proton/Photon Consortium Registry (PPCR). We calculated frequency of anesthesia use by age, grouping patients ≤3 years old, ≥11 years old, and by single years in age between. We then assessed the 6-7-year-old population for characteristics associated with increased risk of anesthesia use. These patients are on the threshold of being able to undergo treatment without anesthesia, and therefore the use of anesthesia reflects more nuanced decisions. We evaluated for association between anesthesia use and gender, primary disease site (CNS vs non-CNS), craniospinal irradiation (CSI), treatment era, race/ethnicity, and English vs non-English speaking. RESULTS A total of 3103 pediatric patients (age range 0 - 21 years old) treated at 17 proton therapy centers in the United States from 2001 - 2021 were included in the current study. Receipt of any anesthesia for a radiation therapy course decreased with age, ranging from 96.6% in ages 0-3 years old to 3.4% in ages ≥11 years old. Within the 6-7-year-old population, 53.1% of patients with a CNS primary received anesthesia vs 37.6% of patients with a non-CNS primary site, (P = 0.01). The difference was more pronounced for CSI, with 74.1% of CSI patients receiving anesthesia vs. 35.9% of non-CSI patients receiving anesthesia, (P < 0.001). Rates of anesthesia use were nearly identical in patients treated before 2016 vs. 2016 and after, (36.9% vs 37.7% for whole cohort, 49.0% vs 48.4% in 6-7 years old). Thirty-five and a half percent of African-American patients received anesthesia, compared with 43.3% of Hispanic patients and 51.3% in all other racial/ethnic groups. However, this difference did not hold when controlling for CNS disease or treatment with CSI. CONCLUSION In this cohort of over 3000 patients, age and receipt of CSI were the most important predictors of anesthesia use with proton therapy. There is no significant difference among different race/ethnicity, or non-English speaking patients when controlling for receipt of CSI.

// Matthias Holdhoff 1 , Gregory J. Cairncross 2 , Thomas M. Kollmeyer 3 , Ming Zhang 1 , Peixin Zhang 4 , Minesh P. Mehta 5 , Maria Werner-Wasik 6 , Luis Souhami 7 , Jean-Paul Bahary 8 , Young Kwok 5 , Alan C. Hartford 9 , Arnab Chakravarti 10 , Srinivasan Yegnasubramanian 1 , Bert Vogelstein 1 , Nickolas Papadopoulos 1 , Kenneth Kinzler 1 , Robert B. Jenkins 3 and Chetan Bettegowda 1 1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 2 Charbonneau Cancer Institute at the University of Calgary, Calgary, AB, USA 3 Mayo Clinic, Rochester, MN, USA 4 NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA 5 University of Maryland Medical Center, Baltimore, MD, USA 6 Thomas Jefferson University Hospital, Philadelphia, PA, USA 7 McGill University Health Centre, Montreal, QC, Canada 8 Centre Hospitalier de l’Universite de Montreal, Montreal University, Montreal, QC, Canada 9 Darthmouth-Hitchcock Medical Center, Lebanon, NH, USA 10 The Ohio State University, Columbus, OH, USA Correspondence to: Matthias Holdhoff, email: // Chetan Bettegowda, email: // Keywords : oligodendroglioma, chemotherapy, survival, genomics, co-deletion 1p/19q Received : October 01, 2016 Accepted : March 21, 2017 Published : March 31, 2017 Abstract Background: The NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not. Methods: We performed whole exome sequencing on matched tumor and normal DNA from all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. hTERT status and rs55705857 genotypes (G-allele) were analyzed in both cohorts. Results: Six STS (survival of

Objective: The Pediatric Proton/Photon Consortium Registry (PPCR) is a comprehensive data registry composed of pediatric patients treated with radiation. It was established to expedite outcomes-based research. The attributes which allow the PPCR to be a successful collaboration are reviewed. Methods and materials: Current eligibility criteria are radiotherapy patients < 22 years treated at one of the 15 US participating institutions. Detailed health and treatment data are collected about the disease presentation and treatment exposures, and annually thereafter, in REDCap (Research Electronic Data Capture). DICOM (Digital Imaging and Communications in Medicine) imaging and radiation plans are collected through MIM/MIMcloud. An optional patient-reported quality-of-life (PedsQL) study is administered at 10 sites. Results: Accrual started October 2012 with 2,775 participants enrolled as of 25 July 2019. Most patients, 62.0%, were treated for central nervous system (CNS) tumors, the most common of which are medulloblastoma (n = 349), ependymoma (n = 309), and glial/astrocytoma tumors (n = 279). The most common non-CNS diagnoses are rhabdomyosarcoma (n = 284), Ewing’s sarcoma (n = 153), and neuroblastoma (n = 130). While the majority of participants are US residents, 18.7% come from 36 other countries. Over 685 patients participate in the PedsQL study. Conclusions: The PPCR is a valuable research platform capable of answering countless research questions that will ultimately improve patient care. Centers outside of the USA are invited to participate directly or may engage with the PPCR to align data collection strategies to facilitate large-scale international research. Advances in knowledge: For investigators looking to carry out research in a large pediatric oncology cohort or interested in registry work, this paper provides an updated overview of the PPCR.

TPS4593 Background: Bone metastases are prevalent in approximately 30% of pts with advanced RCC. Pts with bone metastases have a worse prognosis compared to pts without bone metastases and are at risk of symptomatic skeletal events (SSEs). Cabozantinib, a multitargeted inhibitor of multiple kinases, including vascular endothelial growth factor (VEGF) receptor and MET, has improved survival in pts with metastatic RCC and has enhanced activity in bone. Ra-223, an alpha-emitting radioisotope with natural bone-seeking proclivity, has been shown to prolong survival in men with castration-resistant prostate cancer. We previously conducted a pilot study of Ra-223 with VEGF inhibition and demonstrated safety and declines in markers of bone formation and resorption with the combination (McKay et al, CCR 2018). Given that decreasing rates of SSEs and improving outcomes for pts with RCC with bone metastases are unmet needs in pts with RCC, we designed a randomized phase 2 study through the National Clinical Trials Network (NCTN) investigating cabozantinib with or without Ra-223 in patients with RCC with bone metastases. Methods: This is an open-label multicenter study. Eligible pts have metastatic RCC of any histology with ≥2 metastatic bone lesions untreated with prior radiation therapy and no more than 2 prior lines of systemic therapy. Pts with non-clear cell RCC are eligible and will be capped at 20% of the total accrual goal. Pts must have a Karnofsky performance status of ≥60%, have symptomatic bone pain defined as a prior SSE or need of analgesics, and be on osteoclast-targeted therapy unless otherwise contraindicated. Pts are randomized 1:1 to cabozantinib with (Arm A) or without (Arm B) Ra-223. Starting dose of cabozantinib for Arm A is 40 mg by mouth daily to be escalated to 60 mg daily after cycle 1 (1 cycle = 28 days) if no persistent grade 2 or grade ≥3 toxicity. Ra-223 is administered at a fixed dose of 1.49 microcurie/kg IV every 28 days x 6 doses. The primary endpoint is SSE-free survival. Secondary endpoints include safety, progression-free survival, overall survival, quality of life measures, and correlative analyses including liquid biopsy studies and tumor tissue analysis. The study has 90% power to detect an improvement in 6-month SSE-free survival rate from 65% to 78% with one-sided α = 0.025 significance. To ensure 191 evaluable patients, target accrual is 210 pts. This design includes a safety run-in and an interim analysis for futility when 50% of the expected number of events (72 SSE events) have been observed. Final data analysis will occur when 143 events have been observed. The study was activated in December 2019 and accrual is currently ongoing throughout the NCTN. Clinical trial information: NCT04071223.

Purpose Patients with locally recurrent prostate cancer after definitive prostate brachytherapy have few evidence-based salvage options. We evaluate the efficacy and treatment-related side-effects of salvage external-beam radiotherapy (EBRT) after definitive prostate brachytherapy (PBT). Methods and Materials Eleven patients previously treated with definitive PBT and with biopsy-proven local-only recurrence received salvage reirradiation with EBRT. Genitourinary (GU) function was assessed with International Prostate Symptom Scores. Treatment-related toxicities were graded using CTCAE v 4.03. Results Median follow-up was 26.5 months (range, 1–53.6 months); median age at EBRT salvage was 67 years (range, 61–81 years). Salvage EBRT included the whole pelvis in 8 patients. Two patients were treated with 3D-CRT; 9 underwent IMRT. Five patients (45%) received androgen deprivation therapy concurrent with salvage EBRT as part of long- or short-course hormone therapy. The median prostate dose was 70.2 Gy (range, 64.8–75.6 Gy). Actuarial 3-year overall and biochemical failure–free survival were 77% and 69%, respectively. Five patients (45%) had worsening GU symptoms, and 9 (82%) experienced a decline in erectile function. One patient experienced acute grade 2 GU toxicity. Four patients (36%) experienced late grade ≥2 GI/GU toxicities, including 2 who experienced grade 3 toxicities (rectourethral fistula/incontinence, bladder outlet obstruction). No grade 4/5 toxicities were noted. Conclusions Our data suggest that salvage EBRT can provide similar disease control and treatment-related toxicity to more established salvage therapies. This approach warrants further investigation on a larger scale.

Angiogenesis, a hallmark of glioblastoma, can potentially be targeted by inhibiting the VEGF pathway using bevacizumab, a humanized monoclonal antibody against VEGF-A. This study was designed to determine the efficacy and safety of these regimens in the cooperative group setting. Eligibility included age ≥18, recurrent or progressive GBM after standard chemoradiation. Treatment was intravenous bevacizumab 10 mg/kg and either irinotecan (CPT) 125 mg/m2 every 2 weeks or temozolomide (TMZ) 75–100 mg/m2 day 1–21 of 28 day cycle. Accrual goal was 57 eligible patients per arm. Primary endpoint was 6 month progression-free survival (6-m PFS); a predetermined rate of ≥35 % to declare efficacy. 60 eligible patients were enrolled on TMZ arm and 57 patients on CPT arm. Median age was 56, median KPS was 80. For TMZ arm, the 6-m-PFS rate was 39 % (23/59); for the CPT arm, the 6-m-PFS rate was 38.6 % (22/57). Objective responses: TMZ arm had 2 (3 %) CR, 9 (16 %) PR; CPT arm had 2 (4 %) CR, 13 (24 %) PR. Overall there was moderate toxicity: TMZ arm with 33 (55 %) grade 3, 11 (18 %) grade 4, and 1 (2 %) grade 5 (fatal) toxicities; CPT arm had 22 (39 %) grade 3, 7 (12 %) grade 4, and 3 (5 %) grade 5 toxicities. The 6-m-PFS surpassed the predetermined efficacy threshold for both arms, corroborating the efficacy of bevacizumab and CPT and confirming activity for bevacizumab and protracted TMZ for recurrent/progressive GBM, even after prior temozolomide exposure. Toxicities were within anticipated frequencies with a moderately high rate of venous thrombosis, moderate hypertension and one intracranial hemorrhage.

2518 Background: This study sought to evaluate the prognostic significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/non-codel, and IDHmt/codel) in NRG Oncology/RTOG 0424, a phase II trial of high-risk low-grade gliomas treated with radiation (RT) and concurrent and adjuvant temozolomide (TMZ) after biopsy/surgical resection. Notably, this is the first clinical study to evaluate the prognostic value of the WHO subgroups in RT + TMZ-treated high-risk grade II (G2) gliomas using prospectively-collected long-term survival data. Methods: IDH1/2 mutation status was determined by next-generation sequencing. 1p/19q co-deletion status was determined by Oncoscan and/or 450K methylation data. Overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a post-hoc analysis. Patient pre-treatment characteristics were included as covariates in multivariate analyses. Results: Of all the eligible patients (N=129), 80 (62%) had sufficient quality DNA for both IDH and 1p/19q analyses. Of these 80, 54 (67.5%) were IDHmt, and 26 (32.5%) were IDHwt. Of the 54 IDHmt patients, 26 (32.5% of total, 48% of IDHmt) were IDHmt/codel, and 28 (35% of total, 52% of IDHmt) were IDHmt/non-codel. Both IDHmt subgroups were significantly correlated with longer PFS ( IDHmt/co-del = 8.1yrs (5.2-not reached (NR)); IDHmt/non-codel = 7.5yrs (3.9-11.8); IDHwt = 1.0yr (0.6-1.7), p

BACKGROUND: Children with brain tumors can experience symptom burden throughout their disease continuum. The aim of the study was to evaluate symptom burden reported by children with brain tumors and factors that potentially were associated with their symptoms. METHODS: Data from 199 children with brain tumors aged 7–22 (mean age=14 years; 52% males; 76% white) were analyzed. Symptom burden was assessed using Patient Reported Outcomes Measurement Information System (PROMIS) via computerized adaptive testing (CAT) – Anxiety, Depression, Fatigue, Mobility, Upper Extremity Function, Peer Relationship, and Cognition. Patients and parents completed Symptom Distress Scales (SDS). Test-statistics and ANOVA were used to evaluate relationships between PROMIS measures and potentially influential variables. RESULTS: Significant results (p1 yr). Fatigue and Cognition were associated with educational program (regular classroom without an individualized education plan versus those that had an individualized education plan); Mobility and Upper Extremity Function were associated with time since last radiation. Mobility, Upper Extremity Function and Anxiety were associated with time since last chemotherapy. CONCLUSIONS: Significant associations were found between PROMIS and SDS as well as clinical and demographic characteristics. Brief-yet-precise PROMIS CATs can be used to systematically assess symptom burden experienced by children with brain tumors.

To compare the performance of five prognostic models [RTOG recursive partitioning analysis (RPA), Score Index for Radiosurgery in Brain Metastases (SIR), Barnholtz-Sloan–Kattan nomogram (BSKN), diagnosis-specific Graded Prognostic Assessment (dsGPA), and Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA)] against actual survival in patients with brain metastases treated with SRS +/− WBRT. 100 consecutive patients treated with SRS +/− WBRT between January 2006 and July 2012 were retrospectively analyzed. Patients were binned according to 33 percentiles of the predicted survival distribution for the BSKN and dsGPA models to compare with LungmolGPA, RPA and SIR. Pearson’s correlation coefficients between predicted and observed survival were estimated to quantify the proportion of variance in observed survival. Median survival for the entire cohort was 13.5 months, with predicted vs actual MS by BSKN, SIR, dsGPA, RPA, adenocarcinoma Lung-molGPA, and nonadenocarcinoma Lung-molGPA was 3.8 vs 15.6 months, 7 vs 13.5 months, 9.4 vs 13.5 months, 10.3 vs 13.5 months, 13.7 vs 13.7 months, and 9.8 vs 9.7 months, respectively. The BSKN model and adenocarcinoma LungmolGPA created three groups with a statistically significantly different MS (p = 0.002 and p = 0.01, respectively). All models under-predicted MS and only the BSKN and Lung-molGPA model stratified patients into three risk groups with statistically significant actual MS. The prognostic groupings of the adenocarcinoma Lung-molGPA group was the best predictor of MS, and showed that we are making improvements in our prognostic ability by utilizing molecular information that is much more widely available in the current treatment era.

Background/objectives The Pediatric Proton Consortium Registry (PPCR) was established to expedite proton outcomes research in the pediatric population requiring radiotherapy. Here, we introduce the PPCR as a resource to the oncology community and provide an overview of the data available for further study and collaboration. Design/methods A multi-institutional registry of integrated clinical, dosimetric, radiographic, and patient-reported data for patients undergoing proton radiation therapy was conceived in May 2010. Massachusetts General Hospital began enrollment in July of 2012. Subsequently, 12 other institutions joined the PPCR and activated patient accrual, with the latest joining in 2017. An optional patient-reported quality of life (QoL) survey is currently implemented at six institutions. Baseline health status, symptoms, medications, neurocognitive status, audiogram findings, and neuroendocrine testing are collected. Treatment details of surgery, chemotherapy, and radiation therapy are documented and radiation plans are archived. Follow-up is collected annually. Data were analyzed 25 September, 2017. Results A total of 1,854 patients have consented and enrolled in the PPCR from October 2012 until September 2017. The cohort is 55% male, 70% Caucasian, and comprised of 79% United States residents. Central nervous system (CNS) tumors comprise 61% of the cohort. The most common CNS histologies are as follows: medulloblastoma (n = 276), ependymoma (n = 214), glioma/astrocytoma (n = 195), craniopharyngioma (n = 153), and germ cell tumors (n = 108). The most common non-CNS tumors diagnoses are as follows: rhabdomyosarcoma (n = 191), Ewing sarcoma (n = 105), Hodgkin lymphoma (n = 66), and neuroblastoma (n = 55). The median follow-up is 1.5 years with a range of 0.14 to 4.6 years. Conclusion A large prospective population of children irradiated with proton therapy has reached a critical milestone to facilitate long-awaited clinical outcomes research in the modern era. This is an important resource for investigators both in the consortium and for those who wish to access the data for academic research pursuits.

Background Functional magnetic resonance imaging (fMRI) presents the ability to selectively protect functionally significant regions of the brain when primary brain tumors are treated with radiation therapy. Previous research has focused on task-based fMRI of language and sensory networks; however, there has been limited investigation on the inclusion of resting-state fMRI into the design of radiation treatment plans. Methods and materials In this pilot study of 9 patients with primary brain tumors, functional data from the default mode network (DMN), a network supporting cognitive functioning, was obtained from resting-state fMRI and retrospectively incorporated into the design of radiation treatment plans. We compared the dosimetry of these fMRI DMN avoidance treatment plans with standard of care treatment plans to demonstrate feasibility. In addition, we used normal tissue complication probability models to estimate the relative benefit of fMRI DMN avoidance treatment plans over standard of care treatment plans in potentially reducing memory loss, a surrogate for cognitive function. Results On average, we achieved 20% (P = 0.002) and 12% (P = 0.002) reductions in the mean and maximum doses, respectively, to the DMN without compromising the dose coverage to the planning tumor volume or the dose-volume constraints to organs at risk. Normal tissue complication probability models revealed that when the fMRI DMN was considered during radiation treatment planning, the probability of developing memory loss was lowered by more than 20%. Conclusion In this pilot study, we demonstrated the feasibility of including rs-MRI data into the design of radiation treatment plans to spare cognitively relevant brain regions during radiation therapy. These results lay the groundwork for future clinical trials that incorporate such treatment planning methods to investigate the long-term behavioral impact of this reduction in dose to the cognitive areas and their neural networks that support cognitive performance.

A volumetric analysis of pre- and post-radiosurgery (PreSRS and PostSRS) edema in patients with cerebral metastases was performed to determine factors of a predictive model assessing the risk of developing increased edema relatively early after SRS. One-hundred-fourteen metastases in 55 patients were analyzed. Selection for this analysis required an MRI ≤ 30 days before SRS and an MRI ≤ 100 days after SRS. Tumor volumes were calculated on PreSRS, SRS, and PostSRS T1-weighted postgadolinium images while edema volumes were calculating using PreSRS and PostSRS fluid-attenuated inversion recovery MR images. An increase in edema was defined as an increase in measurable edema of at least 5%. We developed and evaluated a model predicting the relative risk (RR) of increased edema after SRS. Peritumoral edema increased in 18% (21/114) of the analyzed lesions. Melanoma/renal histology, recursive partitioning analysis class III, and prior WBRT carried RRs of developing postSRS edema increase of 2.45, 2.48, and 3.16, respectively (all P values

The objective of this study was to estimate the risk of a cardiovascular event or death associated with modern radiation in a population of elderly female breast cancer patients with varying baseline cardiovascular risk. The data used for this analysis are from the linked Surveillance, Epidemiology, and End-Results (SEER)-Medicare database. The retrospective cohort study included women aged 66 years and older with stage 0-III breast cancer diagnosed between 2000 and 2005. Women were grouped as low, intermediate, or high cardiovascular risk based on the presence of certain clinical diagnoses. The risk for the combined outcome of a hospitalization for a cardiovascular event or death within 6 months and 24 months of diagnosis was estimated using a multivariable Cox model. The median follow-up time was 24 months. Among the 91,612 women with American Joint Committee on Cancer (AJCC) stage 0-III breast cancer: 39,555 (43.2%) were treated with radiation therapy and 52,057 (56.8%) were not. The receipt of radiation therapy in the first 6 months was associated with a statistically significant increased risk for the combined outcome in women categorized as high risk (HR = 1.510; 95% CI, 1.396-1.634) or intermediate risk (HR = 1.415; 95% CI, 1.188-1.686) but not low risk (HR = 1.027; 95% CI, 0.798-1.321). Women with a prior medical history of cardiovascular disease treated with radiation therapy are at increased risk for an event and should be monitored for at least 6 months following treatment with radiation therapy.

Object The object of this study was to assess outcomes in patients with arteriovenous malformations (AVMs) treated by Gamma Knife stereotactic radiosurgery (SRS); lesions were stratified by size, symptomatology, and Spetzler-Martin (S-M) grade. Methods The authors performed a retrospective analysis of 102 patients treated for an AVM with single-dose or staged-dose SRS between 1993 and 2004. Lesions were grouped by S-M grade, as hemorrhagic or nonhemorrhagic, and as small (< 3 cm) or large (≥ 3 cm). Outcomes included death, morbidity (new neurological deficit, new-onset seizure, or hemorrhage/rehemorrhage), nidus obliteration, and Karnofsky Performance Scale score. Results The mean follow-up was 8.5 years (range 5–16 years). Overall nidus obliteration (achieved in 75% of patients) and morbidity (19%) correlated with lesion size and S-M grade. For S-M Grade I–III AVMs, nonhemorrhagic and hemorrhagic combined, treatment yielded obliteration rates of 100%, 89%, and 86%, respectively; high functional status (Karnofsky Performance Scale Score ≥ 80); and 1% mortality. For S-M Grade IV and V AVMs, outcomes were less favorable, with obliteration rates of 54% and 0%, respectively. The AVMs that were not obliterated had a mean reduction in nidus volume of 69% (range 35%–96%). On long-term follow-up, 10% of patients experienced hemorrhage/rehemorrhage (6% mortality rate), which correlated with lesion size and S-M grade; the mean interval to hemorrhage was 81 months. Conclusions For patients with S-M Grade I–III AVMs, SRS offers outcomes that are favorable and that, except for the timing of obliteration, appear to be comparable to surgical outcomes reported for the same S-M grades. Staged-dose SRS results in lesion obliteration in half of patients with S-M Grade IV lesions.

Summary Marizomib, a natural marine product, is an irreversible proteasome inhibitor currently under investigation in relapsed-refractory multiple myeloma (RRMM) and malignant glioma. Central nervous system-multiple myeloma (CNS-MM) is a rare manifestation of extra-medullary disease with few therapeutic options, highlighting the unmet clinical need in these patients. Marizomib demonstrated encouraging activity in RRMM and has emerging clinical activity in glioma, making it a potential CNS-MM therapeutic intervention. Herein, we present two patients with RRMM and CNS involvement who benefited from marizomib-based therapy. These cases provide the first proof of principle for further exploring marizomib in CNS-MM patients.

Purpose Weekly paclitaxel, concurrent radiation, and androgen deprivation (ADT) were evaluated in patients with high-risk prostate cancer (PC) with or without prior prostatectomy (RP). Methods and Materials Eligible post-RP patients included: pathological T3 disease, or rising prostate-specific antigen (PSA) ≥0.5 ng/mL post-RP. Eligible locally advanced PC (LAPC) patients included: 1) cT2b-4N0N+, M0; 2) Gleason score (GS) 8–10; 3) GS 7 + PSA 10–20 ng/mL; or 4) PSA 20–150 ng/mL. Treatment included ADT (4 or 24 months), weekly paclitaxel (40, 50, or 60 mg/m 2 /wk), and pelvic radiation therapy (total dose: RP=64.8 Gy; LAPC=70.2 Gy). Results Fifty-nine patients were enrolled (LAPC, n = 29; RP, n = 30; ADT 4 months, n = 29; 24 months, n = 30; whites n = 29, African Americans [AA], n = 28). Baseline characteristics (median [range]) were: age 67 (45–86 years), PSA 5.9 (0.1–92.1 ng/mL), GS 8 (6–9). At escalating doses of paclitaxel, 99%, 98%, and 95% of doses were given with radiation and ADT, respectively, with dose modifications required primarily in RP patients. No acute Grade 4 toxicities occurred. Grade 3 toxicities were diarrhea 15%, urinary urgency/incontinence 10%, tenesmus 5%, and leukopenia 3%. Median follow-up was 75.3 months (95% CI: 66.8–82.3). Biochemical progression occurred in 24 (41%) patients and clinical progression in 11 (19%) patients. The 5- and 7-year OS rates were 83% and 67%. There were no differences in OS between RP and LAPC, 4- and 24-month ADT, white and AA patient categories. Conclusions In addition to LAPC, to our knowledge, this is the first study to evaluate concurrent chemoradiation with ADT in high-risk RP patients. With a median follow-up of 75.3 months, this trial also represents the longest follow-up of patients treated with taxane-based chemotherapy with EBRT in high-risk prostate cancer. Concurrent ADT, radiation, and weekly paclitaxel at 40 mg/m 2 /week in RP patients and 60 mg/m 2 /week in LAPC patients is feasible and well-tolerated.

Whole brain radiation therapy (WBRT) is one of the most effective modalities for treatment of brain metastases. With increasing cancer control there is growing concern regarding the long-term effects of treatment. These effects are seen as white matter change (WMC) on brain MRI. Severity of WMC is implicated in cognitive and functional decline in many patient groups. Our objective was to identify clinical factors associated with greater accumulation of WMC following WBRT. Through retrospective review of serial MRIs obtained from 30 patients surviving greater than 1 year after WBRT, treated at a single institution between 2002 and 2007, we calculated volumetric WMC over time using segmentation software. Changes related to tumor, secondary effects, surgery or radiosurgery were excluded. Factors that influenced the rate of WMC accumulation were identified through multivariate analysis. Following WBRT, patients accumulated WMC at an average rate of 0.07% of total brain volume per month. In multivariate analyses, greater rates of accumulation were independently associated with older age (β = 0.004, p < .0001), poor levels of glycemic control (β = 0.048, p < .0001) and hypertension diagnosis (β = 0.084, p < .0001). Long-term survivors of cancer allow assessment of late effects of treatment modalities. Radiation injury appears to be related to a steady rate of white matter damage over time, as indicated by progressive accumulation of WMC. Our results suggest that rate of WMC accumulation is enhanced by parameters such as hyperglycemia and hypertension. This has significant clinical impact by clearly identifying hyperglycemia, steroid-induced hyperglycemia, and other vascular risk factors as targets for intervention to decrease WMC in patients receiving WBRT.

PURPOSE OF REVIEW This overview summarizes recent developments in radiation-based therapy for prostate cancer. RECENT FINDINGS Radiation dose escalation continues to be validated as an effective strategy in prostate cancer. Adjuvant radiation therapy became the standard of care after long-term follow-up of the pivotal Southwest Oncology Group 8794 trial demonstrated an overall survival benefit in patients with pT3 disease or positive margin after prostatectomy. Strategies such as hypofractionation and stereotactic body radiation therapy are becoming more common but have yet to be validated in a large trial. New technologies such as Calypso 4D real-time tumor tracking and volumetric-modulated arc therapy promise to potentially increase cure rates and decrease toxicity due to increased accuracy of radiation delivery. SUMMARY Radiation therapy continues to play a prominent role in the management of prostate cancer. However, new strategies and technologies such as hypofractionation, stereotactic body radiation therapy, volumetric-modulated arc therapy, and Calypso tumor tracking must be prospectively validated.

Brain metastasis occurs in approximately 25% of all cancer patients. Magnetic resonance imaging is considered the standard of care diagnostic modality. Prognosis is linked to the recursive partitioning analysis class and Grade Prognostic Assessment as determined by performance status, age, histology, control of primary, and sites of metastatic disease, among other factors. Corticosteroids and anticonvulsants are commonly used for symptom management. Whole brain radiotherapy (WBRT) is the current standard of care for patients with five or more brain metastasis, with the most common schedule being a total dose of 30 Gy in 10 fractions. Surgical resection may immediately relieve significant mass effect, and the utility of surgical resection in single brain metastasis has been tested in three phase III trials—two of which demonstrated an overall survival benefit to surgery plus WBRT versus WBRT alone. Stereotactic radiosurgery (SRS), although not directly compared to surgical resection in a randomized trial, has been proven to result in excellent local control rates of 80–90% when used in conjunction with WBRT. The use of WBRT combined with surgical resection or SRS continues to remain controversial. There have now been six randomized studies that have evaluated the effectiveness of WBRT in conjunction with local therapy. Five of the six trials demonstrated equivalent overall survivals and all of the trials demonstrated superior brain controls with WBRT. Controversy arises from the implication of WBRT on neurocognition. Two trials demonstrate superior outcomes with WBRT (Patchell et al., 1990; Aoyama et al., 2006, 2007) and two trials that demonstrate its negative impact (Chang et al., 2009; Brown, 2015) on neurocognition. The choice of WBRT alone, SRS or surgical resection alone, or the combination of local and whole brain therapies must be individualized based on a patient’s overall prognosis, symptom burden, expectations, and willingness to incur possible side effects for enhanced disease control.

Purpose: To assess efficacy and quality of life (QOL) outcomes associated with gamma-knife radiosurgery (GK-RS) in treating atypical trigeminal neuralgia (ATN) compared with classic trigeminal neuralgia (CTN). Methods and Materials: Between September 1996 and September 2004, 35 cases of ATN were treated with GK-RS. Patients were categorized into two groups: Group I comprised patients presenting with ATN (57%); Group II consisted of patients presenting with CTN then progressing to ATN (43%). Median prescription dose 75 Gy (range, 70–80 Gy) was delivered to trigeminal nerve root entry zone. Treatment efficacy and QOL improvements were assessed with a standardized questionnaire. Results: With median follow-up of 29 months (range, 3–74 months), 72% reported excellent/good outcomes, with mean time to relief of 5.8 weeks (range, 0–24 weeks) and mean duration of relief of 62 weeks (range, 1–163 weeks). This rate of pain relief is similar to rate achieved in our previously reported experience treating CTN with GK-RS ( p = 0.36). There was a trend toward longer time to relief ( p = 0.059), and shorter duration of relief ( p = 0.067) in patients with ATN. There was no difference in rate of, time to, or duration of pain relief between Groups I and II. Of the patients with ATN, 88% discontinued or decreased the use of pain medications. Among the patients with sustained pain relief, QOL improved an average of 85%. Conclusion: This is the largest reported GK-RS experience for the treatment of ATN. Patients with ATN can achieve rates of pain relief similar to those in patients with CTN. Further follow-up is necessary to assess adequately the durability of response.

Background Skeletal related events (SREs) are common in men with metastatic prostate cancer (mPC). Various methods have been used to identify SREs from claims data. The objective of this study was to provide a framework for measuring SREs from claims and compare SRE prevalence and cumulative incidence estimates based on alternative approaches in men with mPC. Methods Several claims-based approaches for identifying SREs were developed and applied to data for men aged [greater than or equal to] 66 years newly diagnosed with mPC between 2000 and 2009 in the SEER-Medicare datasets and followed through 2010 or until censoring. Post-diagnosis SREs were identified using claims that indicated spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (BS), or radiation (suggestive of bone palliative radiation, RAD). To measure SRE prevalence, two SRE definitions were created: ‘base case’ (most commonly used in the literature) and ‘alternative’ in which different claims were used to identify each type of SRE. To measure cumulative incidence, we used the ‘base case’ definition and applied three periods in which claims were clustered to episodes: 14-, 21-, and 28-day windows. Results Among 8997 mPC patients, 46 % experienced an SRE according to the ‘base case’ definition and 43 % patients experienced an SRE according to the ‘alternative’ definition. Varying the code definition from ‘base case’ to ‘alternative’ resulted in an 8 % increase in the overall SRE prevalence. Using the 21-day window, a total of 12,930 SRE episodes were observed during follow up. Varying the window length from 21 to 28 days resulted in an 8 % decrease in SRE cumulative incidence (RAD: 10 %, PF: 8 %, SCC: 6 %, BS: 0.2 %). Conclusions SRE prevalence was affected by the codes used, with PF being most impacted. The overall SRE cumulative incidence was affected by the window length used, with RAD being most affected. These results underscore the importance of the baseline definitions used to study claims data when attempting to understand relevant clinical events such as SREs in the real world setting.

BACKGROUND With advances in the understanding of histopathology on outcome, accurate meningioma grading becomes critical and drives treatment selection. The 2000 and 2007 WHO schema greatly increased the proportion of grade II meningiomas. Although associations with progression-free survival (PFS) and overall survival (OS) have been independently validated, interobserver concordance has not been formally assessed. METHODS Once mature, NRG Oncology RTOG-0539 will report PFS and OS in variably treated low-, intermediate-, and high-risk cohorts. We address concordance of histopathologic assessment between enrolling institutions and central review, performed by a single pathologist (AP), who is also involved in developing current WHO criteria. RESULTS The trial included 170 evaluable patients, 2 of whom had 2 eligible pathology reviews from different surgeries, resulting in 172 cases for analysis. Upon central review, 76 cases were categorized as WHO grade I, 71 as grade II, and 25 as grade III. Concordance for tumor grade was 87.2%. Among patients with WHO grades I, II, and III meningioma, respective concordance rates were 93.0%, 87.8%, and 93.6% (P values < .0001). Moderate to substantial agreement was encountered for individual grading criteria and were highest for brain invasion, ≥20 mitoses/10 high-powered field [HPF], and spontaneous necrosis, and lowest for small cells, sheeting, and ≥4 mitoses/10 HPF. In comparison, published concordance for gliomas in clinical trials have ranged from 8%-74%. CONCLUSION Our data suggest that current meningioma classification and grading are at least as objective and reproducible as for gliomas. Nevertheless, reproducibility remains suboptimal. Further improvements may be anticipated with education and clarification of subjective criteria, although development of biomarkers may be the most promising strategy.

Respiration-induced tumor motion is known to cause artifacts on free-breathing spiral CT images used in treatment planning. This leads to inaccurate delineation of target volumes on planning CT images. Flow-volume spirometry has been used previously for breath-holds during CT scans and radiation treatments using the active breathing control (ABC) system. We have developed a prototype by extending the flow-volume spirometer device to obtain gated CT scans using a PQ 5000 single-slice CT scanner. To test our prototype, we designed motion phantoms to compare image quality obtained with and without gated CT scan acquisition. Spiral and axial (nongated and gated) CT scans were obtained of phantoms with motion periods of 3-5 s and amplitudes of 0.5-2 cm. Errors observed in the volume estimate of these structures were as much as 30% with moving phantoms during CT simulation. Application of motion-gated CT with active breathing control reduced these errors to within 5%. Motion-gated CT was then implemented in patients and the results are presented for two clinical cases: lung and abdomen. In each case, gated scans were acquired at end-inhalation, end-exhalation in addition to a conventional free-breathing (nongated) scan. The gated CT scans revealed reduced artifacts compared with the conventional free-breathing scan.more » Differences of up to 20% in the volume of the structures were observed between gated and free-breathing scans. A comparison of the overlap of structures between the gated and free-breathing scans revealed misalignment of the structures. These results demonstrate the ability of flow-volume spirometry to reduce errors in target volumes via gating during CT imaging.« less

We developed an integrated GRID boost technique for Gamma Knife radiosurgery. The technique generates an array of high dose spots within the target volume via a grid of 4-mm shots. These high dose areas were placed over a conventional Gamma Knife plan where a peripheral dose covers the full target volume. The beam weights of the 4-mm shots were optimized iteratively to maximize the integral dose inside the target volume. To investigate the target volume coverage and the dose to the adjacent normal brain tissue for the technique, we compared the GRID boosted treatment plans with conventional Gamma Knife treatment plans using physical and biological indices such as dose-volume histogram (DVH), DVH-derived indices, equivalent uniform dose (EUD), tumor control probabilities (TCP), and normal tissue complication probabilities (NTCP). We found significant increase in the target volume indices such as mean dose (5%-34%; average 14%), TCP (4%-45%; average 21%), and EUD (2%-22%; average 11%) for the GRID boost technique. No significant change in the peripheral dose coverage for the target volume was found per RTOG protocol. In addition, the EUD and the NTCP for the normal brain adjacent to the target (i.e., the near region) were decreased for the GRID boost technique. In conclusion, we demonstrated a new technique for Gamma Knife radiosurgery that can escalate the dose to the target while sparing the adjacent normal brain tissue.