Purpose/Objective(s) Patients with a Child-Pugh score (CP) of B7 or higher are under-represented in otherwise robust prospective data supporting the use of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). We report the outcomes and toxicity after SBRT for CP ≥B7 HCC patients. Materials/Methods HCC patients with CP ≥B7 who received liver SBRT at our center 2015-2022 were included. Patients were treated with fiducial-less, photon based SBRT using 4D-CT with abdominal compression. The primary endpoint was overall survival (OS). Secondary endpoints were decline in CP score by ≥2 points at 6 months, freedom from local progression (FFLP) defined as progression of treated lesion, intrahepatic progression free survival (IH-PFS, progression outside of treated lesion), and distant PFS. Kaplan-Meier method was used for survival estimates and Cox proportional hazards models for intergroup comparisons. Results Thirty-one HCC patients with CP ≥B7 were included. Median age was 67.7 years (range = 33.5 – 85.9), 29% patients were ECOG≥2, 45% had macrovascular invasion (MVI), and 65%, 23%, 6% and 6% patients were CP classes B7, B8, B9 and C10, respectively. The median maximal tumor dimension was 5.3 cm (range = 2.0 – 16.9), and the median gross tumor volume (GTV) was 79.9 cc (range = 11.3 – 1771.6). Median radiation (RT) dose was 40 Gy (range = 22.5 – 50) in 5 fractions, with 8 patients receiving a biological equivalent dose (BED) > 100 Gy, and 39% receiving systemic therapy. SBRT was well tolerated with 26% patients having any grade toxicity (most commonly nausea; 16%) and no ≥ grade 3 toxicity. None had classic radiation-induced liver disease. The median OS and 1-year OS rate were 7.6 months and 35%, respectively. On univariate analysis, higher RT dose (Hazard ratio (HR) 0.76; 95% CI = 0.60-0.96), BED>100 Gy (HR = 0.20; 95% CI = 0.04-0.60), higher GTV Dmean (HR = 0.95; 95% CI = 0.91-0.99), and lower Liver Dmean (HR = 0.88; 95% CI = 0.80-0.97) were associated with significantly improved OS (all p<.05). Higher Liver-GTV Dmean increased the risk of death, but the difference was not statistically significant (HR = 1.14; 95% CI = 1.00-1.30; p = 0.06). FFLP, IH-PFS, and distant PFS at 1 year were 83%, 51% and 82%, respectively. About 58% patients had any increase in CP score, with 26% increasing by ≥2 points. The increase in CP score was independent of tumor size, performance status, MVI, RT dose, or baseline cirrhosis. Liver-GTV Dmean was higher in patients with increase in CP ≥2, but not statistically significant (15.0 Gy vs 12.8 Gy, p = 0.06). Two patients had a liver transplant after SBRT, with a 1-year OS of 100%. Conclusion SBRT for CP ≥B7 patients is well tolerated and provides excellent local control. Higher tumor BED and lower dose to normal liver improved OS in our patient population. SBRT should be considered in the multidisciplinary treatment of advanced HCCs as well as a bridge to transplant for these patients. Enrollment in prospective clinical trials should be considered.

Purpose/Objective(s) Formalized mentorship in academic medicine is linked to elevated career trajectories and a sustained positive impact on patient care. Our previous needs-based assessment found teaching of mentorship skills is lacking among radiation oncology training programs. We hypothesize the implementation of a resident mentorship curriculum and a formalized resident-medical student mentoring program will increase resident mentorship skills and actively enhance resident experience and career development. Materials/Methods A multi-institutional, prospective, phase 2 intervention study enrolled participants from the Radiation Oncology Education Collaborative Study Group Graduate Medical Education Committee from 4/2022-10/2023. The intervention consisted of a 4-week curriculum and a formalized 1:1 resident-medical student mentorship program during an existing radiation oncology sub-internship. Resident participants completed the Mentorship Competency Assessment (MCA; a validated 26-item survey) before and after the intervention. The primary endpoint was the average change in MCA score (range: -7 to +7). Logistic regression was utilized to assess the association between baseline characteristics and change in MCA score. Results A total of 22/27 enrolled residents (82%) who participated in the study completed pre- and post-intervention surveys. Most were PGY-4/5 (55%), from programs with >10 residents (68%), and did not have prior training in teaching (77%) or mentorship (82%). Most residents (80%) completed at least 2 of 3 components of the curriculum. The faculty check-in component was rated helpful or very helpful (76%), followed by the lecture (39%) then the readings (33%). Residents met with students twice weekly (range: 1-4) for an average of 2.3 hours a week (range: 1-8). After the program, most residents felt confident in being a future mentor to students (91%), overall well-being was positively impacted (80%), and mentorship relationships were positively impacted (70%). All 26 mentorship skills on MCA increased after intervention (mean +1.2/7 per skill). Skills showing greatest improvement were negotiating path to professional independence (+1.7/7), coordinating effectively with other mentors (+1.6/7), helping network effectively (+1.6/7), and setting clear expectations of mentorship relationship (+1.6/7). PGY level, residency size, prior formal teaching experience, or prior formal mentorship experience were not associated with greater change in MCA score (p>0.05). Conclusion A formalized mentorship program can impart mentorship skills to radiation oncology trainees and positively impact their own well-being and mentoring relationships. Future studies should assess how unique strengths of medical residents can be optimally included in student mentorship networks.

Purpose/Objective(s) Elevated LDH is associated with inferior outcomes for R/R BCL patients (pts) receiving chimeric antigen receptor T cells (CAR T). We assessed the proportion of pts who experience LDH normalization following bridging radiotherapy (BRT) and prognostic implications. Materials/Methods We retrospectively analyzed 172 pts across 10 institutions who received BRT prior to CAR T from 2018-2020. LDH was collected both prior to leukapheresis (preBRT) and prior to CAR T infusion (postBRT) and classified as “Hi” or “Lo” based on institutional upper limits of normal. Pts were categorized into 4 groups: HiHi, HiLo, LoHi, and LoLo, based on their two respective LDH values. Progression-free survival (PFS) and overall survival (OS) were calculated from CAR T infusion using the Kaplan-Meier methods and modeled using Cox regression. Results Baseline characteristics were as follows: median age 62, 74% female, 71% diffuse large B cell lymphoma, 74% advanced stage, 39% bulky disease (≥10cm), 66% elevated preBRT LDH, 44% elevated postBRT LDH. 39% of pts received comprehensive BRT and 23% received systemic bridging. Of those with initially elevated LDH, 39% experienced normalization postBRT. Those with HiLo LDH had similar PFS and OS to those with LoLo LDH (p=0.42; p=0.64, respectively), and better PFS and OS compared to those with HiHi (p<0.001; p<0.001, respectively) and LoHi (p=0.002; p<0.001, respectively). Complete response (CR) rates differed between cohorts (p<0.001), with superior CR rates in HiLo and LoLo groups. Excluding pts who received systemic bridging, the PFS and OS differences across LDH subgroups were maintained (Table 1). Cytokine release syndrome grade 3+ events were low among all groups and neurotoxicity occurred less frequently among HiLo and LoLo cohorts (p=0.02). On multivariable analysis, pre-infusion normal LDH values (HR= 0.41, p<0.001) and comprehensive BRT (HR=0.42, p<0.001) maintained superior PFS. In pts with high preBRT LDH, those who achieved normalization were more likely to have received comprehensive BRT (p=0.002). Conclusion Nearly 40% of pts with elevated pre-apheresis LDH experienced LDH normalization following BRT. These pts have superior clinical outcomes compared to those with persistently elevated LDH and comparable outcomes to those with persistently normal LDH. BRT may neutralize risk factors in at-risk pts with LDH response acting as a potential surrogate for treatment response.

In this multi-institutional study, pts receiving BRT prior to CAR T therapy for BCL frequently had bulky disease yet experienced favorable PFS and OS. There were no serious toxicities attributable to BRT, and the rates of CRS and ICANS are comparable to those after CAR T alone. Comprehensive BRT associated with superior PFS.

In this single institutional study, we found MDE is a simple, safe, and effective strategy associated with improved local control, higher R0 resection rates, and similar toxicity to SD CRT for patients with BR/LA PC. Further prospective data is needed to clarify the role of dose-escalated RT in the management of this lethal malignancy.

We present here the largest study evaluating SRS for patients with ≥ 15 BMs. We found that SRS was safe, had favorable cognitive outcomes, and comparable survival outcomes to contemporary studies evaluating WBRT in this patient population. Treatment-naïve patients had a median survival of > 6 months, long enough to benefit from cognitive sparing with SRS. Our study supports further randomized studies comparing SRS and memory avoidance WBRT approaches for patients with ≥ 15 BMs.

Residents are interested in mentorship training and report unpreparedness in several important skills. Future work should focus on formal training and assessment of mentoring skills for residents.

Purpose/Objective(s) As the landscape of oligometastatic care continues to evolve, it has become clear that not all histologies (or anatomic sites) respond equivalently to systemic therapy or radiation. This study aims to gain more insight into metastatic tumor biology by evaluating single base substitution mutations across various metastatic sites and within matched primary-metastatic patient samples. Materials/Methods We evaluated our prospectively collected institutional biorepository for metastatic (Met) tumors which underwent targeted exome sequencing for 1,327 cancer-related genes. The patient cohorts included: 1) non-matched Mets (N-Met; n=794 [707 tumors]) and 2) a subset of matched primary (Pri)-Met (M-Pri-Met; n=207 [390 tumors]). Exome data were enriched for somatic non-silent mutations by filtering out artifacts and known germline and silent mutations. Mutation signatures based on 6 nucleotide base alterations (96 subtypes) were generated and compared across samples followed by hierarchical clustering analysis to assess mutation signature correlation to the COSMIC mutation database. The mutation signatures were assessed across unique histology groups from Prim (n=17) and Met (n=16) sites and compared by Kruskal-Wallis test. Also, counts of individual mutations were related to given mutation signatures. A generalized linear mixed model was used to infer the odds ratio (OR) of mutation incidence in Pri vs Met tumors. Results Across all Mets, we found that C>T and G>A alterations were identified in 23% and 21% of tumors, respectively, whereas T>A was <2%. Notable differences were seen in the proportions of mutation signatures (n=9) across Pri histology (range p < 0.03 to 1.0e−16) and among different Met sites within a given histology. For example, our 6th signature was associated with AID/APOBEC family activity and varied across Pri histology (p = 1.0e−13) and within Met sites (p = 4.3e−09). In contrast, our 4th signature was related to ERCC2 mutation, but only differed across Pri histology and not Met site. The median number of mutations related with mutation signatures was 27 (range: 1-1404) with the highest counts in melanoma. Within our M-Pri-Met analysis, several genes were identified to be either private or shared among tumors. For example, within the M-Pri-Met breast (n=93) group, EPHB4 mutation was concordant in 58% of samples with a LogOR 1.38 (95% CI 1.2-13.2; p=0.02) in Pri vs Met. In contrast, BRAF mutation was 40% concordant with higher odds of being in Met vs Pri (p=0.04). No significant differences were identified in the lung M-Pri-Met cohort (n=45). Though, individual mutations did not appear to be different in lung histology, we did observe differences in the proportions of mutation signatures within individual patient tumors. Conclusion A deeper knowledge of similarities and differences among metastases may aid in biologically-informed metastasis-directed therapy. This analysis highlights diversity in mutation type and incidence among metastases.

Purpose/Objective(s)MRgRT is used to treat UC lung lesions. Adaption is triggered if the original plan does not meet criteria of target coverage or organs at risk (OAR) constraints on recontoured anatomy of the day. Current MRgRT software does not provide composite dose delivered over the complete course, partly because daily anatomy changes make accurate spatial dose accumulation difficult. Previous approaches used DVH point averages to approximate doses from full course. We aimed to more accurately quantify true delivered dose via rigid fusion (RF) of fractional doses and hypothesize that treatment with adaptive MRgRT has superior cumulative doses than non-adaptive treatment.Materials/MethodsWe conducted a single institution analysis of patients receiving 60 Gy in 8 fractions with adaptive MRgRT to UC lesions (per HILUS) between 2/2020 – 1/2022. We created composite doses from 'delivered' treatment plans and 'predicted' treatment plans. For the 'delivered' plans, dose for clinically treated plan (adapted or non-adapted based on daily plan quality) was exported for each fraction with MR contoured anatomy of the day. Using a third-party image registration software, we performed RF for each adaptive fraction focused on aligning two regions: (1) tumor and (2) proximal airway, to separately determine local cumulative dose to those sites. For fractions that were not adapted, the initial plan was fused to daily MR. For the 'predicted' treatment plan, initial plan dose was RF to primary tumor location for each MR contoured anatomy of the day and then summed for composite dose.ResultsEleven consecutive patients with UC lesions were treated with online adaptive MRgRT. Eight (73%) patients had primary lung tumors. Median distance from proximal airway: 0 mm (0-6). Median number of adapted fractions was 7 (6-8). Differences between cumulative delivered and predicted plan dose on daily anatomy GTV D100%, PTV D95%, and Proximal Airway D0.03cc (PA0.03cc) were all statistically significant (p<0.01). The delivered dose had improvement in GTV D100% versus the initial plan (p<0.01), PTV D95% and PA0.03cc were not significant. Median follow up was 7.4 months. No grade 3+ acute or late toxicity was reported.ConclusionOnline adaptive MRgRT resulted in composite delivered doses from treatment on par with initial plan dosimetric quality and significantly outperforms doses delivered with non-adapted treatment. The adapted plan coverage superiority over the non-adapted plan is explained by the 'feathering' of dose that creates a 60 Gy isodose line while respecting OAR, which is underappreciated with just simple summing of changes via adaptive plan DVH values. This is the first ever plan evaluation study of its kind for MRgRT and aids in establishing dosimetric superiority of daily online adaptation.

Purpose/Objective(s) The treatment of oligometastatic disease is an evolving area of research in oncology. This study characterizes urothelial metastases to identify tumor and clinical features which may be used in patient selection. Materials/Methods We evaluated a prospectively collected institutional biorepository for patients with urothelial carcinoma metastases. Metastatic tissue was collected and profiled with Affymetrix GeneChips and the ESTIMATE and CIBERSOFT algorithms were used to infer the immune composition of metastases. Gene set enrichment analysis with select hallmark MSigDB pathways related to DNA damage repair were evaluated. Medical charts were queried for patient demographics as well as tumor and treatment characteristics. Univariable analysis (UVA) with Kaplan-Meier methods was used for time-to-event analysis for overall survival from metastatic collection (OSMC) and time to recurrence at site of MC (TTRMC) and compared by log-rank testing. Cox regression was used to assess ability of variable to predict outcome in a multivariable (MVA) model. Results A total of 24 patients were identified between 2006 and 2009 with urothelial metastases profiled for gene expression with adequate records for chart query. The majority were male (75%) and the media age at MC was 69 years (range 52-89). Twelve patients had synchronous metastases with 29% having >1 metastatic range (range 1-3). The median BMI was 25.3 and 8 patients had diabetes or hypercholesteremia. Five patients were on an ACE-inhibitor. Twenty-one patients received definitive local surgery and 15 had ≥ pT3 or N+ disease. Eleven received chemotherapy and 3 received RT prior to MC. After MC, 58% received chemotherapy and 46% received radiation at the MC site. A total of 17 patients recurred after MC with 10 being at the original MC site. Increased immune cell presence at the MC site had increased TTRMC (9.9 months vs 8.1 months, p=0.04). No specific immune cell type was associated with TTRMC. Receipt of definitive local therapy to the primary tumor (p= 0.015), chemotherapy after MC (p= 0.001) and immune cell presence (HR: 0.9; 95% CI: 0.99-1.0, p=0.019) were associated with OSMC. Enrichment of dendritic cells at the MC site was associated with inferior OSMC (8.32 vs 34.3 months, p <0.001). Only immune cell presence remained predictive (p= 0.04) for OSMC on MVA. Neither DNA damage repair pathways nor presence of patient metabolic dysregulation were associated with outcomes. Conclusion Not all oligometastatic sites are equivalent and may require tailored approaches. Here we find that immune cell enrichment may provide better local metastatic control and survival.

Our survey results show that most (75%) RO PDs believe that UIM persons do not have equal access to tertiary education in the US (17% disagreed and 8% were neutral), but that UIM residents are supported in their department (78%). Most PDs reported that they do not participate in specific activities aimed at recruiting UIM residents, with nearly 1 in 5 programs reporting no interviews of UIM applicants in the last 5 years, and over one quarter of programs acknowledging differential treatment based on race/ethnicity. These data suggest a potential disconnect between DEI perceptions and activities among RO PDs that may be addressed through increased awareness and tailored programs.

Purpose/Objective(s)Melanoma is a more radioresistant and immunogenic histology, associated with a higher mutational burden. However, the influence of metastasis tissue location is unknown. We hypothesize exploiting these differences may allow therapy personalization.Materials/MethodsWe identified metastatic melanoma samples across 6 tissues (brain, liver, lung, lymph node [LN], skin, soft tissue [ST]), which were profiled for gene expression by microarray chips. Intrinsic radiosensitivity was estimated by the radiosensitivity index (RSI), a rank-based gene expression signature, where a higher RSI (scale 0-1) indicates greater radioresistance, with a cut point of 0.375 in other histologies. Degree of inflammation in the microenvironment was calculated by an existing 12-gene chemokine signature (12CK) where a higher 12CK score indicates greater inflammation. A subset (n = 94) underwent targeted exome sequencing (1,327 cancer-associated genes) and somatic mutations (MF) were enriched after filtering known germline/silent mutations and artifacts. Differences by tissue were analyzed with the Kruskal-Wallis H test. Correlations between RSI, 12CK, and MF were tested using Spearman's rho.ResultsFrom 1995 to 2011, 337 metastatic samples were identified from unique patients. Median age at diagnosis was 61 (range 20-97). With a median follow-up of 162 months (95% CI 142.6-181.4), median survival was 59.8 months (95% CI 49.2-70.4). Median values for RSI, 12CK, and MB were 0.451 (interquartile range [IQR] 0.331-0.552), 8.700 (IQR 7.218-9.746), and 101.5 (IQR 73.75-137), respectively. Significant differences existed among tissues for both RSI (P = 0.003) and 12CK (P < 0.001), but not MF (P = 0.498) (Table 1). No pair-wise comparisons were significant after Bonferroni correction for RSI, but for 12CK, Brain-ST (P = 0.044), Brain-Lung (P = 0.013), Brain-LN (P = 0.000), and Liver-LN (P = 0.023) were significant. Correlation between RSI and 12CK was significant (rho = -0.661, P < 0.001), but correlations between MB and RSI/12CK were not significant.ConclusionIn this novel composite genomic analysis of melanoma metastases, all were relatively radioresistant, but higher RSI values for liver and skin metastases may warrant radiotherapy dose escalation. Similarly, the lower inflammatory scores of liver and brain metastases may have implications for selection of patients for immunotherapy. More inflamed tumors may be more responsive to radiation. In contrast to current homogenous approaches to metastases, these results indicate personalized approaches to types/sequencing of therapy for melanoma metastases by tissue type may be warranted.

In this novel exploratory analysis of soft tissue metastases, a number of histologies demonstrated sufficient radiosensitivity (RSI < 0.375) to consider radiotherapy as a component of management. Significant differences across primary histologies also suggest an opportunity for dose personalization. Significant differences in microenvironment inflammation and mutational frequency across primary histologies also may inform personalization of immunotherapy and other targeted therapies.

In patients receiving bridging RT prior to CAR T cell therapy for R/R LBCL, treatment failure was characterized by high rates of genuine in-field relapse after an initial partial or complete response. In a smaller number of patients, no lesion that received a higher dose of RT demonstrated an in-field failure. This calls into question the potential synergistic effects of bridging RT and CAR T therapy at low RT doses in some patients and suggests the need for significant dose-escalation to achieve adequate local control.

Genomic and gene expression heterogeneity between primary cancers and metastases is a known phenomenon that may influence response to treatments including radiotherapy. However, genomic and radiosensitivity differences between matched primary and metastatic tumors in the same patient are lacking. In this analysis, we matched primary and metastatic surgical specimens from the same patient with both microarray and genomic data (targeted 1,321-gene assay). Intrinsic radiosensitivity of tumors was calculated by the radiosensitivity index (RSI) gene expression algorithm. Known germline/silent mutations and artifacts were filtered out and unique/shared mutations quantified. Time to event analysis was performed using the Kaplan-Meier method. Differences in mutational burden (MB) and RSI by histology were analyzed with the Kruskal-Wallis H test. Analyses by primary/metastasis status, prior treatment, and synchronous surgery were analyzed with the Mann-Whitney U test. Associations between MB and RSI were analyzed by Kendall's tau-b. Between August 2005 and October 2010, matched samples from 22 patients were collected (3 colon, 4 melanoma, 10 ovarian, 5 lung). Median age at diagnosis was 68 (range 53-82). With a median follow-up of 100.8 months (95% CI 61.4-140.1), median survival was 34.8 months (95% CI 0-78.5). Fifty-four samples with microarray data were available; 44 of which had targeted genomic data. Thirteen of 22 (59%) metastases were synchronously resected with their matched primary. Median number shared mutations between samples was 634.5, the median number unique to primary samples was161.5 and to metastatic samples was 181. Significant differences in median MB were noted between primary histologies (colon 660, melanoma 833, ovarian 744, lung 1054; p = 0.045), but not in metastases by primary histology (p = 0.313). Metastases had a 13.3% increase in RSI scores denoting more radioresistance, but this was not significant across all specimens or when stratified by histology. No significant differences in MB or RSI scores were found between synchronous metastasectomy and non-synchronous metastasectomy specimens. Two patients had systemic therapy prior to removal of primaries and five had systemic therapy prior to metastasectomy. Systemic therapy prior to resection for both primaries and metastases was associated with an increased RSI score (0.364 vs. 0.486, p = 0.047). Systemic therapy prior to metastasectomy only was associated with higher MB (707 v. 1318, p = 0.01). In this novel genomic and gene expression analysis of matched primary and metastatic samples, MB in metastases do not appear to follow original histologic patterns, but appear to be increased after systemic therapy. Prior systemic therapy also appears to be associated with more radioresistant metastases. Further work is needed to validate these findings in a larger cohort and in the prospective setting as an actionable biomarker.

Patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations are often treated with EGFR inhibitors (EGFRi). However, resistance to therapy develops invariably. Cytoreduction with SBRT in oligoprogressive or in definitive setting may improve local control, slow disease progression, and/or delay the need to change therapy. Safety and control data are lacking for SBRT combined with modern EGFRi. We hypothesized that SBRT with EGFRi therapy is safe and allows patients to continue EGFRi longer than historical standards. We collected data from a prospectively-maintained IRB approved registry (MCC 18883) which include 1764 patients treated with lung SBRT. Patients receiving EGFRi within 6 months of SBRT, defined as 5-10 fractions (fr), were considered eligible for the present study. Toxicity data were prospectively gathered using CTCAE v5.0. and prospectively-collected patient-reported Edmonton Symptom Assessment Scale (ESAS) scores. Dosimetric data were included for all patient. Progression-free (PFS) and overall survival (OS) were estimated using Kaplan Meier analysis. Between 2010-2019, 23 patients with NSCLC were treated with SBRT and received EGFRi within 6 months. 78% (18/23) patients were metastatic. Median age was 68 years (range 33-89), 21/23 (91.3%) were female, and 15/23 (65%) smoked <10 pack-years. In 19 patients EGFRi was started prior to SBRT, while 4 patients started EGFRi within 6 months of SBRT. 21 patients received 50-60 Gy in 5 fr, others received 60 Gy in 8 fr or 50 Gy in 10 fr. Exon 19 E746-A750 or Exon 20 T790M were most common EGFR mutations. EGFR mutational status was not available for 2 patients. EGFRi given were Erlotinib, Osimertinib and Gefitinib in 15, 5, and 3 patients, respectively. Median follow-up after SBRT was 19 months (range, 4-100). Median PFS and OS were 7 months (95% CI 4.2–9.8) and 31 months (95% CI 15.5–46.5); and actuarial 1-year PFS and OS, were 47.8% and 82%, respectively. 2- and 5-year local control rates were 74.1% and 55.6%. Median planning target volume was 41.5 cc (7.9 - 96.1). Mean lung dose was 5.2 Gy (1.1–23.5Gy), and median V5 and V20 were 18.8% and 6.2%, respectively. Grade 1 pneumonitis was observed in 4 patients and Grade 2 in 1 patient. No grade ≥3 pneumonitis was reported. Symptomatic rib fracture (grade 2) noted in 1 patient. All patient completed ESAS; dominant symptoms were fatigue (30.4%), pain (35%), and loss of appetite (30.4%). For unselected patients with EGFR mutated NSCLC, the combination of SBRT and EGFRi was well tolerated with no dose limiting grade ≥3 toxicity. SBRT with EGFRi resulted in high PFS and OS, greater than historical values for patients who only received systemic agents.

The standard of care for muscle invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NACT) followed by cystectomy. Select patients may undergo bladder sparing approaches, characterized by maximum bladder tumor resection followed by concurrent chemoradiation (chemoRT). In this study, we evaluate the experience of bladder preservation for MIBC patients at a high-volume cancer center in the modern era. We retrospectively evaluated the medical records of 48 consecutive MIBC patients treated with bladder preservation from 2010 to 2019. Chi Square tests were used to compare groups. Time to event analyses, including overall survival (OS) and bladder-intact event free survival (BI-EFS) were estimated by Kaplan-Meier methods and compared by the log-rank test, or by Cox regression analysis. Univariable (UVA) and multivariable (MVA) analyses were performed to explore the effect of predictors on defined outcomes. The median age was 69 years (range 39-90). Most patients were male (79%). T category was T2 (85%), T3 (13%) and T4a (2%) with 88% (n = 42) having stage II disease. Seventeen (35%) patients had non-MIBC prior to MIBC diagnosis. The majority (73%) of tumors were urothelial histology only. Mixed histologies included neuroendocrine (10%), squamous (6%), sarcomatoid (6%) and plasmacytoid (4%). Twelve (25%) patients received NACT and of these, 6 had a complete response (CR) at cystoscopy prior to chemoRT. Most patients (83%) were treated with concurrent platinum-based chemoRT. The median radiation dose was 64.5 Gy (range 34.2-64.8). With a median follow-up time of 39.8 months, a quarter of patients progressed after chemoRT with 8 (17%) having local MIBC recurrence and 8 having distant progression. Three patients underwent salvage cystectomy. Only the achievement of a CR after NACT was predictive of less risk for local MIBC recurrence (p = 0.002). The median OS was 66.7 months (range 25.0-108.5), with 2- and 3-yr OS of 77% and 57%, respectively. Predictors of improved OS on UVA included urothelial only histology, lower stage, and no local MIBC recurrence; only urothelial histology was predictive on MVA (HR: 0.20, 95% CI 0.06-0.66, p = 0.008). The median BI-EFS was 52.4 months (range 27.2 - 77.7), with 2- and 3-yr BI-EFS of 65% and 56%, respectively. Urothelial only histology (p = 0.005) and CR after NACT (p = 0.02) were predictive of BI-EFS on UVA, but not MVA. Bladder preservation remains an effective treatment approach for select patients, but mixed histology may portend inferior tumor control. Here we provide modern data from a large cancer center showing a 3-yr BI-EFS similar to the control arm of the accruing SWOG/NRG 1806 trial.

Accumulating evidence has shown a benefit for dose-escalation and stereotactic body radiotherapy (SBRT) in the treatment of unresectable pancreatic cancer. To this end, MR-guided radiotherapy (MRgRT) allows for reduction of dose to organs at risk while accounting for intra- and inter-fraction motion with online treatment plan adaptation to improve target coverage. We sought to report on our early experience in MRgSBRT for pancreatic cancer. This study was a retrospective cohort of biopsy-proven, pancreatic cancer patients that were recommended to undergo high biological equivalent dose (BED) SBRT to their primary disease and were treated on the MR-Linac in 5 fractions. Acute toxicity measured by Common Terminology Criteria for Adverse Events (v5) by a provider during the weekly on-treatment visit, at 1 month following completion of treatment, and at regular 3-month follow-up intervals thereafter. Toxicity occurring greater than 3 months after completion of radiotherapy was deemed late. From April, 2019 until January, 2020 a total of 35 consecutively treated patients (48% borderline resectable, 37% locally advanced; 80% cN0) with a median follow up from diagnosis of 8.3 months were treated to median 45 Gy (Range: 35-50 Gy) on our MRI-Linac. At least three months of induction chemotherapy was given in 88.5% of patients, most commonly FOLFIRINOX (71%) or gemcitabine/abraxane (26%). Twenty-three patients (66%) were treated with online adaptive planning and 4 patients (11%) were treated for locally recurrent, unresectable disease with history of prior radiotherapy (n = 3 prior adjuvant chemoradiation, n = 1 prior definitive SBRT in the lateral decubitus position). Overall, nine patients (25%) experienced any toxicity, predominantly grade 1 fatigue (55%) and nausea (44%). A single patient (2.8%) experienced grade 3 abdominal pain 1.5 weeks after completion of SBRT presumed to be duodenitis from CT imaging. No grade 4/5 or any late toxicity from SBRT has been observed in this cohort to date. At the time of analysis, 9 patients (55% borderline resectable, 22% locally advanced) successfully underwent resection of their primary tumor (100% R0 resection) without perioperative mortality and with 2 reported pathological complete response (TRG 0; 22%), 2 patients with TRG 1 response and 5 patients with TRG 2 response (55%). Overall, no patients had experienced local recurrence based on CT pancreas protocol RECIST criteria and eight patients (22.8%) had distant progression with one reported death (OS: 97%). MRgSBRT for pancreatic cancer appears to be well-tolerated with encouraging early local control and without significant morbidity or increased perioperative mortality. Adaptive treatment parameters and tissue constraints for adaptive and non-adaptive treatment plans minimize toxicity for this increasingly utilized treatment.

The brain is a relatively rare site of metastasis for sarcoma. Sarcoma is also known to be radioresistant, making standard WBRT less appealing. SRS/FSRT may provide better local control but effectiveness data are limited. In this single institution retrospective analysis, we evaluated our experience with LINAC-based SRS and FSRT for sarcoma brain metastases. Time to event analysis was performed with Kaplan-Meier estimates. Univariable (UVA) and multivariable (MVA) Cox regression analyses were performed to assess the impact of patient and disease characteristics on outcomes. Between 2003 and 2018, 24 patients were treated with 34 courses of SRS/FSRT to 58 discrete lesions. Median age at first treatment was 57 years (range 25-87). Systemic therapy was given in 22 patients (19 with cytotoxic, 8 with tyrosine kinase inhibition, and 5 with immunotherapy). The most common primary histologies were spindle cell sarcoma (n=15; 25%) and leiomyosarcoma (n=12; 21%). All patients also had concurrent extracranial metastases (most commonly in the lung, n=21; 88%) and median interval from initial diagnosis to diagnosis of brain metastases was 18.8 months (range 0-172.7). Sixteen patients presented with symptoms (most commonly headache, n=11). Forty-three lesions were treated with SRS to a median dose of 19 Gy (range 15-24) and 17 were treated with FSRT in 3 or 5 fractions to a median dose of 25 Gy (range 25-35). Median follow-up after brain metastases diagnosis was 7.3 months (range 0.2-53.9) for all treated lesions. Six and 12 month local control rates were 89% following stereotactic radiation. Four lesions failed: 2 in post-operative FSRT, 1 in intact FSRT, and 1 in intact SRS. All lesions that failed were of primary spindle cell histology (p<0.001). Distant brain control at 6 and 12 months was 59% and 34%, respectively. Following distant failure, 7 patients were retreated with additional SRS/FSRT and 1 was treated with WBRT. On UVA spindle cell histology had worse distant control (HR 25.8, 95% CI 3.1-536.4; p=0.003). Median overall survival following brain metastasis diagnosis was 6.1 months with 6 and 12 month OS rates of 50% and 38%, respectively. Factors predicting worse OS from brain metastases diagnosis on MVA included spindle cell histology (7.0, 95% CI 2.0-25.4; p=0.003) and KPS <90 (3.4, 95% CI 1.2-10.7; p=0.02). One patient experienced treatment-related symptoms (right sided weakness), which resolved with a steroid taper. In this largest series of sarcoma patients treated with stereotactic radiation, we find SRS/FSRT can provide good local control with minimal symptoms, despite a reputation for radioresistance. Further study is needed to determine the impact of primary histology on control rates and survival following brain metastases diagnosis.

Stereotactic radiosurgery (SRS) and fractionated stereotactic radiation therapy (FSRT) are effective treatment modalities for the local control of brain metastases. Nivolumab and ipilimumab are newly approved systemic treatment options for stage IV renal cell carcinoma (RCC) in poor or intermediate risk patients. In this study, we evaluate whether patients with RCC brain metastases treated with stereotactic radiation therapy (SRT) and nivolumab have improved outcomes compared to those who did not receive immunotherapy. A total of 38 consecutive patients with brain metastases from RCC treated with SRT were identified in our IRB-approved retrospective database from 1/2011 to 6/2018. Distant brain failure analyses were performed on a treatment session basis (n=78). Overall survival analyses were performed on individual patients (n=38) only. The use of nivolumab was considered if it was administered within 6 months of SRT. Dichotomous patient variables and outcomes were compared using the chi-squared test. Time-to-event analyses were performed using the Kaplan-Meier method and log-rank test. Univariable (UVA) and multivariable (MVA) analyses were performed using the Cox regression model. A total of 170 lesions were identified of which 147 (86.5%) were treated with SRS and 23 (13.5%) with FSRT. A total of 14 (36.8%) patients received nivolumab within 6 months of SRT for 64 eligible lesions. Median follow-up was 10.6 months (range: 0.7 – 93.3) and median overall survival from brain metastasis diagnosis was 10.1 months (range: 1.3 – 93.3). Median time from SRT to a subsequent brain failure was 3.7 months (range: 0.66 – 41.2). Median time from SRT to a systemic failure was 2.0 months (range: 0.1 – 87.0). Patients who received nivolumab within 6 months of SRT trended towards an improved overall survival (median: 21.7 months, 13.5 – 29.9) compared to those who did not (median: 7.8 months, 5.2 – 10.5), p=0.059. Patients in the nivolumab group also trended towards having a lower risk of a subsequent systemic failure (HR: 0.238, 0.05 – 1.1) compared to those who were not, p=0.065. Patients who did not have prior whole brain radiation therapy (WBRT) had a longer time to a subsequent brain failure event (median: 4.2 months, 3.6 – 4.7) compared to those who had prior WBRT (median: 1.6 months, 1.3 – 1.8), p=0.009. Patient outcomes in metastatic RCC continue to be poor with rapid brain and non-brain failure rates despite advances in treatment options. Nivolumab given within 6 months of SRT suggests a lower risk subsequent systemic failure and death. Further analyses regarding the appropriate sequence of nivolumab administration and SRT are suggested.