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NRG-CC001, a trial evaluating the neuroprotective effect of HA-WBRT versus standard WBRT in patients with brain metastases (BM), demonstrated a significantly lower risk of NCF decline. Given the heterogeneous BM patient population, we sought to systematically identify subgroups of patients through secondary analysis of trial data that could derive differential benefit from HA. We performed a post hoc analysis of NRG-CC001, a phase III clinical trial in which 518 patients with BM were randomly assigned to WBRT plus memantine or HA-WBRT plus memantine. In this secondary analysis, cumulative incidence function (CIF) estimated NCF failure between arms and subgroups was tested using Gray's test. Covariate and subgroup association with differential treatment response was calculated using Cox proportional hazards modeling; these factors were then tested for interaction with treatment arm. Age (>61), education (=4 months, there was a significant benefit favoring HA-WBRT (p=0.03). We found evidence of heterogeneity of treatment effect based on primary tumor histology (interaction test p=0.01): primary lung histology patients (HR 0.58, 95% CI: 0.43-0.77, p=0.0007) compared to those with non-lung histology primary tumors (HR 1.15, 95% CI: 0.78-1.71, p=0.48). Baseline MD Anderson Symptom Inventory for brain tumor (MDASI-BT) cognitive factor scores were also found to be highly associated with treatment response with significance on test for interaction (p=0.03); those with MDASI-BT baseline scores in quartiles 1-3 had significantly greater differential treatment response (HR=0.64, 95% CI: 0.48-0.85, p=0.002) compared to those with the highest MDASI-BT baseline scores (HR=1.24, 95% CI: 0.76-2.04, p=0.39). There was no significant heterogeneity of treatment effect based on age, education level, and baseline KPS. This post-hoc subgroup analysis of NRG-CC001 evaluating heterogeneity of treatment effect confirmed that the neurocognitive protective benefit of HA-WBRT was most substantial for patients living > 4 months; for those surviving <4 months, statistically significant benefit was not identified, possibly because cognitive decline post-WBRT requires a window of time to manifest. We also found that treatment response was significantly associated with several patient and tumor characteristics. Patients with lung histology as well as those with lower baseline MDASI-BT cognitive factor scores, denoting less severe cognitive impairment at enrollment, had significantly greater benefit from HA-WBRT. These data may better help clinicians decide which subgroups of patients benefit most from HA-WBRT. [ABSTRACT FROM AUTHOR]

Purpose: To generate a reproducible step-wise guideline for the delineation of the lumbosacral plexus (LSP) on axial computed tomography (CT) planning images and to provide a preliminary dosimetric analysis on 15 representative patients with rectal or anal cancers treated with an intensity-modulated radiotherapy (IMRT) technique. Methods and Materials: A standardized method for contouring the LSP on axial CT images was devised. The LSP was referenced to identifiable anatomic structures from the L4–5 interspace to the level of the sciatic nerve. It was then contoured retrospectively on 15 patients treated with IMRT for rectal or anal cancer. No dose limitations were placed on this organ at risk during initial treatment planning. Dosimetric parameters were evaluated. The incidence of radiation-induced lumbosacral plexopathy (RILSP) was calculated. Results: Total prescribed dose to 95% of the planned target volume ranged from 50.4 to 59.4 Gy (median 54 Gy). The mean (±standard deviation [SD]) LSP volume for the 15 patients was 100 ± 22 cm3 (range, 71–138 cm3). The mean maximal dose to the LSP was 52.6 ± 3.9 Gy (range, 44.5–58.6 Gy). The mean irradiated volumes of the LSP were V40Gy = 58% ± 19%, V50Gy = 22% ± 23%, and V55Gy = 0.5% ± 0.9%. One patient (7%) was found to have developed RILSP at 13 months after treatment. Conclusions: The true incidence of RILSP in the literature is likely underreported and is not a toxicity commonly assessed by radiation oncologists. In our analysis the LSP commonly received doses approaching the prescribed target dose, and 1 patient developed RILSP. Identification of the LSP during IMRT planning may reduce RILSP. We have provided a reproducible method for delineation of the LSP on CT images and a preliminary dosimetric analysis for potential future dose constraints. [Copyright &y& Elsevier]

Purpose: To evaluate interobserver variability for contouring the brachial plexus as an organ-at-risk (OAR) and to analyze its potential dosimetric consequences in patients treated with intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. Methods and Materials: Using the Radiation Therapy Oncology Group (RTOG)-endorsed brachial plexus contouring atlas, three radiation oncologists independently delineated the OAR on treatment planning computed-tomography (CT) axial scans from 5 representative patients undergoing IMRT to a prescribed dose of 70 Gy for head-and-neck cancer. Dose-volume histograms for the brachial plexus were calculated, and interobserver differences were quantified by comparing various dosimetric statistics. Qualitative analysis was performed by visually assessing the overlapping contours on a single beam’s eye view. Results: Brachial plexus volumes for the 5 patients across observers were 26 cc (18–35 cc), 25 cc (21–30 cc), 29 cc (28–32 cc), 29 cc (23–38 cc), and 29 cc (23–34 cc). On qualitative analysis, minimal variability existed except at the inferolateral portion of the OAR, where slight discrepancies were noted among the physicians. Maximum doses to the brachial plexus ranged from 71.6 to 72.6 Gy, 75.2 to 75.8 Gy, 69.1 to 71.0 Gy, 76.4 to 76.9 Gy, and 70.6 to 71.4 Gy. Respective volumes receiving doses greater than 60 Gy (V60) were 8.6 to 10.9 cc, 6.2 to 8.1 cc, 8.2 to 11.6 cc, 8.3 to 10.5 cc, and 5.6 to 9.8 cc. Conclusion: The RTOG-endorsed brachial plexus atlas provides a consistent set of guidelines for contouring this OAR with essentially no learning curve. Adoption of these contouring guidelines in the clinical setting is encouraged. [ABSTRACT FROM AUTHOR]

Re-irradiation (re-RT) for recurrent head and neck cancer (rHNC) after prior HNC RT is clinically challenging given prior radiation of nearby organs at risk (OARs). We describe clinical outcomes and toxicity of pencil beam scanning proton therapy (PBS-PT) for recurrent HNC, and report genomic alterations associated with patterns of failure to improve clinical decision making. We performed a retrospective analysis of rHNC patients treated at a single institution with PBS-PT. Baseline demographic, disease and treatment characteristics were recorded. Clinical outcomes were estimated using the Kaplan-Meier method. Univariable (UVA) and multivariable analyses (MVA) were performed to assess patient, disease, and treatment related factors. Acute and late grade 3+ toxicities were assessed per CTCAE v5.0. Next generation sequencing (NGS) and genomic analyses were performed on available samples. Eighty-nine patients treated with PBS-PT for rHNC between 2016 and 2022 with a median follow-up of 12 months (range 0-71) were included. The 1- and 2-year local control rates were 80.8% (95% CI: 70.8-90.8) and 66.2% (95% CI: 50.7-81.7) and 1- and 2-year distant metastasis free survival (DMFS) were 41.0% (95% CI: 30.0-52.0) and 26.3% (95% CI: 15.7-36.9). Median overall survival (OS) was 13 months (95% CI: 9.3-16.7). On UVA and MVA, smaller gross tumor volume was associated with improved OS (HR 1.002, p=.004), DMFS (HR 1.002, p=0.004) and progression free survival (PFS) (HR 1.002, p=0.014). There were 35 late grade 3 or higher toxicity events (30.3%), including one patient that suffered late grade 5 osteoradionecrosis resulting in sepsis. Patients with higher candidate gene specific mutation burden (genes with odds-ratio >2, p<0.05) had inferior PFS. In addition, TP53, NOTCH4 and ARID1B mutations were associated with inferior DMFS (OR>2, p<0.05). Of the top 28 highly mutated genes (mutated in ≥ 3 samples in either group, odd ratio>2), TP53 was the most frequently mutated gene in DMFS alive group with Met(78%), followed by NOTCH4(52%), ARID1B (33%). please see table table1b. Pencil beam scanning proton therapy re-irradiation is effective at achieving local control for recurrent head and neck cancer and is associated with a favorable toxicity profile. Distant metastases comprise the major failure pattern for this patient population and are associated with TP53, NOTCH4 , and ARID1B somatic mutations. Validation of these findings may provide rationale for the inclusion of genomic alterations in the clinical decision process. [ABSTRACT FROM AUTHOR]

For unresectable intrahepatic cholangiocarcinoma (ICC), we previously showed that pre-therapy CT volumetric enhancement (VE) associates with biological (e.g., degree of stromal infiltration and necrosis, genetic mutations, and infiltrating lymphocytes) and clinical outcomes. Further, we showed that a change in VE following radiotherapy (RT) is prognostic. Here, we integrated these baseline and post-treatment imaging features to appraise their joint prognostic value. We retrospectively identified 112 patients (54% female, median age 63 years) who received definitive RT (78% photon, 22% proton; median biologically effective [BED 10 ] dose 86 Gy, interquartile range [IQR] 75-98 Gy) with triple phase CT imaging at diagnosis, prior to RT, and following RT. A technology company's multimodality tumor tracking software was used to quantify tumor VE ≥1 standard deviation of that of healthy parenchyma on each scan. Based on prior work, each patient was stratified into (1) low/high VE at baseline (cutpoint: 32% VE) and (2) VE-based response/non-response to RT (cutpoint: 26% decrease in VE). Overall survival (OS) and local failure-free survival (LFFS) following RT were assessed using the Kaplan-Meier method. Cox analyses were performed to include the 2 radiomic markers and traditional covariates of survival. Concordance indices (C-index) were used to evaluate model performance. At a median follow up of 74 months, 46% failed locally and 85% died. The 2-year OS and LFFS were 40% (95% confidence interval [CI], 30-49%) and 26% (CI, 18-34%), respectively. At baseline, median VE was 25% (IQR 14-45%); VE was categorized as low in 43% and high in 57%. Following RT, median change in VE was +3% (IQR -7% to +176%); change was categorized as non-response for 56% and response in 44%. On multivariable analysis for OS, Stage IV disease (hazard ratio [HR] 2.11, CI 1.35-3.31; P =0.001) was associated with poorer survival. High VE (HR 0.38, CI 0.24-0.59; P <0.001) and VE-based response to RT (HR 0.19, CI 0.12-0.32; P <0.001) were each independently associated with longer survival (C-index 0.77). For LFFS, Stage IV disease (HR 1.61, CI 1.03-2.52; P =0.036) was associated with shorter latency to local failure/death, while high VE (0.40, 95% CI 0.26-0.62; P <0.001) and VE-based response to RT (HR 0.29, CI 0.18-0.46; P <0.001) were associated with longer latency (C-index 0.74). Median OS stratified by cohort is shown in Table 1. For ICC patients treated with definitive RT, VE measured on pre-therapy imaging and pre/post-RT imaging each independently had greater predictive value than conventional patient and disease factors. These metrics, with their biological and clinical associations, may help personalize therapeutic approaches for ICC. External model validation is warranted. [ABSTRACT FROM AUTHOR]

Re-irradiation (re-RT) for recurrent head and neck cancer (HNC) after prior HNC radiation therapy (RT) is clinically challenging given prior radiation of nearby organs at risk (OARs). We describe clinical outcomes and toxicity of pencil beam scanning proton therapy (PBS-PT) for recurrent HNC. We performed a retrospective analysis of recurrent HNC patients treated at a single institution with PBS-PT. Baseline demographic, disease and treatment characteristics were recorded. Local control (LC), locoregional control (LRC), progression free survival (PFS), distant metastasis free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. UVA was completed using logistic regression, and MVA was performed using a backward elimination model. We also report acute and late grade 3+ toxicity outcomes, graded per CTCAE v5.0. A total of 89 patients treated with PBS-PT for recurrent HNC between 2016 and 2022 were included. Primary sites included oropharynx (30.0%), oral cavity (22.5%), sinonasal cavity (15.7%), larynx (12.4%) and nasopharynx (6.7%). The most common tumor histology was SCC (73.0%). Median time to re-RT was 47 months. Median dose of PBS-PT was 60 Gy (range: 40-72) with 50.6% receiving BID treatment. Median GTV volume was 30cc (range 4.8-1083cc). 24% of patients received concurrent systemic therapy (46% cytotoxic, 4.5% immunotherapy). Median follow-up after PBS-PT was 8 months (range: 0-71), and median OS was 13 months (95% CI: 9.3-16.7). The median PFS and DMFS were 7 months (95% CI 5.0-9.0) and 9 months (95% CI 5.3-12.7) respectively. The 1- and 2-year LC rates were 80.8% (95% CI: 70.8-90.8) and 66.2% (95% CI: 50.7-81.7). The 1- and 2-year DMFS were 41.0% (95% CI: 30.0-52.0) and 26.3% (95% CI: 15.7-36.9). On UVA and MVA, smaller GTV volume was associated with improved OS (HR 1.002, p =.004), DMFS (HR 1.002, p = 0.004) and PFS (HR 1.002, p = 0.014). In addition, shorter time to re-RT was associated with worse LRC (HR 1.003, p = 0.002), and higher KPS was associated with improved PFS (HR 0.57, p = 0.04). There were 31 acute grade 3 toxicity events (21 patients), the most common being odynophagia (9.0%) followed mucositis (5.6%), dehydration and dermatitis (both 4.5%). One patient had grade 4 toxicity, laryngeal edema requiring intubation 40 days after completion of re-RT. One patient had acute grade 5 toxicity, an oropharyngeal bleed 74 days after completion of re-RT. There were 35 late toxicity events (n = 27), the most common being dysphagia (n = 7, 7.9%). One patient suffered late grade 5 osteoradionecrosis, which resulted in sepsis. PBS-PT for recurrent HNC results in effective disease control and favorable toxicity. Patients with smaller GTV volume appear to have improved OS, PFS and DMFS, and may be better candidates. Those with shorter time to re-RT also have worse LRC. However, distant failure (DF) comprises a major failure pattern, and biomarkers to identify patients at risk for DF may improve clinical decision making. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Patients with localized prostate cancer (PCA) treated with RT alone have excellent outcomes, making quality of life and minimization of toxicities of great concern. The risk of developing toxicity may evolve with time from treatment which is of interest to patients seen in follow up. The primary objective of this study is to determine the conditional risk of grade 2+ GI or GU toxicity for patients treated with RT. A secondary objective is to determine risk factors associated with the development of late toxicities. We performed a post-hoc analysis of RTOG 0126, which enrolled patients with intermediate risk PCa who were randomized to receive standard dose RT of 70.2 Gy in 39 fractions vs dose escalated dose RT (DE-RT) of 79.2 Gy in 44 fractions. Cumulative incidence was used to calculate risk of grade 2+ GU and grade 2+ GI toxicity at initial time points, as well as for patients who survived 2 years and 5 years without respective grade 2+ toxicity. Risk factors of age, race, urinary incontinence, baseline urinary frequency, acute GU toxicity, treatment arm, RT method (3DCRT vs IMRT), and OAR contouring protocol violation were analyzed using univariate and multivariate Cox proportional hazards modeling for late GU toxicity. Risk factors of age, race, RT method, acute GI toxicity, DE-RT, RT method, and OAR contouring protocol violation were analyzed for late GI toxicity. One thousand four hundred ninety-nine patients with a median follow up of 8.4 years (range 0.02-13 years) were included for analysis. The conditional cumulative 5-year risk of late grade 2+ GI toxicity at enrollment, 2-, and 5-years of grade 2+GI toxicity free survivorship was 14.7%, 6.2%, and 1.8% respectively. The cumulative 5-year risk of late grade 2+ GU toxicity at enrollment, 2-, and 5-years of late grade 2+ GU toxicity free survivorship was 7.9%, 4.7%, and 2.7% respectively. Initially DE-RT (HR 1.401, 95% CI 1.099-1.787; p = 0.0066), acute GI toxicity (HR 1.962, 95% CI 1.271-2.616; P<0.0001), and black race (HR 0.630, 95% CI 0.4-0.993; p<0.0463) were predictive of late GI toxicity. After two years of 2+ GI toxicity free survivorship, only acute GI toxicity (HR 2.015, 95% CI 1.238-3.279, p<0.0048) remained predictive of late GI toxicity on MVA. DE-RT (HR 1.616, 95% CI 1.187-2.2, p<0.0023), IMRT (HR 0.559, 95% CI 0.389-0.804, p = 0.0017), and urinary frequency at baseline (HR 1.377, 95% CI 1-1.895 p<0.0498) were predictive of late GU toxicity at enrollment. This data suggests that as patients proceed further from completion of EBRT, the conditional risk of late toxicity decreases. The majority of grade 2+ GI and GU toxicities occur in the first two years of treatment and patients who have not had a grade 2+ GU or GI toxicity within the first five years are likely to remain toxicity free. Factors such as presence of baseline urinary dysfunction, presence of acute toxicities, DE-RT, and radiation modality predict for late toxicity. These findings are of relevance for clinicians and patients in the post treatment setting. [ABSTRACT FROM AUTHOR]

The prognostic role of race on outcomes for patients with gliomas is debated. Historically, trials reporting on race have enrolled low percentages (<3%) of black patients. The primary objective of this study is to characterize racial factors in relation to treatment and clinicopathologic variables for adult glioma patients treated within a multi-center academic network with a large cohort of black patients. We hypothesize that racial factors may impact tumor biology and treatments rendered, and play a prognostic role in patients with gliomas. A retrospective IRB-approved analysis of 241 patients with gliomas treated with curative intent across 4 radiation oncology centers associated with a single academic institution between August 2004 and March 2021 was done. Chi-square tests were done to compare variables stratified by race. Kaplan-Meier (KM) and cox proportional hazard models were used to analyze overall survival (OS), progression free survival (PFS) and freedom from radiation necrosis/treatment effect (RN) for black (B) vs nonblack (NB) patients. Logistic regression was done to analyze association of race with treatment and clinicopathologic variables. Of the patients included, 140 (58.1%) were male, 101 (41.9%) were female, 33 (13.6%) were black and 208 (86.3%) were nonblack. Black patients were younger (median age 57.5 vs 62.8 yrs; p=0.026) and less likely to receive concurrent temozolomide (TMZ) (71.9% vs 89.9%; p=0.004). Median EQD2 delivered between B vs NB patients was significantly different (50.8 vs 55.4 Gy; p=0.026). There was no significant difference in performance status (p=0.469), MGMT-methylation (p=0.296), IDH-mutation (p=0.447), hypofractionation (p=0.584), adherence to NCCN guidelines (p=0.690), enrollment in clinical trials (p=0.329) or treatment at tertiary sites (p=0.247) for B vs NB patients. On MVA, black race was associated with improved OS (HR 0.555, p=0.027). MGMT methylation was also associated improved OS (HR 0.660, p=0.020). Higher EQD2 was associated with improved OS (HR 0.954, p=0.004) and increased risk of RN (HR1.068, p=0.003). There was no significant difference in median follow up (47.4 vs 36.6 m; p=0.92) or treatment effect (50% survival not reached; p=0.49) between the two groups. Black race improved median PFS (12.7 vs 8.9m, p=0.04) and OS (15.9 vs 10.8m; p=0.063). In this multi-center analysis examining impact of race in patients with gliomas, black patients were found to have improved OS and PFS, despite being more likely to receive a lower EQD2 dose and less likely to receive concurrent TMZ. Prospective studies to further investigate association of race as a prognostic factor for patients with gliomas are warranted. [ABSTRACT FROM AUTHOR]

Patients with low- and intermediate-risk prostate cancer (PCa) treated with radiation (RT) alone have excellent outcomes with anticipated long overall survival (OS). Although biochemical failure (BF) and OS rates are commonly reported from time of diagnosis, the relevance of such data diminishes over time for survivors. Conditional survival analyses can provide more relevant survival estimates for long-term survivors and help patients understand changing recurrence risks. The primary objective of this study was to report conditional OS and BF in patients with low- and intermediate-risk PCa treated with RT. A secondary objective was to determine if prognostic factors at initial treatment remain relevant later in survival. We performed a pooled analysis of patients with low- or intermediate- risk PCa enrolled in RTOG 0126 or 0415 treated with RT alone. OS was calculated (Kaplan–Meier) at various survivorship timepoints. Cumulative incidence (Phoenix definition) was used to calculate BF rates. Risk factors (Gleason score [GS], T stage, prostate-specific antigen (PSA), and EQD2 of prescribed dose) were analyzed at different timepoints using multivariable Cox proportional hazards modeling (MVA). A total of 2,591 patients were included (median age, 69 y; median PSA, 6.4 ng/mL; 48.5% with GS 7; 34.2% with stage T2 disease). Median follow-up was 6.9 y. The 3-, 5-, and 8-y OS from time of treatment were 96.2%, 89.2%, and 41.0%, respectively. Patients with 1-, 3-, and 5y of survival, had an additional 5 y survival rate of 73.3%, 42.6%, and 20.8%, respectively. On MVA at diagnosis, GS 7 (HR 1.352, P = 0.003), increasing age (HR 1.054, P < 0.001), and increasing PSA (HR 1.054, P = 0.01), were associated with all-cause mortality. For patients who survived 5 y, only age (HR 1.071, P < 0.001) was predictive of mortality. The 3-, 5-, and 8-y rates of BF from time of treatment were 7.1%, 12.5%, and 22.3%, respectively. For patients surviving 1, 3, and 5 y without BF, the rates of BF in the next 5 y were 14.2%, 17.2%, and 18.8%, respectively. On MVA, GS 7 (HR 1.907, P < 0.001), T2 disease (HR 1.375, P < 0.001), and increasing PSA (HR 1.114, P < 0.001) were significantly associated with increased risk of BF, whereas increasing EQD2 was associated with decreased BF rates (HR 0.922, P < 0.001). For patients who survived 5 y without BF, all initial prognostic factors remained statistically significant: GS 7 (HR 2.401, P < 0.001), stage T2 (HR 1.344, P = 0.0396), PSA (HR 1.109, P < 0.001), and EQD2 (HR 0.887, P < 0.001). Conditional risk of BF increases over time for patients with PCa initially treated with RT. Initial biologic and treatment variables remain prognostic at long-term follow-up, with dose-escalated RT continuing to be associated with decreased BF. This data can be used to counsel patients for their risk of BF in follow-up and to help decide on the frequency of PSA monitoring. [ABSTRACT FROM AUTHOR]

Patients with low- (LR) and intermediate-risk (IR) prostate cancer (PC) have excellent control rates following definitive radiation therapy (RT), but may experience treatment morbidity that impacts quality-of-life. To decrease normal tissue toxicity, modern techniques such as intensity modulated (IM) RT have largely replaced 3D-Conformal (3D-C) RT for PC. The objective of our study was to describe the comparative benefit of IMRT over 3D-CRT for patients undergoing prostate RT across different RT dosing and fractionation schemes. We performed a post-hoc analysis of patients enrolled on RTOG 0126 and RTOG 0415. RTOG 0126 randomized to dose escalated (DE), conventionally fractionated (CF) RT (79.2 Gy/44 Fx) or standard dose (SD) CF RT (70.2 Gy/39 Fx). RTOG 0415 randomized to hypofractionated (HF) RT (70 Gy/28 Fx) or SD CF RT (73.8 Gy/41 Fx). Treatment with 3D-CRT and IMRT was at the discretion of the treating physician; target OAR dose constraints were the same irrespective of RT modality. We performed a logistic regression analysis of RT modality and acute and late grade 2+ gastrointestinal (GI) or genitourinary (GU) toxicity as per CTCAE criteria across the different dose regimens. A total of 2,590 patients treated in both studies were included in our analysis. The median patient age was 69 and median follow up was 6.9 years. On RTOG 0126, 66.3% and 33.7% were treated with 3DCRT and IMRT respectively, while 20.6% and 78.2% were treated with 3DCRT and IMRT on RTOG 0415, respectively. On both studies combined, the overall rate of acute grade 2+ GI and GU toxicity was 7.7% and 20.9%, respectively; the rate of late grade 2+ GI and GU toxicity was 18.2% and 17.5%, respectively. There was no significant difference in acute grade 2+ GI or GU toxicity between those treated with either RT modality across the different dosing regimens. For patients receiving DE CF RT, IMRT resulted in improved late grade 2+ GI toxicity compared to 3D-CRT (16.8% vs. 23.4%, OR=0.65, 95% CI 0.44-0.96, p=0.03). There was also a significant improvement in late grade 2+ GU toxicity with the use of IMRT compared to 3D-CRT (9.4% vs. 16.1%, OR=0.53, 95% CI 0.32-0.86, p=0.01). However, there was no significant difference in toxicity rates between IMRT and 3D-CRT for late GI or GU toxicity when using SD CF RT or HF RT. Patients undergoing CF dose-escalated RT benefit from IMRT, while patients receiving CF SD (70.2Gy or 73.8 Gy) RT or HF RT did not show a difference in toxicity based on RT modality. These data provide a framework to compare the relative benefit of modern RT techniques (e.g., proton, SBRT, MR-guided RT) to IMRT in future studies. [ABSTRACT FROM AUTHOR]

Salvage radiation therapy (SRT) and androgen-deprivation therapy (ADT) are routinely used in patients with elevated prostate-specific antigen (PSA) levels after radical prostatectomy (RP). Although overall survival (OS) and biochemical-failure (BF) following SRT are useful when counseling patients at the time of treatment, the utility of survival data from time of diagnosis diminishes over time. Conditional survival (CS) can provide more relevant estimates, especially given long-term PCa survivorship. The primary aim of this study was to analyze CS estimates for recurrent PCa patients undergoing SRT ± ADT. The secondary objective was to determine if factors prognostic of OS and BF at diagnosis remain relevant in survivorship. We analyzed data from 760 post-RP patients enrolled in NRG/RTOG 9601 (1998–2003). Eligible patients included men who had undergone prior RP and had pT2/T3 disease without nodal involvement and detectable PSA levels of 0.2–4.0 ng/mL. Patients were randomly assigned to undergo SRT and receive either 24 mo of ADT or placebo. OS was calculated (Kaplan–Meier), cumulative incidence was used to estimate BF rates, and prognostic factors associated with OS and BF were analyzed by multivariable Cox proportional hazards modeling (MVA). Patients were followed for a median of 13 y. The 5- and 10-y OS estimates from diagnosis were 93% and 80%, respectively. At 1- (n = 755), 3- (n = 727), 5- (n = 680), 8- (n = 602), and 10-y (n = 543) survivorship, chances of surviving an additional 5 y were 92%, 89%, 86%, 80%, and 72%, respectively. On MVA at diagnosis, omission of ADT (HR 1.308, P = 0.0403), increasing age (HR 2.761, P < 0.0001), and Gleason score (GS) 8−10 (HR 1.054, P =0.01), were associated with all-cause mortality. For those who achieved survivorship at 5 y, only age (HR 2.973, P < 0.0001) and GS 8–10 (HR 1.801, P = 0.0063) were prognostic of mortality on MVA. The 5- and 10-y rates of BF from diagnosis were 36% and 52%, respectively. For patients who survived 1 (n = 725), 3 (n = 560), 5 (n = 435), 8 (n = 320), and 10 (n = 268) y without BF, chances of BF at an additional 5 y were 39%, 33%, 26%, 20%, and 20%, respectively. On MVA at time of SRT, omission of ADT (HR 2.139, P < 0.0001), GS 7 (HR 1.376, P = 0.0062), GS 8–10 (HR 1.717, P = 0.0005), and higher pretreatment PSA (HR 1.442, P = 0.0215), were associated with BF. For those who survived 5 y after treatment without failure, only omission of ADT (HR 1.407, P < 0.0384) was prognostic of BF. Conditional risk of BF for patients treated with SRT remains elevated at levels similar to those at initial treatment for up to 3 y after SRT, after which BF rates decrease. ADT continues to confer a reduced risk for BF for long-term survivors. This data can be used to inform survivorship care planning and highlights the need for continued PSA surveillance after completion of treatment. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): PD-L1 is often overexpressed in the tumor microenvironment to dampen host immune response and allow tumor proliferation. Radiation works partially through the immune system, but the correlation between PD-L1 expression in primary tumors and oncologic outcomes for metastatic lesions treated with SRS with concurrent immunotherapy (ICI) is unknown. We seek to evaluate the association of PD-L1 expression level of the primary tumor in patients undergoing SRS/fSRT with local control and symptomatic radiation necrosis.Materials/methods: A total of 282 patients with 616 metastatic brain lesions which were treated with SRS or fSRT from 2014-2020 were retrospectively reviewed at a single institution. PD-L1 expression level in the primary tumor was available for 43 patients with 147 metastatic brain lesions, of whom 33 patients with 103 lesions received concurrent ICI. Concurrent ICI was defined as having received ICI within 3 months before, during, or after SRS. PD-L1 expression was categorized as negative (PDn) (< 1%), or positive (PDp) (≥1% - 100%). Patients were excluded if a one month post-treatment MRI was not available or if > 15 lesions were treated. The lesion level endpoint of local failure (LF) and symptomatic radiation necrosis (RN) were analyzed using Kaplan Meyer method with salvage WBRT used as a censoring event. Univariate and multivariate analysis were performed with competing risk adjustment.Results: One-hundred and four lesions (range 1-10) from 33 unique patients were included in the analysis. Ten patients with PDn primary tumors with 31 lesions and 23 patients with PDp primary tumors with 73 lesions were analyzed. After competing risk adjustment, the LF rate at 12 months were rare for both patient cohorts: PDn vs PDp was 3.5% and 1.5% (P = 0.99), respectively. For RN, the event rate at 12 months for PDn vs PDp was 4% vs 14% (HR 0.648; 95% CI 0.05-9.03; P = 0.747). On MVA for local control, factors such as metastasis size (< 2cm vs ≥2 cm; P = 0.181), histology (NSCLC vs other; P = 0.997), or lesion location (supratentorial vs other; P = 0.392) were not found to have a statistically significant association. On MVA for RN, only metastasis size reached statistical significance (HR 32.8; 95% CI 3.56-301.81; P < 0.002).Conclusion: Patients receiving concurrent ICI and SRS for management of brain metastases have an excellent local control, irrespective of PD-L1 status. PD-L1 positive patients may be at an increased risk for RN. These findings require further evaluation in a larger patient cohort.Author Disclosure: G.S. Alexander: None. B.Savla: None. L.J. Berg: None. K. Sun: None. J.S.Remick: None. E.S. Kowalski: None. S. Chen: None. N.Lamichhane: 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. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Intrahepatic cholangiocarcinoma (iCCA) remains a highly lethal disease. Biomarkers are needed to identify pts who may benefit from specific therapeutic strategies. Here, we hypothesized that imaging features derived from pre-therapy CT are associated with histopathological and clinical outcomes.Materials/methods: Retrospectively, we identified 60 pts with localized iCCA (24 M, 36 F, median age 65 [range 26-84]), who received upfront resection as a discovery cohort (D1) and 87 pts with locally advanced iCCA (49 M, 38 F, median age 64 [range 30-88]) who received chemo and radiation therapy as a validation cohort (D2). Using the pre-therapy CT, we contoured the tumors in the arterial phase and used a voxel-based method to quantify the tumors enhancing volume (normalized to liver parenchyma), and called this quantification: volumetric enhancement (VE). Using the training cohort only, we performed receiver operating characteristic (ROC) analysis to evaluate the classification ability of VE in differentiating long vs short (36 months) overall survival (OS), and to obtain an optimal cut-off for validation in D2. Corresponding slides from resection specimens of 38 pts from D1 were stained with H&E and digitally analyzed to quantify the tumor infiltration percentage. We used Pearson correlation coefficient, likelihood ratio, Kaplan-Meier and Cox-proportional hazard for statistical analyses.Results: As a continuous variable, higher VE values were associated with better OS in D1 (RR = 0.97, 95% CI [0.95-0.99], P = 0.0007) and D2 (RR = 0.96, 95% CI [0.95-0.98], P < 0.0001). On multivariate analyses, VE as a continuous variable was an independent prognostic factor for OS accounting for traditional covariates in D1 (RR = 0.97, 95% CI [0.95-0.99], P = 0.002) and D2 (RR = 0.96, 95% CI [0.94-0.98], P < 0.0001). Using D1, VE demonstrated high accuracy in classifying pts with short vs. long term survival (Area under the curve (AUC) = 0.77), with an optimal threshold of 32.2% to dichotomize the VE into low versus high. Kaplan-Meier analysis showed that pts with high VE tumors had better median OS (145 vs 34 months, P = 0.002 and 46 vs 22 months, P < 0.0001), and distant metastasis free survival DMFS (107 vs 11 months, P < 0.0001 and 29 vs 13 months, P < 0.0001) compared to those with low VE tumors in D1 and D2 respectively. Pts with low VE tumors were more likely to have a higher nodal positivity rate compared to those with high VE tumors in D1 (P = 0.002). Tumors with high VE values had higher histopathological tumor infiltration percentage compared to those with lower VE values (⍴ = 0.72, P < 0.0001).Conclusion: A CT-based measure of volumetric enhancement was associated with clinical and biological differences in resectable and unresectable iCCA, which may help personalize use of chemotherapy, radiation, and surgery in this disease. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Functional lung avoidance (FLA) radiotherapy (RT) aims to minimize post-RT respiratory function loss. Current FLA approaches spatially map lung function and preferentially avoid dose to high-functioning lung (HFL). However, current FLA methods do not adequately consider the conducting architecture responsible for gas exchange (airways/vasculature). Previously, we showed that excessive toxicity to airways results in airway collapse, leading to functional loss within downstream lung sub-volumes. We proposed the functionally weighted airway sparing (FWAS) method to spare airways connected to HFL. Here, we propose a novel method that combines both FLA and FWAS to minimize post-RT functional loss.Materials/methods: We estimated post-RT decline in regional airflow and ventilation as a combined measure of functional loss. High-res breath-hold CTs (BHCTs) and simulation 4DCTs from seven lung SAbR patients were analyzed retrospectively. Three functional avoidance IMRT strategies were compared to conventional IMRT planning: (i) FLA - a 4DCT-based ventilation map was used to delineate the HFL, defined as the functional regions of the lung above the mean intensity in the map. FLA plans were optimized such that mean dose and V13.5 in HFL were as low as reasonably achievable while meeting clinical dose constraints. (ii) FWAS - a virtual bronchoscopy software was used to autosegment 12 airway generations on the BHCT. Each terminal airway was connected to a lung sub-volume and assigned a functional weight based on the relative ventilation contribution of the sub-volume based on the ventilation map. For non-terminal airways, the weight was calculated in terms of the cumulative ventilation supported by corresponding downstream airways. These weights were used in the optimization along with airway dose constraints, estimated as a function of airway diameter and 5% probability of collapse. (iii) FLA+FWAS - the two strategies were combined to reduce the dose to both HFL and corresponding upstream airways.Results: Overall, FLA+FWAS provided the highest ventilation preservations with an average improvement, compared to conventional plans, of 12%, followed by FWAS (8%), and FLA (3%). In all cases, clinical objectives for planning target volume and organs at risk were met. Generalized estimated equations with identity link and normal distribution and exchangeable correlation matrix showed that all these improvements were statistically significant (P < 0.04).Conclusion: These initial results suggest that it is crucial to consider the serial as well as the parallel nature of the lung, being airway sparing likely more critical to minimize post-RT functional loss. [ABSTRACT FROM AUTHOR]