PURPOSE To assess whether adding fluoropyrimidine sensitized radiotherapy (CXRT) to adjuvant chemotherapy improves overall survival (OS) after curative intent resection of the pancreatic head. METHODS This was a multicenter, randomized phase III, two step trial. Step 1: gemcitabine versus gemcitabine + erlotinib (previously reported). Step 2: random assignment to sixth chemotherapy cycle ± CXRT after five cycles of step 1 chemotherapy without progression. Outcomes of step 2 random assignment are reported here. Assuming 17 months median OS (chemotherapy alone), the sample size was 354 patients (hazard ratio [HR], 0.76, 80% power, one-sided α = .05, 316 OS events). OS/disease-free survival (DFS) were estimated by Kaplan-Meier and arms compared using the log-rank test. RESULTS A total of 354 patients (median age 63, 55% male, 56% performance status, 1) were randomly assigned to chemotherapy (174) or chemotherapy + CXRT (180). Univariable median and 5-year OS (90% CIs) were 2.6 years (2.1-3.1) and 23.1% (17.7-28.6) for chemotherapy alone, and 2.3 years (2.0-2.6) and 27.9% (22.2-33.6) for chemotherapy + CXRT. The OS primary end point was not met (HR, 0.96 [90% CI, 0.79 to 1.18]; one-sided P = .38, two-sided P = .77). Chemotherapy + CXRT was associated with a trend for improved DFS (univariably; HR, 0.82 [95% CI, 0.65 to 1.03]; P = .089), without increase in grade 4/5 toxicities. However, grade 3 toxicity increased (38% v 19%, P < .001). Significantly, treatment by nodal status interactions showed that CXRT improved OS ( P = .0063) and DFS ( P = .014) in node-negative patients. CONCLUSION Overall, the addition of adjuvant CXRT to adjuvant gemcitabine did not statistically significantly improve OS, DFS, or increase grade 4/5 toxicity. For node-negative patients, CXRT improved OS and DFS. These results, if confirmed in studies with current or future systemic therapies, would support the use of adjuvant/neoadjuvant CXRT for node-negative patients.

BACKGROUND:NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT-Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). METHODS:Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease-free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6-8 weeks post-CRT; one-sided α = 0.05, using a χ2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5-, 2-, and 2-point increases, respectively, from baseline to 6-8 weeks post-CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. RESULTS:From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6-8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6-8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different (p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non-pCR patients, respectively, having improved 1-year ECS scores. CONCLUSIONS:The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

PURPOSE:The NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9804 trial randomized patients with "good-risk" ductal carcinoma in situ (DCIS) to radiation (RT) or no RT following lumpectomy. The Eastern Cooperative Oncology Group-American College of Radiology Imaging Network E5194 trial had a comparable cohort observed without RT. Tamoxifen use was optional in both trials. This ancillary exploratory analysis combining both data sets assessed the effect of tamoxifen on ipsilateral breast recurrence (IBR) in "good-risk" DCIS treated with lumpectomy alone. METHODS AND MATERIALS:A combined database from the non-RT arm of NRG/RTOG 9804 and the "good-risk" cohort from E5194 (low- or intermediate-grade, ≤2.5 cm, excision margins ≥3 mm) was created, and distributions of patient and DCIS characteristics by tamoxifen use were compared by χ2. IBR, invasive IBR, DCIS-IBR, contralateral breast event, and overall survival were estimated, and distributions were compared between tamoxifen use groups. Univariate and multivariable Fine-Gray regression models were used to analyze factors that may be associated with endpoints. RESULTS:Eight hundred and seventy-eight patients were analyzed (317 from NRG/RTOG 9804 and 561 from E5194). The use of tamoxifen overall was 43.1% (65.6% in NRG/RTOG 9804 and 30.3% in E5194). At a median follow-up of 14.85 years, there were 117 IBRs (65 invasive and 52 DCIS). There was a significant association for reduced IBR with tamoxifen use (P = .001); estimated 15-year IBR with tamoxifen is 11.4% (95% CI, 7.9-15.5) and without is 19.0% (15.3-22.9). Tamoxifen use was significantly associated with reduced invasive IBR (P = .0048) but not DCIS-IBR (P = .089). On multivariable analysis, patients who received tamoxifen were 46% less likely to have any IBR (hazard ratio, 0.54; 95% CI, 0.35-0.83; P = .0045), and 57% less likely to have invasive IBR (hazard ratio, 0.43; 95% CI, 0.24-0.77; P = 0.0042). CONCLUSION:For patients with "good-risk" DCIS treated with lumpectomy without RT, tamoxifen use was significantly associated with a reduction in IBR overall and invasive IBR, not DCIS-IBR.

PURPOSE For patients with breast cancer undergoing breast conservation, escalating the dose (boost) of radiation to the lumpectomy cavity after whole-breast irradiation (WBI) reduces ipsilateral breast recurrence (IBR) but extends treatment duration. This phase III trial investigated whether boost delivery during WBI versus after WBI provides noninferior IBR and preserves cosmetic appearance. METHODS NRG/RTOG 1005 randomly assigned patients at higher risk for IBR after lumpectomy and axillary surgery to either a sequential boost of 12 Gy in six fractions(F) or 14 Gy in 7F after WBI of 50 Gy in 25F or 42.7 Gy in 16F (sequential arm) or a concurrent boost of 8 Gy in 15F of 0.53 Gy per day with WBI of 40 Gy in 15F (concurrent arm) using 3-dimensional conformal radiation therapy (RT) or intensity-modulated RT. Based on 1.59% 5-year IBR for the sequential arm, defining the noninferiority margin as a hazard ratio upper limit on the 90% CI of 2.12, 2,312 patients provide 80% power for noninferiority of IBR as first recurrence for the concurrent arm. Secondary end points included disease-free survival and overall survival, adverse events (AEs), and cosmetic outcomes. RESULTS Between May 24, 2011, and June 20, 2014, 2,354 patients were randomly assigned, with 2,255 eligible for analysis (sequential arm, n = 1,118; concurrent arm, n = 1,137). With median follow-up of 7.3 years, there were 56 IBR events; 5- and 7-year IBR were 2.1% and 2.2% on the sequential arm and 1.9% and 2.6% on the concurrent arm, respectively. The noninferiority criterion was met: HR (90% CI): 1.31 (0.84 to 2.04), P = .037. No differences were observed in AEs, cosmetic outcomes, or survival between arms. CONCLUSION Concurrent boost during WBI results in noninferior IBR compared with sequential boost without worsening toxicity or cosmetic outcomes and reduces overall treatment time.

PURPOSE:Definitive chemoradiation (CRT) is standard for patients with medically inoperable esophageal cancer. OBP-301 is a modified adenovirus that adds a human telomerase reverse transcriptase gene promoter, replicating only in tumor cells to cause lysis. METHODS AND MATERIALS:In this phase 1 study, OBP-301 was added to carboplatin/paclitaxel and radiation therapy (RT) (50.4 Gy). Patients received intratumoral OBP-301 via endoscopy 3 days prior to and then at days 12 and 26 of RT. The primary endpoint was protocol-defined dose-limiting toxicity. Secondary endpoints included clinical complete response (cCR) rate, number alive and alive without progression at 1 year. RESULTS:From June 2020 to July 2024, 15 evaluable patients were enrolled. Fourteen patients (93%) received all planned OBP-301 injections and 50.4 Gy RT. No dose-limiting toxicities were observed. The most common treatment-related grade 3/4 toxicities were neutropenia (40%) and lymphopenia (33%). Two patients died prior to restaging: 1 patient developed grade 5 respiratory failure 6 weeks after CRT (suspected RT pneumonitis), whereas a second patient had unrecognized airway involvement at baseline, which led to a tracheoesophageal fistula during Week 3 of CRT. The cCR rate for patients undergoing restaging (n = 13) was 100% (95% CI, 77-100), and 87% (95% CI, 62-96) for all 15 patients. At 1 year, 9 (60%) out of 15 patients are still alive and 8 (53%) are alive without progression. CONCLUSIONS:OBP-301 administration before and during CRT is feasible and safe, resulting in a very promising cCR rate. A randomized study is being planned to further evaluate safety and efficacy.

ImportanceMost patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy.ObjectiveTo determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone.Design, Setting, and ParticipantsThis multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023.InterventionPersonalized SBRT, 27.5 to 50 Gy in 5 fractions.Main Outcomes and MeasuresThe primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life.ResultsOf 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77; 90% CI, 0.59-1.01; 1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72; 95% CI, 0.52-0.99; 2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P < .001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively (P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively.Conclusions and RelevanceIn this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone.Trial RegistrationClinicalTrials.gov Identifier: NCT01730937

435 Background: Definitive chemoradiation (CRT) is a standard-of-care for patients (Pts) with medically inoperable esophageal cancer (EC). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that 58% of control arm Pts have locally persistent disease. OBP-301 is a conditionally-restricted, replication-competent adenovirus derived from human adenovirus type 5 that adds a human Telomerase Reverse Transcriptase gene promoter, replicating only in tumor cells to cause lysis.It may cause immunogenic cell death, enhance RT increasing radiosensitization by blocking DNA repair and improve local control. Methods: In NRG-GI007, a phase 1 study (NCT04391049), OBP-301 was added to weekly carboplatin/paclitaxel and RT (50.4 Gy/28 fxs) for medically inoperable EC Pts with pathologically proven adenocarcinoma or squamous cell carcinoma (SCC) of the esophagus or Siewert Type I/II gastroesophageal junction. Pts receive 1-2mL of intratumoral OBP-301 1×10 12 virus particles/ml via endoscopy 3 days prior to and then at days 12 and 26 of CRT. The primary endpoint was protocol-defined dose-limiting toxicity, already reported. Secondary endpoints reported here are treatment-related (definitely or probably related to any protocol treatment) AEs - all and grade 4+ non-hematologic, and cCR in the primary tumor, defined as negative EGD/biopsy 6-8 weeks post-CRT. Per the protocol design, no statistical testing is done for these endpoints. Results: Initially, 6 evaluable (eligible and started protocol treatment) Pts were enrolled from June 2020 to April 2023. As initial dose level was deemed safe, an additional 9 Pts were enrolled from August 2023 to July 2024, totaling 15 evaluable Pts for secondary endpoints. Median age was 74 years, 9 Pts (60%) with ECOG PS 1. 11 Pts (73%) had adenocarcinoma and 4 had SCC; 11 Pts had N+ disease. 14 Pts (93%) received all planned OBP-301 injections and received 50.4 Gy RT. The most common treatment-related grade 3/4 AEs were decreased neutrophil (6 Pts; 40%) and lymphocyte counts (5 Pts; 33%), expected with CRT. No grade ≥3 OBP-301-related non-hematologic AEs were reported. 2 Pts died prior to restaging neitherdefinitely or probably related to OBP-301: 1 Pt developed grade 5 respiratory failure 6 weeks after CRT (suspected RT pneumonitis), while a 2 nd Pt had an unrecognized tumor invasion of the bronchus at baseline, which worsened during week 3 of CRT, resulting in a grade 5 tracheo-esophageal fistula. 2 Pts have not yet reached time for restaging. All 11 Pts who have been restaged had a cCR, for a preliminary cCR rate of 100% (95% CI: 74.1%, 100%). Conclusions: OBP-301 + CRT is safe and the preliminary cCR rate compares favorably to the historical control from NRG/RTOG 0436. Updated safety and cCR data will be presented. A randomized study is being planned. Clinical trial information: NCT04391049 .

Background: NRG-BR002 randomized patients with OMBC to SOC with vs. without ablation (surgery or radiation) of all visible metastases. The phase II PFS go signal for improvement with ablation was not met. Blood for CTCs was collected from consenting patients and sent for the FDA-approved CellSearch CTC assay and High-Definition Single Cell CTC Analysis (HDSCA). The primary CTC objective was that pretreatment CTCs (PreRX CTCs) would be prognostic for PFS. Secondary objectives included baseline CTCs being predictive for the effect of RX on PFS and CTC post-treatment clearance rate correlating with PFS. Statistical Design and Methods: A secondary endpoint analysis of the prognostic effect of PreRX CTCs on PFS and the interaction between study arm and the PreRX CTCs on PFS were evaluated for both assays using multivariable Cox proportional hazards models (MVA). CellSearch CTCs were dichotomized 0 vs. ≥ 1 and HDSCA CTCs were assessed by < vs. ≥ lowest quartile (Q1). Due to small numbers of CTC+ cases, CTC clearance correlation with PFS was not able to be tested. Descriptive results are presented. Results: Of 125 phase II eligible patients, 108 (86%) consented to blood collection. Among the cohort with CTC data (n=62 for CellSearch, n=60 for HDSCA), demographic and treatment variables were balanced between study arms and similar to the trial population. Thirty-six (58%) and 26 (42%) had CellSearch CTC = 0 and ≥1, respectively. Fifteen (25%) and 45 (75%) had HDSCA CTCs < Q1 and ≥ Q1, respectively. Median follow up at the time of analysis was 48 months. PreRX CTCs (CellSearch and HDSCA) were not prognostic for PFS. In each of the analyses for PreRX CTC (0 or < Q1) being predictive for PFS, after adjusting for number of metastases (1 v >1), the interaction between study arm and CTCs had a HR > 3, reaching statistical significance for HDSCA (p=0.024; HR 5.58, 95% CI: 1.26, 24.77) and trending towards statistical significance for CellSearch (p=0.063; HR 3.39, 95% CI: 0.94, 12.25). Patients in the ablation arm, with HDSCA PreRX CTCs < Q1, experienced better PFS than those with PreRX CTCs ≥ Q1; 78% vs. 33% at 2 years, respectively, as compared to patients on the control arm (17% vs. 55%). Patients in the ablation arm, with CellSearch PreRX CTCs = 0, also experienced better PFS than those with PreRX CTCs ≥ 1; 54% vs. 27% at 2 years, respectively, as compared to patients on the control arm (35% vs. 61%). For CellSearch only, 19/62 patients (9 SOC and 10 ablation) had positive PreRX and PostRX CTC values. In the SOC arm, clearance of CTCs was seen in 6 patients (all progression-free) and no clearance in 3 (2 progressed/1 died). In the ablation arm, clearance (n=5)/decrease (n=2) of CTCs was seen in 7 patients; however, only 3 remained progression-free; and an increase was seen in 3 patients whose disease progressed. For the 9 patients across both arms with PreRX and PostRX CTCs that progressed, all 9 developed new metastatic sites. Conclusion: Lower PreRX CTCs predicted for improved PFS after ablation using the HDSCA assay. The pre-specified CTC analyses provide consistent results using two independent assays highlighting the robustness of the finding. These hypothesis-generating findings suggest that PFS is improved in CTC negative OMBC patients who are treated with ablation. This project was supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), BCRF-23-089, U01CA285013 (LBRL), and U24CA180803 (IROC) from the National Cancer Institute (NCI). Citation Format: Wendy Woodward, Jennifer Moughan, Steven Chmura, Peter Kuhn, Anthony Lucci, Virginia F Borges, Joseph K Salama, Hania Al-Hallaq, Martha M Matuszak, Michael T Milano, Nora Jaskowiak, Stephanie N Shishido, Jeremy Mason, Salyna Meas, Carol Hall, Sachin R Jhawar, Robert A Nordal, Gregory N Gan, Diane C Ling, Imran Zoberi, Sobha Kurian, Kathryn Winter, Eleftherios P Mamounas, , Julia R White. Baseline circulating tumor cells (CTCs) predict for progression-free survival (PFS) after ablation on NRG-BR002, a randomized phase II/III study of ablation vs. standard systemic therapy care (SOC) for oligometastatic breast cancer (OMBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-01-21.

Background The NRG/RTOG 9804 and ECOG-ACRIN E5194 studies sub-classified duct carcinoma in situ (DCIS) into different risk groups after breast conservation surgery (BCS) based on size, DCIS grade, and margin width. NRG/RTOG 9804 randomized patients with “good risk” DCIS (size ≤2.5 cm, grade 1-2, margin ≥3mm) to whole breast radiation (RT) or none, and ECOG-ACRIN E5194 had 2 cohorts, one observing patients with the same “good risk” characteristics after BCS without RT. In both trials, the use of tamoxifen) was optional but tracked. This ancillary analysis of both trials was undertaken to assess the role of tamoxifen alone on ipsilateral breast recurrence (IBR) in this “good risk” group not receiving RT. Methods A combined database from the non-RT arm of NRG/RTOG 9804 and the “good risk” cohort from ECOG-ACRIN E5194 was created and distributions of patient and DCIS characteristics by tamoxifen use (yes vs. no) were compared using the Chi-square test. IBR, invasive IBR, DCIS IBR and contralateral breast event (CBE) were estimated by the cumulative incidence method and distributions between tamoxifen use were compared using Gray’s test. A 2-sided significance level of 0.05 was used. Univariate and multivariable Fine-Gray regression was used to analyze the effects of factors, in addition to tamoxifen use, that may be associated with endpoints. Results 878 patients were analyzed, 317 patients from NRG/RTOG 9804, and 561 from ECOG-ACRIN E5194. Median age was 59, margin width was ≥3mm or negative by re-excision in 97.8%, size was ≤5mm in 48.1%, and grade was 1-2 in 87.5%. The use of tamoxifen in the combined no-RT group was 43.1% (65.6% in NRG/RTOG 9804 and 30.3% in ECOG-ACRIN E5194). Median follow up of all patients was 14.85 years. There were 117 IBR, 65 invasive and 52 DCIS. There was a statistically significant association for reduced IBR with tamoxifen use (p=0.001); estimated 15-year IBR (95% CI) with tamoxifen is 11.4% (7.9%, 15.5%) and without is 19.0% (15.3%, 22.9%). Further analysis showed the reduction to be significantly associated with tamoxifen use for invasive IBR (p=0.0048) but not for DCIS IBR (p=0.089). No associations were seen for CBE. On univariable analysis, pathologic size (≤ 5 mm vs. > 10 mm) was significantly associated with IBR (p=0.0001) as was DCIS grade (1 vs 2, p=0.042). On multivariable analysis for IBR, DCIS grade fell out of the model and after adjusting for pathologic size, tamoxifen use remained statistically significantly associated with reduced IBR. On multivariable analysis for invasive IBR, size fell out of the model and adjusting for grade, tamoxifen use remained statistically significantly associated with reduced invasive IBR. Patients who received tamoxifen were 44% less likely to have any IBR (HR = 0.56, 95% CI: 0.38, 0.84; p=0.0044), and 51% less likely to have invasive IBR (HR=0.49, 95% CI: 0.28, 0.84; p=0.0092), as compared to patients with no tamoxifen. Conclusions For women with “good risk” DCIS who opt for BCS without RT, the use of tamoxifen is significantly associated with a reduction in IBR overall and specifically invasive IBR, not DCIS IBR. Citation Format: Jean Wright, Jennifer Moughan, Habib Rahbar, Amit B Shah, Christopher Comstock, Lesly A Jarvis, Judy A Tjoe, Isabelle Germain, Sunil S Badve, Eric Strom, Abram Recht, Diane C Ling, Laura A Vallow, Joseph J Stephenson, Adam Currey, Eleanor M Walker, Harold Reiter, Michael L. Steinberg, Lori J Pierce, Kathryn Winter, Joseph Sparano, Nancy E Davidson, Antonio C. Wolff, Robert J Gray, and Beryl McCormick. Impact of Tamoxifen Only after Breast Conservation Surgery for "Good Risk" Duct Carcinoma in Situ: Results from the NRG Oncology/RTOG 9804 and ECOG-ACRIN E5194 Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS2-02.

Importance Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy. Objective To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone. Design, Setting, and Participants This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023. Intervention Personalized SBRT, 27.5 to 50 Gy in 5 fractions. Main Outcomes and Measures The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life. Results Of 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77; 90% CI, 0.59-1.01; 1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72; 95% CI, 0.52-0.99; 2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P < .001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively (P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively. Conclusions and Relevance In this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone.

341 Background: Definitive chemoradiation (CRT) is a standard-of-care for patients (Pts) with medically inoperable esophageal cancer (EC). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that about half of Pts have locally persistent disease. OBP-301 is a conditionally restricted, replication-competent adenovirus derived from human adenovirus type 5 that adds a human Telomerase Reverse Transcriptase (hTERT) gene promoter, replicating only in tumor cells to cause lysis. It may cause immunogenic cell death, enhance RT, and improve local control. OBP-301 was previously studied with RT in Japanese esophageal cancer Pts and shown to be safe and has promising activity. 1 Methods: In NRG-GI007, a phase 1 study (NCT04391049), OBP-301 is added to weekly carboplatin/paclitaxel and RT (50.4 Gy/28 fractions) for Pts with medically inoperable EC. Pts receive 1-2mL of intratumoral OBP-301 1×10 12 virus particles/ml via endoscopy 3 days prior to and then at days 12 and 26 of CRT. The primary endpoint is dose-limiting toxicity (DLT), defined as adverse events (AEs, by CTCAE v5) definitely or probably attributed to OBP-301 that meet either of the following: (1) leading to a >14-day cumulative delay in CRT or (2) any grade ≥ 3 AE EXCEPT: grade 3 nausea/vomiting, grade 3 esophagitis or dehydration, first occurrence of grade 3/4 neutropenia, or grade 3/4 lymphopenia. Initially, 6 evaluable Pts (eligible and started protocol treatment) are enrolled. If protocol defined DLT occurs in ≤1 of 6 Pts, the dose will be deemed safe and an expansion cohort of 9 more will be enrolled to further assess safety and obtain a preliminary assessment of clinical complete response. If ≥2 Pts have a DLT then one de-escalated OBP-301 dose will be assessed. Results: From June 2020 to April 2023, 6 evaluable Pts were enrolled. Median age was 73.5 years, all male. Five Pts had adenocarcinoma and 1 had squamous cell carcinoma; 3 Pts had node-positive disease. All Pts received all planned OBP-301 injections, along with 50.4 Gy RT. Four out of 6 Pts received all 5 weekly doses of chemo for > 85% of planned total dose, and 2 got 4 weekly doses for > 70% of planned total dose. No Pt experienced ³7 day treatment delay. The following treatment-related (attributed as definitely, probably, or possibly related to CRT and/or OBP-301) grade 3 AEs were reported across 5 Pts: decreased neutrophil count (3 Pts), decreased lymphocyte count (2 Pts), decreased WBC (2 Pts), and fever and fatigue (1 Pt each). There were 4 Pts with AEs reported as definitely or probably related to OBP-301, all grade ≤2. No DLT occurred. Conclusions: No DLTs in the 6 evaluable Pts were observed and it is concluded that the initial OBP-301 dose level is safe. NRG-GI007 was reopened on August 7, 2023 to the expansion cohort. Full toxicity and treatment data will be presented. 1. Eur J Cancer 2021;153:98. Clinical trial information: NCT04391049 .

4005 Background: If 5FU/Capecitabine sensitized radiotherapy (RT) is beneficial in the adjuvant (adj) management of PA after adj chemotherapy (chemo) is controversial. NRG/RTOG 0848 was designed to address this issue. Methods: This was a 2 step NCTN randomized (rndmzd) trial. Step 1 rndmzd patients (pts) to 5 cycles of gemcitabine +/- Erlotinib. Step 2 rndmzd pts to a 6th cycle of the same chemo +/- 5FU/Capecitabine with 50.4 Gy in 28 fractions RT (chemo+CRT). Step 1 eligibility included: R0/R1 resection, M0, ECOG PS 0-1, CA19-9≤180. Step 2 eligibility included > 4 cycles chemo (gem, gem combo, (m)FOLFIRINOX). RT included real time 3D/IMRT treatment (RX) plan review, scoring, and approval. At Step 2, pts stratified by nodal status (+ vs -), CA19-9 (≤90 vs > 90-180), surgical margins (R0 vs R1), and adjuvant chemo. Primary endpoint was OS. Secondary endpoints are DFS and AEs (CTCAEv4). Assuming 17 months median OS (chemo) and hypothesized 22.5 months (chemo+CRT), sample size was 354 pts (HR = 0.76, 80% power, 1-sided α = 0.05, 316 OS events). Due to lower than projected event rate, trial was amended to report at the earlier of (a) 316 observed OS events or (b) 5 years of follow-up time from Step 2 accrual closure (265 OS events, 72% power, same α). OS and DFS were estimated by Kaplan-Meier and arms compared using log-rank test. Multivariable analyses (MVA) used Cox proportional hazards models. Results: Accrual began 11/2009; closed 10/2018. 354 pts rndmzd (174 chemo, 180 chemo+CRT). Median follow-up for all & alive pts = 2 & 7 years, respectively, with 270 OS events. Median age 63, 45% female, 81% white, 13% AA. 83% R0, 26% node negative, 96% CA19-9 < 90. 13% of chemo+CRT pts did not receive RT. AEs were comparable (grade 4: 10% [chemo] vs 11% [chemo+CRT] and 1 grade 5 AE in each arm). Univariate OS/DFS results shown in Table. In initial MVA, RX, CA19-9, surgical margins were not statistically significantly associated with OS or DFS, but nodal status (OS, DFS) and race (OS) were. In further analyses, significant interactions were found between RX and nodal status for both OS and DFS. Node negative pts treated with chemo+CRT had better outcome than chemo pts; node positive pts did not (Table). Conclusions: Chemo+CRT did not improve OS overall, but did improve DFS. Both OS and DFS were improved with Chemo+CRT in node negative pts. Chemo+CRT did not increase Gr 4 or 5 AEs compared to chemo. Clinical trial information: NCT01013649 . [Table: see text]

Long term follow up confirms no improvement in OS with dose escalation in this study population. However, there are significant improvements in ABF, PBF, DM, LP, and need for salvage therapy. Despite the use of more salvage therapy in the low dose arm, dose escalated RT resulted in lower rates of DM, a clinically relevant endpoint. Patients receiving dose escalation do experience a higher rate of grade 2+ GU and GI toxicity but no worse grade 3+ toxicities.

489 Background: To determine if SBRT followed by sorafenib (SBRT/S) improves overall survival (OS), progression free survival (PFS) and quality of life (QOL) vs. sorafenib alone (S), in patients (pts) with HCC. Methods: Eligible pts had new or recurrent HCC, unsuitable for surgery, ablation or TACE, with Zubrod performance status (PS) 0-2, Child-Pugh (CP) A, BCLC stage B or C, ≤ 5 HCCs, sum of hepatic HCCs ≤ 20 cm, and distant metastases ≤ 3 cm. Pts were randomized 1:1 to S 400 mg BID vs. SBRT (27.5-50 Gy in 5 fractions) followed by S 200 mg BID, increased to 400 mg BID after 28 days. Primary endpoint was OS; reported secondary endpoints - PFS, adverse events (AEs - CTCAEv4), and QOL (improvement in FACT-Hep score by ≥ 5 points from baseline to 6 months). Planned sample size was 292 pts (238 OS events, HR=0.72, 80% power, 1-sided α=0.05). Accrual closed early, due to a change in HCC standard of care. Statistics were amended to report as of 7/1/2022, projecting 155 OS events, with 65% power and the same α. OS and PFS were estimated by Kaplan-Meier and arms compared using log-rank test. Cox proportional hazards models were used to analyze treatment effect. Secondary endpoints were tested with 2-sided α=0.05. Results: Of 193 pts accrued from April 2013 to March 2021 from 23 sites, 177 eligible pts were randomized to S (n=92) vs. SBRT/S (n=85). Median age was 66 yrs (27-84); 41% had Hep. C; 19% had Hep. B or B/C. 82% were BCLC stage C. 74% had macrovascular invasion (MVI), 63% with VP3 or VP4 MVI. 4% had metastases. Median sum of max diameter of HCCs was 8.2 cm for S and 6.7 cm for SBRT/S; 40% had a single HCC. Median follow-up for all and alive pts was 13.2 and 33.7 mo. 22% of S pts received SBRT after discontinuing S. With 153 OS events, median OS was improved from 12.3 mo. (90% CI 10.6, 14.3) with S to 15.8 mo. (90% CI 11.4-19.2) with SBRT/S (HR=0.77, 1-sided p=0.0554). After adjusting for PS, M stage, CP A5 vs. 6, and degree of MVI, OS was statistically significantly improved for SBRT/S (HR=0.72, 95% CI 0.52-0.99, 2-sided Cox p=0.042). Median PFS was improved from 5.5 mo. (95% CI 3.4-6.3) with S to 9.2 months (95% CI 7.5-11.9) with SBRT/S (HR=0.55, 95% CI 0.40-0.75, 2-sided p=0.0001). 8 grade (G) 3+ bleeds were seen: 5 in S arm (1 G3 variceal, 2 G3 upper GI, 1 G3 hepatic, and 1 G4 abdominal) and 3 post SBRT/S (2 G3 upper GI, 1 G3 lower GI). Treatment-related G3+ AEs were not significantly different (S - 42%; SBRT/S - 47%; p=0.52), with 3 G5 AEs (S - 1 hepatic failure, 1 death NOS; SBRT/S - 1 lung infection). 83 (47%) pts consented to QoL. Of 20 S and 17 SBRT/S pts with QoL assessments at baseline and 6 months, 10% on S improved in FACT-Hep score vs 35% on SBRT/S. Conclusions: Compared to S alone, SBRT improved OS & PFS in patients with HCC, with no observed increase in AEs, and a strong suggestion for QOL benefit at 6 months. Supported by U10CA180868 (NRG Onc. Op., U10CA180822 (NRG Onc. SDMC), UG1CA189867 (NCORP), and U24CA180803 (IROC) from the NCI. Clinical trial information: NCT01730937 .

IMPORTANCE For many types of epithelial malignant neoplasms that are treated with definitive radiotherapy (RT), treatment prolongation and interruptions have an adverse effect on outcomes. OBJECTIVE To analyze the association between RT duration and outcomes in patients with esophageal cancer who were treated with definitive chemoradiotherapy (CRT). DESIGN, SETTING, AND PARTICIPANTS This study was an unplanned, post hoc secondary analysis of 3 prospective, multi-institutional phase 3 randomized clinical trials (Radiation Therapy O ncology Group [RTOG] 8501, RTOG 9405, and RTOG 0436) of the National Cancer Institute-sponsored NRG Oncology (formerly the National Surgical Adjuvant Breast and Bowel Project, RTOG, and Gynecologic Oncology Group). Enrolled patients with nonmetastatic esophageal cancer underwent definitive CRT in the trials between 1986 and 2013, with follow-up occurring through 2014. Data analyses were conducted between March 2022 to February 2023. EXPOSURES Treatment groups in the trials used standard-dose RT (50 Gy) and concurrent chemotherapy. MAIN OUTCOMES AND MEASURES The outcomes were local-regional failure (LRF), distant failure, disease-free survival (DFS), and overall survival (OS). Multivariable models were used to examine the associations between these outcomes and both RT duration and interruptions. Radiotherapy duration was analyzed as a dichotomized variable using an X-Tile software to choose a cut point and its median value as a cut point, as well as a continuous variable. RESULTS The analysis included 509 patients (median [IQR] age, 64 [57-70] years; 418 males [82%]; and 376 White individuals [74%]). The median (IQR) follow-up was 4.01 (2.93-4.92) years for surviving patients. The median cut point of RT duration was 39 days or less in 271 patients (53%) vs more than 39 days in 238 patients (47%), and the X-Tile software cut point was 45 days or less in 446 patients (88%) vs more than 45 days in 63 patients (12%). Radiotherapy interruptions occurred in 207 patients (41%). Female (vs male) sex and other (vs White) race and ethnicity were associated with longer RT duration and RT interruptions. In the multivariable models, RT duration longer than 45 days was associated with inferior DFS (hazard ratio [HR], 1.34; 95% CI, 1.01-1.77; P = .04). The HR for OS was 1.33, but the results were not statistically significant (95% CI, 0.99-1.77; P = .05). Radiotherapy duration longer than 39 days (vs <= 39 days) was associated with a higher risk of LRF (HR, 1.32; 95% CI, 1.06-1.65; P = .01). As a continuous variable, RT duration (per 1 week increase) was associated with DFS failure (HR, 1.14; 95% CI, 1.01-1.28; P = .03). The HR for LRF 1.13, but the result was not statistically significant (95% CI, 0.99-1.28; P = .07). CONCLUSIONS AND RELEVANCE Results of this study indicated that in patients with esophageal cancer receiving definitive CRT, prolonged RT duration was associated with inferior outcomes; female patients and those with other (vs White) race and ethnicity were more likely to have longer RT duration and experience RT interruptions. Radiotherapy interruptions should be minimized to optimize outcomes.

PURPOSE To determine whether addition of external beam radiation therapy (EBRT) to brachytherapy (BT) (COMBO) compared with BT alone would improve 5-year freedom from progression (FFP) in intermediate-risk prostate cancer. METHODS Men with prostate cancer stage cT1c-T2bN0M0, Gleason Score (GS) 2-6 and prostate-specific antigen (PSA) 10-20 or GS 7, and PSA < 10 were eligible. The COMBO arm was EBRT (45 Gy in 25 fractions) to prostate and seminal vesicles followed by BT prostate boost (110 Gy if 125-Iodine, 100 Gy if 103-Pd). BT arm was delivered to prostate only (145 Gy if 125-Iodine, 125 Gy if 103-Pd). The primary end point was FFP: PSA failure (American Society for Therapeutic Radiology and Oncology [ASTRO] or Phoenix definitions), local failure, distant failure, or death. RESULTS Five hundred eighty-eight men were randomly assigned; 579 were eligible: 287 and 292 in COMBO and BT arms, respectively. The median age was 67 years; 89.1% had PSA < 10 ng/mL, 89.1% had GS 7, and 66.7% had T1 disease. There were no differences in FFP. The 5-year FFP-ASTRO was 85.6% (95% CI, 81.4 to 89.7) with COMBO compared with 82.7% (95% CI, 78.3 to 87.1) with BT (odds ratio [OR], 0.80; 95% CI, 0.51 to 1.26; Greenwood T P = .18). The 5-year FFP-Phoenix was 88.0% (95% CI, 84.2 to 91.9) with COMBO compared with 85.5% (95% CI, 81.3 to 89.6) with BT (OR, 0.80; 95% CI, 0.49 to 1.30; Greenwood T P = .19). There were no differences in the rates of genitourinary (GU) or GI acute toxicities. The 5-year cumulative incidence for late GU/GI grade 2+ toxicity is 42.8% (95% CI, 37.0 to 48.6) for COMBO compared with 25.8% (95% CI, 20.9 to 31.0) for BT ( P < .0001). The 5-year cumulative incidence for late GU/GI grade 3+ toxicity is 8.2% (95% CI, 5.4 to 11.8) compared with 3.8% (95% CI, 2.0 to 6.5; P = .006). CONCLUSION Compared with BT, COMBO did not improve FFP for prostate cancer but caused greater toxicity. BT alone can be considered as a standard treatment for men with intermediate-risk prostate cancer.

Purpose/Objective(s) The role of SBRT in the treatment of HCC is not well established. The hypothesis of this study was that overall survival (OS) would improve with SBRT followed by sorafenib (SBRT/S) vs. sorafenib alone (S), in patients with advanced HCC. Materials/Methods Eligible patients had new or recurrent HCC, unsuitable for resection, transplant, ablation or TACE, with Zubrod performance status (PS) 0-2, Child-Pugh A, intermediate (B) or advanced (C) Barcelona Clinic Liver Cancer Stage (BCLC), ≤ 5 HCCs, sum of hepatic HCCs ≤ 20 cm, and sum of extrahepatic metastases ≤ 3 cm. Patients were randomized 1:1 to S 400 mg BID vs. SBRT (27.5-50Gy in 5 fractions, with dose individualized based on mean liver dose and other dose constraints) followed by S 200 mg BID then increased to 400 mg BID after 28 days if appropriate. Primary endpoint was OS. Reported secondary endpoints were progression-free survival (PFS), time to progression (TTP), and adverse events (AEs - CTCAEv4). Planned sample size was 292 patients (238 OS events, HR=0.72, 80% power, 1-sided alpha=0.05). Accrual closed early, primarily due to a change in HCC standard of care systemic therapy. Statistics were amended to report data as of 7/1/2022, projecting 155 OS events providing 65% power for the original hypothesis, with the same alpha. OS and PFS were estimated by Kaplan-Meier and arms compared using log-rank test. Cox proportional hazards models were used to analyze treatment effect. TTP was estimated with cumulative incidence and arms compared using Gray's test. Secondary endpoints were tested with 2-sided alpha=0.05. Results Of 193 patients accrued from April 2013 to March 2021 from 23 sites, 177 eligible patients were randomized to S (n=92) vs. SBRT/S (n=85). Median age was 66 years (27-84); 41% had Hepatitis C and 19% had Hepatitis B or B/C. The majority were stage BCLC C (82%), with macrovascular invasion (74%). 4% had metastases. Median follow-up for all and alive patients was 13.2 and 33.7 months, respectively. With 153 OS events, median OS was improved from 12.3 months (90% CI 10.6, 14.3) with S to 15.8 months (90% CI 11.4-19.2) with SBRT/S (HR=0.77, 1-sided p=0.0554). After adjusting for PS, M stage, Child Pugh A5 vs. 6, and degree of vascular HCC, OS was statistically significantly improved for SBRT/S (HR=0.72, 95% CI 0.52-0.99, 2-sided Cox p=0.042). Median PFS was improved from 5.5 months (95% CI 3.4-6.3) with S to 9.2 months (95% CI 7.5-11.9) with SBRT/S (HR=0.55, 95% CI 0.40-0.75, 2-sided p=0.0001). TTP was also improved with SBRT/S (HR=0.69, 95% CI 0.48-0.998, 2-sided Gray's p=0.034). Treatment-related grade 3+ AEs were not significantly different (S - 42%, SBRT/S - 47%; p=0.52). There was one grade 5 treatment-related AE, in the S arm. Conclusion Adding SBRT improved OS, PFS, and TTP in patients with advanced HCC, compared to Sorafenib alone, with no significant increase in AEs.