Importance:The best local therapy approach for patients with locally advanced pancreatic cancer (LAPC) remains undefined. Objective:To evaluate hypofractionated ablative radiation therapy (A-RT) followed by evaluation for surgery in patients with LAPC whose cancer remained unresectable after induction chemotherapy. Design, Setting, and Participants:This was a phase 2 single-arm nonrandomized clinical trial conducted at the Memorial Sloan Kettering Cancer Center, New York, New York, from June 2018 to April 2024. Participants with histologically confirmed pancreatic adenocarcinoma unresectable by multidisciplinary review after 3 or more months of modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) or gemcitabine plus nab-paclitaxel were eligible. Intervention:Hypofractionated A-RT (67.5 Gy in 15 fractions or 75 Gy in 25 fractions) with capecitabine followed by evaluation for resection. Main Outcomes and Measures:Coprimary end points included resectability and 2-year overall survival. Secondary end points included 90-day surgical adverse events (AEs) and 2-year locoregional and distant metastasis rates. Results:Forty-eight participants underwent A-RT (25 [52.1%] male; median [range] age, 67 [50-80] years; median [range] tumor size 4.1 [2.4-8.3] cm; 47 (98%) with arterial and venous involvement; median [range] carbohydrate antigen 19-9, 88 [<1-1601] U/mL). Forty-five patients (94%) received mFOLFIRINOX. Seventeen participants (34%) underwent a laparoscopy, with resection performed in 13 (27%). Resections included 11 pancreaticoduodenectomies (84.6%) and 2 distal pancreatectomies (15.4%). At median follow-up of 3 years, 2-year overall survival from A-RT for the cohort was 38% (95% CI, 26%-54%) overall and 31% (95% CI, 19%-51%) and 54% (95% CI, 33%-89%) in participants with unresected and resected disease, respectively. Two-year rates of local progression were 11% (95% CI, 3.5%-25%) and 15% (95% CI, 2.2%-40%) in unresected and resected groups, respectively. Two-year rate of distant metastasis was 73% (95% CI, 57%-84%). There were no deaths within 90 days of surgery. Eleven surgical AEs (including 4 Clavien-Dindo grade III) occurred in 12 evaluable participants. Acute and late RT-related grade III or higher AEs occurred in 6 (12.5%) and 12 (26.1%) participants, respectively. The most common late AE was ascites in 7 (15.2%; 3 postsurgery). Conclusions:For patients with LAPC with extensive vascular encasement after induction chemotherapy, hypofractionated A-RT prior to possible surgery was associated with promising overall survival for both ultimately resected and unresected groups. A-RT was not associated with an increase in postsurgical morbidity when surgery was performed and was an effective destination therapy when it was not. Further evaluation of this strategy to maximize outcomes regardless of resection is warranted. Trial Registration:ClinicalTrials.gov Identifier: NCT03523312.

Introduction:Thymic malignancies are primarily managed with surgery. Some patients are medically inoperable or technically unresectable. We report the characteristics and outcomes of patients with unresected thymic tumors treated with definitive radiation therapy (RT) at our institution. Methods:Patients treated with curative-intent RT for unresected thymic tumors between 1997 and 2023 were identified. Age at diagnosis, sex, histology, Masaoka or TNM stage, WHO classification, reason for no resection, RT dose and fractionation, presence of paraneoplastic syndrome, chemotherapy use, and toxicities were extracted. Overall and local failure-free survival, patterns of progression, and treatment toxicities were assessed. This retrospective chart review did not require informed consent. Results:A total of 33 consecutive patients were identified (16 females and 17 males) with a median age of 61 years at diagnosis. Overall, 22 patients had thymoma and 11 had thymic carcinoma. T stage was T2 (one), T3 (seven), and T4 (25); N stage was N0 (15), N1 (one), and N2 (17); M stage was M0 (21), M1a (eight), and M1b (four). Median tumor size was 8.1 cm. Three patients were medically inoperable; 30 were technically unresectable. Of the 33 patients, 29 received chemotherapy. The median RT dose was 60 Gy in 2 Gy fractions.Furthermore, 6% developed a grade 3 toxicity and 9% developed grade 2 pneumonitis. No grade 4/5 toxicities were observed. The 2-year overall survival was 69% (95% confidence interval [CI]: 52-92) and 5-year overall survival was 56% (95% CI: 37-85). The 3- and 5-year local failure rates were 20% (95% CI: 6.9-39). Conclusions:In the most advanced stage and one of the largest reports to date, definitive chemo-RT provides high rates of local control in patients with unresected thymic malignancies.

Background and Purpose:Accurate segmentation of cardiac substructures on computed tomography (CT) scans is essential for radiotherapy planning. This study evaluated whether pretrained transformers enabled data-efficient training using a fixed architecture with balanced curriculum learning while achieving robust generalization to imaging and patient variations. Materials and Methods:A hybrid pretrained transformer-convolutional network, self-distilled masked image transformer (SMIT), was fine-tuned using lung cancer patient scans (Cohort I, training N = 180) and tested on held-out Cohort I lung cancer scans (testing N = 60) and breast cancer scans (Cohort II, N = 65). Two configurations were evaluated: SMIT-Balanced (32 contrast-enhanced CTs, 32 non-contrast CTs) and SMIT-Oracle (180 CTs). Performance was compared with nnU-Net and TotalSegmentator. Segmentation accuracy was assessed primarily using the 95th percentile Hausdorff distance (HD95), along with radiation dose and overlap-based metrics as secondary endpoints. Results:SMIT-Balanced approached SMIT-Oracle performance despite using 64% fewer training scans, with mean HD95 of 6.6 versus 5.4 mm in Cohort I and 10.0 versus 9.4 mm in Cohort II. On the Cohort I held-out test set, SMIT-Balanced mean HD95 was within 1.0 mm of nnU-Net. Cross-cohort testing showed larger accuracy degradation with nnU-Net than SMIT-Balanced (62% versus 50%, absolute change 4.5 mm versus 3.4 mm). Dose metrics derived from SMIT-Balanced were equivalent to manual delineations. Conclusions:Balanced curriculum training reduced labeled data requirements within the SMIT architecture. SMIT-Balanced was comparable to nnU-Net on Cohort I held-out data and showed smaller cross-cohort HD95 degradation.

Patients with anal squamous cell carcinoma (ASCC) who fail chemoradiation (CRT) have poor outcomes, underscoring the need for biomarkers to guide risk stratification. In a real-world two-center cohort of 84 adults with non-metastatic ASCC treated with curative-intent CRT, we prospectively evaluate a tumor-informed circulating tumor DNA (ctDNA) assay (SignateraTM, Natera). Here we show that across 647 plasma specimens, ctDNA is positive at pre-treatment in 79% (61/77), including 89% (24/27) with stage III disease. End-of-treatment ctDNA positivity identifies patients with inferior one-year outcomes: 63% overall survival, 44% progression-free survival, and 39% locoregional failure. Conversely, patients who were ctDNA-negative at baseline or who cleared ctDNA during-treatment have 100% locoregional failure-free survival. During surveillance, ctDNA re-emergence precedes clinical or radiographic relapse in every case. These findings support the consideration of ctDNA as a dynamic, treatment-responsive biomarker warranting prospective validation for risk-adapted surveillance and adjuvant therapy in ASCC.

Importance The best local therapy approach for patients with locally advanced pancreatic cancer (LAPC) remains undefined. Objective To evaluate hypofractionated ablative radiation therapy (A-RT) followed by evaluation for surgery in patients with LAPC whose cancer remained unresectable after induction chemotherapy. Design, Setting, and Participants This was a phase 2 single-arm nonrandomized clinical trial conducted at the Memorial Sloan Kettering Cancer Center, New York, New York, from June 2018 to April 2024. Participants with histologically confirmed pancreatic adenocarcinoma unresectable by multidisciplinary review after 3 or more months of modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) or gemcitabine plus nab-paclitaxel were eligible. Intervention Hypofractionated A-RT (67.5 Gy in 15 fractions or 75 Gy in 25 fractions) with capecitabine followed by evaluation for resection. Main Outcomes and Measures Coprimary end points included resectability and 2-year overall survival. Secondary end points included 90-day surgical adverse events (AEs) and 2-year locoregional and distant metastasis rates. Results Forty-eight participants underwent A-RT (25 [52.1%] male; median [range] age, 67 [50-80] years; median [range] tumor size 4.1 [2.4-8.3] cm; 47 (98%) with arterial and venous involvement; median [range] carbohydrate antigen 19-9, 88 [<1-1601] U/mL). Forty-five patients (94%) received mFOLFIRINOX. Seventeen participants (34%) underwent a laparoscopy, with resection performed in 13 (27%). Resections included 11 pancreaticoduodenectomies (84.6%) and 2 distal pancreatectomies (15.4%). At median follow-up of 3 years, 2-year overall survival from A-RT for the cohort was 38% (95% CI, 26%-54%) overall and 31% (95% CI, 19%-51%) and 54% (95% CI, 33%-89%) in participants with unresected and resected disease, respectively. Two-year rates of local progression were 11% (95% CI, 3.5%-25%) and 15% (95% CI, 2.2%-40%) in unresected and resected groups, respectively. Two-year rate of distant metastasis was 73% (95% CI, 57%-84%). There were no deaths within 90 days of surgery. Eleven surgical AEs (including 4 Clavien-Dindo grade III) occurred in 12 evaluable participants. Acute and late RT-related grade III or higher AEs occurred in 6 (12.5%) and 12 (26.1%) participants, respectively. The most common late AE was ascites in 7 (15.2%; 3 postsurgery). Conclusions For patients with LAPC with extensive vascular encasement after induction chemotherapy, hypofractionated A-RT prior to possible surgery was associated with promising overall survival for both ultimately resected and unresected groups. A-RT was not associated with an increase in postsurgical morbidity when surgery was performed and was an effective destination therapy when it was not. Further evaluation of this strategy to maximize outcomes regardless of resection is warranted. Trial Registration ClinicalTrials.gov Identifier: NCT03523312

OBJECTIVE:Patients with stage IV non-small cell lung cancer (NSCLC) often present with substantial symptom burden that impairs quality of life and tolerance of systemic therapy. Quad Shot (QS), a cyclical hypofractionated radiotherapy (RT) regimen, could provide effective symptom palliation while allowing concurrent systemic therapy. We evaluated the safety, feasibility, and patient-reported outcomes (PROs) of delivering up to three cycles of QS concurrently with systemic therapy. METHODS:This prospective phase I dose-escalation trial enrolled patients with stage IV NSCLC from June 2020 to February 2024. Allowable systemic therapy included immunotherapy alone, immunotherapy plus chemotherapy, or chemotherapy alone at the treating medical oncologist's discretion. Each QS cycle consisted of 14.8 Gy in 4 fractions delivered twice daily over 2 consecutive days within 1 week of systemic therapy. The primary endpoint was to determine the maximum tolerated number of QS cycles (MTD) using a modified 3+3 design, defined as a dose-limiting toxicity (DLT) rate ≤17% (1 of 6 patients). Secondary endpoints included feasibility, systemic therapy disruptions, RT-related toxicities, and PROs. RESULTS:Forty-five patients were enrolled in this study. One DLT occurred in the two-cycle cohort, and none occurred with three cycles, establishing three cycles as the MTD. In the expansion cohort, three patients developed grade 3 RT-related toxicities. All systemic therapies were administered without any interruptions. Among symptomatic patients, PROs demonstrated improvement in dyspnea (67%), cough (62%), and hemoptysis (100%). CONCLUSIONS:Three cycles of QS were associated with limited high-grade toxicities, no disruption of systemic therapy, and high rates of patient-reported symptom improvement, supporting its use as a palliative option within multidisciplinary care for advanced NSCLC.

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.

OBJECTIVE:To investigate how the Siewert classification of gastroesophageal junction adenocarcinomas correlates with genomic profiles. BACKGROUND:Current staging and treatment guidelines recommend that tumors with an epicenter <2 cm into the gastric cardia be treated as esophageal cancers, whereas tumors with an epicenter >2 cm into the cardia be staged and treated as gastric cancers. To date, however, few studies have compared the genomic profiles of the 3 Siewert classification groups to validate this distinction. METHODS:Using targeted tumor sequencing data on patients with adenocarcinoma of the gastroesophageal junction previously treated with surgery at our institution, we compared genomic features across Siewert classification groups. RESULTS:A total of 350 patients were included: 121 had Siewert type I, 170 type II, and 59 type III. Comparisons by Siewert location revealed that Siewert types I and II were primarily characterized as the chromosomal instability molecular subtype and displayed Barrett metaplasia and p53 and cell cycle pathway dysregulation. Siewert type III tumors, by contrast, were more heterogeneous, including higher proportions of microsatellite instability and genomically stable tumors, and more frequently displayed ARID1A and somatic CDH1 alterations, signet ring cell features, and poor differentiation. Overall, Siewert type I and II tumors demonstrated greater genomic overlap with lower esophageal tumors, whereas Siewert type III tumors shared genomic features with gastric tumors. CONCLUSIONS:Overall, our results support recent updates in treatment and staging guidelines. Ultimately, however, molecular rather than anatomic classification may prove more valuable in determining staging, treatment, and prognosis.

PURPOSE:Patients with extensive-stage small cell lung cancer are commonly treated with induction systemic therapy and consolidative thoracic radiotherapy (TRT). PARP inhibitors have demonstrated radiosensitization in preclinical lung cancer models. We performed an investigator-initiated, multi-institutional, single-arm, open-label phase I study of concurrent olaparib with TRT. PATIENTS AND METHODS:Patients without progression after induction platinum/etoposide ± atezolizumab were treated with oral olaparib for 3 weeks and concurrent low-dose TRT (30 Gy/10 fractions) in weeks 2 and 3. Olaparib dose started at 50 mg twice daily and escalated in 50 mg/dose increments in cohorts of three patients each. Primary objectives were the safety and maximum tolerated dose (MTD) of olaparib + TRT. Secondary objectives included in-field local recurrence rate, progression-free survival, and overall survival. RESULTS:Between October 2018 and March 2022, 24 patients with a median age of 68 years were treated (median follow-up, 11.4 months) with platinum/etoposide and 30 Gy/10 fractions TRT; 10 patients also received atezolizumab. The MTD of olaparib with TRT was 200 mg twice daily. There were three grade 3 (G3) dose-limiting adverse events (AE), including pneumonitis/pneumonia, esophagitis, and abdominal pain. The most common G2 to G3 treatment-related AE were esophagitis (n = 12) and pneumonitis/pneumonia (n = 2). There were no G4 or G5 AE. The 12-month cumulative incidence of local recurrence was 27%, and the median progression-free survival and overall survival were 3.6 and 17.7 months, respectively. CONCLUSIONS:This study established the MTD and recommended a phase II dose of olaparib at 200 mg twice daily with concurrent low-dose TRT, and the combination seemed safe without unexpected toxicities.

12011 Background: NRG-CC003, a phase II/III study, randomized 393 patients with small cell lung cancer to prophylactic cranial irradiation (PCI) with or without Hippocampal Avoidance (HA). “Hopefulness” is a cognitive construct based on 3 components: goals; pathways to reach those goals; and agency (i.e., motivation to embark on the pathway). Hope can be measured with validated instruments. Since hope is cognitive in nature, the existence of a “hope center” in the brain -- most likely in the hippocampus -- has been hypothesized. One exploratory objective of NRG-CC003 posited that if hope levels (measured pre- and post-PCI) were better maintained in patients randomized to PCI+HA (in comparison to patients treated by PCI without hippocampal protection), then the hippocampus would, indeed, be implicated as part of the mechanism of hopefulness. Methods: In both arms, PCI consisted of 10 fractions of 2.5 Gy. The Adult Hope Scale (AHS) was administered at time-zero and at 6-months. With regard to patient reported outcome (PRO) measures, the EORTC QLQ-C30 was administered at baseline and then at 3, 6-, 12-, 18- and 24-month intervals. Comparisons of AHS scores by arm were made using Wilcoxon-Mann-Whitney tests, and correlation of AHS with EORTC QLQ-C30 by Pearson correlation coefficients. Results: Approximately 95% of patients completed the AHS at baseline and 67% filled out the questionnaire at 6-months which paralleled the completion rates of the conventional tools for QOL and neurocognition that were employed in the study. When comparing hope levels (change from baseline to 6 months) there was no significant difference (p > 0.05) between the two arms of the trial (PCI vs PCI + HA). There was a significant correlation for the components of hopefulness with QOL; specifically, between change in agency score and QLQ-C30 global health status (p < 0.0001) as well as between change in pathways score and QLQ-C30 global health status (p = 0.022). Conclusions: It is feasible to study hopefulness in the context of prospective trials conducted within the NCTN. The hippocampus could not be implicated as a critical structure in a central pathway that coordinates hopefulness. Whether these data categorically refute the “hope-hippocampal hypothesis” will be discussed vis-à-vis several caveats (e.g., selection of AHS; presence of sufficient cognitive reserve post-irradiation; adequacy of the dose-delta between the 2 arms to cause differential levels of damage to the purported hope center). For the first time, a validated tool prospectively established a relationship between hope and quality of life among patients with cancer. Given previous NRG studies correlating QOL with oncologic endpoints (e.g., local control and survival), modelling will be carried out to determine if hope mediates, results from, or is associated with these endpoints. Clinical trial information: NCT02635009 .

BACKGROUND:Anal squamous cell carcinoma is a rare cancer with increased occurrence of multiple cancers before and after the anal squamous cell carcinoma diagnosis. However, there are limited data on this aspect. This multi-institutional analysis aimed to define the occurrence of malignancies before and after anal squamous cell carcinoma, time trends, and impact on survival and to identify prognostic factors. METHODS:Initial primary malignancy was defined as a malignancy occurring before the anal squamous cell carcinoma. Second primary malignancy was defined as a distinct primary cancer that developed after anal squamous cell carcinoma diagnosis. Retrospective multi-institutional chart review was done. Progression-free survival (PFS), overall survival, and prognostic factors were evaluated. RESULTS:A total of 647 patients with anal squamous cell carcinoma treated with curative intent were analyzed. Median age was 61.2 years with 72% as females. Of these, 150 (23.3%) patients had multiple malignancies with initial primary malignancy in 16% and second primary malignancy in 8%. Patients without prior cancer had better 5-year PFS (81.2% vs 67.2%, P = .011) and overall survival (81% vs 69%, P = .008) compared with those with prior cancer. Second primary malignancies had a statistically significant adverse impact on PFS (hazard ratio [HR] = 4.22) and overall survival (HR = 3.56). Females had better 5-year PFS (82% vs 70%, P = .016) as compared with males. The median time interval for developing anal squamous cell carcinoma (as second primary malignancy) after initial primary malignancy was 9.32 years. CONCLUSIONS:Anal squamous cell carcinoma patients have an increased risk of multiple malignancies. These patients who have prior cancers have inferior outcomes. Second primary malignancy is a poor prognostic factor in patients with anal cancer. Second primary malignancy can develop years after treatment of primary anal squamous cell carcinoma.

Background and purpose:Early onset radiation pneumonitis (RPEarly) after concurrent chemoradiotherapy (cCRT) can lead to consolidation immunotherapy (IO) discontinuation, and poor survival in locally advanced non-small cell lung cancer (LA-NSCLC). This work assessed the external validity of a previously published RPEarly risk model. Material and methods:The RPEarly risk model utilizes pretreatment 18F-FDG PET/CT imaging of the normal lungs and the mean lung dose (MLD). The 90th percentile of the standardized uptake value (SUVP90) and the MLD model parameters from the previous derivation cohort (N = 160) were applied in the independent cohort (50 consecutive LA-NSCLC patients treated with cCRT and IO) where model performance was evaluated (area under the receiver-operating characteristic curve (AUC), p-values, and the Hosmer-Lemeshow test (pHL)). Results:Seven patients (14 %) developed RPEarly. Model performance of the previously developed SUVP90 and MLD model improved with re-fitting (AUC = 0.76 vs. 0.72; p = 0.01 vs. 0.10; pHL = 0.66 vs. 0.94). Above a clinically desirable 10 % predicted RPEarly, after refitting model coefficients in the combined derivation and validation cohorts (N = 210), the MLD was 13 ± 2.2 EQD23 Gy (SUVP90 = 1.2 ± 0.3) above the RPEarly risk threshold vs. 8.5 ± 2.6 EQD23 Gy (0.9 ± 0.2) below the threshold. For an SUVP90 of 1.1 and an MLD of 11 Gy EQD23 Gy, 25/27 patients developing RPEarly were captured. Conclusion:The previously developed SUVP90 and MLD-based risk model for RPEarly demonstrated a high probability to correctly predict RPEarly in the independent cohort. This now validated RPEarly risk model with derived high-risk indications could enable personalized thoracic RT planning to reduce the risk of RPEarly and of discontinuing life-prolonging IO post-cCRT.

PURPOSE:Hippocampal avoidance (HA) during therapeutic whole-brain radiotherapy reduces the risk of neurocognitive function (NCF) toxicity in patients with brain metastasis. This trial hypothesized that HA during prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) leads to noninferior intracranial relapse (ICR) and reduction in NCF toxicity. METHODS:This randomized phase II/III trial enrolled patients with SCLC, no brain metastases, and response to chemotherapy. The primary end points were 12-month ICR (noninferiority design, randomized phase II) and 6-month Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall (DR) failure (phase III). Secondary end points were failure in any NCF test, health-related quality of life (HRQOL), overall survival (OS), and toxicity. RESULTS:From December 2015 to June 2022, 393 patients were randomly assigned. The median age was 64 years. Stage and memantine usage were balanced. The median follow-up was 17.0 months (all patients) and 30.8 months (alive patients). HA-PCI had noninferior 12-month ICR rate (PCI 14.8% v HA-PCI 14.7%, P < .0001). Six-month HVLT-R DR deterioration was not significantly different (PCI 30.0% v HA-PCI 25.5%, P = .28). Addition of HA to PCI reduced the risk of failure in any NCF test (adjusted hazard ratio [HR], 0.78; 95% CI [0.61 to 0.99]; P = .039). Addition of HA to PCI was not associated with longitudinal change in any HRQOL domain. There were no differences in OS (adjusted HR, 0.88 [95% CI, 0.67 to 1.14]; P = .33) or grade ≥3 toxicity (PCI 31.4% v HA-PCI 30.7%, P = .88). CONCLUSION:Although the study did not meet its primary end point of DR preservation, HA during PCI reduces the risk of overall neurocognitive toxicity with noninferior ICR risk and similar survival.

Purpose We sought to identify factors associated with second pelvic malignancies (SPM), as well as second nonpelvic malignancies (SNPM), after chemotherapy with or without radiation therapy (RT) for locally advanced rectal cancer (LARC). Methods and Materials Patients diagnosed with stage II-III LARC. Cumulative incidence of second malignancies was analyzed using a 2-year landmark analysis with death as a competing risk. Results Among 2624 patients with LARC, 460 received chemotherapy and 2164 received RT with concurrent chemotherapy (CXRT). With a median follow-up of 6 years in both cohorts, 7 SPMs were diagnosed in the chemotherapy cohort and 68 SPMs were diagnosed in the CXRT cohort. The 5- and 10-year cumulative incidence of SPM in the chemotherapy cohort were 2.3% and 4.2%, respectively, compared with 2.1% and 5.8% in the CXRT cohort (P = .3). Older age (>50) was significantly associated with development of SPM on multivariable analysis (hazard ratio [HR], 3.03; P = .005). Intensity-modulated RT was associated with reduced risk of SPM compared with conventional RT (P = .014). Of the total 75 SPMs, 72 were genitourinary cancers and only 3 were sarcomas. For SNPM, the 10-year cumulative incidence was significantly higher in the CXRT group compared with the chemotherapy group (11.0% vs 4.4%). Older age (>50) was associated with increased risk of SNPM (HR, 2.48; P < .001). Diabetes was associated with more SNPM (HR, 1.51; P = .028), whereas abstaining from tobacco was associated with decreased risk of SNPM (HR 0.63, P = .013). Conclusion The CI of SPM was not significantly higher in patients who received CXRT compared with chemotherapy alone for LARC. SNPM CI was increased in the CXRT compared with chemotherapy-alone cohort, and higher in smokers, diabetics, and patients >50 years.

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 .

The role of plasma circulating tumor DNA (ctDNA) as a prognostic biomarker in locally advanced esophageal cancer has not been well defined. We aim to evaluate the prognostic value of pre- and on-treatment ctDNA detection. In this retrospective single institution study, patients with esophageal cancer undergoing definitive local therapy via endoscopic resection (ER), esophagectomy, or definitive chemoradiation (CRT) underwent baseline and post-treatment ctDNA analysis utilizing a plasma-based tumor informed assay. ctDNA detection and quantification was annotated to clinicopathologic characteristics. Between 2022 and 2024, 37 treatment-naïve esophageal cancer patients with stage I-IVA disease were analyzed. Overall, 28 underwent esophagectomy, 7 underwent definitive CRT, and 2 underwent ER. At baseline, ctDNA was detectable in 62% (23/37), with a mean 2.74 mean tumor molecules per milliliter of plasma (MTM/ml) (SD 6.37). Among those with detectable baseline ctDNA, 87% (13/15) achieved ctDNA clearance within a median of 45 days postoperatively. The rate of achievement of ctDNA clearance did not differ between the surgical or CRT groups (92% v. 83%, p>0.99). Of those patients who underwent surgery, 79% (22/28) had neoadjuvant therapy. Baseline ctDNA was detectable in 73% (16/22) of those patients, with a mean ctDNA level of 2.34 MTM/ml (SD 6.10). ctDNA remained detectable in 18% (3/17) after neoadjuvant therapy. Following surgery, 93% (14/15) achieved ctDNA clearance. When examining pathologic response among patients that had neoadjuvant therapy, 27% (6/22) had no residual disease at the time of resection. Patients with no residual disease had significantly lower ctDNA at baseline than those who did have residual disease (0.37 MTM/ml v 1.51 MTM/ml, p=0.005). Of the 14 patients that were detectable at baseline who achieved ctDNA clearance preoperatively, only 3 of those had no residual disease. Among the 28 esophagectomy patients, 11 had nodal metastases. While ctDNA detection rates at baseline were similar between pN0 and pN+ patients (58% v. 64%, p=0.70), patients with nodal metastases had significantly higher pre-treatment ctDNA levels (3.0 MTM/ml vs. 1.2 MTM/ml, p<0.001). Local therapy for esophageal cancer effectively clears ctDNA. Additionally, quantitative analysis of baseline ctDNA may be a useful prognostic indicator for patients likely to have nodal metastases and poor treatment response at the time of surgery. Marisa Sewell, Matthew Bott, Katherine Gray, Steve Maron, Yelena Janjigian, Hans Gerdes, Pari Shah, Abraham Wu, Bernard J. Park, David R. Jones, Daniela Molena. Circulating tumor DNA as a prognostic biomarker in locally advanced esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3256.

BACKGROUND:Radiation dose escalation for locally advanced pancreatic cancer (LAPC) using stereotactic magnetic resonance (MR)-guided online adaptive radiation therapy (SMART) or computed tomography (CT)-guided moderately hypofractionated ablative radiation therapy (HART) can achieve favorable outcomes although have not previously been compared. METHODS:We performed a multi-center retrospective analysis of SMART (50 Gy/5 fractions) vs. HART (75 Gy/25 fractions or 67.5 Gy/15 fractions with concurrent capecitabine) for LAPC. Gray's test and Cox proportional regression analyses were performed to identify factors associated with local failure (LF) and overall survival (OS). RESULTS:A total of 211 patients (SMART, n = 91; HART, n = 120) were evaluated, and none had surgery. Median follow-up after SMART and HART was 27.0 and 40.0 months, respectively (p < 0.0002). SMART achieved higher gross tumor volume (GTV) coverage and greater hotspots. Two-year LF after SMART and HART was 6.5% and 32.9% (p < 0.001), while two-year OS was 31.0% vs. 35.3% (p = 0.056), respectively. LF was associated with SMART vs. HART (HR 5.389, 95% CI: 1.298-21.975; p = 0.021) and induction mFOLFIRINOX vs. non-mFOLFIRINOX (HR 2.067, 95% CI 1.038-4.052; p = 0.047), while OS was associated with CA19-9 decrease > 40% (HR 0.725, 95% CI 0.515-0.996; p = 0.046) and GTV V120% (HR 1.022, 95% CI 1.006-1.037; p = 0.015). Acute grade > 3 toxicity was similar (3.3% vs. 5.8%; p = 0.390), while late grade > 3 toxicity was less common after SMART (2.2% vs. 9.2%; p = 0.037). CONCLUSIONS:Ablative SMART and HART both achieve favorable oncologic outcomes for LAPC with minimal toxicity. We did not observe an OS difference, although technical advantages of SMART might improve target coverage and reduce LF.