Haddock, Michael G.

ABSTRACT Purpose We studied histologic Ewing sarcoma (ES) tumor response at local control surgery to explore associations between histologic response and chemotherapy practice changes over time and confirm its prognostic significance in the modern era. Methods We reviewed clinical data for 126 patients with ES treated at Mayo Clinic from 1977 to 2022, analyzing the percentage necrosis as a prognostic factor across chemotherapy regimens (including modern interval‐compressed VDC‐IE). Results In the historical cohort, 5‐year event‐free survival (EFS) and overall survival (OS) for patients with ≤5% versus greater than 5% viable tumor were 76% versus 59% ( p = 0.01) and 83% versus 62% ( p = 0.01). Review of 104 specimens by two pathologists identified the percentage remaining viable tumor as more reproducible than the percentage necrosis and/or fibrosis. On multivariable analysis of patients with localized disease ( n = 87), pelvic tumors and greater than 5% viable tumor remained independent risk factors for poor survival (EFS: hazard ratio [HR] 3.1, p < 0.01; OS: HR 2.1, p = 0.048). The modern cohort consisted of 22 patients. No patients with tumor size less than 8 cm at diagnosis and 100% necrosis after surgery had events; four of seven with tumors greater than 8 cm had events despite 100% necrosis. Conclusions Our results validate the historical threshold of greater than 5% viable tumor with older chemotherapy regimens but not with modern interval‐compressed VDC‐IE. In addition, inter‐rater reliability for the percentage viable is more reproducible than the percentage necrosis. Although numbers are small, tumors less than 8 cm with no viable tumor appear to be a favorable subgroup and suggest risk stratification using a combination of tumor size and any viable tumor should be evaluated in ES.

Abstract 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 χ 2 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.

Background/Objectives: We performed a systematic review of preclinical literature on the use of high-LET particle therapy, DDRi, and/or immunotherapy specifically in pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, and carbon) or X-ray radiation either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICIs) in pMMR colorectal cancer models. Results: In total, 131 studies met the inclusion criteria, including 70 preclinical studies. These studies consistently demonstrate that high-LET radiation amplifies immunogenic cell death, increases cGAS-STING pathway activation, and enhances tumor antigen presentation, thereby fostering greater immune infiltration and systemic antitumor responses. Concurrent irradiation with DDRi enhances persistent DNA damage and cytosolic DNA accumulation. In murine models, high-LET therapies show excellent local control, with manageable toxicity profiles. Combination regimens with ICIs exhibit improved local control and elicit systemic antitumor immune responses. Conclusions: High-LET particle radiation and/or the use of concurrent DDRi with ICI have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increased response rates to immunotherapy. The clinical evidence will be reviewed in the companion manuscript.

Background/Objectives: We performed a systematic review of the current clinical and preclinical literature on the use of particle therapy, DDRi, and/or immunotherapy, specifically for pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, carbon) either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICI), or X-ray radiotherapy (XRT) in combination with DDRi/ICI. Results: In total, 133 studies met the inclusion criteria, including 62 clinical studies. Clinically, particle therapies show excellent local control and normal tissue sparing, with manageable toxicity profiles. Trials with any form of radiation and DDRi are few, potentially owing to toxicity concerns. ICI combinations showed promising efficacy with XRT, with no randomized trials comparing them to particle radiation. Conclusions: Particle radiation and/or DDRi have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increase response rates to immunotherapy (presented in the companion manuscript). Despite strong preclinical evidence and rationale, clinical trials including all three modalities are scarce. Existing evidence suggests a potential benefit based on extrapolation from photon-based studies and supports prospective evaluation with careful attention to treatment-related toxicity, which remains a concern.

Objectives: For locally advanced rectal adenocarcinoma (R-ACA), a nonoperative management (NOM) approach has emerged as a guideline-supported treatment option. However, the variables associated with NOM receipt are unknown. Methods: Utilizing the National Cancer Database, we performed a retrospective cohort study of adults with stage 1 to 3 R-ACA managed with curative intent from 2004 to 2018. The primary outcome was the proportion of patients receiving NOM versus surgery. The secondary outcome was survival among NOM patients. Results: A total of 128,297 patients were included. In all, 115,888 (90.3%) received surgery and 12,409 (9.7%) received NOM. Receipt of NOM was associated with age above 70, Charlson-Deyo score of 0, race (Black, Asian or Pacific Islander, or other vs. White), insurance status, geographical region, treatment in a community facility, year of diagnosis (2012-2018 vs. 2004-2011), tumor grade 1 versus ≥ 2, clinical T-stage ≥ 2, and clinical N1 or N2 versus N0. In the NOM cohort, poorer overall survival was associated with age 70 and above, male sex, Charlson-Deyo score ≥ 1, insurance status, geographical region, rural urban density versus metro/urban, treatment in a community facility, year of diagnosis (2004-2011 vs. 2012-2018), clinical T4 versus T1, clinical N1 or N2 versus N0, grade 3 versus 1, treatment with a radiotherapy dose <45 Gy versus 45 to 54 Gy, and omission of chemotherapy. Conclusions: Several demographic factors and social determinants of health were associated with receipt of NOM and overall survival. With the increasing utilization of NOM, it will be important to understand the drivers of treatment decisions and influences on access to the desired treatment approach.

Abstract Background We retrospectively assessed volumetric response of myxoid liposarcoma (MLPS) with preoperative radiotherapy (RT) and sought to identify disease and treatment characteristics associated with response. Patients and methods We identified all patients with a histologic diagnosis of MLPS who received preoperative RT from 2013 to 2021 at our institution. We used cone beam computed tomography (CBCT) to assess changes in tumor volume and greatest dimension during treatment. Tumors were contoured on CBCT images prior to treatment and at the end of each week of RT. Percentage change in tumor volume and greatest dimension were calculated based on pre-treatment and final week contours. Patients with tumors incompletely visualized on CBCT were excluded from volume analysis but included on greatest dimension analysis. Magnetic resonance imaging (MRI) was used to evaluate pre- and post-RT radiographic features. Surgical pathology was reviewed to record pathologic characteristics. Results Twenty patients met inclusion criteria. Most tumors (18/20) were low grade. The most frequent dose/fractionation scheme was 50 Gy in 25 fractions (16/20), with 3 patients receiving 36 Gy in 18 fractions. Median pre-RT volume and greatest dimension were 120 cc (interquartile range [IQR]: 56–399) and 11.2 cm (IQR: 8.4–14.1), respectively. Median percentage change in volume and greatest dimension were -37% (IQR: -57 to -29) and -10% (IQR: -20 to -7). All evaluable tumors decreased in volume during RT. Between pre- and post-RT MRI, most patients had a decrease in intratumoral (16/20) and peritumoral edema (11/20). Sixteen patients exhibited extensive pathologic response. There were no significant associations between radiographic and pathologic features and volumetric change. Local failure at 3 years was 9% (95% confidence interval: 1–59). Conclusions We report significant decreases in MLPS tumor size during preoperative RT. There may be a role for adaptive RT planning to reduce target volumes and minimize RT-associated morbidity.

e14551 Background: Extracellular vesicles (EVs) are microscopic particles released by all cell types with a distinct fingerprint reflecting the cell of origin. In patients with prostate cancer, PSMA+EVs have been associated with clinical outcomes. In this study, we investigated tumor-derived EVs (tdEVs) using the tumor-specific CD326 marker as a novel biomarker for pancreas ductal adenocarcinoma (PDAC). Methods: The study included patients with localized PDAC treated on a prospective phase 2 clinical trial evaluating a 15-fraction chemoradiation (CRT) regimen. Blood samples were obtained after induction chemotherapy (C) (prior to CRT) and in follow-up. 20 healthy controls were included. High-resolution flow cytometry enumerated levels of fluorescent antibody labelled tumor-specific CD326 (EpCAM)-positive EVs. All samples were de-identified and randomly coded. The technologist responsible for EV analysis was blinded to patient information and clinical data. Each sample was run in triplicate. Flow cytometry data was analyzed with custom-built software to automatically determine and apply gates and generate reports with scatter plots and EV concentrations for each combination of markers and data summaries. Results: tdEV data were analyzed from 70 patients with pre-CRT samples. Patients had mean age 66 years (9.0 standard deviation), with 60% ECOG 0, 43% borderline resectable and 48% locally advanced. Patients had a median 8 cycles of C prior to CRT, and 70% proceeded to surgery after CRT. 2-year overall survival (OS) was 54%. Patient samples showed elevated total CD326 EVs compared to the healthy controls (p = 0.0005). Furthermore, patient CD326 EVs revealed two distinct subpopulations: small (120-1,000nm) and large (1,000-3,000nm) size CD326 EVs. No large CD326 subpopulation was found in healthy donor samples. Higher pre-CRT levels of total CD326 and large CD326 EVs were associated with decreased progression-free survival (PFS) (hazard ratio (HR) = 2.38, p = 0.013 and HR = 2.017, p = 0.021) on multivariable models with surgical resection. Resection was associated with increased PFS (p < 0.0001), and the interaction terms did not meet significance (p = 0.083 and p = 0.21). No differences in pre-CRT total or large CD326 EVs were identified between patients with or without surgical resection (p = 0.72 and p = 0.83). CA19-9 levels were not predictive of clinical outcomes in this trial and showed no association with EV levels. Conclusions: We present an association between clinical outcomes and tdEVs in PDAC, highlighting their potential as a novel, independent biomarker. If validated, tdEVs may offer an opportunity to personalize care and improve risk stratification.

Abstract 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/Objectives: Our objective was to describe the use of intraoperative radiation therapy (IORT) for the treatment of recurrent/persistent cervical or endometrial cancer and assess predictors of postoperative complications and 3-year mortality. Methods: In this multi-site retrospective study, data were abstracted for recurrent/persistent endometrial or cervical cancer patients who underwent IORT from June 2004 to May 2021. Complications were graded on the six-point Accordion scale. Variables associated with complications were analyzed with univariate logistic regression, while variables associated with death within 3 years were analyzed with Cox proportional hazards modeling. Survival was analyzed with the Kaplan–Meier method. Results: Eighty patients had planned IORT for recurrent/persistent endometrial (n = 35) or cervical cancer (n = 45). The mean age of the cohort was 56.8 years (SD = 13.7), and the median disease-free interval from primary disease to recurrence was 20.0 months (IQR 10.0–63.1). The overall survival at 3 years was 48.6% (95% CI: 38.3–61.6%) with a median survival of 2.8 years. Within 30 days postoperative, 16 patients (20.1%) had grade 3–5 complications and one death (1.3%) occurred. Factors associated with grade 3+ complication included ECOG PS 2–3 (OR 18.00, p = 0.04), neoadjuvant chemotherapy and/or immunotherapy (OR 6.98, p < 0.01), and pelvic sidewall involvement (OR 8.80, p = 0.04). Factors associated with death within 3 years of surgery included ECOG PS 2–3 (HR 8.97, p < 0.01), neoadjuvant chemotherapy and/or immunotherapy (HR 2.34, p = 0.03), whether exenteration was performed (HR 2.64, p = 0.01), and positive resection margin (HR 3.37, p < 0.01). Conclusions: In well-selected patients, IORT is a feasible and safe option for the treatment of recurrent/persistent gynecologic malignancy with an appreciable survival benefit.

Abstract Objective . An algorithm was developed for automated positioning of lattice points within volumetric modulated arc lattice radiation therapy (VMAT LRT) planning. These points are strategically placed within the gross tumor volume (GTV) to receive high doses, adhering to specific separation rules from adjacent organs at risk (OARs). The study goals included enhancing planning safety, consistency, and efficiency while emulating human performance. Approach . A Monte Carlo-based algorithm was designed to optimize the number and arrangement of lattice points within the GTV while considering placement constraints and objectives. These constraints encompassed minimum spacing between points, distance from OARs, and longitudinal separation along the z -axis. Additionally, the algorithm included an objective to permit, at the user’s discretion, solutions with more centrally placed lattice points within the GTV. To validate its effectiveness, the automated approach was compared with manually planned treatments for 24 previous patients. Prior to clinical implementation, a failure mode and effects analysis (FMEA) was conducted to identify potential shortcomings. Main results. The automated program successfully met all placement constraints with an average execution time (over 24 plans) of 0.29 ±0.07 min per lattice point. The average lattice point density (# points per 100 c.c. of GTV) was similar for automated (0.725) compared to manual placement (0.704). The dosimetric differences between the automated and manual plans were minimal, with statistically significant differences in certain metrics like minimum dose (1.9% versus 1.4%), D5% (52.8% versus 49.4%), D95% (7.1% versus 6.2%), and Body-GTV V30% (20.7 c.c. versus 19.7 c.c.). Significance. This study underscores the feasibility of employing a straightforward Monte Carlo-based algorithm to automate the creation of spherical target structures for VMAT LRT planning. The automated method yields similar dose metrics, enhances inter-planner consistency for larger targets, and requires fewer resources and less time compared to manual placement. This approach holds promise for standardizing treatment planning in prospective patient trials and facilitating its adoption across centers seeking to implement VMAT LRT techniques.