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Analysis of peripheral blood leukocyte composition among patients with progression and non-progression as best response

Metal Conjugated Antibodies for Mass Cytometry Analysis

Supplementary Methods

Microwave (MW) ablation and stereotactic body radiation therapy (SBRT) have potentially complementary advantages and limitations for treating inoperable renal cell carcinoma (RCC). Combining SBRT and MWA may optimize tumor control and toxicity for patients with larger (>5 cm) RCCs or those with vascular involvement. We retrospectively reviewed patients at our institution with RCC treated between 2014 – 2018 to identify patients treated with a combination of SBRT and MW ablation. Seven patients with RCC were treated with combination of SBRT and MW ablation, median tumor size of 6.4 cm. Local control was 100% with a median follow-up of 15 months. Four patients experienced grade 2 nausea during SBRT. Three patients experienced toxicities after MW ablation, two with grade 1 hematuria and one with grade 3 retroperitoneal bleed/collecting system injury. Median eGFR preceding and following SBRT and MW ablation was 69 mL/min/1.73m2 and 68 mL/min/1.73m2 (p=0.19) respectively. In patients who are not surgical candidates, larger RCCs or those with vascular invasion are challenging to treat. Combination treatment with SBRT and MW ablation may balance the risks and benefits of both therapies and demonstrates high local control in our series. MW ablation and SBRT have potentially complementary advantages and limitations.

PURPOSE: The median overall survival (OS) for metastatic pancreatic ductal adenocarcinoma (mPDAC) is < 1 year. Factors that contribute to quality of life during treatment are critical to quantify. One factor—time spent obtaining clinical services—is understudied. We quantified total outpatient time among patients with mPDAC receiving palliative systemic chemotherapy. METHODS: We conducted a retrospective analysis using four patient-level time measures calculated from the medical record of patients with mPDAC receiving 5-fluorouracil infusion, leucovorin, oxaliplatin, and irinotecan; gemcitabine/nab-paclitaxel; or gemcitabine within the University of Pennsylvania Health System between January 1, 2011 and January 15, 2019. These included the total number of health care encounter days (any day with at least one visit) and total visit time. Total visit time represented the time spent receiving care (care time) plus time spent commuting and waiting for care (noncare time). We performed descriptive statistics on these outpatient time metrics and compared the number of encounter days to OS. RESULTS: A total of 362 patients were identified (median age, 65 years; 52% male; 78% white; 62% received gemcitabine plus nab-paclitaxel). Median OS was 230.5 days (7.6 months), with 79% of patients deceased at the end of follow-up. On average, patients had 22 health care encounter days, accounting for 10% of their total days survived. Median visit time was 4.6 hours, of which 2.5 hours was spent commuting or waiting for care. CONCLUSION: On average, patients receiving palliative chemotherapy for mPDAC spend 10% of survival time on outpatient health care. More than half of this time is spent commuting and waiting for care. These findings provide an important snapshot of the patient experience during ambulatory care, and efforts to enhance efficiency of care delivery may be warranted.

Background: Radiotherapy (RT) is part of the standard of care management of most gastrointestinal (GI) cancers. Even with advanced RT, systemic therapy, and surgical techniques, locoregional recurrences or second primary cancers can still occur within previously irradiated fields, which can present challenges in delivering effective and safe treatment. Options for reirradiation are often limited, but given the favorable dosimetric aspects of proton-beam RT, it may provide an effective and safe re-irradiation option for patients with recurrent or second primary GI cancers. Methods: We conducted a systematic review as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol, assessing for reports of proton-beam reirradiation for recurrent or second primary GI cancers, primarily via PubMed. From the initial 373 articles identified, 7 articles were ultimately included in the analysis. Results: The 7 included studies reported on proton-beam re-irradiation for the following disease sites: esophageal (n=2), pancreas (n=1), liver (n=2), rectal (n=1), and anal (n=1). Study sizes varied from as few as 1 to as many as 83 patients. Across studies, in patients who presented with tumor-related symptoms, palliation (stability/improvement) was achieved in 80–100% of the cases. Local control rates, with variable follow-up, ranged from 36–100%. All median overall survival values, when reported, were greater than 1 year. Across both liver studies, there were no cases of radiation-induced liver disease (RILD) from proton-beam re-irradiation. Across all studies, there were 2 acute (esophagopleural fistula in esophageal cancer, small bowel perforation in pancreatic cancer) and 1 late (esophageal ulcer in esophageal cancer) grade 5 toxicities, all favored to be due to progressive disease, rather than proton-beam re-irradiation. Two studies (1 esophageal, 1 rectal) generated comparison photon plans. One found that proton therapy reduced mean heart and lung doses, spinal cord dose, and lung V5Gy as compared to photon treatment, while resulting in higher lung V20Gy and V30Gy. The other found that protons decreased bowel V10Gy, V20Gy, and the dose to 200 and 150 cc of bowel, as compared to photons. Conclusions: Based upon the published experiences, proton-beam re-irradiation for recurrent or second primary GI cancers appears effective for palliation, with good disease-control, limited toxicity, favorable dosimetry, and overall compares well with published non-proton-beam experiences. Given short follow-up, additional studies are warranted to determine if dosimetric advantages from proton therapy will translate into comparative toxicity benefits.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

Accelerated partial breast irradiation and lumpectomy cavity boost radiation therapy plans generally use volumetric expansions from the lumpectomy cavity clinical target volume to the planning target volume (PTV) of 1 to 1.5 cm, substantially increasing the volume of irradiated breast tissue. The purpose of this study was to quantify intrafraction lumpectomy cavity motion during external beam radiation therapy to inform the indicated clinical target volume to PTV expansion.Forty-four patients were treated with a whole breast irradiation using traditional linear accelerator-based radiation therapy followed by lumpectomy cavity boost using magnetic resonance (MR)-guided radiation therapy on a prospective registry study. Two-dimensional cine-MR images through the center of the surgical cavity were acquired during each boost treatment to define the treatment position of the lumpectomy cavity. This was compared with the reference position to quantify intrafraction cavity motion. Free-breathing technique was used during treatment. Clinical outcomes including toxicity, cosmesis, and rates of local control were additionally analyzed.The mean maximum displacement per fraction in the anterior-posterior (AP) direction was 1.4 mm. Per frame, AP motion was5 mm in 92% of frames. The mean maximum displacement per fraction in the superior-inferior (SI) direction was 1.2 mm. Per frame, SI motion was5 mm in 94% of frames. Composite motion was5 mm in 89% of frames. Three-year local control was 97%. Eight women (18%) developed acute G2 radiation dermatitis. With a median follow-up of 32.4 months, cosmetic outcomes were excellent (22/44, 50%), good (19/44, 43%), and fair (2/44, 5%).In approximately 90% of analyzed frames, intrafraction displacement of the lumpectomy cavity was5 mm, with even less motion expected with deep inspiratory breath hold. Our results suggest reduced PTV expansions of 5 mm would be sufficient to account for lumpectomy cavity position, which may accordingly reduce late toxicity and improve cosmetic outcomes.

Immune checkpoint inhibitors have limited clinical activity in pancreatic cancer. Based on preclinical data, we hypothesized that hypofractionated radiation may cooperate with dual checkpoint inhibition in patients (Rech AJ, et al, Cancer Research, 2018). We therefore designed a phase 1 study to evaluate the safety and feasibility of two schedules of hypofractionated radiation with durvalumab (anti-PDL1) and tremelimumab (anti-CTLA-4) in patients with metastatic pancreatic, lung, and breast cancers and melanoma. Here, we present the data for pancreatic adenocarcinoma. Methods: Patients with metastatic pancreatic cancer treated with at least one prior line of therapy with measurable disease by RECIST in addition to an index lesion amenable to hypofractionated radiation were enrolled sequentially to two cohorts – cohort A evaluating 3 fractions of 8 Gy or cohort B evaluating 1 fraction of 17 Gy. Patients received 4 cycles of tremelimumab 1 mg/kg IV and durvalumab 20 mg/kg IV every 4 weeks for 4 doses followed by durvalumab 10 mg/kg IV every 2 weeks until progression. Radiation was given in week 2 of treatment. Patients were replaced if they did not receive week 5 of therapy on trial, but were included in safety/feasibility analysis. Blood and, when feasible, baseline and on-treatment biopsies were obtained for exploratory biomarker evaluation. Results: 10 patients were treated in cohort A and 21 patients in cohort B. All patients were included in the safety and feasibility assessment. Overall, treatment was well tolerated in both cohorts. The most common adverse events were grade 1 or 2 fatigue (A 30%, B 23.8%), diarrhea (A 10%, B 14.3%), pruritis (A 10%, B 14.3%), AST/ALT elevation and constipation (each A 10%, B 9.5%). Grade 3 diarrhea, elevated bilirubin, pneumonitis, and syncope were noted in 1 patient each, all in cohort B. Grade 5 pneumothorax occurred after baseline biopsy in 1 patient. Grade 2 hyperthyroidism (A) and pneumonitis (B) were noted each in 1 patient. 8 patients in cohort A and 13 patients in cohort B were evaluable for response. In cohort A, 50% of patients had stable disease as best response, and median overall survival was 4.9 months. In cohort B, 23.1% had PR and 30.8% had SD as best response and mOS was 5.2 months. Responses occurred more frequently when metastatic lung nodules were radiated – SD in 3/5 (60%) patients in cohort A, PR in 3/10 (30%) and SD in 4/10 (40%) patients in cohort B, compared to SD in 1/3 (33%) patients in cohort A and 0/3 (0%) patients in cohort B who underwent radiation to a liver lesion. Biomarker analysis will be presented. Conclusions: The combination of durvalumab, tremelimumab with hypofractionated radiation is safe and feasible in a refractory pancreatic adenocarcinoma patient population. Encouraging clinical activity warrants further evaluation, especially when hypofractionated radiation is delivered to lung nodules. Citation Format: Mark H. O'Hara, Adham S. Bear, Max M. Wattenberg, Ursina R. Teitelbaum, Kim A. Reiss, Thomas B. Karasic, Charles J. Schneider, Peter J. O'Dwyer, Edgar H. Ben-Josef, Andrzej P. Wojcieszynski, Amit H. Maity, Rosemarie H. Mick, Robert H. Vonderheide. Phase 1 study of hypofractionated radiation in combination with tremelimumab and durvalumab in refractory metastatic pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A016.

Purpose: This study evaluates the toxicity and tumor response with concurrent nab-paclitaxel chemoradiotherapy (CRT) compared with standard (5-fluorouracil or gemcitabine) CRT. Materials and Methods: Fifty patients with borderline resectable or unresectable pancreatic adenocarcinoma from 2014 to 2017 were divided into 2 groups: concurrent nab-paclitaxel (100 to 125 mg/m2 weekly) CRT (median: 2.1 Gy fraction size and 52.5 Gy total) or standard CRT (median: 1.8 Gy fraction size, 54.5 Gy total). The primary endpoint was toxicity, and secondary endpoints were local failure and conversion to resectability. Comparisons were made using rank-sum or Fisher exact test and multivariable competing risk regression for the cumulative incidence of local failure. Results: There were 28 patients in the nab-paclitaxel CRT group and 22 in the standard CRT group; 88% had the unresectable disease. The median follow-up was 18 months. The median duration of chemotherapy before concurrent CRT was 1.9 and 2.3 months in the nab-paclitaxel and standard CRT groups (P=0.337), and radiotherapy dose was 52.5 Gy (range, 52.5 to 59.4 Gy) and 54.5 Gy (range, 45.0 to 59.4 Gy), respectively. There were no statistically significant grade ≥2 toxicities. The nab-paclitaxel CRT group experienced a nonstatistically significant lower incidence of local failure (hazard ratio=0.91, 95% confidence interval: 0.27-3.03, P=0.536). More patients in the nab-paclitaxel CRT group proceeded to surgery (9/28 compared with 3/22 in the standard CRT, P=0.186); of which 6 (25%) in the nab-paclitaxel CRT and 2 (10%) in the standard CRT groups were initially unresectable. Conclusions: Nab-paclitaxel CRT had similar toxicity compared with standard CRT in the treatment of borderline resectable or unresectable pancreatic cancer. Its use was associated with an arithmetically lower cumulative incidence of local failure and an arithmetically higher conversion to resectability, both of which were not statistically significant.

Background and aim This study quantifies how changes in healthcare utilization and delivery during the first months of the COVID-19 pandemic have altered the presentation, treatment, and management of patients with gastrointestinal (GI) malignancies within an academic health system. Methods and results Patients diagnosed with a GI malignancy (ICD10: C15-C26) who received medical care within the health system during the observation period (first 44 weeks of 2019 and 2020) were identified for a retrospective cohort study. Deidentified patient encounter parameters were collected for this observation period and separated into pre-pandemic (weeks 1-10) and early pandemic (weeks 11-20) study periods. Difference-in-difference analyses adjusted for week-specific and year-specific effects quantified the impact of the COVID-19 pandemic on care delivery between pre-pandemic and early pandemic study periods in 2020. Across all GI malignancies, the COVID-19 pandemic has been associated with a significant decline in the number of patients with new patient visits (NPVs) (p = 1.2 × 10-4 ), Radiology encounters (p = 1.9 × 10-7 ), Surgery encounters (p = 1.6 × 10-3 ), Radiation Oncology encounters (p = 4.1 × 10-3 ), and infusion visits (6.1 × 10-5 ). Subgroup analyses revealed cancer-specific variations in changes to delivery. Patients with colorectal cancer (CRC) had the most significant decrease in NPVs (p = 7.1 × 10-5 ), which was significantly associated with a concomitant decrease in colonoscopies performed during the early pandemic period (r2 = 0.722, p = 2.1 × 10-10 ). Conclusions The COVID-19 pandemic has been associated with significant disruptions to care delivery. While these effects were appreciated broadly across GI malignancies, CRC, diagnosed and managed by periodic screening, has been affected most acutely.

Electronic health records (EHR) have been implemented successfully in a majority of United States healthcare systems in some form. There has been a rise in secondary uses of EHR, especially for research. EHR data is large, heterogenous, incomplete, noisy, and primarily created for purposes other than research. This presents many challenges, many of which are beginning to be overcome with the application of computer science artificial intelligence techniques, such as natural language processing and machine learning. EHR are gradually being redesigned to facilitate future research, though we are still far from a "complete EHR."

Purpose Daily magnetic resonance (MR)–guided radiation has the potential to improve stereotactic body radiation therapy (SBRT) for tumors of the liver. Magnetic resonance imaging (MRI) introduces unique variables that are untested clinically: electron return effect, MRI geometric distortion, MRI to radiation therapy isocenter uncertainty, multileaf collimator position error, and uncertainties with voxel size and tracking. All could lead to increased toxicity and/or local recurrences with SBRT. In this multi-institutional study, we hypothesized that direct visualization provided by MR guidance could allow the use of small treatment volumes to spare normal tissues while maintaining clinical outcomes despite the aforementioned uncertainties in MR-guided treatment. Methods and materials Patients with primary liver tumors or metastatic lesions treated with MR-guided liver SBRT were reviewed at 3 institutions. Toxicity was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4. Freedom from local progression (FFLP) and overall survival were analyzed with the Kaplan-Meier method and χ2 test. Results The study population consisted of 26 patients: 6 hepatocellular carcinomas, 2 cholangiocarcinomas, and 18 metastatic liver lesions (44% colorectal metastasis). The median follow-up was 21.2 months. The median dose delivered was 50 Gy at 10 Gy/fraction. No grade 4 or greater gastrointestinal toxicities were observed after treatment. The 1-year and 2-year overall survival in this cohort is 69% and 60%, respectively. At the median follow-up, FFLP for this cohort was 80.4%. FFLP for patients with hepatocellular carcinomas, colorectal metastasis, and all other lesions were 100%, 75%, and 83%, respectively. Conclusions This study describes the first clinical outcomes of MR-guided liver SBRT. Treatment was well tolerated by patients with excellent local control. This study lays the foundation for future dose escalation and adaptive treatment for liver-based primary malignancies and/or metastatic disease.

PURPOSE/OBJECTIVE(S) Patients undergoing concurrent chemoradiotherapy (CRT) for head and neck cancer often experience significant toxicities. Proton therapy permits decreased dose delivery to non-target structures and the potential for superior organs-at-risk sparing. The aim of this study was to evaluate if proton therapy is associated with decreased acute grade ≥3 toxicities compared to photon therapy in the setting of concurrent CRT for head and neck cancers. MATERIALS/METHODS This study included 654 adult patients with nonmetastatic, locally advanced head and neck cancer treated with definitive concurrent CRT from January 1, 2011 to April 30, 2019 at one institution. 90-day toxicity data were prospectively collected as defined by Common Terminology Criteria for Adverse Events, version 4. Acute toxicities were grouped into five categories for analysis: mucosal (mucosal infection, mucositis), oral cavity (dry mouth, dysgeusia), swallow (aspiration, dysphagia), constitutional (fatigue, anorexia, dehydration), and skin (dermatitis, edema, superficial soft tissue necrosis, alopecia) toxicities. Modified Poisson regression models with covariate adjustment were used to model toxicity risk following multiple imputation for missing covariate values. Ten hypotheses were tested. Thus, the Bonferroni multiple testing correction was applied and statistical significance was assessed at the 0.005 level. RESULTS One hundred and six patients received proton therapy and 548 received photon therapy. Patients receiving proton therapy were older (mean age [SD] 61.2 [12.2] vs 58.9 [9.30], P = 0.029) and were more likely to be HPV-positive (67.0% vs 57.0%, P = 0.036). Proton therapy patients had lower dose to the parotid glands (right mean [SD], 21.8 Gy [12.9] vs 27.9 [11.3], P < 0.001; left 23.1 Gy [12.7] vs 27.2 [11.0], P = 0.001), oral cavity (13.7 Gy [9.88] vs 28.8 [10.8], P < 0.001) and constrictor muscle (35.6 Gy [10.37] vs 43.7 [9.24], P < 0.001) compared to photon therapy patients. Charlson-Deyo comorbidity scores were similar for both groups (mean [SD] 6.18 [1.74] vs 6.40 [2.57], P = 0.39), as were the distributions for sex (P = 0.118), race (P = 0.16), cancer stage (P = 0.163), and baseline ECOG (P = 0.57). In covariate-adjusted analyses, proton therapy was associated with a significantly lower relative risk of any 90-day grade ≥3 toxicity (0.57, 95% CI 0.40-0.83, P = 0.003). For acute grade 2 toxicity proton therapy was associated with significantly reduced relative risk of oral cavity toxicity (0.74, 95% CI 0.61-0.90, P = 0.002) but higher skin toxicity (1.35, 95% CI 1.14-1.59, P = 0.0004). CONCLUSION Concurrent chemoradiotherapy with proton therapy for head and neck cancers was associated with lower dose to nontarget structures and significantly reduced acute grade ≥3 toxicity and acute grade 2 oral cavity toxicity compared to photon therapy. Grade 2 skin toxicity favored photon therapy.

Purpose/Objective(s) Tumor thrombus (TT) in HCC is a negative prognostic marker. dRT can provide durable tumor control with some risk of decompensation/death from RT liver injury. We sought to identify subsets of patients (pts) who stand to benefit most from RT. Materials/Methods The medical record of HCC pts with any thrombus receiving dRT (defined as prescribed dose of ≥50 Gy) between 2010 and 2019 was reviewed. TT was classified per Sarin (Gastroenterol 2019). We conducted univariate (UV)/multivariate (MV) Cox regressions for overall survival (OS), progression-free survival (PFS), and time-to-decompensation (TTD; liver decompensation with death as a competing risk). Variables with UV P-values Results Select characteristics for the 61 identified pts are listed in the Table. With a median follow-up of 8.0 months (mo.), 37 pts had progressed (local - 9 (24%), regional - 26 (70%), and distant - 19 (51%)). Median PFS/OS were 5.7 mo. (IQR 2.8-14.2) and 8.8 mo. (IQR 4.3-21.0), respectively. Decompensation was observed in 36 pts (59%) with a median TTD of 6.8 mo. On UV OS analysis, ECOG performance status (PS) (2-3 vs. 0: HR 9.2, 95% CI 3.5-23.8, P 292cc (GTV292; median) (HR 1.7, 95% CI 1.0-3.0, P = 0.06) trended towards significance. On MV OS analysis, only PS (2-3 vs. 0; HR 8.5, 95% CI 2.9-284.9, P Conclusion In this retrospective analysis of HCC pts with thrombus, OS after dRT was significantly associated with PS and ALBI. While validation of these findings is needed, in pts with TT, those with PS 0-1 and ALBI G1 should be considered for dRT.

TGFβ is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFβ enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFβ inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients (n = 15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150 mg orally twice a day) on days 1 to 14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15 to 28 of cycle 1. Site of index lesions treated with SBRT included liver (9 patients), lymph node (4 patients), and lung (2 patients). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia, possibly related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from nonprogressors. Nonprogressors also had increased CD8+PD-1+TIGIT+ T cells in the blood after treatment. We found galunisertib combined with SBRT to be well tolerated and associated with antitumor activity in patients with HCC. Pre- and posttreatment immune profiling of the blood was able to distinguish patients with progression versus nonprogression.

Objective To report outcomes and toxicity in patients who received definitive concurrent chemoradiation (DCCRT) for non‐operable esophageal cancer (EC) in the modern era, and to identify markers of overall and disease‐free survival (OS/DFS). Methods We conducted a retrospective cohort study of patients with unresectable EC who received DCCRT at our institution between 1/2008 and 1/2019. Descriptive statistics were used to report disease‐control outcomes and CTCAE v4.0–5.0 toxicities. Univariable and multivariable Cox regression, and stepwise regression were used to identify associations with survival. Results At a median follow‐up of 19.5 months, 130 patients with adenocarcinoma (AC) (62%) or squamous cell carcinoma (SCC) (38%) were evaluable (Stage II‐III: 92%). Patients received carboplatin/paclitaxel (75%) or fluorouracil‐based (25%) concurrent chemotherapy. Median total RT dose was 50.4 Gy (range, 44.7–71.4 Gy) delivered in 28 fractions (24–35). Locoregional and distant recurrence occurred in 30% and 35% of AC, and 24% and 33% of SCC, respectively. Median OS and DFS were 22.9 and 10.7 months in AC, and 25.7 and 20.2 months in SCC, respectively. On stepwise regression, tumor stage, feeding tube during DCCRT, and change in primary tumor PET/CT SUVmax were significantly associated with OS and DFS. Most severe toxicities were acute grade 4 hematologic cytopenia (6%) and radiation dermatitis (1%). Most common acute grade 3 toxicities were hematologic cytopenia (35%), dysphagia (23%), and anorexia (19%). Conclusions Treatment of non‐operable EC with DCCRT has acceptable toxicity and can provide multi‐year disease control for some patients, even in AC. Continued follow‐up and investigation in large studies would be useful., Treatment of non‐operable esophageal cancer with definitive concurrent chemoradiation has acceptable toxicity and can provide multi‐year disease control for some patients, even in adenocarcinoma.

Introduction The optimal management of locally advanced recto-sigmoid cancer is unclear. Although some experts advocate for upfront surgery, others recommend neoadjuvant chemoradiation followed by surgery. We used the National Cancer Database to characterize patterns-of-care and overall survival (OS) associated with these treatment strategies. Patients and Methods Patients with clinical stage II or III recto-sigmoid cancer who underwent surgery with or without adjunctive chemotherapy and/or radiotherapy from 2006 to 2014 were identified, and dichotomized into: (1) upfront surgery, and (2) neoadjuvant chemoradiation cohorts. Patterns-of-care were assessed using multivariable logistic regression. The association between neoadjuvant chemoradiation use and OS was assessed using Cox proportional hazards analysis with propensity score-matching. Results Of 9313 identified patients, 6756 (73%) underwent upfront surgery and 2557 (27%) received neoadjuvant chemoradiation. Treatment at academic facilities and higher clinical T stage were predictors of neoadjuvant chemoradiation use. Compared with upfront surgery, neoadjuvant chemoradiation resulted in fewer positive circumferential resection margins (384 [11%] patients vs. 108 [8%] patients; P = .001), and 478 [18.7%] patients achieved a pathologic complete response at surgery. In propensity score-matched analysis, neoadjuvant chemoradiation use was associated with improved OS (hazard ratio, 0.79; 95% confidence interval, 0.69-0.90) compared with upfront surgery; 5-year estimated OS was 77.0% versus 72.0%, respectively. The improvement in OS persisted in landmark analysis of patients who survived at least 12 months. Conclusion Only a small percentage of patients with locally advanced recto-sigmoid cancer receive neoadjuvant chemoradiation even though its use might result in improved OS relative to upfront surgery. Prospective research is warranted to validate and standardize therapeutic strategies in patients with recto-sigmoid cancer.

IMPORTANCE: Concurrent chemoradiotherapy is the standard-of-care curative treatment for many cancers but is associated with substantial morbidity. Concurrent chemoradiotherapy administered with proton therapy might reduce toxicity and achieve comparable cancer control outcomes compared with conventional photon radiotherapy by reducing the radiation dose to normal tissues. OBJECTIVE: To assess whether proton therapy in the setting of concurrent chemoradiotherapy is associated with fewer 90-day unplanned hospitalizations (Common Terminology Criteria for Adverse Events, version 4 [CTCAEv4], grade ≥3) or other adverse events and similar disease-free and overall survival compared with concurrent photon therapy and chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, nonrandomized comparative effectiveness study included 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent from January 1, 2011, through December 31, 2016, at a large academic health system. Three hundred ninety-one patients received proton therapy and 1092, photon therapy. Data were analyzed from October 15, 2018, through February 1, 2019. INTERVENTIONS: Proton vs photon chemoradiotherapy. MAIN OUTCOMES AND MEASURES: The primary end point was 90-day adverse events associated with unplanned hospitalizations (CTCAEv4 grade ≥3). Secondary end points included Eastern Cooperative Oncology Group (ECOG) performance status decline during treatment, 90-day adverse events of at least CTCAEv4 grade 2 that limit instrumental activities of daily living, and disease-free and overall survival. Data on adverse events and survival were gathered prospectively. Modified Poisson regression models with inverse propensity score weighting were used to model adverse event outcomes, and Cox proportional hazards regression models with weighting were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach. RESULTS: Among the 1483 patients included in the analysis (935 men [63.0%]; median age, 62 [range, 18-93] years), those receiving proton therapy were significantly older (median age, 66 [range, 18-93] vs 61 [range, 19-91] years; P

Purpose The optimum adjuvant treatment for Stage II endometrial cancer patients is unknown. External beam radiation therapy (EBRT) is often considered the standard of care; however, retrospective series suggest that brachytherapy (BT) alone may be sufficient for selected patients. As randomized data are lacking, we used a large database to explore this question. Methods and Materials The National Cancer Data Base was queried for patients with pathologic International Federation of Gynecology and Obstetrics Stage II disease. Demographic, clinic-pathologic, and treatment details were compared between patients. Multivariable analysis was used to determine factors associated with receiving radiation therapy (RT). To account for imbalances between groups, a matched-pair analysis was completed. Results Eight thousand one hundred forty patients were included. RT was associated with overall survival (OS), with EBRT (hazard ratio [HR] 0.64), BT (HR 0.47), and combination (HR 0.54) showing increased OS on univariate analysis. Facility, urban location, diagnosis year, hysterectomy type, and chemotherapy did not reach significance. On multivariate analysis, RT was associated with OS, with EBRT (HR 0.69), BT (HR 0.60), and combination (HR 0.54) showing benefit. Using propensity-score matching, RT continued to show improved OS regardless of type: BT (82% vs. 73% 5-year OS) and EBRT (77% vs. 71%). BT as compared to EBRT had equivalent survival (81% vs. 79%, not statistically significant). Conclusion This study of over 8,000 patients demonstrates that adjuvant RT confers a survival benefit in Stage II endometrial cancer and supports the continued use of RT in these patients. BT alone may be reasonable in carefully selected patients.

Purpose/objective(s) Higher levels of physical activity assessed by step count have been associated with lower risk of hospitalization during cancer treatment. We hypothesize that it is feasible to use activity data to identify patients undergoing concurrent chemoradiation for gastrointestinal (GI) malignancy who are at high risk for emergency department (ED) visits and hospitalizations, and to successfully trigger and execute triage visits for symptom management. Materials/methods This prospective study randomized patients to activity monitoring versus observation. Each group was provided an activity monitor. If a patient in the intervention arm had 20% decreased activity or 20% increase in heart rate from their baseline, a triage visit was triggered to evaluate and treat symptoms. In the observation group, activity data was recorded but no triage visit was triggered. Baseline step count and heart rate were established during a one-week period between radiation simulation and treatment start. The primary endpoint was to demonstrate an increased rate of triage visits in the activity monitoring group compared to observation. Secondary outcomes included rates of ED visits and hospitalizations. Crude and adjusted odds ratios (OR) were computed using logistic regression modeling. Results A total of 40 patients were enrolled on the study: 22 in the intervention group and 18 in the observation group. Primary disease sites included anus (n = 4), gastric/esophagus (n = 14), hepatobiliary (n = 4), pancreas (n = 7), and rectum (n = 11). Median age was 60 years in the intervention arm and 62.5 years in the observation arm (P = 0.69). The median radiation dose and fractionation were similar among the two groups. Average baseline daily step counts were similar in the two groups (5,103 in intervention group vs. 5,668 in observation group, P = 0.43). Average daily step counts decreased from week 1 to week 5 in both groups (-960 steps in observation group and -1,164 steps in the intervention group). There was an increased rate of triage visits in the intervention arm compared to the observation arm (86.4% v 38.9%, OR 9.95, 95% CI 2.12-46.56, P = 0.015). Rates of ED visits and hospitalizations were numerically lower in the intervention group compared to the observation group (9.1% vs 22.2%, P = 0.31; 4.5% vs 16.7%, P = 0.31, respectively). Patients with anal (-1456 steps) cancer showed the largest decrease in mean daily step count over the treatment course. Medical intervention was more common in the intervention group compared to observation (P Conclusion This study supports the feasibility of actively monitoring patient's daily step and heart rate data to successfully trigger triage visits for patients at high risk for toxicity. Further studies are ongoing and may support the use of automated activity monitoring to decrease the rates of ED visits and hospitalizations.

Purpose Concurrent chemoradiation therapy is a curative treatment for squamous cell carcinoma of the anus, but patients can suffer from significant treatment-related toxicities. This study was undertaken to determine whether intensity modulated proton therapy (IMPT) is associated with less acute toxicity than intensity modulated radiation therapy (IMRT) using photons. Materials and Methods We performed a multi-institutional retrospective study comparing toxicity and oncologic outcomes of IMRT versus IMPT. Patients with stage I-IV (for positive infrarenal para-aortic or common iliac nodes only) squamous cell carcinoma of the anus, as defined by the American Joint Committee on Cancer's AJCC Staging Manual, eighth edition, were included. Patients with nonsquamous histology or mixed IMPT and IMRT treatment courses were excluded. Acute nonhematologic toxicities, per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4, were recorded prospectively at all sites. Acute and late toxicities, dose metrics, and oncologic outcomes were compared between IMRT and IMPT using univariable and multivariable statistical methods. To improve the robustness of our analysis, we also analyzed the data using propensity score weighting methods. Results A total of 208 patients were treated with either IMPT (58 patients) or IMRT (150 patients). Of the 208 total patients, 13% had stage I disease, 36% stage II, 50% stage III, and 1% stage IV. IMPT reduced the volume of normal tissue receiving low-dose radiation but not high-dose radiation to bladder and bowel. There was no significant difference between treatment groups in overall grade 3 or greater acute toxicity (IMRT, 68%; IMPT, 67%; P = .96) or 2-year overall grade 3 or greater late toxicity (IMRT, 3.5%; IMPT, 1.8%; P = .88). There was no significant difference in 2-year progression-free survival (hazard ratio, 0.8; 95% CI, 0.3-2.0). Conclusions Despite reducing the volume of normal tissue receiving low-dose radiation, IMPT was not associated with decreased grade 3 or greater acute toxicity as measured by CTCAE. Additional follow-up is needed to assess whether important differences arise in late toxicities and if further prospective evaluation is warranted.

Purpose: Magnetic resonance imaging–guided radiation therapy has entered clinical practice at several major treatment centers. Treatment of early-stage non-small cell lung cancer with stereotactic body radiation therapy is one potential application of this modality, as some form of respiratory motion management is important to address. We hypothesize that magnetic resonance imaging–guided tri-cobalt-60 radiation therapy can be used to generate clinically acceptable stereotactic body radiation therapy treatment plans. Here, we report on a dosimetric comparison between magnetic resonance imaging–guided radiation therapy plans and internal target volume–based plans utilizing volumetric-modulated arc therapy. Materials and Methods: Ten patients with early-stage non-small cell lung cancer who underwent radiation therapy planning and treatment were studied. Following 4-dimensional computed tomography, patient images were used to generate clinically deliverable plans. For volumetric-modulated arc therapy plans, the planning tumor volume was defined as an internal target volume + 0.5 cm. For magnetic resonance imaging–guided plans, a single mid-inspiratory cycle was used to define a gross tumor volume, then expanded 0.3 cm to the planning tumor volume. Treatment plan parameters were compared. Results: Planning tumor volumes trended larger for volumetric-modulated arc therapy–based plans, with a mean planning tumor volume of 47.4 mL versus 24.8 mL for magnetic resonance imaging–guided plans ( P = .08). Clinically acceptable plans were achievable via both methods, with bilateral lung V20, 3.9% versus 4.8% ( P = .62). The volume of chest wall receiving greater than 30 Gy was also similar, 22.1 versus 19.8 mL ( P = .78), as were all other parameters commonly used for lung stereotactic body radiation therapy. The ratio of the 50% isodose volume to planning tumor volume was lower in volumetric-modulated arc therapy plans, 4.19 versus 10.0 ( P < .001). Heterogeneity index was comparable between plans, 1.25 versus 1.25 ( P = .98). Conclusion: Magnetic resonance imaging–guided tri-cobalt-60 radiation therapy is capable of delivering lung high-quality stereotactic body radiation therapy plans that are clinically acceptable as compared to volumetric-modulated arc therapy–based plans. Real-time magnetic resonance imaging provides the unique capacity to directly observe tumor motion during treatment for purposes of motion management.

e18671 Background: Patients undergoing concurrent radiation therapy and systemic therapy often experience significant toxicities, which can adversely affect their quality of life. We sought to determine if activity monitoring and early outpatient intervention could lead to improved quality of life (QoL) in patients with gastrointestinal malignancies undergoing chemoradiotherapy. Methods: In this prospective randomized trial, patients with gastrointestinal malignancies undergoing concurrent chemoradiotherapy were randomized to activity monitoring versus standard of care (observation). Each group was provided a commercially available fitness tracker but only the intervention group was actively monitored. If a patient in the intervention arm had a 20% decrease in step count or 20% increase in heart rate from their baseline, a triage visit was triggered to further evaluate and manage symptoms. In the observation group, step count and heart rate were recorded but no triage visit was triggered. All patients had weekly on treatment visits and access to standard communication methods for symptom management during and after-hour business hours. The primary endpoint was the rate of completed triage visits. QoL was a secondary endpoint and was collected from both arms at radiation simulation (baseline) and weekly during treatment using the EORTC QLQ-C30 (v.3). The mixed model for repeated measures was used for longitudinal analysis of global health status (GHS) and overall QoL scores (range 1-7) to determine the impact of intervention and time on QoL. Results: A total of 40 patients were evaluable in this study: 22 in the intervention group and 18 in the observation group. The primary endpoint was met with an increased rate of triage visits in the active monitoring group compared to the observation group (86.4% vs 39.9%, OR 9.95, 95% CI 2.12 -46.56, p = 0.015). EORTC QLQ-C30 questionnaires were completed by 97.5% of patients. The baseline QoL scores were similar in both arms (mean GHS 5.06 vs 5.50, p = 0.28 and mean QoL 4.98 vs 5.73, p = 0.09 in observation vs intervention group, respectively). There was a trend towards improved mean GHS, and QoL scores in the intervention group at all timepoints, although it did not reach statistical significance. Overall, GHS and QoL scores deteriorated from week 1 to week 6 during treatment in both groups (mean QoL 5.06 to 4.46, p = 0.16 in observation; mean QoL 5.55 to 5.03, p = 0.16 in intervention group). Conclusions: This study supports the feasibility of using activity monitor to actively track step count and heart rate to successfully trigger triage visits for patients at high risk for toxicity. Early outpatient intervention with the use of activity monitoring may improve quality of life in patients undergoing chemoradiotherapy.

30 Background: Changes in healthcare utilization and delivery during the first months of the COVID-19 pandemic have altered the presentation, treatment, and management of patients with gastrointestinal (GI) malignancies. We hypothesize this has contributed to diagnostic and treatment delays that will increase disease morbidity and mortality. Methods: We performed a retrospective cohort study comparing healthcare utilization of patients with diagnosed GI malignancy (ICD10:C15-C26) during and prior to the COVID-19 pandemic within our health system. Deidentified patient encounter parameters were collected for the first 20 weeks of both 2019 and 2020, including the number of: new patient visits (NPVs), hospital admissions, and specialty encounters. Difference-in-difference analyses adjusted for week-specific and year-specific effects quantified the impact of the COVID-19 pandemic on care delivery, with week 11 of 2020 marking the start of the pandemic period. Results: The 2019 and 2020 cohorts of patients had similar demographic compositions on the basis of sex and ethnicity (2019: n = 23,536, 56.8% M, 70.4/16.3/1.9% White/Black/Hispanic; 2020: n = 25,773, 57.0% M, 70.3/16.3/2.0% White/Black/Hispanic). Across all GI malignancies, the COVID-19 pandemic period was associated with a significant decrease in NPVs (-50.0/week, -45% from 2019, p < 1e-3). Colorectal cancer (CRC) had the largest decrease in NPVs among GI malignancies (-25.3/week, -53% from 2019, p < 1e-4). Of note, there was a parallel decrease in colonoscopies during this time (-682/week, -91% from 2019, p < 1e-11). For patients with diagnosed GI malignancies, the COVID-19 pandemic was associated with statistically significant declines in hospital admissions (-31.7/week, -37% from 2019, p < 1e-5), radiology encounters (-177/week, -38% from 2019, p < 1e-6), radiation oncology encounters (-18.2/week, -12% from 2019, p < 0.01), chemotherapy infusion visits (-62.2/week, -17% from 2019, p < 1e-4), and surgery encounters (-71.1/week, -15.7% from 2019, p < 0.01). Subgroup analyses revealed these reductions were most significant in patients with CRC (radiology encounters, surgery encounters, hospital admissions), anal cancer (radiation oncology encounters), and pancreatic cancer (chemotherapy infusion visits). Conclusions: These data demonstrate that the COVID-19 pandemic is associated with significant disruptions to care delivery. While these effects were appreciated broadly across GI malignancies, CRC—diagnosed and managed by periodic screening—has been affected most acutely. The precipitous drop in screening colonoscopies likely contributed to the decline in NPVs, specialty encounters and hospital admissions. These findings underscore the importance of reinstating regular GI cancer screening and management. Future work will assess the impact of these and other changes to cancer care delivery on long term morbidity and mortality.

7049 Background: Proton therapy may increase the tolerability/efficacy of concurrent chemoradiotherapy (CRT) but is controversial & generally not covered by private insurers. There is little data on the comparative effectiveness (CE) of proton vs photon CRT among private insurance pts to guide payers on proton coverage policies. Methods: We conducted a CE study of adult non-metastatic cancer pts with private insurance treated with curative-intent proton vs photon CRT from 2011-2016 at Penn. The choice of radiation modality was heavily influenced by the insurer’s proton coverage policy. Data on adverse events (AEs) & survival were gathered prospectively using standardized templates. Primary endpoint was 90-day AEs associated with unplanned hospitalizations (CTCAEv4 grade ≥3 AEs). Secondary endpoints included 90-day grade ≥2 AEs, decline in ECOG performance status (PS) during treatment, disease-free survival (DFS) & overall survival (OS). Modified Poisson regression models with inverse propensity score weighting were used for adverse event outcomes. Weighted Cox proportional hazards models were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach. P0.05 for all). 11.2% of proton pts had grade ≥3 AE’s vs 26.8% of photon pts. On propensity score weighted-analyses, proton CRT was associated with significantly lower relative risk (RR) of 90-day grade ≥3 AEs (RR 0.51, 95%CI 0.32-0.81, p

7053 Background: Patients' symptoms and side effects have traditionally been assessed by clinicians. There is increasing evidence that patient self-reported symptom severity often differs from clinician assessment, and that collecting patient-reported outcomes (PRO) can improve communication, symptom management, and even survival. However, the implementation of routine PRO collection across a large healthcare system poses operational and informatics challenges. Methods: Using native electronic health record (EHR) functionality, we implemented a standardized PRO questionnaire across a large academic cancer center and associated community-based practices. The questionnaire is based on the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) developed by the National Cancer Institute. It assesses eleven common side effects of cancer care and is available for completion from home via the EHR patient portal or in clinic via tablet PC. Implementation was stepwise, beginning with a disease-specific patient population in the main academic cancer center and expanding over two years to include all cancer types, three specialties (radiation oncology, hematology/oncology, gynecologic oncology), and multiple satellite practice locations. Results: PRO collection was initiated for patients with gastrointestinal malignancies in two clinic locations at the main cancer center in 12/2017. During the first 3 months of implementation (12/2017-2/2018), questionnaires were completed for 1838 (56.3%) of 3267 eligible patient visits. Work with practice managers and staff to refine operational workflows led to improvement to a 75.6% capture rate for the period 3/2018 – 5/2018. From 6/2018 through 6/2019, the program was expanded to all multidisciplinary clinics in the main cancer center, as well as eight satellite practices. Aggregate capture rates from 7/2018 through 12/2019 have shown sustained performance, with 101,082 (76.7%) of 131,720 eligible visits captured. Of twelve total clinics participating, eleven have sustained capture rates above 70%, and nine capture over 80% of eligible visits. Questionnaires were completed through the online patient portal 12.1% of the time, with the remainder completed in clinic via tablet PC. Conclusions: Routine PRO collection as standard-of-care is possible across a variety of practice environments in a large, complex health system, with sustained capture of approximately three-fourths of eligible visits. Most patients prefer to complete the questionnaire in clinic.

4575 Background: TGF-β is a pleiotropic cytokine with immunosuppressive activity. In mouse models, blockade of TGF-β signaling enhances the activity of radiation and invokes T cell dependent anti-tumor immunity. We previously reported preliminary safety and efficacy results from a pilot study combining galunisertib (LY2157299), an oral TGF-β inhibitor, with SBRT for the treatment of patients with advanced HCC. Here, we investigate immunological mechanisms and potential biomarkers associated with therapeutic activity. Methods: Patients with advanced HCC who had progressed on or refused sorafenib were treated with galunisertib (150 mg PO BID) on days 1-14 of each 28-day cycle. SBRT (18 Gy) was delivered in a single dose between days 15-28 of cycle 1. Blood was collected at baseline, following two weeks of galunisertib and following SBRT for high-dimensional analysis using a 37-marker CyTOF panel. Patients were dichotomized based on best response as either progressor (PD) or non-progressor (PR+SD). The frequency of immune subsets was compared between groups. Results: Fifteen patients were enrolled and treated. One patient was not evaluable. The most common adverse event was grade 1 or 2 fatigue in 53% of patients. The only possibly-related grade 3 event was achalasia in one patient which coincided with disease progression. Two patients achieved a PR and six patients had SD (DCR 57%) with a median progression-free survival of 3.7 months and a median overall survival of 9.0 months. For most patients, regardless of outcome, galunisertib treatment was associated with a decrease in activated Ki67+ Treg cells. However, pre-treatment immune composition within the blood of progressors and non-progressors was distinct. At baseline, progressors had an increased frequency of naive-like CD8+ T cells, whereas non-progressors had an increased frequency of non-classical monocytes. After combination therapy, only non-progressors showed a significant increase in CD8+PD1+TIGIT+ T cells. Conclusions: Galunisertib combined with SBRT was well-tolerated with modest efficacy. Immune profiling of the blood revealed distinct pre- and post-treatment signatures that differentiated patients with progression versus non-progression. These findings show that the combination of anti-TGF-β therapy with radiation can mediate disease control and identify potential correlates of efficacy. Clinical trial information: NCT02906397 .

Magnetic resonance-guided radiation therapy (MRgRT) offers advantages for image guidance for radiotherapy treatments as compared to conventional computed tomography (CT)-based modalities. The superior soft tissue contrast of magnetic resonance (MR) enables an improved visualization of the gross tumor and adjacent normal tissues in the treatment of abdominal and thoracic malignancies. Online adaptive capabilities, coupled with advanced motion management of real-time tracking of the tumor, directly allow for high-precision inter-/intrafraction localization. The primary aim of this case series is to describe MR-based interventions for localizing targets not well-visualized with conventional image-guided technologies. The abdominal and thoracic sites of the lung, kidney, liver, and gastric targets are described to illustrate the technological advancement of MR-guidance in radiotherapy.

6521 Background: Concurrent chemo-radiotherapy is standard-of-care curative treatment for many cancers, but is associated with substantial morbidity. Proton therapy may increase the tolerability or effectiveness of concurrent chemo-radiotherapy by reducing radiation to normal tissues. Methods: We conducted a comparative effectiveness study of adult non-metastatic cancer patients treated with curative intent with proton chemo-radiotherapy vs. photon chemo-radiotherapy from 2011-2016 at the University of Pennsylvania. Re-irradiation and disease sites treated with photon-only therapy were excluded. Data on adverse events and survival was gathered prospectively. Primary endpoint was 90-day adverse events associated with unplanned hospitalizations (CTCAEv4 grade ≥3 adverse events). Secondary endpoints included decline in ECOG performance status during treatment, 90-day grade ≥2 adverse events, disease-free survival (DFS) and overall survival (OS). Modified Poisson regression models with inverse propensity score weighting were fit for both outcomes. Propensity scores were estimated using an ensemble machine-learning approach. Results: 1,483 patients were included (391 proton/1,092 photon). Proton patients were significantly older (median 66 vs. 61), had less favorable Charlson-Deyo comorbidity scores (median 3.0 vs. 2.0), and had lower integral radiation dose to tissues outside the target (p < 0.05 for all). Baseline toxicity and performance status were similar (p > 0.05). In propensity score weighted-analyses, proton chemo-radiotherapy was associated with significantly lower relative risk (RR) of 90-day grade ≥3 adverse events [11.5%(95%CI 8.3-14.7%) for protons; 27.6%(95%CI 24.9-30.2%) for photons; RR 0.31, 95%CI 0.15-0.66, p < 0.01]; 90-day grade ≥2 adverse events (RR 0.78, 95%CI 0.65-0.93, p < 0.01); and decline in performance status during treatment (RR 0.51, 95%CI 0.37-0.71, p < 0.01). There was no difference in DFS or OS. Conclusions: In adults with locally advanced cancer, proton chemo-radiotherapy was associated with significantly reduced acute adverse events causing unplanned hospitalizations with similar disease-free and overall survival.

BACKGROUND The addition of chemoradiation (CRT) to surgery has been shown to improve survival in patients with esophageal cancer. In the current study, the authors determined whether the sequencing of CRT has an effect on survival and cardiopulmonary mortality in patients with esophageal cancer. METHODS Patients with the following inclusion criteria were identified within 17 Surveillance, Epidemiology, and End Results registries from 1988 through 2007: adenocarcinoma or squamous cell carcinoma of the esophagus and having undergone esophagectomy. Patients who died within 90 days of surgery were excluded. Demographic, tumor, and survival data were compared between patients receiving preoperative and postoperative RT. Cox proportional hazards regression models were calculated to identify parameters associated with cause-specific survival and overall survival. A competing risk analysis was performed to account for death due to esophageal cancer in the calculation of cardiopulmonary mortality. RESULTS Of 5512 patients, 1881 received preoperative RT, 901 received postoperative RT, and 2730 did not receive RT. Patients receiving preoperative RT had improved 5-year cause-specific survival (41% vs 31%; P < .0001) and overall survival (33% vs 23%; P < .0001) compared with those receiving postoperative RT. No differences in adjusted cardiopulmonary mortality were found between patients who received RT versus those who did not (8% vs 10% at 10 years; hazards ratio [HR], 0.84 [95% confidence interval (95% CI), 0.64-1.12] [P = .24]) or between those treated with preoperative RT versus those treated with postoperative RT (HR, 0.70; 95% CI, 0.46-1.08 [P = .11]). CONCLUSIONS These population-based data support the use of preoperative RT in patients with locally advanced esophageal cancer. RT should not be withheld out of concern for cardiopulmonary mortality. Cancer 2013;119:1976–1984. © 2013 American Cancer Society.

Purpose: Dose limiting structures, such as the duodenum, render the treatment of pancreatic cancer challenging. In this multi-institutional study, we assess dosimetric differences caused by interfraction pancreas-to-duodenum motion using MR-IGRT to determine the potential impact of adaptive replanning. Methods: Ten patients from two institutions undergoing MRI-guided radiotherapy with conventional fractionation (n=5) or SBRT (n=5) for pancreatic cancer were included. Initial plans were limited by duodenal dose constraints of 50 Gy (0.5 cc)/31 Gy (0.1 cc) for conventional/SBRT with prescriptions of 30 Gy/5 fractions (SBRT) and 40–50 Gy/25 fractions (conventional). Daily volumetric MR images were acquired under treatment conditions on a clinical MR-IGRT system. The correlation was assessed between interfractional GTV-to-duodenum positional variation and daily recalculations of duodenal dose metrics. Positional variation was quantified as the interfraction difference in Hausdorff distance from simulation baseline (ΔHD) between the GTV and proximal duodenal surface, or volume overlap between GTV and duodenum for cases with HD0=0 (GTV abutting duodenum). Adaptation was considered indicated when daily positional variations enabled dose escalation to the target while maintaining duodenal constraints. Results: For fractions with ΔHD>0 (n=14, SBRT only), the mean interfraction duodenum dose decrease from simulation to treatment was 44±53 cGy (maximum 136 cGy). A correlation was found between ΔHD and dosimetric difference (R2=0.82). No correlation was found between volume of overlap and dosimetric difference (R2=0.31). For 89% of fractions, the duodenum remained overlapped with the target and the duodenal dose difference was negligible. The maximum observed indication for adaptation was for interfraction ΔHD=11.6 mm with potential for adaptive dose escalation of 136 cGy. Conclusion: This assessment showed that Hausdorff distance was a reasonable metric to use to determine the indication for adaptation. Adaptation was potentially indicated in 11% of the treatments (fractions where GTV-to-duodenum distance increased from simulation), with a feasible average dose escalation of 7.0%. MB, LH, JO, RK, PP: research and/or travel funding from ViewRay Inc. PP: research grant from Varian Medical Systems and Philips Healthcare