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PURPOSE To determine the specific types, durations, and intensities of recreational physical activity associated with the greatest improvements in disease-free survival (DFS) of patients with colon cancer. METHODS We conducted a prospective cohort study nested within a randomized multicenter trial of stage III colon cancer that compared 3 versus 6 months of fluorouracil, leucovorin, and oxaliplatin with or without celecoxib. We measured recreational physical activity in the first 3 months of chemotherapy and again 6 months after completion of chemotherapy. The primary end point was DFS. RESULTS During a median follow-up of 5.9 years, 457 of 1,696 patients experienced disease recurrence or death. For total recreational physical activity volume, the 3-year DFS was 76.5% with < 3.0 metabolic equivalent task hours per week (MET-h/wk) and 87.1% with ≥ 18.0 MET-h/wk (risk difference [RD], 10.6%; 95% CI, 4.7 to 19.4; P < .001). For light-intensity to moderate-intensity activities, the 3-year DFS was 65.7% with 0.0 h/wk and 87.1% with ≥ 1.5 h/wk (RD, 21.4%; 95% CI, 9.2 to 37.1; P < .001). For vigorous-intensity activity, the 3-year DFS was 76.0% with 0.0 h/wk and 86.0% with ≥ 1.0 h/wk (RD, 10.0%; 95% CI, 4.5 to 18.9; P < .001). For brisk walking, the 3-year DFS was 81.7% with < 1.0 h/wk and 88.4% with ≥ 3.0 h/wk (RD, 6.7%; 95% CI, 3.0 to 13.8; P < .001). For muscle strengthening activity, the 3-year DFS was 81.8% with 0.0 h/wk and 88.8% for ≥ 0.5 h/wk (RD, 7.0%; 95% CI, 3.1 to 14.2; P = .003). CONCLUSION Among patients with stage III colon cancer enrolled in a trial of postoperative treatment, larger volumes of recreational physical activity, longer durations of light- to moderate-intensity aerobic physical activity, or any vigorous-intensity aerobic physical activity were associated with the greatest improvements in DFS.

Treatment with the mTOR inhibitor everolimus improves progression-free survival in pancreatic neuroendocrine tumors, but it is not known if the addition of a VEGF pathway inhibitor to an mTOR inhibitor enhances antitumor activity. We performed a randomized phase II study evaluating everolimus with or without bevacizumab in patients with advanced pancreatic neuroendocrine tumors. One hundred and fifty patients were randomized to receive everolimus 10 mg daily with or without bevacizumab 10 mg/kg IV every 2 weeks. Patients in both arms also received standard dose octreotide. The primary endpoint was progression-free survival, based on local investigator review. Treatment with the combination of everolimus and bevacizumab resulted in improved progression-free survival compared to everolimus (16.7 months compared to 14.0 months; one-sided stratified log-rank p=0.1028; HR 0.80 (95% CI 0.56–1.13), meeting the predefined primary endpoint. Confirmed tumor responses were observed in 31% (95% CI 20%, 41%) of patients receiving combination therapy, as compared to only 12% (95% CI 5%, 19%) of patients receiving treatment with everolimus (P=0.0053). Median overall survival duration was similar in the everolimus and combination arm (42.5 months and 42.1 months, respectively). Treatment-related toxicities were more common in the combination arm. In summary, treatment with everolimus and bevacizumab led to superior progression-free survival and higher response rates compared to everolimus in patients with advanced pancreatic neuroendocrine tumors. Although the higher rate of treatment related adverse events may limit the use of this combination, our results support the continued evaluation of VEGF pathway inhibitors in pancreatic neuroendocrine tumors.

PURPOSE Current tools in predicting survival outcomes for patients with colon cancer predominantly rely on clinical and pathologic characteristics, but increasing evidence suggests that diet and lifestyle habits are associated with patient outcomes and should be considered to enhance model accuracy. METHODS Using an adjuvant chemotherapy trial for stage III colon cancer (CALGB 89803), we developed prediction models of disease-free survival (DFS) and overall survival by additionally incorporating self-reported nine diet and lifestyle factors. Both models were assessed by multivariable Cox proportional hazards regression and externally validated using another trial for stage III colon cancer (CALGB/SWOG 80702), and visual nomograms of prediction models were constructed accordingly. We also proposed three hypothetical scenarios for patients with (1) good-risk, (2) average-risk, and (3) poor-risk clinical and pathologic features, and estimated their predictive survival by considering clinical and pathologic features with or without adding self-reported diet and lifestyle factors. RESULTS Among 1,024 patients (median age 60.0 years, 43.8% female), we observed 394 DFS events and 311 deaths after median follow-up of 7.3 years. Adding self-reported diet and lifestyle factors to clinical and pathologic characteristics meaningfully improved performance of prediction models (c-index from 0.64 [95% CI, 0.62 to 0.67] to 0.69 [95% CI, 0.67 to 0.72] for DFS, and from 0.67 [95% CI, 0.64 to 0.70] to 0.71 [95% CI, 0.69 to 0.75] for overall survival). External validation also indicated good performance of discrimination and calibration. Adding most self-reported favorable diet and lifestyle exposures to multivariate modeling improved 5-year DFS of all patients and by 6.3% for good-risk, 21.4% for average-risk, and 42.6% for poor-risk clinical and pathologic features. CONCLUSION Diet and lifestyle factors further inform current recurrence and survival prediction models for patients with stage III colon cancer.

Purpose: CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent. Patients and Methods: In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment. Results: In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10–2.06; cetuximab HR, 0.94; 95% CI, 0.71–1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19–2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68–1.24; Pinteraction = 0.0097). Conclusions: In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725

BackgroundThe incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal cancer (mCRC).MethodsWe studied the association of age with survival in 2326 mCRC patients enrolled in the Cancer and Leukemia Group B and SWOG 80405 trial, a multicenter, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan-Meier method and compared among younger vs older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided.ResultsOf 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs 62.5 years in patients aged 50 years and older. There was no statistically significant difference in OS between yoCRC vs older-onset patients (median = 27.07 vs 26.12 months; adjusted HR = 0.98, 95% CI = 0.88 to 1.10; P = .78). The median PFS was also similar in yoCRC vs older patients (10.87 vs 10.55 months) with an adjusted hazard ratio of 1.02 (95% CI = 0.92 to 1.13; P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs 26.12 months in older-onset patients with an adjusted hazard ratio of 1.08 (95% CI = 0.81 to 1.44; Ptrend = .93).ConclusionIn this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients aged 50 years and older.

PURPOSE To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma. METHODS After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy. RESULTS Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached. CONCLUSION Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.

Background Quality measurement has become a priority for national healthcare reform, and valid measures are necessary to discriminate hospital performance and support value‐based healthcare delivery. The Commission on Cancer (CoC) is the largest cancer‐specific accreditor of hospital quality in the United States and has implemented Quality of Care Measures to evaluate cancer care delivery. However, none has been formally tested as a valid metric for assessing hospital performance based on actual patient outcomes. Methods Eligibility and compliance with the Quality of Care Measures are reported within the National Cancer Database, which also captures data for robust patient‐level risk adjustment. Hospital‐level compliance was calculated for the core measures, and the association with patient survival was tested using Cox regression. Results Seven hundred sixty‐eight thousand nine hundred sixty‐nine unique cancer cases were included from 1323 facilities. Increasing hospital‐level compliance was associated with improved survival for only two measures, including a 35% reduced risk of mortality for the gastric cancer measure G15RLN (HR 0.65, 95% CI 0.58–0.72) and a 19% reduced risk of mortality for the colon cancer measure 12RLN (HR 0.81, 95% CI 0.77–0.85). For the lung cancer measure LNoSurg, increasing compliance was paradoxically associated with an increased risk of mortality (HR 1.14, 95% CI 1.08–1.20). For the remaining measures, hospital‐level compliance demonstrated no consistent association with patient survival. Conclusion Hospital‐level compliance with the CoC’s Quality of Care Measures is not uniformly aligned with patient survival. In their current form, these measures do not reliably discriminate hospital performance and are limited as a tool for value‐based healthcare delivery., The Commission on Cancer is the largest cancer‐specific accreditor of hospital quality in the United States and has implemented Quality of Care Measures to evaluate quality cancer care delivery. This study represents the first comprehensive evaluation of the Quality of Care Measures as valid metrics for assessing hospital performance based on actual patient outcomes.

Purpose Diagnosing primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is challenging because it is a clinicopathologic entity that shares characteristics with other lymphomas and lacks pathognomonic features. We sought to investigate the fidelity between a working diagnosis of PMBCL at our institution and the clinicopathologic criteria established within the 2017 World Health Organization (WHO) classification. Patients and Methods Medical records and archived tissue of patients treated for stage I-II PMBCL from 1998 to 2018 were retrospectively reviewed for clinical and pathologic conformity with current WHO criteria. Disease was characterized as definitely PMBCL if all of the following were present: anterior mediastinal mass with or without lymph node involvement, no extranodal disease, B-cell antigen expression, Epstein-Barr virus negativity, and at least one supportive feature: female gender under age 40, bulky primary tumor, CD30 weakly positive, compartmentalizing alveolar fibrosis, lack of surface immunoglobulin expression, and MUM1 or CD23 positivity. Disease without supportive features or other pathologic findings more suggestive of other entities was characterized as equivocal for PMBCL. Lack of an anterior mediastinal mass, presence of distant lymph node involvement or extranodal disease, lack of B-cell antigen expression, or Epstein-Barr virus positivity were characterized as definitely not PMBCL. Clinical management and outcomes were also assessed. Results Of 63 patients treated for presumed stage I-II PMBCL, 58 (92%) met the criteria for PMBCL. The most common reason for a discordant diagnosis was lack of an anterior mediastinal mass (n = 3). Two additional patients were characterized as having disease equivocal for PMBCL. In retrospect, one patient most likely had a mediastinal gray zone lymphoma due to CD15 positivity and another diffuse large B cell, not otherwise specified, at pathologic review. Five-year progression-free and overall survival were 67% (95% confidence interval, 54-77) and 81% (95% confidence interval, 68-89), respectively, for all patients. Conclusion Despite the complexity of the clinicopathologic criteria of PMBCL, most patients (92%) who were treated for stage I-II PMBCL at our institution appear to have been accurately diagnosed.

Purpose: We previously reported on the clinical outcomes of treating oligometastases with radiation using an elective simultaneous integrated boost technique (SIB), delivering higher doses to known metastases and reduced doses to adjacent bone or nodal basins. Here we compare outcomes of oligometastases receiving radiation targeting metastases alone (MA) versus those treated via an SIB. Methods: Oligometastatic patients with ≤5 active metastases treated with either SIB or MA radiation at two institutions from 2013 to 2019 were analyzed retrospectively for treatment-related toxicity, pain control, and recurrence patterns. Tumor metastasis control (TMC) was defined as an absence of progression in the high dose planning target volume (PTV). Marginal recurrence (MR) was defined as recurrence outside the elective PTV but within the adjacent bone or nodal basin. Distant recurrence (DR) was defined as any recurrence that is not within the PTV or surrounding bone or nodal basin. The outcome rates were estimated using the Kaplan–Meier method and compared between the two techniques using the log-rank test. Results: 101 patients were treated via an SIB to 90 sites (58% nodal and 42% osseous) and via MA radiation to 46 sites (22% nodal and 78% osseous). The median follow-up among surviving patients was 24.6 months (range 1.4–71.0). Of the patients treated to MA, the doses ranged from 18 Gy in one fraction (22%) to 50 Gy in 10 fractions (50%). Most patients treated with an SIB received 50 Gy to the treated metastases and 30 Gy to the elective PTV in 10 fractions (88%). No acute grade ≥3 toxicities occurred in either cohort. Late grade ≥3 toxicity occurred in 3 SIB patients (vocal cord paralysis and two vertebral body compression), all related to the high dose PTV and not the elective volume. There was similar crude pain relief between cohorts. The MR-free survival rate at 2 years was 87% (95% CI: 70%, 95%) in the MA group and 98% (95% CI: 87%, 99%) in the SIB group (p = 0.07). The crude TMC was 89% (41/46) in the MA group and 94% (85/90) in the SIB group. There were no significant differences in DR-free survival (65% (95% CI: 55–74%; p = 0.24)), disease-free survival (60% (95% CI: 40–75%; p = 0.40)), or overall survival (88% (95% CI: 73–95%; p = 0.26)), between the MA and SIB cohorts. Conclusion: Both SIB and MA irradiation of oligometastases achieved high rates of TMC and similar pain control, with a trend towards improved MR-free survival for oligometastases treated with an SIB. Further investigation of this technique with prospective trials is warranted.

Purpose Early indication of treatment outcome may guide therapeutic de-escalation strategies in patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC). This study investigated the relationships between tumor volume and 18F-FDG-PET parameters before and during definitive radiotherapy with treatment outcomes. Methods and Materials Patients undergoing definitive (chemo)radiation for HPV-related/p16-positive OPC were prospectively enrolled on an IRB-approved study. 18F-FDG-PET/CT scans were performed at simulation and after 2 weeks at a dose of ∼20 Gy. Tumor volume and standardized uptake value (SUV) characteristics were measured. SUV was normalized to blood pool uptake. Tumor volume and PET parameters associated with recurrence were identified through recursive partitioning (RPART). Recurrence-free survival (RFS) and overall survival (OS) curves between RPART-identified cohorts were estimated using the Kaplan-Meier method and Cox models were used to estimate the hazard ratios (HR). Results From 2012 to 2016, 62 patients with HPV-related OPC were enrolled. Median follow-up was 4.4 years. RPART identified patients with intra-treatment SUVmax (normalized to blood pool SUVmean) > 6.7 with intra-treatment SUV40% > 2.75 as less likely to recur. For identified subgroups, results of Cox models showed unadjusted HR for RFS and OS (more likely to recur vs less likely) of 7.33 (90% CI 2.97 – 18.12) and 6.09 (90% CI 2.22 – 16.71), respectively and adjusted HR of 6.57 (90% CI 2.53 – 17.05) and 5.61 (90% CI 1.90 – 16.54) for RFS and OS, respectively. Conclusions PET parameters after 2 weeks of definitive radiotherapy for HPV-related OPC are associated with RFS and OS, thus potentially informing an adaptive treatment approach.

PURPOSE Patients undergoing outpatient radiotherapy (RT) or chemoradiation (CRT) frequently require acute care (emergency department evaluation or hospitalization). Machine learning (ML) may guide interventions to reduce this risk. There are limited prospective studies investigating the clinical impact of ML in health care. The objective of this study was to determine whether ML can identify high-risk patients and direct mandatory twice-weekly clinical evaluation to reduce acute care visits during treatment. PATIENTS AND METHODS During this single-institution randomized quality improvement study (ClinicalTrials.gov identifier: NCT04277650 ), 963 outpatient adult courses of RT and CRT started from January 7 to June 30, 2019, were evaluated by an ML algorithm. Among these, 311 courses identified by ML as high risk (> 10% risk of acute care during treatment) were randomized to standard once-weekly clinical evaluation (n = 157) or mandatory twice-weekly evaluation (n = 154). Both arms allowed additional evaluations on the basis of clinician discretion. The primary end point was the rate of acute care visits during RT. Model performance was evaluated using receiver operating characteristic area under the curve (AUC) and decile calibration plots. RESULTS Twice-weekly evaluation reduced rates of acute care during treatment from 22.3% to 12.3% (difference, −10.0%; 95% CI, −18.3 to −1.6; relative risk, 0.556; 95% CI, 0.332 to 0.924; P = .02). Low-risk patients had a 2.7% acute care rate. Model discrimination was good in high- and low-risk patients undergoing standard once-weekly evaluation (AUC, 0.851). CONCLUSION In this prospective randomized study, ML accurately triaged patients undergoing RT and CRT, directing clinical management with reduced acute care rates versus standard of care. This prospective study demonstrates the potential benefit of ML in health care and offers opportunities to enhance care quality and reduce health care costs.

Non-Alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. Epigenetic alterations, such as through DNA methylation (DNAm), may link adverse childhood exposures and fatty liver and provide non-invasive methods for identifying children at high risk for NAFLD and associated metabolic dysfunction. We investigated the association between differential DNAm and liver fat content (LFC) and liver injury in pre-adolescent children. Leveraging data from the Newborn Epigenetics Study (NEST), we enrolled 90 mother-child dyads and used linear regression to identify CpG sites and differentially methylated regions (DMRs) in peripheral blood associated with LFC and alanine aminotransferase (ALT) levels in 7–12yo children. DNAm was measured using Infinium HumanMethylationEPIC BeadChips (Illumina). LFC and fibrosis were quantified by magnetic resonance imaging proton density fat fraction and elastography. Median LFC was 1.4% (range, 0.3–13.4%) and MRE was 2.5 kPa (range, 1.5–3.6kPa). Three children had LFC ≥ 5%, while six (7.6%) met our definition of NAFLD (LFC ≥ 3.7%). All children with NAFLD were obese and five were Black. LFC was associated with 88 DMRs and 106 CpGs (FDR

BACKGROUND Uterine leiomyosarcoma is a rare malignant smooth muscle tumor originating in the uterine wall that generally responds poorly to chemotherapy and radiation. AIM We investigated the in vitro effects of a novel nutrient mixture containing lysine, proline, ascorbic acid, and green tea extract on the human leiomyosarcoma cell line SK-UT-1 by measuring cell proliferation, invasiveness, apoptosis, and expression of matrix metalloproteinases (MMP). We also tested the effects of nutrient mixture in vivo using nude mice. MATERIALS AND METHODS Human leiomyosarcoma SK-UT-1 cells were treated with different concentrations of nutrient mixture. Cell proliferation was determined by MTT assay; MMP expression by gelatinase zymography; invasion by Matrigel assay; migration by scratch test; apoptosis using Live Green caspase kit. In vivo studies were conducted on 5-6 weeks old female nude mice inoculated subcutaneously with 3 • 106 SK-UT-1 cells. The mice were fed a regular diet or a diet supplemented with 0.5% nutrient mixture. After four weeks, the mice were sacrificed and the tumors were weighed and processed for histology. RESULTS In vitro, nutrient mixture treatment was not toxic to SK-UT-1 cells at 250 µg/ml but exhibited 20% and 40% cytotoxicity at 500 and 1000 µg/ml respectively. Zymography did not show bands for either MMP-2 or MMP-9 in SK-UT-1 cells. However, treatment with phorbol myristate acetate stimulated the expression of MMP-9, both active and inactive forms in equal proportion. Nutrient mixture inhibited the secretion of both active and inactive forms in a dose dependent manner. Invasion through Matrigel and migration by scratch test were inhibited in a dose dependent fashion, with both invasion and migration inhibited at 250 µg/ml. Live Green Caspase apoptosis assay demonstrated slight apoptosis at 100 µg/ml and significant apoptosis at 250 to 1000 µg/ml. The results of in vitro studies were further confirmed in vivo by showing 50% decrease in tumor weight, 40% reduction in tumor burden compared to the tumors from mice fed regular diet. CONCLUSION The results suggest a therapeutic potential for nutrient mixture in uterine leiomyosarcoma treatment.

The purpose of this study was to assess baseline variability in histogram and texture features derived from apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI (DW-MRI) examinations and to identify early treatment-induced changes to these features in patients with head and neck squamous cell carcinoma (HNSCC) undergoing definitive chemoradiation. Patients with American Joint Committee on Cancer Stage III–IV (7th edition) HNSCC were prospectively enrolled on an IRB-approved study to undergo two pre-treatment baseline DW-MRI examinations, performed 1 week apart, and a third early intra-treatment DW-MRI examination during the second week of chemoradiation. Forty texture and six histogram features were derived from ADC maps. Repeatability of the features from the baseline ADC maps was assessed with the intra-class correlation coefficient (ICC). A Wilcoxon signed-rank test compared average baseline and early treatment feature changes. Data from nine patients were used for this study. Comparison of the two baseline ADC maps yielded 11 features with an ICC ≥ 0.80, indicating that these features had excellent repeatability: Run Gray-Level Non-Uniformity, Coarseness, Long Zone High Gray-Level, Variance (Histogram Feature), Cluster Shade, Long Zone, Variance (Texture Feature), Run Length Non-Uniformity, Correlation, Cluster Tendency, and ADC Median. The Wilcoxon signed-rank test resulted in four features with significantly different early treatment-induced changes compared to the baseline values: Run Gray-Level Non-Uniformity (p = 0.005), Run Length Non-Uniformity (p = 0.005), Coarseness (p = 0.006), and Variance (Histogram) (p = 0.006). The feasibility of histogram and texture analysis as a potential biomarker is dependent on the baseline variability of each metric, which disqualifies many features.

Background Limited and conflicting findings have been reported regarding the association between social support and colorectal cancer (CRC) outcomes. We sought to assess the influences of marital status and living arrangement on survival outcomes among patients with stage III colon cancer. Patients and Methods We conducted a secondary analysis of 1082 patients with stage III colon cancer prospectively followed in the CALGB 89803 randomized adjuvant chemotherapy trial. Marital status and living arrangement were both self-reported at the time of enrollment as, respectively, married, divorced, separated, widowed, or never-married, and living alone, with a spouse or partner, with other family, in a nursing home, or other. Results Over a median follow-up of 7.6 years, divorced/separated/widowed patients experienced worse outcomes relative to those married regarding disease free-survival (DFS) (hazards ratio (HR), 1.44 (95% CI, 1.14-1.81); P =.002), recurrence-free survival (RFS) (HR, 1.35 (95% CI, 1.05-1.73); P = .02), and overall survival (OS) (HR, 1.40 (95% CI, 1.08-1.82); P =.01); outcomes were not significantly different for never-married patients. Compared to patients living with a spouse/partner, those living with other family experienced a DFS of 1.47 (95% CI, 1.02-2.11; P = .04), RFS of 1.34 (95% CI, 0.91-1.98; P = .14), and OS of 1.50 (95% CI, 1.00-2.25; P =.05); patients living alone did not experience significantly different outcomes. Conclusion Among patients with stage III colon cancer who received uniform treatment and follow-up within a nationwide randomized clinical trial, being divorced/separated/widowed and living with other family were significantly associated with greater colon cancer mortality. Interventions enhancing social support services may be clinically relevant for this patient population. Trial Registration ClinicalTrials.gov Identifier: NCT00003835

Background Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. Methods All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). Results A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1–14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60–84%). Median PFS and OS were 3.9 months (95% CI, 2.3–4.5) and 7.1 months (95% CI: 5.8–10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. Conclusion The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. Trial registration This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

PURPOSE Regular physical activity is associated with reduced risk of recurrence and mortality in patients with nonmetastatic colorectal cancer. Its influence on patients with advanced/metastatic colorectal cancer (mCRC) has been largely unexplored. PATIENTS AND METHODS We conducted a prospective cohort study nested in Cancer and Leukemia Group B (Alliance)/SWOG 80405 (ClinicalTrials.gov identifier: NCT00265850 ), a National Cancer Institute–sponsored phase III trial of systemic therapy for mCRC. Within 1 month after therapy initiation, patients were invited to complete a validated questionnaire that reported average physical activity over the previous 2 months. On the basis of responses, we calculated metabolic equivalent task (MET) hours per week to quantify physical activity. The primary end point of the clinical trial and this companion study was overall survival (OS). Secondary end points included progression-free survival (PFS) and first grade 3 or greater treatment-related adverse events. To minimize confounding by poor and declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and used Cox proportional hazards regression analysis to adjust for known prognostic factors, comorbidities, and weight loss. RESULTS The final cohort included 1,218 patients. Compared with patients engaged in less than 3 MET hours per week of physical activity, patients engaged in 18 or more MET hours per week experienced an adjusted hazard ratio for OS of 0.85 (95% CI, 0.71 to 1.02; PTrend = .06) and for PFS of 0.83 (95% CI, 0.70 to 0.99; PTrend = .01). Compared with patients engaging in less than 9 MET hours per week, patients engaging in 9 or more MET hours per week experienced an adjusted hazard ratio for grade 3 or greater treatment-related adverse events of 0.73 (95% CI, 0.62 to 0.86; PTrend < .001). CONCLUSION Among patients with mCRC in Cancer and Leukemia Group B (Alliance)/SWOG 80405, association of physical activity with OS was not statistically significant. Greater physical activity was associated with longer PFS and lower adjusted risk for first grade 3 or greater treatment-related adverse events.

PURPOSE CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS. PATIENTS AND METHODS Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested. RESULTS Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability–high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/ KRAS/ BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors ( P < .001). CONCLUSION In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.

Background: Malignant mesothelioma is a highly aggressive and fatal cancer of older people. Consistently associated with asbestos exposure, mesothelioma is diagnosed when it is extensively metastasized and it has a dismal prognosis. Purpose of the study: Surgery, chemotherapy, and radiotherapy are the mainstay of treatment yet they are ineffective in increasing the mesothelioma patient survival. Therefore, a different approach is needed. A novel nutrient mixture containing green tea extract, ascorbic acid, lysine, and proline exhibited anti-cancer effects in various cancers. In our previous studies, the nutrient mixture was seen to block MMP secretion and invasion through MatrigelTM by mesothelioma cells. In the current study, we wanted to explore if the nutrient mixture could induce apoptosis in mesothelioma cells

Background Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2, COX-2)-prostaglandin E2 (PGE2) pathway promotes tumour progression. Considering evidence suggesting increased PGE2 synthesis by BRAF mutation in tumour cells, we hypothesised that the association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality might be stronger in BRAF-mutated tumours than in BRAF-wild-type tumours. Methods Using 1708 patients, including 1200 stage I-IV colorectal carcinoma cases in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) and 508 stage III colon cancer cases in a National Cancer Institute–sponsored randomised controlled trial of adjuvant therapy ( CALGB /Alliance 89803), we evaluated tumour PTGS2 (COX-2) expression status using immunohistochemistry. We examined the prognostic association of PTGS2 (COX-2) expression in strata of BRAF mutation status by multivariable Cox proportional hazards regression models to adjust for potential confounders, including disease stage, tumour differentiation, microsatellite instability status and KRAS and PIK3CA mutations. Results In NHS and HPFS, the association of PTGS2 (COX-2) expression with colorectal cancer-specific survival differed by BRAF mutation status (Pinteraction = 0.0005); compared with PTGS2 (COX-2)-negative/low carcinomas, the multivariable-adjusted hazard ratios for PTGS2 (COX-2)-high carcinomas were 2.44 (95% confidence interval, 1.39–4.28) in BRAF-mutated cases and 0.82 (95% confidence interval, 0.65–1.04) in BRAF-wild-type cases. Differential prognostic associations of PTGS2 (COX-2) expression in strata of BRAF mutation status were similarly observed in CALGB/Alliance 89803 trial (Pinteraction = 0.03). Conclusions The association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality is stronger in BRAF-mutated tumours than in BRAF-wild-type tumours, supporting interactive roles of PTGS2 (COX-2) expression and BRAF mutation statuses in prognostication of patients with colorectal cancer; ClinicalTrials.gov Identifier, NCT00003835 .

Background Disparities in colon cancer outcomes have been reported across race and socioeconomic status, which may reflect, in part, access to care. We sought to assess the influences of race and median household income (MHI) on outcomes among colon cancer patients with similar access to care. Methods We conducted a prospective, observational study of 1206 stage III colon cancer patients enrolled in the CALGB 89803 randomized adjuvant chemotherapy trial. Race was self-reported by 1116 White and 90 Black patients at study enrollment; MHI was determined by matching 973 patients’ home zip codes with publicly available US Census 2000 data. Multivariate analyses were adjusted for baseline sociodemographic, clinical, dietary, and lifestyle factors. All statistical tests were 2-sided. Results Over a median follow-up of 7.7 years, the adjusted hazard ratios for Blacks (compared with Whites) were 0.94 (95% confidence interval [CI] = 0.66 to 1.35, P = .75) for disease-free survival, 0.91 (95% CI = 0.62 to 1.35, P = .65) for recurrence-free survival, and 1.07 (95% CI = 0.73 to 1.57, P = .73) for overall survival. Relative to patients in the highest MHI quartile, the adjusted hazard ratios for patients in the lowest quartile were 0.90 (95% CI = 0.67 to 1.19, Ptrend = .18) for disease-free survival, 0.89 (95% CI = 0.66 to 1.22, Ptrend = .14) for recurrence-free survival, and 0.87 (95% CI = 0.63 to 1.19, Ptrend = .23) for overall survival. Conclusions In this study of patients with similar health-care access, no statistically significant differences in outcomes were found by race or MHI. The substantial gaps in outcomes previously observed by race and MHI may not be rooted in differences in tumor biology but rather in access to quality care.

Purpose/objective(s) Management of HCC without surgical resection or transplantation is poorly defined with no standard. Stereotactic body radiation therapy (SBRT) or hypofractionated image-guided radiotherapy (HIGRT), is an evolving, non-invasive, therapeutic option for patients with HCC delivering ablative doses with modest toxicity. Materials/methods We retrospectively identified all patients with unresectable, non-metastatic HCC treated with SBRT/HIGRT who presented to our University and Veterans Affairs (VA) radiation oncology departments from 2013 to 2019. Primary study endpoints included freedom from local progression, progression free survival, overall survival, and treatment-related toxicity. Results 149 patients were included in our analysis with median delivered radiation dose of 50 Gy in 5 fractions. This included a total of 172 treatment courses, as 21 patients received more than one course (19 patients received 2 courses; 2 patients received 3 courses). Twenty-two of the re-treatment courses were to previously unirradiated lesions, while one course was delivered to a previously treated lesion exhibiting local progression. Sixty-nine percent (69%) of patients were Child-Pugh A and 89% had a baseline ALBI grade of 1-2 prior to treatment. A majority of patients (59%) had a single lesion with a median size of 2.70 cm (Q1 2.00, Q3 3.95). Fifty-seven percent (57%) of patients received a biologically effective dose (BEDα/β = 10) of at least 75 Gy and 48% of patients had undergone prior liver-directed therapy. All patients completed their intended treatment course with 1 patient (0.7%) experiencing Grade 3+ acute and 4 patients (2.6%) experiencing Grade 3+ late toxicities. Fifteen treatment courses (8.7%) resulted in non-classical radiation-induced liver disease (RILD), defined as an increase of 2 or more points in Child-Pugh score following radiation. With median follow up of 40 months, median overall survival was 25 months (95% CI 18-30 months). The 2-year freedom from local progression was 75% (95% CI 65-83%) overall, 64% (95% CI 48-77%) among patients who received BED ≤75 Gy and 86% (95% CI 72-93%) among those who received BED > 75 Gy. Median progression free survival was not reached. During the study period, 8.1% of patients developed regional nodal progression and 18.8% developed distant metastatic disease (42.9% osseous, 50.0% lung, 46.4% soft tissue/peritoneal/other involvement; multiple patients with more than one site of metastatic involvement). Conclusion SBRT/HIGRT results in high rates of local control with minimal treatment related toxicities. Randomized, prospective trials should seek to establish SBRT/HIGRT as a standard local therapeutic option for patients with unresectable, non-metastatic HCC.

The mainstays of cancer treatment are surgery, chemotherapy, radiation, and immunotherapy. Although each has benefits, none of them is ideal because the quality of life is compromised with all these strategies. Therefore it is not surprising that 80% of cancer patients seek alternative therapy, which includes antioxidants and other essential micronutrients (NM). We have developed new approaches to prevent cancer development, progression, and metastasis using naturally occurring NM containing lysine, proline, ascorbic acid, and green tea extract and other NM that act synergistically by strengthening collagen and connective tissue. It has been demonstrated that NM exhibited anticancer activity in vitro and in vivo in a number of cancer cell lines derived from organ malignancies by inhibiting several of the hallmarks of cancer, including cell proliferation, invasion, metastasis, angiogenesis, and induction of apoptosis. The NM inhibited in vitro proliferation of a wide variety of cancer cells in a dose-dependent fashion. NM also inhibited growth of cancer cells implanted as xenografts in athymic mice. In addition, NM also inhibited N-methyl-N-nitrosourea-induced mammary carcinogenesis, urethane-induced lung carcinogenesis, and dimethylbenzoanthracene-induced skin carcinogenesis in rodent models. Further, NM also inhibited invasion of a variety of tumor cells through Matrigel and reduced cancer cell migration in scratch tests in a dose-dependent manner. Our studies also demonstrated that NM inhibited pulmonary, hepatic, testicular, peritoneal, splenic, kidney, and heart metastasis in mouse models. Upregulation of activities of MMP-2 and MMP-9 and uPA and downregulation of tissue inhibitors of metalloproteinases (TIMPs) are associated with cancer metastasis. In a number of cancer cell lines, NM inhibited the activity of MMP-2, MMP-9, and uPA and increased the activity of TIMPs, suggesting that this could be the mechanism by which the NM exerts its effects on metastasis. Further, NM also inhibited angiogenesis in an in vivo model of the chick chorioallantoic membrane assay in a chicken embryo, inhibited b-FGF-induced vessel growth in a mouse Matrigel plug assay, inhibited blood vessel formation in tumors in a xenograft mouse model, and also inhibited capillary tube formation. At a biochemical level, NM decreased in vitro expression of pro-angiogenic factors such as VEGF, angiopoietin, b-FGF, platelet-derived growth factor, and TGFβ-1. Furthermore, NM induced apoptosis in a number of cancer cell lines by upregulating and downregulating several genes including caspases and bcl2. NM also modulated inflammatory proteins Cox-2 and iNOS. In summary, these results clearly indicate that NM inhibits all the hallmarks of cancer development and offers unique benefits in fighting cancer.

TPS6108 Background: Despite aggressive multimodal treatment that typically includes radiation therapy (RT), recurrence rates approach 50% for patients with non-HPV-related locally advanced HNSCC. Treatment options for unresectable recurrent or metastatic HNSCC are limited, though PD-1 inhibitors improve survival for a subset of patients. Radiation resistance contributes to locoregional recurrence—a major driver for HNSCC morbidity and mortality. In preclinical studies, we observed significant HNSCC radiosensitization by targeting ataxia telangiectasia and Rad 3-related (ATR) kinase with small molecule inhibitor BAY 1895344. ATR inhibition with RT has also been shown preclinically to increase antigen presentation and anti-tumor T cell activity. Similarly, preclinical data suggest synergy between BAY 1895344 and anti-PD-1 therapy. We hypothesize that treating recurrent HNSCC with concurrent anti-PD-1 therapy, ATR inhibition and RT will improve tumor control through radiosensitization and stimulating a host anti-tumor immune response. An ongoing clinical trial (NCT04095273) is assessing concurrent BAY 1895344 and pembrolizumab, but BAY 1895344 with concurrent RT has not been evaluated in patients. To determine the safety and optimal dosing of concurrent RT and BAY 1895344, we opened a multi-institutional, CTEP-sponsored phase I trial (NCT04576091) evaluating reirradiation with stereotactic body radiation therapy (SBRT) combined with BAY 1895344 and pembrolizumab for patients with recurrent HNSCC. Methods: Eligible patients for this single-arm trial are adults with recurrent, unresectable HNSCC who received prior head and neck RT and cisplatin. Exclusion criteria include gross skin or mandible involvement, disease encasing >180° of the carotid artery, and prior RT < 6 months before enrollment. Patients with oligometastatic disease (4 AE within 90 days of RT completion. An 18-patient expansion cohort will be enrolled at the MTD. Pre-treatment tissue and serial blood samples will be collected for correlative studies. This trial opened to accrual in November 2021, with no patients enrolled as of February 2022. Clinical trial information: NCT04576091.

3571 Background: In colorectal cancer (CRC), mutations in KRAS, NRAS, and BRAF predict resistance to anti-EGFR therapies. In pancreatic ductal adenocarcinoma (PDAC), ~90% of patients harbor KRAS mutations, while KRAS wild-type tumors often have clinically actionable fusion alterations. Thus, in both cancers, the accurate ascertainment of RAS and BRAF driver status is essential. Sequencing of cell-free DNA (cfDNA) from plasma allows convenient assessment of a tumor’s molecular profile, but sensitivity can be limited by low ctDNA shedding. We sought to establish a ctDNA shedding threshold at which actionable driver mutations can be reliably detected. Methods: Molecular reports and matched clinical data were obtained from the Duke Molecular Registry of Tumors and the SCRUM-Japan GOZILA and GI-SCREEN. CRC or PDAC patients with a pathogenic KRAS, NRAS, or BRAF activating point mutation (“driver”) present on tissue next-generation sequencing (NGS) assays and who also had cfDNA assay available were included. Tissue NGS included Foundation One CDx and Oncomine Comprehensive Assay. Guardant 360 (G360) was the sole plasma cfDNA assay. 131 CRC and 24 PDAC cases with 189 total G360 assays met criteria and were included. Samples were analyzed according to detection of the driver mutation and the maximum mutant allele frequency (MAF) of non-driver mutations on G360. An optimal cut-point for max MAF was explored among the CRC and PDAC patients using a maximally selected Wilcoxon rank statistic method. Results: 76.8% of driver mutations were in KRAS, 22.6% in BRAF, and 1.9% in NRAS with an overlap of 1 BRAF and 1 NRAS mutation with a KRAS mutation. Overall sensitivity of G360 for drivers was 83.0% for CRC and 54.2% for PDAC. No variants were detected on G360 in 9.1% of CRC and 37.5% of PDAC. Sensitivity for driver mutations increased with higher maximum non-driver MAF, with MAF > 1% predicting sensitivity > 98% (Table). Optimal cut-point analysis identified MAF of > 0.34% (p < 0.0001), above which the driver was identified in 97% of patients and below which only 27%. Conclusions: In our study, non-driver MAF > 1% on cfDNA NGS predicts high sensitivity for RAS and BRAF mutations and thus is adequate to guide clinical decisions such as anti-EGFR therapy in CRC, evaluation for fusions in PDAC, and validity in clinical trials. MAF ≤0.34% is a clear threshold to consider an assay inadequate and thus seek alternative testing. Sensitivity rises for MAF between 0.35 and 1% but will require greater patient numbers to establish clinically relevant sensitivity thresholds. These results will be updated with additional data for final presentation. [Table: see text]

3580 Background: Monoamine oxidases (MAOs), including MAOA and MAOB, are mitochondrial enzymes responsible for catalyzing monoamine oxidation. Increased expression of MAOs were found in several cancer types and high MAOB was associated with worse disease stage and poorer survival in CRC. Positive and negative correlations of MAOB expression with mesenchymal type and epithelial type gene expressions, respectively, have been reported. Hence, we investigated whether MAOB expression is predictive for targeted therapies in mCRC. Methods: 430 mCRC pts treated with either bevacizumab (BEV, n = 224) or cetuximab (CET, n = 206) in combination with first-line chemotherapy within the CALGB/SWOG 80405 trial were included in the analysis. MAOB RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of MAOB expression into high (H), medium (M) and low (L). Hazard ratios (HR) and 95% confidence intervals (CI) were computed from multivariable Cox proportional hazards model, adjusting for age, sex, location, number of metastases, KRAS, MSI status, and treatment with FOLFOX or FOLFIRI. Sensitivity analyses were conducted after stratifying by sex. Logrank P-values describe differences without adjustment for patient characteristics. Results: In CET-treated pts, MAOB-L showed significantly longer OS (median 39.2 vs 30.9 vs 15.9 months, logrank P = 4.7E-05, L vs H (as reference) adjusted HR 0.42, 95% CI [0.27, 0.65]) and PFS (median 13.2 vs 11.8 vs 7.6 months, logrank P = 0.006, L vs H adjusted HR 0.59 [0.40, 0.88]) compared to MAOB-M and MAOB-H, respectively. Similar results were observed when evaluating MAOB expression as a continuous variable. In BEV-treated pts, no significant differences were observed when comparing MAOB expression tertiles; however, pts with lower MAOB expression had significantly better OS, but not PFS, when evaluating MAOB as a continuous variable (Cox LRT P = 0.015, covariate adjusted). In CET-treated pts, the effect of MAOB expression was observed in male but not female pts (OS: median 40.3 vs 30.9 vs 16.1 months by MAOB-L, M, H, respectively, logrank P = 6.8E-05, L vs H adjusted HR 0.33 [0.19, 0.59]; PFS: median 13.8 vs 12.6 vs 7.9 months, logrank P = 0.001, L vs H adjusted HR 0.46 [0.28, 0.79]). A significant interaction was observed between MAOB expression and treatment for OS ( P = 0.010) in males and females combined, but only in males ( P = 0.018) when stratified by sex. Conclusions: Our results suggest that pts with MAOB-L tumors may have greater benefit from CET-based treatment and that targeting MAOB may be a promising strategy to improve patient outcomes. Further validation studies are warranted to develop a novel personalized approach based on MAOB expression in mCRC pts. Clinical trial information: NCT00265850.

3553 Background: Higher levels of plasma 25-hydroxyvitamin D [25(OH)D)] are associated with better outcomes in mCRC, but underlying biologic mechanisms are unknown. Key components of the VitD metabolic pathway include CYP27B1 (encodes 1-α-hydroxylase, converts 25(OH)D to active calcitriol), VitD receptor (VDR), and CYP24A1 (encodes 24-hydroxylase, degrades calcitriol and 25(OH)D into excreted metabolites). Since these factors may affect 25(OH)D levels and potentially mediate VitD activity in mCRC, we examined the relationship between tumoral gene expression (GEx) of CYP27B1, VDR, and CYP24A and pt outcome in a study nested in a randomized phase III trial of first-line chemotherapy plus biologics in mCRC pts, CALGB/SWOG 80405. Methods: We determined GEx of CYP27B1, VDR, and CYP24A1 by RNA sequencing (RNA-Seq) of archival tumor samples using the Illumina TruSeq platform. Primary endpoints were overall (OS) and progression-free survival (PFS). Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for prognostic and molecular characteristics. Results: 562 pts with RNA-Seq data were included. Pts with higher CYP27B1 expression (>median) were less likely to have BRAF wild type (WT) (79% vs 90%) compared to pts with lower expression (p=0.0007). Pts with higher VDR expression (>quartile 1 [Q1]) were younger (median age 59 vs 62 years; p=0.03), more likely to have left-sided (63% vs 46%; p=0.0005) and BRAF WT tumors (89% vs 70%; pmedian) were more likely to have left-sided tumors compared to pts with lower expression (63% vs 54%; p=0.03). On multivariable analysis, pts with higher CYP27B1 expression had significantly improved OS (HR 0.84; 95% CI, 0.75-0.93; p=0.002) and PFS (HR 0.89; 95% CI, 0.80-0.99; p=0.04). Higher VDR expression (up to Q1) was associated with significantly improved PFS (HR 0.69; 95% CI, 0.53-0.91; p=0.007) but not OS (HR 0.85; 95% CI, 0.66-1.09; p=0.20). Above Q1, this improvement attenuated. Higher CYP24A1 GEx was not associated with improved OS (HR 0.98; 95% CI, 0.88-1.08; p=0.66) or PFS (HR 0.98; 95% CI, 0.89-1.08; p=0.68). We found no significant interactions between GEx of CYP27B1, VDR, or CYP24A with baseline plasma 25(OH)D levels (p for interaction ≥0.10 for all). Conclusions: Our findings suggest an association between GEx of VitD pathway markers, particularly CYP27B1 and VDR, and survival in pts with mCRC, lending biologic plausibility to a role of VitD in CRC pathogenesis. Future studies are needed to confirm these findings and elucidate underlying mechanisms of action. Clinical trial information: NCT00265850 .

Importance Several compounds found in coffee possess antioxidant, anti-inflammatory, and insulin-sensitizing effects, which may contribute to anticancer activity. Epidemiological studies have identified associations between increased coffee consumption and decreased recurrence and mortality of colorectal cancer. The association between coffee consumption and survival in patients with advanced or metastatic colorectal cancer is unknown. Objective To evaluate the association of coffee consumption with disease progression and death in patients with advanced or metastatic colorectal cancer. Design, Setting, and Participants This prospective observational cohort study included 1171 patients with previously untreated locally advanced or metastatic colorectal cancer who were enrolled in Cancer and Leukemia Group B (Alliance)/SWOG 80405, a completed phase 3 clinical trial comparing the addition of cetuximab and/or bevacizumab to standard chemotherapy. Patients reported dietary intake using a semiquantitative food frequency questionnaire at the time of enrollment. Data were collected from October 27, 2005, to January 18, 2018, and analyzed from May 1 to August 31, 2018. Exposures Consumption of total, decaffeinated, and caffeinated coffee measured in cups per day. Main Outcomes and Measures Overall survival (OS) and progression-free survival (PFS). Results Among the 1171 patients included in the analysis (694 men [59%]; median age, 59 [interquartile range, 51-67] years). The median follow-up time among living patients was 5.4 years (10th percentile, 1.3 years; IQR, 3.2-6.3 years). A total of 1092 patients (93%) had died or had disease progression. Increased consumption of coffee was associated with decreased risk of cancer progression (hazard ratio [HR] for 1-cup/d increment, 0.95; 95% CI, 0.91-1.00;P = .04 for trend) and death (HR for 1-cup/d increment, 0.93; 95% CI, 0.89-0.98;P = .004 for trend). Participants who consumed 2 to 3 cups of coffee per day had a multivariable HR for OS of 0.82 (95% CI, 0.67-1.00) and for PFS of 0.82 (95% CI, 0.68-0.99), compared with those who did not drink coffee. Participants who consumed at least 4 cups of coffee per day had a multivariable HR for OS of 0.64 (95% CI, 0.46-0.87) and for PFS of 0.78 (95% CI, 0.59-1.05). Significant associations were noted for both caffeinated and decaffeinated coffee. Conclusions and Relevance Coffee consumption may be associated with reduced risk of disease progression and death in patients with advanced or metastatic colorectal cancer. Further research is warranted to elucidate underlying biological mechanisms.

Background Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study. Methods Baseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided. Results Median follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03). Conclusions Among patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

BackgroundThere remains a significant need to eliminate the risk of recurrence of resected cancers. Cancer vaccines are well tolerated and activate tumor-specific immune effectors and lead to long-term survival in some patients. We hypothesized that vaccination with alphaviral replicon particles encoding tumor associated antigens would generate clinically significant antitumor immunity to enable prolonged overall survival (OS) in patients with both metastatic and resected cancer.MethodsOS was monitored for patients with stage IV cancer treated in a phase I study of virus-like replicon particle (VRP)-carcinoembryonic antigen (CEA), an alphaviral replicon particle encoding a modified CEA. An expansion cohort of patients (n=12) with resected stage III colorectal cancer who had completed their standard postoperative adjuvant chemotherapy was administered VRP-CEA every 3 weeks for a total of 4 immunizations. OS and relapse-free survival (RFS) were determined, as well as preimmunization and postimmunization cellular and humoral immunity.ResultsAmong the patients with stage IV cancer, median follow-up was 10.9 years and 5-year survival was 17%, (95% CI 6% to 33%). Among the patients with stage III cancer, the 5-year RFS was 75%, (95%CI 40% to 91%); no deaths were observed. At a median follow-up of 5.8 years (range: 3.9–7.0 years) all patients were still alive. All patients demonstrated CEA-specific humoral immunity. Patients with stage III cancer had an increase in CD8 +TEM (in 10/12) and decrease in FOXP3 +Tregs (in 10/12) following vaccination. Further, CEA-specific, IFNγ-producing CD8+granzyme B+TCM cells were increased.ConclusionsVRP-CEA induces antigen-specific effector T cells while decreasing Tregs, suggesting favorable immune modulation. Long-term survivors were identified in both cohorts, suggesting the OS may be prolonged.

BackgroundIn nonmetastatic colorectal cancer, overweight and mild-to-moderately obese patients experience improved outcomes compared with other patients. Obesity’s influence on advanced or metastatic colorectal cancer (mCRC) is relatively unexplored.MethodsWe conducted a prospective body mass index (BMI) companion study in Cancer and Leukemia Group B (now Alliance)/SWOG 80405, a phase III metastatic colorectal cancer (mCRC) treatment trial. BMI was measured at trial registration. Primary and secondary endpoints were overall and progression-free survival, respectively. To minimize confounding by poor and rapidly declining health, we used Cox proportional hazards regression to adjust for known prognostic factors, comorbidities, physical activity, and weight loss during the 6 months prior to study entry. We also examined weight loss prior to enrollment as an independent predictor of patient outcome. All statistical tests were two-sided.ResultsAmong 2323 patients with mCRC, there were no statistically significant associations between BMI and overall or progression-free survival (adjusted Ptrend = .12 and .40, respectively). Weight loss during the 6 months prior to study entry was associated with shorter overall and progression-free survival; compared with individuals with stable weight ±4.9%, individuals with weight loss greater than 15% experienced an adjusted hazard ratio of 1.52 for all-cause mortality (95% confidence interval [CI] = 1.26 to 1.84; Ptrend < .001) and of 1.23 for disease progression or death (95% CI = 1.02 to 1.47; Ptrend = .006).ConclusionsIn this prospective study of patients with mCRC, BMI at time of first-line chemotherapy initiation was not associated with patient outcome. Weight loss prior to study entry was associated with increased risk of patient mortality and disease progression.

Fiberoptic laryngoscopy (FOL) is a critical tool for the diagnosis, staging, assessment of treatment response, and detection of recurrence for head and neck (HN) malignancies. No standardized recommendations exist for procedural FOL education in radiation oncology. We therefore implemented a pilot simulation workshop to train radiation oncology residents in pertinent HN anatomy and FOL technique.A 2-phase workshop and simulation session was designed. Residents initially received a lecture on HN anatomy and the logistics of the FOL examination. Subsequently, residents had a practical session in which they performed FOL in 2 simulated environments: a computerized FOL program and mannequin-based practice. Site-specific attending physicians were present to provide real-time guidance and education. Pre- and postworkshop surveys were administered to the participants to determine the impact of the workshop. Subsequently, postgraduate year (PGY)-2 residents were required to complete 6 supervised FOL examinations in clinic and were provided immediate feedback.Annual workshops were performed in 2017 to 2019. The survey completion rate was 14 of 18 (78%). Participants ranged from fourth-year medical students to PGY-2 to PGY-5 residents. All PGY-2 residents completed their 6 supervised FOL examinations. On a 5-point Likert scale, mean HN anatomy knowledge increased from 2.4 to 3.7 (standard deviation = 0.6, P.0001). Similarly, mean FOL procedural skill confidence increased from 2.2 to 3.3 (standard deviation = 0.7, P.0001). These effects were limited to novice (fourth-year medical students to PGY-2) participants. All participants found the exercise clinically informative.A simulation-based workshop for teaching FOL procedural skills increased confidence and procedural expertise of new radiation oncology residents and translated directly to supervised clinical encounters. Adoption of this type of program may help to improve resident training in HN cancer.

Purpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood. Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes. Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure. Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. Clin Cancer Res; 24(19); 4734–44. ©2018 AACR.

PurposeObservational studies have reported increased colon cancer recurrence and mortality in patients with states of hyperinsulinemia, including type 2 diabetes, obesity, sedentary lifestyle, and high glycemic load diet. Nut intake has been associated with a lower risk of type 2 diabetes, metabolic syndrome, and insulin resistance. However, the effect of nut intake on colon cancer recurrence and survival is not known.Patients and MethodsWe conducted a prospective, observational study of 826 eligible patients with stage III colon cancer who reported dietary intake on food frequency questionnaires while enrolled onto a randomized adjuvant chemotherapy trial. Using Cox proportional hazards regression, we assessed associations of nut intake with cancer recurrence and mortality.ResultsAfter a median follow-up of 6.5 years, compared with patients who abstained from nuts, individuals who consumed two or more servings of nuts per week experienced an adjusted hazard ratio (HR) for disease-free survival of 0.58 (95% CI, 0.37 to 0.92; Ptrend= .03) and an HR for overall survival of 0.43 (95% CI, 0.25 to 0.74; Ptrend= .01). In subgroup analysis, the apparent benefit was confined to tree nut intake (HR for disease-free survival, 0.54; 95% CI, 0.34 to 0.85; Ptrend= .04; and HR for overall survival, 0.47; 95% CI, 0.27 to 0.82; Ptrend= .04). The association of total nut intake with improved outcomes was maintained across other known or suspected risk factors for cancer recurrence and mortality.ConclusionDiets with a higher consumption of nuts may be associated with a significantly reduced incidence of cancer recurrence and death in patients with stage III colon cancer.

PURPOSE/OBJECTIVE(S) Radiation is increasingly used to treat oligometastatic patients (OM). Following metastasis directed radiation therapy, progression in nearby nodal basins or bones is common. We previously reported clinical outcomes of OM treated with an elective simultaneous integrated boost (SIB) technique delivering higher doses to known metastases and reduced doses to adjacent bones/nodal basins. Here we compare outcomes of OM receiving radiation to metastases alone (MA) versus those treated via an SIB. We hypothesized that use of SIB would maintain treated metastasis control (TMC) while reducing MR. MATERIALS/METHODS OM patients with ≤5 active metastases treated with either SIB or MA at our IRB approved sites from 2013-2018 were analyzed for toxicities, pain control, and recurrence patterns. TMC was defined as absence of progression in high dose planning target volume (PTV). Marginal recurrence (MR) was defined as recurrence outside elective PTV, but within the adjacent bone or nodal chain. Distant recurrence (DR) was defined as any recurrence outside of the treatment PTVs not meeting other criteria. Outcome rates were estimated using the Kaplan-Meier method. Patients treated with the two techniques were compared using the log rank test. RESULTS 101 patients were treated to 90 SIB (58% nodal and 42% osseous) and 46 MA (22% nodal and 78% osseous) sites. The most common primary tumors were prostate (37%), lung (15%), and breast (7%). Median follow up among surviving patients was 24.6 months (range 1.4-71.0). Of the MA treated patients, doses ranged from 18 Gy in 1 fraction (22%) to 50 Gy in 10 fractions (50%). Most patients treated with SIB received 50 Gy to the treated metastases and 30 Gy to the elective PTV in 10 fractions (88%). No patients in either cohort experienced acute grade ≥3 toxicity. Late grade ≥3 toxicity occurred in 3 SIB patients (vocal cord paralysis n = 1, vertebral body compression n = 2) and no MA patients. There was similar crude pain relief between cohorts: 82% with MA (9/11 patients reporting improved pain) and 86% with SIB (19/22). Crude MR were more frequent in the MA group 13% (n = 6) compared to SIB group 2% (n = 2). MR-free survival at 2 years was 87% (95% CI: 70%, 95%) in the MA group and 98% (95% CI: 87%, 99%) in the SIB group (P = 0.07). Crude TMC was 89% (41/46) in the MA group and 94% (85/90) in the SIB group. There were no significant differences found in DR-free survival (P = 0.24) or Disease-free survival (P = 0.4) and Overall survival (P = 0.26) between MA and SIB cohorts. CONCLUSION Both SIB and MA irradiation of OM achieved high rates of TMC and similar pain control, with a trend towards improved MR-free survival for OM treated with SIB. Although more late grade 3 toxicities were seen in the SIB cohort, these were mechanistically related to the high dose PTV and not the elective volume, with differences in treated metastasis location/characteristics. Further investigation of this technique with prospective trials is warranted.

Purpose/Objective(s) Stereotactic body radiation therapy (SBRT) is an established treatment option for stage I non-small cell lung cancer. SBRT often causes acute inflammatory changes in the lung as well as chronic fibrosis. These radiologic findings evolve over time and complicate the interpretation of surveillance imaging. Evolving inflammatory/fibrotic changes in the lung can be difficult to distinguish from malignant progression and radiologists and radiation oncologists (ROs) may interpret the same imaging study differently. With increasing access to the electronic medical record, patient's discovery of these disagreements can lead to confusion, fear, or mistrust. We assessed the frequency of discordant radiologic interpretations between radiologists and ROs after lung SBRT and investigated whether certain variables are associated with a higher frequency of inconsistencies. Materials/Methods As part of an IRB-approved study, data were collected on patients treated with SBRT at our institution for stage I NSCLC between 2007 and 2014. Every RO encounter that included a CT or PET-CT scan was evaluated. Based on language used, interpretations were scored as “concerning for progression” (CFP), “neutral differential” (ND), or “favor stability or post-radiation changes” (FS). ND required that malignancy was included. Results were considered discordant if one provider interpreted the imaging as CFP and the other as either ND or FS. Results were scored as concordant if radiology interpretations and RO interpretations were both scored as CFP or both scored as either ND or FS. A univariate analysis was conducted exploring the relationship between discordance and the type and timing of scans. Results During the time interval, 97 patients underwent SBRT for stage I NSCLC. Median follow-up was 15 months. Median (Q1, Q3) number of follow-up scans per patient was 3 (2, 5). Of 273 encounters, 18 (6.6%) had discordant interpretations. A ND was listed more frequently by radiology (18% vs 5%). When ND was listed by radiology (n = 49), RO interpretations favored stability 92% of the time. Local failure occurred in 9 cases, of which 2 patients had discordant reads prior to recurrence. Both were read as CFP by radiology (ND and FS by RO). The remaining 7 were concordantly read as CFP. Neither the type of scan (CT vs PET-CT), year of scan, nor the time from treatment were associated with discordant interpretations on univariate analyses. Conclusion Surveillance imaging after lung SBRT is often interpreted differently by radiologists and ROs. While outright discordance between impressions at our institution was low, radiologists were more likely to list a differential that included disease progression. In these cases, ROs more often favored stability or post-radiation changes. A recognition of these discrepancies is important when considering patient's access to their medical record.

PURPOSE/OBJECTIVE(S) Mortality prediction is critical to appropriate cancer care planning. This has become a topic of interest, with machine learning (ML) tools demonstrating accurate binary predictions for mortality at specific time points. There are limited prospective data validating the clinical utility of health care ML tools. We previously developed a ML algorithm which predicts risk of acute care (ER visits or hospitalizations). SHIELD-RT was a randomized controlled study which demonstrated that a ML algorithm could direct supplemental clinic visits to reduce the rate of acute care during RT from 22% to 12%. While the algorithm was trained for acute care visits, we sought to determine whether ML risk would facilitate multiple clinical uses through survival prediction in this prospective study. MATERIALS/METHODS Patients who initiated RT from 1/7/2019-6/30/19 at a single institution were evaluated during the first week of treatment by the electronic health record-based ML algorithm. High risk patients (> 10% risk of acute visit) were randomized to standard weekly evaluations (S) or twice weekly evaluations (TW). Patient, disease, and treatment factors were collected prospectively. Survival was recorded retrospectively. Unadjusted OS was estimated with the Kaplan Meier method and compared between arms with the log rank test. Cox proportional hazards models were used to estimate the association of covariates with OS after adjustment for study arm. Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported. RESULTS Patients undergoing 311 distinct courses were randomized to S (n = 157) or TW (n = 154) evaluations. The 1-year OS was similar for those who underwent S (58%, 95% CI 50%-65%) or TW (66%, 95% CI 58%-73%) evaluations, P = 0.35. ML risk on a continuous basis was significantly associated with survival (HR 4.27, 95% CI 0.98-18.6, P = 0.05). Other factors associated with OS included age (HR 1.01, 95% CI 1.00-1.03, P = 0.04), palliative treatment vs curative treatment (HR 6.59 (95% CI 4.62-9.41, < 0.001), widely metastatic disease vs no metastatic disease (HR 6.86, 95% CI 4.74-9.92, P < 0.001). Treatment of certain disease sites were also associated with OS: brain metastases (HR 5.00, 95% CI 3.16-7.93, P < 0.001), bone metastases (HR 4.69, 95% CI 3.09-7.12, P < 0.001), thoracic (HR 2.44, 95% CI 1.61-3.7, P < 0.001), head and neck cancer (HR 0.44, 95% CI 0.22-0.91, P = 0.03), genitourinary cancer (HR 0.32, 95% CI 0.12-0.85, P = 0.02). Admission during RT + 15 days was associated with decreased OS (HR 2.32, 95% CI 1.58-3.40, P < 0.001). CONCLUSION Our ML algorithm, developed to predict acute care, also predicted OS. This supports the correlation between the two event types and demonstrates the utility of ML to provide multiple predictive functions. Implementation of predictive ML algorithms into oncology clinical workflows may aid in prognostication to guide personalized patient care and influence treatment decisions. (NCT03775265).

Purpose/Objective(s) To date there is no clear standard non-surgical therapeutic option for HCC patients. Ablative radiation therapy (SBRT/HIGRT) is an emerging non-invasive treatment for patients with HCC. However, there is concern about the risk for radiation-induced liver toxicity following radiation in patients with decompensated liver function (Child-Pugh B/C). Materials/Methods We retrospectively identified all patients with unresectable, non-metastatic HCC treated with SBRT/HIGRT and underlying Child-Pugh B or C liver function prior to radiation therapy at our University and Veterans Affairs (VA) radiation oncology departments from 2014 to 2019. Primary endpoints included treatment-related toxicity, as well as, evaluation of dosimetric parameters for OAR. Results 38 patients (39 treatment courses) were included. Most patients (97%) had Child-Pugh B7-B9 (62% CP B7, 21% CP B8, 15% CP B9) or ALBI grade 2-3 (69% ALBI grade 2, 31% ALBI grade 3) liver disease prior to radiation therapy. A single patient had Child-Pugh C10 liver function. The most commonly utilized regimens include 50 Gy in either 5 or 10 fractions. The median delivered dose was 50 Gy (range 30-50) in an average of 7.5 fractions (range 5-10). Most patients had a single lesion (63%) with a median lesion size of 3.2 cm (range 1.10-7.40 cm). The mean liver dose was 9.40 Gy (range 3.38-23.94) with a liver D800cc of 4.14 Gy (range 0.35-17.31). All patients completed their intended treatment course with a median follow up of 43 months. Four (10.3%) treatment courses resulted in non-classical radiation-induced liver disease (RILD) (defined as an increase of 2 or more points in Child-Pugh score), compared to 8.3% for patients with Child-Pugh A liver function treated during a similar time period. Otherwise, one patient (2.6%) experienced acute grade 3+ (non-RILD) hepatobiliary toxicity (transient transaminitis). Two-year freedom from local progression was 73% (95% CI 37-90%), median overall survival 12 months (95% CI 5-25 months), and median progression free-survival was not reached. Conclusion Ablative radiation therapy as definitive management for patients with unresectable, non-metastatic HCC appears to be reasonably well tolerated in patients with decompensated liver function at baseline (Child-Pugh B7-B9), with low rates of RILD and encouraging local control. With careful selection, these patients appear to be reasonable candidates for consideration of SBRT/HIGRT. Our analysis did not include enough patients with Child-Pugh C10+ disease to draw meaningful conclusions.

Purpose/objective(s) Patients undergoing radiotherapy during the COVID-19 pandemic have experienced unique changes to care, including increased use of telehealth for radiotherapy on-treatment visits (OTVs). The objective of this study was to determine telehealth utilization and provider perceptions towards effectively assessing, managing and treating patients via telehealth OTVs during the pandemic. Materials/methods As part of this IRB-approved single institution study, a survey was developed to capture the percentage of OTVs that were conducted via telehealth and provider perceptions on management effectiveness. Participants included attending and resident physicians and advanced practice providers (APPs). Likert scale questions assessed the provider perceptions in the following areas: ability to fully evaluate patient, manage symptoms, minimize acute care, and prevent COVID19 exposure. The survey was sent at 3 timepoints: April 15th, May 22nd, and December 18, 2020 (1, 2, and 7 months since declaration of COVID-19 as a national emergency). Respondents were not linked across the 3 surveys. Response frequencies and percentages are presented for each survey and global trends in responses are described. Results Surveys were sent to 34 radiation oncology providers. 22 (65%), 20 (59%), and 21 (62%) participants responded to the April, May, and December survey, respectively. 13, 12, 13 attending physicians; 8, 6, and 3 resident physicians; and 2, 2, and 5 APPs responded to the 3 surveys, respectively. In the April survey 59% of respondents indicated that 75-100% of patients were evaluated weekly by telehealth. This percentage dropped to 8% in May and 0% in December. Most respondents reported agreement with the ability to fully evaluate patients (70% vs 55%; 55%), manage symptoms (80% vs 59%; 60%) and minimize acute care (70% vs 64%; 60%) with in-person OTVs (% December vs April; May). Agreement of an appropriate balance of patient care and COVID-19 risk prevention dropped from 86% in April to 75% in May and 68% in December. Respondents reported a preference for patient-specific management strategies (telehealth vs in-person visits) at all time points (95% in April and May; 90% in December). Conclusion Based on our results, telehealth was widely used during the beginning of the pandemic, but shifted to essentially zero by December 2020. The increase of in person visits by December appears to correlate with agreement to fully evaluate a patient, manage symptoms, and minimize acute care. However, as in person OTVs increased, there was more concern for COVID-19 prevention by providers. By implementing systems into our electronic medical record that can accurately predict patients that may imminently require acute intervention, we may strike a balance of providing the best care for our cancer patients and minimize exposure risk.

Purpose/objective(s) Post-operative radiotherapy (PORT) is utilized in select prostate cancer patients. IMRT has been associated with improved dosimetry and acute toxicity. Smaller treatment margins for PORT have been recommended when using image guidance (IG), which has also been associated with reduced toxicity. Compared to intact prostate IG-IMRT, however, PORT is delivered to a space at risk for recurrence with no grossly visible target, so using targeted conformal techniques with less margin for error may compromise tumor control. Our institution initiated IG-IMRT for PORT in 2005 and adopted larger planning target volumes (PTV) in 2012. We hypothesized that smaller PTV and surgical clip-based IG-IMRT associate with increased biochemical failure (BF). Materials/methods Patients who underwent post-prostatectomy IG-IMRT without concurrent androgen deprivation therapy (ADT) from 1/2005 to 12/2016 were included, with division into pre-2012 and post-2012 cohorts. Demographics and tumor/treatment variables were recorded retrospectively. Oncologic outcomes included BF (initiation of ADT and/or PSA > 0.2 ng/ml and rising) and late toxicities (defined by RTOG criteria, occurring > 90 days after RT). Results 133 patients met criteria: 73 treated pre-2012 and 60 treated post-2012, with a median follow-up of 5 and 9 years, respectively. Compared to the pre-2012 cohort, patients in the post-2012 cohort were more often treated with salvage vs adjuvant RT (P = 0.007), and had higher pre-PORT PSA (0.38 vs 0.20, P = 0.01). 5-year BF did not differ between cohorts (36% vs 43%, P = 0.48). Pre-2012, a smaller percentage of patients underwent on-treatment alignment to surgical clips (40% vs 58%, P = 0.033), vs bony anatomy. Alignment to surgical clips was associated with increased BF in the pre-2012 cohort (HR 2.13, P = 0.041) but not in the post-2012 cohort. Notably, significantly more patients received IG with CBCT in the post-2012 cohort (82% vs 33%). Pre-2012, the median PTV was 198.63 cc versus 242.59 cc post-2012 (P = 0.002). Among the entire cohort on univariate analysis, however, clinical target volume (CTV), CTV-PTV ratio and PTV as continuous variables were not associated with increased risk of BF. Late toxicities were not different between the two cohorts. Conclusion This retrospective analysis reports on toxicity and oncologic outcomes of post-prostatectomy patients treated with IG-IMRT. Despite changes in tumor/treatment characteristics, dosimetric parameters, and image guidance techniques, toxicity and cancer-related outcomes remain similar over a 7-year period. Clip-based IG-IMRT in conjunction with small target volumes may be associated with higher risk of BF, and use of CBCT IG may offset this risk. Additional dosimetric and treatment analyses will be presented. These findings should be validated in prospective datasets.

Melanoma, an extremely aggressive cancer, causes the most skin cancer-related deaths, due to metastasis to other areas of the body, such as lymph nodes, lungs, liver, brain or bone. It is characterized by high levels of matrix metalloproteinase (MMP)-2 and -9 secretions that degrade the extracellular matrix and basement membrane, allowing cancer cells to spread to distal organs. Various cytokines, mitogens, growth factors, inducers and inhibitors control MMP activities. We investigated the roles of these in regulation of MMP-2 and -9 in human melanoma A-2058 cells. Human A-2058 cells were grown in DMEM supplemented with 15% FBS and antibiotics in 24-well tissue culture plates. At near confluence, the cells were washed with PBS and incubated in serum-free media with phorbol 12-myristate 13-acetate (PMA) at 10, 25, 50 and 100 ng/ml; TNF-α and IL-1β at 0.1, 1, 10 and 25 ng/ml; LPS at 10, 25, 50 and 100 µg/ml; epigallocatechin gallate (EGCG) and doxycycline (Dox) at 10, 25, 50 and 100 µM without and with PMA; a nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract without and with PMA at 10, 50, 100, 500 and 1,000 µg/ml; actinomycin D and cyclohexamide at 2 and 4 µM; retinoic acid and dexamethasone at 50 µM. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by zymography and densitometry. Melanoma A-2058 demonstrated strong expression of MMP-2 and slight expression of MMP-9. PMA at 100 ng/ml showed no effect on MMP-2 secretion but potently upregulated MMP-9 secretion to 400% that of control. TNF-α showed no significant overall effect on expression of MMP-2 but potent dose-dependent increased MMP-9 secretion with 200% of control at 25 ng/ml. IL-1β showed no significant effect on MMP-2 or MMP-9 secretion by A-2058 cells, except at 25 ng/ml where MMP-2 level was reduced by ~40% and MMP-9 secretion ~50%. LPS treatment showed no significant effect on MMP-2 secretion and enhanced MMP-9 secretion up to 25 µg/ml followed by decreased level. EGCG, NM and doxycycline, without and with PMA, downregulated the expression of MMP-2 and MMP-9 in a dose-dependent manner. Actinomycin D, cyclohexamide and retinoic acid had inhibitory effects on MMP-2, while dexamethasone showed slight stimulatory effect on MMP-2 secretion. Our results showed that select cytokines, mitogens and inhibitors modulated A-2058 MMP-2 and MMP-9 expression. They suggest the clinical potential of MMP inhibitors, especially the non-toxic ones, such as the nutrient mixture and its component EGCG in management of melanoma.