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Background: The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB)., Methods: A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring ≤2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment., Results: A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring <1 cm (T1a/T1b). Approximately 94.2% of patients had negative surgical margins (815 patients) and 46.9% (410 patients) received adjuvant therapy. The median OS was significantly different for patients who received adjuvant therapy compared with patients who did not (70.7 months vs 46.9 months; P = .0001). For patients with tumors measuring <1 cm, survival was not found to be significantly different between patients who received adjuvant treatment compared with those who did not (not reached vs 85.3 months; P = .54). In the multivariable analysis, none of the covariates (treatment group, Charlson-Deyo Score, age, insurance, and facility status) demonstrated significant differences for patients with tumors measuring <1 cm., Conclusions: The current study is the first to demonstrate no survival benefit for adjuvant therapy in patients with resected subcentimeter PDAC., (© 2018 American Cancer Society.)

Background: Stage II and III rectal cancers have been effectively treated with neoadjuvant chemoradiotherapy (NCRT) followed by definitive resection. Advancements in surgical technique and systemic therapy have prompted investigation of neoadjuvant multiagent chemotherapy (NMAC) regimens with the elimination of radiation (RT). The objective of the current study was to investigate factors that predict for the use of NCRT versus NMAC and compare outcomes using the National Cancer Data Base (NCDB) for select stage II and III rectal cancers., Methods: In the NCDB, 21,707 patients from 2004 through 2012 with clinical T2N1 (cT2N1), cT3N0, or cT3N1 rectal cancers were identified who had received NCRT or NMAC followed by low anterior resection. Kaplan-Meier analyses, log-rank tests, and Cox-proportional hazards regression analyses were conducted along with propensity score matching analysis to reduce treatment selection bias., Results: The 5-year actuarial overall survival (OS) rate was 75% for patients who received NCRT versus 67.2% for those who received NMAC (P < .01). On MVA, those who received NCRT had improved OS (hazard ratio, 0.77. P < .01), and this effect was confirmed on propensity score matching analysis (hazard ratio, 0.72; P = .01). In the same model, the following variables improved OS: age < 65 years, having private insurance, treatment at an academic center, living in an affluent zip code, a low comorbidity score, receipt of adjuvant chemotherapy, and a shorter interval before surgery (all P < .05). African Americans, men, patients with high-grade tumors, those with cT3N1 tumors, and those who underwent incomplete (R1) resection had worse OS (all P < .05)., Conclusions: In this series, the elimination of neoadjuvant RT for select patients with stage II and III rectal adenocarcinoma was associated with worse OS and should not be recommended outside of a clinical trial. Cancer 2017;123:783-93. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: In considering treatment allocation for patients with early esophageal adenocarcinoma, the incidence of lymph node metastasis is a critical determinant; however, this has not been well defined or stratified by the relevant clinical predictors of lymph node spread., Methods: Data from the Surveillance, Epidemiology, and End Results database of the National Cancer Institute were abstracted from 2004 to 2010 for patients with early-stage esophageal adenocarcinoma. The incidence of lymph node involvement for patients with Tis, T1a, and T1b tumors was examined and was stratified by predictors of spread., Results: A total of 13,996 patients with esophageal adenocarcinoma were evaluated. Excluding those with advanced, metastatic, and/or invasive (T2-T4) disease, 715 patients with Tis, T1a, and T1b tumors were included. On multivariate analysis, tumor grade (odds ratio [OR], 2.76; 95% confidence interval [95% CI], 1.58-4.82 [P<.001]), T classification (OR, 0.47; 95% CI, 0.24-0.91 [P =.025]), and tumor size (OR, 2.68; 95% CI, 1.48-4.85 [P = .001]) were found to be independently associated with lymph node metastases. There was no lymph node spread noted with Tis tumors. For patients with low-grade (well or moderately differentiated) tumors measuring <2 cm in size, the risk of lymph node metastasis was 1.7% for T1a (P<.001) and 8.6% for T1b (P = .001) tumors., Conclusions: For patients with low-grade Tis or T1 tumors measuring ≤2 cm in size, the incidence of lymph node metastasis appears to be comparable to the mortality rate associated with esophagectomy. For highly selected patients with early esophageal adenocarcinomas, the results of the current study support the recommendation that local endoscopic resection can be considered as an alternative to surgical management when followed by rigorous endoscopic and radiographic surveillance. Cancer 2016;122:2150-7. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: Pancreatic adenocarcinoma (PAC) has low overall survival (OS) rates and high recurrence rates following surgical resection. The role for preoperative radiation therapy (prRT) for PAC versus postoperative RT (poRT) remains uncertain. The authors used the National Cancer Data Base (NCDB) to report prRT outcomes for the largest multi-institutional patient cohort to date., Methods: NCDB data were obtained for all patients who underwent resection and external beam radiation (RT) for PAC from 1998 to 2002. Patients with metastatic (M1) disease, intraoperative RT, RT both before and after surgery, missing OS, or missing RT variables were excluded. Univariate (UV) and multivariate (MV) analysis were run using treatment characteristics, tumor characteristics, and patient demographics. The difference in patients' known characteristics was described by a chi-square test or analysis of variance., Results: A total of 5414 patients were identified. Of these, 277 received prRT and 5137 received poRT. Overall, 92.9% received chemotherapy and 7.1% received RT alone; 56% (2990 of 5307) of patients had stage III disease, according to American Joint Commission on Cancer (AJCC) staging manual, 5th edition. Median tumor size was 3 cm (range: 0-9.9 cm); 82% (199 of 244) of patients with prRT had negative surgical margins; 72% (3383 of 4699) of patients with poRT had negative margins. Forty-one percent (71 of 173) of patients with prRT were lymph node (LN)-positive; 65% (3159 of 4833) of patients with poRT were LN-positive. Median OS for patients with prRT was 18 months (95% CI = 18-19 months) and for patients with poRT, 19 months (95% CI = 17-22 months)., Conclusions: Receipt of prRT was associated with lower stage, higher rates of negative margins, and lower rates of lymph node positivity at resection. However, there was no significant difference in median OS versus that of the poRT group., (© 2013 American Cancer Society.)

Background: Excision repair cross-complementing gene-1 (ERCC1) and thymidylate synthase (TS) are key regulatory enzymes whose expression patterns are associated with overall survival (OS) in several malignancies. Their expression patterns and prognostic value in resected gastric adenocarcinoma (GAC) are not known., Methods: In total, 109 patients who underwent resection for GAC between January 2000 and June 2011 had tissue available for analysis. The primary objective was to assess for the differential expression of ERCC1 and TS using immunohistochemistry. The secondary objective was to assess for the association between OS and the expression of ERCC1 and TS., Results: The median follow-up was 21.2 months, and the median OS was 28.8 months. Resected GAC exhibited differential expression of ERCC1 (high expression, 23%; n = 25) and TS (high expression, 43%; n = 47). ERCC1 and TS expression were not associated with OS. In a subset analysis of patients who received chemotherapy (n = 73), high ERCC1 expression was associated with decreased OS (16.7 months vs 53.8 months; P = 0.03). After controlling for known adverse pathologic features, high ERCC1 expression persisted as a negative prognostic factor in multivariate Cox regression analysis (hazard ratio, 2.5; 95% confidence interval, 1.03-6.0; P = .04). Conversely, in patients who underwent resection only (n = 35), high ERCC1 expression demonstrated a trend toward improved OS (40.4 months vs 12.7 months; P = .10); a positive prognostic influence also was present on multivariate analysis (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .03)., Conclusions: Resected GAC exhibited differential expression of TS and ERCC1. Among all patients, ERCC1 and TS expression levels were not associated with OS. High ERCC1 tumor expression was associated with decreased OS in the patients who received chemotherapy but was associated with increased OS in those who underwent surgery alone. ERCC1 expression had prognostic value in resected gastric cancer, and further investigation is warranted., (Copyright © 2013 American Cancer Society.)

Background: Mixed lineage kinase domain-like protein (MLKL) is a necrosome component mediating programmed necrosis that may be an important determinant of cancer cell death. The goal of the current study was to evaluate the prognostic value of MLKL expression in patients with pancreatic adenocarcinoma (PAC)., Methods: Tissue from 80 patients was collected from a prospectively maintained database of patients with PAC who underwent pancreaticoduodenectomy between January 2000 and October 2008. Immunohistochemistry analysis was performed and scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival (RFS) and overall survival (OS) for all patients and for patients receiving adjuvant chemotherapy. MLKL scores were correlated with RFS and OS using univariate and multivariate Cox regression analyses incorporating clinically relevant covariates., Results: The median age of the patients was 63 years and 53% were men. Low MLKL expression was associated with decreased OS (6 months vs 17 months; P = .006). In the subset of 59 patients who received adjuvant chemotherapy, low MLKL expression was associated with decreased RFS (5 months vs 15 months; P = .006) and decreased OS (6 months vs 19 months; P < .0001). On multivariate analysis, low MLKL expression was associated with poor OS in all patients (hazards ratio, 4.6 [95% confidence interval, 1.6-13.8]; P = .006) and in patients receiving adjuvant chemotherapy (hazards ratio, 8.1 [95% confidence interval, 2.2-29.2]; P = .002)., Conclusions: Low expression of MLKL is associated with decreased OS in patients with resected PAC and decreased RFS and OS in the subset of patients with resected PAC who receive adjuvant chemotherapy. The use of this biomarker in patients with PAC may provide important prognostic information., (Copyright © 2013 American Cancer Society.)

Background: Adjuvant radiotherapy (A-RT) for patients with resected pancreatic adenocarcinoma (PAC) is controversial. In the current study, the authors aim to determine whether there is an association between overall survival (OS) and A-RT dose., Methods: National Cancer Data Base (NCDB) data were obtained for all patients who received A-RT for resected PAC from 1998 through 2002. Univariate and multivariate survival analyses were performed along with Kaplan-Meier estimates for A-RT levels < 40 grays (Gy), 40 Gy to < 50 Gy, 50 Gy to < 55 Gy, and ≥ 55 Gy., Results: A total of 1385 patients met the inclusion criteria. The median age of the patients was 64 years (range, 29 years-87 years). All patients underwent surgical resection and A-RT with or without chemotherapy. A total of 231 patients were diagnosed with stage I disease, 273 were diagnosed with stage II disease, 734 were diagnosed with stage III disease, and 126 were diagnosed with stage IVA disease (according to the fifth edition of the American Joint Committee on Cancer); 21 were found to have an unknown stage of disease. The median A-RT dose was 45 Gy (range, 1.63 Gy-69 Gy). The median OS was 21 months (95% confidence interval [95% CI], 19 months-23 months). On multivariate analysis, an A-RT dose < 40 Gy (hazards ratio [HR], 1.30 [95% CI, 1.03-1.66]; P = .031), an A-RT dose of 40 Gy to < 50 Gy (HR, 1.17 [95% CI, 1.00-1.37]; P = .05), and an A-RT dose ≥ 55 Gy (HR, 1.44 [95% CI, 1.08-1.93]; P = .013) predicted worse OS compared with the reference category of 50 Gy to < 55 Gy., Conclusions: A-RT doses of < 40 Gy, 40 Gy to < 50 Gy, and ≥ 55 Gy were found to be associated with an inferior OS. The dose of A-RT delivered appears to influence OS and a prospective study evaluating the addition of optimally delivered A-RT for patients with resected PAC is needed., (Copyright © 2013 American Cancer Society.)

Background: Tumor expression of excision cross-complementing gene-1 (ERCC1), human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase subunit M1 (RRM1), and ribonucleotide reductase subunit M2 (RRM2), is associated with the efficacy of platinum and gemcitabine chemotherapy. The authors of this report recently demonstrated that high ERCC1 and RRM2 expression levels are independent negative prognostic markers for survival in early stage pancreas cancer. The differential expression and prognostic value of these biomarkers in biliary tract malignancy (BTM) is unknown., Methods: In total, 63 patients who had tissue available for analysis were selected from a prospective database of all patients (n = 104) who underwent resection of BTM (intrahepatic, hilar, or distal cholangiocarcinoma; gallbladder carcinoma) between January 2000 and December 2008. Immunohistochemistry for ERCC1, hENT1, RRM1, and RRM2 expression was performed. Staining was scored by a single pathologist who was blinded to patient outcomes., Results: The median patient age was 67 years. The median overall survival (OS) was 16.2 months, and the median follow-up was 32.7 months. Only 3 BTMs (4.8%) had high ERCC1 expression, and 92.1% and 81% of BTMs exhibited high hENT1 and RRM1 expression, respectively. RRM2 expression varied, and 32% of tumors demonstrated high RRM2 expression. ERCC1 and RRM1 were not associated with OS. High RRM2 expression was associated with a trend toward improved OS (30.8 months vs 16.2 months; P = .06), and high hENT1 expression was associated with improved OS (17.7 months vs 9.5 months; P = .04)., Conclusions: Most BTMs exhibited low ERCC1 expression and high hENT1 and RRM1 expression, whereas RRM2 expression levels varied. High expression of hENT1 was associated with improved OS. These findings may have implications for the selection of chemotherapy agents (gemcitabine vs platinum) and the stratification of patients in chemotherapy trials that assess outcome., (Copyright © 2012 American Cancer Society.)

Background: Tumor overexpression of excision repair cross-complementing gene-1 (ERCC1) may be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Human equilibrative nucleoside transporter-1 (hENT1) and ribonucleoside reductase subunits M1 and M2 (RRM1 and RRM2) are integral to cellular transport and DNA synthesis and are implicated as poor prognostic factors in other malignancies. To the authors's knowledge, their role in PAC is not defined., Methods: A prospective database was used to randomly select 95 patients who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Immunohistochemical analysis was performed on tumor samples for hENT1, RRM1 and RRM2, and ERCC1. Main outcomes were recurrence-free survival (RFS) and overall survival (OS)., Results: The median follow-up, RFS, and OS were 49 months, 10.6 months, and 15.5 months, respectively. The median tumor size was 3 cm. Approximately 26% of patients had positive microscopic margins, 61% had lymph node involvement, and 88% and 45% had perineural and lymphovascular invasion, respectively. High tumor expression of hENT1, RRM1, RRM2, and ERCC1 was present in 85%, 40%, 17%, and 16%, respectively, of patients. High hENT1 expression was associated with reduced RFS (9.5 months vs 44.5 months; P = .029), but not with OS. RRM1 expression was not associated with survival. High RRM2 expression was associated with reduced RFS (6.9 months vs 16.0 months; P < .0001) and decreased OS (9.1 months vs 18.4 months; P < .0001). High ERCC1 expression was associated with reduced RFS (6.1 months vs 15 months; P = .04) and decreased OS (8.9 months vs 18.1 months; P = .03). After accounting for known adverse tumor factors, high expression of RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS. A subset analysis of patients who received adjuvant therapy (n = 74) revealed the same negative effect of high RRM2 and ERCC1 expression on RFS and OS., Conclusions: High tumor expression of RRM2 and ERCC1 are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help to personalize adjuvant therapy., (Copyright © 2012 American Cancer Society.)