bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II study of RX-3117, an oral antimetabolite nucleoside, in combination with nab-paclitaxel (nab-pac) as first-line treatment of metastatic pancreatic cancer (met-PC): Preliminary results.
Authors: Babiker Hani M. , Schlegel Peter J. , Hicks Lee G. , Bullock Andrea J. , Burhani Nafisa , Benaim Ely , Peterson Christine , Heaton Callie , Ocean Allyson J.
Published: January 2019

420

Background: RX-3117 is an oral small molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by cancer-enriched uridine cytidine kinase 2. Single agent RX-3117 has demonstrated efficacy in a phase III single agent clinical study of RX-3117 in met-PC and bladder cancer. RX-3117 in combination with nab-pac is being evaluated as first line treatment of met-PC cancer. Methods: This is a multicenter, open label phase I/II study (NCT03189914). Eligible subjects (aged ≥ 18 years) have histologically or radiologically proven met-PC with no prior therapies for metastatic disease, ECOG PS 0-1, and normal lab values. phase I identified the MTD dose that is being further evaluated in the phase II: RX-3117 (700 mg administered orally once-daily for 5 consecutive days with 2 days off per week) and nab-pac (125 mg/m2 administered once weekly) for 3 weeks with 1 week off per 4-week cycle. The Safety Committee reviewed data from phase I before moving to phase II. The primary endpoint of phase II (dose expansion) is an adequate number of responders based on PFS at 4 months and/or objective clinical response per RECIST v1.1. Results: As of September 21, 2018, 8 phase I subjects and 13 phase II subjects were enrolled and treated (9 males and 12 females, median age 67 years). The most common (≥ 15%) related adverse events were nausea, diarrhea, fatigue, alopecia, decreased appetite, rash, vomiting, and anemia. Fourteen subjects had at least one on-study scan (after 2 cycles). One subject experienced a complete response (CR) after 6 cycles of therapy with normalization of CA19.9 (-76%). Three subjects exhibited a partial response (PR): two after 2 cycles (39-47%) and one after 4 cycles of therapy (36%). Eight subjects had stable disease for at least 2 months, and 4 subjects had PFS of at least 4 months. The disease control rate (CR+PR+SD) was 86% in evaluable subjects while the overall response rate (CR+PR) was 29%. Conclusions: RX-3117 in combination with nab-pac appears to be safe and well tolerated in subjects with met-PC. Antitumor activity per RECIST was observed in 12 subjects. Phase II of the clinical study is currently ongoing. Clinical trial information: NCT03189914.
A new clinically based staging system for gallbladder cancer.
Authors: Yadav Siddhartha , Prasai Kritika , Mady Mohamed , Hassan Mohamed Abdelrahim Muddathir , Roberts Lewis R. , Mahipal Amit
Published: January 2019

433

Background: Current staging systems for gallbladder cancer (GBC) are inadequate, as they are based on surgical pathology, and therefore are not relevant for unresectable patients and patients undergoing neoadjuvant chemotherapy. Methods: Patients with a confirmed diagnosis of GBC who were seen at Mayo Clinic between the years 2000 and 2016 were included in this analysis. Data on demographic and tumor characteristics and outcomes were collected by retrospective review of electronic medical records. A model predictive of overall survival was developed using Cox proportional hazard regression analysis. Harrel’s C-statistic was calculated to evaluate the predictive accuracy of the model and compared with the TNM staging system. Results: A total of 523 patients were included in the final analysis, with a median age of diagnosis of 68 years. The median duration of follow up of the entire cohort was 12 months. In multivariate analysis, factors predictive of poorer overall survival were: ages 65-74 years (HR : 1.80, 95% CI: 1.33–2.43) and ages 75+ years (HR: 2.93, 95% CI: 2.12–4.06) compared to age <55 years; tumor size ≥ 5 cm by imaging (HR: 1.24, 95% CI: 1.01–1.55); nodal involvement by imaging (HR:1.61, 95% CI: 1.23–2.10); involvement of distant organs by imaging (HR: 2.85, 95% CI: 2.16–3.75); ECOG performance score of 2 or higher (HR: 1.78, 95% CI: 1.36–2.32) compared to ECOG 0-1; albumin level <3.5 g/dL (HR: 1.40, 95% CI: 1.08–1.81); and alkaline Phosphatase level ≥ 200 IU/L (HR: 1.49, 95% CI: 1.21–1.84). Using these seven predictive factors of survival we created a four-tier staging system. The median survivals of Stages I, II, III and IV created in our novel system were 64, 34, 20 and 7 months with corresponding hazard ratios of 1, 1.5, 2.5 and 8.5 respectively. The C-statistic for this novel staging system was 0.68 compared to C-statistic of 0.69 for the TNM staging system, indicating similar performance in predicting survival. Conclusions: We have created a novel clinically-based staging system for patients with GBC based on nonoperative information at the time of diagnosis which performs on par with the current surgical pathology based TNM staging system.
Comparison of neoadjuvant and adjuvant therapy for resectable pancreatic cancer using Markov decision modeling.
Authors: Choi Minsig , Ishizawa Sayaka , Liang Yan , Rashidian Sina , Sasson Aaron R. , Feinberg Eugene
Published: January 2019

448

Background: Meta-analysis of smaller studies have shown that neoadjuvant chemotherapy is more beneficial for patients with resectable pancreatic cancer than upfront surgery by comparing life expectancy (LE) and quality-adjusted life expectancy (QALE) computed from Markov models. The study results utilized literature data using several small clinical trials but no individual patient data was used and only gemzar based therapy was studied. Methods: Markov model was used to calculate the LE and QALE for adjuvant and neoadjuvant chemotherapy and individual patient parameters was used in the model to refine certain clinical outcome datapoints. We used 278 patients pancreatic cancer data from 2008 to 2017 from Stony Brook University and used the literature data from randomized clinical trials studying gemzar (GEM), gemzar and capecitabine (GEM+CAP) and modified FOLFIRINOX (mFOL). The median OS for each model was obtained by computer simulation. Results: Intensive adjuvant chemotherapy using mFOL had best simulation outcome with median OS (52.5 months), LE (81.5 months), and QALE (65.0 quality-adjusted life months) compared to using GEM (40.5, 66.5, and 52.9 months for median OS, LE, and QALE), GEM+CAP (16.5, 28.0, and 21.9 months for median OS, LE, and QALE), and 5-FU (16.5, 26.9, and 21.1 months for median OS, LE, and QALE). The neoadjuvant chemotherapy approach improved LE and QALE but not in median OS when compared to adjuvant therapy. Conclusions: Mathematical modeling confirms the improved clinical outcome for modified FOLFIRINOX in resectable pancreatic cancer. The benefit of neoadjuvant chemotherapy approach suggest further clinical trials are needed to determine the better treatment strategy for pancreatic cancer patients.
Neoadjuvant therapy for body and tail pancreatic adenocarcinoma: Propensity score matched analysis using the National Cancer Database.
Authors: Ivanics Tommy , Leonard-Murali Shravan , Han Xiaoxia , Steffes Christopher P. , Kwon David S. , Shah Rupen A.
Published: January 2019

450

Background: The role of neoadjuvant systemic therapy in the management of body and tail pancreatic ductal adenocarcinoma (PDAC) is unknown. The aim of our study was to investigate the outcomes associated with neoadjuvant therapy for early stage body and tail PDAC. Methods: The National Cancer Database (NCDB) was queried for stage I and II body and tail PDAC between 2006-2014. Groups were defined according to treatment sequencing strategies into an upfront resection group (UR), resection followed by adjuvant therapy (R+AT), neoadjuvant therapy followed by resection (NAT+R), and neoadjuvant therapy followed by resection and adjuvant therapy (NAT+R+AT). Patients who underwent neoadjuvant therapy followed by resection were matched by propensity score with patients who underwent upfront resection. Overall survival was compared using Kaplan-Meier method and Cox proportional hazards regression model. Results: 441 patients received NAT+R with or without AT compared to 1323 patient who underwent UR with or without AT. NAT+R had lower pathologic stage, lymph node positivity and a higher rate of margin negative resections compared to the matched UR cohort. In the propensity matched cohort, the median survival (MS) was higher in the neoadjuvant (NAT+R/NAT+R+AT) group compared to the upfront resection (UR/R+AT) group (28.6 vs. 22.9 mo; p<0.001). When further stratified by treatment sequencing the MS was longer in a NAT+R+AT cohort compared to the R+AT group (36.0 vs. 25.3 mo; p<0.05) (Table). However, there was no difference in MS between R+AT and NAT+R cohorts. On multivariable analysis, receipt of NAT represented an independent factor for survival (NAT+R+AT HR 0.41, 95% CI 0.32-0.54; NAT+R HR, 0.53, 95% CI 0.44-0.64; R+AT HR 0.61, 95% CI 0.53-0.70). Conclusions: There appears to be a survival benefit with neoadjuvant systemic therapy in patients with early stage body and tail PDAC. A systemic perioperative treatment sequencing approach (NAT+R+AT) appears to have the greatest survival benefit. [Table: see text]
Impact of neoadjuvant radiation on survival in patients with pancreatic cancer undergoing neoadjuvant chemotherapy followed by pancreatectomy.
Authors: Macedo Francis Igor , Azab Basem , Picado Omar , Yakoub Danny , Livingstone Alan S , Franceschi Dido , Dudeja Vikas , Merchant Nipun B.
Published: January 2019

453

Background: Pancreatic adenocarcinoma (PDAC) carries a dismal prognosis. Neoadjuvant chemoradiation therapy (NACR) has been introduced to enhance the outcomes of patients with borderline resectable and locally advanced PDAC, however the role of radiation therapy remains largely unknown. Methods: The National Cancer Database (NCDB) was queried for patients with stage I-III PDAC who underwent surgical resection from 2004 to 2014. Patients undergoing NACR were compared to those undergoing neoadjuvant chemotherapy (NAC) alone. The association between clinical characteristics and overall survival (OS) was assessed using the Kaplan-Meier method and multivariable Cox regression model. Results: Of 3,133 patients, 2,351 (75%) patients underwent NACR and 782 (25%), NAC alone. Most patients were Caucasians (84%), treated at academic institutions (67%) and underwent pancreaticoduodenectomy (74%). Median follow-up time was 32 months (IQR, 22-50 months). Median number of lymph nodes examined (LNE) and number of positive nodes (NPN) were significantly decreased in NACR (13 vs. 16, p < 0.001 and 0 vs. 1, p < 0.001, respectively). Rates of margin positivity, median OS and 5-year OS were similar between 2 groups (NACR vs. NAC: 15% vs. 17%, p = 0.545; 25.7 months (95% CI 24.4–26.7) vs. 25.1 months (95% CI: 23.9–27.5), and 20% vs. 22%, p = 0.616, respectively, Figure 1). Subgroup analysis of high-risk features (R1/R2 and N1) also showed no difference in survival outcomes. Neoadjuvant radiation was not an independent predictor associated with OS, whereas advanced age, R1/R2, T3/T4, N1, and poorly differentiated histology were independent negative prognostic factors. Conclusions: NACR is associated with lower rates of lymph node positivity, however this did not translate in survival or margin positivity benefit compared to NAC alone. The role of radiotherapy in PDAC continues to evolve, however no convincing data is currently available to advocate the widespread use of radiotherapy in the neoadjuvant setting. Further evidence with prospective clinical trials is still warranted to confirm these findings.
Resection margin distance in extrahepatic cholangiocarcinoma: How much is enough?
Authors: Rahnemai-Azar Amir A. , Ronnekleiv-Kelly Sean , Abbott Daniel , Ethun Cecilia Grace , Poultsides George A. , Tran Thuy , Fields Ryan , Krasnick Bradley Aaron , Martin Robert C. G. , Scoggins Charles Raben , Idrees Kamran , Isom Chelsea A , Hatzaras Ioannis , Shenoy Rivfka , Shen Perry , Perkins James D. , Pawlik Timothy M. , Maithel Shishir K. , Weber Sharon M.
Published: January 2019

455

Background: Surgical resection is required for curative treatment of patients with extra-hepatic cholangiocarcinoma (EH-CCA). The objective of this study was to determine if the distance of surgical margin was associated with outcome. Methods: Patients who underwent curative-intent resection for EH-CCA between 2000 and 2015 at 10 hepatobiliary centers across the U.S. were evaluated using prospectively collected data. Cox proportional hazard model was utilized to evaluate the influence of the extent of the margin on outcome. Results: 538 patients with EH-CCA who underwent curative-intent resection were included: 383 (71%) undergoing R0 resection, 153 (28%) undergoing R1 resection, and 2 with R2 resection. A negative surgical margin (R0) was associated with improved recurrence-free (RFS) and overall survival (OS) (RFS: 10.5% vs. 3.6% (R1) and OS: 25.8% vs. 9.3% (R1). Subsequently, further analysis on 161 patients with complete data on distance of resection margin, all undergoing R0 resection, was performed to assess the impact of extent of margin on outcome. On multi-variable analysis, the resection margin distance, analyzed as a continuous variable, was not associated with either improved RFS (RR 1.00, 95% CI 0.96-1.05; p 0.71) or OS (RR 0.99, 95% CI 0.96-1.01; p 0.49). Increasing age, increased tumor size, and LN metastasis were identified as independent predictors of OS; while RFS were mainly dependent on tumor size and LN metastasis (Table). Conclusions: Achieving R0 resection is acceptable for EH-CCA tumors, and obtaining additional margin does not confer a benefit on overall survival. Increasing age, tumor size, and LN metastasis are independent predictors of RFS and OS, but increased margin width is not associated with improvement in either. Multivariable analysis of factors affecting OS of patients with extra-hepatic CCA who underwent surgical resection, with significant factors noted in bold. [Table: see text]
Racial/ethnic disparities in the use of high-volume centers for hepatobiliary and pancreatic cancer surgery.
Authors: de Geus Susanna W , Sachs Teviah E. , Ng Sing Chau W , McAneny David B. , Tseng Jennifer F.
Published: January 2019

457

Background: The impact of hospital volume on the outcomes of cancer surgery has been well established. The present studies investigates how race/ethnicity influences the utilization of high-volume centers for hepatobiliary and pancreatic surgery. Methods: Patients that underwent surgery for hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), ampullary adenocarcinoma (AC), or pancreatic ductal adenocarcinoma (PDAC) between 2006 and 2015 were identified from the National Cancer Data Base. Hospitals were divided into low- and high-volume centers based on the medium number of cancer surgeries per year. Multivariable logistic regression analyses predicting receipt of care at a low-volume center based on age, sex, race/ethnicity, comorbidities, insurance, income, travel distance, geographic location, urban/metro location, and tumor stage were performed. All analyses were performed separately by tumor type. Results: 8,962 patients with HCC, 2,119 with ICC, 3,973 with ECC, 5,125 with AC, and 25,231 with PDAC were identified. Non-Hispanic black patients were more likely to undergo resection for AC (vs. non-Hispanic white: AOR, 1.326; p = 0.0125) or PDAC (vs. non-Hispanic white: AOR, 1.187; p = 0.0002) at a low volume centers. Hispanic patients more often underwent surgery for ECC (vs. non-Hispanic white: AOR, 1.731; p < 0.0001) or PDAC (vs. non-Hispanic white: 2.030; p < 0.0001) cancer at a low-volume center. Patients of Asian descent were significantly less often treated for HCC at a low volume center (vs. non-Hispanic white: AOR, 0.644; p < 0.0001) compared to non-Hispanic whites. Non-Hispanic black, Hispanic, or Asian race/ethnicity did not impact the likelihood of receiving care at a low volume center for any other tumor types. Conclusions: The results of this study suggest that race/ethnicity influences the likelihood of receiving care at a high-volume cancer center, even after controlling for other barriers to access to care, including insurance status, income and travel distance.
Does a longer waiting period after neoadjuvant radiochemotherapy improve the oncological prognosis of rectal cancer?: Three-year follow-up results of the GRECCAR-6 randomized multicenter trial.
Authors: Lefevre Jeremie H. , Mineur Laurent , Cachanado Marine , Rullier Eric , Rouanet Philippe , De Chaisemartin Cecile , Meunier Bernard , Mehrdad Jafari , Cotte Eddy , Desrame Jérôme , Karoui Mehdi , Benoist Stephane , Kirzin Sylvain , Berger Anne , Panis Yves , Piessen Guillaume , Saudemont Alain , Prudhomme Michel , Simon Tabassome , Parc Yann ,   The French Research Group of Rectal Cancer Surgery (GRECCAR)
Published: January 2019

483

Background: There are controversial data on the impact of a long waiting period between radiochemotherapy (RCT) and resection for rectal cancer on the rate of complete pathological response (pCR = ypT0N0). The impact on the oncological prognosis is also unknown. We present the 3 years survival results of the GRECCAR6 trial. Methods: The GRECCAR6 trial was a phase III, multicentre, randomized, open-label, parallel-group, controlled trial. Patients with cT3/T4 or TxN+ tumours assessed by radiological examination (MRI and/or endo-ultrasound) of the mid or lower rectum who had received RCT (45-50 Gy with intravenous 5-FU or capecitabine) were included and randomized between 7 weeks or 11 weeks of waiting period. Primary endpoint was the pCR rate. Secondary endpoints were overall, disease-free survival and rate of recurrences. Results: A total of 265 patients from 24 participating centres were enrolled between October 2012 and February 2015. Among them, 253 patients underwent surgery with mesorectal excision. The rate of pCR was 17% (43/253). Mean follow-up from surgical resection was 32±8 months. 25 deaths occurred with a 89% OS at 3 years. DFS was 67.7% at 3 years due to 77 deaths or recurrences. 3-years local and distant recurrences rates were 9.2% and 24.9%, respectively. The group of randomization had no impact on the OS (p = 0.9486) and the DFS (p = 0.8672). Distant (p = 0.8589) and local (p = 0.5780) recurrences were also not influenced by the waiting period. Patients with a pCR had an excellent prognosis with an overall survival of 94.5% versus 87.9% for the remaining patients at 3 years (p = 0.232) and a DFS of 89.6% versus 63.4% (p = 0.0025). On multivariate analysis, DFS was influenced by low rectal tumors (OR=1.74; [1.03; 2.94], p = 0.037), R1 resection (OR = 2.03; [1.18; 3.50], p = 0.011), ypT3-T4 (OR = 2.4; [1.12; 5.19], p = 0.0245) and N+ (OR = 2.85; [1.76; 4.61], p < 0.001). Conclusions: Waiting 4 weeks longer after radiochemotherapy has no influence on the oncological outcomes of T3/T4 rectal cancers. Clinical trial information: NCT01648894.
Total neoadjuvant therapy with short course radiation compared to concurrent chemoradiation in rectal cancer.
Authors: Chapman William , Kim Hyun , Bauer Philip , Makhdoom Bilal , Trikalinos Nikolaos , Pedersen Katrina , Glasgow Sean , Roy Amit , Roach Michael Charles , Mutch Matthew G , Parikh Parag , Hunt Steven
Published: January 2019

486

Background: Total Neoadjuvant Therapy (TNT), or delivery of all radiation and chemotherapy prior to surgery, has improved complete response and downstaging rates compared to adjuvant therapy in patients with rectal cancer. Data regarding the use of short course radiation in the setting of TNT (SC-TNT) are limited. This study compares the pathologic complete response rate (pCR), Neoadjuvant Rectal (NAR) Score – a validated predictor of outcome based on tumor downstaging, and recurrence rates for patients receiving SC-TNT versus chemoradiation (CRT). Methods: Patients who underwent neoadjuvant therapy followed by total mesorectal excision for Stage II or III rectal cancer from 2009 to 2018 were included in this retrospective cohort study. CRT recipients (50-55Gy/25-28 fx with concurrent 5-FU or capecitabine) comprised one cohort; the other included SC-TNT recipients (25-35Gy/5 fx followed by CAPOX or FOLFOX chemotherapy). The primary outcome of pCR rate was assessed in univariate analysis; the secondary outcome of NAR score was calculated and categorized as “Low” ( < 8), “Intermediate” (8–16), and “High” ( > 16). Finally, recurrence rates were measured and classified as local, distant, or both. Results: Of 388 eligible patients, 236 (60.8%) were treated with CRT and 152 (39.2%) underwent SC-TNT. On univariate analysis, the SC-TNT cohort had more advanced disease (77% Stage III disease vs. 67%, p = 0.04) and longer elapsed time between radiation completion and surgery (Median 131 vs. 63 days; p < 0.01). SC-TNT achieved a numerically higher pCR rate compared to CRT (25.0% vs. 19.1%, p = 0.16). Odds of achieving a “low” NAR Score trended higher among the SC-TNT cohort (OR 1.49, 95% CI 0.96 – 2.31). Recurrence rates were also similar (14.3% vs. 14.9%, p = 0.87) over comparable follow-up (CRT = 30.5 months [IQR 11.1 – 49.0]; SC-TNT = 22.3 months [IQR 10.8 – 61.0]; p = 0.82). Conclusions: SC-TNT yielded a pCR rate of 25% and overall recurrence rate of 14.9% among patients with locally advanced rectal cancer. Short course radiation with neoadjuvant multiagent chemotherapy is at least as effective as long-course CRT. [Table: see text]
Metastatic patterns and prognostic significance of signet ring cell carcinoma of the colon: Retrospective analysis of SEER database.
Authors: Khoury John , Chacko Rebecca , Macari David , Gbadamosi Bolanle , Ezekwudo Daniel , Blankenship Leann , Anderson Joseph M , Jaiyesimi Ishmael A.
Published: January 2019

488

Background: Signet ring cell carcinoma of the colon (SRCC) represents less than 1% of all colon carcinomas. We retrospectively examined the metastatic patterns and prognosis of SRCC in comparison to adenocarcinoma (AC) of the colon. Methods: A total of 763 patients diagnosed with SRCC and 42,875 patients with AC of the colon from 2010 to 2012 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Age, race, gender, primary site, grade, stage, metastatic site and survival data were collected. Results: Out of 43,638 patients, 78.7% were white, 12.5% black and 8.8% other races. Median age of diagnosis was 67.5 years for SRCC as compared to 69.1 years for AC . SRCC was more likely to be grade III or IV (92% vs 21.6%; p < 0.001), to be found in the right colon (63.7% vs 49.4%; p < 0.001) and to present as advanced stage (40.2% vs 29.4% for stage III and 37.1% vs 22.3% for stage IV; p < 0.001). SRCC was more likely to present with metastases to the brain (11.0% vs 1.3%; p < 0.001) and bone (6.4% vs 4.1%; p < 0.001), while AC subjects were more likely to present with metastases to the liver (77.0% vs 22.1%; p < 0.001) and lung (21.2% vs 5.8%; p < 0.001). The 5 year overall survival rate (5-YSR) was 28.2% (CI, 24.5% to 32.4%) for SRCC compared to 50.8% (CI, 50.1% to 51.6%) for AC (Hazard ratio for death, 1.38; CI, 1.26 to 1.52; P < 0.001). The differences in stage specific 5-year survival rates for SRCC and AC were not statistically significant for stage I and stage II. However, SRCC had a lower 5-YSR for stage III (34.5% vs 55.4%) and stage IV (3.3% vs 10.8%). Conclusions: SRCC of the colon has worse survival rates for advanced stages when compared to AC. SRCC presents at earlier age, with advanced tumor grade and stage at diagnosis. The metastatic behavior of SRCC is different than AC with a higher incidence of brain and bone metastases at diagnosis.
Impact of cardiac comorbidity on use and outcomes of adjuvant chemotherapy (ADJ) for colorectal cancer (CRC): A real-world population-based study.
Authors: Liu Shiru Lucy , Gill Sharlene , Cheung Winson Y.
Published: January 2019

491

Background: Cardiac comorbidities such as myocardial infarction (MI) and congestive heart failure (CHF) may pose challenges in the treatment of CRC. As the population ages, cancer patients (pts) will be increasingly affected by cardiac comorbidities. We performed a population-based analysis of CRC to evaluate the prevalence of MI and CHF, use of ADJ, and survival outcomes. Methods: We evaluated 8601 pts diagnosed with resected stage 2 or 3 CRC from 2004 to 2015 in Alberta, Canada. Baseline patient, tumor, and treatment characteristics were compared between those with and without MI or CHF. Survival analysis was conducted using Kaplan-Meier methods and Cox regression models. Results: In total, 506 (5.9%) patients (pts) had MI and 440 (5.1%) had CHF. CRC patients with prior MI or CHF were older (median 76 and 79 years, respectively) and had worse Charlson Comorbidity Index (median CCI 2 for both) than those without cardiac comorbidities (median age 67 and CCI 0) (p < 0.001). Only 24% and 15% of pts with a MI or CHF history, respectively, received ADJ when compared to their counterparts (52% and 53%, respectively, p < 0.001). Among those who received ADJ (N = 3409), an oxaliplatin-based regimen was used in 26% of MI pts versus 42% of those without MI (p = 0.002), and in 31% of CHF pts versus 42% of those without CHF. Kaplan-Meier analysis revealed significantly worse overall survival (OS) in pts with prior MI (9.1 vs 4.3 years, p < 0.001) or CHF (9.2 vs. 2.7 years, p < 0.001) when compared to those without. However, cancer-specific survival (CSS) was not statistically different with or without MI (p = 0.348) and with or without CHF (p = 0.611). In Cox regression that adjusted for use of ADJ, MI was no longer a significant predictor of OS (HR = 1.01, 95% confidence interval (CI) 0.88-1.15), but CHF remained significant (HR 0.65, 95% CI 0.57-0.74). Neither MI nor CHF were predictors of CSS (HR 1.09, 95% CI 0.98-1.33, and HR 0.94, 95% CI 0.77-1.15). Conclusions: CRC pts with MI or CHF experienced lower use of ADJ and worse OS, but no difference in CSS was observed. ADJ-treated pts with prior MI appeared to benefit while worse outcomes in pts with prior CHF appear to be driven by non-cancer related causes.
Immunological nomograms predicting prognosis and guiding adjuvant chemotherapy in stage II colorectal cancer.
Authors: Peng Junjie , Li Yaqi , Feng Yang
Published: January 2019

499

Background: The type, abundance, and location of tumor-infiltrating lymphocytes (TILs) have been associated with prognosis in colorectal cancer. The objective of this study was to assess the prognostic role of TILs and develop a nomogram for accurate prognostication of stage II colorectal cancer. Methods: Immunohistochemistry was conducted to assess the densities of intraepithelial and stromal CD3+, CD8+, CD45RO+ and FOXP3+ TILs, and to estimate PD-L1 expression in tumor cells for 168 patients with stage II colorectal cancer. The prognostic roles of these features were evaluated using COX regression model, and nomograms were established to stratify patients into low and high-risk groups and compare the benefit from adjuvant chemotherapy. Results: In univariate analysis, patients with high intraepithelial or stromal CD3+, CD8+, CD45RO+ and FOXP3+ TILs were associated significantly with better relapse-free survival (RFS) and overall survival (OS), except for stromal CD45RO+ TILs, whereas PD-L1 expression wasn't associated with RFS or OS. In multivariate analysis, patients with high intraepithelial CD3+ and stromal FOXP3+ TILs were associated with better RFS (p < 0.001 and p = 0.032, respectively), while only stromal FOXP3+ TILs was an independent prognostic factor for OS (p = 0.031). The nomograms were well calibrated and showed a c-index of 0.751 and 0.757 for RFS and OS, respectively. After stratifying into low and high-risk groups, the high-risk group exhibited a better OS from adjuvant chemotherapy (3-year OS of 81.9% v 34.3%, p = 0.006). Conclusions: These results may help improve the prognostication of stage II colorectal cancer and identify a high-risk subset of patients who appeared to benefit from adjuvant chemotherapy.
Safety and efficacy of durvalumab following trimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Early efficacy results from Big Ten Cancer Research Consortium study.
Authors: Mamdani Hirva , Schneider Bryan J. , Abushahin Laith I. , Birdas Thomas J , Kesler Kenneth , Lee Ahran , Burney Heather , Perkins Susan , Jalal Shadia Ibrahim
Published: January 2019

5

Background: The standard of care for locally advanced esophageal adenocarcinoma(LA-EAC) is concurrent chemoradiation (CRT) followed by esophagectomy. Approximately 30% of patients (pts) achieve complete pathologic response (pCR) with this approach. The risk of relapse in the remaining 70% of pts is high, with 1-yr relapse free survival (RFS) of 50%. No adjuvant therapies have been shown to improve survival. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown upregulation of PD-1 pathway with radiation +/- chemotherapy. Methods: We conducted a phase II study evaluating safety and efficacy of durvalumab (durva), a monoclonal antibody against PD-L1, in pts with LA-EAC and GE junction (GEJ) adenocarcinoma who do not achieve pCR after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1 yr after surgery. Primary objective was 1-yr RFS. Secondary objectives were incidence and severity of treatment related adverse events (AEs). Results: Twenty-four pts were enrolled from Apr 2016 to Jan 2018 (median age: 60yrs (range, 43-74)). Fourteen pts had GEJ adenocarcinoma and 10 had distal EAC. Eighteen received carboplatin/paclitaxel and six received cisplatin/5-FU concurrently with 50-50.4Gy radiation. Nineteen pts (79%) had positive lymph nodes at the time of surgery after neoadjuvant CRT, including three (12.5%) with N3, nine (37.5%) with N2, and seven (29%) with N1 disease. Among N0 pts, two had T3N0, one had T2N0, and two had T1N0 disease. At median follow-up of 11.7 mo (range 1.7-23.9 mo), seven pts (29%) have relapsed (five alive, two died); 17(67%) are disease free (six on treatment, seven completed treatment, three off-treatment); 1-yr and projected 26 mo RFS are 78.6% and 62.9%, respectively. Five pts (20.8%) developed grade 3 AEs: diarrhea (n = 1), hepatitis (n = 1), encephalopathy (n = 1), hyperglycemia (n = 1), hypoglycemia (n = 1). Most common grade 1 and 2 AEs were fatigue (33.3%), nausea (25.0%), and cough (20.8%). Conclusions: Adjuvant durva in pts with residual disease following trimodality therapy for EAC and GEJ adenocarcinoma is safe and feasible with 1-yr RFS of 78.6% compared to historical rate of 50%. Clinical trial information: NCT02639065.
MSI-H testing via hybrid capture based NGS sequencing of liquid biopsy samples.
Authors: Gowen Kyle , Clark Travis A , Gregg Jeffrey P. , Greene Mandy Z. , Murphy Annie , White Jared , Chung Jon , Kennedy Mark , Elvin Julia Andrea , Ross Jeffrey S. , Miller Vincent A. , Hughes Jason D. , Lipson Doron , Dennis Lucas
Published: January 2019

504

Background: Microsatellite instability (MSI) testing has become critically important in clinical cancer care of patients with cancer given the recent pan-tumor FDA approval of pembrolizumab for use in patients with MSI-High (MSI-H) tumors. We previously demonstrated the robustness of a novel proprietary algorithm for determination of MSI status via NGS from solid tumor biopsy specimens (J Clin Oncol 34, 2016 (suppl; abstr 1523)). Traditional MSI tests such as PCR or IHC are impractical for pan-tumor adoption, as MSI-H prevalence outside of gastrointestinal and endometrial cancers is usually < 1%. NGS-based ctDNA profiling provides an opportunity for both MSI and actionable alteration testing in patients in whom tissue-based biopsy is not available. Methods: Genomic DNA (gDNA) from five previously characterized MSI-H cell lines: (DLD1, 22Rv1, LNCap, RL952, CL188), and one MSS cell line (SCC9) was enzymatically-fragmented to simulate ctDNA and titrated to various dilution levels with DNA from a healthy hapmap subject (NA12878). Samples were screened with a 70-gene panel, FoundationOne Liquid, that includes 180 mononucleotide repeat sequences (8-26bp long in the human reference genome). Length variability in the 180 repeat loci was utilized to generate an overall MSI score via principal components analysis. The NGS based MSI algorithm was applied to all the samples. Results: Assessment of these six cell lines, targeting five dilution levels confirmed by SNP mixing ratios, show that our NGS based MSI test for liquid biopsies has 96% sensitivity at > 2% tumor fraction with 100% PPV. The regression intercept of the MSI-H dilution samples with the pre-established MSI-H calling threshold shows our method has a LOD of 1.03% tumor fraction. MSI-H prevalence data from liquid biopsies of gastrointestinal tumors obtained during clinical care will also be presented. Conclusions: These data demonstrate the feasibility of using NGS-based liquid biopsy assays for MSI testing. This ctDNA-based approach will allow for increased access to checkpoint inhibitors in a pan-tumor setting, which would be especially relevant for cancers where routine MSI testing is impractical or when tissue is not available.
Review of updated colorectal cancer disease management data in the Colombian National Administrative Cancer Registry.
Authors: Hsu Robert , Ramirez Paula , Acuña Lizbeth , Lopes Gilberto
Published: January 2019

508

Background: The Office of High Cost of the Colombian Health Ministry created the National Administrative Cancer Registry (NACR) in 2015 to obtain nationwide cancer data to find areas for improvement in cancer delivery. From initial data, a collaboration of healthcare experts identified 15 disease management indicators in colorectal (CRC) cancer in Colombia. In this study, we look at 2017 NACR data to investigate significant findings. Methods: We obtained NACR data compiled from the Department of Health Ministry from January 2, 2016-January 1, 2017 consisting of 32 departments and 1122 municipalities. The 2017 NACR data for CRC includes 11 of 15 updated disease management indicators - time to diagnosis, proportion of patients with colorectal cancer in situ, proportion of new cases identified in early stages, proportion of patients with TNM staging, proportion of patients with TNM staging before treatment, time before treatment, time between neoadjuvant therapy and surgery, time between surgery and adjuvant therapy, proportion of stage I and II patients receiving curative surgery, proportion of patients with nutritional support, mortality rate, and incidence. Results: The incidence of CRC was 5.2 cases per 100,000 people and the mortality was 3.6 cases per 100,000 people. The time to diagnosis was on average 50.7 days. 3.6% of CRC cases were in situ. 35.6% of cases were identified in early stages, and 51.3% of cases had TNM staging with 45.1% staged prior to treatment. The time to initial treatment was 63.7 days. The time between neoadjuvant therapy and surgery was 116.1 days and the time between surgery and adjuvant therapy was 75.5 days. 24.2% of stage I and II patients received curative surgery. 9.8% patients received nutritional support. Conclusions: The updated NACR data show significant wait times for treatment and exaggerated wait times for patients needing neoadjuvant or adjuvant therapies. The findings show significant work is needed in providing supportive services. There needs to be further investigation into follow-up after initial treatment. Further directions should include more data collection of adjuvant and neoadjuvant wait times and outcomes data of specific treatment modalities.
Prospective clinical study using expressed sequencing variants on stool-derived eukaryotic RNA transcripts (seRNA) for colorectal cancer screening.
Authors: Barnell Erica Kay , Kang Yiming , Campbell Katie Marie , Barnell Andrew Ross , Kruse Kimberly Ray , Wurtzler Elizabeth Marie
Published: January 2019

516

Background: Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States. The high mortality rate is largely attributable to the high frequency of late-stage diagnoses, caused by low patient compliance with screening guidelines. A reliable and noninvasive screening alternative is needed for the 40 million noncompliant patients. The development of a novel nucleic acid extraction method to isolate stool-derived eukaryotic RNA (seRNA) permits reliable and noninvasive evaluation of biomarkers derived from the gastrointestinal (GI) epithelium. This method enables sequencing-based tools for the detection of patients with CRC and adenomas. Methods: Stool samples were obtained from 96 individuals prior to undergoing a screening colonoscopy. Fecal immunochemical tests (FITs) were obtained for each sample. RNA isolates underwent custom library preparation, next-generation sequencing, and somatic variant identification. An seRNA assay assessed the probability of CRC risk using results from the FIT, mutational burden of transcripts implicated in precancerous change (APC), and mutational burden of transcripts associated with malignant transformation (KRAS / TP53). Results: When compared to results from a colonoscopy and subsequent biopsy, the seRNA risk assessment attained a 100% sensitivity for CRC, a 71.4% sensitivity for advanced adenomas, and an 88.5% specificity for no neoplastic findings. Conclusions: A single-center, IRB-approved, prospective and blinded clinical study is being conducted in 450 patients to further develop this seRNA assay. Supplemental data will include expression from 408 seRNA transcripts. Preliminary analysis described herein indicates this assay could be the most sensitive noninvasive screening test for the detection of CRC and adenomas. [Table: see text]
High-serum blood sugar level significantly enhances oxaliplatin resistance in stage III colorectal cancer patients.
Authors: Wang Jaw-Yuan
Published: January 2019

532

Background: FOLFOX4 chemotherapy is one of the most widely used adjuvant therapies in patients with stage III colon cancer after surgical resection. However, chemotherapy resistance is associated with a poor prognosis. The prognostic impact of high blood sugar levels on oxaliplatin resistance in CRC patients is an unexplored topic. Methods: A total of 157 patients with stage III CRC were classified according to their serum blood sugar level (≥ 126 or < 126 mg/dL). Clinicopathological features and clinical outcomes (oxaliplatin resistance) of the two groups were analyzed. Results: Through multivariate analysis, both disease-free and overall survival of CRC patients was found to be significantly associated with serum blood glucose levels (both P < 0.05) but not DM history. In vitro cell proliferation assay was performed through D-(+)-glucose administration. After metformin administration, enhanced proliferation of CRC cells with D-(+)-glucose administration could be reversed and oxaliplatin sensitivity considerably increased ( P < 0.05). Furthermore, phosphorylation of two glycolysis-related target proteins, SMAD3 and MYC, notably increased with high glucose concentration. Conclusions: In summary, hyperglycemia could affect clinical outcomes in CRC patients receiving adjuvant chemotherapy, with the underlying oxaliplatin resistance mechanism possibly associated with increasing phosphorylation of SMAD3 and MYC and upregulation of G9A expression.
Anal adenocarcinoma: Treatment outcomes and trends in a rare disease entity.
Authors: White Richard , Hasan Shaakir , Raj Moses , Monga Dulabh K. , Finley Gene Grant , Kirichenko Alexander V. , McCormick James , Wegner Rodney E
Published: January 2019

538

Background: Primary Adenocarcinoma of the rectum is a rare disease with a poor prognosis and thus tends to have a more aggressive treatment algorithm, typically involving a surgical approach. Prior to 2001, a few retrospective studies outlined improved outcomes with the incorporation of surgery with chemoradiation. However, since the publication of these studies, advancement in radiotherapy modalities and imaging have left the question of improved outcomes while reserving surgery for salvage. We conducted this NCDB-driven, retrospective study to analyze treatment trends and outcomes in the current time from 2004-2015 with respect to chemoradiation and surgery. Methods: We queried the NCDB for with AJCC stage 1-3 anal adenocarcinoma diagnosed between 2004-2015. Propensity score-matched multivariable cox regression analysis determined the association of incorporation of surgery into the definitive management of anal adenocarcinoma on survival. Results: Of the 1729 patients eligible patients in this study, 1028 were treated with surgery as up front management and 701 had definitive chemoradiation. Median overall survival for all patients was 55 months with a 5 year survival rate of 55%. Patients treated without surgery had worse overall survival, median survival of 45 months compared to 87 months (p < .0001) with 5 year survivals of 42% and 55% in favor of incorporation of surgery. Analysis across patients treated with surgery alone, surgery followed by adjuvant chemoradiation, neoadjuvant chemoradiation followed by surgery, and chemoradiation alone had median survival rates of 78, 83, 92, and 46 months, respectively (p < 0.0001). Propensity score adjusted multivariable analysis identified older age, grade 3, high comorbidity score, and lack of surgery as predictive of worse outcome. Conclusions: The results of the NCDB analysis indicate improved overall survival with the incorporation of surgery into the initial management of anal adenocarcinoma when compared to chemoradiation alone, despite the omission of surgery in up to 50% of the cases logged. Our results corroborate earlier studies published prior for surgery to be included in the definitive management of anal adenocarcinoma.
The prognostic role of PD-L1 expression according to MSI status in stage III colon cancer after curative resection.
Authors: Cho Sang-Hee , Hwang Jun Eul , Bae Woo Kyun , Chung Ik-Joo
Published: January 2019

555

Background: Tumors expressing PD-L1 can render immune inactivated via triggering of PD-1 receptor on T cells with various pathways. Based on these mechanism, the blockade PD-1/PD-L1 pathway based been used as a therapeutic target for metastatic CRC. In the present study, we evaluated the prognostic role of PD-L1 expression associated with microsatellite status in surgically resected stage III colon cancer patients. Methods: PD-L1 expression was performed by immunohistochemistry from 182 stage III colon cancer patients after curative resection. Using the immunohistochemical stain, percentages of PD-L1 positive tumor cells and staining intensity were evaluated and categorized as ‘strong’ and ‘weak’ positive group. Clinical and histopathologic parameters including of MSI status and survival outcomes were analyzed with IDO expression which stands for the suppressive immune environment. Results: Strong PD-L1 expression was observed in 29% of all patients. PNI and lymphocyte response response were more frequently shown in strong PD-L1 patients. Among these patients, MSI was shown in 23 patients (12%). Although there was no significant difference between MSI and PD-L1 status, strong PD-L1 tended to better OS in MSS colon cancer (P = 0.056). In contrast, strong PD-L1 expression significantly correlated with significantly worse prognosis in disease free survival (P = 0.001) and overall survival (P < 0.001) than weak PD-L1 expression inMSI patients regardless of adjuvant chemotherapy. In MSI patients, the strong IDO expression was tended to be more frequently shown in strong PD-L1 expression patients (36.4%) than weak PD-L1 expression patients (14.3%). Conclusions: The expression of PD-L1 is differently affected on the survival according to the status of microsatellite. There is no significant relationship between the expression of PD-L1 and prognosis in MSS stage III colon cancer patients. However, in MSI colon cancer which has been well known as a highly immunogenic property, strong PD-L1 expression is significantly associated with poor prognosis on survival outcomes reflecting of immunosuppressive microenvironment in curative resected stage III colon cancer patient.
PD-1/PD-L1 immune check points blockade to attenuate growth of metastatic colon cancer in the CBP/β-catenin inhibited liver.
Authors: Kimura Kiminori , Osawa Yosuke , Nishikawa Koji , Kimura Masamichi , Kawakami Yutaka
Published: January 2019

556

Background: Immune check points blockade with specific antibodies can accelerate anti-tumor immunity, resulting in a clinical response in patients with various types of cancer. Thus, a wide variety of treatment combinations based on PD-L1/ PD-1 pathway blockage are under development to enhance the therapeutic effect. Here, the effects of the combination treatment of PRI-724, a selective inhibitor of the CBP/β-catenin, with anti-PD-L1 antibody were examined in a mouse model of the liver metastasis of colon cancer. Methods: Mice were inoculated with SL4 colon cancer cells into the spleen to produce metastatic liver tumors. The animals were intraperitoneally injected with or without PRI-724 and/or anti-PD-L1 antibody (10F.9G2) 3 times a week. A part of mice treated with PRI-724 and anti-PD-L1 antibody was administrated with anti-mouse CD4 or CD8 antibody 3 times a week. First, to evaluate anti-tumor effect in those mice, we analyzed liver histology and survival rates after treatment. Next, to examine immune response in the liver, intrahepatic lymphocytes were analyzed by FACS for CD8 memory phenotype, Treg cells, macrophages, and dendritic cells, and the cytokine production from these cells (TNFa, IFNg etc.). Furthermore, inflammatory cytokines and chemokines mRNAs levels and PCR array concerned to Wnt signaling in the liver and serum cytokines levels were also analyzed. Results: The combination of the treatments resulted in regression of tumor growth, whereas monotherapy of each treatment did not show any anti-tumor activity. PRI-724 increased T lymphocytes recruitment, including CD8+ T cells, in the tumor, which may have been induced by inflammatory chemokines and a change of the macrophage property to the cytotoxic phenotype in the liver. Anti-PD-L1 antibody induced CD69+-activated T lymphocytes in the PRI-724-treated livers of mice inoculated with SL4. Administration of anti-CD8 antibody canceled the anti-tumor effects of the combination treatments of PRI-724 and anti-PD-L1 antibody. Conclusions: Targeting CBP/β-catenin combined with PD-1/PD-L1 immune check points blockade shows potential as a new therapeutic strategy for treating the liver metastasis of colon cancer.