bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of AdipoR agonist in cholangiocarcinoma.
Authors: Bui Khac Cuong , Nguyen Mai Ly Thi , Barat Samarpita , Chen Xi , Bhuria Vikas , Xing Jun , Nguyen Linh Toan , Le Huu Song , Velavan Thirumalaisamy P. , Wilkens Ludwig , Malek Nisar P , Bozko Przemyslaw , Plentz Ruben R
Published: January 2019

323

Background: Adiponectin is the key adipokine, which plays an important role in health and disease such as obesity, diabetes, and cancer. Adiponectin is reduced in different tumor types, especially in obesity-related cancer, and recent studies showed that Adiponectin had a potential anti-cancer effect. Obesity is a risk factor for various tumor diseases including cholangiocarcinoma (CC), the second most common primary hepatic cancer. The aim of this study is to investigate for the first time the anti-cancer effect of AdipoR agonist in CC cell lines and a CC engineered mouse model. Methods: Human CC cell lines (TFK-1 and SZ-1) and CC engineered mice (Alb-Cre/KRASG12D/p53L/L) were used to investigate the anti-cancer effects of an AdipoR agonist (2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide). Cell proliferation, migration, invasion, colony formation, apoptosis assay were applied to evaluate the effect of AdipoR agonist in vitro. In addition, important cancer signalling pathways and targets were analysed by Western Blot. Mice (n = 12) were treated with AdipoR or verhicle and tumor burden and survival were monitored. Results: AdipoR agonist suppressed proliferation, migration, invasion, colony formation and apoptosis in CC cells. AdipoR agonist regulated the expression of different proteins such as EMT markers, pAMPK, pSTAT3, and PARP, which have pivotal functions in cholangiocarcinogenesis. AdipoR agonist also prolonged survival time in a CC engineered mouse model. Conclusions: Our data revealed that AdipoR agonist inhibited successfully cell proliferation, migration, invasion, colony formation and apoptosis in vitro, and prolonged mice survival in vivo through regulation of crucial signaling pathways in cholangiocarcinogenesis. These results suggested that AdipoR agonist might become a new potential candidate for CC treatment in the future.
Chemotherapy choice in advanced pancreatic cancer: What patient and disease factors influence prescription patterns?
Authors: Raskin William , Guo Helen , Beca Jaclyn Marie , Isaranuwatchai Wanrudee , Qiao Lucy , Earle Craig , Berry Scott R. , Biagi James Joseph , Welch Stephen , Meyers Brandon Matthew , Mittmann Nicole , Coburn Natalie G. , Pardhan Aliya , Arias Jessica , Schwartz Deborah , Gavura Scott , Forbes Leta Marie , McLeod Robin , Kennedy Erin Diane , Chan Kelvin K.
Published: January 2019

327

Background: FOLFIRINOX (FFX), gemcitabine+nab-paclitaxel (GnP) and gemcitabine monotherapy (Gem)) are universally funded as first-line chemotherapy regimens for advanced pancreatic cancer (APC) in Ontario, Canada. However, there is scarce real-world data on factors that may influence choice of chemotherapy regimens in APC. Methods: Patients who received first-line chemotherapy for APC between April 2015-March 2016 in Ontario were identified from CCO’s New Drug Funding Program database and linked to the Ontario Cancer Registry and other provincial databases to ascertain baseline factors. Multinomial logistic regressions were used to examine the associations between the prescribed chemotherapy regimen and baseline factors. Results: 546 patients were identified, with a mean age of 65 and 43.6% female. 9.9% and 9.7% had received adjuvant gemcitabine and radiation treatment respectively. 17.6% had previous pancreatic resection. 68.3% had zero Charlson score and 30.6% had ECOG performance status (PS) of 0. 72.7% had metastatic disease. The majority of the patients received FFX (52.4%) compared to GnP (35.7%) and Gem (11.9%). Age and ECOG PS were strongly associated with choice of chemotherapy regimens. (See Table) Conclusions: In Ontario, increased patient age and worse ECOG PS are strongly associated with choice of Gem compared to GnP and FFX. Previous treatments and stage of disease also impact chemotherapy choice. Understanding how providers choose chemotherapy in APC aids in comprehending our practices. Odds ratio (OR) and p value from multinomial logistic regressions. [Table: see text]
Adaptive versus non-adaptive MRI-guided radiation treatments for pancreatic cancer: A dosimetric study.
Authors: Spieler Benjamin Oren , El Bared Nancy , Padgett Kyle , Brown Karen Moya , Portelance Lorraine , Mellon Eric Albert
Published: January 2019

336

Background: Combination MRI and radiation therapy systems enable magnetic resonance image guided radiation therapy (MR-IGRT). MR-IGRT allows clear visualization of the target and organs at risk (OARs) allowing for dose adaptation. Using adaptive MR-IGRT with Cobalt-60 for stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (LAPC), we hypothesized that MR-IGRT would improve dose to pancreatic tumor without increasing doses to OARs. Methods: Ten LAPC patients received five fraction SBRT with a total dose of 33-40 Gy. For each fraction, the original plan dose was compared to the dose that would be delivered if the original radiotherapy plan was applied to the anatomy that day (non-adaptive). An adaptive plan was then created for each fraction. The plan was re-optimized based on the anatomy as seen on the daily MRI and re-normalized so the volume of the PTV receiving 100% of the prescription (PTV100) would be 90%. Both the non-adaptive and adaptive doses to the target volume and the OARs were recorded to evaluate the value of adaptation. We used a paired t-test to compare PTV100 between the adaptive and non-adaptive techniques and Chi2 tests to compare the probability of dose constraint failures for OARs. Results: Adaptive MR-IGRT improved target coverage. Mean PTV100 for adaptive and non-adaptive techniques was 89.9% [88.4-90.4] and 78.4% [27.3-96.6] respectively, p = 0.0017. There were no statistically significant differences for violations of dose constraints of OARs using adaptive vs. non-adaptive techniques. Point maxima violations above 35 Gy to duodenum occurred in 6 adaptive fractions (renormalized to 90%) vs. 12 non-adaptive fractions (p = 0.118); to stomach in 8 adaptive fractions vs. 9 non-adaptive fractions (p = 0.790), and to bowel in 9 adaptive fractions vs. 6 non-adaptive fractions (p = 0.401). When adapting, attention must be paid to other OARs in the area: Spinal cord point maxima were violated in 4 adaptive fractions. Conclusions: This study demonstrates that adaptive techniques significantly increase SBRT dose delivered to LAPC without significantly increasing dose constraint violations to OARs. Adaptive MR-IGRT may allow for further SBRT dose escalations.
Importance of detoxification capacity of albumin for assessing state of gastric cancer patients and effective treatment planning.
Authors: Kit Oleg Ivanovich , Goroshinskaya Irina A. , Maslov Andrey A. , Medvedeva Dar'ja E. , Surikova Ekaterina Igorevna , Nemashkalova Ludmila A. , Kaminskiy Gennadiy V. , Tishchenko Irina , Malinin Sergey A. , Chilhahyan Lusegen
Published: January 2019

34

Background: The aim of the study was measuring biochemical indices reflecting endotoxicosis syndrome in gastric cancer patients with adenocarcinoma of different grades and signet ring cell carcinoma. Methods: The study included 67 patients with gastric cancer divided into 4 groups depending on the tumor histotype: well- and moderately-differentiated adenocarcinoma (G1-2); poorly-differentiated adenocarcinoma (G3); signet ring cell carcinoma (SRCC); combined gastric tumors; and 12 healthy donors. The content of medium mass molecules (MMM254 and MMM280), total and effective albumin concentrations (TCA and ECA), toxicity index (IT = TCA/ECA-1) and intoxication factor (IF = MMM254/ECA⋅1000) were used to assess the level of endogenous intoxication. The Statistika 6.0 software package was used. Results: IT, reflecting the functional state of the albumin molecule, significantly exceeded the level in donors: by 2.3 times in G1-2, by 3.3 times in G3, by 3.2 times in SRCC (p < 0.01-0.001), by 2.2 times in mixed tumors (p < 0.05). The greatest increase in IT – by 4.6 times – was observed in patients with serosal invasion and tumor spread to the adjacent structures (T4 in the TNM classification). IF, which is an integral indicator of endotoxemia, in all groups of patients was significantly (p < 0.01-0.00001) higher than in donors. The increase was 55.2% in patients with G1-2, 132.7% for G3, 234.6% for T4, 66.8% for SRCC, and 59.6% for mixed tumors. The dynamic observation of patients showed that a sharp increase in the studied parameters was followed by relapses. Conclusions: The increase in IT and IF in all groups of patients indicated an enhancement of endotoxemia in gastric tumors, mainly due to the decreased detoxification capacity of albumin, as high levels of MMM were observed only in some patients. The changes were significantly more expressed in patients with G3, with the maximal changes in all the studied endotoxicosis parameters in T4. The results demonstrated the diagnostic significance of the detoxification ability of albumin for the evaluation of the state of gastric cancer patients and for the adequate treatment planning.
Early occurrence of hepatocellular carcinoma in patients with and without cirrhosis after HCV treatment with direct-acting antivirals.
Authors: Finkelmeier Fabian , Dultz Georg , Kronenberger Bernd , Peiffer Kai Henrik , Krauss Franziska , Zeuzem Stefan , Sarrazin Christoph , Vermehren Johannes , Waidmann Oliver
Published: January 2019

356

Background: The aim of the study was to evaluate the risk of HCC development after treatment with direct-acting antivirals (DAA) and to compare hepatocellular carcinoma (HCC) occurrence to patients treated with interferon (IFN)-based therapies. Methods: We analyzed a large cohort with chronic HCV patients for the onset of new hepatocellular carcinoma after DAA treatment. A historic interferon treated cohort was investigated for comparison. Results: 819 patients were included in the DAA group, 269 (32.8%) had established cirrhosis. Median follow up was 263 days (0-1001). 25 patients (3.1%) were diagnosed with de novo HCC within the observation time. All of these patients had established cirrhosis. Patients with new HCC were mostly male, older, treatment experienced, had a lower SVR12 rate and higher levels of liver inflammation markers. Investigation of the subcohort of 269 cirrhotic patients yielded a HCC rate of 9.3% during the follow-up of approximately one year. Non-SVR12 was an independent risk factor for de novo HCC (OR 4.983, 1.39-17.88, 0.014). Most HCCs were diagnosed in early stage BCLC A. In the historical cohort of 351 IFN treated patients the rate of de novo HCC was 5.4% overall and 11.8% in patients with already established cirrhosis (n = 68). In the multivariate analysis failed SVR (OR 5.386, 1.155-25.108, p = 0.032) remained an independent risk factor for de novo HCC. In a combined analysis of all patients (DAA and IFN treated) in a multivariate approach male gender, failed SVR and cirrhosis were independent factors for HCC development. Conclusions: DAA treatment in cirrhotic patients does not seem to reduce the risk of HCC development in the short term. HCC rates were not different between DAA-treated patients and those who received interferon. Achievement of SVR seems to be the most important aim to prevent HCC development.
Clinical benefit of maintenance therapy for patients with advanced biliary tract cancer without progression on first-line gemcitabine plus cisplatin.
Authors: Hyung Jaewon , Yoo Changhoon , Kim Kyu-Pyo , Kim Bum Jun , Jeong Jae Ho , Chang Heung-Moon , Ryoo Baek-Yeol
Published: January 2019

357

Background: Gemcitabine plus cisplatin (GP) is the standard first line chemotherapy for patients with advanced biliary tract cancer (BTC). In the pivotal ABC-02 study, patients received up to 24 weeks (6-8 cycles) of three-weekly GP. In daily practice setting, however, patients without progression often receive GP more than 6-8 cycles. It is uncertain whether maintenance treatment has clinical benefit in patients without progression on GP. Methods: Advanced BTC patients treated with GP between April 2010 and February 2015 in Asan Medical Center, Seoul, Korea, were retrospectively analyzed. Among the patients who did not progressed and stopped GP after 6-8 cycles, patients were stratified according to the further treatment; those with or without further cycles of GP (maintenance group vs observation group). Primary endpoint was overall survival (OS). Results: Among 740 patients, 231 patients (31.2%) were eligible for this analysis; 111 for observation group, 120 for maintenance group. In observation group, 76 patients (68.5%) stopped GP due to completion of scheduled chemotherapy and 27 patients (24.3%) due to the patients’ request or toxicity. There were no statistically significant differences in baseline characteristics between two groups. Median OS from the initiation of GP was 20.5 months [95% CI 15.4-25.6] and 22.4 months [95% CI 17.0-27.8] in the observation and maintenance group, respectively (p = 0.32). Median progression-free survival (PFS) was 10.4 months [95% CI 7.0-13.8] and 13.2 months [95% CI 11.3-15.2], respectively (p = 0.22). These were consistent in the multivariate analyses for OS and PFS after the adjustment of prognostic factors. Conclusions: In our analysis, maintenance therapy of GP was not associated with improved survival outcomes. Considering the potential disadvantages such as cumulative toxicities, maintenance therapy may not be beneficial in patients who did not progressed on 6-8 cycles of GP.
A phase II pilot trial of nivolumab (N) + albumin bound paclitaxel (AP) + paricalcitol (P) + cisplatin (C) + gemcitabine (G) (NAPPCG) in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Borazanci Erkut Hasan , Jameson Gayle S. , Borad Mitesh J. , Ramanathan Ramesh K. , Korn Ronald Lee , Caldwell Lana , Ansaldo Karen , Hendrickson Kristin , Marceau Katie , Von Hoff Daniel D.
Published: January 2019

358

Background: Effective therapy for the treatment of PDAC remains one of the greatest unmet oncology clinical needs. The addition of C to G and AP has shown promising clinical data in a previously reported study [J Clin Oncol 35, 2017 (suppl 4S; abstract 341)]. In preclinical work, vitamin D (Vit D) analog therapy decreases myeloid derived suppressor cells and regulatory T cells, turning PDAC into a more immune-friendly microenvironment. This trial combines AP/C/G with Vit D analog P and the anti-PD-1 antibody N as a combination therapy for patients with previously untreated metastatic PDAC. This trial evaluates the efficacy and safety of NAPPCG in that patient population (NCT02754726). Methods: Eligibility criteria include Stage IV PDAC, no prior chemotherapy for systemic disease, KPS ≥ 70, and measurable disease. Doses are AP 125 mg/m2 undiluted, G 1000 mg/m2 in 250 ml of normal saline (NS), each infused over 30 minutes with C 25 mg/ m2 in 500 ml of NS infused over 60 minutes on days 1, 8, 22, and 29 of a 42-day cycle. N is given at a fixed dose of 240 mg as a 60 minute infusion on days 1, 15, and 29. P is given at a fixed dose of 25 µg IV twice weekly. Primary objective is to determine the efficacy of the combination for patients with previously untreated metastatic PDAC through determining CR, ORR, PFS, and OS. The secondary objective is to evaluate safety in patients with previously untreated metastatic PDAC. Results: Trial was initiated May 2016 and10 patients have been enrolled in the initial phase of the study and are evaluable (baseline and ≥1 follow up CT scan). Most common drug-related grade (Gr) 3-4 adverse events (AE’s), n = 10, are thrombocytopenia 100% (gr 3 = 50%, gr 4 = 50%) with no serious bleeding events, anemia 50% (gr 3 = 50%, gr 4 = 0%), and colitis 20% (gr 3 = 20%, gr 4 = 0%). By RECIST 1.1 criteria, the best response is 8 PR and 2 SD, yielding an 80% ORR. Median PFS is 8.2 months. Median OS has not been reached. Conclusions: Although a small study, the high response rate is encouraging. This regimen is being expanded to 25 patients with plans to include exploratory inflammatory biomarkers. Clinical trial information: NCT02754726.
Major arterial resection for stage 3 adenocarcinoma of the pancreas.
Authors: Loveday Benjamin , Tomiyama Koji , Zilbert Nathan , Tremblay St-Germain Amélie , Serrano Aybar Pablo Emilio , Fox Adrian , Segedi Maja , Scholtz Paul , O'Malley Martin , Borgida Ayelet , Bianco Teresa , Dodd Anna , Krzyzanowska Monika K. , Moore Malcolm J. , Kim Joon-Hyung J. , Wei Alice Chia-chi , Gallinger Steven , Dhani Neesha C. , McGilvray Ian M
Published: January 2019

362

Background: Stage 3 pancreas ductal adenocarcinoma (PDAC) is defined by arterial involvement, and its resection remains controversial. The objective of this study was to evaluate clinical and oncologic outcomes for patients with stage 3 PDAC who entered a treatment program of neoadjuvant therapy (NAT) and pancreatic resection, with comparison between those who underwent arterial (AR) vs. standard resection (SR). Methods: This cohort study included patients from 2009-2016 in a single academic institution, with biopsy-proven potentially resectable stage 3 PDAC who entered a treatment program of NAT followed by surgical exploration if non-progressive disease on imaging. AR was performed if required to achieve R0 resection. Oncological outcomes were analyzed as intention to treat from diagnosis date. Results: Eighty-nine patients met inclusion criteria, of whom 87 (97.8%) received chemotherapy and 50 (56.2%) received radiotherapy. 46/89 (51.7%) underwent surgical exploration; 31 underwent pancreas resection (AR n = 20, SR n = 11), and 15 were found to have metastatic or unresectable disease. The AR group had a longer operative time (681 vs. 563 minutes, p = 0.0059) and more blood loss (1600 vs. 575 mL, p = 0.0004) compared with SR, with no difference between groups for blood transfusion, overall complications, pancreatic fistula, length of stay, reoperation, readmission or mortality. R0 rate was 100% for resected patients. Post-operative 90-day mortality was 1.1%. Median overall survival of resected patients was longer than in non-resected patients (25.9 vs. 14.8 months, p = 0.01), while AR had comparable overall survival to SR (19.7 vs. 28.4 months, p = 0.41). Conclusions: Patients with non-progressive stage 3 PDAC after NAT should be considered for pancreas resection. AR had comparable clinical and oncologic outcomes to SR. Resection may offer a survival advantage over non-surgical therapy alone, and AR should be considered if required to obtain a negative resection margin.
First line gemcitabine and nab-paclitaxel chemotherapy for localized pancreatic ductal adenocarcinoma.
Authors: Gulhati Pat , Prakash Laura , Katz Matthew H. G. , Wang Xuemei , Javle Milind M. , Shroff Rachna T. , Fogelman David R. , Lee Jeffrey Edwin , Tzeng Ching-Wei David , Lee Jeffrey H , Weston Brian , Tamm Eric P. , Bhosale Priya , Koay Eugene Jon , Maitra Anirban , Wang Huamin , Wolff Robert A. , Varadhachary Gauri R.
Published: January 2019

369

Background: Chemotherapy is widely used as a component of treatment of localized pancreatic ductal adenocarcinoma (PDAC). Pre-operative chemotherapy is associated with early treatment of micro-metastases and guaranteed delivery of all components of multimodality therapy. For locally advanced (LA) PDAC, induction chemotherapy is standard of care. We evaluated the use of gemcitabine and nab-paclitaxel (Gem/nab-P) as first-line therapy in localized PDAC. Methods: Records of pts with localized PDAC who initiated Gem/nab-P at a single institution from 2013-2015 were retrospectively reviewed. Clinicopathologic features, dose and outcomes were evaluated. Pts were staged using our previously published criteria: potentially resectable (PR), borderline type A (BR-A) (anatomy amenable to vascular resection), BR-B (biology suspicious for metastatic disease including high CA19-9), BR-C (co-morbidities requiring medical optimization), and LA. Co-morbidities were classified using adult comorbidity evaluation-27 score. Overall survival (OS) was analyzed using Kaplan Meier method. Results:99 pts [M/F: 50/49; median age: 70 yrs (range 30-85); PR/BR/LA: 45/14/40] were treated with Gem/nab-P. Clinical staging showed PR+BR-A/BR-B+C: 20/39. BR-B+C included one or more of the following factors: age ≥80 yrs [13%], ECOG PS ≥2 [13%], moderate/severe co-morbidities [55%], CA19-9≥1000 [28%], suspicion for metastatic disease [21%]. Majority of pts received biweekly Gem/nab-P dosing [standard/biweekly/other: 10/80/9] with minimal grade 4 toxicity. 45/99 pts received chemoradiation after Gem/nab-P [30Gy/50.4Gy: 15/30]. 12/20 (60%) PR+BR-A, 2/39 (5%) BR-B+C and 1/40 (3%) LA pts underwent pancreatectomy. 13/15 resected pts received adjuvant chemotherapy. At median follow-up of 26 mo, median OS was 18 (95% CI: 15.6-20.5) mo for all, 17 (95% CI: 14.6-19.5) mo for unresected and not reached for resected pts (p = 0.03). Conclusions: A significant number of pts with resectable PDAC albeit aggressive biology (BR-B) and/or medically inoperable disease (BR-C) received first-line Gem/nab-P; resection rates were lower compared to PR/BR-A pts. Biweekly dosing is being used in localized PDAC and is well tolerated.
Effect of adjuvant radiation on survival for extra-hepatic cholangiocarcinoma.
Authors: Takahashi Caitlin , Shridhar Ravi , Huston Jamie , Patel Anjan Jayantilal , Brown Richard H. , Koehler Kevin , Briceno Pedro , Meredith Ken Lee
Published: January 2019

377

Background: Extra-hepatic cholangiocarcinomas (EHC) are low-incidence cancers that are difficult to diagnose and associated with a dismal prognosis. Surgery remains the only option for durable survival however R1 resections are high. We sought to examine the impact of adjuvant therapies on survival in patients with EHC. Methods: Utilizing the National Cancer Database we identified patients who underwent resection for EHC. We then stratified by adjuvant therapy (chemo(AC) or chemoradiation(CRT). Baseline comparisons of patient characteristics were made using Mann-Whitney U, Kruskal Wallis and Pearson’s Chi-square test as appropriate. Survival analyses were performed using the Kaplan-Meier method. Multivariable cox proportional models (MVA) were developed to identify predictors of survival. All statistical tests were two-sided and α < 0.05 was considered significant. Results: We identified 4334 patients who underwent EHC resection: AC = 775, CRT = 1254, no adjuvant (NA) therapy = 2305 and a median age of 67 (18-90) years. R0 resections was performed in 71.6% of patients and the median LN harvest was 9 (3-18). R0 resections and lymph node negative patients demonstrate improved survival p < 0.001 and p < 0.001. Adjuvant therapy did not improve survival in R0 resections, p = 0.2. However survival was benefited in R1 patients, with those receiving CRT demonstrating the most significant improvement: median and overall 5-year survival AC = 16.7 months 8%, CRT = 23.1 months, 20.4%, and NA = 16.1 months and 11.6% p < 0.001. In LN- patients CRT (47.3 months, 47%) but not AC (45 months, 44.5%) demonstrated benefit in survival compared to NA (37.8 months, 40.1) p = 0.04 and p = 0.7. Additionally, patients with LN+ and R1 resection had survival benefit when treated with (CRT 24.9 months and 24.3%), compared to NA (20.2 and 21.1%), p = 0.02. AC (24 months and 24%) did not demonstrate survival in these patients, p = 0.21. MVA demonstrated that age, T-stage, LN+, R0 resection and CRT were predictors of survival. Conclusions: Adjuvant CRT improves survival for patients with EHC who underwent R1 resections, and in LN- and LN+ patients. However, AC only benefited node positive patients with R0 resections. Patients with resected EHC should be referred for adjuvant CRT.
Phase 2 study of carfilzomib for the treatment of patients with advanced neuroendocrine cancers.
Authors: Singh Jaswinder , Shipley Dianna , Cultrera Jennifer , Chua Cynthia , Cohn Allen Lee , Soriano Andres O. , Bendell Johanna C.
Published: January 2019

382

Background: Carfilzomib (CFZ) is an irreversible proteasome inhibitor (PI) that exhibits anti-proliferative and pro-apoptotic activity in solid and hematologic tumor cells i n vitro, and is US FDA approved for multiple myeloma. Proteasomes degrade cell cycle inhibitor proteins and inhibition of these proteins offers a novel therapy for the treatment of patients with neuroendocrine tumors (NET). This phase 2 study evaluated the efficacy of CFZ for patients with advance NETs. Methods: Pts with biopsy-proven, advanced, well-to-moderately differentiated NETs, including typical carcinoid and pancreatic islet cell tumors, were treated with CFZ 20 mg/m2 IV Days (D) 1 and 2, then 56 mg/m2 IV D 8, 9, 15, and 16 of Cycle (C) 1, followed by CZF 56 mg/m2 IV D 1, 2, 8, 9, 15, and 16 of C 2 and beyond. Pts continued study treatment (tx) until intolerable toxicity, disease progression, or withdrawal of consent. Restaging occurred every 3 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were disease control rate (DCR), progression free survival (PFS), and toxicity. Results: 62 pts were enrolled: median age 63 yrs, 61% female, 50% ECOG 0/50% ECOG 1. 65% of pts had carcinoid tumors and 35% of pts had pancreatic NET. The most common primary sites of disease were the pancreas (34%) and the small intestines (21%). 74% of pts had prior systemic therapy, 42% had prior surgery and 16% had prior radiotherapy. Median tx duration was 11 wks. At the time of data cutoff, 31% of pts remained on tx. 32% of pts discontinued due to progressive disease, 16% due AE, and 21% due to pt or physician decision. Two pts (3%) had a confirmed partial response (PR) and 1 pt (2%) had an unconfirmed PR; 4 ongoing patients have not yet been evaluated for response. The ORR was 3.23% (95% CI 0.4%, 11.2%), the DCR was 53.23% (CI 95% 40.1%, 66.0%), and median PFS was 8.1 months. The most frequently reported tx-related AEs were nausea (52%; Grade 3/4 [G3/4], 2%), fatigue (42%; G3/4, 3%), vomiting (36%; G3/4, 2%), and diarrhea (27%; G3/4, 5%). Conclusions: CFZ tx was well-tolerated in this pt population. Future plans will be determined once response data are available on all patients. Updated results will be presented. Clinical trial information: NCT02318784.
Prognosis of hepatic failure with the albumin-bilirubin model for hepatocellular carcinoma after stereotactic body radiotherapy with and without transplant.
Authors: Hasan Shaakir , Kirichenko Alexander V. , Renz Paul , Kudithipudi Vijay , Vincent Molly , Machado Lorenzo , Uemura Tadahiro , Thai Ngoc
Published: January 2019

384

Background: The Albumin-Bilirubin (ALBI) model is a validated prognostic assessment of cirrhosis in hepatocellular carcinoma (HCC), stratifying patients to grades 1(ALBI-1), 2(ALBI-2), or 3(ALBI-3). We reported that ALBI distinguishes patients at higher risk for hepatic failure(HF) after stereotactic body radiotherapy (SBRT) within the Child Pugh(CP) A population. We now apply the ALBI model to both CP-A and CP-B patients after SBRT with or without orthotropic liver transplant (OLT), and assess its prognostic capability of overall survival (OS) and HF relative to the CP model. Methods: From 2009-2017, 68 patients with 81 HCC lesions and CP-A (45) or CP-B (23) cirrhosis completed SBRT in this IRB approved study. The median dose was 45 Gy (35 - 57 Gy) in 4-7 fractions. Initial ALBI and CP scores were measured against OS and progression of CP class, which was recorded every 3-4 months. Median follow-up = 18 months. Results: The median age = 62 and tumor size = 3.5 cm (1.1 Ð 11 cm). 26 patients were ALBI-1, 31 ALBI-2, and 11 ALBI-3 prior to SBRT. For all patients, 2-year local control was 96%. 1 and 2 year OS was 77% and 54%, disease free survival was 71% and 40%, and freedom from CP progression was 71% and 56%, respectively. OS was significantly different between ALBI-1, ALBI-2, and ALBI-3 patients (P = 0.01), as was progression of CP class (P<0.001). When stratified by initial CP class, there were no significant differences in survival or CP progression [Table 1]. In a subset of 37 CP-A and 15 CP-B without OLT, rates of progressive cirrhosis were better predicted by ALBI (P<0.001) than CP class (P=0.09). Conclusions: Compared to the CP model, the ALBI index more precisely predicted HF and OS in HCC patients for both early and intermediate cirrhosis. Its application may help better select candidates for OLT after SBRT, who may be at higher risk for HF than initially predicted. [Table: see text]
Surgical treatment of hepatocellular carcinoma with advanced portal vein tumor thrombus combined with pre-operative radiotherapy.
Authors: Wakayama Kenji , Kamiyama Toshiya , Orimo Tatsuya , Nagatsu Akihisa , Shimada Shingo , Yokoo Hideki , Kamachi Hirofumi , Taketomi Akinobu
Published: January 2019

385

Background: Hepatocellular carcinoma (HCC) with advanced portal vein tumor thrombus (PVTT) in the main portal trunk (MPT) or the first branch of portal vein has poor prognosis. We attempted a multidisciplinary treatment to irradiate the PVTT prior to surgical resection. In this study, we evaluate the therapeutic effect of preoperative radiotherapy (Pre-RT) for HCC with advanced PVTT. Methods: The postoperative prognosis was retrospectively examined in 75 patients with advanced PVTT out of 1,045 patients who underwent hepatectomy for HCC between 1990 and 2015 in our institute. The treatment outcome was compared between the patients who underwent Pre-RT (30Gy/10fr) for PVTT before operation (RT group, n = 34) and patients not underwent Pre-RT (non-RT group, n = 41). Results: Among 75 patients with advanced PVTT, there was no difference in age, sex, extent of PVTT (MPT or first branch of PV), HBV, HCV, T-Bil, PT(%), ICG R15%, Child-Pugh classification, AFP, DCP, intra-operative blood loss, tumor size, tumor number, coexisting hepatic vein or bile duct tumor thrombus, presence of the residual tumor between RT and non-RT group other than adjuvant chemotherapy administration (p = 0.0009). The 5-year overall survival rate of all 75 cases was 18.5%. There was a significant overall survival extension in RT group with 29.4% compared to 16.2% in non-RT group (p = 0.039, log-rank test). Surgery without residual lesions was performed in 64 patients, of which the 5-year recurrence-free survival rate was 10.9%. The 5-year recurrence-free survival rate of RT group (n = 30) (16.1%) was significantly better than non-RT group (n = 34) (5.5%) (p = 0.027, log-rank test). Univariate analysis using Cox proportional hazard model demonstrated that the Pre-RT was the only significant prognostic factor (HR 0.595, 95% CI 0.356 - 0.981, p = 0.042) for overall survival, and the Pre-RT and tumor size over 10cm for recurrence-free survival among these patient’s factors. Conclusions: Multidisciplinary treatment combined preoperative radiotherapy to PVTT and subsequent surgical resection improve the prognosis for the patients of HCC with advanced PVTT extend to MPT or first branch of PV.
An easy-to-use nomogram to predict overall survival (OS) at 6 months after initiation of FOLFIRINOX first-line chemotherapy in patients (pts) with metastatic pancreatic cancer (mPC).
Authors: Fornaro Lorenzo , Leone Francesco , Vienot Angelique , Casadei Gardini Andrea , Vivaldi Caterina , Lombardi Pasquale , Meurisse Aurelia , Passardi Alessandro , Vasile Enrico , De Luca Emmanuele , Edeline Julien , Musettini Gianna , Satolli Maria Antonietta , Neuzillet Cindy , Spadi Rosella , Vernerey Dewi , Falcone Alfredo , Clerico Mario , Lievre Astrid , Montagnani Francesco
Published: January 2019

394

Background: FOLFIRINOX achieved a significant step forward in the treatment of mPC. However, patient prognosis remains dismal, and better discrimination of outcomes could be useful to guide clinical decision-making and patient stratification. We aimed at developing and validating a prognostic model and nomogram able to predict the risk of early death (within 6 months post-treatment initiation) in mPC pts treated with first-line FOLFIRINOX. Methods: Data from 137 mPC treated with the GONO FOLFOXIRI schedule at a single institution were used as developing set. Univariate associations with death in the first 6 months after treatment initiation were investigated. Based on the multivariate model, a nomogram was developed assigning points equal to its weighted relevance to each significant variable. The nomogram was externally validated on an independent, parallel cohort of 206 mPC pts treated with FOLFIRINOX at different Italian and French centers. Predictive ability was assessed with the concordance index (C-index) and visual inspection of the calibration plot. Results: 4 out of the 27 considered variables were retained in the multivariable model: ECOG performance status (PS), neutrophils-to-lymphocytes ratio (NLR), liver metastases, and basal serum CA19.9. The nomogram demonstrated adequate discriminative ability in the validation set with a C-index of 0.754. When grouped in different prognostic categories (according to none, 1, 2, or > 2 risk factors), pts included in our study showed significantly different outcomes with median OS ranging from 6.2 ( > 2 risk factors) to 19.5 months (no risk factors, P < 0.05). Conclusions: PS, NLR, liver metastasis, and CA19.9 were the major determinants of 6-month OS. Our nomogram may help clinicians in discussing with pts the benefits and risks of therapy, and in designing future clinical trials. A visual format of the nomogram will be presented. [Table: see text]
Percutaneous radiofrequency versus microwave ablation for the treatment of colorectal liver metastases.
Authors: Bonne Lawrence , De Paepe Katja , Fotiadis Nicos , Starling Naureen , Chau Ian , Gerlinger Marco , Rao Sheela , Watkins David J. , McCall James , Koh Dow-Mu , Brown Gina , Cunningham David
Published: January 2019

401

Background: Microwave (MWA) and radiofrequency (RFA) ablation are commonly used for the treatment of unresectable liver metastases from colorectal cancer (CRC). MWA has a few theoretical advantages over RFA (active heating, less affected by heat sink effect, larger ablation zones, faster) however limited data exists on this field. Our aim was to analyse the safety and efficacy of MWA and RFA in the treatment of CRC liver metastases. Methods: All patients with unresectable CRC liver metastasis who were treated with RFA or MWA in a single center between March 2006 and December 2016 were included. Medical records and imaging studies were reviewed retrospectively for demographic data, to assess for local tumour recurrence and overall survival and to evaluate ablation-related adverse events. Results: 456 ablations were performed in 193 patients (123 men) with a median age of 66 (range 32-91). The majority of patients had a history of surgery of the primary tumour (n=170, 88,1%) and systemic chemotherapy (n=183, 94,8%). 68 patients had a history of liver surgery (35,2%). RFA was used in 343 procedures (75,2%) and MWA in 113 (24,8%). Median number of procedures per patient was 2 (range 1-10). Median lesion size was 17mm (range 3-80mm). Mean follow-up per lesion was 2.0 years in the RFA group and 1.3 years in the MWA group. Local tumour recurrence rate was 45% for RFA and 28% for MWA, with a hazard ratio of 0.6 in favour of MWA (95% CI 0.4-0.9). Two and five year overall survival rates from diagnosis of liver metastasis were 88% and 35% for RFA and 89% and 66% for MWA, respectively. Complications were reported in 43 of 456 procedures (9,4%); In 8,2% of RFAs (n=28) and 13,3% of MWAs (n=15). Complications classified as CTCAE grade 3 or higher were: haemothorax requiring surgery (n=1 for RFA), biloma (n=2 for RFA & MWA), biliary stricture (n=2 for RFA and n=1 MWA), liver failure (n=2 for RFA), liver abscess (n=1 RFA), pneumonia (n=2 for RFA) and pulmonary embolism (n=1 RFA). Segmental portal vein occlusion was only seen with MWA (n=2; 1,8%). One patient died due to multi-organ failure post RFA. Conclusions: MWA could achieve better local tumour control compared with RFA in the treatment of CRC liver metastasis, with slightly higher complication rate.
Association of adjuvant chemotherapy with overall survival in resected pancreatic adenocarcinoma previously treated with neoadjuvant therapy.
Authors: Swords Douglas S. , Garrido-Laguna Ignacio , Mulvihill Sean J. , Stoddard Gregory J. , Firpo Matthew A. , Scaife Courtney L.
Published: January 2019

404

Background: Guidelines for adjuvant chemotherapy in patients with resected pancreatic adenocarcinoma (PDAC) who received neoadjuvant chemotherapy are equivocal. A lymph node ratio (LNR) ≥ 0.15 may predict lack of benefit, but conflicting results are reported. Methods: The National Cancer Database was searched to identify patients who were resected after neoadjuvant chemotherapy in 2006-2013. Exclusions: metastases at surgery, 90-day postoperative mortality, adjuvant radiation, and outlier interval from diagnosis to surgery (<2.5 or >10 months). The association between adjuvant chemotherapy and overall survival (OS) from diagnosis was examined using multivariable Cox regression and inverse propensity of treatment weighted (IPTW) Cox regression. An IPTW based estimator of the average treatment effect (ATE) was used to quantify the population average survival benefit of treatment. Outcomes were examined in all patients and in those with LNR < 0.15 and ≥ 0.15. Results: 681/2488 patients (27%) received adjuvant chemotherapy. In multivariable Cox regression, adjuvant chemotherapy was associated with improved OS in the overall cohort and in patients with LNR < 0.15. A trend towards improved OS was also observed for those with LNR ≥ 0.15. After accounting for indication bias using IPTW, a significant survival benefit for was observed only for patients with LNR < 0.15. The ATE among LNR < 0.15 patients was 3.3 (95% CI 1.0, 5.7) months, indicating that the average survival of the population would be 3.3 months longer if all received treatment. Conclusions: Adjuvant chemotherapy in resected PDAC patients who received neoadjuvant therapy appears to be beneficial in patients with negative lymph nodes or minimal nodal burden. High LNR after neoadjuvant therapy may be an indicator of adverse tumor biology that is less likely to derive a therapeutic benefit. [Table: see text]
Clinical outcomes of gemcitabine plus nab-paclitaxel (GnP) in initially diagnosed locally advanced pancreatic cancer.
Authors: Hashimoto Yusuke , Takahashi Hideaki , Ohno Izumi , Imaoka Hiroshi , Sasaki Mitsuhito , Umemoto Kumiko , Watanabe Kazuo , Kimura Gen , Mitsunaga Shuichi , Ikeda Masafumi
Published: January 2019

407

Background: Gemcitabine plus nab-Paclitaxel has shown improved survival in patients with metastatic pancreatic cancer in MPACT. Many studies have been investigating the survival benefit of GnP in LACP patients. The aim of this study is to clinical outcome of GnP in initially diagnosed LAPC in our single tertiary institution. Methods: LACP patients who received GnP as initial chemotherapy were identified between December 2014. and December 2016 from our database retrospectively. Demographic characteristics, disease status, response, conversion to resection and survival was reviewed. Resectability was determined at our hepatobiliary pancreatic tumor board, reflecting Japanese guideline of pancreatic cancer. Results: We identified 55 LACP patients initially treated with GnP (median age: 67 year old, female was 49%, ECOG PS 0/1, 62%/38%, pancreatic head 58%, baseline tumor size: median 32mm (18-62), CA19-9: median 139ng/ml (3.9-12956)). Best objective response rate was 58% and median time to partial response was 60 days (40-212). Median overall survival (mOS) was 24.7 months (95%CI :15.5-not reached). Nine patients (16%:9/55) were re-evaluated as resectable with CT and normalized CA19-9/CEA and subsequently proceeded to conversion to resection. Seven patients (13%:7/55) achieved R0 resection and sequentially performed adjuvant six- month duration of GnP. Median time to resection from initial GnP administration was 5.2 months (4.0-7.3). LAPC patients who achieved conversion to resection was associated with better overall survival than non-resected LAPC in log-rank test (mOS: all alive :12.1-25.4months vs 21.5 months 95%Cl:15.5-, HR:0.493 range: NA, P = 0.043). Shrinking tumor minimal size from the baseline was the factor to successful conversion in univariate analysis (P = 0.006). Conclusions: GnP showed promising results of response and overall survival in uLAPC patients. Conversion to resection in carefully selected uLAPC currently suggests an early surgical benefit, but longer follow-up and more cases will be required to assess the potential long-term benefit of conversion therapy.
Hand-foot skin reaction (HFSR) and overall survival (OS) in the phase 3 RESORCE trial of regorafenib for treatment of hepatocellular carcinoma (HCC) progressing on sorafenib.
Authors: Bruix Jordi , Merle Philippe , Granito Alessandro , Huang Yi-Hsiang , Bodoky Gyorgy , Yokosuka Osamu , Rosmorduc Olivier , Breder Valeriy Vladimirovich , Gerolami René , Masi Gianluca , Ross Paul J. , Qin Shukui , Song Tianqiang , Bronowicki Jean-Pierre , Ollivier-Hourmand Isabelle , Kudo Masatoshi , Xu Lei , Baumhauer Annette , Meinhardt Gerold , Han Guohong ,   on behalf of the RESORCE Investigators
Published: January 2019

412

Background: Skin toxicity is a known adverse effect of multikinase inhibitors, and was shown to be a predictor of OS in patients (pts) with HCC treated with sorafenib (Reig M, 2014). In the RESORCE trial, regorafenib improved OS versus placebo in pts with HCC progressing on sorafenib (HR 0.62, 95% CI 0.50, 0.78; Bruix J, 2017). This retrospective analysis explored whether HFSR with regorafenib was associated with OS in RESORCE. Methods: Pts in RESORCE who were randomized to regorafenib 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether or not they had HFSR. Estimates of OS (95% CI) were calculated using the Kaplan–Meier method. Pts who were randomized, but not treated, were included in the no HFSR group for the analysis of survival. Results: Of 379 pts randomized, 374 received at least one dose of regorafenib. Of the treated pts, 53% (n = 199) had HFSR of any grade and 13% (n = 47) had grade 3 HFSR. Among pts with HFSR at any time during the study, 77% (n = 153) had the first HFSR event (any grade) during Cycle 1. Subgroups of pts with and without HFSR at any time had some imbalances in baseline characteristics (Table). OS was improved in pts who had HFSR at any time versus those who did not (Table). Pts who had a HFSR event during Cycle 1 also had improved OS versus those who did not (median OS 13.2 vs 8.5 months; HR 0.66, 95% CI 0.51, 0.86). Conclusions: In this post-hoc exploratory analysis, HFSR with regorafenib was associated with improved OS, as was previously shown for sorafenib. The potential confounding influence of baseline factors requires further investigation. Clinical trial information: NCT01774344. [Table: see text]
Phase I study of hepatic arterial infusion (HAI) therapy with floxuridine (FUDR) combined with systemic gemcitabine and oxaliplatin in patients with locally advanced intrahepatic cholangiocarcinoma (ICC).
Authors: Grierson Patrick , Oza Aabha , Doyle Maria Majella , Fowler Kathryn , Fields Ryan , Hawkins William G. , Hammill Chet , Wang-Gillam Andrea , Amin Manik A. , Pedersen Katrina , Lim Kian-Huat , Morton Ashley , Cordova Christine , Tan Benjamin R. , Chapman William C.
Published: January 2019

417

Background: The standard of care for unresectable ICC is palliative systemic chemotherapy with cisplatin and gemcitabine. HAI therapy with FUDR in ICC resulted in high response rates [Kemeny 2011]. The use of HAI FUDR with systemic chemotherapy may improve outcomes. We conducted a phase 1 study of HAI FUDR with systemic gemcitabine and oxaliplatin. Methods: We enrolled patients in 3 cohorts: FUDR 0.16mg/kg/day x 14 days (Cohort 1), FUDR 0.12 mg/kg/day x 14 days with gemcitabine 1000mg/m2 on days 1, 8, 15 (Cohort 2), and FUDR 0.10 mg/kg/day x 14 days with gemcitabine 800mg/m2 days 1, 15 and oxaliplatin 85mg/m2 days 1, 15 (Cohort 3). The primary endpoint was the recommended phase 2 dose (RP2D) for Cohort 3. DLTs were assessed during cycle 1. Secondary objectives were response rate and survival. Results: We enrolled 24 patients, 6 male, age range 42-81 years (median 64). No DLTs were observed in Cohort 1 (FUDR). In Cohort 2 (FUDR + Gem), the addition of gemcitabine at 1000mg/m2 days 1, 8, 15 resulted in grade 3 LFT elevation in 2 patients; for subsequent patients, the gemcitabine dose was reduced to 800mg/m2, and no further DLT were noted. No DLT were observed in Cohort 3 (FUDR + GemOx). 10 patients experienced partial responses and conversion to resectable disease occurred in all cohorts. No other significant toxicities occurred. Conclusions: FUDR via HAI with systemic gemcitabine and oxaliplatin is well-tolerated in patients with unresectable cholangiocarcinoma, with a high rate of response and disease control, allowing for resection in some patients. Our RP2D is FUDR 0.10 mg/kg/day x 14 days, with gemcitabine 800mg/m2 days 1, 15 and oxaliplatin 85mg/m2 days 1, 15. Collaboration with MSKCC is ongoing. Clinical trial information: NCT01525069. [Table: see text]
Real-world analysis of treatment patterns and persistence of octreotide LAR and other agents in patients with advanced gastrointestinal neuroendocrine tumors (GI NET): A multicenter study.
Authors: Kulke Matthew H. , Benson Al Bowen , Dasari A. , Huynh Lynn , Cai Beilei , Totev Todor , Roesner Nina , Duh Mei Sheng , Neary Maureen , Bergsland Emily K.
Published: January 2019

424

Background: Limited data are available to document recent treatment paradigms that span NET disease course. This study aims to report long-term, real-world treatment patterns of advanced GI NET patients (pts) based on data from four tertiary cancer centers (Dana-Farber, MD Anderson, UCSF and Northwestern). Methods: Retrospective chart review was conducted in pts diagnosed with advanced, well differentiated GI NET at age ≥18 years and treated with somatostatin analogs (SSAs), targeted therapy (TT), cytotoxic chemotherapy (CC), peptide receptor radiotherapy, liver-directed therapy (LDT) or interferon from 7/2011-12/2014. Eligible pts were followed from advanced NET diagnosis date (earliest recorded diagnosis: 3/1987) to end of follow-up/death (latest recorded date: 5/2017). Analyses of treatment and dosing patterns were performed and persistence of therapy was estimated using Kaplan-Meir analysis. Results: 273 pts were included with mean age of 59 years at advanced NET diagnosis; 64% had functional NET; 57% had ileum as primary tumor site; and 63% had carcinoid syndrome (CS). Most common CS symptoms were diarrhea (87%) and flushing (73%). Majority of pts received octreotide alone (88%) or in combination (2%) with LDT, TT or CC as first-line. Of the 161 pts on second-line, 88% received octreotide alone or in combination; 5 pts (3%) received lanreotide. Most common dose at initiation for octreotide was 30mg/4 weeks (51%) and 20mg/4 weeks (32%); 68% of pts never received > 30mg/4 weeks over the entire treatment course. Median time to treatment discontinuation was 145 months (mos) for octreotide (functional NET: 145; non-functional NET: 117), 13 mos for TT and 6 mos for CC. Conclusions: This study showed that octreotide is the mainstay of treatment for advanced GI NET, as 90% of pts received octreotide alone or in combination with other treatment modalities agents as first-line therapy. 74% continued octreotide alone or in combination with other treatment modalities in the second-line. Most commonly prescribed dose was 30 mg/4 weeks. Pts remained on octreotide long term, with median treatment duration of 12 years.