bluuebunny/crossref_metadata_2025 huggingface dataset:
RXÂ 3117: Activity of an oral antimetabolite nucleoside in subjects with pancreatic cancerâ€“Preliminary results of stage II of the phase Ia/IIb study.
Authors: Chung Vincent M. , Merchan Jaime R. , Ocean Allyson J. , Rasco Drew W. , Babiker Hani M. , Oliff Ira , Paluri Ravi Kumar , Roman Eloy , Poore Julie , Benaim Ely
Published: January 2019

396

Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 2 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 2 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle. Eligible subjects (aged ≥ 18 years) had relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% of evaluable subjects with a partial response rate or better. Results: As of Sep 2017, 44 subjects have been enrolled (22 females, 22 males). The median age was 68 years, ECOG performance statuses were 0 (13 subjects) and 1 (31 subjects) and 6 subjects had received 4 or more prior therapies. One subject had an unconfirmed partial response and 21 subjects met the primary endpoint of stable disease with a duration of 30-224 days. The most frequent adverse events were mild to moderate anemia (19%), mild to moderate fatigue (15%), mild to moderate diarrhea (11%), and severe anemia (9%). Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. The study continues to enroll subjects with advanced pancreatic cancer into stage 2. A phase 2 study with nab-paclitaxel in first-line patients with advanced pancreatic cancer has been started. Clinical trial information: NCT02030067.
Folfirinox versus gemcitabine/nab-paclitaxel for neoadjuvant treatment of resectable and borderline resectable pancreatic adenocarcinoma: A propensity matched analysis.
Authors: Dhir Mashaal , Zenati Mazen S , Hamad Ahmad , Singhi Aatur D. , Bahary Nathan , Hogg Melissa Ellen , Zeh Herbert , Zureikat Amer H.
Published: January 2019

402

Background: Comparative effectiveness of FOLFIRINOX and Gemcitabine/nab-paclitaxel (G-nP) in the neoadjuvant treatment (NAT) of pancreatic ductal adenocarcinoma (PDA), remains unknown. The aim of this study was to perform a propensity matched analysis of neoadjuvant FOLFRINOX vs G-nP for resectable(R) and borderline resectable (BR) PDA. Methods: A single institution retrospective review of all R and BR PDA patients who underwent resection after NAT with FOLFIRINOX or G-nP was performed. Comparative effectiveness analysis was conducted using inverse-probability-weighted estimators. Primary endpoint was overall survival (OS) from the time of diagnosis. Results: A total of 193 patients (FOLFIRINOX=73, G-nP=120) who underwent resection from 01/11-03/17 were included. Median OS was 28.9 months (95% CI 26.1-39.7). Patients treated with FOLFIRINOX were younger (median age 63 vs. 69 y), had less comorbidities (median CCI 4 vs. 5), more frequent BR disease (79 vs. 59%), and larger tumors (median CT size 2.9 v 2.7 cm) compared to G-nP (all p < 0.05). Duration of NAT was similar and both regimens were equally effective in achieving a 50% or 80% decline in CA19-9 (logistic regression, P 0.9). Rates of R0 resection were also similar (80%), but folfirnox was associated with a reduction in pN1 disease (56% vs. 72%, p =0.028). Receipt of adjuvant therapy was similar in both groups (74 vs. 75%, p =0.79). In a multivariable cox regression analysis utilizing only preoperative variables (FOLFIRINOX v G-nP, age, gender, CT tumor size, BR vs. R, pre NAT CA19-9 and number of NAT cycles), only the number of neoadjuvant cycles was an independent predictor of survival (HR 0.49, 95% CI 0.34-0.71, p < 0.001). In a propensity matched analysis of 166 patients using the same preoperative variables, the average treatment effect of FOLFIRINOX was to increase OS by 4.9 months above G-nP (p=0.012). Conclusions: FOLFIRINOX and Gem Abraxane are viable options for neoadjuvant treatment of PDA. In this study, FOLFIRINOX was associated with a 4.9 month improvement in OS when compared to G-nP in the neoadjuvant setting after adjusting for covariates.
Resection of pancreatic cancer following induction chemotherapy.
Authors: Shaib Walid Labib , Sayegh Layal , Alese Olatunji , Maithel Shishir , Cardona Kenneth , Sarmiento Juan , Belalcazar Astrid , Ip Andrew , Qu Yuesheng , Akce Mehmet , Zhang Chao , Wu Christina Sing-Ying , Chen Zhengjia , El-Rayes Bassel F.
Published: January 2019

406

Background: Survival of resectable pancreas cancer (RPC) treated with resection and adjuvant therapy is 22-28 months (mo). Locally advanced unresectable pancreatic cancer (LAPC) treated with combination chemotherapy have a median survival of 24 mo. The objective of this project is to evaluate the effect of neoadjuvant treatment on survival outcome of localized PC. Methods: Charts of localized PC patients treated at Emory University from 2009 to 2016 were reviewed. Information on demographics, stage and treatment was collected. Survival rates were estimated by Kaplan-Meier method and compared with log-rank test. A Cox proportional hazard model was fitted to estimate the adjusted effect of treatment on overall survival(OS). Results: A total of 415 patients were included; 144 RPC, 158 borderline resectable (BRPC) and 108 LAPC. Stage was determined at the multidisciplinary conference. The median age was 67.7 years (30-92); 49% male, and 63% Caucasians. The median OS for RPC, BRPC, and LAPC was 16.9, 14.6 and 10.9 mo, respectively. Stage, type of chemotherapy and age were significant predictors of OS after adjusting for gender, race, age, surgery, stage, chemotherapy, margins and radiation. Of the 144 RPC, 137 underwent surgery and 3 received neoadjuvant treatment; 73 RPC were followed in outside facility with missing follow up data. Of the 71 RPC treated at Emory; 91% received adjuvant gemcitabine. Of the 158 BRPC, 84 underwent surgery; 44 received FOLFIRINOX neoadjuvant therapy, 23 received gemcitabine/nab-paclitaxel, and 16 received gemcitabine single agent. BRPC patients who underwent resection had a median OS of 18.5 mo (95%CI: 14.2, 26.4), significantly longer than RPC (P = 0.044). Combination chemotherapy was significantly associated with improved OS at 36 mo (38.9%) when compared to single agent gemcitabine (6.3% at 36 mo) (p = 0.009). BRPC patients who received FOLFORINOX and surgery had a median OS of 31.5 mo. Conclusions: Overall survival of BRPC patients who undergo resection after FOLFIRINOX is significantly improved (more than doubled) compared to upfront resection for RPC. Preoperative therapy provides the best approach for systemic disease early in the course of treatment.
Oxaliplatin (OX), chronomodulated capecitabine, and UGT1A1 genotype-directed dosing of irinotecan (IR) triplet chemotherapy (OXIRI) in patients (pts) with advanced pancreatic cancer (APC).
Authors: Seet Amanda Oon Lim , Chen Sylvia , Yu Yingnan , Choo Su Pin , Tai David Wai-Meng , Lam Justina Yick Ching , Chang Yvonne , Chowbay Balram , Ng Matthew CH
Published: January 2019

411

Background: The FOLFIRINOX regimen is highly active in APC, but its use is limited by toxicity. Irinotecan (IR) toxicity is correlated with UGT1A1 genotype status and chronomodulated delivery of fluoropyrimidines may reduce toxicity and increase efficacy. We have presented the dose escalation (DES) of OXIRI. In dose expansion (DXP), several pts required dose reduction after cycle 1 and we evaluated a lower starting dose. We now present data of the recommended Phase II dose (RP2D) and DES combined. Methods: Pts with APC and ECOG performance status ≤2, adequate organ function were enrolled. Previous OX or IR exposure was disallowed. During DES, APC pts homozygous for UGT1A1*6/*6 or UGT1A1*28/*28 were excluded. During DXP, only pts progressing on ≥ 1 line prior chemo was allowed and IR was dosed according to UGT1A1 genotype. At RP2D, pts received iv OX 37.5mg/m2 and IR 50mg/m2 on D1, 8 and po capecitabine 2650mg once at midnight on D1-14 every 21D until progression. Results: A total of 25 pts were enrolled, 17 in DES and 8 in DXP, 21 had metastatic and 4 had locally advanced APC. Male:Female 11:14, median (range) age and ECOG PS was 65yrs (50-77) and 0 (0-1) respectively. Pts with 0, 1 or 2 lines of prior chemo were 4 (16%) , 14 (56%) and 7(28%) respectively. Grade 3/4 AEs (≥5%) related to OXIRI were neutropenia (32%), anaemia (12%), diarrhoea (16%). No events of febrile neutropenia were reported. At data cut-off on 31 Aug 2017, 4 pts are on study. Median progression-free and overall survival was 22 and 35 wks respectively. Response rate (RR) was 5/25 (20%, overall); 5/20 (25%, evaluable pts) including 1 complete response and 1 unconfirmed partial response. Disease control rate for ≥ 12wks was 16/25 (64%) with 3 pts > 52wks. CA19-9 decrease of ≥ 20% was seen in 9/25 pts. Conclusions: OXIRI is an active regimen with RR of 20% despite 84% of pts having prior chemo, with disease control for ≥ 12wks in 64% of pts. Predominant toxicity was neutropenia. This study was supported by the National Medical Research Council Singapore. Clinical trial information: NCT02368860.
Comparative effectiveness of nonsurgical therapies for localized hepatocellular carcinoma: Analysis of the National Cancer Database.
Authors: Rajyaguru Devalkumar , Borgert Andrew , Polewski Peter James , Smith Angela
Published: January 2019

425

Background: Data guiding selection of optimal nonsurgical therapies for management of localized hepatocellular carcinoma (HCC) are lacking. Because there are limited prospective comparative data for these treatment modalities, we aimed to compare the effectiveness of chemotherapy (systemic or arterial directed) versus radiofrequency ablation (RFA) versus radioembolization (RE) in nonsurgically managed patients with stage I and II HCC using the National Cancer Database. Methods: We identified patients who received chemotherapy, RFA or RE for nonsurgically managed Stage I (T1N0M0) and II (T2N0M0) HCC between 2008 and 2013. Patients excluded included those who received upfront lobectomy or resection or extended lobectomy or hepatectomy or transplant, and if they had Ishak fibrosis score of 5-6 or total bilirubin > 3 mg/dl or international normalized ratio (INR) of > 3. Overall survival (OS) was compared between treatment groups using propensity score matched (1:1:1) and weighted analyses. We also verified balance of all available confounders, and assessed sensitivity to unobserved confounding. Results: Overall 2622 (73.2%), 837 (23.3%) and 125 (3.5%) patients with nonsurgically managed stage I and II HCC received chemotherapy, RFA and RE, respectively. RE treated patients tend to be older, live in the areas with a higher median income and higher percentage of high school- educated residents, and have stage II disease. The propensity matched cohort included 303 patients with baseline characteristics well balance between all arms. After propensity matching, 5-year OS was 17.4% (95% CI, 6.6% to 32.3%) in the chemotherapy group, 27.2% (95% CI, 14.2% to 42%) in the RFA group and 36.6% (95% CI, 23.1% to 50.1%) in RE group (p = 0.48). Conclusions: To our knowledge, this is the first study comparing various different nonsurgical therapies for localized HCC. All chemotherapy, RFA and RE are effective treatment options for nonsurgically managed patients with stage I and II HCC. Although these data are retrospective, RE appears to be a reasonable first-line treatment of nonsurgically managed stage I and II HCC in carefully selected patients.
Racial disparities in the initial treatment of hepatocellular carcinoma in the population 65+ years in the United States.
Authors: Costa Stephanie , Delgado David J. , Kaufman Michael Ross , George Brandon , Mitchell Edith P.
Published: January 2019

431

Background: Insufficient evidence exists regarding the initial management of elderly patients with hepatocellular carcinoma (HCC). The purpose of this study was to describe racial differences in initial treatment of 65+ year old patients with HCC diagnosed in the United States (2004-2014). Methods: A retrospective cohort study was conducted using the 1973-2014 Surveillance, Epidemiology and End Results Program (SEER) database of the National Cancer Institute. Patients with primary hepatocellular carcinoma, diagnosed between 2004 and 2014, and with complete information on race, gender, year of diagnosis, age, marital status, region, tumor status at diagnosis and initial treatment were included. Descriptive statistics were used to compare race with sociodemographic and clinical variables. Univariate and multivariate logistic regressions were performed to describe the association of race with receiving any treatment for HCC (local hepatic therapy and surgical treatment versus no treatment). Results: The sample consisted of 25,499 HCC patients: 70.0% White, 9.1% Black, 19.8% API, 1.0% AI; 68.6% male; 46.8% diagnosed in 2004-2009; 54.8% age 65-74, 45.2% 75 and older; 54.7% married, 7.3% Midwest, 13.8% Northeast, 15.7% Southeast; 81.3% first malignant primary indicator, 13.8% metastasis, 49.3% localized site, and 20.9% receiving initial treatment. After controlling for confounding variables, as compared to White patients, African American patients (OR:0.739 95% CI:0.652, 0.839) had decreased odds of receiving initial treatment; and Asian/Pacific Islander patients (OR:1.490 95% CI:1.371,1.618) had increased odds of receiving initial treatment. Conclusions: Racial disparities exist at the presentation of HCC in the 65+ population. African American patients are less likely to receive treatment and Asian/Pacific Islander patients are more likely to receive treatment. Further research is needed to understand these relationships in subpopulations.
Clinical outcomes of FOLFIRINOX and gemcitabine/nab-paclitaxel in the real world setting.
Authors: Franco Fernando Franco , Juan C Camara , Martin Valades Jose Ignacio , Marrupe David , Gutierrez Abad David , Leon Ana , Juez Ignacio , De Torres Maria Victoria , Sánchez-Ruiz Antonio Carlos , Bernal Elsa , Garcia Adrian Silvia , Moreno Diana , Cardena Ana , Hernández Roberto , Ruiz-Casado Ana
Published: January 2019

440

Background: The incidence of pancreatic cancer is increasing in developed countries. Though FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GNP) are associated with increased toxicity and are addressed to a well selected population, there seems to have been a rapid incorporation of these regimens in the real world. Overall survival (OS) was 11.1 months for FFX and 8.5 months for GNP. Survival rate at 18 m with FFX was 18.6%; at 24 m with GNP was 9%. Questions have arisen about external validity of original trials and how could these regimens impact overall survival since they are available nowadays for second line settings. Methods: This is a retrospective study. The Departments of Pharmacy of 5 Spanish hospitals generated the listings of patients (pts) treated in first line with the new regimens, namely FFX or GNP. To avoid bias related to non-prospective data collection, we restricted the analysis to survival data, serious toxicity and 2nd line options. Results: From Jan 2012 to Dec 2016, a total of 136 pts (M/F 52/48 %) were treated. Med age 63 y (38-83 y), 95% adenocarcinoma. 48% head of pancreas. ECOG 88% 0-1. 36 % locally advanced and 64% metastatic. 88% had liver mets. In the 1st line 64% were treated with FFX and 36% with GNP. 5 (3,7%) pts died in the first 3 months of treatment, because of infectious complications. 16 pts were operated after chemotherapy. 60% of the pts could receive a 2nd line (43% GNP, 25% FFX, 32% other). 27 pts (19.8%) were treated with a 3rd line. More pts treated with FFX required G-CSF (85% vs 15%). The median OS was 13 months with no differences between regimens. Survival rate at 30 months was 25% for both regimens. Elevated Ca 19.9 levels and Neutrophil-Lymphocyte ratio (NLR) increased the risk of death during the first-line. Conclusions: Originally reported OS is not only reproduced but improved in the real world despite a less strict inclusion of pts. 25% of patients remain alive 30 months after diagnosis. Superiority could not be demonstrated for any of the schemes. The availability of both regimens seems to dilute the potential differences and it is not so important the election of the 1st line. Both NLR and Ca 19.9 level predicted risk of death during the 1st line impairing the possibility of being treated in 2nd line.
ALBI-RT: A novel radiation therapy specific hepatotoxicity prediction model for hepatocellular carcinoma patients.
Authors: Schaub Stephanie K , Bowen Stephen R. , Chapman Tobias Robert , Nyflot Matthew J. , Apisarnthanarax Smith
Published: January 2019

444

Background: The albumin-bilirubin (ALBI) grade system was optimized to predict survival in hepatocellular carcinoma (HCC) patients; however, its applicability to patients treated with radiation therapy (RT) is unclear. We propose a novel analysis of the ALBI equation, designated ALBI-RT, to assess hepatotoxicity risk after RT. Methods: We retrospectively reviewed 48 consecutive HCC patients treated with RT (2013-2016). Raw ALBI values and Child-Pugh (CP) scores were calculated. Any patient deaths were examined for radiation induced liver disease (RILD). Raw ALBI was assessed as a continuous variable to perform ROC analyses to identify cutoffs for overall survival (OS) and RILD-specific survival (RILD-SS). Univariate predictors of OS and RILD-SS were evaluated using Cox regression to determine hazard ratios (HR). Results: Patient cohort was comprised of 60% CP-A and 39% CP-B/C. Median follow-up and OS was 13 and 10 months, respectively. There were 18 deaths with 6 ascribed to RILD. We identified a raw ALBI cutoff at -1.70 (AUC = 0.94, p = 0.008) that was predictive of RILD-SS with a sensitivity of 100% and specificity of 71%. Dichotimization of RILD-SS cutoff generated two ALBI-RT risk categories: low-risk A < -1.70 (n = 29) and high-risk B ≥ -1.70 (n = 18). ALBI-RT subdivided CP-A patients, identifying 14% at increased risk of RILD; conversely, ALBI-RT grade A identified 21% of CP-B/C patients at a decreased risk of RILD. For OS, raw ALBI as a continuous variable (HR 3.0, p = 0.02), and to a lesser degree ALBI-RT Grade B (HR 2.4, p = 0.06), performed similarly to traditional ALBI grade (HR 3.0, p = 0.01), and CP score (HR 1.4, p = 0.03). In contrast for RILD-SS, raw ALBI as a continuous variable (HR 25.1, p = 0.01) and ALBI-RT Grade B (HR 9.9, p = 0.04) were associated with an elevated relative risk of RILD than traditional ALBI grade (HR 5.8, p = 0.02) and CP score (HR 2.3, p = 0.003). Conclusions: ALBI-RT is a promising metric for pre-treatment assessment of HCC patients for predicting RILD-related death after RT with an elevated relative-risk compared to both CP and conventional ALBI grades. Future prospective evaluation and validation in independent data sets will strengthen the generalizability and utility of ALBI-RT.
Assessing the effectiveness of adjuvant chemoradiotherapy after cholecystectomy in patients with gallbladder cancer.
Authors: Van der Voort Grant McLeod , Martin Brendan , Thomas Tarita
Published: January 2019

455

Background: The study was conducted to compare the overall survival for patients receiving concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) or chemotherapy (CT) alone after cholecystectomy in patients with gallbladder cancer. Methods: Patients with gallbladder cancer who had surgical resection from 2004 to 2015 were identified in the National Cancer Database. The proportional hazards assumption for each predictor was assessed using Martingale residuals. Significance was then determined using univariable and multivariable Cox proportional hazards frailty models that allow for clustering of patients within their treatment facility type. Results: A total of 7,258 gallbladder cancer patients who had undergone cholecystectomy met eligibility criteria: 1,509 (20.8%) received CCRT, 283 (3.9%) received RT alone, 1,368 (18.9%) received CT alone, and 4,098 (56.5%) received no adjuvant therapy. The median survival for this patient sample was 29.11 months with median follow-up of 59.10 months. On multivariable analysis, the hazard of death at any given time for patients who received adjuvant CCRT following surgery was 20% (HR = 0.80, 95 CI: 0.73-0.87) lower than those who only underwent surgery alone (p < .0001). By contrast, the hazard of death at any given time for patients who received CT following surgery was 33% (HR = 1.33, 95 CI: 1.22-1.44) higher than those who only underwent surgery (p <.0001). Conclusions: CCRT is associated with improved OS compared with CT or RT alone after cholecystectomy in patients with gallbladder cancer, suggesting that adjuvant CCRT should be used in this population although prospective data is needed to validate these findings.
Markov decision analysis of neoadjuvant treatment pathway versus surgery first pathway for resectable pancreatic cancer.
Authors: Bradley Alison , McKay Colin , Jamieson Nigel , Dickson Euan , Carter Ross , Van der Meer Robert
Published: January 2019

456

Background: Surgery first (SF) versus neoadjuvant approach (NAT) to management of potentially resectable pancreatic ductal adenocarcinoma (PDAC) is controversial. This study is unique in utilizing institutional data to offer Markov decision-analysis of overall treatment pathways for resectable PDAC. Methods: An advanced Markov decision analysis model was constructed and populated with data from a retrospective institutional database. Patients presenting with resectable PDAC from 2008-2012 were included in the SF arm. Those presenting with resectable PDAC from 2012-2016 and treated within NAT pathway populated the NAT arm. Model uncertainties were tested with one and two-way deterministic sensitivity analysis and probabilistic Monte Carlo sensitivity analysis set to 1000 cycles with variables altered between highest and lowest observed values. Results: NAT pathway gave an additional 0.58 QALMs (22.43 vs. 21.85 QALMs). Monte Carlo analysis reported indifference between treatment strategies. One-way deterministic sensitivity analysis showed that probability of resection in the SF pathway must be greater than 0.82, or below 0.72 in NAT pathway, and probability of receiving adjuvant therapy above 0.6 to alter pathway superiority. Two-way deterministic sensitivity analysis demonstrated treatment superiority depended on resection rate in each pathway and receiving adjuvant therapy in SF pathway. Markov cohort analysis demonstrated superiority of neoadjuvant pathway (Table). Conclusions: Optimal treatment pathway remains debatable on an intention-to-treat Markov decision analysis. Markov cohort analysis of treatment received demonstrated benefit with NAT pathway. [Table: see text]
Prescribing patterns for FOLFIRINOX in the real world.
Authors: Guenther Chad Michael , Bhulani Nizar , Korenke Adam , Li Jenny Jing , Khosama Leticia , Syed Samira K. , Kazmi Syed Mohammad Ali , Cheedella Naga Koteswari , Karri Sirisha , Lohrey Jay , Sanjeevaiah Aravind , Verma Udit N. , Cox John Vernon , Arriaga Yull Edwin , Beg Muhammad Shaalan
Published: January 2019

463

Background: FOLFIRINOX therapy is associated with improved outcome in patients with gastrointestinal cancers. The regimen can be associated with significant toxicity and empiric dose modifications are often used. We analyzed 1) real-world prescribing patterns of FOLFIRINOX and 2) toxicity of therapy. Methods: Patients undergoing FOLFIRINOX chemotherapy at an academic, NCI-Designated Comprehensive Cancer Center were identified and electronic medical records reviewed. Patients who received at least one dose of FOLFIRINOX were included. Chemotherapy dose, growth factor use and toxicity data was abstracted for the first 8 weeks. ‘Standard FOLFIRNOX’ was defined as the regimen utilized by Conroy et al (NEJM 2011). Any empiric reduction/withholding of drug dose for cycle 1 was classified as ‘modified FOLFIRINOX’. Bivariate analysis was performed on the data. Results: There were 111 patients seen between 5/2011-3/2017 and 94% had pancreatic cancer. Age range was 29-87 years and 52% were female. 59% received ‘modified FOLFIRINOX’ and 20% received empiric growth factors. Line of therapy for standard vs modified respectively was 71.1% vs 45.5% for 1st, 17.8% vs 36.4% for 2nd, and 11.1% vs 18.2% for beyond 2nd (p = 0.03). Patients with ‘modified FOLFIRINOX’ were more likely to have metastatic disease (p = 0.01), have received second line or beyond, and higher ECOG score (p = 0.03). Patients with ‘modified FOLFIRINOX’ had a trend toward fewer treatment-related ED visits or hospitalization vs ‘standard FOLFIRINOX’ (27.2% vs 42.2% p = 0.10) and fewer treatment delays (25.8% vs 42.2% p = 0.07). Conclusions: In the real world setting, a majority of patients on FOLFIRINOX receive empiric dose modifications. Although modified dose did not translate to a significant difference in ED visits, hospitalizations or treatment delays, there was a trend toward fewer events.
The effect of socioeconomic factors on the outcome of hepatocellular carcinoma.
Authors: Sellers Cortlandt , Ludwig Johannes M , Uhlig Johannes , Stein Stacey , Taddei Tamar Hamosh , Kim Hyun S
Published: January 2019

466

Background: To investigate the impact of socioeconomic factors on overall survival (OS) for patients with hepatocellular carcinoma (HCC) at an inner-city tertiary care hospital. Methods: Consecutive patients treated for HCC diagnosed between 2005 and 2016 in the cancer registry were studied. Patients were stratified by demographic, socioeconomic variables and treatment course. Kaplan-Meier curves and Cox proportional hazard modeling were performed. Results: Patients were 79% male (770 pts) with mean age of 62.8 yrs (SD 10.2 yrs). 25% of patients (239 pts) had private insurance, 38% (363 pts) with Medicare, and 34% (239 pts) with Medicaid. Median OS stratified by primary insurance demonstrated a survival benefit for private insurance with 27.8 mo (95% CI 23.1–33.1) vs 21.0 mo (95% CI 16.5–26.5) for Medicare (HR 0.82, p = 0.0344) vs 13.3 mo (95% CI 10.2–19.7) for Medicaid (HR 0.80, p = 0.0002) (p = 0.0007). When further stratified by AJCC Stage, median OS in Stage II was 55.3 mo (95% CI: 32.4–67.1 mo) for private insurance vs 26.0 mo (95% CI: 18.7–36.3 mo) in Medicare vs 13.2 mo (95% CI: 9.0–38.1 mo) in Medicaid (p = 0.0309). Private insurance in Stage III had a median OS of 23.8 mo (95% CI: 10.9–39.8 mo) vs 14.6 mo (95% CI: 7.5–30.8 mo) in Medicare vs 6.7 mo in Medicaid (95% CI: 2.5–12.2 mo) (p = 0.0069). No differences were seen in Stage I and Stage IV. Cancer-directed treatments were utilized in 91% of private insurance vs 84% in Medicare vs 78% in Medicaid (p < 0.0001). Median OS stratified by marital status showed 23.7 mo (95% CI: 21.0–28.1 mo) for married (720 pts, 76%) vs 5.2 mo (95% CI: 9.6–20.1 mo) for never-married (227 pts, 24%) (p = 0.0009) (HR 1.4, p = 0.0013). Cancer-directed treatments were utilized by 87% of married vs 77% of never-married (p = 0.0016). Increased age was associated with decreased median OS (correlation -0.14, p < 0.0001). No differences in OS were seen with ethnicity or gender. Multivariate Cox proportional analysis demonstrated survival advantage for private insurance versus Medicaid (HR 1.3, p = 0.0435) and Medicare (HR 1.2, p = 0.0472). Conclusions: Primary insurance and social support appear to affect the OS of patients with HCC. Further investigations to elucidate the socioeconomic determinants to enhance survivals are warranted.
Modified CLIP score with albumin-bilirubin grade in relation to prognostic value in HBV-related hepatocellular carcinoma patients treated with transcatheter arterial chemoembolization therapy.
Authors: Cai Xiu-Rong , Chen Zhan-Hong , Lin Qu , Dong Min , Ma Xiao-kun , Chen Jie , Wen Jing-yun , Wu Xiang-yuan
Published: January 2019

480

Background: Child-Pugh grade is widely used to assess hepatic function reserve, but it is relatively subjective for assessment of hepatic encephalopathy. A newly developed scoring system combining albumin and bilirubin, called ALBI grade, aims to assess liver function objectively. In prognosis prediction of hepatocellular carcinoma (HCC), The Cancer of the Liver Italian Program (CLIP) score is commonly used in clinical practice and includes Child-Pugh evaluation. We substituted ALBI grade for Child-Pugh grade to establish ALBI-CLIP system and conducted this study to validate the prognostic value of ALBI -CLIP in HBV-related HCC patients after TACE therapy. Methods: We retrospectively analyzed HBV-related HCC patients who received TACE therapy. Baseline data were collected and evaluated. Child-Pugh grade and ALBI grade were integrated into CLIP and ALBI-CLIP systems, respectively. Univariate and multivariate analyses were conducted to identify independent prognostic factors for overall survival. Comparisons of receiver operating characteristic (ROC) curves and likelihood ratio test (LRT) were used to compare the value of ALBI-CLIP, CLIP and TNM staging systems in predicting survival. Results: A total of 207 patients were included. 153 (73.9%) and 54 (26.1%) patients were classified as Child-Pugh grade A and B, respectively. But according to ALBI grade, 57 (27.5%), 136 (65.7%) and 14 (6.8%) of them were correspondingly divided into Grade 1, 2 and 3. Comparisons of ROC curves showed that ALBI-CLIP and CLIP had similar areas under the curve, both of which were larger than that of TNM system in predicting 3-month, 6-month, 1-year and 2-year survival. LRT indicated that both ALBI-CLIP and CLIP had larger χ2 values and smaller values of Akaike information criterion (AIC), compared with TNM system (χ2 = 29.771, 29.479, 9.105; AIC = 858.215, 858.069, 879.410 for ALBI-CLIP, CLIP and TNM, respectively). Conclusions: Our current study suggested that modified CLIP score with albumin-bilirubin grade retained prognostic value in HBV-related HCC treated with TACE therapy.
Nivolumab in advanced hepatocellular carcinoma (HCC) and Child Pugh B (CPB) cirrhosis: Safety and clinical outcomes in a retrospective case series.
Authors: Kambhampati Swetha , Bauer Kelly , Hwang Jimmy , Bocobo Andrea Grace , Gordan John Dozier , Kelley Robin Kate
Published: January 2019

496

Background: HCC patients (pts) with Child Pugh B (CPB) cirrhosis have poor prognosis and limited treatment (Tx) options. Nivolumab demonstrated durable responses and acceptable safety in Child Pugh A (CPA) HCC in the CheckMate-040 trial with rates of hepatotoxicity similar to non-HCC populations. The safety and efficacy of nivolumab has not been established in pts with CPB cirrhosis. Methods: Design: Retrospective case series with IRB approval. Key eligibility: HCC with CPB cirrhosis; treated with nivolumab as standard Tx; enrolled in the UCSF Hepatobiliary Tissue Bank and Registry. Study endpoints: Safety during nivolumab Tx including all-cause grade(Gr) ≥ 3 adverse events (AE), serious AE (SAE), any grade immune-related (ir)AE, and systemic steroid (SS) requirement; clinical outcomes including time on Tx (TOT) with nivolumab and overall survival (OS). Results: Thirteen pts were included: male 77%; Asian 38%, white 54%; median age 66 (range: 26-86); HCV Ab+ 31%, HBsAg+ 23%; BCLC B/C 31%/69%; median Child-Pugh score 8; median prior systemic Tx 1 (range: 0-6); prior sorafenib 69%, median duration on prior sorafenib 137 days (range 10-341). The Table depicts safety outcomes on nivolumab. Median TOT on nivolumab: 44 days (95% CI: 32, 98) (range: 17-811+). Median OS from start of nivolumab: 119 days (95% CI: 40, 247) (range: 40-811+). Best response of at least stable disease occurred in 3/13 (23%) of patients, including prolonged stable disease (SD) for 6+ months and complete response (CR) for 24+ months on nivolumab (1 pt each). Conclusions: CPB HCC pts treated with nivolumab experienced high rates of all-cause Gr ≥ 3 AE and SAE and short OS, similar to prior studies in CPB HCC. Rates of irAE attributed to nivolumab were similar to rates reported in CheckMate-040 CPA population, without unexpected AE. A subset of pts experienced prolonged stable disease and CR. Nivolumab warrants further study in CPB HCC.[Table: see text]
RAINFALL: A randomized, double-blind, placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction (G-GEJ) adenocarcinoma.
Authors: Fuchs Charles S. , Shitara Kohei , Di Bartolomeo Maria , Lonardi Sara , Al-Batran Salah-Eddin , Van Cutsem Eric , Ilson David H. , Tabernero Josep , Chau Ian , Ducreux Michel , Mendez Guillermo Ariel , Molina Alavez Alejandro , Takahari Daisuke , Mansoor Wasat , Lacy Jill , Gorbunova Vera , Ferry David , Lin Ji , Das Mayukh , Shah Manish A. ,   For the RAINFALL Study Group
Published: January 2019

5

Background: Ramucirumab, a VEGFR-2 IgG1 human monoclonal antibody, is the only biologic with proven efficacy as both a single-agent and in combination with paclitaxel in the second-line treatment of G-GEJ adenocarcinoma. RAINFALL (NCT02314117) is a global, double-blind, placebo-controlled randomized clinical trial addressing the hypothesis that adding ramucirumab to first-line Cis plus Cape or 5-fluorouracil (5FU) produces significant clinical benefit. Methods: Metastatic G-GEJ cancer patients eligible for first-line chemotherapy with ECOG performance status 0-1 were randomized 1:1 to receive either RAM (8 mg/kg iv D1, D8) or placebo (PL), every 21d. All patients received Cape (or 5FU)+Cis. Cis was given for up to 6 cycles. Cape+RAM/placebo was continued until progressive disease, toxicity or other discontinuation criteria. The primary endpoint was progression-free survival (PFS) for the first 508 patients; overall survival (OS) for ITT population was a powered secondary endpoint. Results: 645 patients were randomized to receive RAM+Cape/Cis (n=326) or PL+Cape/Cis (n=319). PFS was significantly prolonged in patients treated with RAM+Cape/Cis versus PL+Cape/Cis (HR, 0.75; 95% CI 0.61–0.94; p=0.011; median, 5.7 vs 5.4 mos), meeting the primary endpoint. There was no survival benefit for patients treated with RAM+Cape/Cis versus PL+Cape/Cis (HR, 0.96; 95% CI 0.80–1.16; p=0.68; median, 11.2 vs 10.7 mos). ORR in the ITT population was 41.1% in the RAM arm (95% CI 35.8–46.4) and 36.4% (95% CI 31.1–41.6) in the PL arm. Grade ≥3 adverse events in ≥10% of patients in the RAM arm were: neutropenia (26.3% RAM; 27.0% PL), anemia (12.1% RAM; 14.0% PL), and hypertension (9.9% RAM; 1.6% PL). No new safety signals were observed. Conclusions: In treatment-naïve patients with metastatic G-GEJ adenocarcinoma, the addition of ramucirumab to first-line chemotherapy conferred a significant 25% reduction in the risk of disease progression or death in the primary endpoint of PFS; however, ramucirumab was not associated with an improved OS. Clinical trial information: NCT02314117.
An analysis of the efficacy and safety of direct oral anticoagulants (DOACs) in gastrointestinal cancer-associated venous thromboembolism (GI-CAVTE).
Authors: Recio Boiles Alejandro , Babiker Hani M. , Scott Aaron James , Malangone Steve , McBride Ali , Elquza Emad
Published: January 2019

505

Background: Two major trials and meta-analysis of patients (pts) with active cancer and VTE suggests that apixaban (A) and rivaroxaban (R) showed similar efficacy to enoxaparin and warfarin while having less associated major bleeding. GICA is associated with a higher incidence of VTE compared to other tumors. Moreover, bleeding complications of DOACs are not well defined in GICA pts. We compared the efficacy and safety of DOACs in pts with active GICA and VTE at the University of Arizona Cancer Center (UACC). Methods: A retrospective chart review of pts receiving DOACs with GICA and VTE treated at UACC was performed (11/2013-02/2017). GICA subgroup extracted from clinical trial delineations followed: active cancer, defined as cancer diagnosed at any stage +/- 6 months of VTE diagnosis. Efficacy outcomes were recurrent DVT, nonfatal pulmonary embolism (PE), or fatal PE. Safety outcomes for major bleeding were Hg drop of ≥2 g/dL, transfusion of ≥2 units of PRBC, bleeding in a critical site, or bleeding contributing to death. Fisher exact test is used for testing the difference in categorical variables for p-value < 0.05. Results: Our review included pts on A (n = 28) and R (n = 34). Pts had similar baseline characteristics compared to AMPLIFY (n = 81) and pooled-EINSTEIN (n = 71). Recurrent VTE at 6 months were 7.1% and 2.9% for pts on A and R, respectively. VTE historical comparison to AMPLIFY (3.7%) and EINSTEIN (2.8%) showed no significant difference. Major bleeding at 6 months were 7.1% and 14.7% for A and R, respectively, compared to 2.3% AMPLIFY / 2.8% EINSTEIN. R had the one recurrent non-fatal PE event and a significantly worse safety profile with 2 fatal bleeds (hemopericardium and upper GI bleed) and 2 critical bleeding sites (subarachnoid hemorrhage and retroperitoneal) [p = 0.0348], whereas A had non-significant of the before stated. Conclusions: To our knowledge, this is the first retrospective analysis to present long-term outcome data of DOACs in pts with GICA and VTE, which showed a similar risk of recurrent VTE and worse safety profile with R versus A. This data warrants further prospective clinical analysis of the efficacy and safety of DOACs in pts with GICA and VTE.
Postoperative proton therapy for pancreatic cancer patients enrolled on the Proton Collaborative Group (PCG) registry.
Authors: Nichols Romaine Charles , Morris Christopher G. , Prabhu Kiran , Hartsell William F. , Cahlon Oren , Apisarnthanarax Smith , McGee Lisa , Vargas Carlos E.
Published: January 2019

513

Background: The PCG registry is a multicenter registry for patients receiving proton therapy for various malignancies. The current abstract reviews the outcomes for patients receiving postoperative proton therapy for resected pancreatic cancer. Methods: From March, 2013 to August,2016 18 patients with resected pancreatic adenocarcinoma received postoperative proton therapy. The current study reviews the pretreatment characteristics and outcomes of these patients. Results: Median age -70 years (range 52 to 79); Males 12, Females 6; pT Stage -T2–4, T3–13, T4–1; N Stage -N1–12, N0–6; Margin Status -Close-8, Positive-4, Negative-6; Surgical approach -open-16, laparoscopic 2; Operations performed: standard pancreaticoduodenectomy-11, pylorus sparing pancreaticoduodenectomy-4, total pancreatectomy-1; Pancreaticoduodenectomy with portal vein reconstruction –1; Pancreaticoduodenectomy with irreversible electroporation. Median lymph nodes taken-16.50 (range 3 to 72); Median lymph nodes positive-1.5 (range 0 to 7); PNI positive-9, PNI negative-2, PNI unknown-4; LVI positive-7, LVI negative-6, LVI unknown-5; Median tumor size –3.1cm (range 2.2 to 6.2); Median dose delivered –50.51Gy(RBE) (range 27.88 to 54.00); Median treatment duration –38 calendar days (range 25 to 48); One patient died during treatment. One additional patient demonstrated grade 3 toxicity (anorexia, nausea, diarrhea). Only one patient’s treatment was protracted by more than 5 days. Median available follow up is 1.1 years (range 0.07 to 3.4 years); 2 year survival 37%. Conclusions: Postoperative proton therapy after pancreatectomy was well tolerated without treatment interruption or severe toxicity.
Natural history of small nonfunctioning pancreatic neuroendocrine tumors.
Authors: Choi Jin Ho , Lee Sang Hyub , Choi Young Hoon , Kang Jinwoo , Paik Woo Hyun , Ryu Ji Kon , Kim Yong-Tae
Published: January 2019

515

Background: Asymptomatic sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are rare disease but are diagnosed more frequently than before. The aim of this study was to evaluate the natural course of small NF-PNETs. Methods: We performed retrospective study of patients with suspected NF-PNETs from 1999 to 2015. Patients older than 18 years with NF-PNETs diagnosed either by pathology or other clinical evidences were included. Patients with clinical symptoms of hormonal hypersecretion, more than 20 mm in size, local invasion, nodal or distant metastasis, less than two follow-up imaging studies , and follow-up period of less than 6 months were excluded. Results: Small NF-PNETs in patients initially recommended surveillance (n = 69; mean age, 58.9 ± 11.1 yrs) were mainly located in the pancreatic head (n = 32, 46.4%) with mean mass size of 10.9 ± 3.1 mm. The average follow-up period was 52.2 ± 38.7 months. Tumor size changes during the follow-up period were as follows: increased (n = 9, 13.0%), sustained (n = 58, 84.1%), decreased (n = 2, 2.9%). The mean growth rate of increasing tumor was 0.9 ± 2.9 mm/year. Non-hypervascular tumors showed a tendency to increase in size compared to hypervascular tumor. (P = 0.04) Thirteen patients (18.8%) underwent surgery during the follow-up at average 32.9 ± 42.6 months later. According to the WHO 2010 grade classification, grade 1 was found in 18 patients, grade 2 in 1 patient, and grade 3 in 0 patient. The pathologic AJCC TNM stages of surgically resected tumors were Ia in 7 patients, Ib in 1 patient, IIa in 2 patient, IIb in 1 patients. Two patients (10.0%) received reoperation for recurred tumors at 34 and 50 months after surgery. Two patients (2.9%) showed distant metastasis after surgery but no disease-related death occurred. Conclusions: Most of small NF-PNETs do not increase in the size and seldom show metastasis during follow-up. Wait-and-see strategy can be applied for NF-PNETs less than 2cm in size.
The clinicopathologic features and optimal surgical treatment of duodenal gastrointestinal tumor.
Authors: Lee Seungjae , Song Ki Byung
Published: January 2019

519

Background: Because of unclear clinicopathologic features, the optimal surgical procedure for duodenal gastrointestinal stromal tumor (GIST) remains poorly defined. We analyze clinicopathological features and recommend optimal surgical treatment of duodenal GIST. Methods: From July, 2000 to April 2017, 118 patients who had localized duodenal GIST were treated by curative surgical resection at a single institution. We retrospectively reviewed the clinicopathological characteristics and survival outcomes. Results: In survival analysis of all patients, 5-year overall survival (OS) and disease-free survival (DFS) rate were 94.9 and 79.2%, respectively. 19 patients developed recurrent disease at a median of 26.1 months from surgery and most common recurrence site was liver (63.2%). In multivariate analysis, mitotic count was the statistically significant prognostic factors of DFS. Our 20 cases of duodenal GIST in 1st or 4th portion were completely resected by limited resection(LR), regardless of tumor size. 98 patients with GISTs in 2nd or 3rd portion of duodenum underwent LR (n = 53) or pancreaticoduodenectomy (PD) (n = 45). Patients in the LR group had a smaller median tumor size (4.0 vs 5.3 cm, p = 0.026), more antimesenteric-sided location (41 vs 7cases, p < 0.001), less late complications (1 vs 7 cases, p = 0.014) and no postoperative newly developed diabetes mellitus (0 vs 4 cases, p = 0.027) than those in the PD group. When 53 patients in LR group further divided into minimal invasive LR (MILR) (n = 12) and open-LR (n = 41), MILR group had shorter operation time (155.0 vs 218.8 minutes, p = 0.013) and postoperative hospital stay (12.0 vs 19.4 days, p = 0.036). Conclusions: Patients with duodenal GIST who underwent complete surgical resection have favorable survival outcomes. Predictor of disease recurrence at multivariate analysis was mitotic count. LR is feasible and effective surgical treatment for the patients with small-sized, and anti-mesenteric sided duodenal GIST in terms of long-term oncologic outcomes and quality of life. MILR has better perioperative outcomes than open LR. Therefore, we should consider MILR as optimal surgical treatment for the selected patients with duodenal GIST.
Health-related quality-of-life (HRQoL) results from the FAST study: A phase II trial of epirubicin, oxaliplatin, and capecitabine with or without IMAB362 in patients with advanced CLDN18.2+ gastric and gastroesophageal junction adenocarcinoma.
Authors: Morlock Robert , Turnbull James , Blahut Steven , Krukas-Hampel Michelle R , Hawryluk Emily , Tureci Özlem
Published: January 2019

54

Background: In the FAST study, IMAB362 (loading dose 800 mg/m2 then 600 mg/m2 d1 qd21) plus EOX (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 d1, and capecitabine 625 mg/m2 bid) was compared with EOX alone in patients with advanced/metastatic gastric (GA), gastroesophageal (GE), and gastroesophageal junction (GEJ) adenocarcinoma. The FAST study exhibited a clinically relevant benefit in PFS and OS with a manageable safety profile in patients treated with IMAB362. Here we present the HRQoL results from the FAST study. Methods: CLDN18.2-positive patients (intermediate/strong membrane staining in ≥40% of cells) with advanced/metastatic GA/GE/GEJ adenocarcinoma were randomized 1:1 to first-line EOX for a maximum of 8 cycles with or without 600 mg/m2 q3w IMAB362, which after 8 cycles could be continued as monotherapy until disease progression (DP). The EORTC QLQC30 and a gastric cancer specific measure EORTC STO22 were collected at baseline (BL), Cycle 5, end of EOX therapy (EOT) and post-EOT every 12 weeks until DP. Change from BL in EORTC scores over 8 cycles of EOX treatment were analyzed using mixed model repeated measures. Time to deterioration in HRQoL was defined as time from randomization to first minimally clinically important difference (MCID) decline in each HRQoL domain. Results: The HRQoL analysis included 74 EOX and 68 IMAB362 + EOX per protocol patients. There were no significant differences in mean changes from BL in EORTC QLQC30 Global Health Status/QoL Score and STO22 Total Score across the 8 cycles of treatment with EOX. The QLQC30 Nausea and Vomiting domain showed a statistical difference (p = 0.0108) in favor of EOX-only. The median time to first HRQoL MCID deterioration for the QLQC30 Global Health Status was 8.6 mo for EOX + IMAB362 and 6.0 mo for EOX alone (p = 0.008). For patients who remained on IMAB362 post EOT, HRQoL improved from BL. Conclusions: HRQoL was maintained for a longer duration in pts with advanced/metastatic GA/GE/GEJ adenocarcinoma who received EOX + IMAB362 therapy vs EOX alone. HRQoL post EOT was improved for EOX + IMAB362 therapy vs EOX alone. Clinical trial information: NCT01630083.