bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adjuvant therapy for margin positive pancreatic cancer.
Authors: Takahashi Caitlin , Shridhar Ravi , Harris Cynthia L. , Lee Justin , Patel Anjan Jayantilal , Brown Richard H. , Huston Jamie , Kucera Stephen , Meredith Ken Lee 
Published: January 2019

390 Background: Pancreatic cancer continues to have a dismal prognosis despite improvements in surgical care. Approximately 26% of patients are deemed resectable, and at the time of operation, 28% will have R1 resections. Adjuvant chemotherapy (AC) or chemoradiation (CRT) is recommended, however the magnitude of benefit is unclear. We sought to examine the impact these therapies on R1 resected pancreatic cancer. Methods: Utilizing the National Cancer Database we identified patients who underwent pancreatic resection for adenocarcinoma. Patients were stratified by resection status and adjuvant therapy. 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 28,440 patients: 22,005 (77.4%) underwent R0 resections and 6,435 (22.4%) underwent R1 resections with a median age of 67.5 years (18-90) and median tumor size of 3.1 cm (2.4-4.2). Patients with tumor size >2cm were more likely to undergo R1 resections, p<0.001. Within the R1 resection group, AC was administered in 1,802 (19.4%), CRT 2,153 (28.5%), and no adjuvant therapy (NA) 2,480 (21.4%). Adjuvant therapy improved survival in all patients with median and 5-year survival of: AC (21.7 months, 17.45%), CRT (23.3 months, 20.9%) vs NA (19.5 months, 19.1%), p<0.001. In the R1 resection cohort survival was also improved with adjuvant therapy with CRT demonstrating the most significant improvement: AC (15.9 months, 6.5%), CRT (18.7 months. 11.2%) vs NA (12.5 months, 8.7%), p<0.001. Additionally CRT but not AC improved survival in the R1 node negative, p<0.004, and node positive, p<0.001. AC benefited survival in R1 node positive patients, p<0.001. MVA revealed age, tumor grade, tumor size >2cm, T-stage, N-stage, AC, and CRT were predictive of survival. Conclusions: Patients with pancreatic cancer who undergo R1 resection have significant improvement in survival when treated with adjuvant CRT and AC. However, benefits were greater in those receiving adjuvant CRT.
Stereotactic body radiotherapy for hepatocellular carcinoma in patients with poor liver function.
Authors: Chan Jason , Behr Spencer , Pai Jonathan , Feng Mary Uan-Sian , Chang Albert , Haas-Kogan Daphne A. , Anwar Mekhail 
Published: January 2019

397 Background: Stereotactic body radiation therapy (SBRT) may benefit patients with hepatocellular carcinoma (HCC) who are not candidates for other liver-directed therapies due to poor liver function (plf). However, optimal patient selection, safety, and efficacy of SBRT in plf-HCC patients are not known. We studied dosimetric, baseline liver function, and radiographic features at the time of treatment that may help identify HCC patients with liver dysfunction who would benefit most from SBRT. Methods: Medical records of plf-HCC patients with cirrhosis treated with SBRT at a single institution between 2013-2016 were reviewed. Prescription doses were tailored to liver function based on INR and total bilirubin (tBili) and uninvolved liver volume. Time to local progression was evaluated using cumulative incidence analysis (Gray’s test) and competing risks regression analysis. Local progression was defined using RECIST criteria. Overall survival was estimated using the Kaplan-Meier method and Cox proportional hazards model. Results: 26 plf-HCC patients with median baseline MELD 11 (range 1-35), tBili 1.6 (0.5-6.5), INR 1.2 (1.0-9.0), tumor size of 4.1 cm (1.7-8.5 cm), and liver volume 1251 cc (596-2322 cc) were treated with SBRT. 54% received SBRT for retreatment of the same tumor. Patients were heavily pretreated with 50%, 19%, and 8% previously receiving TACE, ethanol ablation, and RFA, respectively. With a median prescription of 30 Gy (8-50 Gy) in 5 fractions (2-5), the median liver dose was 8 Gy (3-14 Gy). Median increase in MELD 90 days post-SBRT was 1.1 (0-19), with 35% experiencing no increase and 25% increasing >2.5. Local control (LC) was 55% at 6 months with one patient bridged to liver transplant. LC was not associated with improved survival (p = 0.39) and median overall survival (MS) was 8.6 months (0.9-31.7 mo). However, longer MS was seen for patients without ascites (MS=16.5 vs. 4.1 mo, p = 0.005), tBili < 2 (MS=16.5 vs. 5.2 mo, p = 0.015) and MS was not reached in patients treated to > 30 Gy (p = 0.04) or with MELD < 11 (p = 0.02). Conclusions: In this cohort of HCC patients with poor liver function, the absence of ascites, tbili < 2, and lower MELD scores were associated with improved survival following SBRT.
Final report: A phase I trial of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and metastatic pancreatic cancer.
Authors: Soares Heloisa P. , Al-Toubah Taymeyah E. , Kim Richard D. , Kim Jongphil , Lewis Neron K , Mahipal Amit 
Published: January 2019

398 Background: The PI3K/mTOR pathway has emerged as a potential target for anticancer therapy. Considerable evidence suggests that targeting a single isoform of PI3K (p110α) would have sufficient antitumor activity and improved therapeutic window. Further, PI3KCA mutations, gene encoding isoform p110α, are described in pancreatic adenocarcinoma (PAC). BYL719 is an oral class I α-specific PI3K inhibitor that showed preclinical anti-tumor activity. The first in human phase 1 trial of BYL719 defined the maximum tolerated dose (MTD) at 400mg QD. Methods: This was a phase I, single center study (standard 3+3 design). The primary objective was to determine the MTD of BYL719 in combination with gemcitabine (G) and nab-paclitaxel (nabP) as frontline therapy in locally advanced or metastatic PAC. BYL719 was given orally daily (Table). Patients (pts) were restaged q2 cycles. The study was closed prematurely due to slow accrual. Results: Fifteen pts were enrolled (median age was 58 years). Three pts each participated in cohorts 1 and 2. Nine pts were enrolled in cohort 3, but 4 were replaced (3 pts withdrew consent prior to evaluation and 1 missed > 10 days of treatment). One pt in cohort 3 had DLT related to grade 3 nausea and vomiting. A total of 19 grade 3 and 4 adverse events were records as probably or possibly associated with BYL719. The most common ones were hyperglycemia, anemia, and neutrophil count decreased. One pt developed Posterior reversible encephalopathy syndrome (PRES) during cycle 7. Although we could not completely exclude BYL719 as a cause, PRES was attributed to G. One pt had sudden death during cycle 4 that was attributed to progression. Only 8 pts were evaluable for response. Two had stable disease, 5 had partial responses and 1 had progression. The median progression-free survival and overall survival were 5.36 months (1.6 to 10 months) and 8.74 months (3.8 to 21.2 months) respectively. Conclusions: The combination of full doses of G + nabP and BYL719 can be safely administered up to BYL dose of 250 mg/day. Clinical trial information: NCT02155088. [Table: see text]
Intraperitoneal immunotherapy with the bispecific anti-EpCAM x anti-CD3 directed antibody catumaxomab for patients with peritoneal carcinomatosis from gastric cancer: Final results of a randomized phase II AIO trial.
Authors: Lordick Florian , Kunzmann Volker , Trojan Jorg , Daum Severin , Schenk Michael , Kullmann Frank , Schroll Sebastian , Behringer Dirk M. , Stahl Michael , Al-Batran Salah-Eddin , Ibach Stefan , Koerfer Justus , Knoedler Maren Kristina 
Published: January 2019

4 Background: The peritoneal surface is a common location for metastases in gastric cancer (GC). Intraperitoneal (i.p.) application of the bispecific (anti-EpCAM/CD3) monoclonal antibody catumaxomab (CATU) in addition to i.v. chemotherapy may improve elimination of peritoneal carcinomatosis (PC). Methods: This randomized open-label phase II study aimed to investigate the efficacy of i.p. CATU following i.v. chemotherapy in patients (pts) with GC and PC (Gilly stages P1-4). Pts were randomly allocated to receive four cycles of FLOT (5FU, LV, Oxaliplatin, Docetaxel) followed by i.p. CATU at escalating doses (10, 20, 50, 150µg) on days 0, 3, 7, 10 or FLOT alone. Secondary gastrectomy and peritonectomy were allowed to achieve complete resection of all malignant lesions. The primary endpoint was to show an increased rate of macroscopic complete remission of PC at second-look surgery. Secondary endpoints included toxicity, progression-free and overall survival (PFS/OS). Results: Of 35 pts screened, 31 were enrolled. Median follow-up time is 52 months. 15 pts were allocated to FLOT-CATU (arm A) and 16 to FLOT alone (arm B). Complete remission rate of PC was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects with i.p. CATU were nausea (15%), fever (23%), abdominal pain (31%), and elevated liver enzymes (gGT 31%, bilirubin 23%). Adverse events tended to be more common during FLOT-CATU compared to FLOT alone. Median PFS was not significantly different in both arms with 6.7 months in arm A compared to 5.4 months in arm B (p = 0.71). Median OS was 13.2 and 13.0 months. Conclusions: Addition of i.p. CATU as part of a multimodal treatment approach revealed feasible and tolerable in pts with GC and PC. Although the primary endpoint was not met, the results are promising for future trials investigating i.p. immunotherapy in this patient population. Clinical trial information: NCT01504256.
Surrogacy of time to prgression for overall survival in advanced hepatocellular carcinoma treated with systemic therapy: A systematic review and meta-analysis of randomized controlled trials.
Authors: Terashima Takeshi , Yamashita Tatsuya , Arai Kuniaki , Toyama Tadashi , Kawaguchi Kazunori , Kitamura Kazuya , Yamashita Taro , Sakai Yoshio , Mizukoshi Eishiro , Honda Masao , Kaneko Shuichi 
Published: January 2019

403 Background: Time to progression (TTP) is widely used as the endpoint in early-phase trials for advanced hepatocellular carcinoma (HCC). However, the relevance of using TTP as a surrogate marker for overall survival (OS) in pivotal trials remains uncertain. Methods: The PubMed database and ASCO meeting library were searched for reports of randomized controlled trials that investigated patients with advanced HCC, included data for both OS and TTP, and were launched between 2009 and 2016. Correlation between hazard ratios (HRs) for TTP and OS was determined using weighted linear regression. Correlations between median OS and TTP, and between median OS and post-progression survival (PPS), defined as the period obtained by subtracting median TTP from median OS, were also evaluated. Results: The database search yielded 24 trials with 50 arms. Overall, TTP HR correlated with OS HR (R = 0.73); however, the coefficient in the regression equation was 0.48. When trials were stratified by treatment line, TTP HR was more strongly correlated with OS HR in second-line (R = 0.91) than in first-line (R = 0.77) settings. Correlation between median OS and median TTP was weak (R = 0.50), whereas the correlation between median OS and median PPS was strong (R = 0.78). Conclusions: In advanced HCC, the OS HR can be predicted from the TTP HR, especially in second-line trials, which is useful when considering whether to proceed to a pivotal trial based on the results of early-phase trials. However, TTP may not be appropriate as a primary endpoint in a pivotal trial if the trial aims to evaluate the survival benefit of novel agents because improvement of TTP cannot fully reflect improvement of OS because of the impact of PPS on OS.
A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma (PDAC) (MOBILITY-002 Trial, NCT02428270).
Authors: Aung Kyaw Lwin , McWhirter Elaine , Welch Stephen , Wang Lisa , Lovell Sophia , Stayner Lee-Anne , Ali Saara , Malpage Anne , Makepeace Barbara , Ramachandran Makilpriya , Dhani Neesha C. , Hedley David W. , Knox Jennifer J. , Siu Lillian L. , Goodwin Rachel Anne , Bedard Philippe L. 
Published: January 2019

409 Background: MEK (mitogen-activated protein kinase kinase) is activated through mutated KRAS in > 90% of PDAC. Focal adhesion kinase (FAK) integrates signals from integrins and growth factor receptors. MEK and FAK are frequently co-activated in PDAC providing a rationale for dual inhibition with GSK2256098, an oral FAK inhibitor, and trametinib, an oral allosteric MEK1/2 inhibitor. Methods: Patients with advanced PDAC patients who progressed after first line chemotherapy were treated with GSK2256098 250mg twice daily and trametinib 0.5mg once daily in 28 day cycles. The primary endpoint was antitumor activity measured by clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks) by RECIST 1.1. We planned to enrol 24 patients using a 2-stage minimax design (p0 = 0.15, p1 = 0.40; alpha = 0.05, power 0.86). The combination would be considered active if > 7/24 response-evaluable patients achieved CB; and inactive if 2/12 or fewer patients achieved CB at the end of stage 1. Response assessment was performed every 2 cycles. Results: Between June/16 and June/17, 16 patients were enrolled. Five were not evaluable for response. Of 11 evaluable patients, 10 had PD as best tumor response and one had SD for 4 months. One response unevaluable patient who had rapidly progressed on 1st line FOLFIRINOX chemotherapy with a basal-like tumor by RNA-sequencing and KRAS amplification achieved clinical stability for 5 months with a > 50% decline in serum CA19-9 after 3 months of treatment and symptomatic improvement. No treatment related Grade≥3 adverse events (AEs) were observed. The most common treatment related grade 2 AEs were acneiform rash (19%), diarrhea (13%), nausea (6%), fatigue (6%), proteinuria (6%), paronychia (6%), and retinal detachment (6%). The median progression free survival was 1.6 (95% CI 1.5-1.8) months and the median overall survival was 3.6 (95% CI 2.7-not reached) months. Conclusions: GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC. Correlative studies are ongoing to evaluate RNA-expression subtypes and dynamic markers of pathway inhibition from serial tumor biopsies and cell free DNA. Clinical trial information: NCT02428270.
Safety and tolerability of 5-FU, irinotecan (IRI), and nab-paclitaxel (FOLFIRABRAX) with genotype-guided dosing of IRI in previously untreated patients with advanced gastrointestinal (GI) malignancies.
Authors: Joshi Smita Suhas , Karrison Theodore G. , Catenacci Daniel V.T. , Peterson Jaclyn D , Zalupski Mark , Phillips Brooke Elizabeth , Sadiq Ahad Ali , Sehdev Amikar , Wade James Lloyd , Picozzi Vincent J. , Amico Andrea Louise , Kozloff Mark , Polite Blase N. , Kindler Hedy L. , Sharma Manish 
Published: January 2019

423 Background: 5-FU, IRI, and nab-paclitaxel (NP) are active in advanced GI cancers; the combination (FOLFIRABRAX) has not been evaluated. UGT1A1 clears SN-38, the active metabolite of IRI. UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. Dose adjustment in patients with this allele may be warranted. Primary objective: to determine the dose-limiting toxicity (DLT) rate of FOLFIRABRAX with genotype-guided dosing of IRI. Secondary objectives included determining objective response rates (ORR) in GI cancers. Methods: Pts with previously untreated GI cancers and ECOG performance status 0/1 received FOLFIRABRAX with prophylactic pegfilgrastim Q14 days. CT scans were obtained Q8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 patients (pts) received initial IRI doses of 180, 135, and 90mg/m2, respectively. 5-FU 2400mg/m2 over 46 hours (no bolus), leucovorin 400mg/m2, and NP 125mg/m2 were given IV Q14 days. DLT during cycle 1 was defined as Grade (Gr) 3/4 febrile neutropenia (FN), Gr 4 neutropenia ≥ 5 days, Gr 3/4 non-hematologic toxicity despite medical management, or treatment delay > 14 days due to toxicity. Doses were tolerable if DLT rate during cycle 1 was ≤ 35%. Enrollment of 17 pts per genotype would allow for an α level of 0.05 with 80% power under a sequential toxicity monitoring procedure, with 6 or fewer DLTs being tolerable. Results: 39 pts are evaluable for toxicity: 23 pancreatic cancer (PC), 6 gastroesophageal cancer (GE), 9 biliary tract cancer (BTC), 1 neuroendocrine. DLTs were observed in 4/20 (20%) *1/*1 pts, 1/15 (7%) *1/*28 pts, and 0/4 *28/*28 pts. DLTs were Gr 3 diarrhea (2 pts), Gr 3 nausea (2), and Gr 3 FN (1). ORR is 6/29 (21%), with responses in PC (3/17 evaluable pts, 18%) and GE (3/5 pts, 60%), but no responses in BTC (0/7 pts). Conclusions: FOLFIRABRAX with genotype-guided dosing of IRI is tolerable in pts with advanced GI cancers and UGT1A1*1*1 or UGT1A1*1*28 genotypes. There is activity in PC and GE but not in BTC. Accrual is ongoing to the 3 genotype cohorts to a goal of 51 pts. Study conducted by the University of Chicago Personalized Cancer Care Consortium Clinical trial information: NCT02333188.
Comparative efficacy and safety of sorafenib in elderly versus non-elderly patients with advanced hepatocellular carcinoma (HCC) with varying liver dysfunction.
Authors: Arora Sukeshi Patel , Ketchum Norma S. , Gelfond Jonathan , Michalek Joel , Mahalingam Devalingam 
Published: January 2019

430 Background: Sorafenib is the only FDA-approved systemic therapy for advanced HCC. The incidence of HCC increases with age, peaking above 70 years; however, we have limited efficacy and safety data in the elderly. Given the prevalence of HCC in South Texas, we assessed the efficacy and safety of sorafenib in the elderly. Methods: Retrospective analysis of HCC patients (pts) receiving sorafenib from 2008-2013. PFS and OS were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events version 4.0. Differences between age groups (65+, < 65) for dose reduction (yes, no), and AEs were analyzed using Fisher’s Exact Test. Results: A total of 118 pts were included. Median age 57 (range 41-93; 65+ 26%). males 81%. Hispanic 73%, Non-Hispanic White 24%. ECOG PS 0–1 93 %. Causes of cirrhosis: Hepatitis C 66%, Hepatitis B 4%, EtOH 58%. Portal vein thrombosis 36%, Extrahepatic disease 38%. Child-Pugh score: A 56%, B 44%. BCLC class: B 13%, C 87%. Among 113 pts 34% were started at 400 mg daily versus 66% started at 800 mg daily. mOS was 11.2 months (mo) (95% CI: 7.8-14.0), mPFS 5.2 mo (95% Cl: 3.9-7.1). In subgroup analysis, mOS for < 65 was 10.2 mo vs 13.5 mo for 65+ (HR 0.67, 95% CI: 0.39-1.16, p = 0.15). mPFS for < 65 was 4.6 mo vs 6.2 mo for 65+ (HR 0.92, 95% CI: 0.58-1.45, p = 0.71). Among 109 pts, dose reductions in < 65 vs 65+ were 64.6 vs 70% (P = 0.66); survival differences were not statistically significant. Among 75 pts there was a trend to improved survival in 65+ patients with AST/Platelet Ratio (APRI) < / = 1.68, but not statistically significant. Sorafenib was tolerated in the elderly. In regards to nausea, fatigue, diarrhea and hand foot syndrome, difference in toxicity was not statistically significant in < 65 versus 65+. Conclusions: In advanced HCC, elderly pts should be offered sorafenib, as it has efficacy and is tolerated in the elderly. Further prospective studies in the elderly are warranted, with evaluation of APRI as a prognostic marker.
A pilot study of vinorelbine safety and pharmacokinetics (PKs) in patients (pts) with varying degrees of liver dysfunction (LD).
Authors: Gong Jun , Cho May Thet , Gupta Rohan , Synold Timothy W. , Frankel Paul Henry , Ruel Christopher , Fakih Marwan , Chung Vincent M. , Lim Dean , Chao Joseph 
Published: January 2019

432 Background: Prospective data to support dosing guidelines for intravenous (IV) vinorelbine in pts with LD are limited. One study recommends standard 30 mg/m2 weekly for total bilirubin ≤2 mg/dL and a 50% dose reduction for bilirubin > 2 mg/dL. Another study recommends no dose modifications for bilirubin up to 3X the upper limit of normal (ULN). This phase I study describes the safety and PKs of vinorelbine in pts with varying degrees of hepatic impairment. Methods: Pts with treatment-refractory solid tumors received weekly IV 30 mg/m2 vinorelbine for normal liver function, 20 mg/m2 for mild LD defined as bilirubin < 1.5 mg/dL but aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 1.5-2.5X ULN or alkaline phosphatase (ALK) 1.5-3X ULN, 15 mg/m2 or 30 mg/m2 for moderate LD defined as bilirubin 1.5-3.0 mg/dL and/or AST/ALT > 2.5 or ALK > 3X ULN, and 7.5 mg/m2 or 20 mg/m2 for severe LD defined as bilirubin > 3.0 mg/dL. Vinorelbine PKs were evaluated to describe its relationship with liver function. Results: 47 patients were enrolled (61.7% gastrointestinal and hepatobiliary cancers) and a total of 248 treatment-related adverse events (AEs) occurred. All-grade myelosuppression was the most common AE overall (41.1%). Out of 71 grade ≥3 AEs, 17 (23.9%) were grade 4 in severity with the majority (15/17) being myelosuppression. Rates of grade 4 hematologic AEs in the normal liver function and the 7.5 mg/m2 severe LD group were low ( < 10%). 4/17 grade 4 hematologic AEs were observed in the mild LD group while the remainder and majority occurred in the moderate-severe LD groups. Vinorelbine PKs were not correlated with the degree of LD, however free drug levels or levels of the active metabolite 4-O-deacetylvinorelbine were not measured. Conclusions: Weekly vinorelbine at 30 mg/m2 and 7.5 mg/m2 appears safe with normal liver function and severe LD, respectively. High rates of grade 4 myelosuppression with 15-30 mg/m2 vinorelbine in moderate-severe LD raise concerns for its safety in this population. Vinorelbine PKs are not affected by LD. However, it is possible that levels of the active metabolite could be higher in pts with LD if its elimination is impacted by LD to a greater extent than the parent drug. Clinical trial information: NCT00540982.