bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline anemia in patients with biliary tract cancer (BTC) and its association with survival: A retrospective cohort study.
Authors: Doherty Mark , Moignard Stephanie , Sapisochin Gonzalo , O'Kane Grainne M. , McNamara Mairead Geraldine , Horgan Anne M. , Jang Raymond Woo-Jun , Hedley David W. , Dhani Neesha C. , Knox Jennifer J.
Published: January 2019

426

Background: The prognostic significance of anemia in BTC is unknown, but is common and may be multifactorial; data regarding its causes are limited. This study interrogated a large institutional database to examine the effect of anemia on overall survival (OS) in BTC, and explore factors associated with anemia. Methods: This Princess Margaret Cancer Centre cohort study included patients with BTC with available baseline hemoglobin (Hb) (1987-2016). Anemia was defined as Hb < 132 mg/dL for men > 60 years, < 137mg/dL for men aged 20-59, and < 122mg/dL in women. Additional relevant covariates were included in multivariable Cox regression for OS, and linear regression for association with Hb. Results: Of 1398 patients included, 711 (51%) were anemic at baseline (mean Hb 112 mg/dL). Anemic versus non-anemic patients were older (median age 66 vs 64 yrs, p = 0.006), had worse ECOG PS (12% ECOG 2-3 vs 6%, p < .001), BMI < 20 (31% vs 27%, p = 0.006) and elevated neutrophil:lymphocyte ratio (NLR), (64% vs 47%, p < .001), but cancer staging was not significantly different. Anemia was associated with shorter OS on univariate (HR 1.35, p < .001) and multivariable (HR 1.39, p < .001) regression (Table). Factors associated with lower Hb included older age, male gender, worse ECOG PS, tumor site, thrombocytopenia, elevated NLR. Conclusions: Baseline anemia was associated with shorter survival following diagnosis of BTC, independent of tumor stage or ECOG PS. Clinicians should be aware of this prognostic marker; validation in prospective datasets is warranted. [Table: see text]
Second-line chemotherapy in patients with advanced biliary tract cancer.
Authors: Takahara Naminatsu , Nakai Yousuke , Isayama Hiroyuki , Sasaki Takashi , Ishigaki Kazunaga , Saito Kei , Mizuno Suguru , Kogure Hirofumi , Tada Minoru , Koike Kazuhiko
Published: January 2019

429

Background: The current standard of care for patients with advanced biliary tract cancer (BTC) is a palliative chemotherapy. Although the survival benefit of first-line chemotherapy (CT1) including gemcitabine and cisplatin (GC) had been established in prospective randomized trials, the safety and efficacy of second-line chemotherapy (CT2) have yet to be elucidated. Methods: Consecutive advanced BTC patients receiving CT1 followed by CT2 between 2000 and 2016 were enrolled. We investigated factors associated with receiving CT2, treatment outcomes of CT2, and the prognostic factors for overall survival (OS) with CT2 to determine which patients could be expected to benefit from CT2. Results: Among 309 advanced BTC patients receiving CT1, including those with 108 intrahepatic bile duct cancer, 96 gallbladder cancer, 88 extrahepatic bile duct cancer and 17 papilla cancer, CT2 was given in 139 patients (45%). Compared to patients without CT2, younger patients (median; 67 vs. 70 years, p < 0.01) and patients with better PS (PS 0-1; 98% vs. 94%, p = 0.06), and those who achieved higher tumor response by CT1 (response rate; 19% vs. 7%, p < 0.01) had higher chance to receive CT2. Objective response rate and disease control rate of CT2 were 4% and 50%, respectively. Median progression-free survival (PFS) and overall survival (OS) from the beginning of CT2 were 2.8 and 7.7 months, respectively. Prognostic factors impacting OS with CT2 were PS (0 vs. 1-2, hazard ratio [HR] 1.28, p=0.05), tumor response to CT1 (PR-SD vs. PD, HR 1.62, p = 0.02), and CEA (<5.0 vs. ≥5.0 IU/mL, HR 1.52, p = 0.03). Conclusions: Although the efficacy of CT2 was modest at present, it may deserve to be considered in patients who maintained systemic condition in clinical practice. Further investigations are necessary both to to develop more effective regimens and to select patient who will benefit from CT2 in order to maximize the efficacy and to avoid unnecessary toxicity and expense.
Did neoadjuvant chemotherapy provide better long term outcomes in borderline resectable with arterial involvement (BR-A PC)?
Authors: Saito Kei , Nakai Yousuke , Sakamoto Yoshihiro , Ishigaki Kazunaga , Takahara Naminatsu , Arita Junichi , Watadani Takeyuki , Isayama Hiroyuki , Koike Kazuhiko
Published: January 2019

434

Background: Recently high rates of conversion (or adjuvant) surgery were reported after neoadjuvant chemo(radiation)therapy (NAC) for borderline or locally advanced pancreatic cancer (BR/LA PC) including our phase II trial of gemcitabine, S-1 and leucovorin (GSL) combination therapy for BR PC with arterial involvement (BR-A PC) and LA PC. In our phase II trial, a high recurrence rate of 78% was noted despite a high R0 resection of 76%. Herein, we conducted a retrospective analysis of BR-A PC who underwent NAC, upfront surgery and palliative chemotherapy to evaluate the long term outcomes of NAC. Methods: Consecutive patients with BR-A PC at the University of Tokyo Hospital were retrospectively studied. Clinical outcomes in patients who underwent (NAC group) were compared with those in patients who underwent upfront surgery or palliative chemotherapy (non-NAC group). NAC was introduced in our institution from January 2014. Results: A total of 45 patients (22 non-NAC and 23 NAC group) were diagnosed with BR-A PC between January 2008 and December 2016. There were no significant differences in patient characteristics between non-NAC group and NAC group: Median age of 63 vs. 64, male in 72% vs. 52%, Performance status of 0 in 63% vs. 65%, median pretreatment CA19-9 of 175 vs. 205 U/ml. In non-NAC group, 17 underwent palliative chemotherapy as follows 8 gemcitabine alone, 3 gemcitabine and S-1 combination chemotherapy and 6 other regimens. The remaining 5 patients underwent upfront surgery with an R0 resection rate of 80%. In NAC group, a median duration of neoadjuvant chemotherapy was 4 months. A total of 14 patients underwent surgical resection with an R0 resection rate of 76%. The remaining 9 patients had disease progression during NAC and received 2nd line chemotherapy. The median follow-up time was 16.5 months in non-NAC group and 15.3 months in NAC group. The median overall survival (OS) were 19.3 vs. 21.9 months (p = 0.25). Conclusions: Both R0 resection rate and the median OS were comparable between non-NAC group and NAC group. An ideal regimen of NAC or its duration needs further investigation to prolong OS in BR-A PC.
A retrospective review of borderline resectable-locally advanced pancreatic adenocarcinoma (BR-LAPC) undergoing neoadjuvant chemotherapy followed by stereotactic body radiation therapy (SBRT) at the University of Colorado Cancer Center.
Authors: Cuny Claymore Joey , Hoyle John , O'Bryant Cindy L. , Meguid Cheryl Lauren , Lieu Christopher Hanyoung , Davis Sarah Lindsey , Messersmith Wells A. , Leong Stephen
Published: January 2019

436

Background: Metastatic pancreatic chemotherapy regimens are often used as neoadjuvant treatment in the LAPC setting. The University of Colorado has a treatment paradigm for BR-LAPC which consists of 2-4 months of chemotherapy followed by SBRT then reevaluated for surgical resection. Methods: Retrospective analysis of patients with pathologically confirmed BR-LAPC who received all neoadjuvant treatment (chemotherapy and SBRT) with intention of undergoing surgical resection at the University of Colorado Cancer Center from 2012 to 2017. Baseline data collected includes demographics, comorbidities, disease characteristics and chemotherapy regimen FOLFIRINOX or Gemcitabine/Nab-Paclitaxel (GNP). The objective of the study is to describe the correlation of neoadjuvant regimens and clinical outcomes. Results: A total of 100 patients were identified with 40 patients collected for the interim analysis. Of these patients 82.5% (N = 33) received FOLFIRINOX and 17.5% (N = 7) received GNP. Patients who received FOLFIRINOX, 78.8% went for surgical resection compared to 85.7% in the GNP group. The number of patients who had a reported College of American Pathology (CAP) grade ≤1, representing no or minimal residual disease, was 3 for the FOLFIRINOX group and no patients in the GNP group. The percent of patients in the FOLFIRINOX group who achieved R0 resections was 90% compared to 83% for the GNP group. Mean initial CA 19-9 was 38.5U/ml, 386.7U/ml, and 1799.8U/ml in CAP grade 1, 2, 3 respectively, while percent reduction in CA 19-9 level during neoadjuvant was 33.3%, 69.7%, and 72.4% respectively. Assessment of the impact of relative dose intensity for each neoadjuvant regimen on clinical outcomes is ongoing. Conclusions: FOLFIRINOX neoadjuvant treatment was associated with improved surgical outcomes including an increased rate of R0 and CAP grade ≤1 resections. Low initial CA 19-9 levels were associated with favorable surgical and pathologic outcomes whereas absolute or relative CA 19-9 reductions with neoadjuvant were not. Final analysis of all 100 patients will be reported.
Prediction of pancreatic cancer surgical outcomes and prognosis based on an objective resectability scoring system.
Authors: Toesca Diego Augusto Santos , Jeffrey Brooke , von Eyben Rie , Poullos Peter D. , Poultsides George A. , Fisher George A. , Visser Brendan C. , Koong Albert , Chang Daniel Tandel
Published: January 2019

446

Background: There is no consensus on the best radiographic criteria to define pancreatic cancer (PCA) resectability. We undertook this study to objectively assess the probability of tumor resection based on quantitative measures of tumor abutment from the main peripancreatic vessels. Methods: Measurements of the circumferential degree and length of solid tumor contact with the superior mesenteric artery, the celiac artery/common hepatic artery, and superior mesenteric vein/portal vein were obtained through curved planar reformations from diagnostic CT images of PCA patients treated at our institution between 2001 and 2015. Results: A total of 399 patients were identified, of which 294 were used for the analysis. Of them, 113 (38.4%) were resected, 71 (62.8%) with negative margins (R0). Based on the individual measurements of vascular involvement, a resectability scoring system (RSS) was created (table), and used in a classification and regression tree model that correlated strongly with resection (p < 0.0001) and R0 resection (p < 0.0001) probabilities. The RSS demonstrated a higher PPV, NPV and accuracy (94.3%; 98.6%; 97%) to predict resection compared to the NCCN (90.8%; 96.7%; 94.5%) and MDACC resectability criteria (87.1%; 97.9%; 93.5%). Moreover, the RSS correlated with overall survival (OS) (p < 0.0001) and metastasis-free survival (p < 0.0001). Conclusions: We developed a PCA resectability scoring system that is objective, reproducible, and highly correlated with surgical outcomes and prognosis. External validation is warranted. [Table: see text]
A SEER-based multiethnic picture of cholangiocarcinoma in the United States pre and post the advent of gemcitabine/cisplatin.
Authors: Mody Kabir , Antwi Samuel O , Hodge David O , Meghji Zahara , Ailawadhi Sikander , Bekaii-Saab Tanios S. , Roberts Lewis R.
Published: January 2019

448

Background: Cholangiocarcinoma (CCA) is a rare, lethal cancer with five-year survival of less than 10%. Although incidence rates have been increasing in the United States, ethnic variations in survival have not been investigated. We examined multi-ethnic variation in overall survival (OS) and CCA-specific survival (CSS) using data from the population-based Surveillance Epidemiology and End Results (SEER) program in the four year periods before and after introduction of gemcitabine/cisplatin as treatment for CCA. Methods: The study included data from 9,975 CCA cases reported in SEER between 2006 and 2013. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated to examine overall and cholangiocarcinoma-specific survival by ethnicity, age, gender and in the pre- and post- gemcitabine/cisplatin era (2006-2009 vs. 2010-2013). Results: Compared to non-Hispanic Whites, Hispanics had poorer 3-year OS (HR = 1.18, 95% CI = 1.10-1.26) and 3-year CCA-specific survival (HR = 1.25, 95% CI = 1.16-1.35). Similarly, non-Hispanic Blacks had 3-year OS (HR = 1.22, 95% CI = 1.12-1.30) and 3-year CCA-specific survival (HR = 1.24, 95% CI = 1.13-1.37). Males and older patients also were found to have shorter survival compared to females and younger patients. Also noted was an increase in CCA incidence rate over time (2006-2013) of 5.93%. Among those < 50 versus ≥50 years old, a 23% higher rate of incidence in those < 50 was noted. Overall survival and CSS were both significantly improved for patients post-advent of Gemcitabine/Cisplatin. Statistically significant improvement in CSS pre- and post-advent of Gemcitabine/Cisplatin was noted in non-hispanic whites (p < 0.001) and Hispanics (p = 0.02). Conclusions: Hispanics and non-Hispanic Blacks have worse survival after diagnosis with CCA. Further studies are needed to determine the determinants of poor survival among these groups toward targeted intervention. Significant improvements in OS and CSS have been seen after the advent of Gemcitabine/Cisplatin. The incidence of CCA is rising faster in young persons, under the age of 50, compared with older patients.
Role of adjuvant therapy in resected gallbladder cancer.
Authors: Hassan Mohamed Abdelrahim Muddathir , Wongjarupong Nicha , Sanhueza Cristobal T. , Hartgers Mindy L. , Hassan Fatima , Roberts Lewis R. , Mahipal Amit
Published: January 2019

452

Background: Surgical resection is the only curative treatment for patients with gallbladder cancer, despite surgical advances many patients ultimately develop recurrent disease. Management of resected gallbladder cancer mostly relies on single-arm trials and retrospective observations. The purpose of our study is to assess the role of adjuvant therapy in stage I-III gallbladder cancer patients who have undergone surgical resection. Methods: Clinical data were collected on 251 patients who underwent surgical resection for stage I-III gallbladder cancer and presented to Mayo clinic from January 2000-December 2015. Patients were then classified into adjuvant treatment group and surveillance only group. Overall survival and recurrence were compared between the two groups. Results: 78 (31.1%) patients received adjuvant therapy while 173 patients were observed only. Patients who received adjuvant tended to be younger (63.0[SD 11] vs 66.2 [SD 13.1]), have higher stage, and underwent extended surgery. Most patients received chemoradiotherapy (55) with 5-Fluorouracil (67.3%) and capecitabine (25.5%) as radiosensitizing agents. 21 patients received additional adjuvant chemotherapy. 27% of patients received chemotherapy as the sole adjuvant treatment. The most common chemo regimens included gemcitabine (52.3%) and gemcitabine plus cisplatin combination (23.8%). On multivariate analysis patients > 65 years(HR 1.53 [1.07-2.19], p = 0.02), males (HR 1.7 [1.2-2.4], p = 0.003), positive margins (2.77 [1.69-4.38], p < 0.01), and stage III (HR 1.91 [1.35-2.70], p < 0.01) had worse overall survival. Patients who underwent extended radical resection (HR 0.73 [0.51-1.05], p = 0.09) had better overall survival. Adjuvant therapy had no statistical significant effect on overall survival (HR 1.10 [0.75-1.59], p = 0.63 or disease free survival (HR 1.05 [0.69-1.59], p = 0.81) on overall population. However, in stage IIIB, patients receiving adjuvant therapy had better overall survival (HR 0.51 [0.25-1.01], p = 0.05) and disease free survival (HR 0.45 [0.19-1.09], p = 0.06). Conclusions: In our study, adjuvant treatment, especially chemoradiation therapy, was only beneficial in patients with stage IIIb gallbladder cancer patients.
The effect of socioeconomic factors on the outcome of intrahepatic cholangiocarcinoma.
Authors: Sellers Cortlandt , Ludwig Johannes M , Uhlig Johannes , Stein Stacey , Lacy Jill , Kim Hyun S
Published: January 2019

465

Background: To investigate the impact of socioeconomic factors on overall survival (OS) for patients with intrahepatic cholangiocarcinoma (ICC) at an inner-city tertiary care hospital. Methods: Consecutive patients treated for ICC 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 52% male (95 pts) and 74% white (136 pts) with mean age of 65.7 yrs (SD 10.7 yrs). 82% of patients were married or had been previously married (148 pts). 11% of patients had Medicaid as their primary insurance (20 pts), 45% of patients had Medicare (78 pts) and 44% of patients had private insurance (77 pts). Patients with private insurance (66 pts, 87%) and Medicare (64 pts, 83%) were more likely to have been married than Medicaid (12 pts, 60%) (p = 0.036). Patients with Medicare (mean 72.0 yrs, SD 6.9 yrs) were older than private insurance patients (mean 60.3 yrs, SD 10.3 yrs) and Medicaid patients (mean 61.8 yrs, SD 12.4 yrs) (p < 0.001). Gender and ethnicity were similarly distributed by primary insurance. Median OS stratified by primary insurance demonstrated median OS in private insurance of 13.2 mo (95% CI: 8.2–18.7 mo) vs 7.3 mo (95% CI: 3.8–10.6 mo) for Medicare (HR 1.3, p = 0.11) vs 4.7 mo (95% CI: 1.7–11.3 mo) for Medicaid (HR 1.8, p = 0.0488), (p = 0.0465). Cancer-directed treatments were utilized by 81% in private insurance vs. 67% in Medicare vs 67% in Medicaid (p = 0.18). Median OS stratified by main treatment demonstrated 43.3 mo in resection (37 pts, 21%), 17.3 mo in locoregional therapy (LRT) (22 pts, 13%), 10.0 mo in chemotherapy or radiation (79 pts, 45%), and 1.4 mo in palliative or no treatment (37 pts, 21%) (p < 0.0001). Increased age was associated with decreased median OS (correlation -0.23, p = 0.0019). No differences in median OS were seen with ethnicity, gender, or marital status. Conclusions: Screening and early treatments appear to affect the OS of patients with ICC. Further investigations for preventive care for vulnerable populations to enhance survivals are warranted.
A phase 2 study of s-1 plus leucovorin in patients with untreated advanced cholangiocarcinoma (CCA).
Authors: Tanasanvimon Suebpong , Ungtrakul Teerapat , Poovorawan Nattaya , Parinyanitikul Napa , Vinayanuwattikun Chanida , Mingmalairak Siyamol , Luangdilok Sutima , Lamlertthon Wisut , Sriuranpong Virote
Published: January 2019

467

Background: Patients with CCA usually present with advanced disease leading to the grave prognosis. Currently, cisplatin and gemcitabine is the standard treatment in advanced CCA. However, the CCA treatment outcomes are still poor and the options of treatment are quite limited. This study aimed to explore the efficacy and safety of S-1 plus leucovorin in patients with untreated advanced CCA. Methods: This single-arm two-center phase 2 study evaluated the efficacy and safety of S-1 40, 50 and 60 mg according to body surface area and leucovorin 15 mg , both given orally twice daily for one week, repeated every two weeks. Treatment was continued until complete 12 cycles, disease progression or unacceptable toxicity. The primary endpoints were overall response rate (ORR) and disease control rate (DCR) per RECIST version 1.1. The secondary endpoints were progression free survival (PFS), overall survival (OS) and toxicity. Results: Of total 32 patients and a median follow up time of 9.5 months, the ORR was 25% (95%CI 9.1-40.9) and the DCR was 62.5% (95% CI 44.8-80.2). In 25 response evaluable patients, the ORR was 32% (95% CI 12.4-51.7). The PFS was 8.0 (95%CI 5.59-10.4) months. The OS was 11.0 (95%CI 9.47-12.53). The most common grade 3 or 4 toxicities were anemia, mucositis and diarrhea. There was one patient discontinuing treatment due to treatment related toxicity. Conclusions: S-1 plus leucovorin was active and tolerable in patients with advanced CCA. Clinical trial information: TCTR20160313001.
Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): Subanalyses of CheckMate-040.
Authors: El-Khoueiry Anthony B. , Melero Ignacio , Yau Thomas Cheung , Crocenzi Todd S. , Kudo Masatoshi , Hsu Chiun , Choo SuPin , Trojan Jorg , Welling Theodore , Meyer Tim , Kang Yoon-Koo , Yeo Winnie , Chopra Akhil , Zhao Huanyu , Baakili Adyb , Dela Cruz Christine Marie , Sangro Bruno
Published: January 2019

475

Background: NIVO (anti–PD-1 mAb) has demonstrated durable responses, long-term OS, and manageable safety in pts with aHCC in CheckMate-040 (El-Khoueiry, Sangro et al. 2017). With anti–PD-1 therapies, meaningful OS benefit may be seen even in pts who do not achieve a conventional response by RECIST v1.1. Here we report nonconventional benefit with NIVO and effect of antitumor activity on OS in sorafenib-experienced (sor-exp) pts with aHCC, including pts with a best overall response (BOR) of progressive disease (PD). Methods: Sor-exp pts received NIVO (3 mg/kg Q2W) in a phase 1/2 dose-expansion cohort regardless of PD-L1 status. Impact of antitumor activity on median OS (mOS) was determined by calculating change in target lesion size from baseline using quartile analyses (25% cutoff). Nonconventional benefit was analyzed by reductions or stabilizations in target lesion size after progression in pts with a BOR of PD. Results: Sor-exp pts (N=145) had a median follow-up of 14.9 mo. The ORR (RECIST v1.1) was 14% and the DCR was 56%. Median duration of stable disease (SD) was 4.3 mo and the DCR with SD ≥6 mo was 27%. Overall, mOS was 15.6 mo. Degree of OS benefit corresponded with antitumor activity in pts with decreases (≥25%, mOS not reached; 0–25%, mOS 17.7 mo) or increases (0–25%, mOS 11.7 mo; ≥25%, mOS 8.9 mo) in target lesion size (Table). In non-responders (n=124; including pts with BOR of SD or PD), mOS was 13.4 mo. Nonconventional benefit was observed in 11 of 56 pts (20%) with a BOR of PD. Updated clinical data with additional follow-up will be presented. Conclusions: In sor-exp pts, mOS with NIVO corresponded to degree of antitumor activity, with OS benefit not limited to RECIST v1.1 responders. Improved OS in non-responders is likely due to nonconventional benefit, supported by disease reduction or stabilization even in pts with a BOR of PD. Clinical trial information: NCT01658878. [Table: see text]
Risk stratification of gastrointestinal stromal tumors by CtBP2 and CD44 analysis.
Authors: Gopie Priya , Rosca Oana C. , Chawla Ayesha , Mei Lin , Almenara Jorge , Glass Edmund , Dozmorov Mikhail , Grossman Steven R. , Idowu Michael , Boikos Sosipatros Alexandros
Published: January 2019

48

Background: C-terminal binding protein 2 (CtBP2) is an oncogenic transcription factor that promotes cancer stem cell (CSC) growth and self-renewal, and controls pathways for tumor initiation, progression, and response to therapy. Expression of CtBP2 is linked to aggressive behavior in ovarian cancer, while genetic or pharmacologic targeting of CtBP2 disrupts CSC growth and self-renewal. CD44 is a cell surface marker that has been linked to CSC populations in many solid tumors, though data is conflicting on its role as tumor suppressor or oncogene. Gastrointestinal stromal tumors (GIST) is an increasingly common malignancy where risk stratification is essential for guiding post-surgical adjuvant therapy. We hypothesized that CtBP2 and CD44 staining would enhance risk stratification of GIST which currently relies on purely non-molecular clinicopathologic criteria. Methods: We identified 149 GIST cases from 1990 to 2016 in the Virginia Commonwealth University Medical Center pathology archive. Clinical data for 121 patients was available. The Armed Forces Institute of Pathology (AFIP) criteria (Miettinen's criteria) was used to risk stratify GISTs using the size, site, and mitotic index of the primary tumor. Immunohistochemistry for CtBP2 and CD44 was then performed on GIST samples with adequate tumor (86, CD44; 87, CtBP2). Stains were scored 0 (negative) to 3 (maximum) by two independent pathologists. Statistical analysis (χ2) correlating AFIP risk category with CD44 and CtBP2 staining was performed using PRISM6. Results: Moderate and high risk GISTs, based on AFIP criteria, significantly correlated with high CtBP2 expression (score = 3, p = 0.046) and low CD44 expression (score = 0-2, p = 0.034). Conclusions: CD44 and CtBP2 staining can be used to risk stratify GIST, and may enhance and complement current clinical risk stratification systems. Our data also suggests a potential tumor suppressive role of CD44 in GIST. Additionally, based on our findings, investigation of therapeutics that target CtBP2 in GISTs should be pursued.
FOLFIRINOX in advanced pancreatic cancer patients with the double-variant type of UGT1A1 polymorphism: A multicenter, retrospective study.
Authors: Umemoto Kumiko , Takahashi Hideaki , Morizane Chigusa , Yamada Ikuhiro , Shimizu Satoshi , Shioji Kazuhiko , Yoshida Yukio , Motoya Masayo , Mizuno Nobumasa , Kojima Yasushi , Terashima Takeshi , Uesugi Kazuhiro , Ikeda Masafumi , Ueno Makoto , Furuse Junji
Published: January 2019

484

Background: UGT1A1 *28 or *6 polymorphism is associated with reduced enzyme activity and severe toxicity of irinotecan, especially in patients homozygous for UGT1A1*28 or *6 and heterozygous for both UGT1A1*28 and *6 (double-variant-type: DV). FOLFIRINOX (FFX) is one of the standard treatments in patients with advanced pancreatic cancer (APC). In Japanese guideline for FFX in patients with APC, full-dose regimen of FFX is not recommended in patients with DV, but dose adjustment for patients with DV is not established yet. The purpose of this study was to evaluate the safety and efficacy of FFX in Japanese APC patients with DV. Methods: APC patient of DV treated with FFX from December 2013 to March 2016 in 16 hospitals in Japan were enrolled. Results: A total of 31 patients were enrolled. Irinotecan were variously administered at the first cycle of dose ranged from 70 to 180mg/m2. The proportion of the patients receiving standard dose of oxaliplatin, 5-FU infusion and 5-FU continuous infusion at the first cycle of FFX were 97%, 19% and 97%, respectively. Severe adverse events were observed 8 of 31 patients. Main grade 3 or 4 adverse events were included neutropenia (65%), febrile neutropenia (13%) and diarrhea (6%). Response rate (RR) and overall survival (OS) receiving FFX as first-line treatment were 23% and 13.5 months, respectively. In this study, patients receiving irinotecan 150mg/m2 was high frequency of 80% (4/5), otherwise, grade 4 neutropenia in all patients was observed in 29% (9/31) Conclusions: The results of neutropenia in this study indicated that irinotecan 150mg/m2 may not be tolerable in DV patients. RR and OS were almost the same as previous reports. We are planning the dose finding study of FFX in APC patients with DV.
Implementation of a standardized approach to borderline resectable pancreatic cancer in a community oncology program.
Authors: Bleeker Jonathan Scott , Sumey Christopher Joseph , Powell Steven Francis , Steen Preston D. , Keppen Michael D. , Lohr Michele , Thambi-Pillai Thavam C. , Kurniali Peter , Mazurczak Miroslaw , Gitau Mark Mutuota , Blanchard Miran Joel , Nowak Ryan Kenneth , McGraw Steven , Sticca Robert , Tuvin Daniel , Timmerman Gary
Published: January 2019

493

Background: Treatment paradigms for borderline resectable pancreatic cancer (BRPC) continue to evolve with increasing use of neoadjuvant chemotherapy (NAC) and chemoradiation (NACR). Variations in the definition of BRPC and in neoadjuvant approaches have made standardization of care for BRPC difficult. We report an effort to standardize management of BRPC throughout Sanford Health, a largely rural community oncology (CO) network in the Upper Midwest. Methods: Starting in February 2014, cases of PC without evidence of metastatic disease were categorized as BRPC if they met one or more of the following criteria: 1) abutment of superior mesenteric, common hepatic or celiac arteries with < 180o involvement 2) venous involvement deemed potentially reconstructable and/or 3) biopsy proven regional lymph node involvement. Patients with BRPC were treated with NAC followed by reimaging and surgery if resectable; if disease remained BRPC, patients underwent NACR and surgical re-evaluation. NAC was administered at 5 CO sites in the Sanford network; NACR and surgery were performed at 2 high volume centers. Results: Forty-three patients from 2/2014-4/2017 were diagnosed with BRPC. Median age of patients was 64 (range 39-83); 56% were male. 42/43 patients received NAC as initial therapy, with 1 receiving NACR due to patient preference. 90% of patients receiving NAC received mFOLFIRINOX (38/42), with FOLFIRI (1) and gemcitabine/nab-paclitaxel (3) also utilized. 11/42 (26%) patients had resectable disease after NAC and underwent surgery; 23 (55%) proceeded to NACR. Overall, 26/43 (61%) went to surgery with 18 (42%) able to undergo resection. Of those, 12/18 (67%) attained R0 resection and 10/18 (56%) were pathologic N0. Primary tumor location (head v. body/tail), age, pretreatment CA19-9, change in CA19-9 with treatment and NACR were not associated with a higher likelihood of resection. Conclusions: This report demonstrates the feasibility of implementing a standardized approach to BRPC across multiple CO sites over a wide geographic area. Adherance to protocol therapies was good and surgical outcomes are similar to many reported series; survival data is maturing and will be presented at the meeting.
Initial and maintenance dose of sorafenib in female patients with advanced hepatocellular carcinoma should be modified to maximize therapeutic effect.
Authors: Tsuchiya Kaoru , Kubota Yohei , Takaura Kenta , Takada Hitomi , Tamaki Nobuharu , Yasui Yutaka , Nakanishi Hiroyuki , Itakura Jun , Kurosaki Masayuki , Izumi Namiki
Published: January 2019

497

Background: Sorafenib is the only approved first-line agent in patients with advanced HCC and patients who showed progressive disease after sorafenib therapy have an opportunity to receive regorafeib as 2nd-line agent. Therefore, it is very important to maintain sorafenib therapy until sorafenib resistance occurs. We retrospectively analyzed initial and maintenance dose especially in female patients. Methods: A total of 232 patients with advanced HCC who received sorafenib in our institution from July, 2009 until May, 2017 were enrolled. Overall survival (OS), radiological response evaluated by modified RECIST criteria and dose of sorafenib were analyzed. Results: The 232 patients included 179 males and 53 females, with a mean age of 71 ± 9 years. The majority of patients (N = 131, 56.4%) were HCV Ab positive and HBs Ag was positive in 29 patients. Eighty-six patients had extrahepatic metastasis and 50 patients showed major portal invasion defined as VP3 or VP4 by Liver Cancer Study Group of Japan. The overall survival rates of the 232 patients at 6, 12 and 18 were 72.4%, 53.6% and 41.9%, and MST was 14 months. In all patients no existence of major portal invasion, serum Albumin level ≧3.5g/dl before administration of sorafenib, and post-sorafenib anticancer therapy were independently associated with OS. The mean age of female patients was 75 years and mean body weight was 49kg. In female patients only 5 patients (9.4%) showed over 60kg. The dose reduction of sorafenib was necessary in all female patients and 26 female patients could receive post-sorafenib anticancer therapy including regorafenib. The muscle mass calculated by direct segmental multifrequency bioelectrical impedance analysis method was associated with duration of sorafenib therapy, dose reduction of sorafenib and possibility of post-sorafenib anticancer therapy. Conclusions: The modification of sorafenib dose according to sex and muscle mass is clinically important to improve overall survival in patients with advanced HCC treated with sorafenib. It is associated with duration of sorafenib therapy and the possibility for induction of other therapies after sorafenib failure.
Effect of treatment center volume on outcomes in gastroenteropancreatic neuroendocrine tumor patients.
Authors: Baeg Kiwoon Joshua , Harris Cynthia , Lee Mi Ri , Martin Jacob Andrew , Rustgi Sheila , Mhango Grace , Wisnivesky Juan P. , Kim Michelle Kang
Published: January 2019

502

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare tumors, where patients seek care at medical centers with varying levels of expertise. While treatment center volume is associated with better survival in multiple cancers, it remains unknown whether the same applies to GEP-NETs. The objective of this study was to assess the impact of center volume on GEP-NET treatment outcomes. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare claims data in this study. We included patients diagnosed between 1995-2010 who had no HMO coverage, participated in Medicare parts A and B, were older than 65 at diagnosis, had full tumor grade information, and had no secondary cancer. We used Medicare claims to identify the medical centers at which patients received GEP-NET treatment (surgery, chemotherapy, somatostatin analogues, or radiation therapy). Center volume was divided into tiers – low, medium, and high – based on the number of unique GEP-NET patients treated by a medical center over two years. Kaplan-Meier curves and Cox regression were used to assess the association between volume and disease-specific survival (DSS). Results: We identified 1025 GEP-NET patients, of whom 65%, 28%, and 7% received treatment at low, medium, and high volume centers, respectively. Surgery was the most common first treatment (84-90%). Comorbidity and tumor stage distribution were similar across tiers, but the distribution of patients with poorly-differentiated tumors differed significantly (p < 0.001). Median DSS for patients at low and medium centers were 3.7 years and 6.6 years, respectively, but was not reached for patients at high volume centers. After adjusting for confounders, patients treated at high volume centers had better survival than those treated in low volume centers (HR: 0.55, 95% CI: 0.30-0.99). However, no difference in survival was noted at medium volume centers (HR: 0.98, 95% CI: 0.78-1.22). Conclusions: Our results suggest that centers with expertise in GEP-NET treatment have better patient outcomes. Thus, centralization of care, particularly of more difficult cases, may lead to improved patient outcomes.
Final toxicity results from a phase II study of 5-fluorouracil, oxaliplatin, and dasatinib (FOLFOX-D) in previously untreated metastatic pancreatic adenocarcinoma.
Authors: George Thomas J. , Starr Jason Scott , Parekh Hiral D. , Ivey Alison Marguerite , Dang Long H. , Daily Karen Colleen , Allegra Carmen Joseph , DeRemer David L. , Hughes Steven J. , McEwan Margaret A. , Cioffi Jessica L , Trevino Jose Gilberto
Published: January 2019

504

Background: Systemic chemotherapy for pancreatic adenocarcinoma (PCa) improves survival but most targeted agents have consistently failed to demonstrate clinical benefits. Src is overexpressed in PCa and promotes an aggressive cancer phenotype. Dasatinib (D) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation through inhibition of Src, Bcr-Abl, CKit and other pathways. Inhibition of Src is associated with biologic modifications favorably modifying the PCa phenotype and has synergy with restoring inherent chemosensitivity. Src inhibition can also increase oxaliplatin activity and modulate Tcell responses. The addition of D to the well-established backbone of FOLFOX represents a multifaceted line of scientific investigation. Methods: This single arm phase II trial is to determine activity and toxicity of FOLFOX + D in previously untreated metastatic PCa. Pts must have at least 1 RECIST measurable target lesion, ECOG PS 0-2, normal QTc and adequate organ function. Treatment is standard q14d cycles of mFOLFOX6 with continuous D (150mg PO daily). Tumor assessments occur q8w. Endpoints are PFS (primary), objective and biochemical response rates, clinical benefit rate, freedom from metastases, overall survival (OS), toxicity, and quality of life. Exploratory tissue, circulating tumor cell and serum analyses to identify predictors of response are planned, particularly in those with durable disease control or exceptional response. Sample size is based on a 50% improved median PFS from 4 (historical) to 6 months. Results: Enrollment is now closed on this prospective phase II study with 42 of 42 evaluable pts. Baseline demographics are in Table 1. Toxicity and outcomes continue to be assessed. Conclusions: Final toxicity data will be presented at the meeting for this novel combination treatment in advanced PCa. Clinical trial information: NCT01652976. [Table: see text]
Advancing evidence-based decisions in the management of pancreatic cancer.
Authors: Herrmann Tara , Littman Gwen , Piatt Leah
Published: January 2019

506

Background: As a result of updates to pancreatic cancer treatment guidelines, oncologists face a host of escalating treatment challenges that may hinder their abilities to select the most appropriate regimen for patients. A study was conducted to determine if simulation-based educational interventions could improve decisions of oncologists in the management of pancreatic cancer. Methods: A cohort of US-practicing oncologists who participated in a virtual patient simulation (VPS)-based education initiative was evaluated. The VPS consisted of 2 cases presented on a platform that allowed oncologists to assess each patient and make decisions limited only by an extensive database of treatment possibilities matching the scope and depth of actual practice. Clinical decisions made by participants were analyzed using a decision engine, and instantaneous clinical guidance (CG) employing current evidence-based and expert faculty recommendations was provided immediately after each decision. Oncologists were allowed a second chance at each decision point; decisions before and after CG were compared using a 2-tailed paired T-test. P values are shown as a measure of significance; P values < .05 are statistically significant. Results: 410 oncologists made clinical decisions within the VPS. Significant improvements were observed in: Selecting the most appropriate first-line regimen in a patient with a PS of 2 (29%, P< 0.001); Ordering an anti-emetic in patients who are receiving chemotherapy (24% , P< 0.001); Evidence-based treatment selection for individuals whose disease progressed on therapy (17%, P= .003); and Ordering adverse event education and counseling (11% and 16%, P= .001). In addition, this study revealed that up to 55% of oncologists would test patients for BRCA mutations while 52% would consider enrolling a patient in a clinical trial if they have progressed on therapy. Conclusions: This study showed improvements in evidence-based practices of oncologists in the management of advanced pancreatic cancer across the continuum of care, thus demonstrating that VPS-based instruction can result in an increase in evidence-based clinical decisions. Therefore, VPS may have a role in improving the quality of care and patient outcomes.
Treatment and survival rates of stage IV pancreatic cancer at VA hospitals: A nationwide study.
Authors: Azar Ibrahim , Virk Gurjiwan , Esfandiarifard Saghi , Wazir Ali , Khreis Tariq , Mehdi Syed
Published: January 2019

507

Background: Metastatic Pancreatic Cancer (MPC) is associated with an extremely high mortality. Current NCCN guidelines recommend systemic therapy, as it is superior to best supportive care. Undertreatment of MPC continues to be an issue. Recent treatment and survival data of MPC in Veterans’ Affairs’ (VA) hospitals have not been published. The relationship between treatment and American College of Surgeons’ (ACS) Committee on Cancer (CoC) accreditation has not been studied. Methods: Nationwide data from the National Veterans Affairs Cancer Cube Registry was analyzes. 7,585 patients were diagnosed with MPC between 2000 and 2017. Systemic therapy was only looked at as it is the standard of treatment for MPC. CoC accreditation of each VA hospital was obtained using the ACS website. Local IRB approval was obtained. Results: MPC constitutes 52.44% of pancreatic cancer diagnosed (7,585 out of 14,464 cases). The near totality were men (97.43%). The 60-70 age group constitutes the most common age at diagnosis (38.7%). The anatomic site distribution was: head (38.2%), tail (18.77%) and body (12.25%) with the rest unspecified or overlapping sites. Treatment rate over the years has increased from 32.03% in 2000-2004 to 41.17% in 2010-2014. The use of oxaplatinin and nab-paclitaxel as part of combination drugs has increased over the years as NCCN guidelines changed. This has corresponded with an increase of 1-5 years survival of 7.84% in 2000-2004 to 14.87 % in 2010-2014. Treatment rates in CoC- accredited and non-CoC accredited VA hospitals were similar (38.94% and 38.12%, respectively). Survival rates in CoC- accredited and non-COC accredited VAs were similar with a 1-5years survival rate of 8.89% and 8.57%, respectively. Conclusions: Treatment and survival of MPC have risen significantly in the past decade at VA hospitals. CoC accreditation is not associated with a change in treatment or survival rates. [Table: see text]
The antidiarrheal efficacy of a proprietary amino acid mixture in gastroenteropancreatic neuroendocrine patients.
Authors: Chauhan Aman , Miller Rachel C , Yu Qian , Aslam Bilal , Weiss Heidi , Anthony Lowell Brian
Published: January 2019

509

Background: Based on SEER database, gastroenteropancreatic neuroendocrine tumor incidence has increased 6 fold from 1 in 100,000 cases to about 6 in 100,000 cases over past 3 decades. North American Neuroendocrine Tumor Society estimates that over 100,000 GEPNET patients are currently living in the United States. One of the common quality of life limiting symptom seen in GEPNET patient is diarrhea. Diarrhea in these patients could be due to excessive serotonin production, secondary to post-operative short gut syndrome, steatorrhea from somatostatin analogs, bile acid colitis or intestinal bacterial overgrowth. A novel amino acid based oral rehydration solution (Enterade) is currently being evaluated in a Phase II clinical trial for antidiarrheal effects in post bone marrow transplant patients (NCT02919670). We conducted a pilot study of Enterade in neuroendocrine tumor patients with quality of life limiting diarrhea to evaluate its antidiarrheal efficacy. Methods: Medical records of all the GEPNET patients treated with Enterade for symptomatic diarrhea were evaluated. Patients were treated at Markey cancer center between May 2017-August 2017. Results: Total 8 patients were treated with Enterade. Five were small bowel NETs and 3 were pancreatic NETs. Five patients had prior bowel resections for removal of primary tumor; 5 patients were on somatostatin analogs at the time of initiation of Enterade. Five (62%) patients reported improvement in diarrhea within 6 days of initiating Enterade. The responders had 50 % reduction in their stool output. Mean stools dropped from 6 per day to 3 per day in responders. Conclusions: These pilot data suggest that Enterade may be an effective option in diarrhea control in NET patients. A prospective Phase II study of Enterade in gastroenteropancreatic neuroendocrine tumor patients with quality of life limiting diarrhea is planned.
Survival of chemotherapy (chemo) refractory gastric or gastroesophageal junction cancer (GC/GEJC) patients from Flatiron Health (FH): Matched clinical characteristics to ATTRACTION-2 and CHECKMATE-032.
Authors: Janjigian Yelena Yuriy , Le Dung T , Ott Patrick Alexander , Korytowsky Beata , Le Hannah , Le Trong Kim , Zhang Ying , Sanchez Teresa , Maglinte Gregory , Laurie Melissa , Patel Dhiren , Shangguan Tong , Chau Ian
Published: January 2019

51

Background: Treatments for advanced/metastatic (adv/met) GC/GEJC after failure of second-line (2L) chemo are limited. Nivolumab (NIVO) demonstrated encouraging anti-tumor activity and long-term OS in adv/met GC/GEJC Asian patients (pts) in ATTRACTION-2 compared with placebo (12-month OS rate, 26% vs 11%; HR, 0.63; P < .0001) and in CHECKMATE-032 (CM-032) in Western pts (12-months OS rate, 45%). This study explored outcomes in US GC/GEJC pts by establishing real world (RW) standard of care (SOC) comparators, against placebo in Asian pts and NIVO in Western pts. Methods: Data were captured from FH electronic health record database. Median OS, estimated by Kaplan-Meier, was calculated from last treatment for adv/met GC/GEJC to death. To create a US RW SOC arm to the ATTRACTION-2 placebo pts, a 2-step matching process was applied: (1) similar inclusion/exclusion (I/E) criteria (2) frequency matching based on significant differences in baseline characteristics associated with survival, identified by univariate analysis. A similar approach was used to create a US RW SOC arm to NIVO treated pts in CM-032. Results: 742 adv/met GC/GEJC pts with ≥ 2 prior lines of therapy were identified in FH from Jan11-Apr17. Two-step matching resulted in 90 US RW SOC vs. 163 ATTRACTION-2 placebo pts, and 100 US RW SOC vs. 42 CM-032 pts. All pts had ECOG performance status (PS) of 0 or 1. Median OS of US RW SOC arm was similar to matched placebo in ATTRACTION-2. Comparison of RW SOC to NIVO-treated pts in CM-032 showed a favorable median OS with NIVO therapy (Table). Conclusions: These analyses highlight the grave outcomes in US adv/met GC/GEJC pts in FH and signal a need for more effective treatments. The data also suggest favorable outcomes with NIVO vs. SOC in both Asian and Western pts with 3L adv/met GC/GEJC. [Table: see text]
A phase I fixed-dose feasibility study of MK615 and gemcitabine in patients with advanced or metastatic pancreatic cancer.
Authors: Moriyama Ichiro , Ikejiri Fumiyoshi , Kawakami Koshi , Inoue Masaya , Kumanomido Satoshi , Shinichiro Matsuda , Takahashi Fumimasa , Ito Shunsuke , Okada Yusuke , Mochida Hiroshi , Shimazaki Yasumasa , Ugata Norimi , Okada Takahiro , Jo Yumi , Onishi Chie , Takahashi Tsutomu , Miyake Takaaki , Suzuki Ritsuro , Suzumiya Junji
Published: January 2019

510

Background: The medical agent MK615 is produced from Japanese apricot and contains a number of cyclic triterpenes. Antitumor activity of MK615 and its additive effect when combined with gemcitabine in pancreatic cancer cell line. MIAPaCa-2 was previously reported by our group. The objective of this phase I trial was to evaluate safety and feasibility of combined MK615 and gemcitabine therapy in patients with advanced or metastatic pancreatic cancer. Methods: Patients with untreated pancreatic cancer or those who underwent chemotherapy without gemcitabine were enrolled. Gemcitabine was infused at 1000 mg/m2 over 30 minutes once weekly for 3 weeks of each 28-day treatment cycle. Three packets of MK615 were orally administered daily during each 28-day treatment cycle, until any discontinuation criteria were met. If severe toxicity occurred, dose was reduced. Results: All five patients enrolled were evaluable for toxicity and response. Median age was 72 (54-79) years. Three patients had performance status (PS) 0, one had PS 1, and one PS 2. Three of five patients had been treated with chemotherapy; two with FOLFIRINOX and one with S-1. One of five patients treated had grade 4 neutropenia and two were administered granulocyte-colony stimulating factor. No patient had febrile neutropenia or adverse event leading to death. Relative dose intensity was 96.6% and 69.8% for MK615 and gemcitabine, respectively. No patients had objective response (complete response + partial response), while 2 of 5 patients (40%) had disease control (objective response + stable disease). Conclusions: Combined MK615 and gemcitabine therapy was well-tolerated and showed antitumor activity in patients previously treated without gemcitabine or untreated patients with advanced or metastatic pancreatic cancer. Currently, we are planning phase II trials for elderly or frail people.