bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of postoperative apatinib treatment after resection of hepatocellular carcinoma with portal vein invasion: A phase II study.
Authors: Sun Hui-Chuan , Zhu Xiao-Dong , Zhou Jian , Gao Qiang , Shi Ying-Hong , Ding Zhen-Bing , Huang Cheng , Qiu Shuang-Jian , Ren Ning , Shi Guo-Ming , Sun Jian , Ye Qing-Hai , Huang Xiao-Wu , Yang Xin-Rong , Fan Jia
Published: February 2020

514

Background: Adjuvant therapy for hepatocellular carcinoma (HCC) is an unmet need. Apatinib, a VEGFR2 inhibitor, showed antitumor activity and tolerable toxicity for advanced HCC in a phase 2 study. We were aiming to explore the safety and efficacy of apatinib in adjuvant settings after resection of HCC with portal vein tumor thrombosis (PVTT). Methods: This is a single-center single-arm phase 2 study. The key inclusion criteria were: (1) pathologically confirmed HCC; (2) underwent liver resection with curative intention within 4-6 wk before recruitment; (3) PVTT assessed by preoperative imaging or intraoperative findings. Eligible pts received apatinib at 500 mg/day for a maximum of 12 mo until unacceptable toxicity or tumor recurrence. The primary outcome was recurrence-free survival (RFS) defined as the interval between surgery and the diagnosis of tumor recurrence or death from any causes whichever comes first. The secondary outcome is overall survival (OS) and treatment safety. Results: From Aug 17, 2017 to Dec 18, 2018, 49 pts were screened, and 30 pts were recruited. PVTT were classified as Vp1 (n = 7), Vp2 (n = 11), and Vp3 (n = 12) according to the LCSGJ classification. As the data cutoff on Aug 22, 2019, 4 pts are still on treatment. The median follow-up was 14.3 mo (IQR 12.3-19.3). Median duration of treatment was 4.8 mo (IQR 2.0–8.8). 20 recurrence and 2 death occurred including one death without recurrence. The mRFS was 7.6 mo (95% CI, 3.7-11.5), and the 1-year RFS rate was 36.1%. The mOS was not reached, and 1-year OS rate was 93.3% (standard error, 4.6%). Treatment-related adverse events occurred in 29 pts (96.7%). Grade 3 or 4 adverse events were reported in 14 pts (46.7%) (Table). Dose modification due to adverse events was recorded in 23 pts (76.7%). Conclusions: Apatinib is tolerant in most pts after resection for HCC with PVTT. A controlled study is warranted to prove its efficacy on tumor recurrence. Clinical trial information: NCT03261791.

[Table: see text]
The Prospective Dutch Colorectal Cancer (PLCRC) Cohort: Towards a unique patient-reported outcome enriched “real-world” data cohort.
Authors: Derksen Jeroen W.G. , Elferink Marloes A.G. , Vink Geraldine R. , Roodhart Jeanine M.L. , May Anne Maria , Koopman Miriam ,   On behalf of the PLCRC Working Group
Published: February 2020

52

Background: The initiation of high-quality pan-population cohort studies is a major research priority for the improvement of colorectal cancer (CRC) outcomes as advocated by regulators and the research community. In 2013, the PLCRC cohort of the Dutch Colorectal Cancer Group was initiated in which longitudinal clinical data and patient-reported outcomes (PRO) are collected, along with pathology data and biospecimens, to serve as an infrastructure for a broad body of observational and (randomized) interventional research. Here we report on the cohort’s progress and investigate whether it develops in the direction of a nation-wide cohort of “real-world” nature. Methods: Clinical and demographical data of PLCRC participants, as prospectively collected in the Netherlands Cancer Registry by qualified data managers, were compared with the total Dutch CRC population with incidence between 2013-2017 (ref. population) which was also obtained from the Netherlands Cancer Registry. Variable distributions are compared using t-tests and χ2-tests, whereas cohort characteristics are descriptive. Results: In June 2019, 5,746 patients were enrolled in 52 / 75 Dutch hospitals, and 81% consented to receive repeated PROs. Compared to patients enrolled between 2013-16 (N = 1,093, 1-17 recruiting hospitals), we found a small shift towards the Dutch ref. population (N = 74,692) for patients enrolled between 2017-19 (N = 4,653, 17-52 hospitals) in terms of age at diagnosis (mean 64.6±10.2 years in 2013-16, 65.2±10.8 in 2017-19, and 69.5±10.9 in the ref. group), sex (65% males in 2013-16, 61% in 2017-19, and 56% in the ref. population), location of primary tumor (56% rectum in 2013-16, 40% in 2017-19, and 31% in the ref. population) and TNM stage (35% stage I-II in 2013-16, 41% in 2017-19, and 48% in the population). Conclusions: Over the past years, the number of PLCRC recruiting centers and participating patients, with high consent rates for PROs, steeply increased. Further improvements in recruitment methodologies and multidisciplinary enrolment of patients will continue to enhance PLCRC’s representation of the “real-world” and its ability to supplement trial-based evidence.
Phase III study of pembrolizumab (pembro) versus best supportive care (BSC) for second-line therapy in advanced hepatocellular carcinoma (aHCC): KEYNOTE-240 Asian subgroup.
Authors: Kudo Masatoshi , Lim Ho Yeong , Cheng Ann-Lii , Chao Yee , Yau Thomas , Ogasawara Sadahisa , Kurosaki Masayuki , Morimoto Naoki , Ohkawa Kazuyoshi , Yamashita Tatsuya , Lee Kyung-Hun , Chen Erluo , Siegel Abby B. , Ryoo Baek-Yeol
Published: February 2020

526

Background: Pembro received accelerated approval for second-line therapy in aHCC based on KEYNOTE-224 (phase 2). KEYNOTE-240 (NCT02702401) is a randomized, phase 3 study of pembro v BSC in previously treated aHCC. We report outcomes for the Asian subgroup. Methods: Pts with a radiographic/pathologic HCC diagnosis, radiographic progression with/intolerance to sorafenib, Child-Pugh A disease, and ECOG PS 0/1 were randomized 2:1 to pembro (200 mg) + BSC or PBO + BSC Q3W (≤35 cycles or until confirmed PD/unacceptable toxicity). Pts were stratified by geographic region (Asia without Japan; non-Asia with Japan), AFP, and macrovascular invasion. Response was assessed Q6W (RECIST v1.1, central review). Primary end points: OS, PFS; secondary end points: ORR, DOR, safety. Data cutoff: Jan 2, 2019. Results: 413 pts were randomized (overall cohort: n = 278 pembro, n = 135 PBO; Asian subgroup [Hong Kong, Japan, Philippines, S Korea, Taiwan, Thailand]: n = 107, n = 50). HBV+ status and BCLC stage C were higher in Asian subgroup (HBV+: 51% v 24.5% overall; stage C: 86.6% v 79.4%). Median follow-up: pembro (21.3 mo overall; 23.5 mo); PBO (21.5 mo overall; 23.0 mo). Pembro improved OS v PBO (median OS [95% CI]: 13.9 [11.6-16.0] v 10.6 [8.3-13.5] mo; HR: 0.781; 95% CI, 0.611-0.998; P = 0.0238) and PFS (HR: 0.718; 0.570-0.904; P = 0.0022) for overall cohort and Asian subgroup (median OS: 13.8 [10.1-16.9] v 8.3 [6.3-11.8] mo; HR: 0.548; 0.374-0.804; P = 0.0009; PFS: HR: 0.475; 0.324-0.696; P < 0.0001). Differences did not meet prespecified significance level for overall cohort. ORR in overall cohort was 18.3% (14.0-23.4) for pembro; 4.4% (1.6-9.4; P = 0.00007) for PBO; in Asian subgroup, 20.6% (13.4-29.5) and 2.0% (0.1-10.6; P = 0.00135). Safety was consistent with that previously reported in pembro studies. No HBV/HCV flares were identified. Conclusions: Pembro reduced risk for death by 22% in overall cohort and 45% in Asian subgroup and improved PFS v PBO. Safety was comparable to that of pembro monotherapy. Results are consistent with KEYNOTE-224 and magnitude of OS benefit was enhanced in Asian subgroup, supporting a favorable risk-benefit balance for second-line pembro in HCC. Clinical trial information: NCT02702401.
Objective response (OR) by mRECIST to predict overall survival (OS) in patients with hepatocellular carcinoma (HCC) treated with sorafenib in the SILIUS trial.
Authors: Kudo Masatoshi , Ueshima Kazuomi , Ogawa Chikara , Chiba Yasutaka
Published: February 2020

534

Background: In SILIUS (NCT01214343) trial, combination of sorafenib and hepatic arterial infusion chemotherapy did not significantly improve OS in patients with advanced HCC compared with sorafenib alone (Kudo M, et al. Lancet Gastroenterol Hepatol 2018). In this study, we explored the relationship between OR and OS in the sorafenib group in the SILIUS trial. Methods: Association between OR and OS in patients treated with sorafenib ( n = 103) were analyzed. The median OS of responders was compared with that of non-responders by using Mantel-Byar test to exclude guarantee-time bias. Landmark analyses were performed, as sensitivity analyses, and the effect on OS was evaluated by Cox regression analysis with OR as a time-dependent covariate, with other prognostic factors. Results: OS of responders ( n = 18) was significantly better than that of non-responders ( n = 78) ( p < 0.0001), where median OS was 27.2 (95% CI, 16.0–not reached) months for responders and 8.9 (95% CI, 6.5–12.6) months for non-responders. HRs from landmark analyses at 4, 6, and 8 months were 0.45 ( p = 0.0330), 0.37 ( p = 0.0053), and 0.36 ( p = 0.0083), respectively. OR by sorafenib was an independent predictor of OS based on unstratified Cox regression analyses. Conclusions: In the SILIUS trial, OR achieved by sorafenib per mRECIST is an independent predictor for OS in patients with HCC.

[Table: see text]
SHR-1210 combined with GEMOX as first-line treatment in patients with advanced biliary tract cancer.
Authors: Chen Xiaofeng , Wu Xiaofeng , Wu Hao , Shao Qianwen , Zhu Feipeng , Qian Xiaofeng , Zhao Fengjiao , Mao Weidong , Sun Jing , Wang Jian , Han Gaohua , Li Changxian , Seesaha Poshita kumari , Wang Quanren , Li Huajun , Shao Yang , Gu Yanhong , Li Xiangcheng , Shu Yongqian
Published: February 2020

535

Background: This study aimed to evaluate the efficacy and safety of SHR-1210 (a humanized anti-programmed cell death receptor 1 antibody) plus gemcitabine and oxaliplatin (GEMOX) as first line treatment in patients (pts) with biliary tract cancer (BTC). Methods: This was a single-arm, single-center, exploratory trial, which included advanced BTC pts. Pts received SHR-1210 (3mg/kg, total dose ≤200mg, ivd, D1/2W) combined with gemcitabine (800 mg/m2, ivd, D1/2W) and oxaliplatin (85mg/m2, ivd, D2/2W). Combined chemotherapy lasted for no more than 12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take SHR-1210 as single agent until disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS) rate. Results: From February 2018 to April 2019, 37 eligible pts were enrolled. The median age was 64 (range 41-74) years, male/female was 70.3/29.7%, and bile duct cancer/gallbladder cancer was 59.5/40.5%. All 37 pts were included in the safety analysis. The overall AE incidence rate was 97.3%. The incidence of grade ≥3 AEs was 73.0%, which mainly included increased GGT (gammaglutamyltransferase, 18.9%), hypokalemia (18.9%), and fatigue (16.2%). Particularly, the incidence of fever is 73.0%, in which 2 pts experienced grade 3/4 fever. Among 36 evaluable pts, 19 pts got partial response (PR, 52.8%), 14 pts stable disease (SD, 38.9%), and 3 pts progressive disease (PD, 8.3%) at best. The primary endpoint 6-month PFS rate was 50.0% (95% CI 32.4-65.4), which indicated that the primary endpoint of the study was reached, and mPFS was 6.2 months (95% CI 4.2-7.1). The 12-month overall survival (OS) rate was 50.5% (95% CI 30.6-67.4), and mOS was 12.1 months (95% CI 8.0-NA). Conclusions: This study has reached the pre-defined primary endpoint with a high response rate. Predictive biomarker analysis was reported in another abstract. Further study is needed to validate the efficacy of this combination. Clinical trial information: NCT03486678.
Adjuvant chemotherapy (AC) for stage III colorectal cancer (CRC) in the elderly: An Irish experience.
Authors: Harrold Emily , Greally Megan , Peters Niamh , Sui Jane Sze Yin , McCaffrey John
Published: February 2020

54

Background: Since 2004 6 months of adjuvant Oxaliplatin containing regimens (OCR) has been standard of care for Stage III CRC despite cumulative neurotoxicity. The IDEA collaboration evaluated 3 versus 6 months of OCR in high/low risk pts with regard to peripheral neuropathy (PN) and efficacy.The median pt age was 64; individual studies included pts ≤85. Methods: This study is part of a retrospective review of the clinicopathological records of consecutive CRC pts referred to the multi-disciplinary CRC team at an Irish tertiary referral centre from 2002-2018. We recorded pt characteristics, Rx received and outcomes. Overall Survival (OS) was assessed using Kaplan-Meier analysis. Results: 869 pts were identified; 37% (328) female. 63% (551/869) < 70 and 37% (318/869) ≥ 70. Median OS for < 70 cohort was 31.5 months versus 19 months in ≥ 70 cohort (p < 0.0001).Stage distribution in < 70: ≥70 cohorts was Stage II 14%( 79/551):20% (63/318), Stage III 47% (260/55):46% (142/318) and Stage IV 38% (207/551):34% (111/318). In < 70 Stage III cohort 7% (37/551) pts received no AC, 42%(230/551) received FOLFOX, 3%(16/551) received FLOX or XELOX, 7%(38/551) received 5FU/LEU. 32%(78/246) of pts < 70 developed PN with persistence at 6 months in 18%(44/256). In ≥ 70 Stage III cohort 58%(83/142) did not received AC. 23%(32/142) received an OCR and 16%(23/142) received 5FU/LEU; there was a statistically significant survival difference with an OCR. 47% (15/32) of pts ≥70 receiving OCR developed PN which persisted at 6 months in 28% (9/32). In < 70 cohort there was no significant survival difference in the IDEA-trial-defined low risk group between 12 versus < 12 FOLFOX. There was a numerical survival difference in the < 70 high risk group between 12 versus < 12 FOLFOX; this was not statistically significant. In the ≥70 age group there was no survival difference in either IDEA risk groups for 12 versus < 12 FOLFOX. Conclusions: > 50% of Stage III CRC patients ≥ 70 did not receive AC. OCRs were associated with a significant OS improvement but with higher PN than in < 70 cohort and higher persistence at 6 months. Irrespective of IDEA-defined risk groups,there was no statistically significant survival difference for Stage III CRC ≥70 receiving 12 versus < 12 FOLFOX.
Capecitabine and cisplatin as a second-line chemotherapy for patients with advanced biliary tract cancer.
Authors: Shin Kabsoo , Lee In Seok , Hong Tae Ho , Kim Joori , Lee Myung Ah
Published: February 2020

543

Background: Few data are available on second-line chemotherapy for patients with advanced biliary tract cancer. We retrospectively analyzed the efficacy and safety of capecitabine and cisplatin combination as second-line chemotherapy for advanced biliary tract cancer. Methods: Between Mar, 2014 and Dec, 2018, advanced BTC patients who received second-line capecitabine and cisplatin after the failure of the gemcitabine-platinum combination were analyzed. Progression‐free survival (PFS) and overall survival (OS) were estimated with the Kaplan‐Meier method. Cox models were used for multivariate analyses. Results: Of total 40 patients, male: female was 24(60%) to 16(40%), and the median age was 68 years old (range: 45-77) . As primary tumor site, 8(20%) was intrahepatic, 16(40%) was extrahepatic and 16(40%) was gallbladder. Initially metastatic disease was 22(55%), and recurrent disease after curative surgery was 17(42.5%) and locally advanced unresectable disease was 1(2.5%). 30(75%) patients had ECOG performance status of 0-1. The mean number of the chemotherapy cycles was 3.3 ± 2.0. Objective response rates and stable disease were 12.5% and 25%, respectively. Median PFS and median OS from the beginning of the capcitabine and cisplatin combination were 2.8 and 7.0 months, respectively. Grade 3-4 adverse event were neutropenia (n = 7, 17.5%), anemia(n = 3, 7.5%), hand-foot syndrome (n = 3, 7.5%), nausea and vomiting(n = 2, 5%), peripheral neuropathy (n = 2, 5%) and mucositis(n = 1, 2.5%). And there was no treatment related death. Conclusions: This study showed the possible survival benefit of capecitabine and cisplatin combination as second-line chemotherapy for advanced biliary tract cancer.
Pattern of progression in advanced HCC treated with ramucirumab/placebo: Results from two randomized phase III trials (REACH/REACH-2).
Authors: Reig Maria , Galle Peter R. , Kudo Masatoshi , Finn Richard S. , Llovet Josep M. , Schelman William R. , Liang Kun , Wang Chunxiao , Widau Ryan C. , Abada Paolo , Zhu Andrew X.
Published: February 2020

544

Background: REACH (NCT01140347) and REACH-2 (NCT02435433) studied ramucirumab (RAM) in pts with advanced hepatocellular carcinoma (HCC) following sorafenib; REACH-2 enrolled pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL, and met its primary endpoint of overall survival (OS) for RAM vs placebo. This post-hoc analysis examined radiological progression patterns (RPP) incidence every 6 weeks per RECIST v1.1, and if RPP were related to OS and post-progression survival (PPS). Methods: Pts with advanced HCC, Child-Pugh A, and ECOG PS 0-1 with prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to receive RAM 8 mg/kg or placebo Q2W. Among pts with ≥1 RPP (new extrahepatic lesion [NEH], new intrahepatic lesion [NIH], extrahepatic growth [EHG], or intrahepatic growth [IHG]), results were analyzed by trial and for pooled individual patient data of REACH-2 and REACH (AFP ≥400 ng/mL). Cox models evaluated treatment effect of RPP on OS, and prognostic implications of RPP on OS (adjusting baseline ECOG PS, AFP, macrovascular invasion, arm) and on PPS (adjusting ECOG PS, AFP at progression). Results: RPP incidence in the pooled population was: NEH 39%; NIH 24%; EHG 39%; IHG 37%. When examining NEH vs other RPP, PPS was worse among those with NEH in REACH (HR 2.33, 95% CI 1.51, 3.60), REACH-2 (HR 1.49, 95% CI 0.72, 3.08), and the pooled data (HR 1.75, 95% CI 1.12, 2.74). Use of post-discontinuation therapy may have influenced results. OS was also significantly reduced in those with NEH across studies (Table). RAM provided OS benefit in the pooled population, including pts with NEH (HR 0.56, 95% CI 0.39, 0.80). Conclusions: Acknowledging limitations of post-randomization RPP analysis, the emergence of NEH on RAM or placebo may be an independent poor prognostic factor for PPS. The impact of RAM on OS was consistent across all RPP subgroups. Clinical trial information: NCT01140347 and NCT02435433.

[Table: see text]
Exploring the genomic landscape of hepatobiliary cancers to establish a novel molecular subtype classification.
Authors: Scholer Anthony Joseph , Garland-Kledzik Mary , Ghosh Debopyria , Santamaria-Barria Juan , Khader Adam , Orozco Javier , Goldfarb Melanie , Marzese Diego M.
Published: February 2020

562

Background: The current understanding of the genomic landscape of hepatobiliary cancer (HBC) is limited. Recent genomic and epigenomic studies have demonstrated that various cancers of different tissue origins can have similar molecular phenotypes. Therefore, the aim of this study is to evaluate the genomic alterations of HBCs as a first step towards creating a novel molecular subtype classification. Methods: A multidimensional analysis of next-generation sequencing for the genomic landscape of HBCs was conducted using mutational data from the AACR-Genomics Evidence Neoplasia Information Exchange database (v. 5.0). From 61 gene mutation platforms, we found 42 genes common to all HBC cases. Associations between histomolecular characteristics of HBCs (hepatocellular (HCC), cholangiocarcinoma (CCA), and gallbladder carcinoma (GBC)) with gene mutations (classified by COSMIC CENSUS) were analyzed using Pearson’s χ2 test. Results: A total of 1,017 alterations were identified in 61 genes (516 missense variant, 157 gene amplifications, 101 inactivating mutations, 106 truncating mutations, 84 upstream gene variants, 37 gene homozygous deletions, 16 gene rearrangements) in 329 patients: 115 (35%) CCA, 87 (26.4%) GBC, and 127 (38.6%) HCC. The majority 77.8% (256) of tumors harbored at least two mutations and 38.9% (128) had at least one alteration, with GBC having a higher average number of alterations (3.28) than HCC (3.23) and CCA (2.49) However, HCCs had the higher maximum number of alterations compared to CCA and GBC (p < 0.05). The ten genes most frequently altered across all the HBCs were TP53, TERT, CTNNB1, KRAS, ARID1A, CDKN2A, IDH1, PIK3CA, MYC, and SMAD4 with disparities in the distribution of genes altered repeatedly observed (p < 0.001). IDH1 mutations were associated with CCA, CTNNB1 and TERT mutations with HCC, and TP53 mutations with both HCC and GBC. Conclusions: HBC subtypes appear to have unique mutational landscapes, but also significant overlap of genetic signatures. Therefore, further exploratory genetic and epigenomic research is needed to develop a histomolecular classification algorithm that can be used for prognostic and therapeutic stratification of these cancers.
Hepatocyte-derived intrahepatic cholangiocarcinoma requires Yap and Sox9: A clinical and preclinical analysis.
Authors: Monga Satdarshan , Ko Sungjin , Molina Laura , Tao Junyan , Singhi Aatur D. , Bell Aaron
Published: February 2020

582

Background: Intrahepatic cholangiocarcinoma (ICC) is a liver tumor of increasing incidence and devastating prognosis. WGS and WES have identified numerous molecular pathways and fusions in ICC. Recent studies have also suggested hepatocyte as a cell source in a subset of ICCs, especially those associated with chronic liver insult such as non-alcoholic steatohepatitis (NASH) or primary sclerosing cholangitis (PSC). Methods: Since co-expression of myristoylated AKT (myrAKT) & Notch intracellular domain (NICD) in hepatocytes using sleeping beauty transposon/transposase-based hydrodynamic tail vein injection (SB-HTVI) lead to ICC, we initiated a comprehensive analysis of mechanism of ICC development in patients and in this preclinical model. Results: Over 90% of CC samples exhibited high levels of nuclear SOX9 & YAP, in addition to a significant positivity for pAKT in ICCs as compared to extrahepatic CC. We also identified upregulation of p-AKT, SOX9 & YAP in hepatocytes of patients with PSC and NASH. This was also seen in many murine models of cholestatic injury and NASH. While co-expression of myrAKT+NICD led to hepatocyte-derived ICC, conditional deletion of either Yap or Sox9 significantly delayed and almost completely abrogated ICC development. While Yap deletion impaired the initial HC-to-BEC fate conversion, Sox9 elimination had no such effect on reprograming. Interestingly, following deletion of either Yap or Sox9 we observed a few AKT/NICD-driven ICC tumors expressing either Sox9 or Yap but not both. This also occurred in a small subset of human CC tumors which may be Sox9+Yap- (4%) or Sox9-Yap+ (3.7%), showing that deletion of Yap or Sox9 is not sufficient to completely abrogate ICC development. We finally demonstrated that conditional deletion of both Yap & Sox9 completely blocked development of ICC tumors in the myrAKT+NICD model. Conclusions: Thus, we show that cholestatic injury or NASH in humans and mice induces hepatocyte-to-cholangiocyte reprograming to increase the risk of ICC development. We also provide evidence for critical but distinct roles of Yap and Sox9 in ICC development and demonstrate the therapeutic potential of targeting these factors for treatment of subsets of ICC.
Evaluation of the current treatment strategies for pancreatic neuroendocrine tumors.
Authors: Meredith Kenneth Lee , Maramara Taylor , Blinn Paige , Huston Jamie , Shridhar Ravi
Published: February 2020

611

Background: The management of pancreatic neuroendocrine tumors (PNET) varies between observation (O), pancreatic resection (PR) and enucleation (E). Currently, size, grade and location are used to determine which treatment strategy may be employed. We sought to evaluate each strategy and further clarify the role for surgery. Methods: Utilizing the National Cancer Database we identified patients with pancreatic neuroendocrine tumors. Tumors were stratified based upon size <1cm, 1-2cm and >2 cm. Mann-Whitney U and Kruskal were used to compare continuous variables and Pearson’s Chi-square test was used to compare categorical variables. Unadjusted survival analyses were performed using the Kaplan-Meier method. Multivariate analysis (MVA) was performed to identify predictors of survival. All statistical tests were two-sided and p<0.05 was considered significant. Results: We identified 17,921 patients. (<1cm, 1214, 1-2cm, 4325, and >2cm, 12,382) with a median age of 61.5 (18-90). Males more often presented with tumors >2cm, 56% vs 44%, <0.001. Tumors >2cm were more likely to be poorly differentiated (PD), p<0.001, have node positive disease, p<0.001 and less likely to undergo R0 resection, p<0.001. Tumors <1cm and well differentiated (WD) the median and overall 5-year survival in the O group was not reached (NR) (77%) vs 142.6 months (87%) in the surgery groups, p<0.04; in the 1-2 cm WD group 95.7 months and 60% vs NR and 94%, p<0.001. Similarly in the PD tumors <1cm the median and overall survival was 32.9 months and 24% in the O vs NR and 81%, p<001; in the 1-2 cm group 14.8 months and 19% vs NR and 73%, p<0.001. There were no differences in survival in patients undergoing PR or E, p=0.09. MVA revealed age, grade, Charleson Deyo score, tumor size, tumor location, and surgery (PR or E) were all independent predictors of survival. Conclusions: While observation is currently an acceptable option for the management of small <1cm WD PNET, we found an improvement in survival in the patients undergoing surgery. Additionally, 1-2 cm PNET benefited from the surgical approach. Enucleation and pancreatic resection did not differ in overall survival. Surgery for PNET should be considered as the first line treatment of these patients.
Exploring telotristat ethyl’s antiproliferative effects in patients with carcinoid syndrome (TELEACE): A real-world observational study.
Authors: Morse Michael , Liu Eric , Joish Vijay N. , Huynh Lynn , Cheng Mu , Totev Todor , Duh Mei S. , Lapuerta Pablo , Metz David C.
Published: February 2020

618

Background: Serotonin may have proliferative effects on neuroendocrine tumors (NETs). Inhibition of tryptophan hydroxylase (TPH), with resulting reduction of serotonin, may impact tumor size and growth (TG) in patients with NETs. We investigated the effects of TPH inhibitor telotristat ethyl (TE) on TG among patients receiving TE in clinical practice. Methods: A chart review study of 200 patients who had initiated TE was conducted. All patients had ≥2 radiological scans in the past 12 months prior to TE initiation and ≥1 scan post-TE initiation. Data were collected via a secure online portal. Descriptive statistics summarized physician and patient characteristics, and documented background NET treatment (i.e., somatostatin analog [SSA] and/or non-SSA). Longitudinal analyses of TG were assessed using a generalized linear regression model after controlling for documented background NET treatment and time since first scan. Results: Most physicians (71/114) were community-based oncologists. On average, patients were 61 ± 10 years old when initiating TE, 57% male, and 74% white; 61% had well-differentiated tumor with 61% of gastrointestinal origin. Patients received TE for an average of 12.0 ± 7.3 months and 82% (n = 163) were still receiving TE treatment at the time of data collection. The mean time from first scan to TE initiation was 5.6 ± 4.7 months and from TE initiation to last scan was 7.2 ± 6.3 months. Significant mean reductions in tumor size, after TE initiation, of 0.6 cm (p = 0.006) and TG of 8.5% (p = 0.045) were observed. Documented background NET treatment prior to initiating TE and time since first scan were not significant predictors of TG reduction. Results were consistent in a subset (n = 65) of patients who had no change in documented background NET treatment before and after initiating TE (mean reductions in tumor size 0.6 cm, p = 0.044 and TG 8.1%, p = 0.203). Conclusions: Treatment with TE may impact TG in patients with NETs. Prospective clinical studies are warranted to further examine the antiproliferative effects of TE.
Incidence and survival patterns of pancreatic neuroendocrine tumors over the last two decades: A SEER database analysis.
Authors: Sonbol Mohamad Bassam , Mazza Gina L. , Starr Jason Scott , Hobday Timothy J. , Halfdanarson Thorvardur Ragnar
Published: February 2020

629

Background: Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms with outcome varying by stage, grade, and clinical presentation. We present an analysis of the epidemiology and prognosis of patients (pts) with PNETs over the last two decades using a large population-based database. Methods: Using 2000-2016 data from the SEER 18 registry, we identified pts with PNETs using a combination of ICD-O-3 and histology codes. Age-adjusted incidence rates were calculated using SEER*Stat 8.3.5. Using SAS 9.4, overall survival (OS) was analyzed using the Kaplan–Meier method, and prognostic factors were investigated using a multivariate Cox proportional hazards model. Results: We identified 8,944 pts with PNETs. Annual incidence rates increased over the study period from 0.27 to 1.00 per 100,000. This was largely explained by a significant increase in number of pts diagnosed with localized disease in recent years (2012-2016). Median OS (mOS) for the entire cohort was 68 months (95% CI 64-73) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for pts diagnosed between 2009-2016 (mOS 85 months) compared to those diagnosed between 2000-2008 (mOS 46 months) (HR 0.66; p < .001). In addition, pts with grade I/II metastatic disease who underwent surgery experienced significantly longer OS (mOS 84 months) compared to those who did not undergo surgery (mOS 18 months) (HR 0.31; p < .001). In the multivariate analysis, more recent diagnosis, younger age, female sex, surgery, early stage, and lower grade favorably predicted OS. On the other hand, functional status and race did not predict OS. Conclusions: There has been a steady increase in the incidence of PNETs with notable stage migration as most patients are diagnosed in early stages of disease in recent years. Additionally, this increase in incidence is accompanied by a significant improvement in survival across different disease stages.
Causes of death following neuroendocrine tumors diagnosis: A United States population-based analysis.
Authors: Saad Anas M. , Halfdanarson Thorvardur Ragnar , Sonbol Mohamad Bassam
Published: February 2020

630

Background: Neuroendocrine tumors (NET) are heterogeneous in terms of prognosis based on location, grade, and stage. In this study we report causes of deaths (COD) in patients with NET. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) Program to query data of NET patients diagnosed between 2000 and 2016 and report COD following NET diagnosis. Results: We reviewed 94,399 NET cases of which 38,692 died during the follow-up period. The highest number of deaths (5,721) occurred within less than a year following grade 3 (G3) NET diagnosis while most deaths in grade 1/2 (G1/G2) cases occurred within 1-5 years of diagnosis (1,889 and 987, respectively). During the first year of diagnosis, most deaths were from NETs (73%), followed by other cancers (11.2%) and cardiac diseases (CD) (4.6%). As time passed, NET deaths decreased to be responsible for 24.3% of deaths after > 10 years of diagnosis, while other cancers (14%) and CD (19.7%) became more common. When dividing NET cases by grade, NETs were responsible for 42.8%, 63.4%, and 81.2% of deaths in G1, G2, and G3, respectively, while other cancers were responsible for 16.2%, 11.8%, and 7.2% of deaths, respectively and CDs were responsible for 12.3%, 7.2%, and 3.2% of deaths, respectively. For G1 localized NET: non-NET cancers (22.2%) was the most common COD followed by NET (19.7 %) and CD (16.8%). For G2 localized NET, NET was COD in 31.1% of cases followed by non-NET cancers (22.4%) and CD (13.8%). In metastatic disease, NET was the most common COD regardless of grade. Conclusions: In G1 and G2 localized NET, deaths were mostly secondary to non-NET causes. Therefore, counseling patients regarding survivorship with cancer-screening and focusing on prevention from non-cancer deaths is important. On the other hand, NET is responsible for most deaths in metastatic NET regardless of grade. Further advances in systemic therapies are needed to improve the outcomes of advanced disease.
Randomized Phase III Study of FOLFOX Alone and with Pegilodecakin as Second-line Therapy in Patients with Metastatic Pancreatic Cancer (SEQUOIA).
Authors: Hecht J. Randolph , Lonardi Sara , Bendell Johanna C. , Sim Hao-Wen , Macarulla Teresa , Lopez Charles D. , Van Cutsem Eric , Martin Andres J. Munoz , Park Joon Oh , Greil Richard , Lin Yong , Rao Sujata , Ryoo Baek-Yeol
Published: February 2020

637

Background: Effective therapies are limited for advanced metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) who have progressed after 1st line gemcitabine-based chemotherapy (Gem). FOLFOX has clinical benefit in Gem-refractory PDAC pts. A phase 1 trial demonstrated promising activity with pegilodecakin (PEG; pegylated IL-10) and FOLFOX in Gem-refractory PDAC pts, providing rationale for the phase 3 trial (SEQUOIA; NCT02923921). Methods: SEQUOIA is a randomized phase 3 study of FOLFOX alone or with PEG in Gem-refractory PDAC pts. Pts were randomized 1:1, excluding pts with prior surgery and radiation, and received FOLFOX ( dI-Leucovorin [400 mg/m2], oxaliplatin [85 mg/m2] followed by bolus 5-FU [400 mg/m2], and a 46-48 hr infusion of 5-FU [2400 mg/m2]) on day 1 of a 14-day cycle up to 12 cycles. PEG + FOLFOX arm received PEG (0.4 mg/d if ≤80kg and 0.8mg/d if > 80 kg) on Days 1-5 then Days 8-12 + FOLFOX. Pts could continue PEG monotherapy (0.8mg/d if ≤ 80 kg and 1.6 mg/d if > 80 kg) after FOLFOX discontinuation. Primary objective was OS. Secondary objectives included PFS, ORR per RECIST 1.1, and safety. Assuming OS HR of 0.74, the study was powered to 85% at 2-sided α = 0.05 with ~566 pts to detect superiority of PEG + FOLFOX. Results: As of Sept 9, 2019, 567 pts were randomized to PEG + FOLFOX (283) or FOLFOX (284). The majority (94.7%) had 1st line Gem+nab paclitaxel. The mOS was similar between FOLFOX + PEG arm [5.8 months] and FOLFOX arm [6.3 months] with HR = 1.045 (95% CI [0.863, 1.265], p = 0.6565). No statistical difference was observed for PFS, mPFS was 2.1 months in both arms with HR = 0.981, (95% CI [0.808, 1.190], p = 0.8144). ORR was 4.6% on the PEG+FOLFOX arm and 5.6% on the FOLFOX arm. Grade ≥3 adverse events that were 5% higher on the PEG+FOLFOX arm included thrombocytopenia (25.2% vs. 3.6%), anemia (16.2% vs. 4.0%), neutropenia (29.5% vs. 22.7%), and fatigue (17.6% vs. 10.8%). Conclusions: The addition of PEG to FOLFOX did not improve efficacy (OS, PFS, ORR) in advanced PDAC pts who have progressed after 1st line Gem-containing therapy. Safety findings were consistent with previous data observed from PEG + chemotherapy; toxicity was manageable and tolerable. Clinical trial information: NCT02923921.
Evaluation of ICD codes and phecodes for the identification of pancreatic cancer in a large genomic database.
Authors: Isom Chelsea Anne , Gamazon Eric R. , Tan Marcus Chuan Beng
Published: February 2020

642

Background: Large genomic databases linked to electronic health records promise to shed light on molecular mechanisms underlying rare diseases, such as pancreatic cancer. However, accurately identifying patients with the desired phenotype can be challenging. This is particularly the case for pancreatic tumors, since ICD codes do not distinguish between pancreatic adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (pNET). Previous studies have shown that ICD codes aggregated by phenotype, known as “phecodes”, have a higher accuracy in identifying specific phenotypes than ICD codes themselves; however, their performance in identifying cancers of the pancreas has not been studied. Methods: From a large deidentified genomic database, two queries were performed to identify all adults with pancreatic cancer for a GWAS study, one using ICD-9/10 codes and the other using phecodes. The medical records for all patients identified from both queries were then reviewed to confirm the presence and histologic type of pancreatic cancer. Results: Of the 91,985 genotyped adults in the database, ICD-9/10 codes identified 1,247 patients with pancreatic cancer, compared with only 422 patients identified by the phecode query. All patients in the phecode cohort were also found in the ICD cohort. Of the 1,247 patients in the ICD cohort, 760 were confirmed to have pancreatic cancer on review of the health records (594 with PDAC, 166 with pNET) whereas in the phecode cohort, only 251 were confirmed to have pancreatic cancer (159 with PDAC, 92 pNET). The positive predictive value (PPV) for PDAC in the ICD query was 47%, compared with 38% for the phecode cohort. The ICD and phecode cohorts had similarly low numbers of pre-malignant cystic tumors (5% in each cohort) and other periampullary cancers (3%). Conclusions: In this large genomic database, the use of ICD-9/10 codes for pancreatic cancer was able to identify nearly three times as many patients with pancreatic cancer and had a higher PPV compared to using phecodes. Therefore, ICD codes, rather than phecodes, should be used to identify patients with pancreatic cancer for subsequent genotyping analysis, though caution is required because the PPV is still low.
Detection of circulating tumor DNA in pancreas cancer.
Authors: King Daniel , Alizadeh Ash A. , Fisher George A.
Published: February 2020

645

Background: Pancreas cancer remains a leading cause of cancer-related death. Improved detection of early relapse or early failure of chemotherapy also has the potential to further improve outcomes. Exploring circulating tumor DNA (ctDNA) in this setting is an area of active investigation. Methods: We previously developed an approach, CAPP-Seq, combining high-depth sequencing with several strategies of error-suppression to identify minute amounts of circulating tumor DNA. We then trained and validated a new capture panel for pancreas cancer from 640 tumors from three data sources (TCGA, ICGC, UTSW), targeting 265 kb of the genome. We enrolled two cohorts of patients with pancreatic cancers at Stanford Cancer Center: (1) patients with localized tumors undergoing resection with curative intent, and (2) patients with unresectable or metastatic disease undergoing systemic therapy. Results: As of August 2019, we recruited 131 patients with at least one blood collection, with 63% having resectable disease and 27% having advanced disease; 59 patients had 2 or more blood collections. Stage distribution included 34% stage I, 33% stage II, 18% III, 16% IV disease. Approximately 15% had normal CA19-9 levels. Deep sequencing (4,000x unique depth) of an initial set of resected pancreatic tumors and matched germline specimens identified 1-6 non-synonymous coding mutations per case (median=3, n=14), with the most frequently mutated genes involving KRAS (79%), TP53 (50%), SMAD4 (29%). Among newly diagnosed treatment-naïve patients with resectable adenocarcinoma (n=9), we detected ctDNA in 4 patients (44%) prior to surgery including with AFs ranging from 0.27% - 0.88%. Subsequent sequencing will compare patients with and without neoadjuvant therapy prior to resection, selection of unresectable patients across a larger range of tumor burden and across multiple timepoints, and integration of large-scale copy number variant detection using low-pass whole-genome sequencing. Conclusions: Circulating tumor DNA monitoring with CAPP-Seq shows promise for improved detection of PDAC. Two key applications include early detection of minimal residual disease after resection and early assessment of response to chemotherapy.
Survival outcomes based on sequence of therapy using FOLFIRINOX and nab-paclitaxel + gemcitabine in metastatic pancreatic ductal adenocarcinoma.
Authors: Baron Kelsey , Nevala-Plagemann Christopher Duane , Moser Justin , Haaland Benjamin , Wang Xuechen , Garrido-Laguna Ignacio
Published: February 2020

657

Background: Optimal sequence of therapy for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) is unknown. FOLFIRINOX (FFX) and Gemcitabine + Nab-paclitaxel (AG) are standard first line (1L) therapies. They have never been prospectively compared. Therefore, we retrospectively compared the overall survival (OS) of patients treated with 1L AG and second line (2L) FFX compared to those treated with 1L FFX and 2L AG. Methods: Patients with mPDAC treated with 1L FFX followed by 2L AG, or vice versa were identified using the Flatiron Health EHR-derived nationwide database. To avoid immortal time bias, patients who received no 2L were included. OS from the initiation of 1L was compared with Kaplan Meier curves and log rank analysis. A cox model, stratified by deciles of propensity score (PS), was used to estimate the effect of treatment on OS with adjustment for differences between the groups. Results: 3,042 patients were identified. 2001 patients received 1L AG. Among these patients, 1446 received 2L FFX, and 555 received no 2L. 1041 patients received 1L FFX. Among these patients, 496 received 2L AG, and 545 received no 2L. Median OS and 1-year OS for those treated with 1L AG followed by 2L FFX or no therapy was 6.1 months (95% CI:5.6 – 6.5) and 25% (95% CI: 0.23 – 0.28). Median OS and 1-year OS for patients treated with 1L FFX followed by AG or no therapy was 8.7 months (95% CI: 7.9 – 9.2) and 36% (95% CI: 0.33 – 0.39). The propensity stratified hazard ratio between these two groups was 0.76 (95% CI: 0.69 – 0.83), favoring 1L FFX. Median OS for patients treated with 1L FFX and 2L AG versus 1L AG and 2L FFX was not significantly different (12.0 m vs. 12.5 m; HR 1.04; 95% CI: 0.90 - 1.20). Conclusions: In this analysis of real-world data, 1L FFX was associated with increased OS in propensity analysis. For patients who received both FFX and AG, median OS was similar, regardless of the sequence.
Effects of duration of initial treatment on postoperative complications in pancreatic cancer.
Authors: Takeda Naoya , Yamada Suguru , Takami Hideki , Sonohara Fuminori , Hayashi Masamichi , Yoshioka Isaku , Shibuya Kazuto , Matsui Koshi , Hirano Katsuhisa , Watanabe Toru , Tohmatsu Yuuko , Kimura Nana , Hojo Shozo , Sawada Shigeaki , Okumura Tomoyuki , Nagata Takuya , Kodera Yasuhiro , Fujii Tsutomu
Published: February 2020

658

Background: Early studies raised concerns over whether preoperative treatment led to postoperative complications or even death. In contrast, recent studies have reported that initial treatment (IT) prior to resection of pancreatic ductal adenocarcinoma (PDAC) is safe, with no significant increase in overall morbidity or mortality, despite evidence for more advanced disease. In this study, we analyzed the clinical impact of chemotherapy or chemoradiotherapy as IT, focusing on treatment duration, on morbidity and mortality in patients with resected PDAC. Methods: We enrolled 509 consecutive patients, with 417 in the upfront surgery group and 92 in the IT group. The IT group was subdivided into 72 patients treated for < 8 months and 20 treated ≥8 months. We compared rates of postoperative Clavien–Dindo grade ≥III complications between the groups. Multivariate logistic regression analysis was used to find independent predictors of complications. Results: The upfront surgery and IT groups did not significantly differ in overall postsurgical complications. The rate of postoperative pancreatic fistula was significantly less in the IT group. Rates of other complications did not significantly differ, except for severe infection and delayed gastric emptying. Initiation of adjuvant chemotherapy was later in the IT group than in the upfront surgery group (43.2 vs 57.8 days, P < 0.001). In contrast, rates of overall complications significantly differed between the < 8 months and ≥8 months IT groups, although their background clinical factors did not differ. In multivariate analysis, operative procedure (distal pancreatectomy and distal pancreatectomy with celiac axis resection) (odds ratio [OR] 6.950, P = 0.0416) and IT ≥8 months (OR: 4.508, 95%, P = 0.0156) were independent predictive factors for postoperative complications. Conclusions: The incidence of postoperative complication was similar between the upfront surgery group and the IT group, however, it was significantly higher in the ≥8 months IT group in patients who underwent PDAC resection.
The role of neoadjuvant chemotherapy in elderly patients with borderline or locally advanced pancreatic cancer: Is it safe and feasible?
Authors: Oba Atsushi , Lieu Christopher Hanyoung , Meguid Cheryl Lauren , Davis Sarah Lindsey , Leal Alexis Diane , Purcell Tom , King Gentry Teng , Goodman Karyn A. , Schefter Tracey E. , Gleisner Ana Luiza , Ahrendt Steven Arthur , Leong Stephen , Messersmith Wells A. , Shulick Richard D. , Del Chiaro Marco
Published: February 2020

685

Background: For borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC), neoadjuvant (NAT) FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP) are standard treatment options and these regimens have shown a survival advantage over single-agent gemcitabine. However, the role of these modern therapeutic regimens in elderly patients is debatable. In this analysis, we evaluated the outcomes of neoadjuvant treatment (NAT) with combination chemotherapy in elderly patients. Methods: 230 consecutive patients who underwent neoadjuvant treatment for BRPC/LAPC discussed and planned for NAT at the University of Colorado Cancer Center from January 2011 to March 2019 were reviewed. 214 patients who received FOLFIRINOX (n = 143) or GnP (n = 71) were eligible for analysis. We divided all patients into three groups ( < 70, 70-74, ≥75 years) and compared the short-term and long-term outcomes. Results: Of 214 patients, patients < 70 (n = 147) received FOLFIRINOX more frequently than the other groups (p < 0.001): FOLFIRINOX: 115 cases, GnP: 32 cases, 70-74 years (n = 33): FOLFIRINOX: 15 cases, GnP: 18 cases, and ≥75 years (n = 34): FOLFIRINOX: 13 cases, GnP: 21 cases. Resection rates were not statistically different between three groups ( < 70: 62%, 70-74: 70%, ≥75 years: 56%, p = 0.504). There was a slight trend towards worse survival in the two older groups (Median Survival Time [MST]: < 70: 23.2 mo., 70-74: 19.5 mo., ≥75 years: 17.6 mo., p = 0.075) The FOLFIRINOX group was superior to GnP group in all three groups (MST: < 70: 25.6 vs 18.2 mo., p = 0.017; 70-74: 33.2 vs 16.1mo., p = 0.029; ≥75 years: not reached vs 16.1 mo., p = 0.135). There were no toxic deaths or 30 day mortality after pancreatectomy in the study population. Conclusions: Neoadjuvant combination chemotherapy regimens were safe and feasible for elderly patients. Neoadjuvant therapy with FOLFIRINOX was associated with a survival advantage vs GnP and is an good option for fit and elderly patients ≥75 years.