bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical impact of preoperative biliary drainage on postoperataive complications in pancreaticoduodenectomy.
Authors: Okabe Hirohisa
Published: January 2019

302

Background: Biliary drainage is sometimes necessary for patients undergoing pancreaticoduodenectomy (PD) because of tumor invasion to the biliary tract. The current study aims to explore the clinical impact of preoperative biliary drainage (PBD) on postoperative complication in PD. Methods: One hundred sixty-six patients who underwent PD from 2012–2017 were enrolled in this study. Clinical impact of PBD on clinical course was examined. Results: There were 66 patients (40%) undergoing PBD. Patients with PBD showed significantly higher infection rate of bile juice collected at surgery (p < 0.0001) and contamination rate of ascites collected from intraperitoneal drain on postoperative day 3 (POD3) (p < 0.0001) than patients without PBD. Severe postoperative complication (Clavien Dindo ≥ IIIB)was associated with contaminated ascites on POD3 (p = 0.031), but not with PBD. Among patients with PBD, fifty-two patients (79%) received preoperative ERBD. Infection of bile juice at surgery was not associated with the procedure of PBD (ERBD, ENBD or PTCD), but correlated with the duration of drainage. Receiver operating characteristic analysis revealed that patients with PBD for more than 28 days occurs contamination of bile juice at surgery. Among patients with both the contaminated bile juice at operation and the contaminated ascites on POD3 (n = 24), both were consistent in 19 patients (79%). Although Enterococcus faecalis was the most species seen in their bile juice, patients with the contamination of other species of Enterobacter (36%) and Streptococcus (2%) showed higher severe postoperative complication rate than others (p = 0.049). Conclusions: PBD was not directly associated with severe postoperative complication, but the duration of drainage for > 28 days was correlated with contamination of the bile juice. Contaminated ascites on POD3 caused by infectious bile juice at surgery was an only factor associated with severe postoperative complications and therefore needs careful management of the drain removal and selection of antibiotics after surgery.
Real-world outcomes among patients (pts) treated with gemcitabine (GEM)-based therapy post-FOLFIRINOX (FFOX) failure in advanced pancreatic cancer (APC).
Authors: Tsang Erica S , Spratlin Jennifer L. , Cheung Winson Y. , Kim Christina , Kong Shiying , Xu Yuan , Gill Sharlene
Published: January 2019

303

Background: Limited evidence exists for the selection of chemotherapy in APC after first-line (1stL) FFOX. Gemcitabine/nab-paclitaxel (GEMNAB) is publicly funded for second-line (2ndL) use in the provinces of Alberta (AB) and Manitoba (MB), but is not covered in British Columbia (BC). We compared population-based outcomes by region to examine the utility of 2ndL GEMNAB versus GEM alone. Methods: We identified pts treated with 1stL FFOX between 2013-2015 across BC, AB, and MB. Baseline characteristics and treatment regimens were compared between AB/MB and BC. Survival outcomes were assessed by the Kaplan-Meier, and compared with log-rank test. Results: 370 pts treated with 1stL FFOX were identified (145 AB/MB, 225 BC), with a median age of 61y, 42% female, and 68% with metastatic disease (similar in both groups). Receipt of 2ndL therapy was 49% AB/MB vs 44% BC ( p = 0.35), and time from diagnosis to 2ndL therapy measured 7.6 mos AB/MB versus 9.4 mos BC ( p = 0.1). The distribution of 2ndL gemcitabine use was: 72% GEMNAB, 23% GEM in AB/MB versus 27% GEMNAB, 66% GEM in BC ( p < 0.001). Median overall survival (OS) from diagnosis was similar: 12.4 mos in AB/MB versus 10.9 mos in BC ( p = 0.75). On Cox regression analysis, region was not significant. A secondary survival analysis by 2ndL regimen demonstrated a median OS of 18.0 mos with GEMNAB versus 14.3 mos GEM ( p < 0.01). Conclusions: In our population-based comparison of APC pts treated with 1stL FFOX, survival outcomes were comparable regardless of publicly funded access to 2ndL GEMNAB versus GEM. OS by regimen favored 2ndL GEMNAB, but patient selection may be largely responsible for this difference. Randomized trials are needed to demonstrate the benefit of GEMNAB post-FFOX in APC.
A multicenter, open-label, phase I study of nivolumab alone or in combination with gemcitabine plus cisplatin in patients with unresectable or recurrent biliary tract cancer.
Authors: Ikeda Masafumi , Ueno Makoto , Morizane Chigusa , Kobayashi Satoshi , Ohno Izumi , Kondo Shunsuke , Okano Naohiro , Kimura Keisuke , Asada Suguru , Namba Yoshinobu , Okusaka Takuji , Furuse Junji
Published: January 2019

306

Background: This phase 1 study evaluated the safety and efficacy of the immune checkpoint inhibitor nivolumab (monotherapy or combined with chemotherapy) in Japanese patients with biliary tract cancer (BTC). Methods: In the monotherapy cohort (N = 30), patients with unresectable/recurrent BTC refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg, 2-week intervals). In the combined therapy cohort (N = 30), chemonaïve patients with unresectable/recurrent BTC received nivolumab (240 mg, 2-week intervals) plus cisplatin-gemcitabine chemotherapy. The primary objective was tolerability and safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) (central assessment). Results: The most frequently reported nivolumab-related adverse events were decreased appetite (5/30, 17%), malaise (4/30, 13%), and pruritus (4/30, 13%) in the monotherapy cohort, and malaise (8/30, 27%) and decreased appetite (7/30, 23%) in the combined therapy cohort. Median duration of follow-up for efficacy (Table) was 5.1 months (mo; monotherapy cohort) and 8.2 mo (combined therapy cohort). In the monotherapy cohort, median OS and median PFS were longer in patients with programmed death-ligand 1 (PD-L1) ≥ 1% (including the patient who responded) than in those with PD-L1 < 1% (Table). In the combined therapy cohort, the ORR was higher, but median OS and median PFS were lower, in patients with PD-L1 ≥ 1% than in those with PD-L1 < 1% (Table). Conclusions: Nivolumab was well tolerated, with a manageable safety profile and signs of clinical activity, in this phase 1 study in patients with unresectable/recurrent BTC. PD-L1 expression status may predict clinical activity of nivolumab in advanced BTC. Clinical trial information: JapicCTI-153098. [Table: see text]
Comparison of clinical and pathologic staging in esophageal cancer.
Authors: Scholer Anthony Joseph , Uppal Abhineet , Ghosh Debopriya , Kledzik Mary , Santamaria-Barria Juan , Khader Adam , Fischer Trevan D , Goldfarb Melanie
Published: January 2019

31

Background: Randomized trials have demonstrated improved disease-free survival for more advanced esophageal cancer treated with neoadjuvant chemo radiation (NCXRT). However, accurately treating a patient relies on the accuracy of pre-treatment T and N staging with endoscopy ultrasound and cross-sectional imaging, which is unknown, and can lead to over or under-treatment. Therefore, the objective of this study is to compare the clinical and pathologic staging in patients with early esophageal cancer that would be impacted by inaccurate clinical staging. Methods: Primary, non-metastatic esophageal cancer patients who had upfront esophagectomy without neoadjuvant CXRT between 2004 and 2013 were identified in the National Cancer database. The Kappa index was used to determine patient and tumor characteristics that effected concordance between clinical and pathologic T and N staging (p > 0.05 shows discordance). Results: Of 1810, 43 % of clinical T2 tumors were upstaged compared to 38% of T1 and 13% of clinical T2 were downstaged. Clinically positive N1 disease had the greatest concordance (91%) between clinical and pathologically staging, compared to clinical N0, where 57% were upstaged. Some patient groups significantly impacted the concordance rates of staging. T-Stage was less accurate (more discordant) in females (68%, kappa 0.41, p = 0.057) and Blacks (59%, kappa 0.023, p = 0.069) whereas overall N-stage was more discordant in Hispanics (83%, kappa, 0.67, p = 0.165). Conclusions: Accurate staging for esophageal adenocarcinoma can significantly impact the course of treatment. Upfront surgical resection of clinical T1 lesions and node negative tumors are at risk for under-treatment due to poor concordance with pathological stage, which may lead to decreased survival compared to a regimen of NCXRT. Clinicians should be aware of patient and tumor characteristics that increase the likelihood of discordance between clinical and pathologic staging when discussing treatment options for patients with esophageal cancer.
An updated retrospective review of the safety and efficacy of sorafenib for recurrent hepatocellular carcinoma post-liver transplantation.
Authors: Feng Sophie , Fallah-Rad Nazanin , Cao Yanshuo , Knox Jennifer J. , Jang Raymond Woo-Jun , Dhani Neesha C. , Sapisochin Gonzalo , Grant David , Greig Paul D , Lilly Leslie , Gorgen Andre , Chen Eric Xueyu
Published: January 2019

313

Background: Orthotopic liver transplantation (OLT) is a potentially curative treatment for hepatocellular carcinoma (HCC). Despite an estimated recurrence rate between 15%-20%, there is currently no proven systemic therapy for the treatment of HCC relapse post OLT. Sorafenib has been a standard therapy for advanced HCC however data is lacking for the safety and efficacy of sorafenib in the setting of concurrent immunosuppressive agents. Methods: A retrospective review was performed of patients who received sorafenib for HCC relapse after OLT. Data on patient characteristics, treatment toxicity and efficacy was collected. The primary objectives were to evaluate toxicity and safety of sorafenib when used in combination with immunosuppressive therapies such as calcineurin and mTOR inhibitors. Secondary objectives were objective response rate, progression free survival (PFS), and time on therapy. Results: 35 patients over the last 11 years received sorafenib for HCC recurrence following OLT. 54.3% of patients received concurrent immunosuppression with tacrolimus. Toxicity from sorafenib was as expected, with no cases of acute or chronic organ rejection whilst on treatment. The median maximum tolerated dose was 400 mg a day with 40% of patients requiring dose reductions. The incidence of any adverse events (AEs) was 88.6%, with 17.1% having Grade 3-4 toxicity. Incidence of Grade 3-4 liver dysfunction was higher than historical studies at 6%. The overall response rate was 2.8% with a median PFS of 2.8 months. Median time on sorafenib was 3.1 months. Conclusions: There is a paucity of evidence guiding treatment of HCC recurrence following OLT. This retrospective review is one of the largest in the literature and shows that sorafenib used concurrently with immunosuppressive therapy for organ transplant is safe, with no precipitation of acute or chronic rejection, although liver function should be monitored closely. The median PFS in our cohort was shorter than expected. The efficacy of other agents should be explored in this population.[Table: see text]
Gemcitabine/nab-paclitaxel (G/A) alternating with 5-FU/leucovorin/irinotecan (FOLFIRI) in first-line metastatic pancreatic cancer (MPC): Updated results.
Authors: Picozzi Vincent J. , Lin Bruce Shih-Li , Mandelson Margaret T.
Published: January 2019

314

Background: Both gemcitabine- and 5-FU-based chemotherapy (chemoRx) have demonstrated efficacy in MPC. Alternating these two regimens may 1) decrease toxicity 2) slow emergence of resistant cancer biology, and 3) provide a broader platform for addition of other (non)chemotherapeutic (CT) agents to the base regimen. The strategy using alternating G/A and FOLFIRI in MPC was first tested in the SEENA-1 trial (Picozzi et.al. GI Cancer Symposium 2017) and further suggested to be of benefit both at our own institution (Picozzi et.al. ASCO 2018 ) and elsewhere (Assenat et.al. ASCO 2018). We extend and update our observations here. Methods: Eligible patients (pts) had the following characteristics: 1) bx proven de novo MPC, 2) chemoRx naive, 3) ECOG PS 0/1, and 4) bi-dimensionally measurable disease. Treatment (Rx) consisted of 1) gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/2d 1,(8),15 alternating every 8 weeks (2 cycles) with FOLFIRI. Pts were radiographically restaged every 8 weeks. Rx was continued for up to 48 weeks, at which time additional Rx was given per physician/patient decision. Results: As of 9/2018, 61 pts have been treated at our institution via this method. Median age is 67; ECOG PS 0/1 58/42%. Disease site involvement included liver, lung, peritoneum 79%, 39%, and 23% respectively. Toxicity is less than typical with either individual regimen (e.g. no ≥ grade 3 neuropathy or diarrhea has been seen to date). Of pts followed for ≥ 4 months , 45/51 (88%) received ≥ 4 cycles Rx. Median number Rx cycles received was 9; 15/34 (44%) pts followed for > 1 year completed 48 weeks Rx. Disease control rate at 16 weeks in 45 evaluable patients is 89% (47% PR, 42% SD, 11% PD). 27/61 pts (44%) are currently on Rx (4 transferred care from region, 30 deceased). Currently, median f/u is 11.8 mo; median OS is 14.1 mo ( 95% CI 10.6-20.3 mo) 6,12, 18 and 24 mo OS are 88%,57 %, 34%, and 15% respectively. Conclusions: 1) Alternating G/A and FOLFIRI in MPC appears to have a more favorable toxicity profile than either individual regimen. 2) Median OS in MPC using this Rx is at least competitive with other reports. 3) The above method has potential to integrate other therapeutic agents/ treatment approaches.
Efficacy and safety of nivolumab in first-line or further treatment of advanced metastatic biliary tract cancer.
Authors: Gou Miaomiao , Zhang Yong , Si Haiyan , Dai Guanghai
Published: January 2019

315

Background: PD-1 inhibitors have improved efficacy in many cancers. There are few report of nivolumab for metastatic biliary tract cancer (MBTC). This study reviewed the efficacy and safety of nivolumab for MBTC to improve efficacy and survival. Methods: Thirty patients with MBTC were voluntarily treated with non-clinical nivolumab at the PLA General Hospital. Nivolumab 200 mg or 180 mg was administered according to patient tolerance. Progression free survival (PFS), overall survival (OS) was evaluated by kaplan-meier and univariate analysis were carried out among clinical characteristics. Objective response rates (ORR), disease control rates (DCR), and treatment-related adverse events (AEs) were also evaluated. Results: The median treatment cycle is 4 cycles. One case was complete response (CR), 5 cases partial response (PR), 12 cases stable (SD). ORR was 20%, DCR was 60%. PFS was 3.1m (95% CI: 2.13~4.06 months). The AEs of nivolumab monothrapy were fatigue (3 cases), fever (2 cases), hypothyroidism (1 case), skin reaction (1 case). Nivolumab combined with chemotherapy related 1-2 hematologic toxicity were leukopenia (5 cases), thrombocytopenia (2 cases), and grade 3-4 were leukopenia (3 cases). Non-hematologic toxicity grade 1-2 were nausea and vomiting (4 cases), fatigue (4 cases), fever (3 cases), peripheral neurotoxicity (3 cases), and hypothyroidism (1 case). Univariate analysis showed that PFS was 4.20m in patients older than 53 years, slightly higher than those younger than 53 years (3.0 m, P = 0.047). PFS of nivolumab combined with chemotherapy was statistically significant compared with nivolumab monothrapy (4.1 m vs 2.3 m, p = 0.031). Patients with metastatic number > 2 had a shorter PFS than those < 2 (1.4 m vs 4.1 m, P = 0.05). PD-L1 expression positive have no better PFS compared with PD-L1 negative (3.6 m vs 3.1 m , p = 0.801). Multivariate analysis show nivolumab combined with chemotherapy was only independent factor for longer PFS (HR: 0.432, P < 0.05). Conclusions: the safety of nivolumab in MBTC is controllable. Subgroup analysis suggests that further selection of superior populations is needed and sample size need to be expanded to improve the efficacy of nivolumab in MBTC.
Safety and efficacy of lenvatinib by starting dose (8 mg or 12 mg) based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT.
Authors: Okusaka Takuji , Ikeda Kenji , Kudo Masatoshi , Finn Richard S. , Qin Shukui , Han Kwang-Hyub , Cheng Ann-Lii , Piscaglia Fabio , Kobayashi Masahiro , Sung Max W. , Chen Minshan , Wyrwicz Lucjan , Yoon Jung-Hwan , Ren Zhenggang , Stepan Daniel E. , Dutcus Corina E. , Tamai Toshiyuki , Ren Min , Hayato Seiichi , Kumada Hiromitsu
Published: January 2019

316

Background: Lenvatinib (LEN) demonstrated statistical confirmation of noninferiority versus sorafenib (SOR) for overall survival (OS), and improved progression-free survival (PFS), time to progression, and objective response rate (ORR) in pts with uHCC in REFLECT (Kudo M et al, Lancet 2018). We report the efficacy and safety of LEN by starting dose, which was based on body weight (BW). Methods: In REFLECT, a multicenter, open-label, noninferiority trial, pts with uHCC were randomized 1:1 to LEN (BW < 60 kg: 8 mg/d; BW ≥ 60 kg: 12 mg/d; QD) or SOR (400 mg BID). Efficacy was analyzed by intention-to-treat; safety was analyzed in pts who received treatment, in each dose group. Results: Of 478 pts randomized to LEN, 151 (male, 70%; median age, 65 y) and 327 (male, 91%; median age, 62 y) were included in the LEN starting dose groups of 8 mg/d or 12 mg/d, respectively. In the 8-mg group, 14% of pts were from Western regions; 86% from Asia-Pacific. In the 12-mg group, 42% were from Western regions; 58% from Asia-Pacific. Median OS was 13.4 (95% CI: 10.5–15.7) and 13.7 months (95% CI: 12.0–15.6); ORR was 22.2% and 24.9% for pts with BW < 60 kg and ≥ 60 kg, respectively. Median PFS was 7.4 months in both groups. Median duration of treatment: 8-mg group, 5.6 months; 12-mg group, 6.3 months. Mean LEN relative dose intensity: 8-mg group, 87.7%; 12-mg group, 87.5%. Most common any-grade adverse events (AEs; 8-mg vs 12-mg) were hypertension (43% vs 42%), diarrhea (35% vs 40%), decreased appetite (33% vs 35%), weight loss (29% vs 32%), and fatigue (28% vs 31%). Adjusted by treatment duration, AE rates (episodes/patient-year) were similar for 8-mg versus 12-mg: hypertension (0.79 vs 0.78), diarrhea (1.06 vs 0.99), decreased appetite (0.63 vs 0.59), weight loss (0.50 vs 0.51), and fatigue (0.52 vs 0.47). Pharmacokinetic profiles were similar between groups. Conclusions: LEN efficacy was comparable between groups. Exposure to LEN was greater for the 12-mg versus 8-mg group. When AEs were adjusted by treatment duration, no notable differences in the AE profiles between the starting doses were observed. Altogether, these results support the 8-mg and 12-mg starting doses based on BW of < 60 kg and ≥ 60 kg, respectively, in REFLECT. Clinical trial information: NCT01761266.
A multicenter, phase Ib/2 study of varlitinib plus gemcitabine and cisplatin (gem/cis) for treatment of naïve, advanced, or metastatic biliary tract cancer (BTC).
Authors: Oh Do-Youn , Yong Wei-Peng , Chen Li-Tzong , Kim Ji-Won , Chang Alex Yuang-Chi , Park Jin Hyun , Hsieh Chih-Yi , Shih Hsuan-Jen , McIntyre Nicola , Chen Ying-Chen , Chang Wei-Ling , McHale Mark , Lindmark Bertil
Published: January 2019

319

Background: BTC is a rapidly progressing cancer with limited response to chemotherapy. First line therapy (gem/cis) was defined in the ABC-02 study (Valle et al), where a 26% response was seen. HER family receptors are overexpressed and may be involved in tumour proliferation and survival in BTC. Varlitinib, a reversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, shows potent activity as monotherapy in preclinical BTC models and clinical activity in BTC patients (pts) in phase (ph) 1 trials. We conducted a ph Ib/2 study of varlitinib plus gem/cis in BTC to understand the safety profile and determine the maximum tolerated dose (MTD) of the combination. Methods: A modified 3+3+3 escalation design was used in Ph1b, with 2 varlitinib dose levels (200 and 300 mg BID) plus gem/cis on Day 1 and 8 in a 3 week cycle. The primary objectives are to determine the MTD and to characterize the safety profile. Secondary objectives are to assess the preliminary efficacy and to evaluate the pharmacokinetics of varlitinib and any circulating metabolites. Results: As of 10 Sep 2018, 21 pts were enrolled (11 in 200 mg cohort and 10 in 300 mg cohort, with 9 and 4 evaluable for MTD, respectively). Dose limiting toxicities (DLTs) were observed in 3 pts (1 G3 unconjugated hyperbilirubinemia and 1 G3 ALT transaminitis/G4 AST transaminitis in 200 mg cohort; 1 G4 thrombocytopenia/G3 febrile neutropenia/G3 AST elevation in 300 mg cohort). In 19 pts who were on varlitinib ≥ 1 month, 7 had partial response and 10 achieved stable disease (all > 12 weeks), giving the overall response rate of 37% and the disease control rate of 89%. The median PFS for the 200 mg cohort was 248 days and was not reached for the 300 mg cohort. The most common (≥ 30%) all-grade adverse events (AEs) regardless of causality were thrombocytopenia (62%), neutropenia (52%), anorexia (38%), nausea (38%), diarrhoea (38%), and anaemia (33%); the most common (≥ 15%) grade ≥ 3 AEs were neutropenia (48%), thrombocytopenia (33%), and anaemia (19%). Conclusions: Varlitinib plus gem/cis was well tolerated in the 200 mg cohort; the 300 mg cohort is ongoing. Preliminary anti-tumour activity was observed. Data will be updated at the time of presentation. Clinical trial information: NCT02992340.
Chemotherapy-induced neutropenia as a prognostic factor in patients with unresectable pancreatic cancer treated with gemcitabine and nab-paclitaxel.
Authors: Kan Motoyasu , Imaoka Hiroshi , Ikeda Masafumi , Mitsunaga Shuichi , Ohno Izumi , Hashimoto Yusuke , Sasaki Mitsuhito , Takahashi Hideaki , Watanabe Kazuo , Umemoto Kumiko , Kimura Gen , Shibuki Taro
Published: January 2019

324

Background: Chemotherapy-induced neutropenia (CIN) has been reported to be associated with a longer survival in patients with various cancers. The aim of our study was to assess whether CIN could also be a prognostic factor in patients with unresectable pancreatic cancer receiving treatment with gemcitabine (GEM) and nab-paclitaxel (nab-PTX). Methods: We retrospectively analyzed the medical records of pancreatic cancer patients who had been treated with GEM and nab-PTX as first-line chemotherapy. CIN was categorized on the basis of the worst WHO grade during chemotherapy: absent/mild (≦ grade 2), or severe (≧ grade 3). The background characteristics and CIN as time-varying covariates (TVCs) were analyzed as potential prognostic factors using a Cox proportional hazards model. Results: We analyzed a total of 291 patients (absent/mild CIN: 116 patients; severe CIN: 174 patients). The median time to severe CIN was 14 days (interquartile range: 10–39 days). The median overall survival (OS) was significantly longer in the severe CIN group than in the absent/mild CIN group (19.2 vs. 11.3 months; p < 0.001) After adjustments, severe CIN was identified as an independent predictor of the OS (HR, 0.54; 95% CI, 0.38–0.77; p = 0.001). In the TVC model also, severe CIN was identified as an independent factor (HR, 0.79; 95% CI, 0.68–0.92; p = 0.002). Conclusions: Severe CIN was associated with a longer survival in patients with pancreatic cancer treated with GEM and nab-PTX.
External beam radiotherapy for hepatocellular carcinoma with right atrium tumor thrombus.
Authors: Bitterman Danielle Sara , Edgington Samantha K. , Noe Bridget N. , Kim Daniel W. , Eyler Christine E. , Goyal Lipika , Zhu Andrew X. , Wo Jennifer Yon-Li , Hong Theodore S.
Published: January 2019

328

Background: Hepatocellular carcinoma (HCC) with right atrium tumor thrombus (RATT) via progression through hepatic veins into the inferior venal cava is a challenging entity with limited treatment options. Given the significant clinical sequelae of RATT, improved locoregional treatments are needed. We examined our experience with palliative right atrium-directed radiotherapy for HCC RATT. Methods: We conducted a retrospective study of 10 patients with HCC RATT treated with radiotherapy between 2011-2018. Patients with localized (n = 5) and metastatic (n = 5) disease were included. Clinical and treatment factors were collected. Results: Median follow-up was 3 mos. Baseline Childs Pugh score was A in 3 patients and B in 7 patients. The table below shows prescription and dosimetric data. No patients experienced grade ≥ 3 toxicity. The only major adverse cardiac event observed after radiotherapy was heart failure in 2 patients, and it was difficult to determine the contribution of treatment versus RATT. Three months post-radiation, 2 patients experienced a Childs Pugh score decline of > 2 points. At last follow-up, 5 patients were deceased, 4 patients were alive without progression, and 1 patient was alive with progression. Median progression free and overall survival was 3 mos (0.5-7 mos) and 3.5 mos (range 0.5-13 mos), respectively. RATT progression occurred in 1 patient, hepatic progression outside the treatment field occurred in 1 patient, and distant progression occurred in 2 patients. Causes of death included RATT progression (n = 1), HCC progression elsewhere (n = 2), hepatic decompensation (n = 1), and aspiration (n = 1). Conclusions: This unique series suggests HCC RATT-directed radiotherapy may be safe and locally effective. Prospective study is needed to understand the optimal treatment of these patients. [Table: see text]
Patterns of care and outcomes of definitive external beam radiotherapy and radioembolization for localized hepatocellular carcinoma: A propensity score-adjusted analysis.
Authors: Bitterman Danielle Sara , Sanford Nina Niu , Niemierko Andrzej , Mahal Brandon Arvin Virgil , Qadan Motaz , Ganguli Suvranu , Blaszkowsky Lawrence Scott , Zhu Andrew X. , Hong Theodore S. , Devlin Phillip M. , Goyal Lipika , Wo Jennifer Yon-Li
Published: January 2019

329

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. Most patients with localized HCC are not surgically operable or transplantation candidates, thus there is an increasing role for nonsurgical locoregional therapies. Ablative external beam radiotherapy (XRT) and transarterial radioembolization (TARE) are two emerging radiotherapeutic treatments for localized HCC. However, there are little data comparing their efficacy. We therefore sought to evaluate their utilization and efficacy in a large nationwide cohort. Methods: We conducted an observational study of 2,685 patients from the National Cancer Database diagnosed with American Joint Committee on Cancer 7th edition clinical stage I-III HCC between 2004-2015, treated with definitive-intent XRT delivered in 1-15 fractions or TARE. The association between treatment modality (XRT versus TARE [referent]) and overall survival (OS) was defined using propensity score-weighted Kaplan-Meier estimators and propensity score-weighted multivariable Cox regressions. Results: Among 2,685 patients, 2,007 (74.7%) received TARE and 678 (25.3%) received XRT, with increasing usage for both from 2004-2015 ( Ptrend < 0.001), but with overall greater uptake and absolute usage of TARE. Patients who received TARE were more likely to have elevated alpha fetoprotein and more advanced stage ( P < 0.05 for all). Median OS was 14.5 months for the entire cohort. XRT was associated with an OS advantage compared to TARE on propensity score-unadjusted analysis (adjusted hazard ratio [AHR] 0.80, 95% CI 0.67-0.95, P = 0.013), but not on propensity score-adjusted analysis (AHR 0.93, 95% CI 0.76-1.14, P = 0.491). Conclusions: Our study demonstrates that while both XRT and TARE usage have increased with time, there was greater uptake and absolute use of TARE, especially in advanced disease. Nevertheless, we found no difference in survival between XRT and TARE after propensity score-adjustment. Given their equivalence on retrospective study, prospective trials are necessary.
Lower risk of gastric atrophy and intestinal metaplasia in MALT lymphoma patients despite of H. pylori infection.
Authors: Lee San Min , Cheung Dae Young , Kim Jin Il , Park Soo-Heon
Published: January 2019

33

Background: Atrophic gastritis and intestinal metaplasia are sequential consequences of chronic H. pylori infection. H. pylori infection is a well-known risk factor for gastric adenocarcinoma and MALT lymphoma of stomach. Atrophic gastritis and intestinal metaplasia increase the risk of gastric adenocarcinoma development. The relationship between gastric MALT lymphoma and atrophic gastritis-intestinal metaplasia has not been on the spot of interest. We investigated the clinical characteristics of gastric MALT lymphoma and co-presence of atrophic gastritis and intestinal metaplasia. Methods: Study was conducted by review of electronic medical record of patients who were diagnosed with gastric MALT lymphoma at an academic institute, the Yeouido St. Mary's Hospital, Seoul, Korea, from January 2001 to March 2018. Results: A total of 51 subjects were enrolled consecutively during the study period and analyzed retrospectively. The mean age was 57.5-year-old. The male to female ratio was 1.04 (26/25). On histologic examination, background atrophic gastritis was accompanied in 64.7% (33/51). Serum pepsinogen I, II and gastrin level, as serological marker for atrophy, were evaluated in 21 subjects. Thirteen out of 21 (61.9%) were compatible with serological atrophic gastritis (pepsinogen I / II ratio of less than three or pepsinogen I < 70 ng/mL). Conclusions: Prevalence of background mucosal atrophy or intestinal metaplasia was around 60% in patients with gastric MALT lymphoma. This is comparable to that of general population and lower than that of patients with gastric adenocarcinoma. Even though age can be a confounding factor, this result suggests different carcinogenic pathway of gastric MALT lymphoma from adenocarcinoma.
In vitro and in vivo efficacy of the combined treatment of 150 khz tumor treating fields (TTFields) and sorafenib in hepatocellular carcinoma.
Authors: Weinberg Uri , Davidi Shiri , Gotlib Karnit , Zeevi Einav , Tempel- Brami Catherine , Schneiderman Rosa S. , Voloshin Tali , Giladi Moshe , Kinzel Adrian , Kirson Eilon David , Palti Yoram
Published: January 2019

333

Background: Hepatocellular carcinoma (HCC) is the third cause of cancer related mortality and the primary cause of cancer death. Sorafenib, an oral multikinase inhibitor is approved for patients with advanced HCC, yet its survival benefit is still limited. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. The aim of this work is to explore the potential of the use of TTFields alone and in combination with Sorafenib as a treatment for HCC. Methods: HepG2 and Huh-7D12 cells were treated with various TTFields frequencies for 72 hours using the inovitro system. Efficacy of the combined treatment of TTFields and Sorafenib (36-3000 nM) was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, induction of apoptosis, cell cycle and clonogenic potential were determined. N1S1 HCC cells were injected to the left lobe of the liver of SD rats. After 1 week, TTFields (1.2 V/cm) and Sorafenib (10 mg/kg) were applied for 6 days and tumor growth was followed using MRI. Healthy rats were used to study safety of the use of TTFields (150 kHz) applied to the abdomen. Results: The optimal TTFields frequency was found to be 150 kHz for both cell lines. TTFields application (1.0 - 1.7 V/cm, 72 hours) at 150 kHz led to 53-64% reduction in cell counts and to additional reduction of over 70% in the clonogenic potential. The combined treatment of TTFields and Sorafenib led to a significant reduction in the number cells (2-way ANOVA, p < 0.001) as compared to each treatment alone. Tumor growth was significantly reduced by the combined group compared to the control group (student t test, p < 0.01). Safety studies did not reveal any adverse event associated with TTFields application to the rat abdomen. Conclusions: The results presented in this work demonstrate that TTFields can be a safe and effective treatment against HCC cells and that the combination with Sorafenib may further enhance treatment efficacy.
Impact of glycemic control on treatment efficacy and safety during nabpaclitaxel plus gemcitabine therapy in unresectable pancreatic cancer.
Authors: Tauchi Junko , Shinohara Akira , Ohashi Ken , Shibuki Taro , Kimura Gen , Umemoto Kumiko , Watanabe Kazuo , Sasaki Mitsuhito , Takahashi Hideaki , Hashimoto Yusuke , Imaoka Hiroshi , Ohno Izumi , Mitsunaga Shuichi , Ikeda Masafumi , Kawasaki Toshikatsu
Published: January 2019

337

Background: Diabetes mellitus (DM) and hyperglycemia have been widely considered to be associated with the risk of pancreatic cancer. However, the aim of this study was to evaluate the relationship between glycemic control and the efficacy or safety in pancreatic cancer pts receiving treatment with nab-Paclitaxel (nab-PTX) plus Gemcitabine (GEM). Methods: We retrospectively reviewed 285 pts with unresectable pancreatic cancer with nab-PTX plus GEM as the first-line chemotherapy from December 2014 to March 2017 at the National Cancer Center Hospital East, Kashiwa, Japan. The pts were divided into two groups, average blood glucose level during the period of chemotherapy was less than 160 mg/dL (Group GC: Good glycemic control group) and more than 160 mg/dL (Group PC: Poor glycemic control group). Results: A total of 285 pts were enrolled. Median age was 66 years (range: 26-84) and males/females: 180/105, PS (0-1/2-3): 272/13, stage (III/IV): 77/208. There were 226 pts in GC group and 59 pts in PC group. No significant differences were seen in the overall survival between Group GC and PC (median: 16.1 months vs. 13.8 months, p = 0.344) and in the progression free survival between the two groups (median: 7.5 months vs. 8.2 months, p = 0.862). The incidence rate of grade 2-3 chemotherapy-induced peripheral neuropathy (CIPN) was significantly higher in Group PC compared with Group GC (Group GC 28.3%, Group PC 45.8%, p = 0.010). Univariate and multivariate analyses identified glycemic control as significant independent factors associated with the incidence of grade 2-3 of CIPN (Odds ratio 2.182, 95% CI 1.20-3.96, p = 0.010). There was no significant difference in the relative dose intensity of nab-PTX between two groups (median, 56.6% in group GC, 56.5% in group PC, p = 0.952). Conclusions: Glycemic control during the chemotherapy with nab-PTX plus GEM in unresectable pancreatic cancer was not associated with OS. The incidence of severe CIPN was higher in pts with poor glycemic control compared with good glycemic control.
Liver injury by immune checkpoint inhibitors in patients with hepatocellular carcinoma.
Authors: Personeni Nicola , Pressiani Tiziana , Capogreco Antonio , Dal Buono Arianna , D'Alessio Antonio , Prete Maria Giuseppina , Smiroldo Valeria , Bozzarelli Silvia , Giordano Laura , Aghemo Alessio , Santoro Armando , Rimassa Lorenza
Published: January 2019

341

Background: In patients with hepatocellular carcinoma (HCC) and baseline liver dysfunction, hepatic immune-related adverse events (HIRAEs) during immunotherapy have not been adequately characterized and their impact on subsequent treatment outcomes is not known. Methods: 40 patients with advanced/unresectable HCC and Child Pugh score A have been enrolled in first and second-line clinical trials of anti-programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs). HCC etiologies were: hepatitis C (32.5%), hepatitis B (7.5%), alcohol abuse (27.5%), other (32.5%). 7 received anti-PD-1 mAbs alone and 33 received combined regimens that included anti-PD-1 mAbs plus either anti-cytotoxic T lymphocyte antigen 4 (30.4%) or tyrosine kinase inhibitors (TKIs) (54.5%), or both (15.1%). We reviewed their liver function tests and HIRAEs onset was related to time to treatment failure (TTF). Results: Overall, 12 patients (30%) developed grade ≥ 3 hepatitis according to Common Toxicity Criteria for Adverse Events v. 4.03, resulting in 4 cases of grade 2 drug-induced liver injury per DILI Working Group criteria. Time between therapy initiation and hepatitis onset was 1.4 months (0.4-2.8) and median peak aminotransferase (AT) level was 258 IU/L (85-869). Out of 6 permanent treatment discontinuations due to adverse events (AEs), 4 were linked to hepatitis. Higher AT median levels at baseline were significantly linked to grade ≥ 3 hepatitis compared with lower grades (95 IU/L vs. 36 IU/L, respectively; p = 0.008). Etiology, age, treatment did not predict HIRAEs onset. TTF in patients in patients with grade ≥ 3 hepatitis was shorter than in the whole cohort (1.4 vs. 3.8 months, p = 0.041), while overall survival did not differ (p = 0.125). Conclusions: We observed a 30% incidence of clinically significant HIRAEs. HIRAEs represent the most frequent AEs leading to treatment discontinuation in patients with HCC undergoing treatments with immune checkpoint inhibitors. Baseline AT levels may identify patients at increased risk of grade ≥ 3 hepatitis.
The clinical outcomes of combination chemotherapy in elderly patients with advanced biliary tract cancer: An exploratory subgroup analysis of JCOG1113.
Authors: Yamada Ikuhiro , Morizane Chigusa , Okusaka Takuji , Ogawa Gakuto , Sato Yuya , Ueno Makoto , Ikeda Masafumi , Sugimori Kazuya , Fukutomi Akira , Shimizu Satoshi , Mizuno Nobumasa , Yanagimoto Hiroaki , Sano Keiji , Tobimatsu Kazutoshi , Yane Kei , Nakamori Shoji , Sata Naohiro , Nishina Tomohiro , Ishii Hiroshi , Furuse Junji
Published: January 2019

349

Background: JCOG1113 is a randomized phase III trial to confirm the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for advanced biliary tract cancer (BTC) in overall survival (OS). In the final analysis, GS demonstrated non-inferiority to GC in OS and was considered as a new option of standard of care for advanced BTC. However, there are few reports on the efficacy and safety of combination chemotherapy in elderly patients with advanced BTC. Therefore, this study aimed to explore the clinical outcomes of combination chemotherapy in elderly patients with advanced BTC. Methods: Among all enrolled patients in JCOG1113, ≥ 75 years old patients were included in this exploratory subgroup analysis. Cox regression analysis was performed to investigate the influence of age at baseline on OS and PFS. Clinically relevant adverse events (AEs) were defined as any of grade 2 or more fatigue, appetite loss, nausea, vomiting, oral mucositis, and diarrhea, and were compared using Fisher’s exact test. Results: Among all enrolled patients, 155 patients in GC and 139 patients in GS were included in < 75 years old cohort and 20 patients in GC and 40 patients in GS were included in ≥ 75 years old cohort.The HR of ≥ 75 years old cohort to < 75 years old cohort for OS was 0.96 (95% CI 0.71–1.30) in all enrolled patients. The HR of ≥ 75 years old cohort to < 75 years old cohort for OS was 1.26 (95% CI 0.77–2.04) in GC, and 0.84 (95% CI 0.56–1.24) in GS. The HR of ≥ 75 years old cohort to < 75 years old cohort for PFS was 1.01 (95% CI 0.63–1.61) in GC, and 0.78 (95% CI 0.54–1.12) in GS. Clinically relevant AEs were 36.1% in < 75 years old cohort and 25.0% in ≥ 75 years old cohort in GC, and 29.5% in < 75 years old cohort and 32.5% in ≥ 75 years old cohort in GS. Conclusions: The clinical outcomes of combination chemotherapy in elderly patients were comparable to non-elderly patients. Clinical trial information: 000010667.
Effectiveness of laparoscopic surgery in patients with large gastric GIST (diameter > 5cm).
Authors: Li Fei , Gao Chongchong
Published: January 2019

35

Background: Recently, the application of laparoscopic or DaVinci surgery in relatively small gastrointestinal stromal tumors (GIST) has been increasingly recognized. However, the use in large stromal tumors, especially with a diameter greater than 5 cm, remains controversial for fear of tumor rupture. The aim of our study is to observe the effectiveness of laparoscopic approach in treatment of large gastric GIST. Methods: Patients who were diagnosed with gastric GIST (diameter > 5cm) at Xuanwu Hospital, China and underwent laparoscopic surgery from May 2011 to May 2018 were assessed. We set intraoperative tumor rupture as primary outcome. Secondly outcomes were conversion rate, operating time, estimated blood loss, length of postoperative hospital stay and recurrence rate at the end of the follow-up. Results: Fourty patients were included in our study with tumor size (7.54 ty-tw) cm (range, 5.0~13.8 cm). There was no intraoperative tumor rupture occurred. The median duration of operation was (76.3±29.9) minutes with estimated blood loss (28.7±15.2) mL. The median time for length of postoperative hospital stay was (5.8±4.1) days. The follow-up period for all the patients was 23.1 months (range, 2.4~51months). No local or distant recurrence was observed. Conclusions: Laparoscopic resection for large gastric GIST is feasible and effective. Laparoscopic surgery can substitute for open surgery as standard approach for gastric stromal tumors.
Provider-volume associated with variable receipt of therapy and outcomes for noncurative pancreas adenocarcinoma: A population-based analysis.
Authors: Hallet Julie I. , Davis Laura , Mavros Michail , Mahar Alyson L. , Beyfuss Kaitlyn , Liu Ying , Kennedy Erin Diane , Earle Craig , Coburn Natalie G.
Published: January 2019

352

Background: While high-volume providers for pancreatic adenocarcinoma (PA) surgery yield better outcomes, variation in practice and the role of provider-volume has not been investigated for systemic therapy. We examined variation in practice and outcomes in the management of non-curative PA, based on medical oncology provider-volume. Methods: We conducted a population based retrospective cohort study of non-resected PA over 2005-2016 by linking administrative healthcare datasets. High-volume (HV) medical-oncology providers were defined as the 5th quintile of number of PA seen per provider per year. Outcomes were receipt of chemotherapy and overall survival (OS). Brown Forsythe Levene (BFL) test for equality of variances assessed outcomes variability between provider-volume quintiles (Q1 to 5). Multivariate regressions examined the association between management by HV provider and receipt of systemic therapy and OS. Results: Of 10,881 non-curative PA patients, 7,062 consulted with medical oncology. Among 341 medical oncology providers, 3% were HV, defined as > 16 patients/year. There was variability in receipt of chemotherapy based on provider-volume, with 44% (IQR: 25-54) for Q1 and 47% (IQR: 43-54) for Q5, and in median survival, with 4.1 months (IQR: 2.7-6.2) for Q1 and 7.5 months (IQR: 6.6-8.0) for Q5. Variability between provider-volume quintiles was significant for receipt of chemotherapy and median survival (both BFL p < 0.001). After adjusting for age, sex, comorbidity burden, rurality, income quintile, and diagnosis year, HV provider was independently associated with higher odds of receiving chemotherapy (OR 1.19 [1.05-1.34]), and superior OS (HR 0.79 [0.74-0.84]). Conclusions: There was significant variation in non-curative management and outcomes of PA based on provider-volume. Management by a HV provider was independently associated with higher odds of receiving chemotherapy and superior OS, after adjusting for case-mix. This information is important to inform disease care pathways and care organization. Cancer care systems could consider initiatives to increase the number of HV providers to reduce variation and improve outcomes.
Real-world treatment characteristics for first-line therapy (1L) of advanced hepatocellular carcinoma (HCC) in Canada and Europe.
Authors: Gill Sharlene , Jaffe Dena H , DeCongelio Marc , DuBell Arnold N. , Shi Jing , Wisniewski Tami , Thompson Gwilym
Published: January 2019

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Background: Sorafenib is indicated for the treatment of HCC. This study captures and describes real-world use of 1L therapy for advanced unresectable or metastatic HCC across Canada and Europe. Methods: A retrospective, non-interventional survey of 278 physicians in Canada (7.5%) and Europe (92.5%) (France, Germany, Italy, Spain and UK) was conducted between Feb-Mar 2018. Clinical and treatment data were collected from medical charts for patients aged ≥18y, who initiated and completed systemic 1L treatment for HCC within 2 years of data collection, and a Child-Pugh [CP] A/B at 1L initiation. Descriptive statistics compared 1L systemic therapy, sorafenib vs. other. Results: 706 patients were included (n = 504 sorafenib; n = 202 other [83% chemotherapy; 10% targeted therapy; 7% checkpoint inhibitors]) with a mean age at 1L of 62.7±9.3y and 79% males. Comorbidities did not differ by sorafenib vs. other for alcoholism (33%), Hepatitis C (14%), and nonalcoholic steatohepatitis and/or nonalcoholic fatty liver disease (9%) but did for Hepatitis B (12% vs. 6%) and cirrhosis (31% vs. 18%) (both p < 0.05). At diagnosis, more patients treated with sorafenib vs. other had portal vein invasion (56% vs. 35%, p < 0.001). At 1L initiation, sorafenib patients had better performance status (PS) (ECOG 0-1: 80% vs. 67%, p < 0.05) and preserved liver function (CP A: 58% vs. 47%, p < 0.05). The results indicated that sorafenib was used less compared to other systemic therapies among those with poor performance (ECOG 2-4) and poor liver function (CP B) (71% vs. 83%, p = 0.068). Median treatment duration was shorter for sorafenib (2 vs. 4 months, p < 0.001). The most common grade 3 adverse events were fatigue (9%), diarrhea (5%), and hand/foot skin reaction (4%). Conclusions: In this real-world chart survey of Canadian and European physicians, sorafenib remains the most commonly used 1L systemic therapy for advanced HCC. Patients treated with sorafenib were more likely to have cirrhotic liver disease, portal vein invasion, better PS and preserved liver function, but sorafenib use was not limited to CP A. Understanding determinants of 1L therapy is important as the treatment landscape of HCC is evolving to address unmet need.
Toxicity of FOLFOX-abraxane (FOLFOX-A) on phase II Brown University Oncology Group (BrUOG) trials.
Authors: Safran Howard , Breakstone Rimini , Charpentier Kevin , Vatkevich John , Marks Eric I , Cavanagh Lindsey , Mitchell Kristen , Renaud Jen , Beard Rachel , Rosati Kayla
Published: January 2019

354

Background: FOLFIRINOX increases survival in pancreatic cancer. The Brown University Oncology Group developed the FOLFOX-A regimen in a phase I study. (Am J Clin Oncol, 2016). We subsequently opened phase II studies of FOLFOX-A in patients with metastatic pancreatic cancer (BrUOG 292), locally advanced/borderline pancreatic cancer (BrUOG 318) and adjuvant disease following resection (BrUOG 295). The BrUOG Data Safety Monitoring Committee met on May 22, 2018. Toxicity of FOLFOX-A reviewed at the May meeting aligned with data lock in April on phase II FOLFOX-A studies and is summarized. Methods: Patients received oxaliplatin, 85mg/m2 day 1, nab-paclitaxel, 150mg/m2 and leucovorin 400mg/m2 day 1 and fluorouracil 2400mg/m2 by continuous IV infusion over 46 hours. Myeloid growth factor support was optional. Cycles were repeated every 14 days for up to 10-12 cycles. Oxaliplatin was dose reduced to 68mg/m2 for grade 2 neurotoxicity. CTCAE version 4 toxicity scales were utilized. Results: A total of 81 patients were accrued, (22 adjuvant, 36 metastatic, 23 locally advanced disease). Cumulative fatigue was the most common toxicity and required dose reduction in 50% of patients. The incidences of grade 2, 3 and 4 neutropenia were 26%, 17% and 6%, respectively. Grade 2,3 and 4 diarrhea were 9%, 15% and 0%. The rates of grade 2,3 and 4 neuropathy were 29%, 2% and 0%. Conclusions: FOLFOX-A is well tolerated with low incidences of grade 3 neuropathy and gastrointestinal toxicity. Toxicities were less frequent in patients treated in the adjuvant setting. Clinical trial information: NCT02080221, NCT02022033, NCT02578732.