bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose modifications of liposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) in NAPOLI-1: Impact on efficacy.
Authors: Wang-Gillam Andrea , Hubner Richard , Mirakhur Beloo , de Jong Floris A , Belanger Bruce , Chen Li-Tzong
Published: January 2019

388

Background: In NAPOLI-1 (NCT01494506), a randomized phase 3 study in patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV improved overall survival (OS; primary endpoint) vs 5-FU/LV (6.1 mos vs 4.2 mos; HR = 0·67, 95% CI 0.490.92; P = 0.012). This exploratory analysis examined the impact of dose modifications or delays used to manage adverse events (AEs) on OS. The study protocol allowed ≤2 dose reductions for nal-IRI and 5-FU and for up to 3 weeks. Methods: Patient who had a dose delay or reduction within the planned first 6 weeks of the study were included. Delays were defined as any delay in dosing > 3 days from target dosing date and dose reductions were defined as any reduction in dose from initial administered dose. OS was compared within the nal-IRI+5-FU/LV arm and with the 5-FU/LV arm. Comparisons were made using the cohort of 5-FU/LV and nal-IRI+5-FU/LV patients enrolled under protocol version 2. Median OS was based on Kaplan-Meier estimates and Cox regression analysis was used to calculate HRs. Results: More patients in the nal-IRI+5-FU/LV treatment group experienced AEs that required dose delay and/or reduction than in the 5-FU/LV treatment group (62% vs 33%). Within the nal-IRI+5-FU/LV arm, median OS was numerically but not significantly different between patients who did (n = 34) vs did not (n = 83) have a dose reduction (9.3 vs 5.4 mos; HR = 0.66 [95% CI 0.43, 1.01]) and for those who did (n = 49) vs did not (n = 68) have a dose delay (8.4 vs 5.6 mos; 0.82 [95% CI 0.56, 1.23]). Between treatment arms, OS was greater in the nal-IRI+5-FU/LV arm regardless of dose delay or reduction (Table). Conclusions: Dose modifications in the nal-IRI+5-FU/LV arm did not significantly impact OS compared with those who did not need a dose modification, and OS remained greater than in 5-FU/LV-treated patients. This suggests that appropriate dose modification of nal-IRI+5-FU/LV for AEs may not adversely affect outcomes. Clinical trial information: NCT01494506. [Table: see text]
Retrospective analysis of patients using olaparib (O) in pancreatic cancer (PC).
Authors: Borazanci Erkut Hasan , Guarnieri Carol , Haag Susan , Korn Ronald Lee , Snyder Courtney Edwards , Hendrickson Kristin , Caldwell Lana , Von Hoff Daniel D.
Published: January 2019

389

Background: Molecular analysis has revealed four subtypes of PC giving clinicians further insight into treating this deadly disease. One subtype that was elucidated termed “unstable” is significant for the presence of DNA damage repair deficiency and can be targeted therapeutically. One such therapy, O, from the drug class poly ADP ribose polymerase (PARP) inhibitors, has already been FDA approved for individuals with BRCA mutated ovarian cancers. We performed a retrospective analysis on patients with PC treated at a single institution who have DNA damage repair deficiency mutations and have been treated with O. Methods: A chart review identified pancreatic cancer patients with DNA repair pathway mutations who were treated with O. The primary objective examined ORR in patients with PC with DNA repair mutations receiving O. Secondary objectives included tolerability, overall survival (OS), CA 19-9 change, and changes in quantitative textural analysis (QTA) on CT. Results: 11 individuals were identified, 5 carriers of a pathogenic germline (g) BRCA2 mutation, 1 carrier of a pathogenic g ATM mutation, 1 carrier of a pathogenic g BRCA1 mutation. Variants of uncertain significance (VUS) included 1 g ATM mutation, 1 g PALB2 mutation, 1 somatic (s) C11orf30 mutation, and 1 s BRCA2 mutation. Median age at diagnosis was 59, with 4 M and 7 F. No patients met criteria for familial PC and 7 had a family history consistent for breast and ovarian cancer syndrome. All individuals had metastatic PC and had progressed on at least 1 line of systemic therapy. ORR was 18%. Median time of therapy on O was 5 months (mo) (Range 1.4 to 29.567 mo) with 5 of the individuals still undergoing treatment at the time of analysis. Mean OS was 12.35 mo, 9 of the 11 individuals still alive. QTA of baseline CTs from subjects with liver (8/11) and pancreatic tumors (7/11) revealed a strong association between lesion texture and OS (Pearson correlation coefficient (PCC): hepatic mets = 0.952, p = 0.0003) and time on O (PCC: panc lesions = 0.889, p = 0.006). Conclusions: In individuals with metastatic PC with mutations involved in DNA repair, O may provide clinical benefit. QTA of individual tumors may allow for additional information that predicts outcomes to PARP inhibitors in this population.
Clinical impact of obesity-related factors in perioperative management of esophageal cancer.
Authors: TAKEUCHI HIROYA , Kikuchi Yuji , Kawakubo Hirofumi , Suda Koichi , Kitagawa Yuko
Published: January 2019

39

Background: Obese patients with esophageal cancer have been increasing worldwide. However, the impact of obesity on esophagectomy still remains controversial. In this study, we clarified the relations between obesity and postoperative outcomes after esophagectomy in patients with esophageal cancer. Methods: A total of 215 patients who underwent esophagectomy for esophageal cancer between 2008 and 2014 were retrospectively assessed. We qualified the body mass index (BMI), visceral fat area (VFA) and subcutaneous fat area (SFA) using CYNAPSE VINCENT™. Clincopathological factors, postoperative morbidity, and survival after esophagectomy were assessed with these obesity-related factors. Results: The mean BMI, VFA, and SFA were 22.0 kg/m², 83.0cm², and 87.3cm². BMI, VFA and SFA were significantly correlated each other (P < 0.001). The prevalence of diabetes mellitus and hypertension were significantly more in high SFA than normal SFA (20% vs 10%, 30% vs 14%). When the patients were divided to two groups according to BMI (< 25 or ≥25kg/m²), VFA ( < 100 or ≥100cm²) and SFA ( < 100 or ≥100cm²), operative time was significantly longer in high SFA (P = 0.03) than normal SFA, and tended to be longer in high BMI, but blood loss were similar in each groups. Maximum level of postoperative CRP was significantly higher in high BMI (P < 0.001), in high VFA (P < 0.001), and in high SFA (P < 0.001). Length of systemic inflammatory response syndrome was significantly longer in high BMI than normal BMI (1.9 days vs 1.4 days P = 0.04), and length of ventilator support was significantly longer in high SFA than normal SFA (3.0 days vs 2.2 days P = 0.006). The incidence of anastomotic leakage and surgical site infection were significantly higher in high SFA than normal SFA (27% vs 10%, 37% vs 19%). There were no significant difference in overall survival, however, patients in high VFA tended to be longer survival than those in normal VFA (P = 0.078). Conclusions: Anastomotic leakage and surgical site infection occurred more frequently in high SFA. It might be useful to examine SFA preoperatively in obese patients with esophageal cancer for prevention of postoperative complications. Patients in high VFA tended to be longer survival than those in normal VFA.
Effect of multiagent chemotherapy and chemoradiotherapy on rates of resection and survival in patients with locally advanced pancreatic cancer: a National Cancer Database Analysis.
Authors: David John , Kim Sungjin , Anderson Eric , Torossian Arman , Lo Simon , Nissen Nicholas N. , Hendifar Andrew Eugene , Tuli Richard
Published: January 2019

391

Background: The role of multiagent chemotherapy (MAC) has not been prospectively investigated in LAPC and data are extrapolated from randomized trials in patients with metastatic disease. Data regarding the use of chemoradiation (CRT) for LAPC is mixed and similarly there is no prospective data investigating its use after MAC. Herein, we investigate clinical outcomes associated with the use of MAC and CRT. Methods: The National Cancer Database (NCDB) was utilized to identify LAPC patients treated with single agent chemotherapy (SAC), MAC, surgery, and/or CRT. Univariate (UVA) and multivariate (MVA) Cox regression were performed to identify the impact of MAC and CRT on surgical resection and median overall survival (mOS) rates. Results: From 2004-2014, a total of 10139 patients were identified. The median age was 66 years (range 22-90) with median follow up of 49 months (46-52 months); 49.9% were male and 50.1% female. All patients had clinical stage 3/T4 disease irrespective of nodal metastases. All patients who received post-op RT were excluded. Surgical resection was performed in 506 (5%) patients. Median OS rates for patients who received SAC vs. MAC was 9.8 months vs 13.7 months (p < 0.001), respectively. Median OS rates for patients who received SAC/MAC vs. SAC/MAC+CRT was 9.9 months vs. 12.9 months (p < 0.001), respectively. Odds ratio for undergoing surgical resection in patients receiving MAC vs. MAC+RT was not significant. Of the 5% of patients who underwent resection after neoadjuvant therapy, mOS for those who received MAC vs. MAC+RT were 19.4 months and 25.6 months (p = 0.001), respectively. Conclusions: Median OS was improved in patients receiving MAC versus SAC. The use of CRT after chemotherapy led to increased mOS compared to chemotherapy alone. In all patients undergoing surgical resection, the addition of neoadjuvant CRT after MAC led to improved mOS rates. Treatment with MAC followed by CRT should be utilized for all patients with LAPC.
Treatment at high-volume facilities and academic centers in relation to overall survival in patients with locally advanced pancreatic cancer: A National Cancer Database analysis
Authors: David John , Kim Sungjin , Anderson Erik , Torossian Arman , Lo Simon , Nissen Nicholas N. , Hendifar Andrew Eugene , Tuli Richard
Published: January 2019

392

Background: Numerous studies have shown that treatment at a high volume facility (HVF) for patients (pts) with pancreatic cancer is associated with improved outcomes, particularly with pancreatectomy. In fact, a recent study showed that pts undergoing a pancreatectomy at an academic center (AC) is independently associated with improved outcomes. However, the role of chemotherapy (CT) and radiation (RT) in the treatment of locally advanced pancreatic cancer (LAPC) at HVF and AC, to our knowledge, has not been studied. Herein, we investigate the benefit of treatment at HVF and AC compared to low volume facilities (LVF) and non-academic centers (NAC) with CT or chemoradiation (CRT) in pts with LAPC. Methods: The National Cancer Database (NCDB) was utilized to identify LAPC patients treated at all facility types. All patients were treated with CT or CRT. Univariate (UVA) and multivariate (MVA) Cox regression were performed to identify the impact of HVF and AC on overall survival (OS) when compared to LVF and NAC, respectively. HVF was defined as the top 5% of facilities by number of pts treated. Results: From 2004 – 2014, a total of 10139 pts were identified. The median age was 66 years (range 22-90) with median follow up of 48.8 months (46-52.1 months); 49.9% were male and 50.1% female. All pts had clinical stage 3/T4 disease irrespective of nodal metastases. Of these, 4779 pts were treated at an AC and 5260 were treated at a NAC and 588 were treated at HVF and 9551 were treated at LVF. On UVA, age, high median income, high education level, comorbidities, and recent year of diagnosis were associated with improved OS. ACs were associated with improved OS when compared to non-AC (HR 0.92 95% CI 0.88 – 0.96, p = 0.004), as were HVF when compared to LVH (HR 0.84 95% CI 0.76 – 0.92, p < 0.001). Odds ratio for undergoing surgical resection at HVF and AC was 1.68 and 1.37 (p < 0.001), respectively, when compared to LVF and NAC. Conclusions: The treatment of LAPC patients with CT or CRT at an AC led to significantly improved rate of surgical resection and OS. In the absence of prospective data, these results support the referral of pts with LAPC to HVF and/or AC for evaluation and treatment.
Safety and outcomes of an oncologic robotic whipple program.
Authors: Powers Benjamin D , Pimiento Jose Mario , Saeed Sabrina D , Deperalta Danielle , Hodul Pamela Joy , Fleming Jason B. , Malafa Mokenge Peter
Published: January 2019

393

Background: Robotic-assisted surgery is a new technology being used more commonly in surgical oncology. We evaluated the outcomes of robotic pancreaticoduodenectomy over time from a single U.S. cancer center. Methods: The Moffitt Cancer Center Tumor Registry was queried for robotic pancreaticoduodenectomy cases performed by two surgeons from 2012-2017 after IRB approval. Descriptive statistics and analyses with t-test and chi-square test were performed. Results: 61 case were analyzed; the first cohort comprised 31 cases and the second cohort comprised the next 30 cases. The most common pre-operative diagnosis was adenocarcinoma. For the entire cohort, the estimated blood loss was 498mL, ASA class was 2.5, and OR duration 546 minutes. The first cohort had 14 conversions to open Whipple and the second cohort had 11. There were no anesthesia or surgical complications. There was one 30-day mortality and one R1 resection. There was no significant difference in EBL, OR transfusions, or post-op transfusions. There was a significant decrease in the operative time between the two cohorts. Additionally, there was a significant increase in total number of nodes examined in the second cohort, though no difference in the number of positive nodes. Conclusions: In selected patients, robotic pancreaticoduodenectomy is a safe alternative to open pancreaticoduodenectomy. Published data suggest a learning curve of approximately 60-80 cases. In our cohort we observed a significant decrease in OR time and an increase in lymph node retrieval after 31 cases, suggesting an earlier inflection point. Further studies are needed to examine additional follow-up and outcome variables. [Table: see text]
Time to sustained improvement in bowel movement frequency with telotristat ethyl: Analysis of the phase III telecast study.
Authors: Dillon Joseph , Lapuerta Pablo , McKee Chad
Published: January 2019

395

Background: Telotristat ethyl (TE) is approved to treat inadequately controlled carcinoid syndrome (CS) diarrhea in combination with somatostatin analog (SSA) therapy. Understanding the time to onset of sustained BM frequency improvement is important when considering the use of TE in patients with CS diarrhea. We present data on time to sustained improvement and worsening in BM frequency during the double-blind treatment (DBT) period of TELECAST, a phase 3, randomized, placebo-controlled, double-blind study in patients with CS that required additional treatment, primarily due to gastrointestinal symptoms. Methods: Stable dose SSA was not required. Patients were treated with TE 250 mg 3 times per day (tid), TE 500 mg tid, or placebo tid. Sustained response was defined as the time from the first double-blind dose date to the first day of 2 consecutive weeks with BM frequency change of at least 30% from baseline. The time to the first sustained response in the TELECAST study was examined among treatment groups and analyzed using Cox regression. Results: There were 26 patients on placebo and 25 patients on either 250 mg or 500 mg telotristat groups. Sustained improvement in BM frequency over the 12-week DBT period was achieved in 6, 16, and 16 patients on placebo, TE 250 mg, and TE 500 mg treatment groups. Median time to sustained ≥ 30% improvement was 4-5 weeks with TE at both dosing levels, with no median reached on placebo. First occurrence of sustained improvements in BM frequency occurred within 4-68 days. Time to sustained worsening was delayed on the 500-mg dose of TE (no percentile reached) and is statistically significant (p = 0.021, HR: 0.25) Conclusions: Treatment with telotristat ethyl may provide sustained BM frequency reduction within 4-5 weeks (median) of initiating therapy. No median was reached on placebo due to fewer patients with sustained improvement. Additionally, TE 500 mg tid may also offer additional clinical benefit by reducing sustained BM worsening. Clinical trial information: NCT02063659.
Precision oncology in pancreatobiliary cancers: A longitudinal study.
Authors: Sadaps Meena , Estfan Bassam N. , Sohal Davendra , Khorana Alok A.
Published: January 2019

399

Background: Precision oncology – the use of next-generation sequencing (NGS) to identify therapeutic options for advanced cancer patients – is being used widely, but its utility in patients with pancreatobiliary (PB) cancers has not been studied systematically. We evaluated the prevalence of actionable alterations and their impact on therapeutic decision-making in patients with PB cancers. Methods: We conducted a retrospective cohort study of consecutive patients seen at the Cleveland Clinic between 2013 and 2016 with incurable solid tumor malignancies, in whom FoundationOne™ (Cambridge, MA) NGS was ordered. All results were reviewed at a multidisciplinary genomics tumor board (GTB), which determined actionability and made therapeutic recommendations. Treatment decisions (on label, off label, or clinical trials) based on said recommendations were reviewed. Results: The study population was 600 patients, of whom 53 had PB cancers. For these 53, median age was 59.6 years; 62.2% (33/53) were female; 86.8% (46/53) were Caucasian. Eight samples (15.1%) had inadequate tissue; of 45 resulted cases, 21 (46.7%) were recommended treatment, including clinical trials (n = 19) and off-label drugs (n = 2). The most common targets for therapy were FGFR (5/21) and CDKN2 (3/21). Of 21 patients with recommendations, only two (9.5%) received genomics-driven therapy, compared with 31.7% (86/271) of patients with other solid tumor malignancies (p = 0.03). One received an IDH1 inhibitor, and one received dabrafenib and trametinib for a BRAF alteration; both on clinical trials. At time of last follow-up, best responses were unknown and partial response, respectively. Unavailability of clinical trials in the vicinity (9.5%), and clinical trial ineligibility, mainly due to poor performance status (9.5%), were common reasons for lack of actionability. Conclusions: Benefit from precision oncology in the PB population is low, with only 4.4% (2/45) of patients with NGS results eventually receiving genomics-driven therapy. Benefit to patients will not improve until access to clinical trials is enhanced and patients are evaluated for these trials earlier in the course of their disease, when their performance status is likely to be higher.
Effect of region and hospital attribute on outcome of gastric patients treated with apatinib: Data from post-marketing phase IV study.
Authors: Zhong Haijun , Qin Shukui , Li Jin , Deng Wenying , Wen Lu , Wang Junsheng , Zhang Guifang , Jia Tongfu , Yang Jianwei , Ba Yi , Bai Yuxian , Wang Mei , Wang Lin , Liu Likun , He Yifu , Tao Min , Xie Congying , Ye Feng , Wu Xiang-yuan , Lin Xiaoyan
Published: January 2019

40

Background: The single-arm, open-label, multi-center, Phase IV trial of apatinib was conducting in patients (pts) with advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction with a target sample size of 2000+. We aimed to analyze the effect of region and hospital attributes on clinical outcomes. Methods: From April 2015 to July 2017, 1037 subjects were enrolled, among which 820 were evaluable in the survival analysis. Results: The incidences of adverse events (AEs) and severe AEs (SAEs) are listed in Table. Overall, both incidences were higher in Southern center compared to Northern Center (p=0.002 and <0.001). More SAEs occurred in developed cities (p=0.028) and in hospitals not specialized in oncology (p=0.028). For efficacy, the median overall survival (mOS) of subjects in Northern Center and Southern centers were 8.71 and 5.72 mos (p<0.001), and the median progression free survival (mPFS) was 5.36 and 3.25 mos (p=0.002), respectively. The mOS of subjects in developed and developing cities were 6.18 and 5.72 mos (p=0.105), and the mPFS was 3.02 and 4.73 mos (p=0.013), respectively. The mOS of subjects in hospital specialized and those not in oncology were 7.59 and 5.78 mos (p=0.014), and the mPFS was 4.73 and 3.84 mos (p=0.068), respectively. Conclusions: Region and attribute hospital can affect the safety and clinical outcome of apatinib in treating gastric cancer in the real world. Patients Northern, developing city or hospitals specialized in oncology experience less SAEs but have better clinical benefit. Clinical trial information: NCT02426034. [Table: see text]
Improvement of carcinoid syndrome (CS) symptoms and quality of life (QoL) in CS patients treated with somatostatin analogs (SSAs): Results from longitudinal patient surveys.
Authors: Halperin Daniel M. , Huynh Lynn , Beaumont Jennifer L , Cai Beilei , Bhak Rachel , Narkhede Sahil , Duh Mei Sheng , Neary Maureen , Cella David
Published: January 2019

400

Background: Limited information is available on the longitudinal impact of CS symptoms and QoL in CS patients (pts) who received SSAs in real-world setting. This study aimed to examine change in CS symptoms and QoL in CS pts treated with SSAs using the validated FACT-G instrument. Methods: Pts with CS symptoms in the US were recruited through an advocacy group to complete a two-part, anonymous online survey. Time point 1 (T1) survey was fielded from July-October 2016 and time point 2 (T2) was administered 6 months later. Eligible pts were ≥ 18 years old with CS symptoms and treated with SSA or non-SSA. Analyses were performed to assess change in FACT-G QoL scores between T1 and T2. Severity ratings of CS symptoms in the past month were classified as mild, moderate, severe, or not applicable. Duration of SSA treatment was categorized as ≤ 2, > 2-5, and > 5 years. Results: Among 89 pts who completed T1 and T2 surveys, 98% were treated with SSA (T1 or T2; median duration of 5 years). Higher proportion of pts in T2 did not report diarrhea (16% vs. 7%, p < 0.05) or flushing (28% vs. 18%, p < 0.05) vs. T1. Among pts treated with SSAs for ≤ 2, > 2-5 and > 5 years, mean change in FACT-G total score was +3.7, 0.0, and -1.2, respectively. Pts treated with SSAs for ≤ 2 years showed a clinically relevant improvement in QoL on FACT-G by exceeding the minimal important difference (MID) of > 3.0. Additionally, in a subgroup of pts who experienced improvement in flushing (N=17) and diarrhea (N=31), a mean change of +3.0 in FACT-G total score was observed for flushing, indicating better QoL, whereas a nominal mean change was reported for diarrhea. Pts whose flushing and diarrhea symptoms worsened had a mean change of -2.2 and -1.2 in FACT-G total score, respectively, showing worsened QoL. Conclusions: This longitudinal survey study showed that improvement in flushing resulted in positive benefit in QoL, while worsening of flushing/diarrhea resulted in decline in QOL. Improvement in CS symptoms and QoL was most pronounced in the early years after SSA treatment initiation. Less impact on change in QoL may be observed in later years possibly due to disease progression and late-effects of cancer treatment.
Predictors of recurrence in patients with surgically resected pancreatic neuroendocrine tumors.
Authors: Harris Cynthia , Kim Michelle Kang , Baeg Kiwoon Joshua , Lee Mi Ri , Starr Julie , Brais Lauren K. , Ward Stephen , Stashek Kristen , Chan Jennifer A. , Labow Daniel M. , Sarpel Umut , Schwartz Myron E. , Sung Max W. , Wisnivesky Juan P. , Warner Richard R. P. , Metz David C. , Kulke Matthew H.
Published: January 2019

408

Background: Current surveillance guidelines regarding follow up of patients with resected pancreatic neuroendocrine tumors (PNETs) are based on limited data, and there have been few studies evaluating recurrence risk in such patients. We assessed disease-free survival (DFS) in a large, multi-institutional cohort of patients with resected PNETs. Methods: Patients with surgically resected, non-metastatic PNETs between 1990-2017 were identified using institutional databases at three institutions: Mount Sinai Hospital, Dana-Farber Cancer Institute, and University of Pennsylvania. Recurrence date was defined as the imaging date documenting first recurrence (n = 56); if an imaging date was not available, then July 1 of that year was used in calculations (n = 9). Kaplan-Meier analysis was used to estimate DFS; multivariate Cox regression analysis was used to assess DFS adjusted for patient and disease-related characteristics, including tumor stage and grade. Results: We identified a total of 418 patients with surgically resected, non-metastatic PNETs between 1990-2017. Of these patients, 299 patients had complete stage and tumor grade information and were used for subsequent analysis. Patients were 48.6% male with a median age of 57.5 years at time of surgery. The distribution of AJCC stage and grade was as follows: 170 (56.9%) patients were stage I, 129 (43.1%) were stage II; 167 (55.9%) had grade 1, 121 (40.5%) had grade 2, and 11 (3.7%) had grade 3 tumors. Median follow-up was 2.6 years (interquartile range = 4.2); during this time, 65 (21.7%) patients developed disease recurrence. After adjusting for potential confounders, patients with more advanced stage and higher tumor grade were significantly more likely to develop disease recurrence (Hazard Ratio (HR): 6.9, 95% CI: 2.5-19.1 for stage II; HR 4.0 (1.7-9.5) for grade 2; HR 2.6 (0.4-17.8) for grade 3). Both higher stage and tumor grade were associated with decreased DFS (p < 0.0001 for both). Conclusions: In surgically resected PNETs, with a median follow-up time of 2.6 years, both higher stage and higher grade are associated with decreased DFS. Further follow up of this cohort is planned.
Predictive factors of submucosal fibrosis before endoscopic submucosal dissection for superficial squamous esophageal neoplasia.
Authors: Kim Byung Wook
Published: January 2019

41

Background: Endoscopic submucosal dissection (ESD) is an effective treatment modality for superficial squamous esophageal neoplasia (SSEN). However, submucosal fibrosis is an important obstacle to successful ESD. The aim of this study was to determine the ESD outcome in relationship to the degree of submucosal fibrosis of SSEN and to identify factors for predicting submucosal fibrosis. Methods: We retrospectively analyzed endoscopic and pathologic factors related to submucosal fibrosis in 41 patients with SSEN who underwent ESD. Also, en bloc resection, complication rate, and procedure time according to the degree of submucosal fibrosis were evaluated. Masson’s trichrome staining was used to evaluate histologic submucosal fibrosis. Results: A depressed type tumor (vs. nondepressed type tumor, P= 0.002), longer diameter of tumor greater than 20 mm (vs. longer diameter of tumor ≤ 20mm, P= 0.036), and delayed ESD after initial diagnosis (vs. immediate ESD after initial diagnosis, P= 0.005) were independent factors predictive of submucosal fibrosis. The severity of submucosal fibrosis was significantly associated with a higher complication rate such as bleeding and perforation. Also, as the severity of the submucosal fibrosis increased, the amount of time required for the ESD procedure increased. Conclusions: Longer diameter of tumor greater than 20 mm and macroscopic depression are endoscopic predictive factors of submucosal fibrosis in SSEN. Moreover, to avoid submucosal fibrosis, ESD should be attempted immediately after biopsy for the diagnosis of SSEN.
Subgroup analysis by baseline (BL) weight-associated parameters: A phase III study of liposomal irinotecan (nal-IRI)±5-fluorouracil/leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based (gem) therapy.
Authors: Macarulla Teresa Mercade , Hubner Richard , Blanc Jean-Frédéric , Wang-Gillam Andrea , Li Chung-Pin , Bodoky Gyorgy , Dean Andrew Peter , Yanshen Shan , Jameson Gayle S. , Lee Kyung-Hun , Chiu Chang-Fang , Schwartsmann Gilberto , Braiteh Fadi S. , Cunningham David , Chen Li-Tzong , Von Hoff Daniel D. , Mamlouk Khalid Kevin , de Jong Floris A , Siveke Jens T.
Published: January 2019

410

Background: We report prognostic evaluation of BL weight-associated parameters (body-mass index [BMI], body surface area [BSA] and weight) in pts with mPDAC after progression following gem-based therapy (NAPOLI-1 trial; NCT01494506). Pts received nal-IRI+5-FU/LV, nal-IRI monotherapy or 5-FU/LV in NAPOLI-1, an international, randomised, phase 3 trial; nal-IRI+5-FU/LV treatment resulted in a 45% increased median OS vs. 5-FU/LV (unstratified HR = 0.67; p = 0.012). Methods: This exploratory subgroup analysis compares outcomes by BL BMI, BSA and weight, using primary survival analysis data from the ITT population for all treatment arms combined (n = 417) and the nal-IRI+5-FU/LV arm on its own (n = 117). Results: OS and PFS were not significantly different between BL BMI, BSA and weight median subgroups in the entire NAPOLI-1 ITT population (HR range 1.06–1.15; log-rank p-value range 0.21–0.60; Table) and in the nal-IRI+5-FU/LV arm (HR range 0.94–1.19; log-rank p-value range 0.43–1.00). Conclusions: This post-hoc subgroup analysis did not detect any prognostic impact on treatment outcome by BL BMI, BSA and weight for mPDAC pts progressed following gem-based therapy. This observation rules out a treatment-independent effect. No evidence of a predictive effect on nal-IRI+5-FU/LV efficacy was found. Clinical trial information: NCT01494506. [Table: see text]
Folfirinox (FFX) versus gemcitabine with nab‐paclitaxel (GNP) in the first line treatment (1LTx) of metastatic pancreatic cancer (mPC): A tertiary center experience.
Authors: Barrera Ivan , Hamalova Sabina , Ranger Jill , Rho Henry , Mamo Aline , Batist Gerald , Kavan Petr
Published: January 2019

414

Background: The efficacy of FFX and GNP as 1LTx of mPC were established in phase 3 trials against Gemcitabine alone. However, no head‐to‐head trial has been performed. This analysis was conducted to compare the use of the two regimens in the 1LTx of mPC patients (pts). Methods: Retrospective study collected data of pts diagnosed with mPC (ECOG 0‐1) that received FFX or GNP as 1LTx at the Jewish General Hospital between 2010‐2016. Pt selection for 1LTx was based in ASCO Guidelines 2016 Criteria (AGC2016). Progression free survival (PFS) and overall survival (OS) were estimated using a Kaplan Meier method. Rate of 1LTx discontinuation and start of 2LTx was compared using two‐sided Fisher's exact test. Results: Among 75 pts with mPC (median age 69), 44 (59%) received FFX and 31 (41%) received GNP. In the FFX group 57% were male and 24 pts (55%) had primary tumors localized in the pancreatic head (PTPH). The majority of patients [n = 36 (82%)] had ECOG 1 at the start of FFX. The most common grade 3‐4 adverse events (AEs) were gastrointestinal symptoms (GI) [n = 12 (27%)], neutropenia (N) [n = 9 (20%)], fatigue (F) [n = 5 (11%)], and peripheral sensory neuropathy (PSN) [n = 2 (4%)]. In the GNP group 61% were male and 20 pts (65%) had PTPH. The majority of pts [n = 23 (74%)] had ECOG 1 at the start of GNP. The most common grade 3‐4 AEs were F [n = 8 (26%)], N [n = 4 (13%)], GI [n = 3 (10%)], and PSN [n = 2 (7%)]. Similar rates of 1LTx discontinuation due to AEs were seen in both groups: 5 pts (11%) in the FFX group due to GI, 2 pts (6.5%) in the GNP group due to F (p = 0.69). In the FFX cohort, 68.2% (30/44) went on to 2LTx whereas in the GNP cohort, 32% (10/31) received 2LTx (p = 0.0001). Of the FFX cohort receiving 2LTx, 40% (12/30) received GNP. The median PFS for the FFX and GNP groups were 5.75 and 4.63 months, respectively, and were not statistically significant (p = 0.523). The OS with FFX and GNP was 9.23 vs. 6.6 months (p = 0.09). Conclusions: For pts selected as per ASC2016, FFX and GNP cohorts showed similar PFS, OS, AEs, and 1LTx discontinuation rate. Our data highlight the importance of optimal therapeutic sequencing to prolong OS. A randomized trial will be needed to confirm 1LTx in mPC.
Clinical implication of nutrition for neoadjuvant therapy and impact of nutritional support in pancreatic cancer.
Authors: Tashiro Mitsuru , Yamada Suguru , Fujii Tsutomu , Hattori Norifumi , Takami Hideki , Suenaga Masaya , Niwa Yukiko , Hayashi Masamichi , Iwata Naoki , Kanda Mitsuro , Tanaka Chie , Kobayashi Daisuke , Nakayama Goro , Sugimoto Hiroyuki , Koike Masahiko , Fujiwara Michitaka , Kodera Yasuhiro
Published: January 2019

416

Background: Several studies have shown that nutritional support is important to reduce chemotherapy-related toxicities and improve tolerance to chemotherapy, but little is known about the nutritional influence of neoadjuvant therapy (NAT) for pancreatic cancer. The aim of this study was to assess the influence of NAT on nutritional status and the effectiveness of postoperative nutritional support in patients with NAT for pancreatic cancer. Methods: Between 2010 and 2017, 169 consecutive patients who underwent pancreatoduodenectomy of pancreatic cancer were enrolled, and divided into the neoadjuvant group (NAG, n = 70) and the control group (CG, n = 99). We assessed the change of nutritional index (body weight, albumin and rapid turnover proteins; retinol binding protein, prealbumin and transferrin), inflammatory index, and inflammation-based prognostic scores during NAT. Perioperative change of rapid turnover proteins at the point of pre-operation, postoperative day (POD) 5, POD12 and POD21, and perioperative and oncological outcomes between NAG and CG were evaluated. Finally, we divided NAG into nutrition group (n = 27) who received postoperative enteral immunonutrition from POD 1 to POD 21 and without nutrition group (n = 41), and compared perioperative change of rapid turnover proteins between two groups. Results: After NAT, the retinol binding protein, prealbumin, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio and prognostic nutrition index significantly got worse in NAG (P < 0.05). The recovery of rapid turnover proteins after POD5 was significantly worse in NAG compared to CG (P < 0.05). There was no significant difference in the incidence of postoperative complications and time to adjuvant therapy between two groups. The recovery of retinol binding protein and prealbumin after POD12 was significantly better in nutrition group compared to without nutrition group (P < 0.05). Conclusions: NAT for pancreatic cancer could decrease nutritional status and its postoperative recovery. Postoperative enteral nutrition could be effective in patients with NAT for pancreatic cancer. Based on these results, we plan to perform the nutritional support at earlier stage of therapy.
Effect of cytoreductive surgery and HIPEC on survival in comparison to palliative chemotherapy for biliary carcinoma with peritoneal metastasis: A multi-institutional cohort from PSOGI and BIG RENAPE groups.
Authors: Mercier Frederic , Amblard Iris , Bartlett David L. , Levine Edward Allen , Baratti Dario , Piso Pompiliu , Morris David L. , Rau Beate , Tentes Antonios Apostolos K , Tuech Jean-Jacques , Quenet Francois , Akaishi Eduardo Hiroshi , Pocard Marc , Yonemura Yutaka , Lorimier Gerard , Delroeux Delphine , Villeneuve Laurent , Glehen Olivier , Passot Guillaume
Published: January 2019

418

Background: Peritoneal metastasis from biliary carcinoma (PMC) is associated with poor prognosis when treated with chemotherapy. The objective was to evaluate the impact on survival of cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and compare with conventional palliative chemotherapy for patients with PMC. Methods: A prospective multicenter international database was retrospectively searched to identify all patients with PMC treated with a potentially curative CRS/HIPEC (CRS/HIPEC group). The overall survival (OS) was compared to patients with PMC treated with palliative chemotherapy (systemic chemotherapy group). Survival was analyzed using Kaplan-Meier method and compared with Log-Rank test. Results: Between 1995 and 2015, 34 patients were included in the surgical group, and compared to 21 in the medical group. In the surgical group, median peritoneal cancer index was 9 (range 3-26), macroscopically complete resection was obtained for 25 patients (73%). There was more gallbladder localization in the surgical group compared to the medical group (35% vs. 18%, p= 0.001). Median OS was 21.4 and 9.3 months for surgical and medical group, respectively (p =0.007). Three-year overall survival was 30% and 10% for surgical and medical group, respectively. Conclusions: Treatment with CRS and HIPEC for cholangiocarcinoma with peritoneal metastasis is feasible and may provide survival benefit when compared to palliative chemotherapy.
First-in-human phaseⅠstudy of JPH203 in patients with advanced solid tumors.
Authors: Okano Naohiro , Kawai Kirio , Yamauchi Yoshiya , Kobayashi Takaaki , Naruge Daisuke , Nagashima Fumio , Endou Hitoshi , Furuse Junji
Published: January 2019

419

Background: Uptake of amino acids is essential for cancer growth. L-type amino acid transporter-1 (LAT-1) is overexpressed in various cancers, and uptake of LAT-1 substrate amino acids is known to have a critical role in cancer growth. JPH203 is a novel, selective, LAT-1 inhibitor. A first-in-human phase I study of JPH203 was designed to determine the safety, maximum-tolerated dose (MTD) and recommended dose. This study included evaluation of the anti-tumor effect, pharmacokinetics, and pharmacodynamics of JPH203 and analyzed plasma free amino acids. Methods: JPH203 was administered intravenously for 7 days followed by 21 days’ rest at planned doses ranging from 12 to 110 mg/m2 in patients with advanced solid tumors refractory to standard therapy. Before starting this schedule, we confirmed safety of a single dose of JPH203. Dose-limiting toxicity was evaluated during the first cycle, using a 3+3 design. Results: 17 patients were enrolled from January 2015 to August 2016. One patient was discontinued after a single dose of JPH203 because of tumor progression. Dosage was escalated up to 85 mg/m2. Grade 3 liver dysfunction occurred in 1 of 6 patients at 60 mg/m2 and in the first patient at 85 mg/m2. Therefore, it was determined that MTD was 60 mg/m2. Common treatment-related adverse events were increased ALT/AST, malaise, nausea, hypertension and fever of Grade 1 or 2. Partial response was achieved in a patient with biliary tract cancer (BTC) who continued JPH203 for two years without progression. Disease control (PR+SD) was observed in 3 of 5 patients with BTC and 2 of 6 with colorectal cancer. LAT-1 substrate amino acids and branched chain amino acids including LAT-1 substrate amino acids were higher in patients with BTC than in those with other cancers. All patients with disease control had a body mass index more than the median of 20.5 kg/m2. In exploratory analysis, longer survival was achieved in patients with high inhibition of uptake of LAT-1 substrate amino acids, compared with patients with low inhibition of uptake. Conclusions: JPH203 was well tolerated, resulting in promise against BTC. This phase I study suggested that LAT-1 could be targeted in treatment for advanced BTC, because LAT-1 substrate amino acids in plasma tended to remain high. Clinical trial information: UMIN000016546.
Volume reduction rate of the primary tumor as an objective clinical measure to evaluate efficacy of neoadjuvant chemotherapy for esophageal squamous cell carcinoma.
Authors: Nagasawa Shinsuke , Ogata Takashi , Hara Kentaro , Osakabe Hiroaki , Nakazono Masato , Kumazu Yuta , Hayashi Tsutomu , Yamada Takanobu , Rino Yasushi , Masuda Munetaka , Yoshikawa Takaki
Published: January 2019

42

Background: Neoadjuvant chemotherapy (NAC) followed by surgery is a standard treatment for esophageal squamous cell carcinoma (ESCC) in Japan. Efficacy of NAC on the primary tumor is clinically evaluated during NAC and before surgery and is pathologically examined after surgery. Clinical evaluation of the primary tumor is sometimes difficult because primary tumor is nonmesurable lesion and is usually evaluated subjectively, while pathological finding is objective and a gold standard to evaluate efficacy of NAC. In the present study, we tried to evaluate clinicaly efficacy objectively by calcurating tumor volume by esophagography and concordance between volume reduction rate and pathological efficacy. Methods: This retrospective study examined 53 patients who fullfilled the following criteria; (1) thoracic ESCC, (2) underwent resection following NAC between January 2011 and February 2017, and (3) T2-3N0 before surgey. Clinically, volume of the primary tumor was calculated by multiplying length and thickness in the lateral view of esophagography. Pathological efficacy was examined by the proportion of the tumor disappearance of the primary tumor and was classified as Grade 0-1 when degeneration area was < 2/3, Grade 2 when those area was > 2/3 and < 3/3, and Grade 3 when there was no residual tumor. Volume reduction rate calculrated by the difference of pre- and post-NAC was compared by stratifying pathological grade. Results: T2/T3 was 23/30, respectively. Regimen of neoadjuvant chemotherapy was 5-FU/CDDP in 50 patients,docetaxel/5-FU/CDDP in 1,and 5-FU/CDDP and Radiotherapy in 2. Overall volume reduction rate was 58.9% in median (range -127-100%). Pathological response (Grade 0-1/2/3) was 28/18/4, respectively. Median volume reduction rate (range) was 38.5% (-127-100%) in Grade 0-1, 72.2% (21.7-100%) in Grade 2, and 91.1% (75.5-100%) in Grade 3, which was significantly different (p < 0.01). Conclusions: The volume reduction rate of the primary tumor was correlated with pathological efficacy, suggesting that volume reduction rate could be a objective measure to evaluate efficacy of neoadjuvant chemotherapy for ESCC.
Locally advanced gallbladder cancer: Contemporary outcomes for aggressive surgical management.
Authors: Ito Hiromichi , Takahashi Yu , Mise Yoshihiro , Inoue Yosuke , Ishizawa Takeaki , Saiura Akio
Published: January 2019

420

Background: Patients with gallbladder cancer (GBCA) often present at advanced stages and their prognosis is dismal. Surgery for locally advanced (LA) disease has been controversial and the optimal indication for resection needs to be defined. Methods: Patients who underwent curative resection for GBCA of T1b or greater with curative intent at our institution from Jan. 2006 through Jun. 2017 were included. “Locally advanced disease” was defined as GBCA deemed to invade the hepatic hilum, or the extrahepatic organs either by the preoperative imaging. Perioperative management, operative procedures, and the short- and long-term for the patients with LA-GBCA were evaluated and compared with those for the patients with localized GBCA (L-GBCA). Results: Total 102 patients were identified and 35 patients were with LA-GBCA. Nineteen patients (54%) with LA-GBCA presented with jaundice, and all of them had biliary stent placed preoperatively. Preoperative portal embolization was performed for 22 patients (63%). Extended resections included hepatopancreaticoduodenectomy (n = 14, 40%), major hepatectomy (lobectomy or greater, n = 29, 83%), with partial duodenectomy (n = 7, 20%), with partial colectomy (n = 6, 17%), and with major vascular resection/reconstruction (n = 9, 26%). R0 resection was achieved in 87% of the patients with LA-GBCA by extended resection, while it was achieved in 91% of those with L-GBCA by standard radical cholecystectomy ( p= 0.13). The 5-year recurrence-free and overall survival (RFS and OS) rates for the patients with LA-GBCA were 19% and 26%, compared with 57% and 66% for those with L-GBCA ( p< 0.001 for RFS, and p < 0.001 for OS, respectively). In the multivariate analysis for all the patients with GBCA, T3 or greater, nodal metastasis and R1 resection remained as significant risk factors for both recurrence and death after resection with curative intent. Conclusions: Although extended resection for locally advanced cancer is safe and feasible, its long-term outcomes remained poor. Appropriate patient selection criteria needs be established to avoid aggressive operation without benefit for the patients with LA-GBCA.
Epidemiology and treatment of high-grade gastrointestinal neuroendocrine tumors (HG-GI-NETs).
Authors: Alese Olatunji B. , Jiang Renjian , Shaib Walid Labib , Wu Christina Sing-Ying , Akce Mehmet , Behera Madhusmita , El-Rayes Bassel F.
Published: January 2019

421

Background: High grade neuroendocrine tumors of the gastrointestinal tract are rare tumors. Management strategies are modeled after small cell lung cancer (SCLC). Treatment patterns and outcomes have not been studied. Methods: Data were obtained from all US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2013. Univariate and multivariate testing was done to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between patient characteristics and survival. Results: A total of 1,861 patients were identified for the 10 years of the study. The mean age was 63 years (SD±13), with a male preponderance (53.3%). The vast majority of patients (78.1%) were non-Hispanic Whites. The most common primary sites were pancreas (PNET = 19.4%), large intestine (18.1%), esophagus (17.8%) and rectum (15.5%). About 27.9% of the cases were resectable at the time of diagnosis, and distribution across stages 1-IV was 6.6%, 10.5%, 18% and 64.6% consecutively. Liver was a common site of metastases (50.4%), followed by bone (11.3%) and lungs (10.8%). Only 3.5% of the patients had brain metastases. On univariable analysis, age < 65years (HR 0.72; 0.66-0.8; p < 0.001) and treatment at an academic center (HR 0.88; 0.79-0.99; p < 0.034) were associated with improved survival. Multivariable analysis confirmed prognostic advantage of treatment at an academic center. Patients treated with chemotherapy had a median overall survival (OS) of 11.2 months, compared with 1.7 months for those who did not. The median OS for high grade PNET was 6 months, compared to 9.9 months for other HG-GI-NETs. One year and 5-year survival rates were 27.5% vs. 41% and 4.5% vs. 12.3% respectively. Conclusions: This is the largest series of HG-GI-NET. Almost two-thirds of the cases present with metastatic disease. Pattern of metastasis differs from SCLC. Survival is short. Treatment at high volume academic center, younger age and use of chemotherapy are associated with improved survival.