bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of American Indian and Alaska Native ethnicity on the presentation and surgical treatment of gastric cancer: An NCDB analysis from 2004-2014.
Authors: Vuong Brooke , Klempner Samuel Jacob , Nguyen Trang , Young Stephanie , Dehal Ahmed , Graff-Baker Amanda , Chang Shu-Ching , Bilchik Anton J. , Goldfarb Melanie , Fischer Trevan D
Published: January 2019

13

Background: American Indian/Alaska Natives (AI/ANs) with gastric adenocarcinoma (GC) have an incidence and mortality nearly double that of matched Non-Hispanic Whites (NHW) in historical data sets. However, the impact of AI/AN ethnicity on disease presentation and treatment is underrepresented in gastric cancer epidemiologic studies and has not been evaluated in a contemporary population. Methods: The National Cancer Data Base (NCDB) was queried from 2004-2014 to identify patients with gastric cancer who identify as AI/AN or NHW. Patient demographics, tumor characteristics, and treatment details, including surgical quality metrics, were compared using Chi-square and Student's t-tests. Results: There were 22,286 NHW and 115 AI/AN GC patients with complete staging information. Compared to NHW, AI/ANs were younger (age ≤65) at diagnosis (p < 0.001), which translated to a younger median age at death (NHW:70 years, AI/ANs:60 years, p < 0.001). AI/ANs more often lived over 100 miles from their treatment facility (p < 0.001) in non-metropolitan cities (p < 0.001). Stage distribution was not different for the AI/AN population when compared to the NHW population: 37% vs. 35% Stage I; 33% vs. 37% Stage II; 10% vs. 11% Stage III; and 19% vs. 16% Stage IV (p = NS). However, AI/ANs had a higher rate of signet ring cell histology and linitis plastica (26% vs. 15%, p = 0.002) compared to NHWs. More AI/AN patients compared to NHW patients had delays over eight weeks to initiation of treatment, 19% vs. 11% (p = 0.008). There were no statistically significant differences for surgical quality metrics, including type of surgery, rate of ≥15 lymph nodes retrieved, margin positivity, or 30-day mortality (p = NS). Conclusions: Both biological and social disparities are evident for AI/ANs with gastric cancer. AI/ANs develop and die from gastric cancer at younger ages compared to NHWs and present with higher rates of aggressive histology. They also travel longer distances for treatment and experience greater treatment delays. These features may partly underlie the higher mortality rates previously described.
Prospective, multicenter, noninterventional and registry clinical study of apatinib in patients with advanced gastric cancer.
Authors: Bai Chunmei , Zhong Diansheng , Zhang Ruixing , Ren Xiubao , Liu Likun , Du Nan , Yu Junyan , Yang Mudan , Zang Aimin , Diao Jianfeng , Ren Yuchuan , Fu Zhanzhao , MA Liwen , Zhang Lei , Gao Jinghua , Li Guozhong , Guo Jun , Zhang Junping , Jia Junmei , Zhang Wenzheng
Published: January 2019

137

Background: The aim of this study was to observe the safety of apatinib in the real world with wider inclusion criteria. The efficacy of apatinib was evaluated including overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). Methods: This trial enrolled patients from 32 centers in china with advanced gastric adenocarcinoma who had progressed after undergoing at least two lines of systemic chemotherapy, or patients who were considered to benefit from the treatment. We recommended starting from oral administration of 500mg qd, 28 days for a cycle. Dose could be appropriately adjusted according to the patients’ physical condition. Results: Between March 2015 and September 2017, 326 patients were enrolled. The average age was 62 years old, and the ratio of male to female was about 2:1. Patients received perioperative, first-line, second-line, and third-line or more treatment were 1,39,69 and 217 people respectively. There were 192 patients received efficacy evaluation, 9 patients achieved partial response(PR), 125 had disease stability(SD). The ORR and DCR were 4.6% and 69.8% respectively. The median PFS and median OS were 3.7 months and 7.3 months respectively. In the 326 patients, there were 153 patients with initial dose of 500 mg, 3 and 55 patients achieved PR and SD, respectively. The ORR and DCR were 3.3% and 63.7%, respectively. The median PFS and median OS were 3.5 months and 8.4 months, respectively. There were 237 patients in all 326 patients received safety analysis. Common adverse events were hypertension (57%), hand-foot skin reactions (26.6%), fatigue (29.5%), proteinuria (19.0%), bleeding (10.1%) and diarrhea (8.0%). The grade 3 to 4 adverse events were hypertension (6.3%), hand-foot skin reactions (3.8%), proteinuria(3.0%) and bleeding (2.1%). Conclusions: This real-world data in which more patients were given apatinib 500mg or less qd showed similar efficacy to Phase III clinical trial (850mg qd).The incidence of adverse events was consistent with that of Phase III clinical data,there was no new adverse events had been seen. Clinical trial information: NCT02668380.
Nonoperative management of locally advanced esophageal and junctional (GEJ) cancers: The University of Rochester experience.
Authors: David Rachel Julie , Baran Andrea , Katz Alan W. , Dunne Richard Francis , Noel Marcus Smith , Hezel Aram F. , Tejani Mohamedtaki Abdulaziz
Published: January 2019

144

Background: Neoadjuvant (NA) chemoradiation (CRT) followed by surgery is a standard treatment for locally advanced esophageal/GEJ tumors. The optimal management strategy is less clear for unresectable tumors or in patients (pts) who are medically inoperable. Methods: We retrospectively identified all pts with stage II/III esophageal/GEJ cancers treated without surgery at our institution from 2011-2015. Objectives were to describe treatment regimens used and assess outcomes based on clinicopathologic features. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier curves. Results: 38 pts were identified. 66% were male; median age was 69 years (range 43-91). 19 pts had adenocarcinoma, 18 had squamous cell, and 1 had small cell. Primary sites were distal (n = 22), mid (n = 13), and cervical esophagus (n = 3). 31 pts were treated with curative intent, 7 with best supportive care. 30 pts underwent CRT: 16 in a NA setting, 14 in a definitive setting. Chemotherapy regimens used were Carboplatin/Paclitaxel (19 pts) and Cisplatin/5-FU (10 pts). Median NA radiation (RT) dose was 45 Gy vs 50.4 Gy in the definitive setting (p = 0.008). Best response included 6 pts with complete responses (CR), 12 with partial responses, and 12 with progressive disease/death (PD). In the NA group, resection was avoided due to PD (n = 10), comorbidities (n = 4), unresectability (n = 1), and CR (n = 1). Median PFS and OS for all 38 patients were 6.5 and 11.1 months (mos). Median PFS and OS for adenocarcinoma pts were 4.6 and 7.2 mos, compared to 9.1 and 12.5 mos for pts with squamous. Compared to NA CRT, pts treated with definitive CRT had significantly prolonged PFS (18.5 vs 2.5 mos, p = 0.001) and OS (27.1 vs 5.3 mos, p = 0.03). Conclusions: In the absence of resection, outcomes for locally advanced esophageal/GEJ tumors remain poor, especially for adenocarcinoma pts who progress during NA CRT. A PET-directed approach as suggested by CALGB 80803 may help to identify these pts earlier in their course, allowing for treatment change. Multidisciplinary assessment to identify non-surgical candidates at diagnosis is critical since RT doses used in the definitive setting are generally higher.
Potential of SUSD2 as a predictor of recurrences after curative resection of gastric cancer.
Authors: Umeda Shinichi
Published: January 2019

15

Background: Gastric cancer (GC) is the third common leading cause of cancer-related death worldwide with a high recurrence rate. Development of sensitive biomarkers to predict recurrences is needed to improve patient management. Methods: We conducted a recurrence pattern-specific transcriptome analysis of 57751 molecules for screening of candidate molecules specific for hematogenous metastasis with stageⅢ GC patients who underwent curative resection followed by S-1 adjuvant. Subsequently, mRNA expression analysis, PCR array analysis and siRNA-mediated knockdown experiments were performed using GG cell lines. Expression levels in primary GC tissues from 154 patients with resectable GC were determined and correlated to clinicopathological factors. Results: We identified 21 candidate molecules overexpressed significantly specifically in the hepatic recurrence group and decided to focus on Sushi domain containing 2 (SUSD2). PCR array analysis revealed that SUSD2 expression levels are positively correlated with Frizzled-7 , Cadherin 2 and ZEB1. Functional analysis revealed that knockdown of SUSD2 significantly reduced the proliferation, migration and invasion abilities of GC cells. Patients with high SUSD2 expression had a significantly higher prevalence of hematogenous recurrences and were more likely to experience shorter disease-free and overall survival, particularly in stage III patients. Conclusions: SUSD2 may serve as predictor of recurrences after curative resection of GC.
Dosimetric analysis of distal esophageal adenocarcinoma patients treated by intensity-modulated proton therapy with small spot size.
Authors: Liu Chenbin , Sio Terence Tai Weng , Bhangoo Ronik S , Rule William G. , Ross Helen J. , Paripati Harshita , Jaroszewski Dawn E. , Beamer Staci , Fleischer David , Ramirez Francisco , Ding Xiaoning , Bues Martin , Ashman Jonathan Ben , Liu Wei
Published: January 2019

159

Background: Intensity-modulated proton therapy (IMPT) with small spot size has the potential to reduce dose to normal tissues but also introduces new confounding factors such as setup uncertainty, range uncertainty, and interplay effects due to breathing motion. We investigated plan quality and robustness of IMPT with small spot size for distal esophageal adenocarcinoma (DEA). Methods: 19 patients with DEA treated by IMPT were retrospectively evaluated. Spot sizes ranged from 2 to 6mm, with spot spacing of 5mm. All plans were generated using a commercial treatment planning system. In-house-developed dose-evaluation software modeled time-dependent spot delivery to incorporate interplay effects. Dose-volume-histogram (DVH) indices were used to evaluate plan quality and robustness was evaluated using the DVH band method. Results: For plan quality, median values of clinical target volume D95% and D5%-D95% (normalized to the prescribed doses), total lung mean dose, heart mean dose, and cord Dmax were 1.014, 0.035, 3.82Gy[RBE], 7.73Gy[RBE], 39.16Gy[RBE], respectively. For plan robustness, median band widths of the aforementioned DVH indices were 0.018, 0.048, 0.60Gy[RBE], 4.17Gy[RBE], and 2.36Gy[RBE], respectively. For interplay effects, median values of the aforementioned DVH indices were 0.99, 0.061, 4.07Gy[RBE], 7.87Gy[RBE], and 39.66Gy[RBE], respectively. Seven patients underwent esophagectomy after neoadjuvant chemoradiation, and five, three, and one of them achieved downstaging, near complete response, and pathologic complete response, respectively; R0 resection was achieved in all cases. For all patients, acute side effects were mostly limited to grades 1-2 only. The only grade 3 adverse events were related to feeding tube placement (8 patients); there were no RT-induced pneumonitis or other lung-related toxicities. Conclusions: IMPT plans with small spot size for DEA have good target dose coverage, homogeneity and normal tissue protection. Treatment plans are also robust to uncertainties and interplay effects. Early clinical results demonstrate low acute toxicity and encouraging clinical and pathologic response.
Patient-level costs of treating metastatic gastric cancer by treatment strategy.
Authors: Jeong Yunni , Mahar Alyson L. , Zagorski Brandon , Coburn Natalie
Published: January 2019

167

Background: Half of gastric cancer patients in North America present with metastatic disease. The appropriate management of these patients is complex and few guidelines exist to definitively guide treatment; as a result, practice variation exists. This variation may lead to care inefficiencies with adverse outcomes. We therefore aimed to conduct a patient-level exploration of metastatic gastric cancer management costs, by treatment strategy, and identify predictors of cost. Methods: We performed a patient-level cost analysis of metastatic gastric cancer patients diagnosed between 2005 and 2008 using a 26-month time horizon and the healthcare system’s perspective. Clinical data was derived from a provincial chart review. Costs associated with supportive care, radiation only, chemotherapy only, chemoradiation, gastrectomy, and gastrectomy with chemotherapy +/- radiotherapy were derived using administrative data from a universal healthcare system. Costs were inflated to 2017 United States dollars (USD) Linear regression was used to identify factors predictive of cost. Results: The absolute mean costs of metastatic gastric cancer management increased with increasing level of intervention and ranged from $34,002 to $72,778 (USD); supportive care was associated with the lowest costs and gastrectomy with chemotherapy +/- radiotherapy was associated with the highest costs. Age over 70 and lower Charlson Comorbidity Index were predictors of lower costs while supportive care, radiotherapy, chemoradiation, and gastrectomy were associated with higher costs. Conclusions: Practice variation has known clinical implications, but economic impact also needs to be considered. Variation in the management of metastatic gastric cancer may reflect dissimilar resource availability between health regions as well as differential access to palliative care. Evidence-based guidelines directing appropriate care for metastatic gastric cancer patients to reduce inefficiencies in care and governmental intervention to implement equitable resource allocation to bridge gaps in care are necessary.
Pharmacokinetics (PK) of S-1 monotherapy in plasma and in tears for gastric cancer patients (pts).
Authors: Kawakami Takeshi , Kashiwagi Hiroya , Mori Keita , Omae Katsuhiro , Kasai Jun , Yoshisue Kunihiro , Kawahira Masahiro , Tsushima Takahiro , Machida Nozomu , Fukutomi Akira , Yamaguchi Ken , Yasui Hirofumi
Published: January 2019

175

Background: S-1 is an oral anticancer drug that contains of tegafur (FT), which is a prodrug of 5-FU, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. S-1 is a key, important drug for the treatment of various cancers including gastric cancer. Recently, we demonstrated that Grade 2 or 3 watering eyes was observed in 25% of gastric cancer pts who received S-1 as adjuvant treatment for 1 year (Tabuse H, et al. Gastric Cancer 2017;19:894-901). However, the mechanism of watering eyes caused by S-1 is still unclear. The aim of this study is to investigate the association of the PK of FT, 5-FU, and CDHP, which are components of S-1, in plasma and tears. Methods: We prospectively investigated the PK of FT, 5-FU, and CDHP in plasma and in tears of gastric cancer pts who were treated with S-1 monotherapy at the dose of 80 mg/m2/day. Plasma and tears from both eyes were obtained 1, 2, 4, and 8 hours after S-1 administration on day 1 and 14 of cycle 1. Results: Total of 8 pts were enrolled. PK parameters on day 14 was shown in Table. The concentration of 5-FU in the tears tended to be higher than that in the plasma. There was a strong association between the PK of FT, 5-FU and CDHP in the plasma and that in the tears on day 14 (correlation coefficients r2, right eye/left eye: r2= 0.7778/0.7773, 0.7687/0.7913, and 0.7823/0.7717, respectively). Conclusions: There is a strong association between the PK of FT, 5-FU and CDHP in the tears and that in the plasma. Therefore, the concentration of S-1 in the plasma may be substituted for that in the tears. Clinical trial information: UMIN000021610. [Table: see text]
An evaluation of the surgical treatment strategy for the adenocarcinoma of the esophagogastric junction: A retrospective single center study in Japan.
Authors: Sugita Shizuki , Tokunaga Masanori , Kaito Akio , Watanabe Masahiro , Tonouchi Akiko , Kinoshita Takahiro
Published: January 2019

177

Background: The incidence of Siewert type II adenocarcinoma of the esophagogastric junction (AEG II) has been increasing in the East, and total gastrectomy (TG) has been a standard treatment procedure.　However, it is reported that the incidence of distal perigastric lymph node (LN) metastasis is low, and thus proximal gastrectomy (PG) could be a treatment option. The aim of this study was to demonstrate the oncological safety of PG for patients with AEG II. Methods: This study included 99 patients with AEG II who underwent gastrectomy with lower esophagectomy from Jan. 2008 to June 2017. Patients with esophageal invasion over 30 mm, and those with positive LN in the upper/middle mediastinum were excluded. PG was selected when more than half of the stomach could be preserved, and no obvious distal perigastric LN metastasis was found. Surgical approach was selected at the patients’ discretion. Short- and long-term outcomes were compared between patients who underwent TG (N = 43) and PG (N = 56). Results: Laparoscopic surgery was the predominant procedure (75.0%) in the PG group while open surgery was most frequently selected (79.1%) in the TG group. Intraoperative and short-term surgical outcomes were not different between the groups except for intraoperative blood loss, which was less in the PG group than in the TG group. Survival outcomes tended to be better in the PG group than in the TG group (3-/5-year OS, 91.1%/ 91.1% vs 67.4%/ 65.1%), presumably due to the predominance of early stage cancers in the PG group. After stratification by pStage, however, survival outcomes were not significantly different between the groups in any pStage. In the PG group, distal perigastric LN reccurence was not found during the follow-up period. In the TG group, 2 patients (4.7%) had distal perigastric LN metastasis, and both died within 2 years of surgery. Conclusions: Therapeutic value of distal perigastric LN dissection is quite limited in patients with AEG II. PG seems to be as oncologically safe as TG, and could be a suitable treatment strategy for patients with AEG II.
First-line chemotherapy with docetaxel, oxaliplatin, and timed-flat infusion 5Fluorouracil in metastatic gastro-esophageal adenocarcinomas: The experience with FD/FOx regimen.
Authors: Cortellini Alessio , Parisi Alessandro , Cannita Katia , Napoleoni Luca , Lanfiuti Baldi Paola , Venditti Olga , Porzio Giampiero , Ficorella Corrado
Published: January 2019

178

Background: Triplet chemotherapies, with fluoropyrimidines, platin derivates and Docetaxel, represent an option for first line treatment of metastatic Gastro-Esophageal Adenocarcinoma (mGEA). To increase tolerability and dose intensity (DI), we previously developed an alternative way of administration of 5Fluorouracil (5FU), with nocturnal “timed-flat infusion” (TFI) (from 10:00 PM to 10:00 AM), without 5FU bolus and Folinic Acid, in several combination-schedules in breast and colorectal cancers. Methods: We report a retrospective analysis of 27 mGEA patients (pts) treated with FD/FOx regimen, a schedule of weekly TFI/5FU for two nights at 1000 or 900 mg/m2/night, associated to alternating Docetaxel at 50 mg/m2 on days 1 and 15, and Oxaliplatin at 80 mg/m2 on days 8 and 22, cycles repeated every 4 weeks. Results: From June 2007 to July 2017, 17 pts (62.9%) were treated with standard FD/FOx and 10 pts (37.1%) with modified FD/FOx (defined by any projected dose reduction compared to standard) due to age, PS and comorbidities. Median age was 60 years (range 41-80), male/female ratio 19/8, ECOG-PS 0, 7 (26%), 1, 16 (59%), 2, 4 (15%); 17 pts (62.9%) had a Cumulative Illness Rating Scale Intermediate stage, 1 patient (3.7%) a Secondary one. Thirteen pts (48%) had unresected primary tumor. ORR, median PFS and median OS were 73.9% (α0.05, CI±18), 13 and 16 months, respectively. The only G4 toxicity was neutropenia (11.1%); G3 were: neutropenia (29.6%), asthenia (22.2%), diarrhea (22.2%); most relevant G2 toxicities were: nausea (33.3%), anorexia (40.7%), neuropathy (37.0%) and anemia (40.7%). No febrile neutropenia was observed. The received (r)DI were 80% of standard full dose of each drug: Docetaxel 20 mg/m2/week, Oxaliplatin 32 mg/m2/week and 5FU 1440 mg/m2/week. Out of 21 pts who progressed to FD/FOx, 13 pts (48.1%) underwent a second line therapy (6 rechallenges with taxanes). Conclusions: Even if requires a careful management, FD/FOx is a feasible option for first line treatment of mGEA pts, particularly in needing of tumor shrinkage, with significant activity, high rDIs, and acceptable safety profile when compared to literature.
Comparative study of transhiatal and transthoracic thoracoscopic esophagectomy results in adenocarcinoma of the esophagogastric junction.
Authors: Takeda Flavio Roberto , Cecconello Ivan , Ribeiro Ulysses , Sallum Rubens Antonio Aissar
Published: January 2019

185

Background: The surgical treatment of adenocarcinoma of the esophagogastric junction surgical treatment (AGEJ) is still controversial, particularly concerning to survival and postoperative complications. To compare thoracoscopic esophagectomy (group A) with transhiatal esophagectomy (group B) in patients with AGEJ in relation to the occurrence of complications and mortality; number of ressected lymph nodes, the positive and the ratio between the ressected and positive; overall and disease free survival; and survival after relapse. Methods: There was a selection of 147 patients from 2000 to 2017. Epidemiological data were analyzed and compared between the groups. Postoperative complications were evaluated. The anatomopathological staging was evaluated, analyzing the resected lymph nodes. Analysis of overall survival, disease free survival and survival after relapse were made, besides multivariate analysis of survival related factors. Results: In relation to the complications, group A presented greater occurrence of hoarseness and surgical infections. In relation to mortality, group A presented 2 cases (3.7%) and group B presented 4 (4.3%), without statistical difference. In group A, the average number of ressected lymph nodes was 31.88 and in group B was 20.73 (p < 0.001), however the average number of affected lymph nodes was 3.96 in group A and 4.25 in group B. The general overall survival was 42.3%, in group A was 38.9% and in group B was 47.6% (p = 0.298). In the multivariate analysis of overall survival only lymphatic invasion (p = 0.005), diabetes mellitus (p = 0.038) and surgical infection (p-0.001) were significant. However, in tumors with stage until 2B, group A overall survival was 80.4% and group B was 38.5% (p = 0.001). Conclusions: Both methods are safe with similar morbidity and mortality rates. Transthoracic thoracoscopic esophagectomy allows a larger ressection in the number of lymph nodes. Overall survival and disease free survival are similar, however until stage 2B thoracoscopic esophagectomy improves overall survival. Diabetes and lymphatic invasion interfere in overall and disease free survival.
Development of new endoscopic irreversible electroporation ablation device: Animal experimental study.
Authors: Min Geeho , Choi Hyuk Soon , Kim Woojung , Choi Seong ji , Lee Jung Min , Kim Seung Han , Lee Jae Min , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Lee Hong Sik , Chun Hoon Jai , Kim Chang Duck
Published: January 2019

188

Background: Irreversible electroporation (IRE) is a promising novel technique for the ablation of tumors. An advantage of IRE is its mechanism to remove undesired cells by affecting the cell membrane without thermally destructing blood vessels, nerves and the surrounding tissues. Several clinical trials for applying IRE to human organs such as liver, pancreas, and kidney are conducted and studies about IRE ablation for gastrointestinal tumors also have been conducted recently. Here, we developed new endoscopic IRE device, and studied about its effectiveness and feasibility in animal model. Methods: Newly developed endoscopic IRE ablative catheter works with single channel of endoscope. A pair of dipolar electrodes consist of pre-shaped f 0.63mm nitinol wire and the distance between each electrode is 10 mm. The electrodes are loaded within braided tube for stent delivery system then deployed when IRE catheter put in stomach through the endoscope. We performed endoscopy and IRE ablation was done on pig’s stomach mucosa by using endoscopy with newly developed IRE catheter. We divided pig’s stomach into 2 parts(antrum & body), and IRE ablation was applied on each part of the stomach. Pigs were sacrificed after 24hours, and we collected their stomachs with surgical technique. Following fixation, tissues were stained with H&E. Results: Ten male Yorkshire pigs and in vitro stomachs were used in this study. The tissue with H&E stain showed diffuse cell death 24hr after IRE ablation. Consistent with the mechanism of action of IRE on the cell membrane only, there was complete cell death within the IRE lesions without intervening live cells. But there was no difference in histology depending on gastric part in which ablation was applied. During the study, no complication was observed in pigs in 24 hours after ablation. Conclusions: The new endoscopic IRE device, which can perform IRE ablation on gastrointestinal tract using endoscopy showed safe and feasible result.
Clinical significance of surgical treatment for imatinib-resistant gastrointestinal stromal tumors.
Authors: Hashimoto Tadayoshi , Takahashi Tsuyoshi , Kurokawa Yukinori , Kato Ryo , Wada Noriko , Tanaka Koji , Miyazaki Yasuhiro , Makino Tomoki , Yamasaki Makoto , Nakajima Kiyokazu , Mori Masaki , Doki Yuichiro
Published: January 2019

189

Background: The standard first-line treatment for unresectable metastasis or recurrence gastrointestinal stromal tumors (GIST) is imatinib mesylate(IM), a selective tyrosine kinase inhibitor. Although IM has markedly improved the prognosis of patients with advanced GIST, half of the patients experience tumor progression within two years because of resistance to IM. And IM-resistant GIST is basically treated by other kind of TKI, in addition, surgical treatment can be considered as one of treatment options. The aim of this study was to clarify the significance of surgical treatment for IM-resistant GIST in the era of second-line TKI treatment. Methods: We retrospectively analyzed consecutive 35 GIST patients who have developed IM-resistance between 2004 and 2015. We assessed clinicopathological characteristics, postoperative outcomes, imatinib-failure free survival(IFFS), and overall survival(OS) in patients who underwent surgical resection for the IM-resistant lesions. Results: The study enrolled 24 male patients and 11 female patients. The median [range] age was 61 [39-83] years. The primary sites were stomach / small intestine / duodenum: 16 / 14 / 5 cases and resection for primary sites was performed in 32 cases. The median [range] period of IM administration until resistance was 26 [2-119] months, and the resistant lesion sites were liver / peritoneum / primary lesion / local recurrence / bone: 17 / 18 / 2 / 1 / 1 cases (with duplication). Resection for resistant lesions was performed in 18 cases (51%), of which 13 cases (72%) underwent R0 / 1 resection. The postoperative complications ( > Clavien-Dindo classification Grade II) were observed in 3 patients: Biliary leakage, abdominal abscess, and diaphragmatic hernia. IM was resumed promptly after surgery in all 18 patients who underwent resection for IM-resistant lesions, and the median [range] period of IM administration was 22.2 [0.9-56] months. In 5 cases, multiple surgical treatments were performed and second-line TKI was administered in all except for two patients who have still been treated as IM. The median OS was 49 months. Conclusions: It was suggested that surgical treatment for IM-resistant GIST may be safe and effective for appropriate cases.
The impact of the chemoradiation to surgery interval on pathological complete response: Short and long-term overall survival in esophageal cancer patients.
Authors: Azab Basem , Picado Omar , Ripat Caroline , Macedo Francisco Igor , Livingstone Alan S , Franceschi Dido , Yakoub Danny
Published: January 2019

2

Background: The association of the interval between neoadjuvant chemo-radiation and surgery (CRT-S), and cancer outcomes in patients with esophageal cancer is not clear. We aimed to determine the relationship between CRT-S interval and pathological complete response rate (pCR), short and long overall survival (OS). Methods: Patients listed on the National Cancer Data Base from 2004 to 2013 were studied. We included patients with CRT followed by surgery in 15-90 days. All patients had reported pT, pN cancer stages and survival status. CRT-S interval was studied as continuous (weeks) and categorical variables (quintiles). Results: A total of 5181 patients were included; 81% were adenocarcinomas, 84% were males and mean age was 62 years. They were divided into CRT-S interval quintiles (15 to 37, 38 to 45, 46 to 53, 54 to 64 and 65 to 90 days) (n = 1016, 1063, 1081, 1083 and 938 patients), respectively. There was a significant increase of pCR rate across the CRT-S quintiles (18%, 21%, 24%, 25% and 29%, p < 0.001). This advantage persisted when CRT-S was measured as continuous variable in weeks (OR: 1.11, 95% CI = 1.078-1.143, p < 0.001). However, 90-day mortality significantly increased as CRT-S increased across quintiles (5.7%, 6.2%, 6.8%, 8.5% and 8.2%, p = 0.02) and through weeks (OR = 1.05, 95%CI = 1.005-1.106, p = 0.03). Mean OS across CRT-S quintiles was 59.2, 58.8, 55.4, 56.6 and 51.5 months, respectively. Multivariate Cox regression showed significantly worse OS per week increase in CRT-S interval (HR 1.02, 95% 1.003-1.037, p = 0.02), especially among the last quintile (CRT-S = 65-90 days: HR 1.2, 95% CI 1.04-1.32, p = 0.009). Those with no-pCR had worse OS as time to surgery increased (p < 0.001), while pCR group had similar OS across CTR-S intervals. Conclusions: Despite higher pCR rate as CRT-S interval increasing, surgery is preferred to be done in less than 65 days after CRT to avoid worse 90-day mortality and achieve better OS. Further randomized studies are needed to consolidate our findings.
Phase II LAPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC).
Authors: Hammel Pascal , Lacy Jill , Portales Fabienne , Sobrero Alberto F. , Pazo Cid Roberto A. , Manzano Mozo Jose Luis , Terrebonne Eric , Dowden Scot D. , Shiansong Li Jack , Ong Teng Jin , Nydam Thom , Philip Philip Agop
Published: January 2019

204

Background: In the phase 3 MPACT study, treatment with nab-P + G resulted in a > 3-fold reduction in primary pancreatic tumor burden vs G in patients with metastatic PC, suggesting the potential for activity against LAPC. This international, multicenter single arm, phase 2 trial (LAPACT) was designed to evaluate the efficacy and safety of an induction phase regimen of nab-P + G in previously untreated patients with LAPC. Methods: Treatment-naive patients with unresectable LAPC and Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 were enrolled. The induction phase was designed as 6 cycles of nab-P 125 mg/m2 + G 1000 mg/m2 on D 1, 8, and 15 of each 28-day cycle. After induction, patients without progressive disease or unacceptable adverse events were eligible for continued treatment with nab-P + G, chemoradiation, or surgery per investigator’s choice (IC). Surgery could occur prior to completing 6 induction cycles if the investigator deemed there had been a sufficient tumor response. The primary endpoint was time to treatment failure (TTF) in patients treated with nab-P + G as induction therapy followed by IC treatment. Key secondary endpoints included disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Of 107 patients enrolled, 106 were evaluable for the safety analysis. No new toxicities were identified. The most common grade ≥ 3 treatment-emergent adverse events during induction were neutropenia (42%), anemia (11%), and fatigue (10%); grade 3 peripheral neuropathy occurred in 4% of patients. The most frequent reasons for discontinuing induction were adverse events (18%) and progressive disease (7%). Forty-six (43%) patients received IC treatment after induction: 13 (12%) continued nab-P + G, 17 (16%) received chemoradiation, and 16 (15%) underwent surgical resection (R0, n = 7; R1, n = 9). DCR and ORR during induction were 78% and 35%, respectively; with a median TTF of 8.6 months and median PFS of 10.2 months. Conclusion: A nab-P + G induction regimen in LAPC appears tolerable and feasible and is associated with encouraging antitumor activity and promising TTF and PFS. NCT02301143. Clinical trial information: NCT02301143.
A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT #01959139).
Authors: Ramanathan Ramesh K. , McDonough Shannon , Philip Philip Agop , Hingorani Sunil R. , Lacy Jill , Kortmansky Jeremy S. , Thumar Jaykumar Ranchodbhai , Chiorean E. Gabriela , Shields Anthony Frank , Behl Deepti , Mehan Paul Tracy , Gaur Rakesh , Seery Tara Elisabeth , Guthrie Katherine , Hochster Howard S.
Published: January 2019

208

Background: PEGPH20 degrades hyaluronan (HA), a major component of the stroma, increases delivery of gemcitabine and prolongs survival in preclinical models. We evaluated the activity of PEGPH20 in combination with mFFOX in mPC , unselected for tumor HA. Methods: Pertinent eligibility: untreated mPC, PS of 0-1 and adequate organ function. Standard FFOX was modified to add prophylactic growth factor support and omit bolus 5FU. Due to increased thromboembolic (TE) events with PEGPH20, an amendment instituted LMWH prophylaxis in the PEGPH20 arm only. Following a dose finding cohort of mFFOX + PEGPH20, the Phase II study randomized patients (1:1) to the combination arm or mFFOX alone (n = 138). The primary endpoint was overall survival (OS), with a null median OS of 10 mo and an alternative of 15 mo (1-sided type 1 error 0.1, 80% power). Results: PEGPH20 at 3 mcg/kg, q2 weeks was more tolerable than twice weekly dosing. The randomized phase II study began May 2015. The planned interim futility analysis when 35 deaths occurred gave a HR of 0.44 favoring the standard arm, thus the study was closed to accrual (March 2017). As of August 22, 2017 (n = 111), the estimated median OS in the mFFOX arm was 15.1 mo (95% CI 10.1-15.7) vs 7.6 mo (95% CI 4.6-9.2) in the PEGPH20 arm. Conclusions: OS in the mFFOX control arm (15.1 mo) is longest yet reported. Addition of PEGPH20 to mFFOX is not recommended for further study and appears to be detrimental (HR = 0.48). The impact of PEGPH20 on OS was unexpected and in contrast to favorable results reported for the combination of gemcitabine/nab-paclitaxel + PEGPH20 especially in the HA high cohort (Hingorani S et al. A 4008, ASCO 2017). PEGPH20 with mFFOX caused increased toxicity (mostly GI and TE events) and decreased treatment duration compared to mFFOX alone. Tumor HA content will be analyzed. Funding: NIH/NCI grants CA180888, CA180819; and in part by Halozyme Inc. Clinical trial information: 01959139. [Table: see text]
Chemotherapy use in the elderly for stage IV pancreatic cancer: An NCDB analysis.
Authors: Ahmed Aabra , Sitenga Jenna , Aird Gregory , Walters Ryan W , Silberstein Peter T.
Published: January 2019

223

Background: Cancer incidence is higher in the elderly, yet these patients tend to be underrepresented in clinical trials and receive less treatment than their younger counterparts. This study seeks to elucidate the impact of chemotherapy in elderly patients with stage IV pancreatic cancer. Methods: We identified 68,044 patients with stage IV pancreatic cancer over the age of 65 diagnosed between the years 2004-2013. Between-chemotherapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < .05 indicated statistical significance. Results: Statistically significant differences in demographics of patients with and without chemotherapy included that patients given chemotherapy were more likely to live in an area with a median income of $63,000+ (34.9% vs 30.2%, respectively), receive treatment at an academic center (36.6% vs. 30.7% respectively), and have no comorbidities (66.9% vs. 59.4%, respectively) compared to those not given chemotherapy. Statistically significant survival differences were indicated between all chemotherapy groups (all adjusted p < 0.05), such that patients receiving chemotherapy survived longer than those without chemotherapy (median survival 5.5, 1.3 months, respectively). A larger proportion of patients receiving chemotherapy were alive at 6, 12, and 24 months relative to patients receiving no chemotherapy. Use of chemotherapy has increased over time for elderly stage IV pancreatic cancer patients, such that 37.9% of patients diagnosed in 2004 received chemotherapy, while 45.9% of patients diagnosed in 2013 received chemotherapy. Conclusions: To our knowledge, we are the largest trial to investigate treatment of stage IV pancreatic cancer in the elderly. Although the prognosis is overall poor, chemotherapy provided a mild survival benefit. Use of chemotherapy in these patients increased from 2004 to 2013, yet less than half of patients received chemotherapy. [Table: see text]
Single institutional analysis of pancreatic cancer survival trends based on BMI.
Authors: Wiisanen Jeff , McWilliams Robert R. , Bamlet William R
Published: January 2019

234

Background: Body mass index (BMI) has been reported to determine risk for pancreatic cancer in addition to outcome, as those with higher BMI have decreased survival. Since May 2011, therapy for pancreatic cancer has improved with the addition of FOLFIRINOX. This study looks at overall survival in relation to BMI since the advent of the FOLFIRINOX. Methods: 2,277 patients with pancreatic adenocarcinoma were identified through the Mayo Clinic SPORE pancreatic cancer registry from 2000-14. Usual adult and BMI at time of enrollment were utilized as a binary variable ( < 30, ≥30 kg/m2). These were analyzed for association with survival using Kaplan-Meier curves and Cox proportional hazards regression. Results: For the 2000-11 and 2011-14 groups, stage distribution was 4.4%, 34.7%, 21.6%, 39.2% and 1.2%, 39%, 22.2%, 37.6%, respectively for stage 1-4. Since pancreatic cancer commonly causes weight loss, more patients were in the higher usual adult BMI (34.6%) compared to enrollment (17.1%). For the period 2000-11, 33.8% of patients had a usual adult BMI of 30+ vs 37.8% for the 2011-14 patients. As previously reported, there was a difference in survival by BMI for the period 2000-May 2011, however, this was not seen for the period June 2011-14. Conclusions: Based on this cohort of patients, the previously reported detrimental effect of elevated BMI on survival in pancreatic cancer patients is no longer seen. This corresponds with the time period of improvement in pancreatic cancer treatment with FOLFIRINOX. Further studies should be performed to confirm our findings and to identify the causality of this association. [Table: see text]
Prediction of overall survival for metastatic pancreatic cancer treated with gemcitabine monotherapy: Development and external validation of a prognostic nomogram with open clinical trial data.
Authors: Hang Junjie , Wu Lixia , Du Jiadi , Jiang Hua , Xu Kequn
Published: January 2019

237

Background: There is a need for prognostic tools in metastatic pancreatic cancer (MPC) because they have the potential to optimize patients’ selection in clinical trail and guide treatment strategies. We address this issue by developing and validating a prognostic nomogram with open clinical trail data. Methods: Data from the comparator arm of three clinical trails (NCT00844649, NCT01124786 and NCT00574275) in MPC treated with gemcitabine as first-line chemotherapy were analyzed. The former two were taken as training cohort while NCT00574275 was used as validation cohort. Cox regression model was used to investigate prognostic factors from twenty-three baseline characteristics in training cohort. Based on these factors, a nomogram was developed and internally validated with Harrell’s Concordance index (C-index) and calibration plots. It was further externally validated in the validation cohort. Results: In the training cohort (n = 445), performance status, liver metastasis, CA19-9 log-value, neutrophil, platelet (PLT) and albumin were independent prognostic factors for overall survival (OS). A nomogram based on these factors was generated to predict OS and survival probabilities. The nomogram showed an acceptable discrimination ability (C-index: 0.683) and good calibration. The prognostic score based on nomogram could stratify patients into three-risk groups with median OS of 11.7, 7.0 and 3.7 months (P < 0.001). The nomogram was further externally validated in validation cohort (n = 273, C-index: 0.699); median OS of 10.6, 7.3 and 4.0 months for the three-risk groups (P < 0.001). Conclusions: The prognostic nomogram can accurately predict OS for MPC treated with gemcitabine as first-line chemotherapy. [Table: see text]
Palliative care intervention and aggressive care at end-of-life in patients with advanced pancreatic adenocarcinoma.
Authors: Lees Caitlin , Hopman Wilma M , Younis Tallal , Lamond Nathan William Dana , Ramjeesingh Ravi
Published: January 2019

244

Background: Unresectable pancreatic cancer carries one of the worst prognoses amongst malignancies. For these patients, their treatment at end-of-life represents some of the most expensive care they will receive. Resource-intensive care at the end of life contrasts with the preferences of many patients and their family members. We have examined the intensity of end-of-life care in patients diagnosed with unresectable pancreatic adenocarcinoma using a previously published aggressiveness score. Methods: The surveillance and epidemiology unit of the program of care for cancer identified all patients diagnosed with unresectable pancreatic adenocarcinoma in Nova Scotia between January 1, 2011 and December 31, 2014. Charts were then reviewed for demographic data, Charlson Comorbidity Index, and consultation with Palliative Care. An aggressiveness of end-of-life care score, which has been previously described in the literature, was employed. Briefly, scores ranged from 0 to 6, with higher scores representing more aggressive care. One point was assigned for each of the following events in the last 30 days of life: two or more emergency department visits, two or more hospitalizations, 14 or more inpatient days, chemotherapy, intensive care unit admission, death in hospital. One-way ANOVA was then performed to determine factors associated with more aggressive end-of-life care. Results: In total, 264 patients met inclusion criteria. Mean aggressiveness of end-of-life care was 0.92 (95% CI 0.8 – 1.03). On average, patients seen by Palliative Care at any point in their illness had less aggressive treatment than those never seen by Palliative Care (0.83 vs 1.38, p = 0.001). Conclusions: In patients diagnosed with unresectable pancreatic cancer, less aggressive end-of-life care Further work, including prospective studies, is needed to identify a true association between palliative care intervention and less aggressive care at end-of-life. Such an association could lead to benefits for the patient and reduce costly resource-intensive care.
Preclinical study of antitumor activity of trastuzumab emtansine in HER2-positive biliary tract cancer.
Authors: Yamashita-Kashima Yoriko , Fujimura Takaaki , Shu Sei , Yanagisawa Mieko , Mochizuki Marie , Yorozu Keigo , Kouno Mirei , Furugaki Koh , Higuchi Ryota , Shoda Junichi , Harada Naoki , Yoshimura Yasushi
Published: January 2019

256

Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab and DM1 (an anti-microtubule agent derived from maytansine) that is approved for the treatment of HER2-positive metastatic breast cancer. HER2-overexpression rate in biliary tract cancer (BTC) is reported as approximately 10%, and HER2-targeted therapy may enhance therapeutic efficacy in HER2-positive BTC. In this study, we investigated the antitumor activity of T-DM1 in several BTC cell lines and xenograft models. Methods: HER2 expression was detected by flow cytometry and Western blotting in 17 BTC cell lines. The cell growth inhibition activity of T-DM1 and DM1 was examined by quantifying the DNA with Hoechst 33258 nucleic acid stain. In vivo antitumor activity of T-DM1 was evaluated in three xenograft mouse models using cell lines with different levels of HER2 expression. HER2 expression in xenografts was assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), according to gastric cancer criteria. Cell cycle was assessed by flow cytometry after staining with propidium iodide. Apoptosis was assessed by caspase 3/7 activity measurement. Results: In the 17 BTC cell lines, HER2 expression was high in KMCH-1, Mz-ChA-1, and TGBC-18-TKB. Although cell growth inhibition of DM1 was similar in all cell lines (50% inhibitory concentration (IC50): 0.79–7.2 nM), that of T-DM1 was HER2-expression-dependent, with IC50 values in KMCH-1, Mz-ChA-1, and KKU-100 (which has low HER2 expression) of 0.031, 1.3, and 4.3 μg/mL, respectively. In KMCH-1 and Mz-ChA-1 xenograft models, T-DM1 treatment once every 3 weeks for 6 weeks showed significant dose-dependent antitumor activity, and tumor growth inhibition 21 days after first dose at 20 mg/kg T-DM1 was 108% (KMCH-1) and 75% (Mz-ChA-1), whereas there was no significant efficacy in KKU-100 xenograft model. Values for HER2 status (IHC score/FISH ratio of HER2 to CEP17) in KMCH-1, Mz-ChA-1, and KKU-100 tumor tissues were 3+/3.5, 2+/4.7, and 0/1.1, respectively. In KMCH-1, T-DM1 induced M phase arrest and apoptosis, as is reported in HER2-positive breast cancer cells. Conclusions: T-DM1 could be an effective therapy for HER2-overexpressed BTC.