bluuebunny/crossref_metadata_2025 huggingface dataset:
Underweight as a risk factor for esophageal squamous cellcarcinoma: A nationwide population-based study.
Authors: Choi Yoon Jin , Lee Dong Ho
Published: March 2017

14

Background: Obesity is a well-known risk factor for the development of esophageal cancer (EC). However, the impact of underweight on esophageal squamous cell carcinoma (ESCC) has not been fully recognized to date. Therefore, we herein sought to determine the risk of EC in subjects with underweight. Methods: We analyzed the clinical data from a total of 264,084 individuals with the age of 40 years or older, who received healthcare checkups arranged by the national insurance program, between 2003 and 2008. Newly diagnosed EC was identified using the claims data during a median follow-up duration of 7.9 years. Results: The mean body mass index (BMI) of patients was 23.80 ± 3.05kg/m2, and 6,784 individuals (2.6%) were classified as being underweight (BMI < 18.5 kg/m2). During the study period, 278 individuals (0.1%) developed EC. It was determined that underweight and obesity—compared with normal weight—were significantly associated with 73% increased risk and 30% decreased risk of EC, respectively. Excess risk of EC in the underweight group was independent of age, gender, smoking, and alcohol consumption. Heavy alcohol use had a synergistically increasing effect for developing EC among those in the underweight group. Conclusions: The mean body mass index (BMI) of patients was 23.80 ± 3.05kg/m2, and 6,784 individuals (2.6%) were classified as being underweight (BMI < 18.5 kg/m2). During the study period, 278 individuals (0.1%) developed EC. It was determined that underweight and obesity—compared with normal weight—were significantly associated with 73% increased risk and 30% decreased risk of EC, respectively. Excess risk of EC in the underweight group was independent of age, gender, smoking, and alcohol consumption. Heavy alcohol use had a synergistically increasing effect for developing EC among those in the underweight group.
Cisplatin/5-fluorouracil (CF) versus carboplatin/paclitaxel (CT) chemoradiotherapy (CRT) for locoregionally advanced esophageal cancer (LAEC).
Authors: Marquardt Michael , Anderson Carryn M. , Mott Sarah L , Furqan Muhammad , Clamon Gerald H. , Parekh Kalpaj , Allen Bryan G. , Buatti John Michael , Watkins John Morgan
Published: March 2017

140

Background: Disease control and survival outcomes for LAEC are poor despite multimodality treatment with CRT with or without esophagectomy. Without comparative trial data, oncologists select a chemotherapy regimen based on clinical experience and toxicity profile. The present investigation compares LAEC progression free survival (PFS) and overall survival (OS) for CF versus CT. Methods: A retrospective analysis was performed for patients with LAEC from 2003-2012, treated with curative-intent neoadjuvant or definitive concurrent CRT with either CF or CT. Chi-squared tests, Fisher’s exact tests, and t-tests were used to identify significant differences between treatment groups. The Kaplan-Meier method was used to estimate PFS and OS. Results: Of 149 patients with non-metastatic LAEC, 82 met inclusion criteria (n=38 CF, n=44 CT), with 63, 2, and 2 excluded for non-CF/CT CRT, missing data, and <1 month follow-up, respectively. Treatment groups were well balanced, excepting fewer females, lower prior cancer rate, and longer follow-up for the CF group (Table 1). At a median follow-up of 22.7 months (range, 1.8-132.1, median follow-up 58.6 for survivors), 48 patients experienced recurrence (22 CF, 26 CT), and 63 patients died (29 CF, 34 CT). No differences in PFS or OS were demonstrated between treatment groups (Table 1). Conclusions: The present study failed to detect a disease control or survival difference between CF and CT as a component of CRT in neoadjuvant or definitive settings for LAEC. Until randomized trial data are available, oncologists may elect CF or CT based on clinical situations and anticipated sequelae. [Table: see text]
Exclusive chemoradiation with carboplatin-paclitaxel versus FOLFOX-4 in locally advanced esophageal cancer: A matched-pair analysis.
Authors: Miny Joelle , Bertaut Aurelie , Bosset Jean Francois , Boustani Jihane , Rouffiac Magali , Ghiringhelli Francois , Borg Christophe , De Bari Berardino , Crehange Gilles
Published: March 2017

145

Background: The PRODIGE 5 trial has demonstrated the safety and the efficacy of FOLFOX-4 combined with exclusive 50Gy external RT while the CROSS trial showed an improvement in overall survival with Carboplatin-Taxol (C-TAX) when combined with 41.4Gy before surgery. We sought to determine the feasibility and efficacy of exclusive RT with C-TAX compared to FOLFOX-4 regimen. Methods: 46 patients with locally advanced esophageal cancer who were treated with exclusive chemoradiation were matched 1:1 : 23 patients were treated with FOLFOX-4 regimen (group A) and 23 patients with C-TAX (group B). Comparison between the 2 groups was performed using Mac Nemar test for paired data. All tests were two sided and Pvalues were considered significant when less than 0.05. Results: The mean age in group A was 69.4 years (12.5) and 72.4 years (12.6) in group B (p = ns). In each group, 11 patients had a stage III disease at diagnosis (47.8%) with only 2 stage IV in group A (8.7%) vs none in group B. The median delivered RT doses were 50Gy [14-60] in group A while it was 50Gy [20-70] in group B. 6 courses of chemotherapy were delivered in 12 patients in group A (52.2%) and 14 patients in group B (60.9%) (p = 0.51). After chemoradiation, G1 or higher esophagitis was observed in 5 patients (26.3%) in group A and 3 patients (13.0%) in group B of whom 0 vs 2 G3 were observed in group A and B, respectively. Four patients (21.1%) had a pulmonary infection in group A and 3 in group B (13.0%). Two patients (8.7%) vs 4 patients (17.4%) had G3 neutropenia, with only 0 and 2 neutropenic fever in group A and B, respectively. Neither G3 anemia, nor G3 thrombopenia occured. After a median follow-up of 17.7 months [0.0-46.9], 25 patients had died, 14 in group A (60.9%) and 11 in group B (47.8%). The median PFS rates were 14.0 months in group A [7.7-NR] vs 12.1 months [4.4-NR] in group B (p = 0.32). The median OS rates were 20.3 months in group A [6.2-39.3] vs 17.0 months [4.8-NR] in group B (p = 0.82). Conclusions: Exclusive chemoradiation with C-TAX seems feasible with similar toxicity and survival outcomes than FOLFOX-4. The safety and efficacy of the CROSS regimen needs to be tested prospectively with RT doses > 41.4Gy in a phase II or III trial.
Effect of nodal status compared to tumor response after neoadjuvant radiation on outcomes for patients with esophageal cancer.
Authors: Reddy Sushanth , Swords Jacob A. , Waldrop Mary Glenn , Contreras Carlo M. , Heslin Martin J. , Wei Benjamin , Cerfolio Robert J. , Wang Thomas N.
Published: March 2017

147

Background: The CROSS trial established the role of neoadjuvant radiation in the treatment of esophageal adenocarcinoma (EAC). While response to radiation is an important factor in predicting long-term outcomes, the vast majority of patients succumb to systemic disease. The purpose of this study is to assess predictors of survival in patients with EAC following radiation therapy. Methods: All patients who underwent resection after radiation therapy for EAC at a single institution were retrospectively identified from January 2004 to December 2014. Patients who died within 30 days of surgery were excluded. Cox-proportional hazard analyses were performed to identify clinico-pathological factors associated with survival after surgery. Results: In the time period, 334 patients underwent esophagectomy for EAC. Univariable/multivariable analyses are shown in the table. The presence of a pathologic complete response (pCR) did not correlate to survival. The most important factors in predicting outcome were pre-operative albumin and initial lymph node stage by endoscopic ultrasound (EUS). Pre-treatment N0 patients had better survival than N1 patients (median survival 37.2 vs. 16.3 months, P < 0.0001). Patients who remained N0 after radiation had much better outcomes than those that either developed N1 disease after radiation or were initially staged as N1 (stayed N0, N = 126, median survival 52.0 months; N1→N0, N = 85, median survival 22.9 months; N0→N1, N = 30, median survival 15.3 months; persistent N1, N = 44, median survival 11.4 months; P < 0.0001). Conclusions: Pathologic response to radiation does not predict outcomes for patients with EAC. Patients with node positive EAC have poor outcomes even after neoadjuvant radiation therapy. These patients are at an increased risk of distant disease and should be offered additional systemic therapies prior to surgical resection. [Table: see text]
Phase I study of neoadjuvant chemotherapy with xeloda and oxaliplatin (G-XELOX) for locally advanced gastric cancer.
Authors: Satake Hironaga , Kondo Masato , Kotake Takeshi , Okita Yoshihiro , Ogata Takatsugu , Hatachi Yukimasa , Yasui Hisateru , Kaihara Satoshi , Kotaka Masahito , Kato Takeshi , Tsuji Akihito
Published: March 2017

149

Background: Prognosis for locally advanced gastric cancer, such as clinical T4 disease, bulky nodal involvement, type 4 and large type 3 gastric cancer, remains unsatisfactory, even with D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is a promising approach, and combination chemotherapy with Xeloda and oxaliplatin (G-XELOX) is recognized as a potentially promising regimen for gastric cancer. However, the use of neoadjuvant chemotherapy consisting of G-XELOX for locally advanced gastric cancer has not been reported. The aim of this study was to evaluate the incidence of dose limiting toxicities (DLTs) during the neoadjuvant chemotherapy and to determine the maximum tolerated dose (MTD) and recommended dose of preoperative chemotherapy combined with oxaliplatin with a fixed Xeloda dose for locally advanced gastric cancer. Methods: Patients received two cycles of neoadjuvant chemotherapy with oxaliplatin on day 1, as well as Xeloda (2000 mg/m2/day, b.i.d.) for 14 days, repeatedly every 3 weeks. They then underwent gastrectomy with curative D2/3 lymph-node dissection followed by adjuvant S-1 (80 mg/m2/day, b.i.d.) for one year. A decrease of oxaliplatin dose was planned (starting at level 1, 130 mg/m2). Results: Six patients (5 male, 1 female) with a median age of 72 (range 68-79) were enrolled. MTD was not reached at level 1. Oxaliplatin 130 mg/m2 in combination with Xeloda 2000 mg/m2/day, b.i.d. could be administered with acceptable toxicity. No treatment-related death was observed. Most frequent drug-related AEs during the neoadjuvant chemotherapy period were G1 anemia, G1/2 thrombocytopenia and G1 peripheral neuropathy. One patient refused surgical resection, therefore five received resection with curative intent. Of the five patients, all achieved a pathological downstaging after neoadjuvant G-XELOX therapy. The incidence of operative morbidity was tolerable. Conclusions: Neoadjuvant chemotherapy with G-XELOX regimen was feasible by patients with locally advanced gastric cancer. Clinical trial information: UMIN000015950.
Conversion surgery for unresectable gastric cancer following complete response of distant metastasis by systemic chemotherapy.
Authors: Kobayashi Daisuke , Kanda Mitsuro , Tanaka Chie , Iwata Naoki , Hayashi Masamichi , Yamada Suguru , Nakayama Goro , Sugimoto Hiroyuki , Koike Masahiko , Fujii Tsutomu , Fujiwara Michitaka , Kodera Yasuhiro
Published: March 2017

152

Background: In case of gastric cancer (GC), conversion surgery (CS) can be defined as resection of the primary cancer by gastrectomy which had not been originally planned but was indicated after confirming complete response (CR) in the distant metastasis (DM) by chemotherapy. In the present study, we looked at prognostic significance of CS, which is intended to cure originally unresectable GC. Methods: From 2004 to Feb in 2016, 24 GC patients who were treated by chemotherapy and achieved CR in DM underwent CS among 909 patients with gastrectomy in our department. 10 out of 24 patients who had peritoneal metastases (P) as a single non-curative factor underwent intraperitoneal chemotherapy (IP) in addition to systemic chemotherapy. CR was confirmed by CT and/or laparoscopic examination. Results: 15 patients had P, 13 had distant lymph node metastases (LYM), 2 had liver metastases, and 2 had lung metastases. Chemotherapeutic regimens consisted of systemic chemotherapy plus IP of taxane in 10 patients, S-1/CDDP in 7, capecitabine/CDDP/trastsuzumab in 3, and others in 4. Median duration of chemotherapy before surgery was 7.3 months (2.3-17.5). Total gastrectomy was performed in 18 patients and distal gastrectomy in 6, achieving R0 resection in 21 patients and R1 in 3. 10 patients with P who underwent IP relapsed within 12 months postoperatively except for 2 and had significantly shorter overall survival time than those with other DM except for P (median: 20 vs. 42 months, P = 0.004). Among 14 patients who had DM other than P as target lesions, 9 are disease-free with postoperative median follow up time of 35 months (6.8-82), and 5 patients had recurrence (LYM in 4 and P in 1) with postoperative median survival time of 25 months (4.8-45). DM of the patients without recurrence had achieved CR within shorter period (median: 3.6 vs. 6.7 months) and had higher pathological response rate of the primary lesion (89% vs. 40%) compared to patients with recurrence. Conclusions: Outcome of GC patients who underwent CS after achieving CR in DM was promising, especially in those without P. Further issues such as appropriate chemotherapeutic period, and prognostic factors to decide on the indication for CS need to be solved.
Feasibility and acceptability of implementing an electronic patient reported outcome (e-PRO) dysphagia screening tool for routine multidisciplinary care.
Authors: Shani Kishan , Borean Michael , Chen Judy , Li Yuchen , Brown M. Catherine , Vennettilli Ashlee , Lau Anthea , Zheng Dennis , Kuang Qin , Boyd Kevin , Leung Yvonne , Cella David , Mackay Helen , Darling Gail Elizabeth , Wong Rebecca , Patel Deval , Xu Wei , Liu Geoffrey , Howell Doris
Published: March 2017

155

Background: In Ontario, Canada, longitudinal patient self-reporting of 9 common cancer symptoms and a global health scale (Edmonton Symptom Assessment System, ESAS) is mandated and used clinically as a screening tool for multidisciplinary precision care (chemo/rads/surg). However, a common GI symptom, dysphagia, is not assessed in the same setting. Methods: Mostly gastro-esophageal cancer outpatients (some head and neck and lung cancer patients undergoing radiation were also included for generalizability) received one of two versions (V1, V2) of the dysphagia screening tool based on PRO-CTCAE-derived language. The tool included two screening questions, which when answered affirmatively, led to more comprehensive dysphagia/odynophagia questioning. The survey was introduced on iPads with V1. An assessment of acceptability through patient survey was additionally included in V2, and the duration of survey completion was recorded. Exploratory in-depth interviews were conducted with oncologists to assess usability in the clinic setting. Results: Of 101 approached and eligible, 79 consented, and 66 completed the survey. Median completion time was 2.12 ± 0.80 min. 95% were happy to complete survey on a touchscreen tablet, 88% did not find completion of survey time-consuming, and 91% found completion of survey useful in order to tell the clinician how they feel physically and emotionally. The prevalence of dysphagia based on screening question #1 (“difficulty upon swallowing?”) was 38% (25/66), while for screening question #2 (“pain upon swallowing?”) prevalence was 18% (12/66). Five interviewed physicians found the survey to be clinically informative, not burdensome in terms of time consumption, and felt it would be a valuable addition to outpatient clinics. One recurring suggestion was to combine the two screening questions into one. Results were similar across GI, head and neck, and lung cancer sites. Conclusions: The e-PRO dysphagia screening tool is acceptable and feasible for patients, and useful for clinicians. Next, a modified one-question dysphagia tool will be assessed in the multidisciplinary care of gastro-esophageal cancer patients.
Impact of a pre- and postoperative chemotherapy (Ctx) on overall survival (OS) and progression free survival (PFS) in locally advanced gastric cancer (LAGC).
Authors: Manth Ricarda , Schaefer H , Schroeder J , Spiessl G , Nuessler N , Karthaus Meinolf
Published: March 2017

156

Background: Perioperative Ctx has become standard of care for LAGC. Duration of pre- and post-op Ctx is a matter of debate. Our study evaluated effects of varying durations of pre- and post-op Ctx on PFS and OS. Secondary endpoints were toxicity, reasons for cessation of Ctx and response. We compared the outcome to a group of pts receiving no perioperative Ctx as an internal control. Methods: Pts with LAGC were included in a prospective cohort trial from a single institution from 2007 to 2015. Inclusion criteria were T1-T4, N0-3, M0, AEG (n=27) or gastric cancers (n=65). Initial therapy decisions were made by an interdisciplinary tumor board for all pts. Pts received DDP/5-FU (qw d28 mod FFCD-Protocol, Ychou et al. JCO 2011) for 2 mo, and a 3rd mo of pre-op Ctx in case of non-progression after 2 mo and proceeded to Ctx after surgery for a planned total of six mo of Ctx. Results: 92 pts (53 m; 39 f pts) with a median age of 69 ys (range 33-96) were included. A total of 74 pts were recommended periop Ctx and 18 primary surgery (S). A total of 67 (91%) of the periop Ctx received pre-op Ctx (NA) of which 47 (64%) received 3 mo of pre-op Ctx, 19 (26%) two mo, 1 pt (1%) one mo, and 7 pts refused preop Ctx (9%) of which only 3 proceeded to surgery. Only 53 pts (72 %) received post-op Ctx; 25 pts (34%) received three mo, 9 pts (12 %) two mo, and another 10 pts (14 %) one mo of postop Ctx. Nine pts (13%) in the NA group and 20 pts (39%) in the post-op Ctx group had to stop Ctx due to toxicity after 1 (n=11) and <2 (n=9) mo of Ctx. Only 23 pts (31%) received the planned pre- and postop Ctx of 6 mo in total. Up to 07/2016 a total of 36 deaths were observed (39%). 5 yr PFS was 49% in the group of periop Ctx vs 14% in the S group. PFS in pts receiving a total of < 4 mo of Ctx was 36% vs. 61% in pts receiving 6 mo of Ctx. 3 yr OS was 19% in the S group vs 48% in the Ctx group. The OS in pts receiving < 4 mo was 34% vs.43% in pts with 6 mo Ctx. A pCR after preop Ctx was observed in 2 pts, a PR in 47 pts, a SD in 12 pts, while a PD occurred in 3 pts only. Conclusions: Pre-op Ctx was considerably better tolerated than post-op Ctx and led to fewer Tx cessations. We found a better PFS for pts with >4 mo of periop Ctx, as well as OS was affected by a shorter duration of periop Ctx.
A multicenter phase II study of combination therapy with oral S-1 plus cisplatin in elderly patients with advanced gastric cancer.
Authors: Terazawa Tetsuji , Iwasa Satoru , Sasaki Yusuke , Okazaki Shunsuke , Goto Masahiro , Kojima Yasushi , Naganuma Atsushi , Nagashima Kengo , Hirano Hidekazu , Honma Yoshitaka , Takashima Atsuo , Kato Ken , Hamaguchi Tetsuya
Published: March 2017

157

Background: The incidence of gastric cancer increases gradually in individuals aged ≥ 75 years who account for about 40% of all patients. From the SPIRITS study, comparing S-1 monotherapy with S-1 and cisplatin (CDDP) combination therapy (median overall survival [OS]: 11.0 versus 13.0 months, p=0.04), S-1 and CDDP chemotherapy (SP regimen) is recognized as one of the standard first-line regimens for patients with advanced gastric cancer in Japan. However, patients in this trial were aged < 75 years. Methods: The aim of this phase II study was to evaluate the efficacy and safety of SP regimen in elderly patients with chemotherapy-naive advanced gastric cancer. Patients aged ≥ 76 years were given oral S-1 twice daily for 21 days, followed by 14 days rest; CDDP was intravenously infused at day 8, repeated every 35 days, for up to eight cycles. The dose of S-1 (50–120 mg/body) and CDDP (30–60 mg/m2) was adjusted depending on the patient’s body surface area and creatinine clearance (Ccr-adjusted SP regimen). The primary endpoint was OS. The threshold and expected OS were estimated at 8 and 14 months, respectively. Secondary endpoints included response rate (RR), progression-free survival (PFS), time to treatment failure (TTF) and adverse events. Results: From December 2012 to October 2014, 40 patients were enrolled at 15 institutions. Patient characteristics were: gender (M/F) 29/11; median age 78 (range, 76–89); ECOG PS0/1, 13/27; and unresectable/recurrence 30/10. The median cycle for each patient was four (range, 1–8). The median OS was 12.3 months (80% confidence interval, 10.2–14.4 months). The median PFS and TTF were 7.8 and 4.3 months, respectively. The RR was 54%. A dose reduction of S-1 and CDDP was made for 30% and 35% of patients, respectively. The protocol was discontinued in 17 patients (43%) for disease progression, 10 patients (25%) for adverse events and 7 patients (17%) for patient refusal. The main adverse events at a grade 3 or higher were anorexia (25%), neutropenia (23%), hyponatremia (20%) and anemia (18%). Treatment-related deaths did not occur. Conclusions: Ccr-adjusted SP regimen showed promising activity and was tolerated well by elderly patients with advanced gastric cancer. Clinical trial information: UMIN000009349.
Quality of life and self-management strategies after gastroesophageal cancer surgery.
Authors: Sun Virginia , Kim Jae Y. , Ruel Nora , Kim Joseph , Raz Dan , Erhunmwunsee Loretta , Melstrom Laleh Golkar , Chao Joseph , Woo Yanghee , McCorkle Ruth
Published: March 2017

159

Background: Gastroesophageal cancer surgery can result in significant morbidity and decreased quality of life (QOL). The profound physical changes and symptoms that affect eating/digestion can substantially alter psychological and social well-being. We aimed to describe QOL and dietary/behavioral self-management strategies after gastroesophageal cancer surgery. Methods: Patients who were 6-12 months post-resection completed surveys for QOL (EORTC-QLQ-C30), symptoms (EORTC-QLQ-OES18 or QLQ-STO22), diet modifications, and behavioral adjustments. Scores for validated measures were calculated according to guidelines, and summarized using descriptive statistics. Results: 31 patients (11 esophagectomy, 20 gastrectromy) participated in the study. Surgical approach was 71% minimally invasive (laparoscopic, robotic). Patients reported clinically meaningful (≥10 point difference) worse mean scores compared to reference population means for physical (73.3/100 esophagectomy, 78.3/100 gastrectomy vs. 89.8/100 reference populations), role (63.6/100, 73.3/100 vs. 84.7/100), and social functioning (62.1/100, 75.0/100 vs. 87.5/100). Eating problems (48.5/100) was the worst symptom for esophagectomy patients. Thereafter, problems with taste, cough, reflux, and dysphagia were reported frequently. For gastrectomy patients, eating problems was also the worst symptom (28.2/100), followed by body image disturbance, dry mouth, and pain. Time to comfort with eating after surgery was between 3-12 months. The most common behavioral adjustments include chewing food completely (96%), eating multiple meals per day (90%), controlling meal portions (87%), staying or sitting upright after meals (71%), staying at or close to home more (64%), and eating out less (55%). Conclusions: QOL is greatly reduced after gastroesophageal cancer surgery. Eating problems and associated symptoms persist 6-12 months after surgery. Patients used multiple self-management strategies to control eating problems and symptoms. These strategies varied greatly, suggesting that personalized interventions are necessary to help patients adjust to eating after surgery and improve QOL.
Biomarker studies in a phase I trial of DKN-01 in advanced esophageal cancer.
Authors: Strickler John H. , Kagey Michael , Sirard Cynthia A. , Duda Gabriel Dan , Almenara Jorge , Powers Celeste N. , Bendell Johanna C.
Published: March 2017

161

Background: DKK1 is a modulator of Wnt signaling that is frequently overexpressed in tumors and such expression has been associated with worse survival. Preclinical studies have shown that DKK1 can promote tumor growth by increasing angiogenesis and contributing to an immunosuppressive tumor microenvironment. DKN-01 is a humanized IgG4 monoclonal antibody against DKK1 that has shown encouraging efficacy signals in patients (pts) with advanced esophageal (EC) or esophagogastric junction (EGJ) cancer when administered in combination with paclitaxel. Correlative studies are evaluating DKK1 expression and genetics in archived tumor specimens and baseline and on-treatment plasma levels of angiogenesis and inflammation biomarkers as predictors of response. Methods: Formalin fixed paraffin embedded (FFPE) archived tumor tissue was evaluated for DKK1 expression by immunohistochemistry (IHC) and scored for fraction of positive cells, intensity, and localization of DKK1. Genetics were collected if known and/or performed using an Archer VariantPlex Solid Tumor Panel covering 67 genes. Plasma samples, pre- and on DKN-01 treatment were evaluated by multiplexed array for angiogenesis (bFGF, PIGF/PGF, sFLT1/sVEGFR1, sTIE-2/TEK, VEGF, VEGF-C, and VEGF-D) and inflammation (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70 and IL-13) markers (Meso-Scale Discovery) and by ELISA for HGF and SDF-1α (R&D Systems). Results: ~90% of tissue samples showed DKK1+ expression in tumor cells (range 1 to 100%); intensity (weak 1+ to strong 3+); and localization (cytoplasmic and/or nuclear). Early data has not identified a correlation between DKK1 staining and response. One pt with an ongoing durable response had an activating mutation in β-catenin. Analysis of plasma biomarkers is ongoing. Conclusions: Analysis of DKK1 staining, tumor genetics, and prospective angiogenic/inflammatory biomarkers are ongoing to identify a predictive biomarker for DKN-01. The majority of EC/EGJ tumor biopsies were IHC DKK1+. Broader genomic screens are underway to further characterize DKN-01 sensitivity; mechanistically plausible activating mutations in β-catenin may be a biomarker for DKN-01. Clinical trial information: NCT02013154.
Positive radial resection margin after esophagectomy for esophageal cancer patients treated at a tertiary center and its impact on survival.
Authors: Shah Parth Kishore , Cameron Miles , Frakes Jessica M. , Fontaine Jacques , Coppola Domenico , Hoffe Sarah E. , Almhanna Khaldoun , Pimiento Jose Mario
Published: March 2017

162

Background: Although residual tumor at the radial margin can be expected to have a significant impact on the recurrence or overall survival of patient with node negative esophageal cancer (EC), its impact on recurrence and overall survival of patients with node positive EC has not been well characterized. Methods: A retrospective review of patients who underwent esophagectomy for EC at a single institution over a 16 year period (1999-2015) was performed. Pre-operative clinical parameters, stage as well as oncologic management were reviewed as well as the impact of positive radial margin on overall survival of pre-treatment node positive tumors was analyzed using descriptive statistics. Results: The study group consisted of 437 patients (46%) with pre-treatment stage IIB or III out of 945 patients with EC undergoing esophagectomy. The mean age of patients was 63 years with male predominance (85%). Neoadjuvant therapy (NAT) was administered to 87% of patients. Trans-thoracic surgery was performed in 86% of patients and trans-hiatal in 14%. Positive radial margin on final pathology was identified in 14 patients (3.2%); none of these had squamous histology. Neither the surgical approach nor the use of NAT was associated with radial margin positivity (p = 0.6). The median overall survival was significantly lower in the patients with positive radial margin when compared to the rest of the cohort (13.6 months v/s 41.2 months, p = 0.004). Moreover, when focused only on patients with post treatment pathologic T3 and T4 disease, margin positive disease remained associated with worse survival (p = 0.04). However, when final N status is included in multivariate analysis margin positivity loses significance. Conclusions: Radial margin positive disease after surgical resection for EC is associated with worse overall survival. This finding was significant regardless of the pathologic T stage; however, pathologic nodal staging was the most important factor for prognostication in locally advanced EC. Adenocarcinoma is the predominant pathology identified in patients with positive radial margin and concurrent node positivity.
Incidence of brain metastasis from esophageal cancer.
Authors: Ashman Jonathan Ben , Welch Gabrielle , Patel Naresh P. , Jaroszewski Dawn E. , Fleischer David , Rule William G. , Paripati Harshita , Ramirez Francisco , Ross Helen J.
Published: March 2017

165

Background: Distant metastases are common in primary esophageal cancer, but data conflict regarding the rates of brain metastases (BM) ranging from 0% to 13%. We sought to investigate whether the incidence of BM from esophageal malignancies is increasing in the modern era. Methods: After IRB approval, a single institution retrospective review identified 583 patients (pts) treated between 1/1997 and 1/2016 for stage I-IV cancer of the esophagus/esophagogastric junction with at least 3 months follow-up. Data collected included demographic information, primary diagnosis date and staging, histologic subtype, treatment regimens for primary and BM, date of BM diagnosis, status of neurologic symptoms and extracranial disease at BM diagnosis, and date of death. Data were analyzed by Fischer’s exact test and Kaplan-Meier analysis. Results: The overall cohort was comprised of 495 pts (85%) with adenocarcinoma and 82 pts (14%) with squamous cell carcinoma. 492 pts (84%) were male; the median age was 68 years (range 26-90). BM were identified in 22 pts (3.8%) with a median latency of 11 months from the primary diagnosis. Of the pts with BM, the primary histology was adenocarcinoma in 21 pts and squamous cell carcinoma in 1 pt ( P = 0.3). BM developed in 12 pts who were initially treated for locally advanced disease and in 10 pts who presented with distant metastases. Diagnosis of BM was at the time of initial presentation in 4 of these 10 stage IV pts. A solitary BM was identified in 9 pts. Initial treatments of BM were surgical resection followed by stereotactic radiosurgery (SRS; n = 5); surgical resection followed by whole brain radiotherapy (WBRT; n = 1); WBRT alone (n = 13); SRS alone (n = 3). Overall survival (OS) following diagnosis of BM was 18% at 1 year with a median of 4 months. OS was superior for pts who had surgical resection as initial treatment of BM compared to pts treated with WBRT or SRS alone (1-year OS 67 vs. 0%; median OS 13.5 vs. 3 months; P = 0.003). Conclusions: The incidence of BM is low in esophageal cancer with no statistically significant increased rate of BM developing in patients with adenocarcinoma compared with squamous cell carcinoma. Outcomes were poor overall for pts who developed BM, but pts who were appropriate for neurosurgical resection had improved survival.
The efficacy and feasibility of weekly 5-FU and cisplatin based radical concurrent chemoradiation therapy(CRT) in patients with esophageal cancer.
Authors: Jeong Joon Won , Yang Ji Hyun , Ro Sang Mi , Kim In-Ho , Roh Sang Young
Published: March 2017

169

Background: Concurrent chemoradiotherapy(CCRT) has become a promising treatment for esophageal cancer. Mostly, however, 3 week or 4 week interval of conventional FP(5-fluorouracil plus cisplatin) regimen is adopted, which is usually associated with moderate to severe treatment-related toxicities. Studies about weekly regimen of FP CCRT are little known, thus we studied the efficaty, tolerability and toxicities of weekly FP CCRT regimen. Methods: From February 2010 to august 2015, Patients staging from I to III esophageal cancer(according to AJCC 7th edition) were enrolled, who were received radiation therapy with dose of from 50.4Gy to 60Gy(5 days/week) and 5-FU 1000mg/BSA with cisplatin 30mg/BSA weekly. Results: From February 2010 to august 2015, 50 patients: male/female 47/3, median age 71.5 (47-78), all of 50 patients was squamous carcinoma, well/moderately differentiated carcinoma 1/18. 45 patients completed CRT without dose reduction, 9 patients received less than 6 cycles of chemotherapy, 4 patients received less than 50.4Gy of radiotherapy. Major toxicities of grade 3 or less were as follows: neutropenia 52%, thrombocytopenia 21%, nausea & vomiting 10%, fatigue 10%, anemia 5%. Toxicities over grade 4 was seen only in 1 patient. 15 patients showed complete response. The median overall survival was 10.67 months(4-48). The median disease-free survival was 16.9 months. Conclusions: Weekly regimen of concurrent CRT with 5-FU and cisplatin resulted in less toxicities over grade 3. Although, this regimen still showed non-inferiority to previous conventional 4 week-interval FP CCRT regimens in terms of PFS and OS. In this study, 82% of our patients had completed CCRT without any interruption. Hence, our results suggest that CRT with weekly 5-FU and cisplatin as definitive treatment for esophageal cancer could be a tolerable regimen.
One-dimensional and two-dimensional tumor size measurement for prediction of lymph node metastasis in differentiated early gastric cancer with minute submucosal invasion.
Authors: Kim Tae Jun , Lee Hyuk , Pyo Jeunghui , Min Yang Won , Min Byung-Hoon , Lee Jun Haeng , Kim Jae J.
Published: March 2017

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Background: Differentiated minute submucosal cancers ≤ 3 cm that exhibit no lymphovascular invasion are considered eligible for endoscopic resection; however, the ≤ 3 cm criterion remains debatable. The aim of this study was to verify the optimal tumor size cutoff for endoscopic resection eligibility, and to determine whether two-dimensional tumor size measurement would be more accurate for this purpose. Methods: The clinicopathological data of 574 patients undergoing curative surgery for differentiated minute submucosal cancer were reviewed retrospectively. A receiver operating curve analysis and bootstrapped samples were used to identify the optimal cutoff values for predicting lymph node (LN) metastasis. Results: Four hundred fourteen patients were eligible for the study.LN metastasis accompanied 2.5% of differentiated minute submucosal cancers that were ≤ 3 cm in size and lacked lymphovascular invasion. There was no lymph node metastasis in the tumors with 1D sizes ≤ 1.0 cm and 2D sizes ≤ 1.0 cm2. Using 10,000 bootstrapped data, optimal cutoff values were 2.9 cm (LN metastasis: 2.1%) and 8.3 cm2 (LN metastasis: 2.5% incidence) for one- and two-dimensional tumor size, respectively. Although the area under the curve was 0.611 ( P = 0.046) for two-dimensional size, specificity and accuracy were greater for the dichotomized two-dimensional measure than for the dichotomized one-dimensional measure ( P< 0.001, McNemar’s test). In addition, two-dimensional tumor size was the only significant risk factor for LN metastasis (odds ratio 1.09, 95% confidence interval 1.01–1.20). Conclusions: One-and two-dimensional cutoff values of 2.9 cm and 8.3 cm2 might be suitable for patients at high risk of post-operative morbidity and mortality. Two-dimensional tumor size is an acceptable measurement method for estimating the risk of LN metastasis.
Short and long-term effects of two different surgery approaches for remnant gastric cancer.
Authors: Chen Lin , Ren Yingkun , Zheng Yajie
Published: March 2017

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Background: To evaluate the short- and long-term effects of two different surgery approaches for remnant gastric cancer after distal gastrectomy. Methods: Clinical data of 48 remnant gastric cancer patients were collected retrospectively from the period of January 1st 2010 to December 31st 2012 in this matched-pair study. Twenty four patients in the experimental group underwent radical surgery in antegrade approach (starting from the esophagus to the gastrointestinal anastomosis), another 24 matched patients in the control group underwent radical surgery in retrograde approach (starting from the gastrointestinal anastomosis to the esophagus). Constants in the study were patient age, the operating surgeon, Borrmann type, TNM stage and operation range. Pearsonχ2 testor t-test were used to compare the clinicopathological characteristics between the two groups. Survival rates of 1- and 3-years were analyzed with Kaplan-Meier survival curve and compared with Log-rank test. Results: The 48 patients were treated successfully without any mortality during their hospital stay. The mean operative time and bleeding volume in the experimental and control groups were (126.6±5.7) min and (154.1±23.9)ml , and (168.3±11.7) min and (180.8±15.0)ml respectively. The difference in the mean operative times (t = -3.089, P = 0.005) and the mean bleeding volumes (t = -3.269, P = 0.004) were statistically significant. The average hospital stay after surgery and the average number of lymph nodes resected were (9.5±0.9) days and 18.7±1.6 in the experimental group,(9.2±0.8) day and 17.4±1.4 in the control group. There was no statistical differences between the two groups in terms of the average hospital stay (t = 0.692, P = 0.496) and the average number of resected lymph nodes (t = 2.101, P = 0.247). The overall 1- year and 3-years survival rates were 75%, 49% in the experimental group and 67%, 35% in the control group. There was also no statistical difference in the 1-year (P = 0.745) and 3-years (P = 0.878) survival rates. Conclusions: Compared with retrograde approach, performing radical surgery in antegrade way for remnant gastric cancer patients can shorten the operation time, reduce blood loss and simplify the operation procedure.
Adjuvant chemotherapy and outcomes in esophageal carcinoma.
Authors: Saeed Nadia , Mellon Eric Albert , Meredith Kenneth L , Hoffe Sarah E. , Shridhar Ravi , Frakes Jessica M. , Fontaine Jacques-Pierre , Pimiento Jose Mario , Kothari Nishi , Almhanna Khaldoun
Published: March 2017

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Background: Neoadjuvant chemoradiation (NCRT) and surgery is standard treatment for esophageal cancer (EC) in the U.S. The role of adjuvant chemotherapy (ACT) is unclear. Providers assign ACT inconsistently, and both its rationales and benefits have yet to be clearly defined. We sought to evaluate rationales and benefits for ACT in EC. Methods: This single institution retrospective review included 382 patients (pts) with EC who were treated at our tertiary referral center. All pts received NCRT and 46 received ACT. We reviewed medical records to obtain demographic and clinical information. Survival outcomes were analyzed with Kaplan-Meier method from date of death or last follow up and log-rank analysis. Case-control analysis was performed using a 2:1 nearest neighbor propensity score matching algorithm, and included 113 pts, 41 of which received ACT. Results: 46 of the 382 pts in our study who received NCRT and surgery for EC also underwent ACT; two pts had single agent paclitaxel, 9 had 5-F/U and leucovorin, 7 had 5-F/U and cisplatin, 5 had carboplatin and paclitaxel, 2 had carboplatin alone, and the remainder had other combinations. Pts who received ACT were younger (med. age = 60.2 v 63.8 yr, p = 0.047), more likely to have adenocarcinoma (91.3% v 85.1%, p = 0.034), and less likely to have positive LNs on pre-treatment EUS (60.1% v 77.4%, p = 0.018). Pts with pCR were less likely to receive further treatment (6.5% v 45.8%, p < 0.001), and pts with R1 resection were more likely to do so (15.2% v 4.2%, p = 0.007). With case-control analysis, no variables were significantly different between the two groups. The median follow-up times for the entire cohort and case-control analysis were 7.98 years and 8.89 years, respectively. There were no significant differences in overall (p = 0.975) or recurrence-free (p = 0.824) survival associated with ACT in either analysis. Conclusions: The role of CT following NCRT and surgical resection in pts with locally advanced ECis unclear. In the largest series to date, our single institution retrospective review found no significant difference in survival in pts who received ACT and those who did not. Prospective studies are needed to further identify the rationales for delivery of ACT, and to investigate any potential survival benefits.
Gastric linitis plastica: Have we moved beyond surgical palliation?
Authors: Woo Katherine , Luu Carrie , Almhanna Khaldoun , Coppola Domenico , Pimiento Jose Mario , Hodul Pamela Joy
Published: March 2017

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Background: Diffuse type gastric cancer (DGC), especially linitis plastica (LP), is associated with poor survival. Despite curative-intent surgical resection and improvement in perioperative therapy, doubt remains whether long term survival is possible in this aggressive disease. Methods: A retrospective review of the GC database at a comprehensive cancer center was reviewed from 2000 to 2016. Patient demographics, tumor characteristics, and treatment were evaluated. Patients with DGC were assessed. LP was defined as patients with DGC who had circumferential infiltration of the gastric wall for at least a third of the stomach length. Descriptive statistics were used to compare DGC and LP groups; survival was assessed by the Kaplan-Meier method. Results: Of 209 resected GC patients, 114 had diffuse histology; the majority were of the signet ring cell subtype. 38 (33.3%) had LP and 76 (66.7%) had DGC without linitis. LP patients were more likely to present at a later stage, with 27/38 patients (71%) with stage III and 4/38 patients (10.5%) with stage IV compared to 16/76 (21.1%) and 2/76 (2.6%) in the DGC group, respectively, p < 0.001. All patients underwent gastric resection with some for palliative intent including 6 patients found to have metastatic disease on exploration. R0 resection was achieved in 26 patients (68.4%) with LP. Median OS was 31.5 months for the cohort and 13.6 months for LP patients (p < 0.001); survival in LP patients did not improve with R0 resection. When survival was stratified by stage, patients with stage II LP still had a lower median OS than DGC (18.4 vs. 51.2 months, respectively, p = 0.015), though there was no survival differences in stage III and IV. Only half of patients with LP received preoperative chemotherapy or chemoradiation, perhaps due to need for surgical palliation of symptoms; receipt of preoperative therapy was not associated with survival in this subgroup. Conclusions: Gastric LP is associated with a poor prognosis. Early diagnosis and adherence to multimodal therapy may improve survival after surgical resection. Development of novel agents and improvement in neoadjuvant therapy is needed to improve outcomes in this aggressive disease.
Severe toxicity risk factor analysis of salvage radiotherapy for oligo-recurrence in the lymph nodes (LN) of esophagus carcinoma: From multi-institutional retrospective study.
Authors: Matsumoto Toshihiko , Nishina Tomohiro , Niibe Yuzuru , Yamashita Hideomi , Katsui Kuniaki , Kataoka Masaaki , Terahara Atsuro , Shimada Hideaki , Jingu Keiichi
Published: March 2017

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Background: This multi-institutional retrospective study suggested that salvage radiotherapy (RT) or chemoradiation therapy (CRT) for oligo-recurrence in the lymph nodes (LN) of esophagus carcinoma was one of therapeutic options. However risk factors of severe toxicities of these therapies are unclear. Methods: Between January 2000 and April 2015, a total of 237 cases that met the study criteria of oligo-recurrence were treated by RT or CRT in five hospitals. We investigated risk factors of severe toxicities in these patients. We used the fisher’s exact test and Cox proportional hazard model. Toxicities were evaluated by CTCAE v4.0. Results: The median follow-up time for 93 living cases was 29.6 months (range; 1.9-154.0 months). Systemic chemotherapy was administrated to 210 cases (88.6%). Median biological effective dose(BED) was 72 Gy(range: 48-84Gy).The 3-year overall survival (OS) was 37%, local control was 45%, progression-free survival was 24%. Radiation induced Grade 3 or worse adverse events were observed in 11 patients (4.6%), which were fistula (4patients,1.7%), pneumonia (2patients,0.8%), pleural effusion (2patients,0.8%), esophageal bleeding (1 patient, 0.4%), esophageal stenosis (1patient,0.4%), cardiac tamponade (1patient,0.4%), and hyperglycemia (1patient,0.4%) ) Treatment related death occurred in 4 patients, these deaths were attributed to drug-induced or radiation-induced interstitial pneumoniae, pleural effusion, esophageal bleeding, and esophago-bronchial fistula. Severe toxicity was only observed in patients with oligo-recurrence in regional lymph nodes or BED ³a60 Gy. In univariate analysis by Fisher’s exact test, Karnofsky performance status (KPS) <80 (p=0.0006) and oligo-recurrence in regional lymph nodes (p=0.0078) were the risk factor of severe toxicity. In multivariate analysis, KPS<80 (HR:11.81,95% CI: 2.67-51.29, p=0.0017) was the risk factor of severe toxicity. Conclusions: This study suggested that KPS<80 and oligo-recurrence in regional lymph nodes is the risk factor for severe toxicity in patients who received RT or CRT for oligo-recurrence in the LNs of esophagus.
Risk factor analyses of severe cicatricial stricture after chemoradiotherapy for stage II/III (T3) esophageal carcinoma.
Authors: Tsushita Natsuko , Honma Yoshitaka , Nagashima Kengo , Miyamoto Takahiro , Nakamura Shoko , Umezawa Rei , Ito Yoshinori , Shoji Hirokazu , Takashima Atsuo , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Itami Jun , Boku Narikazu
Published: March 2017

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Background: Severe benign cicatricial stricture (SBCS) is a major complication after chemoradiotherapy (CRT) for esophageal carcinoma (EC), and causes oral intake impairment leading to deterioration of quality of life even after being cured. Aim of this study was to investigate risk factors of SBCS. Methods: The subjects of this study were patients with stage II/III (T3) EC who received CRT and achieved complete response (CR) between 2000 and 2011. SBCS was determined as disability of passage by diameter-9mm endoscope. Results: Among 197 patients with Stage II/III (T3) treated by CRT, CR was obtained in 91 patients, who were included in this analysis. The median age was 63 years. Fifteen patients (16.5%) were female. The median follow-up time was 5.1 years. The cumulative incidence of SBCS was 15.0% (95%CI 9.0-24.5). Significant risk factors of SBCS were female (hazard ratio (HR) 3.3 (95%CI 1.1-10.0), p = 0.04), requirement of diced/liquid meal (HR 5.7 (95%CI 1.8-18.2), p = 0.003), tumor occupying 3/4 or grater of esophageal perimeter (HR 7.4 (95%CI 1.3-42.9), p = 0.03) and disability of endoscope passage (HR 12.7 (95%CI 4.2-38.5), p < 0.001) in univariate analysis. Hypoalbuminemia increased the risk of SBCS (HR 2.4 (95%CI 0.8-7.1), p = 0.12) marginally. As for the factors during CRT, grade 2-4 esophagitis significantly increased the risk of SBCS (HR 6.2 (95%CI 1.5-25.7), p = 0.01). Multivariate analysis showed that hypoalbuminemia (HR 3.5 (95%CI 1.1-11.1), p = 0.03) and disability of endoscope passage (HR 14.8 (95%CI 4.3-51.3), p < 0.001) were the significant risk factors of SBCS. Female (HR 1.5 (95%CI 0.5-4.9), p = 0.51) was not a significant risk factor in multivariate analysis. Conclusions: Obstructions before CRT, hypoalbuminemia and severe esophagitis during CRT are considered as risk factors of SBCS. Because SBCS occurred after completion of CRT, prophylactic treatment should be established especially for esophageal carcinoma patients with risk factors of SBCS.