Gastroesophageal Junction Tumor Research Articles

Effectiveness and tolerability of programmed cell death protein-1 inhibitor + chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers.

The combination of programmed cell death protein-1 (PD-1) inhibitor and chemotherapy is approved as a standard first- or second-line treatment in patients with advanced oesophageal or gastric cancer. However, it is unclear whether this combination is superior to chemotherapy alone. To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, or oesophageal carcinoma. We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer. We employed either random or fixed models to analyze the outcomes of each clinical trial, encompassing data on overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events (AEs). Nine phase 3 clinical trials (7016 advanced oesophageal and gastric cancer patients) met the inclusion criteria. Our meta-analysis demonstrated that the pooled PD-1 inhibitor + chemotherapy group had a significantly longer OS than the chemotherapy-alone group [hazard ratio (HR) = 0.76, 95% confidence interval (CI): 0.71-0.81]; the pooled PFS result was consistent with that of OS (HR = 0.67, 95%CI: 0.61-0.74). The count of patients achieving an objective response in the PD-1 inhibitor + chemotherapy group surpassed that of the chemotherapy-alone group [odds ratio (OR) = 1.86, 95%CI: 1.59-2.18]. AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group, regardless of whether ≥ grade 3 only (OR = 1.30, 95%CI: 1.07-1.57) or all AE grades (OR = 1.88, 95%CI: 1.39-2.54) were examined. We performed a subgroup analysis based on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) and noted extended OS and PFS durations within the CPS ≥ 1, CPS ≥ 5, and CPS ≥ 10 subgroups of the PD-1 inhibitor + chemotherapy group. In contrast to chemotherapy alone, the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer, GEJ tumor, or oesophageal cancer. This holds true particularly for individuals with PD-L1 CPS scores of ≥ 5 and ≥ 10.

Addition of trastuzumab to perioperative chemotherapy in HER2-positive gastroesophageal adenocarcinoma patients: A multicenter retrospective observational AGEO study

BackgroundApproximately 10–20% of patients with gastroesophageal adenocarcinoma (GE-ADK) have HER2-positive tumors. The addition of trastuzumab to chemotherapy improves OS in patients with advanced disease. We investigated the effect of perioperative trastuzumab on survival outcomes. MethodsThis French, multicenter, retrospective observational study included HER2-positive GE-ADK patients treated between January 2015 and December 2020. The primary endpoint was DFS at 18 months. Secondary endpoints were pathological complete response rate (pCR), R0 resection rate, OS, and toxicity. ResultsForty-eight patients were included, and they received a median of 6 cycles of preoperative treatment, with grade III/IV adverse events occurring in 23%. Pathologic complete response (pCR) and major pCR according to Mandard system were achieved in 5/48 (10%) and 20/48 (42%) patients, respectively. Loss of HER2 expression was observed in 18/48 (38%) patients. Postoperative complications rate according to the Clavien Dindo classification (≥3) was 37.5%. After a median follow-up of 29 months, the 18-month DFS was 80.4% (95% CI 68.9–93.8) and the 2-year OS rate was 89.0%. Subgroup analysis showed a longer DFS for gastric tumor than gastro-esophageal junction tumor. ConclusionsThis study suggests that perioperative chemotherapy with trastuzumab in patients with HER2-positive GE-ADK is feasible and safe with encouraging survival.

Leptomeningeal carcinomatosis and brain metastases in gastroesophageal carcinoma: A real-world analysis of outcomes, clinical and pathologic characteristics.

2029 Background: Brain metastasis (BM) and Leptomeningeal Carcinomatosis (LC) are uncommon complications in gastroesophageal carcinoma (GEC) patients (pts). These patients have a poor prognosis and are challenging to study. We described the clinicopathologic features and outcomes in the largest real-world cohort of CNS metastasis in GEC pts. Methods: We conducted a single-center retrospective study of GEC pts treated at the Princess Margaret Cancer Centre from 2007 to 2021 who developed BM. Clinicopathologic characteristics and treatment modalities were reviewed. Survival was calculated from the date of BM or LC diagnosis until date of death/last follow-up using the Kaplan-Meier method. A multivariable Cox proportional hazards regression model was used to examine the association of baseline covariates and survival. Results: Of 3283 consecutive pts with GEC, 101 (3.08%) were diagnosed with BM and 20 with LC (0.61%). Most pts with BM were male (75.3%), non-Asian (93%), with a primary gastroesophageal junction tumor (47%) and adenocarcinoma histology (86%). Among pts with known HER2 status (N= 48), 60% were HER2 positive (defined as IHC 3+ or IHC 2+/FISH+). All patients with LC had adenocarcinoma histology; most were signet-ring subtype (85%), poorly differentiated (80%) histology and only 15% (2/13) were HER2 positive. Median survival was 0.8; 3.8; and 7.7 months (mo) in BM pts treated with palliative care only, radiation only and surgery followed by radiation, respectively (p< 0.001). In LC, median survival was 0.7 mo in pts who had palliative care only (7/20) and 2.7 mo for those (13/20) who had whole brain radiation therapy (WBRT) (p .008). Multivariate analysis showed a higher probability of death in patients with number of BM ≥4 (p 0.02) and predicted superior survival in patients who received radiation and surgery followed by radiation (p 0.02). Conclusions: This is the most comprehensive summary of clinicopathologic characteristics and survival in patients with GEC and BM and LC disease to date. Biomarker analysis reveals an enriched frequency of HER2 expression in BM, while this is uncommon in pts with LC. BM pts who were treated with surgery followed by radiation had a significantly improved OS. WBRT benefited patients with LC over palliative care alone. These findings add to our understanding for the management of this understudied population with poor survival. [Table: see text]

Tumor Regression Grade and Overall Survival following Gastrectomy with Preoperative Therapy for Gastric Cancer.

Pre-/perioperative chemotherapy is well-established for management of locoregional gastric cancer (LRGC). The American Joint Committee on Cancer advocates histopathologic assessment of tumor regression grade (TRG) but does not endorse a specific schema. We sought to examine the prognostic value of the recently revised National Comprehensive Cancer Network (NCCN) definition of TRG specifying TRG0 as no disease in primary tumor or lymph nodes. Patients with clinical-stage T2+/N+/M0 LRGC receiving preoperative chemotherapy and curative-intent gastrectomy were identified (2000-2020). TRG using the current NCCN definition was retrospectively assigned. Factors associated with TRG were examined using ordinal logistic regression and overall survival (OS) was assessed using the Kaplan-Meier method and Cox regression. Among 117 patients, the most common chemotherapy regimen was epirubicin, cisplatin, plus fluorouracil or capecitabine (ECF/ECX) (n = 48, 41%), followed by folinic acid, fluorouracil, and oxaliplatin (FOLFOX) (n = 30, 26%), and fluorouracil, leucovorin, oxaliplatin, plus docetaxel (FLOT) (n = 13, 11%). TRG3 was the most common histopathologic response (n = 68, 58%), followed by TRG2 (n = 25, 21%), TRG1 (n = 18, 15%), and, lastly, TRG0 (n = 6, 5.1%). The only preoperative factor independently associated with lower TRG was gastroesophageal junction tumor location (OR 0.24, p = 0.012). Higher TRG was independently associated with worse OS in a stepwise fashion (HR 1.49, p = 0.026). Posttreatment pathologic lymph node status was the strongest prognostic factor (HR 1.93, p = 0.026). Independent prognostic value of TRG and ypT stage could not be shown due to substantial overlap. TRG using the contemporary NCCN definition is associated with OS in LRGC. TRG0 is uncommon but with excellent prognosis. ypN status is the strongest prognostic factor and the revised NCCN definition acknowledging this is appropriate.

Regorafenib (REG) combined with irinotecan (IRI) versus IRI alone as second-line treatment in patients with metastatic gastro-oesophageal adenocarcinomas (mGA): A randomized phase II trial (PRODIGE 58 – UCGI 35 – REGIRI).

387 Background: Several options have been evaluated as 2nd line treatment in mGA after failure of 1st line platinum based chemotherapy including taxanes and IRI as monotherapies or paclitaxel combined with ramucirumab but with a limited efficacy. REG monotherapy showed promising efficacy as 2nd or 3rd line treatment in mGA (Pavlakis N et al, J Clin Oncol. 2016). Methods: This comparative phase 2 multicenter randomized study was designed to evaluate the safety and efficacy of REG + IRI (REGIRI) vs IRI alone as 2nd line treatment in MGA patients (pts). Key eligibility criteria were histologically proven mGA (gastric or gastroesophageal junction (GEJ) tumor Siewert II and III), fluoropyrimidine and platinum-based first-line chemotherapy and ECOG PS ≤1. Pts received IRI 180 mg/m2 IV on D1 and D15. In REGIRI arm REG 160 mg/day was added on D2-D8 and D16-D22 every 28 days. Primary endpoint was overall survival (OS). A total of 122 events (154 pts) were required based on an assumption of 4-month (mo) gain in median OS (from 6 to 10 mo, HR=0.60), with a preplanned interim analysis of safety after 38 pts and efficacy after 40 OS events. Genotyping of cyclin-D1 was performed to evaluate the impact of treatment efficacy. Results: A total of 89 patients (REGIRI, n=44; IRI, n=45) with median age of 62 (range: 28-82) years and a mGA (67.4% with GEJ, 22.8% HER2+) were included out of the 154 initially planned by 21 sites in France. Study was prematurely stopped after interim analysis for unfavourable efficacy/toxicity ratio. With a median follow-up of 19.4 mo, 79 OS events were observed and median OS was 6.3 mo (95%CI[5.2-7.1]) with REGIRI vs 8.2 mo (95%CI[5.2-9.7]) with IRI (HR=1.11 CI95%[0.70-1.74], p=0.66). Median PFS was 2.2 mo vs 1.9 mo (NS) with REGIRI and IRI, respectively. Objective response rate was 15.9% and 13.3% respectively. Disease control rate was 45.5% and 33.3%. AEs grade ≥ 3 related to treatment were reported in 52.3% of pts in REGIRI arm vs 23.3% in IRI arm with 4 toxic deaths (diarrhea, sepsis and thromboembolic events) vs 1 (primary tumour perforation), respectively. The main severe toxicities were diarrhea: 18.2% vs 7% and febrile neutropenia: 8.2% vs 0%. Genotyping of cyclin D1 was performed on 72 pts: 19 presented A/A genotype, 38 A/G and 15 G/G. There were no differences in terms of OS according to genotyping. Conclusions: PRODIGE58/REGIRI trial was prematurely stopped after the interim analysis due to high toxicities reported in REGIRI arm with negative results on its primary endpoint. Further ancillary analysis are expected to identify toxicity risk factors and pts subgroups benefit with this combination. Clinical trial information: NCT03722108 .

286. THORACOPHRENOLAPAROMY FOR SURGICAL TREATMENT OF GEJ CANCER

Abstract Nowadays, there is still a lack of consensus about the optimal surgical management of gastroesophageal junction (GEJ) tumor. The CARDIA-trial results, comparing transthoracic esophagectomy versus transhiatal extended gastrectomy for GEJ type II tumor, are still expected. Thoracophrenolaparotomy (TPL) allows to perform radical resections (higher rate of R0 and more extensive mediastinal lymphadenectomy) with both esophago-gastric or esophago-jejunal anastomoses. The aim of this study is to describe TPL for the treatment of GEJ and gastric cancer. A retrospective analysis of all TPL performed for GEJ and gastric cancer with esophageal involvement at the Amsterdam UMC from January 2019 to October 2021 was conducted. The primary endpoint was the evaluation of R1 resections. The secondary endpoints were postoperative and pathological outcomes. Forty-seven patients were included for the analysis. 18 patients underwent an esophago-cardia resection with gastric conduit reconstruction and 29 patients a total gastrectomy with distal esophagectomy. The main indications for TPL were cT3 (74.5%) and cN+ (55.3%) tumors. Postoperative pneumonia occurred in 4 (8.5%) patients and anastomotic leak in 2 (4.3%) patients. The mean hospital stay was 9.8 (±6.1) days. The mean tumor size was 42.3 (±32.8) mm and the mean proximal margin 31.0 (±20.7) mm. Two (4.3%)patients had a R1 resection of whom only one (2.1%) had a positive proximal margin. The mean number of retrieved lymph nodes was 31.6 (±9.9). Thoracophrenolaparotomy for selected patients with GEJ and gastric cancer is associated with high R0 resection rate, low pneumonia and anastomotic leak incidence, together with a short hospital stay. TPL should still be considered a reliable surgical option, even in high-volume centers for minimally invasive upper gastrointestinal surgery.

Comparison of neoadjuvant regimens for resectable gastroesophageal junction cancer: a systematic review of randomized clinical trials across three decades.

The optimal perioperative treatment for adenocarcinoma of gastroesophageal junction (GEJ) tumor remains uncertain. The systematic review aims to assess the best neoadjuvant modality, namely chemotherapy (CT) versus chemoradiotherapy (CRT) based on randomized controlled trials (RCTs) for resectable gastric, esophageal and GEJ tumors. We performed a comprehensive PubMed database and Cochrane Library search to identify relevant RCTs related to neoadjuvant treatment for resectable GEJ adenocarcinoma. We included all published RCTs (phase 2 or 3) that tested specific neoadjuvant therapies (CT or CRT) if the patient population included GEJ tumors. We applied the Version 2 Cochrane risk-of-bias tool (RoB 2) to all the eligible studies. Outcomes examined included R0 resection and pathological response based on intention-to-treat (ITT) analysis, surgical outcomes, notable adverse events, and overall survival (OS). Each randomized group of every study was noted to be neoadjuvant CRT, CT, or surgery alone in order to compare the outcomes among these treatment approaches. We identified 25 RCTs with 7,855 patients published from 1996 to 2019. Seven studies tested preoperative CT versus surgery alone, 7 tested preoperative radiotherapy (RT) or CRT versus surgery alone, 4 tested preoperative RT or CRT versus preoperative CT, and 7 tested other combinations. The R0 resection ranged 47-100% and the 3-year OS ranged 6-66.1% in all the study arms. In an exploratory analysis, CRT strategies showed a superior R0 resection rate [80.2%; 95% confidence interval (CI): 79.8-80.6%] to surgery alone (60.9%; 95% CI: 60.4-61.3%; P<0.01) and to preoperative CT (63.9%; 95% CI: 63.6-64.2%; P<0.01). When comparing 3- and 5-year OS, improvement was noted when comparing CRT to surgery alone (P<0.01), and perioperative CT to surgery alone (P<0.01), but no definite difference was noted between CRT versus CT. Preoperative CRT showed improvement in R0 resection rate to surgery alone and preoperative CT. However, there is no significant difference in OS between CRT and CT. Both neoadjuvant strategies remain clinically meaningful options for patients with resectable GEJ tumors. Lack of patient-level data and inconsistent reporting of key outcomes across studies were the main limitations of our study.

Preoperative Chemoradiotherapy for Gastroesophageal Junction Adenocarcinoma Modified by PET/CT: Results of Virtual Planning Study.

Background and Objectives: The treatment of gastroesophageal junction (GEJ) adenocarcinoma consists of either perioperative chemotherapy or preoperative chemoradiotherapy. Radiotherapy (RT) in the neoadjuvant setting is associated with a higher probability of resections with negative margins (R0) and better tumor regression rate, which might be enhanced by incrementing RT dose with potential impact on treatment results. This virtual planning study demonstrates the feasibility of increasing the dose to GEJ tumor and involved nodes using PET/CT imaging. Materials and Methods: 16 patients from the chemoradiotherapy arm of the phase II GastroPET study were treated by a prescribed dose of 45.0 Gray (Gy) in 25 fractions. PET/CT was performed before treatment. The prescribed dose was virtually boosted on PET/CT-positive areas to 54.0 Gy by 9 Gy in 5 fractions. Dose-volume histograms (DVH) were compared, and normal tissue complication (NTCP) modeling was performed for both dose schedules. Results: DVHs were exceeded in mean heart dose in one case for 45.0 Gy and two cases for 54.0 Gy, peritoneal space volume criterion V45Gy < 195 ccm in three cases for 54.0 Gy and V15Gy < 825 ccm in one case for both dose schedules. The left lung volume of 25 Gy isodose exceeded 10% in most cases for both schedules. The NTCP values for the heart, spine, liver, kidneys and intestines were zero for both schemes. An increase in NTCP value was for lungs (median 3.15% vs. 4.05% for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy, respectively, p = 0.013) and peritoneal space (median values for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy were 3.3% and 14.25%, respectively, p < 0.001). Conclusion: Boosting PET/CT-positive areas in RT of GEJ tumors is feasible, but prospective trials are needed.

Neoadjuvant versus Postoperative Chemoradiotherapy is Associated with Improved Survival for Patients with Resectable Gastric and Gastroesophageal Cancer

The optimal timing of chemoradiotherapy (CRT) for patients with localized gastric cancer remains unclear. This study aimed to compare the survival outcomes between neoadjuvant and postoperative CRT for patients with gastric and gastroesophageal junction (GEJ) cancer. This retrospective study analyzed 152 patients with gastric (42%) or GEJ (58%) adenocarcinoma who underwent definitive surgical resection and received either neoadjuvant or postoperative CRT between 2005 and 2017 at the authors' institution. The primary end point of the study was overall survival (OS). The median follow-up period was 37.5months. Neoadjuvant CRT was performed for 102patients (67%) and postoperative CRT for 50 patients (33%). The patients who received neoadjuvant CRT were more likely to be male and to have a GEJ tumor, positive lymph nodes, and a higher clinical stage. The median radiotherapy (RT) dose was 50.4Gy for neoadjuvant RT and 45.0Gy for postoperative RT (p<0.001). The neoadjuvant CRT group had a pathologic complete response (pCR) rate of 26% and a greater rate of R0 resection than the postoperative CRT group (95% vs. 76%; p=0.002). Neoadjuvant versus postoperative CRT was associated with a lower rate of any grade 3+ toxicity (10% vs. 54%; p<0.001). The multivariable analysis of OS showed lower hazards of death to be independently associated neoadjuvant versus postoperative CRT (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.36-0.91; p=0.020) and R0 resection (HR 0.50; 95% CI 0.27-0.90; p=0.021). Neoadjuvant CRT was associated with a longer OS, a higher rate of R0 resection, and a lower treatment-related toxicity than postoperative CRT. The findings suggest that neoadjuvant CRT is superior to postoperative CRT in the treatment of gastric and GEJ cancer.

Incidence and Risk Factors for Diaphragmatic Herniation Following Esophagectomy for Cancer.

To evaluate the incidence and risk factors of diaphragmatic herniation following esophagectomy for cancer (DHEC), and assess the results of surgical repair. The current incidence of DHEC is discussed with conflicting data regarding its treatment and natural course. Monocentric retrospective cohort study (2009-2018). From 902 patients, 719 patients with a complete follow-up of CT scans after transthoracic esophagectomy for cancer were reexamined to identify the occurrence of a DHEC. The incidence of DHEC was estimated using Kalbfleisch and Prentice method and risk factors of DHEC were studied using the Fine and Gray competitive risk regression model by treating death as a competing event. Survival was analyzed. Five-year DHEC incidence was 10.3% [95% CI, 7.8%-13.2%] (n = 59), asymptomatic in 54.2% of cases. In the multivariable analysis, the risk factors for DHEC were: presence of hiatal hernia on preoperative CT scan (HR = 1.72 [1.01-2.94], P = 0.046), previous hiatus surgery (HR = 3.68 [1.61-8.45], P = 0.002), gastroesophageal junction tumor location (HR = 3.51 [1.91-6.45], P < 0.001), neoadjuvant chemoradiotherapy (HR = 4.27 [1.70-10.76], P < 0.001), and minimally invasive abdominal phase (HR = 2.98 [1.60-5.55], P < 0.001). A cure for DHEC was achieved in 55.9%. The postoperative mortality rate was nil, the overall morbidity rate was 12.1%, and the DHEC recurrence rate was 30.3%. Occurrence of DHEC was significantly associated with a lower hazard rate of death in a time-varying Cox's regression analysis (HR = 0.43[0.23-0.81], P = 0.010). The 5-year incidence of DHEC is 10.3% and is associated with a favorable prognosis. Surgical repair of symptomatic or progressive DHEC is associated with an acceptable morbidity. However, the optimal surgical repair technique remains to be determined in view of the large number of recurrences.

CROSS or FLOT in Distal Esophageal and Gastroesophageal Cancer.

To compare the chemoradiotherapy for esophageal cancer followed by surgery study (CROSS) and continuous infusion 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) protocols administered in distal esophageal and gastroesophageal junction (GEJ) tumors in terms of effectiveness and toxicity. Descriptive study. Ankara Oncology Training and Research Hospital, Turkey between 2015 and 2020. Patients diagnosed with distal esophageal and GEJ squamous cell carcinoma (SCC) or adenocarcinoma (ADC), older than 18 years of age, in localised or locally advanced stage were included. Metastatic stages were excluded. Kaplan-Meier was used for survival analysis, log-rank test was performed for comparisons between groups. A total of 25 patients (44.6%) were treated with CROSS protocol (15 distal esophageal and 10 GEJ tumor), 31 patients (55.4%) with GEJ tumors were treated with the FLOT regimen. Eight of the patients who were administered the CROSS protocol before the operation demonstrated complete pathologicial response, no patients in the FLOT group had complete response to the treatment. In patients with GEJ tumors and ADC histopathology, CROSS and FLOT group had similar second years survival (60% and 59.3%, respectively) (p = 0.803). The frequency of neutropenia was significantly higher in the CROSS group compared to the FLOT group (p = 0.004.) Conclusion: Postoperative pathological response rate in the CROSS group was significantly higher compared to the FLOT group. CROSS and FLOT protocols contributed to survival similarly in patients with GEJ ADC, hematological side effects were more pronounced in patients receiving CRT. Key Words: GEJ cancer, Esophageal cancer, Cross, Flot.

Evaluation of role of preoperative chemotherapy for carcinoma of the gastro-esophageal junction

Background: Preoperative chemotherapy has become an established management of locally advanced carcinoma of gastro-esophageal junction. Determining the down staging effect and predicting the pathological response to preoperative chemotherapy are mandatory. Methods: This is a prospective study which started by 40 patients presenting with gastro-esophageal junction (GEJ) tumor to the General surgery and Oncology outpatient clinics of the Menoufia University Hospitals during the period from July 2017 to July 2020. Pretreatment staging and multidisciplinary group discussion were done for all patients. Inclusion criteria were patients with locally advanced GEJ carcinoma, performance status≤2 and no previous history of chemo or radiotherapies. We excluded patients with distant metastasis, performance state&gt;2 and previous chemo or radiotherapies. Preoperative chemotherapy ECX regimen (epirubicin, cisplatin, capecitabine) was planned. Only 20 patients completed chemotherapeutic regimen for 3 to 4 cycles followed by a radical surgery. All patients were allocated a clinical stage before and after preoperative chemotherapy and were compared to post-operative pathological stage. Postoperative complications were recorded. Follow up of patients was done for 2 years. Results: Among total number of 40 patients, only 20 patients completed our study by preoperative ECX chemotherapy followed by radical surgery. The median overall survival was 30 months and the 2-year disease free survival ranged from 24-40 months with median time of 25.5 months. Complete pathological response was found in 6 patients (30%). Conclusions: Pre-operative chemotherapy using ECX regimen followed by surgery could be used for treatment of locally advanced GEJ carcinoma and has showed a favourable survival.

A Patient-Derived Orthotopic Xenograft Model of Gastroesophageal-Junction Adenocarcinoma Translated to the Clinic by Tumor-Targeting Fluorescent Antibodies to Carcinoembryonic-Antigen-Related Cell-Adhesion Molecules.

During surgical resection of gastroesophageal-junction (GEJ) adenocarcinoma, the margin status is often difficult to visualize resulting in high recurrence rates. The aim of the present study was to develop a labelling technique that would allow improved visualization of GEJ tumor margins for surgeons to reduce recurrence rates in a patient-like model. A patient GEJ tumor was obtained from an endoscopic biopsy and implanted subcutaneously in a nude mouse. A patient-derived orthotopic xenograft (PDOX) model was established by implanting tumor fragments grown from a subcutaneous model to the cardia of the stomach of nude mice. CC1/3/5-SAB, an antibody to carcinoembryonic-antigen-related cell-adhesion molecules, was conjugated with infrared dye IRDye800 to create SAB-IR800. Forty-eight hours after i.v. injection of SAB-IR800, GEJ-PDOX mice were imaged. Fluorescence imaging with SAB-IR800 brightly visualized the GEJ adenocarcinoma demonstrating specific targeting. In the PDOX model, injection of SAB-IR800 (50 μg) resulted in a tumor to background ratio of 1.78 at 48 hours and 1.86 at 72 hours. PDOX models of GEJ tumors can be established from patients by endoscopic biopsy without undergoing surgical resection. GEJ PDOX models should be useful for developing novel diagnostics and therapeutics for this recalcitrant disease.

Neoadjuvant versus Postoperative Chemoradiotherapy in Gastric Cancer

The optimal timing of chemoradiotherapy (CRT) in patients with gastric cancer remains unclear. We sought to compare the survival outcomes between neoadjuvant CRT (NCRT) vs. postoperative CRT (postCRT) in patients with gastric cancer. We hypothesized that NCRT would be associated with better survival compared to postCRT. We retrospectively reviewed patients with gastroesophageal junction (GEJ) or gastric adenocarcinoma who underwent surgical resection and NCRT or postCRT between 2005-2017 at a single institution. Clinical parameters such as sex, age, performance status, histology, stage, surgical outcomes, chemotherapy (CTX), and radiotherapy (RT) regimen were analyzed. CRT-related toxicity was graded according to CTCAE v5.0. The primary endpoint was overall survival (OS), assessed from the time of diagnosis. Survival analysis was conducted using Cox proportional hazards regression and Kaplan Meier estimates. We identified 152 patients, and median follow-up was 37.5 months. Median age was 63. 77% were male. 93% had an ECOG <2. Tumor location was gastroesophageal junction (GEJ) in 58% and gastric in 42%. Clinical stage was mostly II (44%) or III (44%). 102 (67%) patients underwent NCRT while 50 (33%) underwent postCRT. Patients who received NCRT were more likely to be male (83% vs. 64%; p = 0.013) and have a GEJ tumor (76% vs. 22%, p<0.001), greater number of involved lymph nodes (median 1 vs. 0; p = 0.005), and higher clinical stage (p = 0.002). Median RT dose was 50.4 Gy for neoadjuvant RT and 45.0 Gy for postoperative RT (p<0.001). Concurrent CTX was carboplatin/taxol (47%), cisplatin/fluorouracil (FU; 17%), or FOLFOX (folinic acid/FU/oxaliplatin; 14%) in the neoadjuvant setting and single-agent with FU (86%) in the postoperative setting (p<0.001). The NCRT group had a pathologic complete response (pCR) rate of 26% and had greater rate of R0 resection compared to the postCRT group (95% vs. 76%; p = 0.002). NCRT vs. postCRT was associated with a lower rate of any Grade 3 or higher toxicity (10% vs. 54%; p<0.001). Only 1% had treatment break(s) in the NCRT setting vs. 10% in the postCRT setting (p = 0.015). On multivariable analysis of OS, NCRT vs. postCRT (HR = 0.57 [95% CI 0.36-0.91]; p = 0.020) and R0 resection (HR = 0.50 [95% CI 0.27-0.90]; p = 0.021) were independently associated with lower hazards of death. The estimated 5-year OS was 67% (95% CI 0.55-0.76) in the NCRT group vs. 40% (95% CI 0.26-0.54) in the postCRT group (log-rank p = 0.003). NCRT was associated with a higher rate of R0 resection and longer OS with a lower toxicity compared to postCRT. Our findings suggest NCRT is superior to postCRT and support randomized trials to establish the optimal timing of CRT in gastric cancer.

Tumor Regression Grade in Gastric Cancer After Preoperative Therapy

BackgroundThe Cancer Staging Manual, 8th edition, now includes post-neoadjuvant therapy (ypTNM) staging for gastric cancer patients. Our purpose was to determine whether the tumor regression grade (TRG) of the primary tumor is useful for predicting the survival of these patients. MethodsWe performed a retrospective review of an institutional database and identified patients with clinically non-metastatic gastric adenocarcinoma who underwent preoperative chemotherapy or chemoradiation therapy before gastrectomy. Pathology reports were reviewed, and TRG was classified as follows: 0 (complete response), 1 (viable tumor cells ≤ 1–2%), 2 (viable cells ≤ 50%), or 3 (viable cells > 50%). ResultsOf the 356 patients identified, including 80 (23%) with a gastroesophageal junction tumor, 268 (75%) had undergone preoperative chemoradiation therapy. Fifty-six (16%) had TRG 0, 57 (16%) TRG 1, 128 (36%) TRG 2, and 115 (32%) TRG 3. No association between TRG and pretreatment factors was identified, except for signet-ring cell histologic type and tumor location. A higher TRG was associated with more advanced ypT and ypN categories (both p < 0.001), ypM1 (p = 0.004), and R1 resection (p = 0.052). The median overall survival (OS) duration was 6.6 years, and the 5-year OS rate was 54.1%. TRG 3 was associated with a shorter OS duration than were other TRG scores (p = 0.015), while the OS did not differ significantly among the TRG 0–2 groups (p = 0.803). On multivariable analysis, TRG was not associated with OS after adjustment for ypN status. ConclusionIn gastric cancer patients who underwent preoperative therapy, TRG 3 was associated with advanced ypStage and R1 resection. Patients with TRG 3 had a shorter OS duration because of associated advanced ypStage, particularly ypN+ status.

P59 PREDICTORS FOR ANASTOMOTIC LEAKAGE AFTER ESOPHAGECTOMY AND IMPACT ON SURVIVAL

Abstract Aim To identify predictors for anastomotic leakage after esophagectomy and to determine the influence of anastomotic leakage on short-term and long-term survival. Background and methods Identifying predictors of anastomotic leakage after esophagectomy may contribute to its prevention. The influence of anastomotic leakage on long-term survival is unclear. A retrospective cohort study was conducted in consecutive patients who underwent an esophagectomy with reconstruction in the Amsterdam UMC, location AMC, between January 1993 and January 2019. Logistic regression and Cox regression models were used to assess predictors for anastomotic leakage and to assess survival. Results 1747 patients were included, of which 326 (18.7%) developed anastomotic leakage. Independent predictors of cervical anastomotic leakage were diabetes mellitus, cT4-stage and a gastroesophageal junction tumor. ASA grade 3-5, a non-radical resection, pT2-stage, pN+ and hand sewn anastomosis were independent predictors of intrathoracic anastomotic leakage (table 1). 30-day mortality was 2% in patients without, and 4% of patients with anastomotic leakage (p=0.076). Anastomotic leakage did not significantly influence long-term survival when corrected for confounders (HR 0.96 95%CI 0.81 – 1.14, p=0.618). Conclusion Independent risk factors for anastomotic leakage after esophagectomy are diabetes mellitus, cT4-stage and a gastroesophageal junction tumor for cervical anastomosis, and ASA grade 3-5, a non-radical resection, pT2-stage, pN+ and hand sewn anastomosis for intrathoracic anastomosis. 30-day mortality was higher in the anastomotic leakage group. We found no correlation between anastomotic leakage and long term survival.

1708 Case of Secondary Achalasia Presenting Several Years After Nissen Fundoplication With Improvement After Endoscopic Dilatation: “Rare but Not Forgotten”

INTRODUCTION: Secondary Achalasia is an esophageal motor disorder presenting with clinical, radiographic and manometric features that mimic those of primary achalasia except that it has a known etiology such as gastroesophageal junction (GEJ) tumor, antireflux surgery, gastric banding or gastrectomy. We present a rare case of secondary achalasia as a remote consequence of a laparoscopic Nissen fundoplication (LNF). CASE DESCRIPTION/METHODS: A 59 year old woman with a history of diabetes mellitus, gastroesophageal reflux disease (GERD), hiatal hernia status post LNF with hernia repair eight years ago, presented with dysphagia to solids and liquids with a 24-pound weight loss over the last 3 months. On presentation, physical exam and initial laboratory data were unremarkable. Computerized tomography of the chest showed esophageal dilatation with an obstruction at the GEJ. Upper endoscopy revealed a large amount of impacted food in the lower third of the esophagus which was removed with a Roth net, and the GEJ was traversed by the scope with significant resistance. On retroflexion evidence of a Nissen fundoplication was found at the GEJ with a tight appearing wrap. The GEJ was dilated using Savary dilators over a guide up to a diameter of 14 mm with remarkable improvement of the symptoms. An esophagogram done post dilatation showed transit of the barium contrast through the GEJ. DISCUSSION: GERD is the most common pathologic condition affecting the upper gastrointestinal tract. While most patients respond to medical therapy, LNF has become the gold standard for antireflux surgery in patients with medically refractory disease. Transient dysphagia occurs in 40% to 70% of patients after LNF in the early postoperative period due to edema, slipped, migrated or too tight fundoplication or a missed diagnosis of primary achalasia and nutcracker esophagus. However, it can also occur many years after the operation due to hiatal stenosis secondary to severe fibrotic reaction and anterior angulation of the GEJ. EGD is a good initial diagnostic tool and resistance or inability to pass a gastroscope through the EGJ should raise suspicion of secondary achalasia with a background history of LNF. GEJ tumor should always be ruled out with careful examination. Dilatation of the GEJ is done using wire guided Savary dilators or through the scope balloon dilators. Our case highlights the importance of an aggressive evaluation and careful interpretation of a patient presenting with dysphagia with a remote history of fundoplication.

Esophageal Neuroendocrine Carcinoma Presenting as a Rare Cause of Dysphagia

Introduction: Neuroendocrine carcinomas comprise 0.4-2.0% of all esophageal malignancies and are a rare cause of dysphagia. The prognosis is generally poor as the tumor is usually advanced at the time of symptomology and diagnosis. The following is a case of a 60-year-old male patient with solid food dysphagia found to have a large, friable, gastroesophageal junction tumor during esophagogastroduodenoscopy (EGD). Biopsies confirmed a high-grade neuroendocrine carcinoma with a Ki-67 (proliferative index) of 90%.Figure: Frond-like esophageal tumor seen in the distal esophagus.Figure: Large ulcerated tumor extending into the gastric cardia, retroflex view.Figure: Neuroendocrine carcinoma consisting of a poorly differentiated, high-grade malignant neoplasm of intermediate to large cells with a trabecular architecture resembling neuroendocrine tumor within gastric mucosa (magnification 100x).Case: A 60-year-old male presented with a six-month history of daily solid food dysphagia and a 10lb intentional weight loss. His past medical history was significant for stage 1 squamous cell carcinoma of the larynx diagnosed four years prior and treated with chemotherapy. He had a 30 pack-year smoking history and continued to smoke half a pack of cigarettes daily. His only medication was an ipratropium/albuterol 20-100mg inhaler for chronic obstructive pulmonary disease. EGD demonstrated a large frond-like villous tumor occupying 50% of the circumference of the distal third of the esophagus extending 3cm proximal of the Z-line (figure 1). There was a pseudo lumen within the tumor that led into the stomach, and on retroflexed view there was a 5 cm ulcerated tumor extending into the cardia (figure 2). Biopsy results showed squamous and oxyntic-gastric mucosa containing sheets and packets of pleomorphic cells (figure 3). The cells demonstrated variable immunohistochemical positivity for synaptophysin, chromogranin and CD56. Immunohistochemistry for Ki-67 revealed a proliferation index of greater than 90%, classifying the tumor as Grade 3 or high-grade neuroendocrine carcinoma, denoting poor prognosis per the current National Comprehensive Cancer Network guidelines. Subsequent computed tomography supported findings of a 7.1 x 6.8 x 4.8 cm gastroesophageal junction mass with prominent regional lymph nodes without distant metastasis. The patient was treated with neoadjuvant chemotherapy of cisplatin, etoposide, and dexamethasone and concurrent radiation therapy prior to surgical resection. Discussion: Esophageal neuroendocrine tumors are a very rare cause of dysphagia and represent 0.4-2.0% of all esophageal malignancies. They are not well known by gastroenterologists and present as a mimicker of esophageal adenocarcinoma. Poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas are not well-defined or documented frequently within the medical literature. National cancer guidelines suggest a treatment similar to small-cell lung cancer with platinum-based chemotherapy and radiation therapy either as neoadjuvant therapy or palliative therapy if metastatic disease is present. Generally, there is a poor prognosis of esophageal neuroendocrine tumors due to the advanced nature at diagnosis, but in the absence of metastatic disease, are treated with curative intent.

A Diagnosis to Make You Salivate: The Curious Case of a Gastroesophageal Junction Tumor

A Diagnosis to Make You Salivate: The Curious Case of a Gastroesophageal Junction Tumor

Dosimetric comparison to the heart and cardiac substructure in a large cohort of esophageal cancer patients treated with proton beam therapy or Intensity-modulated radiation therapy

PurposeTo compare heart and cardiac substructure radiation exposure using intensity-modulated radiotherapy (IMRT) vs. proton beam therapy (PBT) for patients with mid- to distal esophageal cancer who received chemoradiation therapy. Methods and materialsWe identified 727 esophageal cancer patients who received IMRT (n=477) or PBT (n=250) from March 2004 to December 2015. All patients were treated to 50.4Gy with IMRT or to 50.4 cobalt Gray equivalents with PBT. IMRT and PBT dose–volume histograms (DVHs) of the whole heart, atria, ventricles, and four coronary arteries were compared. For PBT patients, passive scattering proton therapy (PSPT; n=237) and intensity-modulated proton therapy (IMPT; n=13) DVHs were compared. ResultsCompared with IMRT, PBT resulted in significantly lower mean heart dose (MHD) and heart V5, V10, V20, V30, and V40as well as lower radiation exposure to the four chambers and four coronary arteries. Compared with PSPT, IMPT resulted in significantly lower heart V20, V30, and V40 but not MHD or heart V5 or V10. IMPT also resulted in significantly lower radiation doses to the left atrium, right atrium, left main coronary artery, and left circumflex artery, but not the left ventricle, right ventricle, left anterior descending artery, or right coronary artery. Factors associated with lower MHD included PBT (P<0.001), smaller planning target volume (PTV; P<0.001), and gastroesophageal junction (GEJ) tumor (P<0.001). Among PBT patients, factors associated with lower MHD included IMPT (P=0.038), beam arrangement other than AP/PA (P<0.001), smaller PTV (P<0.001), and GEJ tumor (P<0.001). ConclusionsIn patients with mid- to distal esophageal cancer, PBT results in significantly lower radiation exposure to the whole heart and cardiac substructures than IMRT. Long-term studies are necessary to determine how this cardiac sparing effect impacts the development of coronary artery disease and other cardiac complications.