Esophagogastric Adenocarcinoma Research Articles

674PD - Perioperative FLOT + anti-PD-L1 avelumab (FLOT-A) chemo-immunotherapy in resectable oesophagogastric adenocarcinoma (OGA): Safety and biomarker data from the ICONIC trial safety run-in

BackgroundICONIC is a single arm phase 2 trial investigating the safety and efficacy of 4 cycles pre-operative and 4 cycles post-operative FLOT-A in resectable OGA. We report results from the safety run-in phase and early translational biomarker data. MethodsEligible pts were enrolled into the 3+3 design dose finding stage. Standard dose FLOT was administered with 10mg/kg iv avelumab q2 weeks (dose level 0). Dose limiting toxicities (DLTs) were assessed for 28d. Biopsies were taken at baseline and post cycle 2. ResultsAt data cut-off (12/4/19) 6 pts were enrolled and completed pre-operative treatment. 1/6 pts experienced a DLT (chest pain during 5FU infusion), and dose level 0 was established as the safe dose for the efficacy stage of the trial. During pre-operative FLOT-A all pts experienced at least one grade 1-2 adverse event (AE), most commonly diarrhoea (5/6 pts), fatigue, nausea, peripheral neuropathy and hypokalaemia (all 4/6 pts); 3/6 pts experienced at least one grade 3-4 AE: neutropenia and elevated liver enzymes (1pt), thrombotic event (1pt) and cardiac chest pain (1pt). 4/6 pts reported any grade chest pain and underwent cardiac work up: 1 episode was due to PE, 1 of likely GI origin and 2 cardiac in nature, which then recurred in one pt who was re-exposed to FLOT without avelumab. 3/6 pts completed 4 cycles pre-operative FLOT-A: 1pt discontinued avelumab due to diarrhoea, 2 pts discontinued FLOT-A due to cardiac chest pain and switched to a regimen without 5FU. 5 pts have undergone surgery at data cut-off, without unexpected complications. Immunofluorescence shows changes of CD8-, memory- and regulatory T cell infiltrates between baseline and on-treatment biopsies, and detailed results will be presented. ConclusionsThis is the first data showing that FLOT can be combined with a PD-L1-inhibitor with FLOT-A having a manageable safety profile at dose level 0 (standard dose FLOT + 10mg/kg avelumab). As chest pain of variable aetiologies was observed in 4/6 patients this will be closely monitored and assessed during the efficacy phase. No unexpected complications have been observed during surgery following FLOT-A treatment. Clinical trial identification2016-003306-13. Legal entity responsible for the studyRoyal Marsden Hospitals NHS Foundation Trust. FundingRoyal Marsden Hospital NHS Foundation Trust Institute of Cancer Research, Merck Pharmaceuticals. DisclosureM. Davidson: Travel / Accommodation / Expenses: Celgene. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Honoraria (institution): AstraZeneca. I. Chau: Advisory / Consultancy: Eli-Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (institution): Eli-Lilly. D. Cunningham: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. D. Morganstein: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche. M.D. Forster: Research grant / Funding (institution): Merck; Honoraria (institution): Merck. M. Gerlinger: Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. All other authors have declared no conflicts of interest.

796P - Randomised phase II trial of first-line docetaxel, carboplatin, capecitabine (CTX) and epirubicin, oxaliplatin, capecitabine (EOX) in advanced esophagogastric adenocarcinoma (SEED)

BackgroundChemotherapy is associated with a survival benefit in advanced gastric cancer. Several options exist, including EOX. The regimen docetaxel, cisplatin and 5-fluorouracil (DCF) is toxic and modifications have been developed. In our institution CTX was a standard treatment from 2004 to 2012 when it was replaced by EOX. Afterwards, a randomised trial with CTX was conducted. MethodsSEED was a prospective, single-center, phase 2 trial in unresectable HER2-negative esophagogastric adenocarcinoma. Patients were randomised to either docetaxel 60mg/m2, carboplatin AUC5 and capecitabine 1000mg/m2 bd for 14 days q4w (CTX) or epirubicin 50mg/m2, oxaliplatin 130mg/m2 and capecitabine 625mg/m2 bd for 21 days q3w (EOX). Treatment continued until progression, intolerance or a maximum of 9 cycles. The primary endpoint was 1-year-survival for patients treated with CTX. The trial sought to accept (lower boundary 55%) or reject (higher boundary 40%) CTX for further study without making direct comparisons to EOX. Secondary endpoints included OS, PFS and grade 3/4 toxicities. ResultsFrom 2014 to 2019 a total of 98 patients were randomised (49 in each arm). The median age was 63 (36 - 79). Male/female: 79/19; ECOG PS (0/1): 46/52; oesophageal/GEJ/gastric: 29/44/25; metastatic/non-metastatic: 96/2. As of 26 April 2019, 85 patients had died. The estimated 1-year survival was 32% (95% CI 19 - 46) for CTX and 39% (95% CI 25 - 52) for EOX. The median PFS and OS was 6.2 months (95% CI 5.2 - 7.2) and 9.2 months (95% CI 7.2 - 11.2), respectively, for CTX, and 5.2 months (95% CI 3.5 - 7.0) and 10.2 months (95% CI 7.9 - 12.4), respectively, for EOX. Grade 3/4 related toxicities in>5% were neutropenia (78%), febrile neutropenia (25%), diarrhoea (8%) and fatigue (6%) for CTX, and neutropenia (49%), febrile neutropenia (10%), peripheral neuropathy (8%) and nausea (8%) for EOX. There were no treatment-related deaths. ConclusionsCTX resulted in a 1-year-survival rate of 32% and so is rejected for further study. Also, CTX had a high rate of febrile neutropenia. CTX is not recommended for patients with esophagogastric cancer, except selected patients intolerant of other standard therapies, and then only with G-CSF support. Clinical trial identificationNCT02177552. Legal entity responsible for the studyLene Baeksgaard. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

841TiP - Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK

841TiP - Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK

813P - Increased assessment of HER2 in metastatic gastroesophageal cancer patients: A nationwide population-based cohort study

BackgroundAddition of trastuzumab to first-line palliative chemotherapy in esophagogastric cancer patients with HER2 overexpression has shown to improve survival and is therefore considered standard of care. The aim of this study was to assess HER2 testing, trastuzumab administration and overall survival (OS) in a nationwide cohort of metastatic esophagogastric cancer patients. MethodsPatients with synchronous metastatic esophagogastric adenocarcinoma diagnosed between 2010-2016 that received palliative systemic treatment (N=2846) were identified from the Netherlands Cancer Registry. Details on HER2 assessment were extracted from pathology reports from the Dutch Pathology Registry. For determination of HER2 positivity or negativity, the criteria on HER2 assessment of the ToGA trial were used. Proportions of HER2 tested patients were analyzed between hospital volume categories using Chi-square tests, and over time using trend analysis. OS was tested using the Kaplan Meier method and log rank test. ResultsHER2 assessment was performed in 54% of all 2846 patients that received palliative chemotherapy, and increased from 18% to 88% between 2010 and 2016 (P<0.01). Median OS of all patients increased from 6.9 (IQR 3.5-12.0) months in 2010-2013 to 7.9 (IQR 3.6-13.6) months in 2014-2016 (P<0.001). Between the hospitals, the proportion of tested patients varied between 29-100%, and was the highest in high-volume hospitals (P<0.01). HER2 status was positive in 19%, negative in 67% and unknown in 14% of the 1524 tested patients. Overall, 77% of the HER2 positive patients received trastuzumab. Median OS was significantly higher in patients with both positive (8.8 months) and negative (7.4 months) HER2 status that were diagnosed in 2015-2016, compared with non-tested patients (5.6 months; P<0.05). ConclusionsDaily practice management of metastatic esophagogastric cancer patients has changed due to increased determination of HER2 status and administration of trastuzumab, which might have contributed to the improved survival in these patients. Advances in clinical practice could include a further increase in awareness of HER2 testing among pathologists and clinicians, especially in low-volume hospitals, and in the administration of trastuzumab in case of HER2 overexpression. Legal entity responsible for the studyThe authors. FundingRoche. DisclosureR.H.A. Verhoeven: Research grant / Funding (institution): BMS; Research grant / Funding (institution): Roche. N. Haj Mohammad: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD. J. de Vos-Geelen: Non-remunerated activity/ies: BTG; Research grant / Funding (institution), Non-remunerated activity/ies: Servier; Advisory / Consultancy: Shire. T. Van Voorthuizen: Non-remunerated activity/ies: Astellas; Non-remunerated activity/ies: Ipsen; Non-remunerated activity/ies: Roche; Non-remunerated activity/ies: Bayer. M. van Oijen: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen. H.W.M. van Laarhoven: Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Philips; Research grant / Funding (institution): Roche. All other authors have declared no conflicts of interest.

Standardizing the Treatment of Oesophagogastric Junction Tumours: Centralization, Registries and Surgical Training

Surgical treatment of oesophagogastric junction adenocarcinomas is based on total gastrectomies or oesophagectomies, which are complex procedures with potentially high morbidity and mortality. Population-based registers show a considerable variability of protocols and outcomes among different hospitals and regions. One of the main strategies to improve global results is centralization at high-volume hospitals, a process that should take into account the benchmarking of processes and outcomes at referral hospitals. Minimally invasive surgery can improve postoperative morbidity while maintaining oncological guaranties, but is technically more demanding than open surgery. This fact underlines the need for structured training and mentorship programs that minimize the impact of surgical teams’ training curves without affecting morbidity, mortality or oncologic radicality.

Treatment of relapsed oesophagogastric adenocarcinoma after perioperative chemotherapy and surgery

Treatment of relapsed oesophagogastric adenocarcinoma after perioperative chemotherapy and surgery

Prospective clinical study phase IIa open-label and not randomized of efficacy and toxicity of weekly paclitaxel chemotherapy in patients with advanced esophagogastric adenocarcinoma

Prospective clinical study phase IIa open-label and not randomized of efficacy and toxicity of weekly paclitaxel chemotherapy in patients with advanced esophagogastric adenocarcinoma

Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases

BackgroundClaudin-18 (CLDN18) is a highly specific tight junction protein of the gastric mucosa. An isoform of CLDN18, the Claudin 18.2, has recently emerged as an innovative drug target for metastatic gastric cancer.MethodsWe investigated the immunohistochemical profile of CLDN18, p53, p16, E-cadherin, MSH2, MSH6, MLH1, PSM2, HER2, and PDL-1 in a large series of 523 primary gastric carcinomas (GCs; n = 408) and gastro-oesophageal carcinomas (GECs; n = 115) and 135 matched and synchronous nodal metastases. The status of HER2 and EBER by means of chromogenic in situ hybridisation (CISH) was also evaluated.ResultsHigh membranous CLDN18 expression was present in 150/510 (29.4%) primary cases and in 45/132 (34.1%) metastases. An abnormal expression (i.e. nuclear and/or cytoplasmic) was observed in 115 (22.5%) primary cases and in 33 (25.0%) metastases. A 38.8% of the cases showed significant CLDN18 intratumoural variability among the different tissue microarray cores obtained from the same tumour. Positive membrane CLDN18 expression was statistically associated with non-antral GCs (p = 0.016), Lauren diffuse type (p = 0.009), and with EBV-associated cancers (p < 0.001).ConclusionsCLDN18 is frequently expressed in gastric and gastro-oesophageal cancers; further studies should investigate the prognostic significance of CLDN18 heterogeneity in order to implement its test into clinical practice.

Phase I Dose Escalation Study with Expansion Cohort of the Addition of Nab-Paclitaxel to Capecitabine and Oxaliplatin (CapOx) as First-Line Treatment of Metastatic Esophagogastric Adenocarcinoma (ACTION Study).

First-line triplet chemotherapy including a taxane may prolong survival in patients with metastatic esophagogastric cancer. The added toxicity of the taxane might be minimized by using nab-paclitaxel. The aim of this phase I study was to determine the feasibility of combining nab-paclitaxel with the standard of care in the Netherlands, capecitabine and oxaliplatin (CapOx). Patients with metastatic esophagogastric adenocarcinoma received oxaliplatin 65 mg/m2 on days 1 and 8, and capecitabine 1000 mg/m2 bid on days 1–14 in a 21-day cycle, with nab-paclitaxel on days 1 and 8 at four dose levels (60, 80, 100, and 120 mg/m2, respectively), using a standard 3 + 3 dose escalation phase, followed by a safety expansion cohort. Baseline tissue and serum markers for activated tumor stroma were assessed as biomarkers for response and survival. Twenty-six patients were included. The first two dose-limiting toxicities (i.e., diarrhea and dehydration) occurred at dose level 3. The resulting maximum tolerable dose (MTD) of 80 mg/m2 was used in the expansion cohort, but was reduced to 60 mg/m2 after three out of eight patients experienced diarrhea grade 3. The objective response rate was 54%. The median progression-free (PFS) and overall survival were 8.0 and 12.8 months, respectively. High baseline serum ADAM12 was associated with a significantly shorter PFS (p = 0.011). In conclusion, albeit that the addition of nab-paclitaxel 60 mg/m2 to CapOx may be better tolerated than other taxane triplets, relevant toxicity was observed. There is a rationale for preserving taxanes for later-line treatment. ADAM12 is a potential biomarker to predict survival, and warrants further investigation.

Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma.

DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing (lcWGS) of ctDNA from 30 patients with advanced OGA prior to first-line chemotherapy and on progression. SCNA profiles were detectable pretreatment in 23/30 (76.7%) patients. The presence of liver metastases, primary tumour in situ, or of oesophageal or junctional tumour location predicted for a high ctDNA fraction. A low ctDNA concentration associated with significantly longer overall survival. Neither chromosomal instability metrics nor ploidy correlated with chemotherapy outcome. Chromosome 2q and 8p gains before treatment were associated with chemotherapy responses. lcWGS identified all amplifications found by prior targeted tumour tissue sequencing in cases with detectable ctDNA as well as finding additional changes. SCNA profiles changed during chemotherapy, indicating that cancer cell populations evolved during treatment; however, no recurrent SCNA changes were acquired at progression. Tracking the evolution of OGA cancer cell populations in ctDNA is feasible during chemotherapy. The observation of genetic evolution warrants investigation in larger series and with higher resolution techniques to reveal potential genetic predictors of response and drivers of chemotherapy resistance. The presence of liver metastasis is a potential biomarker for the selection of patients with high ctDNA content for such studies.

Landscape of innate and adaptive immunity targets in oesophagogastric adenocarcinoma (OGA).

4063 Background: Anti-PD-1 therapy modestly improves survival in chemorefractory OGA. Combining PD-1 blockade with novel checkpoint inhibitors, T-cell co-stimulatory molecules, or myeloid suppressors could enhance PD-1 inhibition. Herein, we explore the landscape of known targetable immune markers in non-Asian OGA. Methods: OGA patient biopsies were prospectively collected and clinically annotated from 19 UK cancer centres (Oesophageal Cancer Clinical and Molecular Stratification – OCCAMs network). Genomic (WGS) and transcriptomic (bulk-RNA seq) data were generated using Illumina and processed using a validated in-house pipeline (Frankell, Nat Genetics 2019). Gene expression was computed in transcripts per kilobase. Using unsupervised clustering patient clusters were selected according to the expression of gene targets for immune therapy - PD-L1, LAG3, TIM3, TIGIT, ICOS, CCR2, CCR5, CXCR4, and CSF1R. Immune cell infiltration was extrapolated using GSVA gene set enrichment analysis. Results: RNAseq data were available for 251 patients; 96% had operable tumours (Stage I: 6%, II: 63%, III: 22%, IV: 4%). In untreated patients (n = 156) 3 subgroups were identified: immune low (83, 53%) with low level expression of all 9 markers, immune high (14, 9%) with high expression of all or majority of markers and intermediate (59, 38%) with heterogenous marker expression. Clinicopathological variables (sex, age, smoking, tumour location (gastric/GEJ/esophagus) and tumour regression grade) were similarly distributed across subgroups. In a cohort of 114 patients with matched WGS and RNAseq data tumour mutation burden was not different between subgroups. In post-chemotherapy biopsies (n = 95) a similar co-expression pattern was observed. Gene enrichment analysis supported infiltration by cells of innate and adaptive immune system in immune high patients. Neoantigen results, phenotypic immunohistochemistry and optimised survival outcomes according to lymphoid and myeloid target expression will be presented. Conclusions: High level co-expression of immune regulatory targets in OGA patients may limit the efficacy of anti-PD-1 monotherapy. Combination immune directed therapies may be required in this patient group.

Perioperative atezolizumab in combination with FLOT versus FLOT alone in patients with resectable esophagogastric adenocarcinoma: DANTE, a randomized, open-label phase II trial of the German Gastric Group of the AIO and the SAKK.

TPS4142 Background: Perioperative FLOT chemotherapy has become a standard of care for locally advanced, resectable gastric cancer and adenocarcinoma of the GEJ. However, patient outcomes are still unsatisfactory and 5-year survival in T3-4 or nodal positive disease is still around 50%. Targeting the PD-1/PD-L1 pathway has proven active in different cancers, including esophagogastric cancer, and was associated with response rates in the 10-15% range in unselected, heavily pre-treated gastric cancer patients. Atezolizumab is a PD-L1 inhibitor with established efficacy and tolerability profiles. This study evaluates atezolizumab in the perioperative treatment of locally advanced, potentially resectable gastric or GEJ adenocarcinoma in combination with FLOT. Methods: This is a large, multinational, prospective, multicenter, randomized, investigator-initiated, open label phase II trial. Patients with locally advanced, potentially resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N-positive) without distant metastases are enrolled. Eligibility status is centrally evaluated. Patients are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) followed by surgery and 4 additional cycles of FLOT plus atezolizumab at 840 mg every 2 weeks, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is time to disease progression or relapse after surgery (PFS/DFS) as assessed by the Kaplan-Meier-Method. The statistical design is based on a target HR of 0.68, a power of 0.8, and a significance level of p&lt; 0.05 (1-sided log rank test). A total of 295 patients will be randomized. Main secondary endpoints are rates of centrally assessed pathological regression (rates of complete and nearly complete pathological regression), overall survival, R0 resection, and safety. Recruitment started in Sept 2018; by February 2019, a total of 27 patients have been randomized. Clinical trial information: NCT03421288.

PD-L1 expression in carcinoma of the esophagogastric junction is positively correlated with T-cell infiltration and overall survival

IntroductionIn recent years antitumor immunity and inhibition of checkpoint molecules, such as PD-1 and PD-L1, have emerged as potential therapeutic strategies in advanced stages of various malignancies. We investigated PD-L1 expression in adenocarcinomas of the esophagogastric junction and correlated the results with densitiy of intratumoral T-lymphocytes. MethodsImmunohistochemical staining for PD-L1 was carried out on 135 samples using a tissue microarray. Scoring was done according to the combined positivity score. Results48.1% of tumors (65 cases) showed PD-L1 positivity with a score ≥ 1 while 51.9% were PD-L1 negative (70 cases). A positive correlation between PD-L1 negativity and mucinous and poorly cohesive carcinoma could be shown (p = 0.043), while no association existed for either gender, T-stage, N-stage, grading, surgical resection status, neoadjuvant therapy, distant metastases, lymphovascular or perineural invasion. No correlation of PD-L1 expression and overall survival could be detected (p = 0.497). Again, when stratified according to presence or absence of neoadjuvant therapy, no survival differences could be shown for either group (p = 0.540 and p = 0.736). When PD-L1 expression was correlated with density of tumor-infiltrating T-lymphocytes a positive correlation between PD-L1 positivity and denser T-cell infiltration could be shown (p = 0.001). Concerning overall survival, in PD-L1 negative cases, denser CD8-positive T-cell infiltrates were associated with prolonged survival times (p = 0.045). No differences could be shown for PD-L1 positive cases or CD103-positive T-cells. ConclusionPD-L1 expression is frequent in esophagogastric adenocarcinoma and - when combined with dense CD8 infiltration – PD-L1 negativity correlates with prolonged overall survival.

Proyectos de estandarización del tratamiento del cáncer de la unión esofagogástrica: centralización, registros y formación

Surgical treatment of oesophagogastric junction adenocarcinomas is based on total gastrectomies or oesophagectomies, which are complex procedures with potentially high morbidity and mortality. Population-based registers show a considerable variability of protocols and outcomes among different hospitals and regions. One of the main strategies to improve global results is centralization at high-volume hospitals, a process that should take into account the benchmarking of processes and outcomes at referral hospitals. Minimally invasive surgery can improve postoperative morbidity while maintaining oncological guaranties, but is technically more demanding than open surgery. This fact underlines the need for structured training and mentorship programs that minimize the impact of surgical teams’ training curves without affecting morbidity, mortality or oncologic radicality.

Sentinel Lymph Node Sampling for Early Gastric Cancer—Preliminary Results of A North American Prospective Study

IntroductionAlthough endoscopic resection for early gastric cancer is well established, anatomical resection with regional lymphadenectomy is recommended for lesions at high risk for occult lymph node metastasis (e.g., lymphovascular invasion, poor grade, and deep submucosal invasion). However, 75–95% high-risk early gastric cancer (HR-EGC) patients ultimately have node-negative disease and could potentially have undergone organ-sparing resection. Due to the inadequacy of standard modalities to reliably rule out nodal metastases in HR-EGC patients, sentinel lymph node (SLN) sampling was developed in Asia with promising results. However, the applicability of this technique in the West has been brought into question due to potential differences in tumor histology and body habitus. This prospective study aimed to test SLN sampling for North American EGC patients. MethodsAll patients with biopsy-confirmed T0–2 N0–1 M0 gastric adenocarcinoma at the Montreal General Hospital-McGill University Health Centre were eligible for enrollment. Esophageal and GEJ cancers were excluded due to the high rate of intrathoracic lymph node involvement. Peritumoral submucosal injection with T99 radiocolloid was performed endoscopically 24–30 h prior to surgery. Methylene blue dye injection was performed after induction of anesthesia. SLN basins were identified as those having > 10% of baseline tumor radiation signal or blue color, or both. After basins were individually removed, standard laparoscopic anatomical resection was then performed with D2 lymphadenectomy. (ClinicalTrials.gov identifier: NCT03049345). Data are presented as median (interquartile range). ResultsFrom July 2016–April 2018, 253 patients with esophagogastric adenocarcinoma were evaluated. Of these, 10 met inclusion criteria (90% male, age 66(30) years). Subtotal gastrectomy was performed in nine patients (90%) and length of stay was 4 (2) days. At least one SLN basin was identified in nine cases (90%). The median #SLN basins identified was 2(2) with a median of 5(5) total SLNs retrieved per patient. In the one case for which no SLN basins were identified, only blue dye injection was used, whereas SLNs were identified in all cases using the dual tracer method. Final T-stage was pT1b/T2 in four (40%), pT1a in two (20%), and Tx in four (40%). Two patients (20%) had lymph node metastases on final pathological analysis, both of which were identified by SLN sampling (accuracy 100%; false negative rate 0%). No adverse events related to SLN retrieval were identified. ConclusionsThis study represents the first prospective feasibility evaluation of sentinel lymph node sampling for early gastric cancer in North America with promising preliminary results. The dual tracer method was superior to single agent blue dye in identifying sentinel nodal basins. Considerable further study is necessary to verify the safety and utility of SLN mapping in North American patients with early gastric adenocarcinoma.

S-1 in Patients with Advanced Esophagogastric Adenocarcinoma: Results from the Safety Compliance Observatory on Oral fluoroPyrimidines (SCOOP) Study.

Background and ObjectivesS-1-based regimens have been shown to be as effective as other fluoropyrimidine-based regimens with a better safety profile in patients with advanced esophagogastric adenocarcinoma. However, real-world data on S-1 in European patients with advanced esophagogastric adenocarcinoma are lacking. The Safety Compliance Observatory on Oral fluoroPyrimidines (SCOOP) study evaluated safety and relative dose intensities for patients treated with S-1-based regimens for advanced esophagogastric adenocarcinoma as part of daily practice.MethodsOverall, data for 125 patients with advanced esophagogastric adenocarcinoma were collected at 21 centers in five countries in Europe. Demographics, treatment, and adverse-event data were recorded over a planned treatment of six cycles.ResultsMost patients (87%) received combination treatment of S-1 plus a platinum compound. Adverse events related to S-1 treatment were mostly grade 1 or 2 while reported grade 3–4 serious adverse events related to S-1 occurred in 12 patients and were most often grade 3 neutropenia (n = 4, 3.2%) or diarrhea (n = 5, 4%). The most common adverse events of any grade that were attributable to S-1 treatment included neutropenia, anemia, thrombocytopenia, diarrhea, nausea, vomiting, and fatigue. No patients experienced mucositis, dehydration, or febrile neutropenia, whereas 2% (3/125) of patients experienced hand-foot syndrome.ConclusionThe overall relative dose intensity was 70%. In a real-world setting, patients with advanced esophagogastric adenocarcinoma tolerated S-1 treatment well with high compliance rates. The SCOOP study provides valuable information on S-1 relative dose intensity that can be used for treatment decision making.

A phase I/Ib study of crenolanib with ramucirumab (RAM)/paclitaxel (PTX) as second-line therapy (2L tx) for advanced esophagogastric adenocarcinoma (EGA).

116 Background: PTX/RAM as 2L tx for patients (pts) with EGA is a standard-of-care based on the RAINBOW trial (Lancet Oncol 2014;15:1224). However, benefit is modest. Upregulation of the platelet-derived growth factor (PDGF)/PDGF receptor-β (PDGFR-β) pathway causes resistance to VEGF inhibition. Crenolanib is a selective inhibitor of PDGFR-β. We report initial results of the dose escalation phase of a study of crenolanib plus RAM/PTX in pts with previously treated advanced EGA. Methods: This phase I/Ib study is enrolling ECOG PS 0-1 EGA pts with progression on first-line chemo. PTX 80 mg/m2/ day on day 1, 8, 15 and RAM 8mg/kg q 14 days were administered with escalating doses of crenolanib (60, 80, 100 mg BID) after a 7 day “run-in” of crenolanib to assess crenolanib-related toxicities. The primary objective was to determine the maximum tolerated dose (MTD) of crenolanib plus RAM/PTX. Safety and preliminary efficacy were examined. Results: 15 pts were treated; 12 male, median age 58 (32-73), 66% were ECOG PS 1. Primary site was gastric in nine pts, GEJ in 4 pts and esophageal in two pts. Three pts each received crenolanib 60mg BID and 80mg BID, six pts received 100mg BID and three pts received higher doses. At data cutoff, eight pts continued on treatment. 12 pts have completed the DLT evaluation period across 3 dose levels (60 to 100 mg BID). Median treatment duration was 76 days (35-191). The combination was well tolerated, with no DLTs or serious adverse events (SAEs) attributed to study drug. Treatment related adverse events occurred in two pts (17%), all grade 1. These were fatigue, nausea, vomiting and hypertension. Disease progression was the most common reason for treatment discontinuation; no pt discontinued due to study drug related AEs. Nine pts were evaluable for response. One pt had objective response; the disease control rate was 78%. Median PFS and OS were 4.1 and 11.9 months respectively. Conclusions: Crenolanib plus RAM/PTX appears well tolerated at a dose level of 100mg BID. Further evaluation is needed to determine efficacy. Accrual is ongoing at higher doses. Once the MTD is defined, the dose expansion phase will enroll 25 pts. Updated data with pharmacokinetics and biomarkers will be presented. Clinical trial information: NCT03193918.

Application of positron emission tomography imaging to personalize esophagogastric cancer care

Positron emission tomography can guide staging and perioperative therapies in patients with localized esophagogastric adenocarcinoma. Ongoing research is investigating the clinical usefulness of functional imaging with tumor‐specific radiolabeled molecules to optimize biomarker selection, diagnosis, and treatment.

IGFBP-1 As a Serum Protein Biomarker for Early Detection of Gastrointestinal Cancer

Background: Early detection would significantly improve cancer prognosis. We aimed to identify serum protein biomarker for early cancer detection and assess the diagnostic value in various types of cancers. Methods: We performed a three-stage study, and recruited participants of normal controls and seven different types of cancer patients (oesophageal squamous cell carcinoma (ESCC), oesophagogastric junction adenocarcinoma (EJA), stomach cancer, colorectal cancer, lung cancer, nasopharyngeal cancer and breast cancer) from two medical centres. We applied two different antibody arrays to screen candidate serum protein which were increased in 20 ESCC patients compared with 20 matched normal controls. In biomarker assessment stage, the diagnostic value of the selected protein measured by ELISA was evaluated in seven cancer types, and was validated in two independent cohorts of ESCC patients and controls (cohorts 1 and 2). Receiver operating characteristics (ROCs) with the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to calculate diagnostic accuracy. Findings: We recruited 1628 participants to biomarker assessment stage: 287 with ESCC, 237 with EJA, 207 with stomach cancer, 138 with colorectal cancer, 126 with lung cancer, 150 with nasopharyngeal cancer, 150 with breast cancer and 333 normal controls, and 472 and 452 participants comprised of ESCC patients and controls to the two independent validation cohorts. Serum IGFBP-1 showed elevated level for ESCC in both antibody arrays. A significant increase in the serum IGFBP-1 level on all cancer types except breast cancer was confirmed by ELISA, compared with normal controls. Serum IGFBP-1 provided a high diagnostic accuracy of gastrointestinal tumours (AUC 0·880-0·938, sensitivity 65·22-77·22%, and specificity 90·39%). Similar results were noted for early-stage gastrointestinal tumours (0·858-0·936, 60·29-83·93%, and 90·39%). In two validation cohorts, serum IGFBP-1 maintained diagnostic performance for early stage ESCC (0·849, 68·04%, and 89·09% in cohort 1, and 0·911, 72·34% and 87·37% in cohort 2). Furthermore, when compared with CEA, Cyfra21-1 and SCCA tested alone or together, serum IGFBP-1 had significantly improved diagnostic accuracy for ESCC and early stage ESCC. Interpretation: Serum IGFBP-1 is a potential biomarker with high diagnostic value for the early detection of gastrointestinal cancer. Funding Statement: This work was supported by funding from the Natural Science Foundation of China (31600632, 81772532 and 81872372), the Population-based prospective cohort study of esophageal cancer and precancerous lesions in high risk areas (2016YFC0901404), the National Cohort of Esophageal Cancer of China (2016YFC0901400), and the Guangdong Esophageal Cancer Institute Science and Technology Program (M201713), the Natural Science Foundation of Guangdong Province (2018A030307079) and the Shantou University Medical College Clinical Research Enhancement Initiative (201428). Declaration of Interests: We declare that we have no conflicts of interest. Ethics Approval Statement: The study was approved by the Institutional Review Boards for Human Research at each hospital, and informed consent was obtained from all participants.

Effect of ethyl acetate extract of usnea longissima on esophagogastric adenocarcinoma in rats1.

Purpose To investigate the effects of the EtOAc extract of U. longissima which is uninvestigated previously on esophagogastric cancer induced in rats with N-methyl-N-nitro-N-nitrosoguanidin (MNNG). Methods The anticancer activity of EtOAc extract of U. longissima was examined in the esophagogastric adenocarcinoma models induced in rats with MNNG. EtOAc extract of U. longissima, 50 and 100 mg/kg oral doses were administered once daily for six months. MNNG induced differentiated and undifferentiated type adenocarcinomas in the esophageal and gastric tissues of rats. Results EtOAc extract of U. longissima obtained from U. longissima prevented gastric and esophageal cancerogenesis induced in rats with MNNG. EtOAc extract of U. longissima did not have a lethal effect at doses of 500, 1000 and 2000 mg/kg. The prominent anticarcinogenic activity of EtOAc extract of U. longissima 50 and 100 mg/kg suggests that it is not toxic and it is selective to the cancer tissue. Conclusion This information may shed light on clinical implementation of EtOAc extract of U. longissima in future.