Junction Tumors Research Articles

Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial

SummaryBackgroundPeri-operative chemotherapy and surgery is a standard of care for patients with resectable oesophagogastric adenocarcinoma. Bevacizumab, a monoclonal antibody against VEGF, improves the proportion of patients responding to treatment in advanced gastric cancer. We aimed to assess the safety and efficacy of adding bevacizumab to peri-operative chemotherapy in patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma.MethodsIn this multicentre, randomised, open-label phase 2–3 trial, we recruited patients aged 18 years and older with histologically proven, resectable oesophagogastric adenocarcinoma from 87 UK hospitals and cancer centres. We randomly assigned patients 1:1 to receive peri-operative epirubicin, cisplatin, and capecitabine chemotherapy or chemotherapy plus bevacizumab, in addition to surgery. Patients in the control group (chemotherapy alone) received three pre-operative and three post-operative cycles of epirubicin, cisplatin, and capecitabine chemotherapy: 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 and 1250 mg/m2 oral capecitabine on days 1–21. Patients in the investigational group received the same treatment as the control group plus 7·5 mg/kg intravenous bevacizumab on day 1 of every cycle of chemotherapy and for six further doses once every 21 days following chemotherapy, as maintenance treatment. Randomisation was done by means of a telephone call to the Medical Research Council Clinical Trials Unit, where staff used a computer programme that implemented a minimisation algorithm with a random element to establish the allocation for the patient at the point of randomisation. Patients were stratified by chemotherapy centre, site of tumour, and tumour stage. The primary outcome for the phase 3 stage of the trial was overall survival (defined as the time from randomisation until death from any cause), analysed in the intention-to-treat population. Here, we report the primary analysis results of the trial; all patients have completed treatment and the required number of primary outcome events has been reached. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 46020948, and with ClinicalTrials.gov, number NCT00450203.FindingsBetween Oct 31, 2007, and March 25, 2014, 1063 patients were enrolled and randomly assigned to receive chemotherapy alone (n=533) or chemotherapy plus bevacizumab (n=530). At the time of analysis, 508 deaths were recorded (248 in the chemotherapy alone group and 260 in the chemotherapy plus bevacizumab group). 3-year overall survival was 50·3% (95% CI 45·5–54·9) in the chemotherapy alone group and 48·1% (43·2–52·7) in the chemotherapy plus bevacizumab group (hazard ratio [HR] 1·08, 95% CI 0·91–1·29; p=0·36). Apart from neutropenia no other toxic effects were reported at grade 3 or worse severity in more than 10% of patients in either group. Wound healing complications were more prevalent in the bevacizumab group, occurring in 53 (12%) patients in this group compared with 33 (7%) patients in the chemotherapy alone group. In patients who underwent oesophagogastrectomy, post-operative anastomotic leak rates were higher in the chemotherapy plus bevacizumab group (23 [10%] of 233 in the chemotherapy alone group vs 52 [24%] of 220 in the chemotherapy plus bevacizumab group); therefore, recruitment of patients with lower oesophageal or junctional tumours planned for an oesophagogastric resection was stopped towards the end of the trial. Serious adverse events for all patients included anastomotic leaks (30 events in chemotherapy alone group vs 69 in the chemotherapy plus bevacizumab group), and infections with normal neutrophil count (42 events vs 53).InterpretationThe results of this trial do not provide any evidence for the use of bevacizumab in combination with peri-operative epiribicin, cisplatin, and capecitabine chemotherapy for patients with resectable gastric, oesophagogastric junction, or lower oesophageal adenocarcinoma. Bevacizumab might also be associated with impaired wound healing.FundingCancer Research UK, MRC Clinical Trials Unit at University College London, and F Hoffmann-La Roche Limited.

Incidence and prognostic significance of extramural venous invasion in T3–4 esophageal cancer

44Background: Extra mural venous invasion (EMVI) is known as an adverse prognostic indicator of survival and an important predictor of systemic recurrences in colorectal carcinoma. However, the incidence and significance of EMVI in esophageal cancer (EC) have not been studied well. Aim: To estimate the incidence and the prognostic significance of EMVI in pathological stage T3-4 EC resection specimens without neoadjuvant chemoradiotherapy (nCRT) Methods: From a prospective maintained database we retrospectively review the resected specimens of patients with an EC. For adequate EMVI assessment we only included patients without nCRT and excluded patients without previous malignancies and patients with cardia/gastroesophageal junction tumors. A total of 76 patients were included between 2000 and 2012. EMVI was assessed on haematoxylin and eosin slides and for confirmation additional Elastica van Gieson staining was performed. Disease free survival was analyzed using a multivariable logistic regression and Kap...

Incidence and prognostic significance of extramural venous invasion in T3-4 esophageal cancer.

44 Background: Extra mural venous invasion (EMVI) is known as an adverse prognostic indicator of survival and an important predictor of systemic recurrences in colorectal carcinoma. However, the incidence and significance of EMVI in esophageal cancer (EC) have not been studied well. Aim: To estimate the incidence and the prognostic significance of EMVI in pathological stage T3-4 EC resection specimens without neoadjuvant chemoradiotherapy (nCRT) Methods: From a prospective maintained database we retrospectively review the resected specimens of patients with an EC. For adequate EMVI assessment we only included patients without nCRT and excluded patients without previous malignancies and patients with cardia/gastroesophageal junction tumors. A total of 76 patients were included between 2000 and 2012. EMVI was assessed on haematoxylin and eosin slides and for confirmation additional Elastica van Gieson staining was performed. Disease free survival was analyzed using a multivariable logistic regression and Kaplan-Meier method. Results: Evidence of EMVI was found in 18 patients (23.7%). The incidence of EMVI was significantly higher in squamous cell carcinomas (p < 0.05) and among tumors located in the mid-esophagus (p < 0.05). In the univariate analysis, pathological N- stage (HR 3.6 95%Cl: 1.5-8.5; p = 0.004) and positive circumferential resection margin (CRM) (HR 2.3 95% Cl: 1.2-4.5 p = 0.015) were independent prognostic factors. By stepwise multivariate Cox regression analysis, pathological tumor length (HR 2.5 95%Cl: 1.0-6.5 p = 0.05), pathological N- stage (HR 2.7 95%Cl: 1.3-6.2 p = 0.008), positive CRM (HR 2.3 95% Cl: 1.2-4.5 p = 0.009) and EMVI (HR 2.2 95% Cl: 1.0-4.5 p = 0.04) were shown to be independent prognostic factors for disease free survival. Conclusions: A search for EMVI may provide additional prognostic information in esophageal cancer, especially in squamous cell carcinoma.

Inguinal mass: An unusual presentation of gastroesophageal junction adenocarcinoma

Gastroesophageal junction (GEJ) tumors are inherently aggressive owing to their location near vital structures and early lymphatic spread. The usual symptoms at presentation are dysphagia, regurgitation, and weight loss. Lymphatic involvement is seen early due to abundant submucosal lymphatics and is an important prognostic marker. Nodal involvement is frequently seen in the mediastinum and abdomen as these are the loco-regional nodal basins. Nodal spread beyond these basins is infrequent. We report a case of GEJ adenocarcinoma with inguinal mass secondary to inguinal nodal metastasis as a presenting symptom.

Human Epidermal Growth Factor Receptor-2 (HER2) expression in Gastric adenocarcinoma and relevant clinicopathological features in a cohort of Sri Lankan patients

Introduction Human epidermal growth factor receptor -2 (HER2) gene over-expression heralds adverse prognosis in gastric adenocarcinoma (GCa). HER2 protein over-expression by immunohistochemistry (IHC) ranges from 10%-22.8% and 11.7%-15.74% in Western and Asian studies respectively. We aimed to evaluate HER2 positivity in GCa by IHC and to study relevant clinicopathological relationships, as information is locally unavailable. Methodology Hundred consecutive GCa (excluding gastrooesophageal junction tumours) were recruited prospectively from the National Hospital of Sri Lanka over two years. The diagnosis was made on endoscopic biopsy/gastrectomy specimens. HER2 was assessed in paraffinized tumour using c-erB-2 oncoprotein (DAKO A0485) and Real-TM Envision system. Scores of 2+ and 3+ were considered positive, using standard HER2 expression criteria. Relationship between HER2 and clinicopathological parameters were analyzed using SPSS-21 and Chi-squared test. Results Study included 44 gastrectomies and 56 biopsies. Mean age was 61.1 years (range 32- 82). HER2 was positive in 9 (9%) GCas: 2+ in 3(5.4%) biopsies and 3(6.8%) resections, 3+ in 1(1.8%) biopsy and 2(4.5%) resections. Eight (88.9%) HER2 positive GCa occurred in =T3) (p=0.31). HER2 positive cases showed, poor differentiation (p=0.047), higher nuclear grade (p=0.029), mitotic counts >5/HPF (p=0.003), extracellular mucin (p=0.05), tumour necrosis (p=0.037), perineural invasion (p=0.002) and nodal metastasis (p=0.04) assessed only in gastric resections. Discussion and conclusion HER2 positivity with immunohistochemistry was 9% in the gastric carcinoma cohort and were associated with higher stage, adverse histological parameters and nodal metastasis in gastric resections. Adverse histological features can be used as screening features for HER2 testing in gastric carcinoma in limited resource settings.

Distribution of FDG-avid nodes in esophageal cancer: implications for radiotherapy target delineation

PurposeClinical target volumes (CTV) for radiotherapy (RT) in esophageal cancer (EC) are based on standard expansions of primary tumor volume. Data is needed to define regions at highest risk for occult disease, based on histology and location of the primary tumor. We therefore reviewed PET scans in EC patients to characterize the location of FDG-avid lymph node metastases (LNM).Materials and methodsWe identified 473 EC patients with reviewable pre-treatment PET-CT scans. Tumors were classified by histology and location; 85% were distal or GE junction tumors and 71% were adenocarcinoma. FDG-avid LNM were classified using standard radiographic nodal atlases, and distances from primary tumor to paraesophageal LNM were also measured.ResultsThe most common LNM in upper EC were supraclavicular, retrotracheal and paratracheal. The most common LNM in lower EC were paraesophageal and in the gastrohepatic space. Overall, 55% of paraesophageal LNM were adjacent to primary tumor. Of upper esophageal tumors with paraesophageal LNM, 87% were adjacent to the tumor and none were >6 cm from tumor. However, 57% of lower esophageal tumors with paraesophageal LNM had non-adjacent paraesophageal nodes, 24% of which were >8 cm from the tumor.ConclusionA more data-driven and individualized approach to CTV delineation could improve the therapeutic ratio of RT in esophageal cancer. These results can guide CTV delineation by indicating the potential distribution of nodal involvement in esophageal cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0731-6) contains supplementary material, which is available to authorized users.

The multidisciplinary management of gastro-oesophageal junction tumours: European Society of Digestive Oncology (ESDO): Expert discussion and report from the 16th ESMO World Congress on Gastrointestinal Cancer, Barcelona.

The multidisciplinary management of gastro-oesophageal junction tumours: European Society of Digestive Oncology (ESDO): Expert discussion and report from the 16th ESMO World Congress on Gastrointestinal Cancer, Barcelona.

Is there a role for epidermal growth factor receptor inhibition in the treatment of advanced esophagogastric tumours?

Advanced esophagogastric cancers are aggressive malignancies with an extremely poor prognosis. Palliative chemotherapy remains disappointing, with median survival of <12 months in first line clinical trials. Overexpression of epidermal growth factor receptors (EGFR) in up to 80% of these cancers led to clinical trials testing the addition of EGFR-inhibitors (EGFR-I) to standard chemotherapy. Here we provide a perspective on the recent CALGB 80403 (Alliance)/E1206 trial publication which compared the safety and efficacy of three chemotherapy regimens combined with cetuximab and discuss its clinical practice implications. We identified relevant published data for discussion using a PubMed based search strategy and through the reference lists of identified studies. We focused our discussion mainly on the randomised trials that pertained to esophageal and esophagogastric junction tumours to match the population of the study in focus in this perspective.

Comparison of Clinical Outcomes of ESD vs STER for Esophagus, Esophagogastric Junction, and Gastric Tumor (Cancer) Originating from the Muscularis Propria Layer: A Systematic Review and Pooled Analysis

Comparison of Clinical Outcomes of ESD vs STER for Esophagus, Esophagogastric Junction, and Gastric Tumor (Cancer) Originating from the Muscularis Propria Layer: A Systematic Review and Pooled Analysis

Multimodality Therapy of Localized Gastric Adenocarcinoma.

Surgical resection is the primary method of obtaining a potential cure for patients with gastric adenocarcinoma. However, chemotherapy or chemoradiotherapy offer significant improvement in survival over surgery alone. Much of the difficulty in deciding the optimal treatment strategy is choosing between perioperative chemotherapy or adjuvant chemoradiotherapy. Adding to the complexity is the potential for incorporating treatment strategies based on clinical trials performed in Asia. There is likely a difference in tumor biology between Eastern and Western patients with gastric adenocarcinoma, in addition to the clear differences in screening, pathologic assessment, and surgical technique. Even among tumors in Western populations, heterogeneity of histology, anatomy, and staging among studies make cross-trial comparisons difficult. There is also active controversy surrounding the staging and management of gastroesophageal junction tumors. Lastly, the benefit of extended lymph node dissection is not clear based on the existing studies and has not been firmly established as a surgical standard of care for all patients. Future goals include better classification of gastric cancer, continued pursuit of randomized trials in Western populations, standardization of surgical technique, and incorporation of targeted therapies.

At the Crossroads: Resection of a Gastroesophageal Junctional Tumor

At the Crossroads: Resection of a Gastroesophageal Junctional Tumor

Neurosurgical Management and Outcomes of the Craniovertebral Junction (CVJ) Tumors

Neurosurgical Management and Outcomes of the Craniovertebral Junction (CVJ) Tumors

The multidisciplinary management of gastro-oesophageal junction tumours: European Society of Digestive Oncology (ESDO): Expert discussion and report from the 16th ESMO World Congress on Gastrointestinal Cancer, Barcelona

Background and scopeThe management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe. MethodologyOpinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. ResultsDefinition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible. ConclusionGOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.

Gastroesophageal Junction Tumors.

Gastroesophageal Junction Tumors.

What's the Best Way to Treat GE Junction Tumors? Approach Like Gastric Cancer.

The debate as to the optimal classification, staging, and treatment of gastroesophageal junction (GEJ) tumors wages on, and one must acknowledge that there is no "one-size-fits-all" approach. However, in this review we are charged with defending the position that all GEJ tumors are best treated like gastric cancer. We submit that, as stated, this is not a defensible position and that a clear definition of terms is warranted. Given the rarity of squamous cell carcinoma and the dramatic rise in incidence of adenocarcinoma of the GEJ in the West, we define GEJ "tumors" to mean adenocarcinomas of the GEJ. Furthermore, on the basis of their location, pathogenesis, and biologic behavior, we submit that few would argue with the contention that Siewert type I GEJ tumors are best treated like distal esophageal cancer and that Siewert type III GEJ tumors are best treated like gastric cancer. The real debate concerns the management of Siewert type II GEJ tumors, which arise immediately at the esophagogastric junction. Thus, for the purposes of this review, we have taken the liberty of redefining the question as what's the best way to treat adenocarcinomas of the true GEJ (i.e., Siewert type II tumors), and we submit that these tumors are in fact best treated like gastric cancer. This approach ensures that patients receive those therapies needed for the locoregional and systemic control of their disease together with a surgical procedure that optimizes complete tumor and regional lymph node resection while limiting morbidity.

HER2/neu as target in gastric adenocarcinoma.

Gastric adenocarcinoma (GAC), a heterogeneous disease characterized by epidemiologic and histopathologic differences across countries, is a leading cause of cancer-related death. The modest activity and substantial toxicity of cytotoxic chemotherapy has raised the question, does palliative systemic therapy with available agents have clinical utility? In the setting of metastatic disease, many active chemotherapy agents can produce meaningful response alone or in combination with other agents, but the duration of response is often limited. Recent additions to the armamentarium include trastuzumab and ramucirumab, which have shown some survival advantage when added to cytotoxic(s). The HER2 proto-oncogene is the gene encoding the human EGF receptor 2. HER2 amplification or protein overexpression [found in 20% of gastric cancer (GC)] is clearly associated with accelerated cell growth and proliferation and the response to the monoclonal anti- HER2 antibody, trastuzumab. HER2 was more likely to be positive in patients with esophagogastric junction (EGJ) tumors than in more distal tumors (33% versus 20%); patients with diffuse GC were much less likely to have an HER2- positive (6%) tumor (1).

Yield of Staging Laparoscopy and Lavage Cytology for Radiologically Occult Peritoneal Carcinomatosis of Gastric Cancer.

This study aimed to identify the yield of staging laparoscopy with peritoneal lavage cytology for gastric cancer patients and to track it over time. The medical records of patients with gastric or gastroesophageal adenocarcinoma who underwent pretreatment staging laparoscopy at the authors' institution from 1995 to 2012 were reviewed. The yield of laparoscopy was defined as the proportion of patients who had positive findings on laparoscopy, including those with macroscopic carcinomatosis, positive cytology, or other clinically important findings. To compare the yield of laparoscopy over time, the patients were divided into three 6-year ranges based on the date of diagnosis. Associations between clinicopathologic factors and peritoneal disease were examined using uni- and multivariate analyses. The study included 711 patients. Among these patients, 43.5 % had gastroesophageal junction tumors, 72.9 % had poorly differentiated adenocarcinoma, and 53 % had signet ring cell morphology. Endoscopic ultrasound had most commonly identified T3 (83.9 %) and N-positive (66.4 %) tumors. At laparoscopy, 148 (20.8 %) patients had been found to have macroscopic peritoneal carcinomatosis. Among 514 macroscopically negative patients who underwent peritoneal lavage cytologic analysis, 68 (13.2 %) had positive cytology results for malignancy. The total laparoscopy yield was 36 %, which did not change over time (p = 0.58). Multivariate analysis demonstrated that positive cytology or carcinomatosis was associated with poorly differentiated histology, linitis plastica, and equivocal computed tomography findings. Laparoscopy remains a useful staging procedure to evaluate for peritoneal spread when treatment or surgery is considered, even with the current availability of high-quality imaging.

Mortality in patients with esophageal and gastroesophageal tumors treated with self-expandable stents

Introduction: Esophageal cancer is an aggressive disease and is the eighth cause of malignant tumors worldwide. To treat dysphagia, auto expandable prosthesis (AEP) are used in order to optimize the nutritional status and quality of life of the patients.Objectives: To quantify patients’ mortality and to evaluate variables related with this outcome.Materials and methods: Retrospective cohort study that involved 135 patients with esophageal malignant obstruction that required AEP insertion. Survival and incidence density rates were estimated. The effect of these variables on the probability of death was assessed by using Cox models.Results: Overall mortality rate was 13.7 deaths per 100 patients/month (95%CI: 10.9-17.1). Univariate analysis showed significant differences in survival functions according to pre-intervention albumin levels and the prosthesis size (&gt;12cm). In the Cox model, albumin level (HR=0.53, 95%CI 0.31 to 0.89) was the only significant result.Conclusions: AEP represent a therapeutic option to improve symptoms in patients with advanced esophageal and gastroesophageal junction tumors. This technique has few complications and its clinical success is around 90%. Patients’ nutritional status and length of the stenosis caused by the tumor are variables that must be evaluated before performing a procedure as they seem to be related to mortality.

RAB2A controls MT1-MMP endocytic and E-cadherin polarized Golgi trafficking to promote invasive breast cancer programs.

The mechanisms of tumor cell dissemination and the contribution of membrane trafficking in this process are poorly understood. Through a functional siRNA screening of human RAB GTPases, we found that RAB2A, a protein essential for ER-to-Golgi transport, is critical in promoting proteolytic activity and 3D invasiveness of breast cancer (BC) cell lines. Remarkably, RAB2A is amplified and elevated in human BC and is a powerful and independent predictor of disease recurrence in BC patients. Mechanistically, RAB2A acts at two independent trafficking steps. Firstly, by interacting with VPS39, a key component of the late endosomal HOPS complex, it controls post-endocytic trafficking of membrane-bound MT1-MMP, an essential metalloprotease for matrix remodeling and invasion. Secondly, it further regulates Golgi transport of E-cadherin, ultimately controlling junctional stability, cell compaction, and tumor invasiveness. Thus, RAB2A is a novel trafficking determinant essential for regulation of a mesenchymal invasive program of BC dissemination.

PTU-151 Predicting 30-Day Mortality and Re-Stenting Following Self Expanding Metal Stent (SEMS) Insertion for The Palliation of Dysphagia in Patients with Oesophageal Cancer

Introduction Management of dysphagia due to malignant obstruction of the oesophagus can be challenging. Endoscopically placed self-expanding metal stents (SEMS) remain an important tool and have been performed under direct vision in our institution since 2004. A previous audit suggested a significant morbidity and mortality rate and therefore the aim of this study was to identify risk factors for 30 day mortality and re-intervention. Methods A retrospective review of all patients undergoing oesophageal SEMS insertion was performed over the period 2004–2014. Data collected included patient demographics, tumour stage/position, stent type inserted, survival following SEMS insertion, bioprofile and other therapies. Univariate analysis was performed and was followed by multivariate logistic regression to identify independent variables associated with 30 day mortality and re-stenting. Results 396 patients (median age 74 years, 252 males) had 514 stents were inserted over the study period and were included in the study. Regarding 30 day mortality, univariate analysis showed association with distal tumours (OR 1.6), stent length >10 cm (OR 3.0), oncological treatment (OR 0.4), raised CRP (OR 6.1), raised white cell count (OR 6.0), anaemia (OR 2.8) and low albumin (OR 4.9). Multivariate analysis showed white cell count (OR 8.1, 2.0–21.9, p 70 (OR 0.6), junctional tumours (OR 0.5), stent length >10 cm (OR 0.6), raised CRP (OR 0.5) and raised white cell count (OR 0.4). Multivariate analysis showed age > 70 (OR 0.5, 0.3–0.9, p = 0.032) and raised white cell count (OR 0.4, 0.2–0.8, p = 0.009) were independent predictors of re-intervention. Conclusion Raised inflammatory markers were associated with poorer outcomes following oesophageal SEMS insertion and oncological treatment was protective. Longer survival appears to be associated with re-intervention following initial stent insertion. This data may provide a framework for the creation of a prognostic scoring system prior to SEMS insertion. Disclosure of Interest None Declared