Gastroesophageal Junction Tumors Research Articles

Evaluation of human tissue kallikrein-related peptidases 6 and 10 expression in early gastroesophageal adenocarcinoma.

Kallikreins are a family of serine proteases that are linked to malignancy of different body organs with potential clinical utility as tumor markers. In this study, we investigated kallikrein-related peptidase 6 (KLK6) and KLK10 expression in early gastroesophageal junction adenocarcinoma and Barrett esophagus (BE) with and without dysplasia. Immunohistochemistry revealed significantly increased KLK6 expression in early invasive cancer compared with dysplastic (P = .009) and nondysplastic BE (P = .0002). There was a stepwise expression increase from metaplasia to dysplasia and invasive tumors. Significantly higher KLK10 was seen in dysplastic lesions compared with metaplasia but not between dysplastic lesions and invasive cancers. KLK6 staining intensity was increased at the invasive front (P = .006), suggesting its role in tumor invasiveness. Neither KLK6 nor KLK10 was significantly associated with other prognostic markers, including depth of invasion, indicating their potential as independent biomarkers. Our results should be interpreted with caution due to limited sample size. There was a significant correlation between KLK6 and KLK10 expression both at the invasive front and within the main tumor, indicating a collaborative effect. We then compared KLK6 and KLK10 messenger RNA expression between metaplastic and cancerous tissues in an independent data set of esophageal carcinoma from The Cancer Genome Atlas. KLK6 and KLK10 may be useful markers and potential therapeutic targets in gastroesophageal junction tumors.

40. Not the type of surgical treatment but neoadjuvant treatment influences overall survival in patients with gastro-oesophageal junction tumours in the Netherlands

Background: There may be two different therapeutic strategies for patients with resectable gastro-esophageal junction (GEJ) tumours. Either, they are treated as an esophageal tumour with neoadjvant chemoradiation and a subsequent esophagectomy or as a gastric tumour with perioperative chemotherapy and a gastrectomy. According to the TNM classification, GEJ tumours with the epicentre within 5cm of the GEJ and extension into the esophagus should be staged according to the esophageal classification. Whereas, GEJ tumours within 5 cm of the junction without extension into the esophagus should be staged according to the gastric classification. The objective of this study was to determine the patterns of care for resectable GEJ tumours in the Netherlands and to compare oncological outcome with the different treatment regimes.

PTU-149 Malnutrition And Gastrointestinal (gi) Symptoms In Patients With Upper-gi Cancer

IntroductionPersistent GI symptoms and malnutrition have been associated with poorer quality of life in upper-GI cancer patients. This study aims to assess GI symptoms and nutritional status in patients undergoing...

Patterns of recurrence after trimodality therapy for esophageal cancer

Patterns of failure after neoadjuvant chemoradiotherapy and surgery for esophageal cancer are poorly defined. All patients in the current study were treated with trimodality therapy for nonmetastatic esophageal cancer from 1995 to 2009. Locoregional failure included lymph node failure (NF), anastomotic failure, or both. Abdominal paraaortic failure (PAF) was defined as disease recurrence at or below the superior mesenteric artery. Among 155 patients, the primary tumor location was the upper/middle esophagus in 18%, the lower esophagus in 32%, and the gastroesophageal junction in 50% (adenocarcinoma in 79% and squamous cell carcinoma in 21%) of patients. Staging methods included endoscopic ultrasound (73%), computed tomography (46%), and positron emission tomography/computed tomography (54%). Approximately 40% of patients had American Joint Committee on Cancer stage II disease and 60% had stage III disease. The median follow-up was 1.3 years. The 2-year locoregional control, event-free survival, and overall survival rates were 86%, 36%, and 48%, respectively. The 2-year NF rate was 14%, the isolated NF rate was 3%, and the anastomotic failure rate was 6%. The 2-year PAF rate was 9% and the isolated PAF rate was 5%. PAF was found to be increased among patients with gastroesophageal junction tumors (12% vs 6%), especially for the subset with ≥ 2 clinically involved lymph nodes at the time of diagnosis (19% vs 4%). Few patients experience isolated NF or PAF as their first disease recurrence. Therefore, it is unlikely that targeting additional regional lymph node basins with radiotherapy would significantly improve clinical outcomes.

Is Gastric Cancer Different in Korea and the United States? Impact of Tumor Location on Prognosis

To compare the characteristics and prognoses of gastric cancers by tumor location in Korean and U.S. subjects after curative-intent (R0) resection for gastric cancer (GC). Data were collected for all patients who had undergone R0 resection at one U.S. institution (n = 567) and one South Korean institution (n = 1,620). Patients with gastroesophageal junction tumors or neoadjuvant therapy were excluded. Patient, surgical, and pathologic variables were compared by tumor location. Factors associated with disease-specific survival (DSS) were determined via multivariate analysis. In the Korean cohort, significantly more upper third GC (UTG) patients had undifferentiated, diffuse type, and advanced stage cancers compared to lower third GC (LTG) and middle third GC (MTG) patients. In the U.S. cohort, however, T stage was relatively evenly distributed among UTG, MTG, and LTG patients. The independent predictors of DSS in the Korean cohort were T stage, tumor size, retrieved and positive lymph node counts, and age, but in the U.S. cohort, the only independent predictors were T stage and positive lymph node count. Tumor size significantly affected DSS of Korean UTG patients but not U.S. UTG patients. There were significant differences in tumor characteristics by tumor location within and between both national cohorts. On the basis of these findings, further study to investigate the biological difference between the two countries is needed.

Clinical management of gastroesophageal junction tumors: past and recent evidences for the role of radiotherapy in the multidisciplinary approach.

Gastroesophageal cancers (such as esophageal, gastric and gastroesophageal-junction -GEJ- lesions) are worldwide a leading cause of death being relatively rare but highly aggressive. In the past years, a clear shift in the location of upper gastrointestinal tract tumors has been recorded, both affecting the scientific research and the modern clinical practice. The integration of pre- or peri-operative multimodal approaches, as radiotherapy and chemotherapy (often combined), seems promising to further improve clinical outcome for such presentations. In the past, the definition of GEJ led to controversies and confusion: GEJ tumors have been managed either grouped to gastric or esophageal lesions, following slightly different surgical, radiotherapeutic and systemic approaches. Recently, the American Joint Committee on Cancer (AJCC) changed the staging and classification system of GEJ to harmonize some staging issues for esophageal and gastric cancer. This review discusses the most relevant historical and recent evidences of neoadjuvant treatment involving Radiotherapy for GEJ tumors, and describes the efficacy of such treatment in the frame of multimodal integrated therapies, from the new point of view of the recent classification of such tumors.

Defining the Role of Laparoscopic Gastrectomy for Gastric Cancer

Defining the Role of Laparoscopic Gastrectomy for Gastric Cancer

Potential regulators of HER2 activity in HER2-overexpressing gastric and gastroesophageal tumors: Analysis of HER3 and heregulin expression.

48 Background: HER2 is overexpressed in gastric and gastroesophageal junction (GEJ) tumors. Though treatment of these tumors with the HER2-targeted agent trastuzumab offers clinical benefit, patients ultimately progress. Signaling by HER2/HER3 heterodimers following activation by HER3’s ligand heregulin has been shown to be a resistance mechanism to trastuzumab. The objective of this study was to quantitate HER2, HER3 and heregulin in gastric and GEJ tumor samples to determine whether these tumors express components for signaling through this complex and thus have potential for developing trastuzumab resistance. Methods: A novel immunofluorescent assay was used to quantitate HER2 and cytokeratin in 236 gastric and GEJ tumors. Using image analysis, each cell within a section was classified as tumor or non-tumor based on cytokeratin level. HER2 fluorescence was also quantitated in each cell and converted to number of HER2 receptors per cell using a standard curve from an array of cell lines with defined HER2. The assay’s single cell output enables an assessment of HER2 heterogeneity in any tissue. In those tumors overexpressing HER2, HER3 and heregulin were quantitated using immunofluorescence as for HER2 and by RT-PCR. Results: In concordance with published data, HER2 was overexpressed in ~10% of gastric and ~20% of GEJ tumors. HER2-overexpressing tumors could be divided into two groups with levels of HER2 consistent with IHC scores of 2+ and 3+ as assessed by clinical assays. All HER2-overexpressing samples also expressed HER3 and heregulin. Heregulin expression was detected in both tumor cells and/or in adjacent stroma. Conclusions: HER3 and heregulin are present in HER2-overexpressing gastric and GEJ tumors. To evaluate the importance of HER3 and heregulin in these patients, a randomized open label second line Phase 2 trial has been initiated with MM-111, a HER2/HER3 bispecific antibody that inhibits HER3 activity in HER2-overexpressing cells by blocking heregulin binding. HER2, HER3 and heregulin expression will be retrospectively analyzed in tumor samples from patients in this trial, providing further insight into the role of this complex in gastric and GEJ cancer.

Surgical treatment of gastric cancer: Oncologic outcome of neoadjuvant treatment in the German multicenter observational study II.

139 Background: Neoadjuvant chemotherapy is broadly established in European centers when treating locally advanced gastric cancer. However, there still remain questions as to the benefit of this extended form of treatment in regards to tumor location and stage. Methods: Data obtained in the ongoing prospective, multicenter observational study (German Gastric Cancer Study II) on quality assurance in surgical therapy of gastric cancer containing a total of 2897 patients treated from 01/01/2007 through 31/12/2009 in 145 surgical departments to evaluate. Results: Overall, 506 patients (18.4%) received neoadjuvant treatment in regards to all tumor stages. Of the 530 patients with adenocarcinoma of the gastroesophageal junction (GEJ) 34.5% (n=183) received chemotherapy. In detail, 30.1% (n=873) of the patients were found to be in stage I. In regards to the mean time of survival for advanced stages (III/IV 6th editiion) a survival benefit for patients receiving neoadjuvant treatment (n=356) of 12.0 months was demonstrated versus 10.0 months (p=0.048) for patients not being treated neoadjuvantly. Improved survival through neoadjuvant treatment could not be demonstrated in GEJ tumors, both, comparing different types of GEJ and matching cancer of the GEJ and distal gastric cancer. Overall survival in GEJ tumors is significantly lower (25 months) compared to the overall survival in distal gastric cancers (38 months). In addition, 5-year survival rate of GEJ tumor patients (33.1 %) was distinctly lower than for patients with distal gastric cancer (41.4 %). Conclusions: The results reflect the difficulties of applying currently available study results to daily clinical practice. In order to achieve improved treatment results, requirements in diagnostics, oncological and surgical settings are paramount. Future data of this observational study can provide additional insight for this process.

Mesothelin expression in patients as a novel target in gastric cancer.

61 Background: Novel targets and therapeutics are of profound importance if we are to improve outcomes in gastric cancer. This study assessed the incidence of mesothelin expression in tumors of Western patients with gastric cancer. In addition, gastric cancer cell lines were then tested for their sensitivity to SS1(dsFv)PE38 (SS1P), a mesothelin-targeted immunotoxin. Methods: Tissue specimens from 127 patients with gastric or gastro-esophageal junction (GEJ) tumors were examined by immuno-histochemistry (IHC) for intensity of staining for mesothelin. Expression of HER2-neu, e-cadherin and c-Met were also assessed. Tumors were considered positive for mesothelin if moderate cytoplasmic/membranous or luminal staining was present in at least 10% of the cells. Gastric cancer cell lines were assessed for surface mesothelin expression by flow cytometry and the viability of cells treated with SS1P was measured. Results: Gastric and GEJ cancers were mesothelin positive in 64/127 tumors (50%) while only 9 tumors (7%) were Her2-neu IHC +3 positive and 8 tumors (6%) were c-Met positive (c-Met low 5% and c-Met high 1%). Mesothelin expression rates changed from stage I tumors to stage IV tumors (39% to 56% respectively). We found that both the AGS and MKN28 gastric cancer cell lines express mesothelin and are sensitive to the immunotoxin with EC50 values in the low picomolar range (0.4 and 0.3 ng/mL, respectively). Conclusions: Mesothelin is a cell surface glycoprotein that is expressed in 50% of resected gastric cancers. Gastric cancer cell lines were exquisitely sensitive to SS1P. The high expression of mesothelin and its sensitivity to the immunotoxin SS1P makes it an attractive tumor associated antigen for therapeutic targeting. Based on these observations clinical trials involving novel mesothelin targeted drugs in gastric cancer are currently in development.

The role of endoscopic ultrasound and pet-ct in the staging of oesophageal and gastro-oesophageal junction tumours: A retrospective review of a regional cancer network

The role of endoscopic ultrasound and pet-ct in the staging of oesophageal and gastro-oesophageal junction tumours: A retrospective review of a regional cancer network

A review of the endoscopic management of patients with gastric ulcers

A review of the endoscopic management of patients with gastric ulcers

Genomic alterations in advanced esophageal cancer may lead to subtype-specific therapies.

The development of targeted agents for metastatic esophageal or gastroesophageal junction (GEJ) tumors has been limited when compared with that for other common tumors. To date, the anti-human epidermal growth factor receptor-2 (HER-2) antibody, trastuzumab, in combination with chemotherapy, is the only approved novel agent for these cancers, and its use is limited to the small population of patients whose tumors overexpress HER-2. Despite recent progress in the field, median overall survival remains only 8-12 months for patients with stage IV esophageal or GEJ cancer. In this article, we examine the molecular aberrations thought to drive the development and spread of esophageal cancer and identify promising targets for specific tumor inhibition. Data from clinical studies of targeted agents are reviewed, including epidermal growth factor receptor antibodies, tyrosine kinase inhibitors, HER-2, and vascular endothelial growth factor-directed therapy. Current and future targets include MET, fibroblast growth factor receptor, and immune-based therapies. Evidence from trials to date suggests that molecularly unselected patient cohorts derive minimal benefit from most target-specific agents, suggesting that future collaborative investigation should focus on preselected molecular subgroups of patients with this challenging heterogeneous disease.

Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus

The outcome of patients with locally advanced gastroesophageal adenocarcinoma (adenocarcinoma of the esophagus, gastroesophageal (GE) junction, and stomach) is poor. There is conflicting evidence regarding the effects of perioperative chemotherapy on survival and other outcomes. To assess the effect of perioperative chemotherapy for gastroesophageal adenocarcinoma on survival and other clinically relevant outcomes in the overall population of participants in randomized controlled trials (RCTs) and in prespecified subgroups. We performed computerized searches in the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Review of Effectiveness (DARE), the Cochrane Database of Systematic Reviews (CDSR) from The Cochrane Library, MEDLINE (1966 to May 2011), EMBASE (1980 to May 2011), and LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), combining the Cochrane highly sensitive search strategy with specific search terms. Moreover, we handsearched several online databases, conference proceedings, and reference lists of retrieved papers. We included RCTs which randomized patients with gastroesophageal adenocarcinoma, in the absence of distant metastases, to receive either chemotherapy with or without radiotherapy followed by surgery, or surgery alone. Two independent review authors identified eligible trials. We solicited individual patient data (IPD) from all selected trials. We performed meta-analyses based on intention-to-treat populations using the two-stage method to combine IPD with aggregate data from RCTs for which IPD were unavailable. We combined data from all trials providing IPD in a Cox proportional hazards model to assess the effect of several covariables on overall survival. We identified 14 RCTs with 2422 eligible patients. For eight RCTs with 1049 patients (43.3%), we were able to obtain IPD. Perioperative chemotherapy was associated with significantly longer overall survival (hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.73 to 0.89). This corresponds to a relative survival increase of 19% or an absolute survival increase of 9% at five years. This survival advantage was consistent across most subgroups. There was a trend towards a more pronounced treatment effect for tumors of the GE junction compared to other sites, and for combined chemoradiotherapy as compared to chemotherapy in tumors of the esophagus and GE junction. Resection with negative margins was a strong predictor of survival. Multivariable analysis showed that tumor site, performance status, and age have an independent significant effect on survival. Moreover, there was a significant interaction of the effect of perioperative chemotherapy with age (larger treatment effect in younger patients). Perioperative chemotherapy also showed a significant effect on several secondary outcomes. It was associated with longer disease-free survival, higher rates of R0 resection, and more favorable tumor stage upon resection, while there was no association with perioperative morbidity and mortality. Perioperative chemotherapy for resectable gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should thus be offered to all eligible patients. There is a trend to a larger survival advantage for tumors of the GE junction as compared to other sites and for chemoradiotherapy as compared to chemotherapy in esophageal and GE junction tumors. Likewise, there is an interaction between age and treatment effect, with younger patients having a larger survival advantage, and no survival advantage for elderly patients.

A phase II trial of induction epirubicin, oxaliplatin, and flourouracil, surgery and post-operative concurrent cisplatin and fluorouracil chemoradiotherapy (CRT) in patients (pts) with loco-regionally advanced (LRA) adenocarcinoma (ACA) of the esophagus (E) and gastroesophageal junction (GEJ).

4087 Background: In pts with LRA ACA of the E/GEJ, CRT and surgery results in excellent locoregional control. Distant failure remains common, however, suggesting potential benefit from additional chemotherapy. This single arm phase II study investigated the addition of induction chemotherapy to surgery and post-operative CRT. Methods: Pts with an ultrasound-based clinical stage of T3, N1 or M1a (AJCC 6th) ACA of the E/GEJ were eligible. Induction chemotherapy with epirubicin 50mg/m2 d1, oxaliplatin 130mg/m2 d1, and flourouracil 200mg/m2/day continuous infusion for 3 weeks, was given every 21 days for 3 courses and was followed by surgical resection. Adjuvant CRT consisted of 50-55Gy at 1.8-2.0 Gy/d and 2 courses of cisplatin (20mg/m2/d) and flourouracil (1000mg/m2/d) given as 96 hour infusions during weeks 1 and 4 of radiotherapy. Results: Between 2/08 and 1/12, 60 evaluable pts enrolled; 95% male, 97% white and 78% with GEJ tumors. Resection was accomplished in 54 pts (90%) and adjuvant CRT in 48 (80%). Toxicity included 1 death during induction (2%), and 2 post-operative deaths (4%). Unplanned hospitalization was required in 18% of pts during induction and 19% during adjuvant CRT. Induction chemotherapy produced a symptomatic response in 79% of pts, a clinical (ultrasound) response in 48% and a pathologic response in 41% (5% complete). With a median follow-up of 31 months, the Kaplan-Meier 3-year projected locoregional control (LRC) is 84%, distant metastatic control (DMC) 44%, relapse-free survival (RFS) 39%, and overall survival (OS) 42%. Symptomatic response to induction and the percentage of remaining viable tumor at surgery proved the strongest predictors of DMC, RFS, and OS. Conclusions: Induction chemotherapy, surgery and adjuvant CRT is feasible and produces outcomes similar to other multimodality treatment schedules in LRA E/GEJ ACA. Despite excellent LRC, projected DMC and OS remain poor. A symptomatic response to induction and less residual viable tumor at surgery are associated with improved outcomes. Clinical trial information: NCT00601705.

Unanswered Questions in the Management of Gastroesophageal Junction Adenocarcinoma: An Overview from the Medical Oncologist's Perspective

Patients with gastroesophageal junction (GEJ) adenocarcinoma have multiple treatment options; however, are victims of lack of consensus and wide variation in treatment, sometimes within the same hospital. While there is a consensus that surgery alone is inadequate for locally advanced disease, locoregional treatment has become the point for debate. Only in 2010 was the reclassification of GEJ cancers as esophageal cancers. Treatment options remain as varied as the classification of GEJ cancers: preoperative chemoradiotherapy, definitive chemoradiation, perioperative chemotherapy, and resection followed by postoperative chemoradiation. Several studies have examined the varying treatment paradigms; however, many fall short due to methodology or sample size. The MAGIC study determined perioperative chemotherapy to be an acceptable standard treatment option for patients with gastric cancer, althouth a significant portion of enrolled patients had distal esophageal and GEJ adenocarcinoma. The CROSS study concluded combination chemotherapy and radiation before resection beneficial. Preoperative therapy in cases of GEJ is beneficial for survival, but not as much impact is seen as in esophageal SCC, which exhibits an increased sensitivity to CRT. There is concurrence with two phase III studies from Japan and Korea on the role of adjuvant chemotherapy for gastric cancer. However, the applicability of these studies to GEJ adenocarcinoma remains a question, especially with the significantly different epidemiology of increased proximal and GEJ tumors in the West compared to Asia. To move forward with this increasingly prevalent disease, we will need to do more than understand the multiple treatment paradigms-we will need to select a strategy and examine it.

The Rationale and Evidence for Radiotherapy in the Management of Gastroesophageal Junction Tumors

Adenocarcinoma of the gastroesophageal junction (GE-junction) is a frequent disease with a rising incidence. The optimal treatment of localized disease is the subject of many randomized trials and meta-analyses studying the role of preoperative chemotherapy or preoperative chemoradiation compared with surgery alone. A complicating factor in interpreting the results of these trials is the fact that GE-junction tumors are sometimes regarded as esophageal tumors, although in other studies they are regarded as gastric cancers. A thorough review of the literature including meta-analyses clearly indicates that there is a role for preoperative chemoradiation in locally advanced GE-junction tumors. Based on the available evidence a surgery alone arm in future randomized trials for locally advanced GE junction tumors can no longer be regarded as a standard arm.

Mo1714 Gastroesophageal Junction Tumors Clinically Staged cT2: Accuracy of Staging Results and Therapeutic Consequences At Two Academic Centers

Mo1714 Gastroesophageal Junction Tumors Clinically Staged cT2: Accuracy of Staging Results and Therapeutic Consequences At Two Academic Centers

Targeting the Human Epidermal Growth Factor Receptor 2 in Esophageal Cancer

The importance of human epidermal growth factor-2 (HER2) in terms of prognosis and aggressiveness of growth has long been known in breast cancer, and interruption of its growth cascade by agents such as trastuzumab and lapatinib has markedly improved outcomes for these patients with HER2 overexpression. HER2 overexpression also occurs in many other tumor types, including esophageal cancer. In this disease, a different scoring system for determining overexpression is used. Limited data exist concerning the biological and therapeutic implications of HER2 overexpression in esophageal cancer. One trial, the so-called ToGA trial, included patients with advanced gastric and gastroesophageal junction (GEJ) tumors that overexpressed HER2. Patients who received trastuzumab plus cisplatin-based chemotherapy had more responses and longer progression-free and overall survival than those who received the chemotherapy alone. Enthusiasm concerning these results must be tempered by the facts that only 25% of the study group had GEJ tumors and, of these, only 33% had HER2 overexpression. Thus, the role of trastuzumab in the management of HER2-overexpressing esophageal cancers remains to be determined. In addition to presenting data on the HER2 cascade, the authors review clinical trials performed to date and also present the validated standard scoring system for HER2 overexpression in esophageal cancer.

Primary esophageal and gastro-esophageal junction cancer xenograft models: clinicopathological features and engraftment

There are very few xenograft models available for the study of esophageal (E) and gastro-esophageal junction (GEJ) cancer. Using a NOD/SCID model, we implanted 90 primary E and GEJ tumors resected from patients and six endoscopic biopsy specimens. Of 69 resected tumors with histologically confirmed viable adenocarcinoma or squamous cell carcinoma, 22 (32%) was engrafted. One of 11 tumors, considered to have had a complete pathological response to neo-adjuvant chemo-radiation, also engrafted. Of the 23 patients whose tumors were engrafted, 65% were male; 30% were early stage while 70% were late stage; 22% received neo-adjuvant chemo-radiation; 61% were GEJ cancers. Engraftment occurred in 18/54 (33%) adenocarcinomas and 5/16 (31%) squamous cell carcinomas. Small endoscopic biopsy tissue had a 50% (3/6) engraftment rate. Of the factors analyzed, pretreatment with chemo-radiation and well/moderate differentiation showed significantly lower correlation with engraftment (P<0.05). In the subset of patients who did not receive neo-adjuvant chemo-radiation, 18/41 (44%) engrafted compared with those with pretreatment where 5/29 (17%, P=0.02) engrafted. Primary xenograft lines may be continued through 4–12 passages. Xenografts maintained similar histology and morphological characteristics with only minor variations even after multiple passaging in most instances.