Mark Anderson

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

A Phase II Study of Gefitinib Monotherapy in Advanced Esophageal Adenocarcinoma: Evidence of Gene Expression, Cellular, and Clinical Response

Purpose: At presentation, most cases of adenocarcinoma of the esophagus (ACE) are inoperable. Although chemotherapy can prolong survival, patients eventually die as a result of refractory disease. Epidermal growth factor receptor (EGFR) is almost universally expressed in ACE and is a negative prognostic factor. Experimental Design: This open-label, two-center, noncomparative, two-part phase II trial assessed the EGFR tyrosine kinase inhibitor gefitinib (500 mg/d) in patients with advanced, inoperable ACE. The primary end point was tumor response. The effect of EGFR inhibition was also evaluated by gene expression analysis of tumor biopsies taken before gefitinib treatment and 28 days after. Results: Twenty-seven patients were recruited and evaluable for tumor response and safety. Three patients had a partial response and seven had stable disease, giving a disease control rate (partial response + stable disease) of 37%. Drug-related adverse events were generally mild: diarrhea in 19 (grade 3 in three) and rash in 19 (grade 3 in five) patients, and there were no grade 4 drug-related adverse events. Microarray experiments on tumor biopsies showed that gefitinib also down-regulated oncogenes associated with tumor progression. Ki67 (a marker of tumor growth) expression decreased in five of seven biopsies taken before and after treatment. Conclusion: Gefitinib (500 mg/d) is an active and generally well-tolerated treatment for ACE. Studies on endoscopic biopsies are feasible and indicate that gefitinib inhibits both gene expression and cellular biology at 500 mg/d, and these may provide surrogate end points for predictive biomarkers. Further trials of gefitinib are warranted, particularly as patient response seems to be durable and current second-line chemotherapy options have no proven ability to prolong life.

Met Receptor Signaling: A Key Effector in Esophageal Adenocarcinoma

Purpose: The incidence of esophageal adenocarcinoma is rising, and survival rates remain poor. The hepatocyte growth factor (HGF) receptor Met has been detected in esophageal cancer. The perturbation of cadherin/catenin complexes has also been shown. We sought to investigate a link among Met expression, cadherin/catenin biology, and cell growth. We assessed the prognostic significance of Met expression in esophageal adenocarcinoma. Experimental Design: Met and HGF expression in esophageal tissues were assessed using immunohistochemistry and ELISA. Met-positive cell lines (OE33 and SEG1) and a Met-negative cell line (TE7) were incubated with HGF. Real-time reverse transcription-PCR and Western blotting were used to assess levels of E-cadherin expression. Nuclear TCF/β-catenin signaling was assessed following reporter construct transfection. Agar colony formation was used to assess anchorage-independent growth. A panel of 72 resected esophageal adenocarcinomas were assessed for Met expression by immunohistochemistry and correlated to survival data. Results: An increased expression of Met was seen along the metaplasia- adenocarcinoma sequence. Met-positive cells showed reductions in E-cadherin mRNA (37% and 69%) and protein expression following stimulation with HGF (P < 0.01). OE33 and SEG-1 showed up to a 2-fold increase in the levels of β-catenin nuclear signaling (P < 0.01). TE7 only responded when transfected to express Met; E-cadherin expression decreased by 64% (P < 0.01). HGF stimulation led to increased agar colony formation (P < 0.01). Patients with Met-positive tumors showed lower 6-month survival rates after surgical resection than those with Met-negative tumors (P < 0.05). Conclusions: Met activation induces changes consistent with early invasion, such as down-regulation of E-cadherin, increased nuclear TCF/β-catenin signaling, and anchorage-independent growth. This is supported by ex vivo data associating Met with reduced short-term survival. Inhibitors of Met may be effective treatment for esophageal adenocarcinoma.

The treatment, management and prevention of oesophageal cancer

The combination of a rising incidence and a poor survival rate makes oesophageal cancer a major health issue. Adenocarcinoma of the oesophagus is associated with one of the commonest pre-malignant lesions recognised, Barrett’s metaplasia. This provides a focus for early detection and intervention. The subjects of acid suppression, bile reflux, COX-2 inhibition and ablation therapy will be discussed herewith. Established carcinoma is now rarely treated by surgery alone and this review discusses the benefits of multimodality therapy combined with more accurate staging techniques. Finally an emerging understanding of the molecular events that characterise the transition to carcinoma may provide novel targets in cancer therapy such as epidermal growth factor receptor (EGFR) and TNF-α. This review will focus on some of the future developments in the treatment of oesophageal cancer.

Curing oesophageal cancer: one swallow does not make a summer.

 Single-agent chemotherapy is generally less effective than combination therapy and allows the development of drug-resistant cancer cells.  Ifosfamide has rarely shown complete or partial efficacy in oesophageal cancer and is associated with significant toxicity.  Caution must be used in interpreting single cases of complete response.  Such cases may provide insight into the biological behaviour of oesophageal cancer and add direction in the search for specific predictors of response. The mainstay of curative treatment for oesophageal cancer is currently surgery with neoadjuvant chemotherapy or radiotherapy. In most cases, single-agent chemotherapy has been disappointing and allows the development of resistant cancer cells. Success is more likely with combination therapy, although toxicity may be higher. Ifosfamide is generally no different in this respect, but the report of a complete cure in a case treated solely by ifosfamide is discussed. Such subgroup patients may be important in helping to identify factors that predict the biological behaviour of oesophageal cancers, and may aid us in the search for specific markers of treatment response.

Is there a gender specific response of oesophageal mucosa to acid reflux

Introduction Oesophageal adenocarcinoma has an unexplained male predominance. We hypothesise that male and female oesophageal tissues display differential responses to acid reflux and progression of Barrett9s metaplasia. Aims To characterise the gene expression in male and female normal oesophagus and Barrett9s metaplasia, to detect gender-specific differences. Methods 12 biopsy samples of normal oesophagus and Barrett9s with intestinal metaplasia were obtained (6 males, 6 females). Gene expression profiles were assessed by tissue microarray analysis to determine differences in upregulated gene expression. Real-time PCR was performed to assess differences in the upregulation of key genes (cdx-1, cdx-2, PCNA). Results Using a Venn diagram filter to detect genes that were dysregulated in all three stratification pools (normal vs Barrett9s in males, normal in males vs females, Barrett9s in males vs females), 5 genes were identified: DAZ1, DAZ2, CCL4, RPS4Y1, USP9Y. The expression of DAZ1 is threefold higher in male Barrett9s and is localised to the Y-chromosome. PCR results suggest the upregulation of cdx-2 and PCNA in Barrett9s metaplasia is greater in males. Conclusion We provide evidence of gender-specific differences in the reflux-Barrett9s pathway. We have identified a novel set of biomarkers in male Barrett9s specimens. Further analysis of these genetic markers through immunohistochemistry and rt-PCR is planned.