Medical decision analysis of chemoprevention against esophageal adenocarcinoma

BACKGROUND & AIMS: Chemoprevention of esophageal adenocarcinoma using nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of cancer in patients with Barrett's esophagus. The aim of the study was to assess the cost-effectiveness of this strategy. METHODS: The incremental cost-effectiveness ratio (ICER) of chemoprevention (compared with endoscopic surveillance or with no surveillance) was analyzed with a computer model of a Markov process. RESULTS: Under baseline conditions for all patients with Barrett's esophagus (neoplastic and nonneoplastic), the ICER of chemoprevention ranges between $12,700 and $18,500 US dollars per life-year saved. However, these cost values are sensitive to variations in the costs of chemoprevention, incidence of cancer in patients with Barrett's esophagus, and efficacy of NSAIDs in reducing the incidence of cancer, which can shift the ICER into a cost range that is prohibitively expensive. Conversely, in those patients with Barrett's esophagus and high-grade dysplasia, the ICER ranges between $3900 and $5000 US dollars. Chemoprevention remains a cost-effective option even under rather unfavorable conditions, such as higher cost and lower efficacy of chemoprevention and lower incidence of cancer. CONCLUSIONS: This model suggests that a high incidence of esophageal adenocarcinoma in high-grade dysplasia renders chemoprevention cost-effective even in the presence of less-favorable conditions. However, chemoprevention may not be a cost-effective measure in the general population of all patients with Barrett's esophagus, depending on unknown factors such as cost and efficacy of chemoprevention as well as true incidence of cancer.     

Barrett's esophagus

Barrett's esophagus is an acquired condition resulting from severe esophageal mucosal injury. It still remains unclear why some patients with gastroesophageal reflux disease develop Barrett's esophagus whereas others do not. The diagnosis of Barrett's esophagus is established if the squamocolumnar junction is displaced proximal to the gastroesophageal junction and if intestinal metaplasia is detected by biopsy. Despite this seemingly simple definition, diagnostic inconsistencies remain a problem, especially in distinguishing short segment Barrett's esophagus from intestinal metaplasia of the gastric cardia. Barrett's esophagus would be of little importance were it not for its well-recognized association with adenocarcinoma of the esophagus. The incidence of esophageal adenocarcinoma continues to increase and the 5-year survival rate for this cancer remains dismal. However, cancer risk for a given patient with Barrett's esophagus is lower than previously estimated. Current strategies for improved survival in patients with esophageal adenocarcinoma focus on cancer detection at an early and potentially curable stage. This can be accomplished either by screening more patients for Barrett's esophagus or with endoscopic surveillance of patients with known Barrett's esophagus. Current screening and surveillance strategies are inherently expensive and inefficient. New techniques to improve the efficiency of cancer surveillance are evolving rapidly and hold the promise to change clinical practice in the future. Treatment options include aggressive acid suppression, antireflux surgery, chemoprevention, and ablation therapy, but there is still no clear consensus on the optimal treatment for these patients.     

The evidence base of proton pump inhibitor chemopreventative agents in Barrett's esophagus--the good, the bad, and the flawed!

Gastric acid is believed to be an important etiological factor in the pathogenesis of Barrett's esophagus. Pulsatile acid exposure increases cell proliferation in ex vivo Barrrett's tissue and normalization of esophageal pH reverses this. Proton pump inhibitors (PPIs) are the mainstay of therapy in Barrett's esophagus, and have numerous beneficial effects including symptom control, reduction of inflammation, and promotion of the development of squamous islands. However, PPI therapy causes hypergastrinemia and has not prevented recent increase in the incidences of esophageal cancer. Additionally, evidence presented here by Feagins et al. suggests that acid exposure has a p53-mediated, antiproliferative effect on a nondysplastic Barrett's epithelial cell line, an effect that acid suppression might abrogate. These complex pH, inflammation, and growth factor biological interactions can be most reliably tested in large clinical trials with hard end points like cancer conversion or all causes of mortality. Combining the anti-inflammatory effects of acid suppression with aspirin, a nonsteroidal anti-inflammatory agent, is the subject of the AspECT clinical trial, and this may be the future of chemoprevention in Barrett's.     

Advances in Barrett's esophagus and esophageal adenocarcinoma

Despite advances in diagnosis and therapy, esophageal adenocarcinoma remains an aggressive and usually lethal tumor. This review focuses on the epidemiology of esophageal adenocarcinoma and its presumed precursor lesion, Barrett's esophagus; the pathogenesis of the cancer; advances in treatment of adenocarcinoma and Barrett's esophagus; and strategies for cancer prevention. Emphasis is placed on recent literature. Although the absolute number of cases of adenocarcinoma in the United States is still small, the incidence of this cancer has increased dramatically in the last 40 years, and adenocarcinoma is now the predominant form of esophageal cancer in this country. Recent evidence suggests that Barrett's esophagus is more prevalent in asymptomatic individuals than previously appreciated. The pathogenesis of Barrett's esophagus is poorly understood. Given that some subjects will have repeated bouts of severe erosive esophagitis and never develop Barrett's esophagus, host factors must play an important role. The utility of neoadjuvant radiation and chemotherapy in those with adenocarcinoma, although they are widely practiced, is not of clear benefit, and some authorities recommend against it. Ablative therapies, as well as endoscopic mucosal resection, hold promise for those with superficial cancer or high-grade dysplasia. Most series using these modalities feature relatively short follow-up, and longer-term data will be necessary to better describe the effects of these therapies. The value of chemoprevention in subjects with dysplastic Barrett's esophagus by use of cyclooxygenase 2 inhibitors, nonsteroidal anti-inflammatory drugs, or proton pump inhibitors is unknown. Similarly, although endoscopic screening is widely practiced, its value in patients with chronic gastroesophageal reflux disease symptoms is of unproven value, and recommending bodies are divided as to its practice.     

Chemoprevention for Barrett''s Esophagus Trial. Design and outcome measures

Barrett's esophagus is a premalignant condition in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. It is a known risk factor for the development of esophageal adenocarcinoma. With the incidence of esophageal adenocarcinoma rising, it is reasonable to study Barrett's esophagus as a potential target for therapy that may prevent, delay and/or reverse ongoing tumorigenic processes. Epidemiologic and animal studies support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the chemoprevention of several cancers, including esophageal cancer. Cyclo-oxygenase-2 (COX-2) inhibitors are a new class of NSAIDs that inhibit prostaglandin synthesis by selectively blocking the COX-2 enzyme. The COX-2 enzyme has been reported to be over-expressed in premalignant and malignant states, including in Barrett's esophagus and esophageal adenocarcinoma. The Chemoprevention for Barrett's Esophagus Trial (CBET) is a phase IIb, multicenter, randomized, double-masked, placebo-controlled study of the selective COX-2 inhibitor, celecoxib, in patients with Barrett's dysplasia. The sample size is 200 patients with high or low grade Barrett's dysplasia. Celecoxib is administered orally, 200 mg twice per day; the dosing schedule for placebo is the same. Randomization is stratified by dysplasia grade and by clinic. Endoscopy with biopsies is performed at specified time intervals according to the highest grade of dysplasia determined at randomization. The primary outcome measure is the change from baseline to 1 year in the proportion of biopsies exhibiting dysplasia. Secondary outcomes include change from baseline in the maximal grade, extent and surface area of dysplasia. Tertiary outcomes will include measurements of various relevant biomarkers.     

Barrett's-related esophageal adenocarcinoma: is chemoprevention a potential option?

OBJECTIVE: Review the rationale behind secondary prevention of Barrett's related esophageal adenocarcinoma and critically appraise the emerging literature regarding prevention of neoplasia in Barrett's esophagus with antisecretory and/or cyclo-oxygenase inhibition therapy. METHODS: The existing English language literature regarding secondary cancer prevention in patients with Barrett's esophagus is reviewed and its potential clinical implications discussed. RESULTS: There is biologic plausibility to pursue "chemoprevention" trials with antisecretory and/or cyclo-oxygenase inhibition therapy in patients with Barrett's esophagus. CONCLUSION: Chemoprevention trials using potent antisecretory therapy coupled with cyclo-oxygenase 2 inhibition are warranted and may provide a means of decreasing the occurrence of cancer and cancer-related mortality in this disease.     

Barrett's esophagus and risk of esophageal adenocarcinoma

Barrett's esophagus is most often seen in white men with chronic heartburn who are generally older than 50 years of age. The prevalence of Barrett's esophagus is 10% to 15% in patients who are undergoing endosocopy for gastroesophageal reflux disease and 1% to 2% in asymptomatic American adults. Barrett's esophagus represents metaplastic columnar tissue with specialized intestinal metaplasia, and this condition carries an increased risk of esophageal adenocarcinoma. Patients with Barrett's esophagus have a risk of esophageal adenocarcinoma 30 to 60 times that of the general population with an incidence rate of over 100 times that of the general population. Esophageal adenocarcinoma has increased dramatically over the past few decades with specialized intestinal metaplasia being the most important risk factor for the development of dysplasia and cancer. Barrett's esophagus develops in the presence of persistent gastroesophageal reflux, which is an independent risk factor for adenocarcinoma. Other risk factors for adenocarcinoma in patients with Barrett's esophagus include length of Barrett's epithelium, low-grade dysplasia, and high-grade dysplasia. New data concerning the pathophysiology and biology of Barrett's epithelium may provide answers to prevent or treat esophageal cancer. This article briefly reviews Barrett's esophagus and focuses on the risk factors associated with its progression to adenocarcinoma.     

Natural history of Barrett's esophagus

The natural history of Barrett's esophagus (BE) is difficult to quantify because, by definition, it should describe the course of the condition if left untreated. Pragmatically, we assume that patients with BE will receive symptomatic treatment with acid suppression, usually a proton pump inhibitor, to treat their heartburn. This paper describes the development of complications of stricture, ulcer, dysplasia and adenocarcinoma from this standpoint. Controversies over the definition of BE and its implications in clinical practice are presented. The presence of intestinal metaplasia and its relevance to cancer risk is discussed, and the need to measure the extent of the Barrett's epithelium (long and short segments) using the Prague guidelines is emphasized. Guidelines and international consensus over the diagnosis and management of BE are being regularly updated. The need for expert consensus is important due to the lack of randomized trials in this area. After searching the literature, we have tried to collate the important studies regarding progression of Barrett's to dysplasia and adenocarcinoma. No therapeutic studies yet reported show a clear reduction in the development of cancer in BE. The effect of pharmacological and surgical intervention on the natural history of Barrett's is a subject of ongoing research, including the Barrett's Oesophagus Surveillance Study and the aspirin and esomeprazole cancer chemoprevention trial with interesting results. The geographical variation and the wide range of outcomes highlight the difficulty of providing an individualized risk profile to patients with BE. Future studies on the interaction of genome wide abnormalities in Barrett's and their interaction with environmental factors may allow individualization of the risk of cancer developing in BE.     

Barrett''s esophagus: combined treatment using argon plasma coagulation and laparoscopic antireflux surgery

The treatment of Barrett's esophagus is still controversial. Actually, the only method to prevent the development to cancer is endoscopic surveillance, which ensures good results in terms of long-term survival. An ideal treatment capable of destroying columnar metaplasia, followed by squamous epithelium regeneration could potentially result in a decrease of the incidence of adenocarcinoma. Recently most ablative techniques were used, such as photodynamic therapy, ablation therapy with Nd-YAG laser or argon plasma coagulation and endoscopic mucosal resection. We started a prospective study in January 1998, enrolling 94 patients affected by Barrett's esophagus and candidates for antireflux repair in order to assess the effectiveness and the results of endoscopic coagulation with argon plasma combined with surgery in the treatment of uncomplicated Barrett's esophagus. All patients underwent endoscopic treatment with argon plasma; we observed complete response in 68 patients (72.34%), 27 of them (39.7%) underwent antireflux surgery and the other 41 continued medical therapy. Post-operatively 19 patients (70%) underwent regular surveillance endoscopies and in two cases metaplasia recurred. The final objective of these combined treatments should be the complete eradication of metaplastic mucosa. Our experience was that argon plasma coagulation combined with antireflux surgery or proton pump inhibitor therapy gave satisfactory results, even if follow-up is too short to evaluate the potential evolution of metaplasia to cancer. For this reason, we recommend that this technique should be done only in specialized centres and that these patients continue their endoscopic surveillance program.     

Patient Preferences for the Chemoprevention of Colorectal Cancer

Although evidence suggests that aspirin and celecoxib may reduce the risk of colorectal cancer (CRC), these drugs can also cause harmful side effects. The aim of this study was to characterize patient preferences for celecoxib and aspirin. Participants completed a computer-based patient decision-making questionnaire that included an educational component outlining the benefits and harms of celecoxib and aspirin. Under the base conditions 7.4% would take celecoxib and 43.6% would take aspirin; males were more willing than females to take aspirin. Patients identified the increased risk of myocardial infarction and gastrointestinal events as the primary reasons for their unwillingness to take celecoxib and aspirin, respectively. A majority of subjects would not take either drug, after considering their benefits and harms, although participants were almost six times more likely to take aspirin than celecoxib. These data serve to inform physicians and researchers regarding the variability and factors that affect patient preferences for CRC chemoprevention.     

Barrett's esophagus-is it bad for your health?

Barrett's esophagus is a clearly recognized risk factor for the development of esophageal adenocarcinoma. Despite the rapidly increasing incidence rate of esophageal adenocarcinoma, the vast majority of patients with Barrett's esophagus will never go on to develop this cancer. Furthermore, esophageal adenocarcinoma is a rare cause of death in Barrett's esophagus patients, and most of these patients die from other causes. While some studies demonstrate that the overall survival of patients with Barrett's esophagus is no different than that of the general population, others have suggested that Barrett's esophagus may be associated with increased mortality. Work by Solaymani-Dodran et al., in the current issue of the American Journal of Gastroenterology, found that all cause mortality was increased by 37% and mortality from causes other than esophageal cancer was increased by 23% compared to the general population, differences that were eliminated when adjusted for ischemic heart disease. Findings such as these point out the need for large, well-done epidemiologic studies of Barrett's esophagus cohorts in order to develop a better understanding of the natural history of this disease.     

A Systematic Review of the Association between Barrett's Esophagus and Colon Neoplasms

Objective: Patients with Barrett's esophagus may be at increased risk of colon neoplasms, including cancer. However, different studies of this have yielded conflicting results. The objective of this analysis was to review all existing published data in an attempt to determine whether there is such an association and, if so, to estimate the level of risk.
Methods: We have reviewed all of the published studies examining the prevalence of colon neoplasms in patients with Barrett's esophagus. We have compared these with a cohort of patients drawn from the general population and participating in colorectal cancer screening programs.
Results: The prevalence of colon cancer in patients with Barrett's esophagus was 7.6% compared with 1.6% in the control group. The pooled odds ratio for colon cancer in Barrett's esophagus was 5.19 ( p < 0.0001). In a small subgroup analysis, the odds ratio for colon cancer in patients identified as having Barrett's esophagus with specialized columnar epithelium was 8.71 ( p < 0.0001).
Conclusions: We conclude that patients with Barrett's esophagus have an increased risk of colon cancer. This may be particularly true in those patients with specialized columnar epithelium.     

Rofecoxib inhibits cyclooxygenase 2 expression and activity and reduces cell proliferation in Barrett's esophagus

BACKGROUND & AIMS: Cyclooxygenase 2 (COX-2) is overexpressed in Barrett's esophagus and adenocarcinoma and up-regulated by acid or bile salt exposure. COX-2 inhibition with the selective inhibitor rofecoxib may be important in chemoprevention of esophageal adenocarcinoma by decreasing cell proliferation. METHODS: Biopsy specimens of esophagus, Barrett's esophagus, and duodenum were obtained at baseline from 12 patients and were compared with biopsy specimens obtained after 10 days of therapy with rofecoxib 25 mg orally daily. All patients were maintained asymptomatic on their proton pump inhibitor therapy throughout the study. COX-2 expression, proliferating cell nuclear antigen (PCNA) expression (proliferation marker), and prostaglandin E2 (PGE2) biopsy content (marker of COX activity) were assessed by immunoblotting and enzyme immunoabsorbence assays. RESULTS: At baseline, COX-2 expression was 3-fold higher in Barrett's esophagus than esophagus and duodenum (P < 0.05). After rofecoxib therapy, COX-2 expression in Barrett's esophagus decreased by 77% (P < 0.005). Similarly at baseline, PGE2 content was 2-fold higher in Barrett's esophagus than esophagus or duodenum. After rofecoxib therapy, PGE2 content decreased in Barrett's esophagus by 59% (P < 0.005). At baseline, PCNA expression was also 2-fold higher in Barrett's esophagus than squamous esophagus and duodenum (P < 0.005). After rofecoxib therapy, PCNA expression in Barrett's esophagus decreased by 62.5% (P < 0.005). CONCLUSIONS: Rofecoxib 25 mg orally once daily reduces COX-2 expression, PGE2 release, and cell proliferation in Barrett's esophagus. Together with acid suppressive therapy, rofecoxib may be a promising chemoprevention agent against dysplasia and esophageal adenocarcinoma.     

Screening for Barrett's esophagus

Screening and surveillance for Barrett's esophagus have been proposed as strategies for preventing deaths from esophageal adenocarcinoma. A meaningful discussion on the cost efficacy of screening and surveillance for Barrett's esophagus requires a reasonable estimate of the risk of esophageal cancer in this condition. The primary goal of endoscopic screening for individuals with gastroesophageal reflux disease is to identify patients with Barrett's esophagus who will benefit from an intervention to prevent cancer. There is also indirect evidence to suggest that surveillance for Barrett's esophagus may be beneficial. However, there is much debate over the efficacy of these diagnostic procedures. In the absence of definitive data, investigators have used computer models to study the cost effectiveness of screening and surveillance for Barrett's esophagus. It is important for physicians to recognize that such models do not provide a single, definitive answer.     

Controversies in Barrett's esophagus: management of high grade dysplasia

Barrett's esophagus is the premalignant lesion for adenocarcinoma of the esophagus and the esophagogastric junction. The incidence of esophageal adenocarcinoma has been rapidly rising in the Western world over the last two decades, and Barrett's esophagus is the only known premalignant lesion for this cancer. Esophageal adenocarcinoma develops through the metaplasia-dysplasia sequence with progression from no dysplasia, low grade dysplasia, high grade dysplasia, and ultimately to esophageal adenocarcinoma. The diagnosis and management of high grade dysplasia (HGD) in patients with Barrett's esophagus is extremely controversial. Patients with HGD within Barrett's esophagus are at the highest risk for development of esophageal adenocarcinoma if concurrent adenocarcinoma doesn't already exist. Given the high likelihood of metastatic disease and poor prognosis associated with invasive cancer, detection of HGD within Barrett's esophagus is considered by many as the final endpoint requiring definitive therapy in the form of surgical resection. However, other limited data seem to suggest that a number of patients with HGD may actually regress or persist and not develop cancer, thus suggesting a less aggressive approach for management. Finally with the advent of local endoscopic therapy, reversal therapy is being studied in patients with HGD and may be validated for this major indication. Currently, surgery remains the goal standard and the most definitive therapy for HGD. This articles critically reviews the risks and benefits associated with each approach of managing HGD.     

The Cost of Surveillance for Adenocarcinoma Complicating Barrett''s Esophagus

A review of endoscopic records at the Cleveland Clinic Foundation over a 7-yr period yielded 72 cases of Barrett's esophagus. Ten patients had adenocarcinoma at the time of diagnosis of Barrett's esophagus (14%). Sixty-two were followed for a mean of 31 months (range 2-154 months). During this follow-up period, cancer developed in one patient, an incidence of one cancer per 166 patient yr and an annual incidence of 0.6%. Males predominated in the group with both Barrett's esophagus (55 of 72) and adenocarcinoma (10 of 11). Symptoms were similar in those with simple Barrett's esophagus and those complicated by cancer. Our findings on incidence of cancer in Barrett's was applied to a model surveillance program. The cost of yearly endoscopic surveillance is estimated to be +62,000 and 78 lost work days to discover one cancer during the follow-up period. An endoscopic surveillance program requiring every-other-year studies appears justified and would cost only half as much, annually.     

Screening for esophageal adenocarcinoma: an evidence-based approach

Adenocarcinoma of the esophagus and the gastroesophageal junction is the twentieth most common malignancy in the United States. In developed countries, the incidence of esophageal adenocarcinoma is increasing 5% to 10% per year. Despite the use of endoscopy for earlier detection, mortality from esophageal adenocarcinoma has not declined.Using an evidence-based approach, we review screening methods for esophageal adenocarcinoma, including the use of a symptom questionnaire, identification of patients with a family history of Barrett's esophagus, peroral or transnasal endoscopy, barium swallow, fecal occult blood testing, and brush and balloon cytology. Screening has not been shown to reduce rate of progression of Barrett's esophagus to esophageal cancer. Many treatment options for dysplastic Barrett's esophagus or early carcinoma appear effective, but long-term follow-up data are not available. There is currently insufficient evidence supporting population-based screening for Barrett's esophagus. Several risk factors, including severe reflux symptoms, male sex, and obesity, may identify patients with gastroesophageal reflux disease who are at the greatest risk of the development of cancer.     

EUS followed by EMR for staging of high-grade dysplasia and early cancer in Barrett's esophagus

BACKGROUND: Accurate staging of high-grade dysplasia and of early cancer in Barrett's esophagus is important in the selection of patients for endoscopic therapy. METHODS: Patients with Barrett's esophagus and biopsy specimen proven high-grade dysplasia and adenocarcinoma in focal nodular lesions or in endoscopically unapparent flat lesions in short-segment Barrett's esophagus were initially staged with EUS. In patients with disease limited to the mucosa on EUS, cap-assisted EMR was performed. The depth of tumor invasion on EMR specimens was classified in a similar manner to squamous-cell cancer of the esophagus: m1 (epithelial layer, dysplasia), m2 (lamina propria invasion), m3 (muscularis mucosae invasion), sm (submucosal invasion). RESULTS: EUS was performed in 48 consecutive patients (27 with focal nodular lesions and 21 with microscopic lesions), and submucosal invasion was diagnosed in 8 (confirmed in 7/8 at surgery). EMR was carried out in the remaining 40 patients without significant complications. In the 25 patients with high-grade dysplasia on prior biopsy specimens, EMR confirmed m1 disease in 19; whereas in 6 (24%), invasive adenocarcinoma was detected (to m2 in 4; to m3 in 2). In the 15 patients with invasive cancer on prior biopsy specimens and staged as intramucosal cancer on EUS, intramucosal carcinoma was confirmed in 9 (m2 in 3; m3 in 6); whereas, in 6 patients (40%), submucosal invasion was found. Overall, EUS provided accurate staging in 41/48 patients (85%) with one patient overstaged and 6 patients understaged compared with pathologic staging obtained by surgery or EMR. Of the 34 patients with m1 to m3 staging after EMR, 29 were treated endoscopically and had no evidence of cancer after a mean follow-up of 22.9 months(standard deviation 9.2 months). CONCLUSIONS: EMR provides pathologic staging information that, in addition, may be helpful after EUS if a stage-determined approach is used in the management of high-grade dysplasia and of early cancer in Barrett's esophagus. EMR may be particularly useful for staging of focal nodules or in short-segment Barrett's esophagus with microscopic lesions when endoscopic therapy is an option.     

Present status of photodynamic therapy for high-grade dysplasia in Barrett's esophagus

GOALS: Review recent developments in Barrett's dysplasia including regulatory approval of porfimer sodium photodynamic therapy. BACKGROUND: Barrett's esophagus is thought to be the result of long-standing gastroesophageal reflux disease and is known to be the most important risk factor for the development of esophageal adenocarcinoma. The natural history of Barrett's esophagus is not well known, but the annual incidence of invasive adenocarcinoma is estimated to be 0.5% (reported range, 0.2%-2.0%). This represents an increased risk for esophageal cancer of 30 to 60 times higher than normal subjects. As for colorectal cancer, malignant degeneration is Barrett's esophagus is thought to occur through a continuum of histologic stages: metaplasia, dysplasia and neoplasia. Barrett's high-grade dysplasia (formerly referred to as carcinoma in situ) is the histologic stage of disease that immediately precedes the development of invasive carcinoma. CONCLUSIONS: Previously, Barrett's high-grade dysplasia patients were routinely referred for esophageal resection surgery based upon the assumption of inevitable progression to cancer, the high rate of undiagnosed synchronous cancers, and few treatment alternatives. Important developments in Barrett's high-grade dysplasia include recent publications regarding the natural history of Barrett's high-grade dysplasia and the regulatory approval for endoscopic ablation therapy using porfimer sodium photodynamic therapy (Photofrin PDT).     

Molecular targets for treatment of Barrett''s esophagus

SUMMARY. Esophageal cancer is one of the most deadly forms of gastrointestinal cancer with a mortality rate exceeding 90%. The major risk factors for esophageal adenocarcinoma are gastroesophageal reflux disease (GERD) and its sequela, Barrett's esophagus. GERD commonly leads to esophagitis. In a minority of patients however, ongoing GERD leads to replacement of esophageal squamous mucosa with metaplastic, intestinal-type Barrett's mucosa. In the setting of continued peptic injury, Barrett's mucosa can give rise to esophageal adenocarcinoma. Despite the widespread use of potent acid suppressive therapies for patients with GERD, the incidence of esophageal adenocarcinoma, among white men in the USA, the UK and Europe has continued to rise. Cancers in Barrett's esophagus arise through a sequence of genetic events that endow the cells with six essential physiologic hallmarks of cancer as described by Hanahan and Weinberg in 2000. These cancer hallmarks include the ability to proliferate without exogenous stimulation, to resist growth-inhibitory signals, to avoid triggering the programmed death mechanism (apoptosis), to resist cell senescence, to develop new vascular supplies (angiogenesis), and to invade and metastasize. While the acquisition of these essential attributes is not specific to the neoplastic progression of Barrett's esophagus, this review will focus on the genetic alterations that occur in Barrett's cells that contribute to the acquisition of each of the hallmarks. Moreover, potential diagnostic and therapeutic strategies for Barrett's patients aimed at each of these cancer hallmarks will be reviewed.