Chemoprevention of Barrett’s Esophagus and Adenocarcinoma

14.1 Introduction

Barrett’s esophagus (BE) is an acquired condition in which a metaplastic columnar epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus . Metaplasia commonly is a consequence of chronic inflammation, and intestinal metaplasia results from chronic reflux esophagitis caused by the gastroesophageal reflux of acid, bile, and other hazardous substances .

Approximately 5% of adult population in the United States is affected by BE . Esophageal adenocarcinoma (EAC) is strongly associated with BE and it has become increasingly common in developed countries over the last four decades. While the incidences of most malignancies are decreasing, incidence of EAC is increasing. Based on currently available data, the annual incidence of adenocarcinoma secondary to BE is estimated to range from 0.3% to 0.5% and the prognosis of EAC remains extremely poor, with a 5-year survival rates ranging from 15% to 39% . The lifetime risk of EAC in patients with BE was estimated as 10- to 125-fold higher than general population .

The most important risk factor for development of EAC is BE, and surveillance and early recognition of high-grade dysplasia (HGD) and/or EAC may improve survival .

Regular endoscopic surveillance is one of the mainstays in the management of BE . The aim of surveillance is to identify patients at a preclinical or asymptomatic early stage of cancer and initiate therapy leading to improved long-term outcomes. However, it is unclear whether only endoscopic surveillance leads to reduced mortality from EAC in patients with BE . Also, endoscopic surveillance of all patients with BE is expensive and more cost-effective methods are needed . Therefore, current strategies for improved management of EAC target identifying patients at high risk for progression to EAC and identifying chemopreventive agents. In light of the poor outcomes associated with EAC, combined with the presence of a readily identifiable precursor lesion, BE represents an attractive target for chemoprevention.

Chemoprevention refers to the use of chemical compounds to prevent the development and progression of dysplasia, as well as blocking the invasion of dysplastic epithelial cells throughout the basement membrane.

In contrast to the traditional therapeutic paradigms in EAC, chemoprevention is intended for generally healthy individuals. Therefore, several factors need to be considered prior to decision making. These factors include degree of dysplasia in BE, existing comorbidities, patient preferences, and local expertise. The risk of developing EAC increases progressively from 0.12% to 0.33% per year in nondysplastic to up to 20% chance of cancer per year in high-grade dysplastic BE . Thus, if the patient is relatively healthy with a low risk of progression, it is reasonable to use chemopreventive agents that have been considered safe for use. In this patient population, even a moderate reduction in cancer risk would translate into significant public health benefit as most patients with BE fall under this category. However, patients with preexisting HGD have a relatively higher risk of undergoing neoplastic transformation or a high probability that they may already have developed early EAC. In this patient group, it is important to use more effective chemopreventive treatment even if it carries a higher risk of adverse effects.

In this chapter, we will define suggested targets for chemoprevention of BE and review data about specific chemoprevention agents.

14.2 Suggested Targets and Strategies for Chemoprevention to Prevent or Slow Malignant Transformation of Barrett’s Esophagus

14.2.1 Gastric Acid and Bile Reflux

It is known that in patients with BE complicated with dysplasia and EAC, gastric acid and duodenal bile reflux are significantly more common than nondysplastic BE and GERD . Despite widespread use of acid-suppressing medications, the incidence of EAC is rising. This suggests that refluxed material other than acid might contribute to carcinogenesis . The controlling of reflux symptoms by medical or surgical (repair of lower esophageal sphincter (LES)) treatment do not prevent development of esophageal cancer . A probable explanation for this lack of efficacy is that despite medical treatment, bile reflux into the esophagus persists in approximately one out of three patients. Furthermore, reflux recurs within years of surgical fundoplication in a significant proportion of patients treated with fundoplication . More recently, in an ex vivo study , it was suggested that the pattern of gastric acid reflux may be an important determinant factor in the neoplastic progression of BE. In this study, it was shown that pulsed acid exposure increased cell proliferation but continuous acid exposure decreased cell proliferation .

In animal studies, it has been shown that the reflux of bilious intestinal juice alone is sufficient to cause esophageal cancer in rats . Studies in humans have shown that patients with BE have significantly more esophageal exposure to bile and significantly higher esophageal luminal concentrations of bile salts than patients who have GERD without BE .

In a study conducted on patients with BE , it was shown that deoxycholic acid (DCA) causes DNA damage and induces phosphorylation of proteins in the nuclear factor kappa B (NF-κB) signaling pathway in Barrett’s epithelial cells in vitro and in vivo. Authors also have reported that DCA-induced DNA damage and NF-κB pathway activation are mediated by the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In addition, it was demonstrated that DCA-mediated activation of the NF-κB pathway allows Barrett’s epithelial cells to resist apoptosis in the setting of DNA injury, events which might contribute to neoplastic progression in BE.

Animal studies have shown that chronic gastric acid and/or bile exposure can lead to dysplasia and EAC. The mechanisms by which reflux causes chronic esophageal damage and induce carcinogenesis in BE are suggested as follows.

14.2.1.1 Chronic Injury and Inflammation

In animal model studies, it has been reported that normal cell volume regulatory mechanisms may be inhibited by gastric acid-induced mucosal injury . Reflux of duodenogastric contents (including bile acids) has been shown to cause esophageal damage in synergy with gastric acid in animal studies . These findings have also been confirmed in human studies . Reflux of bile parallels gastric acid and increases with the severity of GERD (BB). However, bile salts can cause esophageal damage in a wide range of pH. Glycine-conjugated bile salts cause damage in pH between 4 and 6, taurine-conjugated bile salts cause damage when the pH is lower than 4, while, unconjugated bile salts cause damage in neutral or alkaline pH states . Long-term use of PPIs lead to deconjugation of bile salts by bacterial colonization of the proximal intestine . In the alkaline pH state associated with PPI use, unconjugated bile salts cause chronic low-grade inflammation and induce carcinogenesis in BE .

14.2.1.2 Arachidonic Acid Pathway

Arachidonic acid pathway is a central regulator of inflammatory response. Gastric acid and duodenal bile acids may contribute to carcinogenesis in BE through activation of this pathway. Low pH and bile acids induce cyclooxygenase-2 (COX-2), which is a central enzyme of the arachidonic acid pathway both in the human BE ex vivo culture model and the EAC cell lines . Expression of COX-2 increases concomitantly with neoplastic progression in BE and this increase supports an association between the arachidonic acid pathway and the development of EAC . The COX-2 enzyme catalyzes conversion of arachidonic acid to different prostaglandins such as prostaglandin E2 (PGE2). PGE2 induces proliferation of Barret’s epithelial cells and its inhibition may slow their growth . PGE2-induced cell proliferation leads to accumulation of replicative errors in premalignant Barrett’s cells. Furthermore, it inhibits tumor surveillance through natural killer cell activity of PGE2. Chronic induction of PGE2 might facilitate accumulation of abnormal cells that have genomic instability and thus inhibition of components of arachidonic acid pathway probably will inhibit carcinogenesis .

14.2.1.3 Oxidative Stress

Bile acids can stimulate both esophageal squamous and Barrett’s epithelial cells to produce substances which can induce esophageal inflammation (ie, interleukin 8 (IL-8) and COX-2) and bile acids also can lead to oxidative stress and DNA damage in these cells .

Epidemiological, animal, and clinical studies suggest that BE develops as a result of injury induced by two major components of refluxate: gastric acid and bile acids. Bile acids in combination with gastric acid induce oxidative stress, DNA damage, and alterations in cell signaling. Moreover, bile acids may induce the expression of proteins associated with a phenotypic switch from normal squamous to intestinal phenotype such as Klf-4, villin, and CDX2 .

Gastric acid and bile salt injury induce ROS in BE . Moreover, decreased levels of glutation and vitamin C in the epithelium show that the antioxidant defense mechanisms are diminished in patients with BE . Low levels of antioxidant enzymes like glutathione- S -transferase and glutathione have been demonstrated in biopsies obtained from patients with BE and EAC. This change in oxidative tissue state promotes mutagenesis to induce neoplasia .

DNA damage incurred by free radicals causes mutations in key cell survival regulatory genes and induces carcinogenesis . In a normal individual, mutated cells do not further proliferate because they are forced to cell cycle arrest or apoptose by p53 . However, bile salts can inhibit this process via proteasome-mediated degradation of p53 . In conclusion, genetically abnormal cells accumulate and carcinogenesis progresses.

14.2.2 You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here