Barrett's Esophagus: Keeping It at Bay

Randolph V. Fugit, PharmD, BCPS, and Melanie R. Bates, PharmD
Published Online: Friday, May 15, 2009

Dr. Fugit is an internal medicine clinical specialist at the Denver Veterans Affairs Medical Center and a clinical assistant professor, Department of Clinical Pharmacy, at the University of Colorado-Denver Health Sciences Center. Dr. Bates is a PGY-1 pharmacy practice resident at Denver Veterans Affairs Medical Center.


Barrett’s esophagus (BE) is considered a premalignant diagnosis, and when identified through endoscopy, increases the relative risk of developing esophageal adenocarcinoma (EAC) 30- to 125-fold.1-4 This corresponds to an overall yearly risk of approximately 0.5%.5-7 This annual risk, however, has been highly debated.7

Evidence has suggested the most likely cause of BE is continuous exposure, and subsequent injury of, the esophageal squamous epithelium from gastric acid and/or bile in susceptible patients.6 Thus, longstanding (usually >10 years) gastroesophageal reflux disease (GERD) has been considered the primary risk factor for the development of BE.6,8-10 Other suggested risk factors include male sex, Caucasian race, history of smoking, hiatal hernia, increased age, and obesity.11

When considering the symptoms associated with GERD (ie, heartburn and regurgitation), the overall prevalence of GERD in the United States is approximately 45%.12 This number, however, does not take into account the substantial population of patients diagnosed with atypical manifestations of GERD (eg, atypical chest pain, asthma, chronic hoarseness, etc), nor does it completely consider asymptomatic patients. Considering these data, it is easy to understand why up to 12% of patients are identified with the presence of BE upon diagnostic upper endoscopy,6 and of these patients, 25% do not describe having a history of esophageal complaints, such as heartburn or acid regurgitation.13

Progression to Esophageal Adenocarcinoma
The issue of most concern with BE is progression to EAC. The longstanding belief that BE progresses through a well-defined sequence—beginning with the initial presence of nondysplastic specialized intestinal mucosa, continuing to low-grade dysplasia, then high-grade dysplasia, and eventually carcinoma—does not appear always to be the case, nor does it always follow in this stepwise fashion.14 It is now understood that not all patients with BE progress to malignancy, and regression (ie, return of normal squamous epithelium) has been described.14

Endoscopic Screening and Surveillance
Significant controversy exists over the role of endoscopic screening and surveillance in BE.14-16 Less than 10% of patients with GERD are identified with BE upon first endoscopy.6 This, coupled with the fact that the progression to EAC is associated with substantial mortality (5-year survival of approximately 10%), has led many experts to recognize the importance of endoscopic screening of high-risk patients for evidence of BE and surveillance in patients with BE to detect progression. 6,14,15

The goal of early recognition of BE is to facilitate timely and appropriate interventions aimed at reducing the incidence and mortality associated with EAC.14 The current guidelines from the American College of Gastroenterology for surveillance of patients with BE suggest yearly endoscopy with biopsies.17 If 2 consecutive yearly endoscopies demonstrate no dysplasia, the interval between surveillance can be increased to every 3 years. Patients with lowgrade dysplasia should continue to have annual endoscopy, and patients with high-grade dysplasia should have surveillance performed every 3 months, as well as undergo either surgical or endoscopic intervention.17 Unfortunately, very little evidence exists at this time to suggest this surveillance is associated with significant benefits to the patient, and long-term prospective studies are needed.14,16,17

The practicality of surveillance is influenced by cost, sampling error in tissue acquisition during biopsy, and differing pathologic interpretations of samples.16,17 Although preventive pharmacotherapy in those patients at risk is key, a number of patients with GERD will still progress to BE.

Gastric Acid Reduction Therapy
Clinical data suggest gastric acid is an important etiologic factor in the pathogenesis of BE, and thus, it should come as no surprise that the management of patients with BE involves similar principles to the treatment of patients who have reflux without BE. In patients with BE, the goal of pharmacologic gastric acid reduction therapy is to control reflux symptoms.17 Therapy is indicated in all patients with BE who have GERD symptoms or erosive esophagitis.17

Proton pump inhibitors (PPIs) are the mainstay of therapy as they provide superior heartburn relief, prevent stricture formation, and are more effective and quicker at healing esophagitis and esophageal ulcers than histamine 2-receptor antagonists (H2RAs).18 Additional benefits of PPIs include the reduction of esophageal inflammation and the potential promotion of BE regression, whereas H2RAs have not been associated with this regression.6,18 Data from several studies suggest that PPI therapy significantly reduces the likelihood of developing dysplasia, compared with no therapy or H2RA therapy. 19,20 These data provide a rationale for treating even asymptomatic BE patients with a PPI.

Conventional-dose gastric acid reduction therapy with PPIs reduces, but may not eliminate, gastric acid secretion in patients with BE. Twice-daily dosing may be necessary in a subgroup of patients. This aggressive gastric acid reduction therapy can cause partial regression of the specialized intestinal metaplasia in BE, and most patients treated with PPIs develop islands of squamous epithelium within their metaplastic columnar lining.21,22 The caveat to these early data suggests that only with complete acid suppression (intraesophageal pH of <4), is this theoretical benefit obtained.6 Recent evidence suggests that up to 80% of patients who are rendered asymptomatic with PPI therapy, and are then monitored with 24-hour esophageal pH testing, continue to have abnormal esophageal acid exposure, especially at night.23 It is not clear that this apparent regression demonstrated with PPIs is beneficial or associated with a reduction in cancer, as some studies have confirmed the presence of underlying intestinal metaplasia when the squamous epithelium is biopsied.6

Little clinical evidence exists to support the notion that PPIs prevent the occurrence of EAC or lead to the regression of BE. Currently, only indirect evidence is available to support this. Nonetheless, some recent studies have demonstrated that brief esophageal acid exposure activates the mitogen‑activated protein kinase (MAPK) pathways that can increase proliferation and decrease apoptosis in BE. This suggests that pulsatile esophageal acid exposure typical of GERD might stimulate hyperproliferation, suppress apoptosis, and promote carcinogenesis in BE. Thus, these data indirectly support the use of PPIs to reduce the risk of EAC by reducing esophageal acid exposure.24,25

Secondary Prevention of EAC
Epidemiologic studies have shown a significant risk reduction in the development of EAC in aspirin and nonsteroidal anti-inflammatory drug (NSAID) users. Specialized intestinal metaplasia of BE exhibits increased expression of cyclooxygenase (COX)-2,26 whereas inhibition of COX-2 has been shown to have antiproliferative and proapoptotic effects in Barrett’s‑associated EAC cell lines.27

Surgical and Endoscopic Interventions
Numerous surgical and endoscopic procedures have been developed for the treatment of advanced dysplasia and EAC. Antireflux surgery (eg, Nissen fundoplication) has been suggested for patients with BE; however, evidence has not demonstrated a significant reduction with regard to risk of developing malignancy when compared with antisecretory pharmacotherapy (ie, H2RAs and PPIs).28

Esophagectomy, the most invasive of surgical procedures, has remained the standard of practice for decades for invasive carcinomas. This procedure includes significant risks, however, including a complication rate of 57% and morbidity and mortality rates of 30% and up to 5%, respectively.29 These risks have led to the development of endoscopically performed treatments with the hope of producing similar outcomes without the requirement of such invasive surgeries. Endoscopic ablative techniques include multipolar electrocautery, photodynamic therapy, argon plasma coagulation, radiofrequency ablation, endoscopic mucosal resection, and cryoablative therapy. Each of these ablative procedures have demonstrated endoscopic and histologic reversal of BE in some patient populations, however few data exist to determine efficacy in prevention of progression to EAC.30

Conclusion
Considering the increased risk of EAC among patients with BE, it is imperative to identify both surveillance and management strategies to reduce the incidence of this potentially lethal diagnosis. Clinicians need to be aware, however, of the significant paucity of data regarding significant benefit from current therapeutic options. A review of the most recent clinical data recommends that appropriate pharmacotherapy for patients with BE should be a PPI dosed once to twice daily. These data suggest the benefits of gastric acid suppression include heartburn relief, prevention of stricture formation, effective and quick healing of esophagitis, a likely reduction in the development of dysplasia, and possibly delaying or preventing the development of EAC.17 In addition, recent data suggest a potential future role for aspirin, NSAIDs, or COX-2 inhibitors for secondary prevention of EAC.

References

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