Sanjeev Slehria, MD, Prateek Sharma, MD

Disclosures

Curr Opin Gastroenterol. 2003;19(4) 

In This Article

Therapy

Patients with Barrett esophagus have been shown to have persistent abnormal 24-hour pH monitoring results even on twice-daily proton pump inhibitor therapy. These findings were confirmed in 45 patients with LSBE on omeprazole 20 mg twice daily.[24] Ten patients (22%) had an abnormal esophageal pH on twice-daily therapy (median percent total time pH < 4 = 8%); abnormal nocturnal in nine and daytime reflux in four patients. The dose was then titrated based on 24-hour pH results. By increasing the dose of omeprazole to 20 mg three times a day, seven of the 10 had "normalization" of their esophageal pH.

Reducing esophageal exposure to gastric acid has been the cornerstone of modern GERD and Barrett esophagus therapy, with the hope that this treatment may reverse Barrett esophagus and halt malignant progression of Barrett esophagus. Unfortunately, results of both antireflux surgery and medical treatment have been disappointing in this regard. A recent study tested the effect of acid suppression (H2 blockers followed proton pump inhibitors) on the malignant progression in Barrett esophagus and also analyzed key genes involved in DNA repair and cell cycle control, particularly p53.[25] Initial and follow-up biopsies were studied from 21 patients. Patients with p53-positive initial biopsies were more likely to have progression in dysplasia grade (P = 0.022) and DNA ploidy status (P = 0.023) than those with p53-negative biopsies. In eight patients antisecretory therapy resulted in significant reduction in oxidative DNA damage in the five patients with p53-negative, but not the in three patients with p53-positive, initial biopsies (P = 0.0007). Previous studies have shown that control of acid reflux into the esophagus in tissue samples of Barrett esophagus may limit cell proliferation and help cell differentiation as measured by villin expression. To explore the potential mechanism whereby acid reflux may affect these, adenocarcinoma cell lines were exposed to acidic media for 3 minutes and then the activities of three mitogen-activated protein kinase pathways were determined.[26] Acid-exposed cell lines exhibited a significant increase in proliferation and a significant decrease in apoptosis. The acid-induced decrease in apoptosis was abolished by inhibition of either ERK or p38, indicating that acid increases proliferation and decreases apoptosis in adenocarcinoma cell lines acting primarily through the mitogen-activated protein kinase pathways.

Increased cyclooxygenase (COX)-2 expression has been shown in both animal models of inflammation and human inflammatory diseases. COX-2 can be mutagenic and tumorigenic and recent evidence has implicated COX-2 in colorectal, gastric, and esophageal carcinogenesis. However, there has been no direct evidence that inhibition of COX-2 either by aspirin, nonsteroidal anti-inflammatory drugs, or selective COX-2 inhibitors can prevent cancer. This was shown recently in an animal model.[27**] Buttar et al. studied the effect of MF-Tricyclic (a selective COX-2 inhibitor), on the development of Barrett esophagus and adenocarcinoma in a rat model. Four weeks after esophagojejunostomy, 105 Sprague-Dawley rats were randomized to a chow containing MF-Tricyclic, sulindac, or placebo. The animals were assessed for the presence of cancer, tumor volume, Barrett esophagus degree of inflammation, and COX-2 expression and activity after therapy. MF-Tricyclic and sulindac reduced the relative risk of development of esophageal cancer by 55% (95% CI = 43%-66%, P < 0.008) and by 79% (95% CI = 68%-87%, P < 0.001), respectively, compared with controls.

A pilot study also explored the use of COX-2 inhibitors in patients with Barrett esophagus. Biopsy specimens of esophagus, Barrett 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.[28] At baseline, COX-2 expression was threefold higher in Barrett esophagus than esophagus and duodenum (P < 0.05). After rofecoxib therapy, COX-2 expression in Barrett esophagus decreased by 77% (P < 0.005). Similarly at baseline, prostaglandin E2 content was twofold higher in Barrett esophagus than esophagus or duodenum, and after rofecoxib therapy prostaglandin E2 content decreased in Barrett esophagus by 59% (P < 0.005). Use of a selective COX-2 inhibitor can reduce COX-2 expression, prostaglandin E2 release, and cell proliferation in Barrett esophagus. Thus, recent studies in both animals and humans have shown that in combination with acid-suppressive therapy, COX-2 inhibition may be promising against dysplasia and esophageal adenocarcinoma development.

Antireflux surgery can be an option for the treatment of GERD symptoms in patients with Barrett esophagus. The failure rate in patients with Barrett esophagus submitted to classic antireflux surgery, ie, Nissen fundoplication has been noted to be approximately 20%. Dysplasia as well as esophageal adenocarcinoma has been shown to develop in patients with Barrett esophagus after antireflux surgery. Investigators from Chili reported on 161 patients who underwent antireflux surgery.[29] Dysplasia developed in 17 (10.5%) and esophageal adenocarcinoma developed in four (2.5%) even after long-term follow-up; adenocarcinoma developed 6 to 8 years after antireflux surgery. The same group[30] also reported on 210 patients subjected to an operation consisting of "acid suppression" (vagotomy-partial gastrectomy) and "duodenal diversion" (Roux-en-Y anastomosis). One hundred forty-two patients underwent a primary operation and 62 a revision surgery. Clinical, radiologic, endoscopic, histologic, and manometric studies were done in the patients. One hundred forty-six patients completed the late follow-up with a mean of 58 months. In patients in whom duodenal operation was a primary operation, 96.7% had none or mild clinical symptoms and during follow-up no patients exhibited dysplasia or adenocarcinoma. This led the authors to speculate that the "suppression diversion" operation completely abolished the injurious components of the refluxate and improved sphincter competence.

Because cancer risk increases with the histologic finding of HGD, some experts advocate the necessity to eradicate HGD, either by esophagectomy or endoscopic therapy. Esophagectomy can be associated with a high mortality and morbidity and endoscopic treatment including mucosectomy or photodynamic therapy are an attractive alternative in this setting, provided that an approach with a low complication rate is chosen. Local endoscopic treatment represents an alternative to esophageal resection in the case of intraepithelial high-grade neoplasia and selected early adenocarcinomas in Barrett esophagus.

In a prospective observational study, 28 patients were treated with endoscopic mucosal resection (EMR), 13 with photodynamic therapy, and three with argon plasma coagulation; six patients received combinations of these treatments.[31*] Complete local remission was achieved in 48 of 49 patients (98%). One patient had to undergo surgery after the first EMR secondary to submucosal tumor infiltration, and treatment was deemed a failure in one patient. A mean of 1.7 ± 1.4 treatment sessions was required for local endoscopic treatment with no associated mortality. During a mean follow-up period of 34 ± 10 months, metachronus intraepithelial high-grade neoplasms or early adenocarcinoma were seen in 11 of 48 patients (23%), who received further successful treatment. One case of bleeding and two stenoses after several EMR procedures were reported and complications were successfully treated endoscopically. Endoscopic therapy can lead to a high local treatment rate but given the detection of metachronus lesions during follow-up, surveillance of these patients is mandatory. Another modality for these patients has been the use of different lasers. In 14 patients with HGD/early adenocarcinoma, treated by Nd:YAG laser, 11 patients achieved complete endoscopic and histologic reversal.[32] The major complications included an esophageal stricture and upper gastrointestinal bleeding.

How important is acid suppression in patients undergoing ablation therapy? In a long-term follow-up of 39 patients with Barrett esophagus who had undergone treatment with argon plasma coagulation and who had received 40 mg of omeprazole daily,[33*] patients were then randomly assigned to receive 20 or 40 mg of omeprazole daily. At the end of a median follow-up of 36 months (range, 12-48 months), complete reversal of Barrett esophagus (ie, endoscopic and histologic reversal of metaplasia) was achieved in 62% of the patients. By multivariate analysis, presence of SSBE and normalization of pH with proton pump inhibitors were the only independent predictors of long-term reversal. These findings were echoed in a study from the United Kingdom in which 50 patients with Barrett esophagus were also treated with argon plasma coagulation.[34] At the end of 1 year, recurrence of Barrett was seen in most of the patients (68%) and was associated with the presence of LSBE and reduction in the dose of proton pump inhibitor. In contrast, in a study of 20 patients who underwent ablation therapy with electrocautery, Barrett esophagus could be completely reversed despite abnormal esophageal acid exposure.[35] Thus the exact role of acid-suppressive therapy in patients undergoing reversal is controversial but it appears to be important for long-term "maintenance" of the neosquamous mucosa.

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