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Volume: Barrett's Esophagus
Chapter: Screening and surveillance

Can complete regression of Barrett's mucosa and dysplasia occur under long-term treatment with proton pump inhibitors?

F.T.M. Peters, E.J. Kuipers, E.C. Klinkenberg-Knol (Groningen, Rotterdam)

The treatment of Barrett's esophagus is aimed at several different targets which include symptom relief, healing of esophagitis, and ultimately prevention of long-term complications such as peptic stenosis. These objectives are nowadays well achieved by medical acid suppression using either H2-blocking agents or preferentially proton pump inhibitors (PPI), and by antireflux surgery. In these aspects Barrett's esophagus is not essentially different from gastroesophageal reflux disease (GERD) in general. However, whether or not profound acid suppressive therapy also has a preventive effect on the longterm complications of Barrett's esophagus, in particular the development of dysplasia and adenocarcinoma is still under debate. The risk for esophageal adenocarcinoma in Barrett patients correlates with the severity of GERD, the length of the Barrett segment, and the local presence of dysplastic intestinal metaplasia (IM). This cancer risk might therefore be decreased by reduction of the length of the Barrett segment, preferentially leading to complete reversion of the metaplasia into normal squamous epithelium, or by decreasing the precancerous character with retention of metaplasia. As Barrett metaplasia results from chronic gastroesophageal reflux, Barrett regression can theoretically be obtained by antireflux treatment, either medical or surgical, or by mucosa ablation by e.g. electrocoagulation, argon plasma coagulation, laser therapy and photodynamic therapy. We will focus on the use of PPI for the prevention of neoplastic complications.

Barrett's metaplasia results from chronic exposure of the (distal) esophagus to gastric acid. For the prevention of such exposure, profound acid suppression is necessary [1-4]. Therapy with PPI also reduces the duodeno-gastroesophageal reflux and hence the exposure to bile acids [5]. The ideal endpoint for studies into the preventive effect of acid suppression with PPIs would be an objectified decrease in the incidence of esophageal adenocarcinoma, and an increase in the length of survival of patients with Barrett's esophagus [6, 7]. Such a prospective study would, however, hardly be feasible because of the required sample size [8], and thus no such prospective randomized research data on this prophylactic treatment with the absence or presence of adenocarcinoma as study endpoint are available. Therefore any conclusions are based on "surrogate" markers like regression of Barrett's metaplasia, regression of dysplasia, and normalization or improvement of biomarkers suggested to correlate with cancer risk. Several case studies into the effect of PPIs on Barrett mucosa initially described regression of the metaplastic tissue [9, 10]. These reports led to further studies using varying doses of PPIs for a more profound suppression of acid secretion and better reduction of acid reflux. These studies initially had a single arm open design [11-16], and were both retrospective and prospective. Randomized prospective studies remained rare [2, 17, 18]. More recently several papers were published with results of combined treatments, i.e. mucosal ablation with concomitant PPI therapy, both for treatment of IM and for (early) adenocarcinoma [19-25]. Only a few studies however checked by ambulatory 24 hour pH-metry whether or not acid suppression in their patients led to normalization of acid reflux. From these studies, it appeared that high PPI doses are necessary to achieve normalization of acid reflux, and that symptom relief is unreliable as measure for normalization. Under such circumstances endoscopic improvement was observed, but remained in most cases restricted to an increase in the number of islands of squamous epithelium, without sub-total regression of the Barrett segment [11-13, 15]. Nevertheless, statistically significant regression was observed after long-term treatment during 1 year [14], 2 years [2, 11], and 5 years [16]; although the last study showed a lack of further regression in the second half of the follow-up period. Complete regression of metaplastic tissue was rare. In a large study of reflux esophagitis patients treated with omeprazole maintenance and followed for a mean 6.5 years (range 1.4-11.2 years), neither regression nor progression of pre-existent Barrett's esophagus was observed [26]. However, new cases of Barrett's esophagus were diagnosed during followup. The conclusion must be that long-term normalization of acid reflux probably results in no more than a partial regression of metaplastic epithelium.

The question then is whether profound acid suppression can bring about changes for the better in the retained metaplastic epithelium. Several markers have been studied in this respect. First of all, epithelial cell proliferation, which correlates with dysplasia [27, 28], decreases during near-elimination of acid reflux [29, 30]. Villin, a marker of differentiation, is more strongly expressed after acid reflux normalization and moreover inversely proportional to proliferation rate [29]. Another marker of improvement is the reduction in sulphomucin-producing mucosa [16]. On the other hand studies in reversed Barrett's epithelium have shown that, in addition to the endoscopic difference, there is also a difference in biomarker expression between complete and partial reversal. The squamous epithelium in partially reversed Barrett's esophagus, treated with omeprazole only, differs from completely reversed epithelium (by multipolar electrocoagulation ablation with concomitant omeprazole): in case of partial reversal in more than half the patients epithelial proliferation was not confined to the basal layer and p53 protein expression was seen in more than 40% of the cases [31].

Is it necessary to suppress acid secretion with mucosa ablation? It is evident from animal studies [32] and epidemiological human studies that IM develops under acidic conditions. The chance of success to achieve reversal of metaplastic epithelium into squamous epithelium by mucosal ablation, with a lasting effect, seems to depend on adequate acid suppression during and after the endoscopic treatment. Mucosal ablation that failed during insufficient acid suppression, was successful during more profound acid suppression [22, 33]. In a short-term study, however, normalization of acid reflux did not appear to be mandatory [34]. On the other hand recurrence of metaplasia was observed after discontinuation of omeprazole maintenance [35]. Consequently, it is correct that practically all studies into the efficacy of any form of mucosal ablation have been performed during concomitant acid suppression with PPIs.

In conclusion, it is still unclear whether profound acid suppression can prevent the development of adenocarcinoma in Barrett's esophagus, but treatment with high dose PPI maintenance therapy can induce endoscopic partial reversal of Barrett's esophagus, as well as improvement in several biomarkers of cancer risk. Such therapy furthermore contributes to the success rate of mucosal ablation. Further studies are needed into the combination of PPI therapy and mucosal ablation, which might in theory enable further regression of Barrett's epithelium and prevent the development of adenocarcinoma of the distal esophagus.


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Publication date: August 2003 OESO©2015