Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Mucosa
 The
 Esophagogastric  Junction
 Barrett's
 Esophagus

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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Screening and surveillance
 

What are the compared rates of regression observed after surgical or prolonged maintenance therapy?

M. France, R. Ackroyd, D.I. Watson (Adelaide, Sheffield)

It is generally accepted that Barrett's esophagus (or columnar lined esophagus) develops as a response to the reflux of both gastric and duodenal contents into the lumen of the distal esophagus, with consequent exposure of the esophageal mucosa to deleterious effects of these substances [1, 2]. It would therefore seem reasonable to hypothesise that eliminating exposure of this mucosa to gastric and duodenal fluids, either by medical or surgical intervention, might be followed by regression of Barrett's esophagus. A knowledge of whether this in fact happens is very important, as Barrett's esophagus is a premalignant condition, which can progress to adenocarcinoma of the esophagus. Furthermore, the incidence of this cancer has risen dramatically over the last three decades [3]. Fortunately, a number of studies have been published which do address the issue of whether either maintenance medical therapy or antireflux surgery is followed by regression of Barrett's esophagus, and these enable the question to be answered with some certainty.

Regression in response to prolonged medical maintenance therapy

Maintenance medical therapy using either H2 receptor antagonists, or more recently proton pump inhibitors (PPI), aims to reduce esophageal mucosal damage by suppressing gastric acid production and the damaging effect of pepsin. Reflux continues to occur, but the gastric fluid refluxed is rendered less noxious. In addition PPI, whilst not directly preventing duodenogastric reflux, secondarily reduce duodenogastroesophageal reflux by reducing the overall volume of gastric secretions, and this reduces the total amount of fluid which reaches the esophageal lumen [4].

Initial reports following the introduction of H2 receptor antagonists of case series of patients with Barrett's esophagus who ingested therapeutic doses of these medications, failed to demonstrate regression of Barrett's esophagus [5-7]. These reports were followed by the first prospective trial of medical therapy which was reported by Wedsorp et al. [8]. In this study a dose of 1.6 gm of cimetidine per day for two years failed to produce any regression in the Barrett's esophagus of 8 patients studied. A much larger study by Sampliner et al. [9] of 67 patients with Barrett's esophagus who used either cimetidine or ranitidine also failed to show regression.

Given that patients with Barrett's esophagus tend to have a higher gastric basal acid output [10], it would be reasonable to conclude from these initial studies that the medically treated patients may have been under treated, especially as symptom control rather than normalisation of the intraesophageal pH profile was used as the end point for treatment. It is known that Barrett's esophagus mucosa can be less sensitive to acid reflux than squamous mucosa, and for this reason clinical symptoms are not a reliable guide for the assessment of the efficacy of antireflux treatment. Furthermore it is likely that if regression is to be achieved, total elimination of intraesophageal acid might be required, and this requires either more potent medications or surgery.

Following the introduction of PPI it was hoped that with more powerful antisecretory action, regression of Barrett's esophagus might be seen, and indeed initial anecdotal reports did describe regression [11]. However, two subsequent prospective trials described mixed results. Gore et al. [12] showed significant regression of Barrett's esophagus in 23 patients who ingested omeprazole at a dose of 40 mg per day for 24 months. On the other hand, Sampliner [13] failed to demonstrate significant regression in length of Barrett's esophagus identified at endoscopy in a group of 27 patients who used lansoprazole at a dose of 60 mg per day, although 77% of the patients did develop islands of regenerated squamous mucosa.

If maintenance therapy is to be successful, then normalisation of pH in the distal esophagus would seem to be a prerequisite for regression. This issue was addressed in a prospective study by Malesci et al. [14]. Fourteen patients with histologically proven Barrett's esophagus received omeprazole 60 mg per day for 12 months. Twenty-four hour pH monitoring was performed after therapy for 10 days, 6 and 12 months, and normalisation of the distal esophageal pH profile was achieved in all but 2 patients. Endoscopy performed at 6 and 12 months showed statistically significant regression of the Barrett's esophagus in all but 3 cases compared with baseline endoscopy. However, all patients had residual Barrett's mucosa, with a mean reduction in the length of Barrett's esophagus of only 53% achieved (decreased from mean 4.5 cm to 2.1 cm length). Contrary to this study, another prospective study 15 of 27 patients with a mean follow-up of 5.7 years failed to demonstrate any significant reduction in the length of Barrett's esophagus.

In a prospective randomized controlled trial a small but significant regression of 8% was seen in 26 patients receiving a large dose of omeprazole (80 mg per day over a 2 year period) compared with 27 patients receiving standard dose ranitidine (150 mg twice daily) [16]. Again the issue of acid suppression appears to be important, as normalisation of pH was confirmed in the omeprazole treatment arm, whilst the ranitidine group continued to have abnormal 24 hour pH studies. Furthermore, the clinical significance of 8% regression could be questioned, as 92% of the original columnar lining remained following medical therapy even with high dose omeprazole. Two further randomized controlled trials comparing omeprazole with H2 receptor antagonists showed statistically significant regression in the group using high dose omeprazole (80 mg per day for 1 year then 40 mg per day for 1 year) [17], whilst another group using only omeprazole 20 mg per day failed to show regression [18].

Given these conflicting outcomes, a failure to demonstrate even statistically significant regression in most series, and the absence of clinically significant (i.e. total or near total) regression in any series, it is not possible to conclude that prolonged maintenance therapy, even with high dose PPI, will lead to regression of columnar mucosa in patients with Barrett's esophagus. Even if partial regression is to be seen following medical therapy, high doses of PPI appear to be required, and the adequacy of acid suppression must be confirmed by 24-hour pH testing. This is unlikely to be worth the effort.

Regression in response to antireflux surgery

By restoring a physical barrier to gastroesophageal surgery not only prevents exposure of the esophagus to acid, but it also prevents duodenal and pancreatic secretions from refluxing into the esophageal lumen. It is thought that both acid and pancreaticobiliary secretions are required for Barrett's esophagus to develop, and then progress to cancer of the esophagus. Theoretically, therefore, we could expect a better response following antireflux surgery than acid suppression.

One of the earliest publications to examine the influence of antireflux surgery on Barrett's esophagus was reported by Brand et al. [19]. This suggested that fundoplication held promise for the treatment of Barrett's esophagus, with complete regression of columnar mucosa described in 4 out of 10 patients who underwent surgery. Subsequent reports, however, have been disappointing with complete regression rarely documented. In a recent review of 11 published series which incorporated a total of 340 surgically treated patients [19-29], only 4% of patients had complete regression of Barrett's esophagus, with a further 12% showing partial regression [30].

Even more disappointing was a prospective study of 152 patients who underwent conventional open surgery using either a Nissen fundoplication or Hill's posterior gastropexy [31]. Long-term mean follow-up of 8.1 years was not followed by regression of Barrett's esophagus, and even worse it was followed by the development of low-grade dysplasia in 15 patients and adenocarcinoma in a further 4 patients. Twenty-four hour pH monitoring and Bilitec™ studies both demonstrated a significant reduction in acid and duodenoesophageal reflux respectively, but values were still elevated compared to normal individuals and this might explain the progression of disease. Probably of greater importance is that progression either to dysplasia or malignancy occurred late at approximately 8 years in all cases and highlights the importance of ongoing endoscopic surveillance in these patients.

On a more favourable note, a more recent, but small series of 14 prospectively followed patients, did demonstrate partial regression with squamous re-epithelialization in 10 patients with classic long segment Barrett's esophagus (more than 3 cm length) [32]. Included in this series were 2 patients with short segment Barrett's who showed complete regression. Given that the incidence of adenocarcinoma in short segment Barrett's is probably significantly less [33] it is difficult to interpret the importance of regression until we know more about the natural history of short segment Barrett's esophagus.

One group of concern is those patients whose Barrett's esophagus progresses following antireflux surgery, either by increasing in length, or progressing to dysplasia or even carcinoma. In a series of 37 patients treated with antireflux surgery at the Lahey clinic, progression to carcinoma occurred in 3 patients despite postoperative manometry recordings which were consistent with a functioning wrap [25]. In our own department, we recently reported the outcome of 81 patients with a Barrett's esophagus who underwent a laparoscopic Nissen fundoplication for symptomatic reflux disease [34]. Four patients in this series progressed to esophagectomy for cancer or high-grade dysplasia approximately 2 years following their original fundoplication. In contrast to this, in the only published randomized trial which has compared medical versus surgical therapy in patients with Barrett's esophagus [29], the only patients who developed dysplasia or malignancy during follow-up, were those patients who were managed with medication, or those who had documented failed antireflux procedures. The difference between the treatment groups in this study reached statistical significance, and led the authors to conclude that there may be some advantages for surgery over standard medical maintenance therapy.

On the other hand, McEntee et al. [35] compared medical treatment with a H2 receptor antagonist in 23 patients with a fundoplication in 21 patients, and demonstrated regression of Barrett's esophagus in only 1 of the patients treated with surgery. Four patients with mild dysplasia regressed to non-dysplastic epithelium following surgery, although 2 patients also progressed; 1 to mild dysplasia, and 1 from moderate dysplasia to severe dysplasia. 24-hour pH monitoring was performed in both study groups, and there was no significant reduction in acid exposure in the group receiving H2 receptor antagonists, whilst in the surgically treated group there was a significant decrease in acid exposure in the esophagus.

From these studies we can conclude that, as with prolonged medical maintenance therapy, surgery is rarely followed by complete regression of Barrett's esophagus, and surgery at best is followed by limited partial regression in approximately 10 to 15% of patients. Nevertheless, in those patients whose Barrett's esophagus does regress, regression undoubtedly relies on a successful antireflux procedure which restores a barrier against gastroesophageal reflux.

Limitations of published studies

One of the most important issues to consider when evaluating or undertaking any study which seeks to investigate regression or regeneration of Barrett's esophagus is the potential for error when measuring the extent of the columnar lining. This can be a significant problem in patients with both Barrett's esophagus and a sliding hiatus hernia. In this situation, definition of the site of the gastroesophageal junction (GEJ), and therefore measurement of the length of Barrett's esophagus, can be particularly difficult, and errors in identification can influence study outcomes. In addition, many patients with Barrett's esophagus have no lower esophageal sphincter tone, and for this reason, locating the GEJ using manometry, is also unlikely to be helpful. In medical trials, measurement issues will probably confound treatment groups equally if a randomized and blinded study design is applied. However, in surgical trials, the identification of the GEJ is much easier once patients who have undergone fundoplication, a short length of the esophagus is compressed by the wrap (and is not visible at endoscopy), and "blinding" of the post-treatment endoscopic assessment is not feasible because an intact fundoplication is immediately obvious to any endoscopist. For all of these reasons, there may be a tendency to "measure" a shorter length of Barrett's esophagus following surgery, or even claim total regression in some patients. However, despite this, surgery can also be followed by the appearance of islands of regenerating squamous epithelium, without an overall change in the length of the columnar lining, and this does represent evidence of partial regression of the metaplastic process.

Conclusion

In the majority of patients with Barrett's esophagus, neither medical maintenance therapy nor antireflux surgery will be followed by regression of Barrett's esophagus. There are a minority of patients whose Barrett's esophagus partially regresses, and a very small number in whom complete regression appears to occur. Nevertheless, reliable regression does not occur following either antireflux surgery or prolonged medical treatment, and for this reason, mucosal ablative techniques are currently under close evaluation to determine whether they offer a better treatment which will achieve clinically significant regression for the majority of patients with Barrett's esophagus.

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Publication date: August 2003 OESO©2015