Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Esophagogastric  Junction

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Volume: Barrett's Esophagus
Chapter: Dysplasia

Can the compared effect of acid-suppression and antireflux therapy on dysplasia be evaluated?

S.R. DeMeester (Los Angeles)

The treatment of patients with Barrett's, whether medical or surgical, is complicated by the fact that Barrett's esophagus really represents end-stage reflux disease. Most patients with Barrett's have significant physiologic and anatomic abnormalities including:
- a defective lower esophageal sphincter (LES),
- poor esophageal body motility,
- moderate to large hiatal hernia,
- delayed gastric emptying,
- and symptoms that are unreliable for determining the adequacy of therapy [1].

These factors make adequate medical therapy quite difficult in patients with Barrett's. While these same factors also complicate the surgical treatment of patients with Barrett's, unlike medical therapy antireflux surgery corrects or improves many of these problems.

Medical versus surgical therapy for patients with reflux disease and Barrett's

Adequate treatment for patients with Barrett's should focus on the following 3 goals:
- stop reflux,
- promote or induce healing or regression of the metaplastic epithelium such that the risk mucosa (intestinal metaplasia) is eliminated,
- and halt progression to dysplasia and cancer.

Repeatedly it has been demonstrated that overall, patients with reflux disease are best treated with antireflux surgery, even when medical therapy consists of proton pump inhibitors [2-5]. Similar to the results of trials comparing medical and surgical therapy for patients with reflux disease, trials that compare medical and surgical therapy for patients with Barrett's esophagus also come out in favor antireflux surgery. In 1996, Ortiz et al. published a randomized trial comparing medical and surgical treatment for reflux disease in 59 patients with Barrett's esophagus [6]. Median follow-up was 5 years. The authors reported that antireflux surgery was more efficient than medical therapy in curing esophagitis and in stabilizing the length of the Barrett's segment. Furthermore, they noted that both medical therapy and a failed fundoplication were associated with a significantly increased risk of progression to dysplasia and cancer. In another study, McCallum et al. prospectively followed 181 patients with Barrett's esophagus [7]. Twenty-nine had antireflux surgery while the remaining 152 patients were treated medically. After a mean follow-up of 62 months in the surgical group and 49 months in the medical group, dysplasia developed in only 3.4% of patients after antireflux surgery compared to 19.7% of patients treated medically (p < 0.025). Further, no patient in the surgically treated group developed adenocarcinoma of the esophagus compared with two medically treated patients (0 versus 1.3%, p < 0.025). The authors concluded that compared to medical therapy an antireflux operation in patients with Barrett's esophagus was associated with significant protection from progression to dysplasia and cancer. Similarly, Katz et al. followed 102 patients with Barrett's for a mean of 4.8 years. By 3 years, approximately 8% of the medically treated patients had developed dysplasia. In contrast, patients treated by antireflux surgery had a significantly reduced risk of developing dysplasia (p = 0.03) [8]. Consequently, compared to medical therapy antireflux surgery appears to be associated with a reduced incidence of dysplasia and adenocarcinoma.

Antireflux surgery and the regression or progression of Barrett's

There have been conflicting reports about whether intestinal metaplasia (IM) regresses following antireflux surgery. Brand, in 1980, described complete regression in 4 of 10 patients with Barrett's who underwent fundoplication [9]. Subsequently, most reports have demonstrated that while some regression of the length of Barrett's is common, complete regression occurs only rarely. Review of the English language literature since 1977 documents follow up on 340 patients after antireflux surgery [6, 9-18]. Complete regression of Barrett's segments = 3 cm was rare (Figure 1). Thus, the available literature would suggest that regression of long-segment Barrett's can not reliably be predicted or anticipated following antireflux surgery.

In contrast to the unreliable regression of long segments of Barrett's, we recently demonstrated that 73% of patients with IM at the gastroesophageal junction had complete regression following antireflux surgery [19]. Similar to other reports in the literature, only 4% of patients with long segments of Barrett's had loss of IM after an antireflux procedure. Many of these patients demonstrated the development of squamous islands or a shorter length of Barrett's, but in our opinion regression should only be considered when there has been complete loss of the mucosa at risk for malignant degeneration. Recently, Low et al. also reported complete regression of Barrett's esophagus after antireflux surgery [20]. In their report, loss of IM occurred in 2 of 14 patients followed for a mean of 25 months postoperatively.

Figure 1. Review of the English language literature identified 11 series in which patients with Barrett's were followed after antireflux surgery. A total of 340 patients were followedup for an overall mean of 4.4 years (range 1-18 years). Most patients (74%) did not have any change in their Barrett's. However, regression occurred in 17% of patients, and progression in 9%.

Perhaps of greater importance is the issue of progression of Barrett's to dysplasia or cancer after surgical treatment of reflux disease. As previously discussed, compared to medical therapy antireflux surgery is associated with a reduced incidence of dysplasia and adenocarcinoma in several reports [7, 8]. One factor complicating any analysis of progression of Barrett's after antireflux surgery is that the cellular and genetic alterations leading to the development of dysplasia and adenocarcinoma may have already occurred prior to performance of the antireflux procedure. It has been estimated to take up to six years for adenocarcinoma to develop within Barrett's with low-grade dysplasia, and thus some cancers, particularly those which present during the first few postoperative years, probably do not represent progression of disease after surgery. McDonald et al. made this point in a study from the Mayo Clinic [18]. They found invasive adenocarcinoma in two patients and carcinoma in situ in one patient during surveillance after antireflux surgery, but they noted that no patient developed carcinoma after 39 months despite a median followup of 6.5 years, and a maximum follow-up of 18.2 years.

Review of the English language literature since 1975 revealed 14 series and a total of 588 patients with IM of the esophagus or gastroesophageal junction followed after fundoplication [6, 7, 9-12, 14-16, 18, 19, 21-23]. Patients were found to have esophageal adenocarcinoma after antireflux surgery in only eight of the fourteen reports. Apart from these series, four isolated reports were found describing adenocarcinoma developing in Barrett's esophagus after an antireflux operation [24-27]. The majority of cancers developed within 5 years of the fundoplication, raising the likelihood that these were prevalent cancers undetected at the time of the antireflux procedure. In all cases, cancers that developed beyond 5 years after antireflux surgery were in patients with recurrent reflux on the basis of symptoms or positive 24-hour pH monitoring (Figure 2). In other words, no patient with a

Figure 2. Review of the English language literature since 1975 has revealed 14 series and a total of 588 patients with intestinal metaplasia of the esophagus or gastroesophageal junction who have been followed-up after antireflux surgery. In 8 of the 14 reports patients were found to develop esophageal cancer. Apart from these series there were 4 isolated reports describing adenocarcinoma developing in Barrett's esophagus after an antireflux operation. Each case of cancer is plotted on the time line at the point where it occurred. Time is marked in 5-year segments with zero representing the time of the antireflux procedure. Note that the maximum as well as the mean or median follow-up for each of the 11 series is displayed. Despite the long follow-up in these series, most cancers are clustered between 0 and 5 years after the antireflux procedure. These cancers probably occurred as a consequence of cellular and genetic alterations that took place prior to the performance of the fundoplication. For each of the cancers occurring beyond 5 years after the antireflux procedure, there was evidence either by recurrence of reflux symptoms or a positive 24-hour pH test that the fundoplication had failed.

functioning fundoplication has been reported to develop adenocarcinoma beyond 5 years postoperatively. Thus, there is increasing evidence to suggest that a functioning fundoplication provides protection against progression of Barrett's to adenocarcinoma.


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Publication date: August 2003 OESO©2015