The Republic of Malta and endoscopic eradication therapy for Barrett’s esophagus

Malta is a southern European island country in the Mediterranean. It has been inhabited since 5900 BC. The population is 460 000 and the gross domestic product (GDP) in 2017 was 19.7 billion dollars. It is one of the 28 countries in the European Union (EU), which has 511 million member citizens and a GDP of 20 trillion dollars. And, although you cannot make predictions about what the EU will look like in 10 years without including a study of Malta, it is not the main determinant of the future of the EU. It is a valuable but small piece of the puzzle.

Radiofrequency ablation (RFA) for the treatment of low grade dysplasia (LGD) in patients with Barrett’s esophagus (BE) has been shown to safely eradicate intestinal metaplasia and dysplasia in Barrett’s patients with LGD and to reduce the rates of progression from LGD to high grade dysplasia (HGD) and cancer in the short term. Because of this, it has been a valuable option for managing patients with LGD. However, it is unlikely that in 2030 RFA (or any other endoscopic eradication therapy [EET]) will be a main determinant in the management and outcome of patients with Barrett’s. It is likely to be a small piece of the puzzle.

All commentary underlies the opinion that the only reason that Barrett’s is important is because it is the main precursor of adenocarcinoma of the esophagus. The investigation of BE provides a template to understand the development of esophageal adenocarcinoma. This editorial comment on the paper of Pandey et al. entitled “Systematic review and meta-analysis of the effectiveness of radiofrequency ablation in low grade dysplastic Barrett’s esophagus” [1] reviews the limitations of the studies that were included in the meta-analysis and outlines future strategies to prevent esophageal adenocarcinoma and to manage BE.

“...in addition to focusing on patients with known Barrett’s, attention must be turned to the “pre-Barrett’s” crowd, both patients with esophageal reflux symptoms and those who are asymptomatic.”

The systematic review and meta-analysis by Pandey et al. is a valuable addition to the literature. It culls the 423 articles on this subject, which were identified in databases, down to eight articles: two randomized controlled trials (RCTs) and six observational cohort studies with a mean follow-up of 20 months [2] [3] [4] [5] [6] [7] [8] [9]. Of the eight studies, six evaluated complete eradication of intestinal metaplasia (CE-IM) and of dysphagia (CE-D). The range of CE-IM was 77 % – 93 %, with an overall pooled rate of 88.17 %. The range of CE-D was 83 % – 98 %, with an overall pooled rate 96.69 %. Three of the eight studies compared progression to HGD or cancer, and patients who had RFA were less likely to progress (odds ratio 0.07, 95 % confidence interval 0.02 – 0.22). Recurrence rates were evaluated in five of the eight studies, with a range of recurrence of intestinal metaplasia of 2.8 % – 25 % and a range of recurrence of dysplasia from 0 – 16 %. Adverse events were listed in five of the eight studies and were very acceptable.

The authors concluded that RFA safely eradicates intestinal metaplasia and dysplasia, and reduces the rates of progression from LGD to HGD or cancer in the short term. Data from the studies reviewed are the foundation upon which the most recent American College of Gastroenterology guidelines [10] and the European Society of Gastrointestinal Endoscopy (ESGE) position statement [11] are based.

Although the systematic review is based on the best data available, the reader should consider the following. First, these results were obtained in expert medical centers by expert endoscopists. Do these results apply to the practicing community? Second, in one of the studies [9], it was not possible to achieve CE-IM in one of five patients, and in another study [3], 17 % did not achieve CE-D.

Third, in the two RCTs, how is it possible that 22 % of patients in the control group in one study [6] and 28 % of the control group in another study [7] had “eradication” of dysplasia? Does that mean that LGD (even after confirmation by two expert pathologists) can regress or does it mean that there is sampling error? The accuracy of endoscopic biopsies for defining histopathology, whether for initial screening, surveillance or post EET, has always been regarded as imperfect. With long-segment BE, less than 5 % of the area is sampled, which may lead to misdiagnosis. Would post-EET surveillance be better carried out with wide-area transepithelial sampling, as a recent RCT [12] suggested? The aforementioned guidelines [10] [11] recommend the use of high definition, high resolution endoscopes. These guidelines also emphasize that resection techniques rather than RFA and other thermal therapies be used for nodular lesions. In three of the referenced eight studies, a combination of endoscopic mucosal resection (EMR) and RFA was used.

Fourth, are buried glands/subsquamous intestinal metaplasia (SSIM) important? The study by Shaheen et al. [7] suggests not. A recent study in treatment-naïve patients found SSIM in 40 % of patients with extension proximal to the squamocolumnar junction in 20 % of patients [13]. Although SSIM was common, the authors emphasize the low neoplasia potential of SSIM. Now that the subsquamous anatomy can be better assessed with volumetric laser endomicroscopy (VLE), should this be the standard of care after EET [14]; will newer technologies coupled with VLE, such as optical coherence angiography, provide even more information; and because there is interobserver variation with VLE, will the new artificial intelligence technology lead not only to standardization of interpretation but also to increased diagnostic accuracy?

Another point to consider is the fact that the meta-analysis evaluates RFA for treatment of LGD, but is RFA even the best EET? It is not recommended for nodular lesions and is designed only to ablate the mucosa. Would it be better to resect some or all of the Barrett’s tissue or to use another thermal modality, such as cryoablation or hybrid argon plasma coagulation (APC) [15]?

And still another point…what about the cost of treatment? A cost analysis from one of the RCTs confirmed that RFA for BE with LGD is more effective but also more expensive than endoscopic surveillance [16]. A recent review looked at additional controversies in EET [15], so the reader/practitioner of EET for Barrett’s has a lot to “chew on.”

Finally, I return to the somewhat far-fetched Malta – RFA for LGD analogy to make the point that the issue of EET is a small piece of the overall management of BE and in 10 years or so – hopefully – it will be an even smaller part. To elaborate this point, the reader is referred to [Fig. 1]. Currently the management of BE is based on histology and histologic progression: BE (intestinal metaplasia with no dysplasia) progresses to LGD, and then to HGD, and then to adenocarcinoma. In this scenario, endoscopic treatment begins after BE is established ([Fig. 1a]). What is often not appreciated is the fact that more than 90 % of the patients diagnosed with adenocarcinoma of the esophagus are not in a Barrett’s surveillance program; when these patients present with symptoms, it is with advanced cancer. [Fig. 1b] points out that if our only focus is on preventing cancer developing in patients that are in a Barrett’s surveillance program, we will not impact/reduce the rise of adenocarcinoma that is being seen. Therefore, in addition to focusing on patients with known BE, attention must be turned to the “pre-Barrett’s” crowd, both patients with esophageal reflux symptoms and those who are asymptomatic. We have already identified several risk factors for Barrett’s/adenocarcinoma (chronic gastroesophageal reflux disease [GERD] symptoms, age > 50 years, male sex, tobacco usage, central obesity, Caucasian race, and first-degree relatives with Barrett’s), so certainly these patients should be screened. Population screening will be most feasible when non-endoscopic screening is done [17].

Fig. 1 Management of Barrett’s esophagus is typically based on histologic stage and progression.

But what about the patients without classic risk factors or those with risk factors who are not being screened – the 90 % who present not with Barrett’s but with adenocarcinoma? Work is now being done to develop a stool, blood, or urine test that would identify patients with precursors of adenocarcinoma, similar to the multitarget stool DNA testing for colorectal cancer [18]. Non-endoscopic approaches using swallowed capsules to assess molecular markers are currently being studied [19]. Iyer et al. reported on highly discriminant methylated DNA markers (MDMs) for non-endoscopic detection of Barrett’s using a sponge on a string that is swallowed. Nineteen MDMs were used and it was possible to discriminate between patients with and without Barrett’s. These results showed high accuracy [19]. And, as the pathophysiology of adenocarcinoma is better defined, there is promise that drugs could be used to interrupt the pathways that lead from “pre-Barrett’s” to Barrett’s to adenocarcinoma [17].

So, in summary, no disrespect is intended for the Republic of Malta’s role in the future of the European Union. Presumably it will remain a small piece of the puzzle. It is my view that the role of EET for the management of Barrett’s will be an even smaller piece of the Barrett’s puzzle.

• References

• 1 Pandey G, Mulla M, Lewis WG. et al. Systematic review and meta-analysis of the effectiveness of radiofrequency ablation in low grade dysplastic Barrett's esophagus. Endoscopy 2018; 50: 953-960
• 2 Guthikonda A, Cotton CC, Madanick RD. et al. Clinical outcomes following recurrence of intestinal metaplasia after successful treatment of Barrett's esophagus with radiofrequency ablation. Am J Gastroenterol 2017; 112: 87-94
• 3 Haidry RJ, Dunn JM, Butt MA. et al. Radiofrequency ablation and endoscopic mucosal resection for dysplastic Barrett's esophagus and early esophageal adenocarcinoma: Outcomes of the UK national Halo RFA registry. Gastroenterology 2013; 145: 87-95
• 4 Komanduri S, Kahrilas PJ, Krishnan K. et al. Recurrence of Barrett's esophagus is rare following endoscopic eradication therapy coupled with effective reflux control. Am J Gastroenterol 2017; 112: 556-566
• 5 Orman ES, Kim HP, Bulsiewicz WJ. et al. Intestinal metaplasia recurs infrequently in patients successfully treated for Barrett's esophagus with radiofrequency ablation. Am J Gastroenterol 2013; 108: 187-195
• 6 Phoa KN, van Vilsteren FG, Weusten BL. et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: A randomized clinical trial. JAMA 2014; 311: 1209-1217
• 7 Shaheen NJ, Sharma P, Overholt BF. et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. NEJM 2009; 360: 2277-2288
• 8 Sharma VK, Jae KimH, Das A. et al. Circumferential and focal ablation of Barrett's esophagus containing dysplasia. Am J Gastroenterol 2009; 104: 310-317
• 9 Small AJ, Araujo JL, Leggett CL. et al. Radiofrequency ablation is associated with decreased neoplastic progression in patients with Barrett's esophagus and confirmed low-grade dysplasia. Gastroenterology 2015; 149: 567-576 e563
• 10 Shaheen NJ, Falk GW, Iyer PG. et al. ACG clinical guideline: Diagnosis and management of Barrett's esophagus. Am J Gastroenterol 2016; 111: 30-50
• 11 Weusten B, Bisschops R, Coron E. et al. Endoscopic management of Barrett's esophagus: European Society of Gastrointestinal Endoscopy (ESGE) position statement. Endoscopy 2017; 49: 191-198
• 12 Vennalaganti PR, Kaul V, Wang KK. et al. Increased detection of Barrett's esophagus-associated neoplasia using wide-area trans-epithelial sampling: A multicenter, prospective, randomized trial. Gastrointest Endosc 2018; 87: 348-355
• 13 Bartel MJ, Srivastava A, Gordon S. et al. Subsquamous intestinal metaplasia is common in treatment-naive Barrett's esophagus. Gastrointest Endosc 2018; 87: 67-74
• 14 Trindade AJ, Inamdar S, Smith MS. et al. Volumetric laser endomicroscopy in Barrett's esophagus: Interobserver agreement for interpretation of Barrett's esophagus and associated neoplasia among high-frequency users. Gastrointest Endosc 2017; 86: 133-139
• 15 Komanduri S, Muthusamy VR, Wani S. Controversies in endoscopic eradication therapy for Barrett's esophagus. Gastroenterology 2018; 154: 1861-1875 e1861
• 16 Phoa KN, Rosmolen WD, Weusten B. et al. The cost-effectiveness of radiofrequency ablation for Barrett's esophagus with low-grade dysplasia: Results from a randomized controlled trial (SURF trial). Gastrointest Endosc 2017; 86: 120-129 e122
• 17 Quante M, Graham TA, Jansen M. Insights into the pathophysiology of esophageal adenocarcinoma. Gastroenterology 2018; 154: 406-420
• 18 Imperiale TF, Ransohoff DF, Itzkowitz SH. et al. Multitarget stool DNA testing for colorectal-cancer screening. NEJM 2014; 370: 1287-1297
• 19 Iyer PG, Taylor WR, Johnson ML. et al. Highly discriminant methylated DNA markers for the non-endoscopic detection of Barrett's esophagus. Am J Gastroenterol