Accepted Manuscript. CGH Editorial: Sound the Alarm for Barrett s Screening! Tarek Sawas, M.D., M.P.H., David A. Katzka, M.D

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1 Accepted Manuscript CGH Editorial: Sound the Alarm for Barrett s Screening! Tarek Sawas, M.D., M.P.H., David A. Katzka, M.D PII: S (18) DOI: /j.cgh Reference: YJCGH To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 3 October 2018 Please cite this article as: Sawas T, Katzka DA, CGH Editorial: Sound the Alarm for Barrett s Screening!, Clinical Gastroenterology and Hepatology (2018), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 CGH Editorial: Sound the Alarm for Barrett s Screening! Tarek Sawas, M.D., M.P.H. and David A. Katzka, M.D. David A. Katzka, M.D. Division of Gastroenterology and Hepatology Mayo Clinic 200 First Ave., S.W. Rochester, MN Tel: Fax: Disclosures: DAK: Research grant, Shire. Advisory Board, Celgene TS: no disclosures The evolving sentiment for screening for and surveillance of Barrett s esophagus is that the glass is half empty. A recent meta-analysis and large single center trial examining endoscopic surveillance trials demonstrated at most a small beneficial effect with surveillance in reducing EAC mortality exists[1, 2]. Notably not one single case study in the meta-analysis alone demonstrated an association between surveillance and EAC-related mortality[1]. Even when sophisticated modeling using demographic and clinical characteristics with and without genetic factors to predict the presence of Barrett s esophagus is performed by several of the world s experts in Barrett s esophagus, the odds ratio of finding Barrett s is only 1.26 [3]. Although some studies continue to support screening and surveillance [4], continued research is essential to solve the puzzle of identifying what patient population will reliably and cost effectively benefit from endoscopic screening and surveillance. Conversely, it is just as important to minimize the use of endoscopy in patient populations where the chance of finding Barrett s or EAC is particularly low. This is what is done in this important study by Lin et al. In this study, Lin et al., searched a large upper endoscopy center data base of over 70,000 patients for the occurrence of Barrett s esophagus and/or EAC in those who lacked the alarm features dysphagia, bleeding, vomiting, or weight loss. The purpose was to determine the burden of patients undergoing putative unnecessary and therefore unindicated screening for Barrett s esophagus on the basis of these symptoms. In this database, 13% of annual upper endoscopies were performed for reflux symptoms without alarm signs. Of those, 5.6% had suspected BE endoscopically and only 25% of these patients had long segment BE. The majority of patients were not high risk for BE and did not meet the American College of Gastroenterology ACG [5] criteria for screening (52% females, 38% younger than 50 and 20% non-white). The study confirmed previously established risk factors of older age, male gender, and White race to be associated with higher prevalence of BE but demonstrated that the prevalence was less than 10% in an endoscopy population. This is particularly important as prior investigators have demonstrated that cost effectiveness for Barrett s diagnosis depends on at least 10% prevalence in the population screened. [6, 7]. Several caveats must be considered in analyzing this study. First, as the authors note, the diagnosis of Barrett s was standardized neither by endoscopic nor histologic criteria. Indeed a large proportion of patients labelled as having short segment Barrett s had only an irregular Z line and/or lack intestinal

3 metaplasia on biopsy. This leads to a high false positive rate and even likely lower prevalence of Barrett s esophagus where the vast majority of the identified BE in this study were short segment (76.7%). Furthermore, few available data for patients with intestinal metaplasia and with <1 cm of columnar appearing epithelium have shown no development of EAC[8]. Thus, should Barrett s have been more rigorously defined in this study, rates of Barrett s diagnosis would likely have been even lower than calculated, further supporting the authors conclusion. Indeed, there is a good reason why guidelines that suggest screening criteria for Barrett s esophagus do not include alarm symptoms. In fact, almost the converse of finding alarm symptoms apply in the face of the esophageal hyposensitivity that is well described in patients with Barrett s esophagus[9, 10]. We all know anecdotally that your typical Barrett s patient is one who has had years of heartburn, often nocturnal, commonly ignored and treated with over the counter antacids. More concernedly, once a patient with Barrett s esophagus presents with dysphagia, it is more typically a stricture, or worse a cancer. A recent study further demonstrates that when patients with adenocarcinoma present with dysphagia, it is usually stage III or greater[11]. On the other hand, one must also consider that the information retrieved from endoscopy performed for reflux symptoms has other implications. For example, reflux esophagitis was found in 15,969 (21.7%) patients with 9.2% classified as severe or LA Class C/D. This is valuable information for guiding treatment as these patients require lifelong PPI therapy at the least. Similarly the prognostication of a normal appearing esophagus on endoscopy in GERD patients is important for removing the worry about developing esophageal cancer in an era where the general risk of reflux related esophageal cancer is overemphasized in the media. This is supported by long term longitudinal data suggesting that it is uncommon for adults with normal baseline esophagoscopy to progress to severe erosive esophagitis and/or Barrett s esophagus[12]. How should we view this important study in the context of Barrett s screening and surveillance. Most importantly, this study further alerts us to the internecine battle we face with adenocarcinoma of the esophagus. In fact, the success of finding Barrett s in this study with or without alarm symptoms is not all that different than what we find when making our best efforts to provide accurate guidelines. Why is it that we cannot solve this dilemma? Many explanations are likely. First is that we are still trying to douse the fire of reflux related EAC with an ocean of water. Although investigators have earnestly and exhaustively identified demographic, symptomatic, morphometric and metabolic criteria for Barrett s screening, the denominator remains impractically high from the view of cost effectiveness and available medical providers to perform endoscopy. In fact, the presence of not only alarm symptoms but even heartburn as an identifier of risk for EAC is questioned given the absence of regular reflux symptoms in up to 20% patients with endoscopically identified BE[13]. This is an opportunity for less expensive and/or invasive devices such as transnasal endoscopy[14], video capsule [15]Cytosponge[16] or liquid biopsy [17] use in select populations where heartburn is not a prerequisite. Second, we still do not understand the essential question of why some patients develop Barrett s and others not. What is different about their esophageal mucosa such that it responds to severe chronic acid exposure with generation of a metaplastic epithelium instead of continually regenerating squamous mucosa? Third, we have made the assumption that our failure to identify 80-95% of patients with EAC with Barrett s esophagus prior to cancer diagnosis is because of our poorly performing screening guidelines[18, 19] and lack of resources. Emerging data, however, suggest that there may be two phenotypes of EAC presentation, one with and one without visible Barrett s epithelium and histologic evidence of intestinal metaplasia[20]. If this holds true, an entirely new means of screening will be needed, focused away from endoscopic screening, for the purpose of finding visible or at least long segment Barrett s esophagus. We stand at several crossroads in the field of Barrett s esophagus. Is heartburn required for screening? Is it time to measure biomarkers, such as P53, routinely in an effort to better identify

4 progressors? Is traditional endoscopy too expensive and should we embrace the new generation of less expensive and invasive screening techniques? Answers to these important questions are being formulated but until that time, we need to more assiduously rely on our current society guidelines particularly with reference to gender, age and race. This study by Lin et al., rightfully emphasizes this point by extending the futility we face not only in general but in performing endoscopy on groups of patients that do not even meet accepted screening criteria. 1. Codipilly, D.C., et al., The Effect of Endoscopic Surveillance in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis. Gastroenterology, (8): p e5. 2. Peters, Y., et al., Incidence of Progression of Persistent Non-Dysplastic Barrett's Esophagus to Malignancy. Clin Gastroenterol Hepatol, Dong, J., et al., Determining Risk of Barrett's Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants. Gastroenterology, (5): p e3. 4. El-Serag, H.B., et al., Surveillance endoscopy is associated with improved outcomes of oesophageal adenocarcinoma detected in patients with Barrett's oesophagus. Gut, (8): p Shaheen, N.J., et al., ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus. Am J Gastroenterol, (1): p ; quiz Gerson, L.B., P.W. Groeneveld, and G. Triadafilopoulos, Cost-effectiveness model of endoscopic screening and surveillance in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol, (10): p Inadomi, J.M., et al., Screening and surveillance for Barrett esophagus in high-risk groups: a costutility analysis. Ann Intern Med, (3): p Jung, K.W., et al., Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett's esophagus: a population-based study. Am J Gastroenterol, (8): p ; quiz Johnson, D.A., et al., Esophageal acid sensitivity in Barrett's esophagus. J Clin Gastroenterol, (1): p Katzka, D.A. and D.O. Castell, Successful elimination of reflux symptoms does not insure adequate control of acid reflux in patients with Barrett's esophagus. Am J Gastroenterol, (7): p Fang, T.C., et al., Utility of dysphagia grade in predicting endoscopic ultrasound T-stage of nonmetastatic esophageal cancer. Dis Esophagus, (6): p Bardhan, K.D., C. Royston, and A.K. Nayyar, Reflux rising! An essay on witnessing a disease in evolution. Dig Liver Dis, (3): p Rubenstein, J.H., et al., Prediction of Barrett's esophagus among men. Am J Gastroenterol, (3): p Moriarty, J.P., et al., Costs associated with Barrett's esophagus screening in the community: an economic analysis of a prospective randomized controlled trial of sedated versus hospital unsedated versus mobile community unsedated endoscopy. Gastrointest Endosc, (1): p e Gupta, M., et al., Screening for Barrett's esophagus: results from a population-based survey. Dig Dis Sci, (8): p Offman, J., et al., Barrett's oesophagus trial 3 (BEST3): study protocol for a randomised controlled trial comparing the Cytosponge-TFF3 test with usual care to facilitate the diagnosis of

5 oesophageal pre-cancer in primary care patients with chronic acid reflux. BMC Cancer, (1): p Cabibi, D., et al., Analysis of tissue and circulating microrna expression during metaplastic transformation of the esophagus. Oncotarget, (30): p Dulai, G.S., et al., Preoperative prevalence of Barrett's esophagus in esophageal adenocarcinoma: a systematic review. Gastroenterology, (1): p Visrodia, K., et al., Systematic review with meta-analysis: prevalent vs. incident oesophageal adenocarcinoma and high-grade dysplasia in Barrett's oesophagus. Aliment Pharmacol Ther, (8): p Sawas, T., et al., Identification of prognostic phenotypes of esophageal adenocarcinoma in two independent cohorts. Gastroenterology, 2018.