1. Barrett’s Esophagus Stuart Jon Spechler, M.D. Chief of Gastroenterology, Dallas VA Medical Center; Professor of Medicine, Berta M. and Cecil O. Patterson Chair in Gastroenterology, UT Southwestern Medical Center at Dallas, Texas

2. A 58 year-old, obese white man has had heartburn for more than 20 years. He read a magazine article saying that heartburn is a risk factor for Barrett’s esophagus, which can lead to cancer of the esophagus. The article scared him, and he asks you what he should do. The article went on to say that people with heartburn should have an endoscopy to look for Barrett’s esophagus.

3. Endoscopy reveals Barrett’s esophagus. Biopsy specimens show high-grade dysplasia.

4. Barrett’s Esophagus The condition in which a metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus AGA Medical Position Statement. Gastroenterology 2011;140:1084. Stratified Squamous Epithelium MetaplasticColumnarEpithelium MetaplasticColumnarEpithelium Affects 5.6% of adult Americans

5. Barrett’s Metaplasia Esophageal Adenocarcinoma

6. Metaplasia One adult cell type replaces another type GERD Stratified Squamous Epithelium (Normal Esophagus) Specialized Intestinal Metaplasia (Barrett’s Esophagus) Response to Chronic Tissue Injury Reflux Esophagitis

7. GEJ (Gastro-Esophageal Junction) Z-Line (Squamo-Columnar Junction) Columnar Lined Esophagus Adapted from Spechler. Gastroenterology 1999;117:218. X Specialized Intestinal Metaplasia

8. Age >50 years Uncommon in children Risk Factors for Barrett’s Esophagus Chronic GERD Heartburn, hiatal hernia Obesity Intra-abdominal fat distribution Male gender White ethnicity Less common in African-Americans Uncommon in Asians and Esophageal Adenocarcinoma

9. Guidelines for Endoscopy in GERD “Upper endoscopy is not required in the presence of typical GERD symptoms.” “Endoscopy is recommended in the presence of alarm symptoms and for screening of patients at high risk for complications [Barrett’s esophagus].” ACG Guidelines. Katz. Am J Gastroenterol 2013;108:308. ACP Guidelines. Shaheen. Ann Intern Med 2012;157:808. “Upper endoscopy is indicated in men and women with heartburn and alarm symptoms (dysphagia, bleeding, anemia, weight loss, and recurrent vomiting).” “Upper endoscopy is indicated in men and women with typical GERD symptoms that persist despite a therapeutic trial of 4 to 8 weeks of twice-daily proton pump inhibitor therapy.”

10. Gastroenterology 2011;140:1084. AGA Medical Position Statement on Endoscopic Screening for Barrett’s Esophagus We recommend against screening the general population with GERD for Barrett’s esophagus. In patients with multiple risk factors associated with esophageal adenocarcinoma, we suggest screening for Barrett’s esophagus. Chronic GERD, hiatal hernia, age ≥50, male gender, white race, elevated BMI, intra- abdominal body fat distribution Norman Barrett

11. U.S. Incidence of Esophageal Adenocarcinoma Has Been Rising 1975198019851990199520002005 0 5 10 15 20 25 30 Incidence per 1,000,000 Incidence Time Trend Pohl H. Cancer Epidemiol Biomarkers Prev 2010;19:1468. 3.6 per million 1973 25.6 per million 2006 7-Fold Increase In 3 Decades

12. 2000s Estimate: 0.5% per year 1 in 200 patients per year Shaheen. Gastroenterology 2000;119:333. 1990s Estimate: 1% per year 1 in 100 patients per year Drewitz. Am J Gastroenterol 1997;92:212. 2014 Estimate: 0.25% per year 1 in 400 patients per year Estimates of Cancer Risk for Individual Patients with Non-Dysplastic Barrett’s Have Been Getting Lower

13. Endoscopic Surveillance Might Not Decrease Mortality from Esophageal Adenocarcinoma Corley DA. Gastroenterology 2013;145:312. 8,272 pts. with Barrett’s esophagus (BE) 351 pts. with esophageal adenocarcinoma (EAC) 70 EAC in pts. with prior diagnosis of BE (≥6 months) Cases 38 pts. with confirmed death from esophageal cancer Controls 101 living Barrett’s pts. matched for age, sex, follow-up duration 55% surveillance endoscopy performed within 3 years 60% surveillance endoscopy performed within 3 years Surveillance endoscopy within 3 years was NOT associated with decreased risk of death from esophageal cancer (adjusted odds ratio 0.99; 95% CI 0.36-2.75)

14. Do Proton Pump Inhibitors (PPIs) Prevent Cancer in Barrett’s Esophagus? Evidence that PPIs prevent carcinogenesis in Barrett’s esophagus is indirect and not proven in controlled trials. PPIs are the most effective medical treatment for reflux esophagitis Decrease gastric acid production Decrease acid reflux Heal reflux esophagitis

15. PPIs Reduce the Risk of Neoplastic Progression in Barrett’s Esophagus PPI Users 540 Barrett’s patients, median follow-up 5.2 years Kastelein F. Clin Gastroenterol Hepatol 2013;11: 382-8. PPI use associated with 75% reduction in risk of neoplastic progression PPI Nonusers

16. Gastroenterology 2011;140:1084. AGA Medical Position Statement on the Treatment of GERD in Barrett’s Esophagus Norman Barrett Age 13 GERD therapy with medication effective to treat GERD symptoms and to heal reflux esophagitis is clearly indicated. Antireflux surgery is not more effective than medical therapy for prevention of cancer in Barrett’s esophagus. We recommend against attempts to eliminate esophageal acid exposure (PPIs in doses >once daily or antireflux surgery) for cancer prevention.

17. Gastroenterology 2011;140:1084. We suggest that endoscopic surveillance [with biopsy] be performed in patients with Barrett’s esophagus. AGA Medical Position Statement on Endoscopic Surveillance for Barrett’s Esophagus We suggest the following surveillance intervals: ▪ No dysplasia: 3-5 years ▪ Low-grade dysplasia: 6-12 months ▪ High-grade dysplasia in the absence of eradication therapy: 3 months Norman Barrett

18. The Cancer Risk for High-Grade Dysplasia in Barrett’s is Sufficient to Warrant Intervention Rastogi. Gastrointest Endosc 2008;67:394. Spechler. Am J Gastroenterol 2005;100:927. AGA Medical Position Statement. Gastroenterology 2011;140:1084. High Grade Dysplasia Cancer ~6% per year

19. Management Options for High-Grade Dysplasia in Barrett’s Esophagus Intensive endoscopic surveillance (every 3 months) Endoscopic ablation Endoscopic mucosal resection Esophagectomy

20. Gastroenterology 2011;140:1084. We recommend endoscopic eradication therapy rather than surveillance for treatment of patients with confirmed high- grade dysplasia in Barrett’s esophagus. AGA Medical Position Statement on the Management of Barrett’s Esophagus Norman Barrett

21. Drawing courtesy of Tom Rice HGDT2T1 Mucosa Submucosa Muscularis mucosae Basement membrane Epithelium Lamina propria

22. Drawing courtesy of Tom Rice T1 T2 T3 T4 T Staging of Esophageal Cancer None considered curable by endoscopic therapy. Mucosa Submucosa Submucosa Mucosa Muscularis mucosae Muscularis propria

23. Drawing courtesy of Tom Rice HGDT2T1 Mucosa Submucosa Intramucosal Carcinoma T1a High Grade Dysplasia T1b Potentially curable with endoscopic therapy Muscularis mucosae T1b: LN mets >10% Potentially metastatic

24. Systematic Review: Risk of Lymph Node Metastases for High Grade Dysplasia (HGD) or Intramucosal Carcinoma (IMC) in Barrett’s Esophagus Dunbar K, Spechler S. Am J Gastroenterol 2012;107:850. Reviewed studies that included: - Patients who had esophagectomy for HGD or IMC and - Final surgical pathology results (lymph node status) Identified 70 relevant articles 1,874 patients who had esophagectomy for HGD (524 patients) or IMC (1,350 patients) Lymph node metastases in 26 of 1,874 patients (1.39%, 95% CI.86% - 1.92% )

25. Accurate T Staging Crucial to Determine if Curative Endoscopic Therapy Feasible High Grade Dysplasia and Intramucosal Carcinoma Lymph node metastases in 1%-2% Curative endoscopic therapy feasible Submucosal invasion Lymph node metastases in >10% Failure rate for endoscopic therapy unacceptable Endoscopic mucosal resection (EMR) the best procedure for T staging

26. EMR is as much a staging procedure as it is a therapeutic procedure. If EMR shows submucosal invasion, then endoscopic therapy is not advised.

27. Radiofrequency Ablation (RFA) Radiofrequency Energy Generator Closely spaced electrodes

28. Radiofrequency Ablation of Barrett’s Esophagus AblatedBarrett’sMetaplasia

29. Shaheen. N Engl J Med 2009;360:2277-88. Randomized, Sham-Controlled Trial of Radio- frequency Ablation for Dysplasia in Barrett’s

30. Radiofrequency Ablation of Dysplasia Prevents Neoplastic Progression at One Year % with Progression Progression of Neoplasia Progression to Cancer Radiofrequency ablation Sham ablation 3.6% 16.3% 1.2% 9.3% Shaheen. N Engl J Med 2009;360:2277-88.

31. Complications of Radiofrequency Ablation in 84 Patients 5 esophageal strictures (6%) 1 UGI Bleed (1%) 2 hospitalizations for chest pain (2%) Shaheen. N Engl J Med 2009;360:2277-88.

32. Endoscopic Therapy for Mucosal Neoplasia In Barrett’s Esophagus 2014 EMR of mucosal irregularities for staging and therapy Ablate the remaining Barrett’s metaplasia to minimize metachronous neoplasia

33. PROPOSAL: Routine Polypectomy for Colon Polyps and RFA for Non-Dysplastic Barrett’s Esophagus Are Intellectually the Same El-Serag HB, Graham DY. Gastroenterology 2011;140:386. RFA, like colonoscopy, is safe and effective Non-dysplastic Barrett’s esophagus is like a small colon polyp Limiting RFA only to Barrett’s with dysplasia is like limiting polypectomy only to polyps that are large or clearly malignant. =

34. 335 pts with HGD (72%), IMC (24%) or LGD (4%) 270 (81%) complete eradication of dysplasia Mean 2.5 RFA treatments Haidry. Gastroenterology 2013. 145:87-95. U.K. Experience with EMR and RFA for Treatment of Mucosal Neoplasia in Barrett’s Esophagus 208 (62%) complete eradication of Barrett’s metaplasia 10 (3%) progressed to invasive cancer 30 (9%) strictures requiring dilation, 1 perforation One year protocol 12 0 243648 Months from end of protocol % free of disease 25 50 75 100 0 Dysplasia Barrett’s Metaplasia

35. RFA for Non-Dysplastic Barrett’s Esophagus? Generally requires several endoscopies for complete eradication Complication rate low, but not trivial Substantial rate of recurrence of metaplasia Efficacy in preventing cancer not established Does not obviate surveillance Frequency and importance of subsquamous intestinal metaplasia not clear

36. Chronic GERD symptoms and ≥1 risk factor(s) for adenocarcinoma (Age>50, male, white, hiatal hernia, obesity, intra-abdominal body fat, smoking) Consider screening endoscopy No more screening No Barrett’s No dysplasiaLow-grade dysplasia High-grade dysplasia or intramucosal Ca Have diagnosis confirmed by expert pathologist Low-grade dysplasia High-grade dysplasia or intramucosal Ca Surveillance endoscopy every 3-5 yrs Endoscopic eradication Surveillance endoscopy every 6-12 months or endoscopic eradication on screening Barrett’s esophagus

37. AGA Medical Position Statement on the Management of Barrett’s Esophagus Gastroenterology 2011;140:1084. Endoscopic eradication therapy is not suggested for the general population of patients with Barrett’s esophagus in the absence of dysplasia. RFA should be a therapeutic option for select individuals with non-dysplastic Barrett’s esophagus who are judged to be at increased risk for progression to HGD or cancer. Specific criteria that identify this population have not been fully defined. Norman Barrett

38. Knowledge is knowing a tomato is a fruit. Wisdom is knowing not to put it in a fruit salad.