1. Best Treatment for Barrett's esophagus is Medical George Triadafilopoulos, MD Clinical Professor of Medicine Stanford University School of Medicine M.I.S.S., Salt Lake City, UT, 2.23.2011

2. Outline Why acid control is important What can we do How good are we

3. Effects of acid: In vitro studies Acid exposure Cultured cells Ex vivo Barrett’s tissue

4. Acid pulses increase proliferation in Barrett’s esophagus cpm/mg protein 1 Esophagus 61824 Time (hrs) 0 500 1000 1500 2000 2500 3000 *P<0.001;**P<0.05. 1 Barrett’s Esophagus 61824 Time (hrs) 0 1000 2000 3000 4000 5000 1 Duodenum 61824 Time (hrs) 0 500 1000 1500 2000 2500 3000 + Acid– Acid ** * * * Fitzgerald, RC, et al, JCI 1996

5. PCNA expression before and after acid suppression + in Barrett’s esophagus Ouatu-Lascar et al. Gastro 1999 PCNA units + Complete: %pH<4% *

6. COX-2 expression in Barrett’s esophagus explants and the effect of acid and/or bile salt exposure Shirvani V, et al. Gastroenterol. 118: 487-496, 2000

7. COX-2 inhibition plus PPI decreases PCNA Expression in Barrett’s esophagus * * * E40 BID + ASA325 (n = 31) E40 BID + R25 (n = 34) E40 BID (n = 30) R25 (n = 36) *P <.05 versus baseline. * * * Triadafilopoulos G et al. APT 2006

8. Acid NOX5-S ROS p16 gene hypermethylation Down-regulation of P16 mRNA Increase in cell proliferation Esophageal carcinogenesis Hong et al. AJP, 2010

9. Acid-Induced P16 hypermethylation contributes to development of esophageal adenocarcinoma via activation of NADPH oxidase NOX5-S Ratio of p16 to 18S

10. Hong et al. AJP, 2010 Acid increases methylation levels of p16 gene promoter in BAR-T cells and OE33 cells Ratio and % control

11. 2 Smith, et al. Annals of Surgery. 252(1):63-69, 2010. Number of methylated genes in biopsies of squamous and columnar mucosa from pH normal and pH abnormal fundoplication subjects and no surgery subjects. Effect of GERD control by fundoplication on aberrant DNA methylation in Barrett Esophagus.

12. Acid control Before Barrett’s esophagus formation No Barrett’s or less (shorter segment) Barrett’s esophagus After Barrett’s esophagus formation Less dysplasia and/or cancer

13. PPI Therapy and Dysplasia H2RA/No Therapy PPI Therapy El-Serag, Am J Gastroenterol. 2004;99:1877.

14. Kaplan–Meier curves of the cumulative proportion of patients who were free of low-grade dysplasia (n = 299*) Hillman L, et al. MJA 2004; 180 (8): 387-391

15. Conclusions In vitro and ex vivo data in cultured cells and Barrett’s esophagus explants suggest that acid exposure is important in Barrett’s carcinogenesis Normalization of intra-esophageal acid exposure -albeit not formally proven in RCT studies- should be beneficial and diminish the likelihood of neoplastic progression of Barrett’s esophagus

16. Barrett’s esophagus Manage GERDPPIFundoplication Cancer prevention EMRAblation

17. Treatment options for Barrett’s esophagus Control of GERD symtoms Healing of co-existing esophagitis Prevention of recurrent esophagitis Control of bile reflux Prevention of stricture formation Regression/elimination of Barrett’s surface Regression/elimination of dysplasia Chemoprevention of dysplasia & adenocarcinoma PPI Rx bid Fundoplication PPI/Fundoplication Ablation + PPI PPI bid + ASA/COX-2

18. Barrett’s metaplasia FundoplicationRFA (+ PPI)

19. RFA+PPI versus surgery: Not directly comparable Symptoms Disease progression Disease regression Time

20. Distinction Where PPIs are only able to decrease acid content in the stomach (and thus change the pH of the refluxate), surgery has the ability to prevent any type of reflux (i.e. bile). Fundoplication does not alter the length of Barrett’s esophagus In contrast, RFA ablates Barrett’s metaplasia, and, used together with PPI therapy that suppresses acid reflux, leads to squamous re-epitheliazation

21. Definitions Progression: A change from either intestinal metaplasia to any form of dysplasia or an increase in grade of dysplasia or development of adenocarcinoma Regression: A change from high-grade dysplasia (HGD) to low-grade dysplasia (LGD) or no dysplasia, change from LGD to metaplasia or loss of metaplasia, and change from IM to squamous epithelium Shortening of the segment or development of squamous cell islands, although considered by some as regression, usually is not accurately measured and reported

22. How good is fundoplication in patients with Barrett’s esophagus? The LOTUS trial 554 patients with GERD 60 had Barrett’s esophagus: 28 randomized to esomeprazole and 32 to LARS. 4 of 60 BE patients on either treatment strategy experienced treatment failure during the 3-year follow-up. Esophageal pH in BE patients was significantly better controlled after surgical treatment than after esomeprazole (p = 0.002) QoL scores were similar for the two therapies at baseline and at 3 years. Operative difficulty was slightly greater in patients with BE than those without There was no difference in postoperative complications or level of symptomatic reflux control Atwood, SJ. J. Gastrointestinal Surg. 2008; 12:1646-54

23. Long-term outcomes of fundoplication in Barrett’s esophagus cohorts % Wassenaar EB et al WJG 2010 11 studies; N=551; f/u 3.4 years

24. Antireflux surgery (ARS) does not decrease cancer risk SIR Lagergren; Gastro. 2010;138:1297–1301 15 year-long population study

25. Medical therapy vs surgery for Barrett’s esophagus 3 studies: PPI:708; Nissen 115 % Wassenaar EB et al WJG 2010

26. Radiofrequency Ablation for Barrett’s Esophagus

27. Multi-center, randomized, sham-controlled study of radiofrequency ablation in patients with dysplastic Barrett’s esophagus 2:1 RFA versus sham Stratified by: - degree of dysplasia (LGD vs. HGD) - length of segment (1-4 cm vs 4-8 cm) Maximum of 4 RFA sessions Identical biopsy protocols, equal sampling Esomeprazole 40 mg orallytwice daily 12 month cross-over Shaheen N, et al. NEJM 2009

28. RCT of Barrett’s dysplasia: Complete Eradication (ITT)

29. RCT of Barrett’s dysplasia: Disease Progression

30. HALO: Long-term data Fleischer D et al. DDW 2010 50 patients followed for 5 years No strictures or mucosal lesions. Mean per pt # of biopsies: 31 In 46 of 50 patients (92%) had CR-IM, while 4 (8%) had IM (6 out of 126 specimens). Single-session focal RFA cleared residual IM RFA is durable and effective at 5 years

31. Conclusions Although both regression and progression have been noted after ARS, surgery does not completely or substantially eliminate metaplasia Esophago-gastric cancer still develops after 15 years of ARS Medical therapy (RFA+PPI) is effective and durable but no data on cancer incidence are (yet) available.