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Best Treatment for Barrett's esophagus is Medical

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, 2.21.2012. Outline. Why acid control is important What can we do How good are we.

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Best Treatment for Barrett's esophagus is Medical

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  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, 2.21.2012

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

  3. Effects of acid: In vitro studies

  4. 5000 3000 3000 2500 2500 4000 2000 2000 3000 1500 1500 2000 1000 1000 1000 500 500 0 0 0 + Acid – Acid Acid pulses increase proliferation in Barrett’s esophagus Barrett’s Esophagus Esophagus Duodenum * * * cpm/mg protein ** 1 6 18 24 1 6 18 24 1 6 18 24 Time (hrs) Time (hrs) Time (hrs) *P<0.001;**P<0.05. Fitzgerald, RC, et al, JCI 1996

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

  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 * * * * * * R25 (n = 36) E40 BID + ASA325 (n = 31) E40 BID + R25 (n = 34) E40 BID (n = 30) Triadafilopoulos G et al. APT 2006 *P < .05 versus baseline.

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

  10. Effect of GERD control by fundoplication on aberrant DNA methylationin Barrett Esophagus. 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. 2

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

  12. 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

  13. 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

  14. 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 PPI Rx bid PPI Rx bid Fundoplication PPI/Fundoplication Ablation + PPI Ablation + PPI PPI bid + ASA/COX-2

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

  16. 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

  17. 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

  18. 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

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

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

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

  22. Radiofrequency Ablation for Barrett’s Esophagus

  23. Multi-center, randomized, sham-controlled study of radiofrequency ablation in patients with dysplastic Barrett’s esophagus Shaheen N, et al. NEJM 2009 • 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

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

  25. RCT of Barrett’s dysplasia: Disease Progression

  26. HALO: Long-term dataFleischer 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

  27. 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.

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