1. Gastroenterology Grand Rounds February 20, 2014 Fellow: David Tang, M.D. Faculty: Marcelo Vela, M.D.

2. Case Presentation 36 year old White man Heartburn x 10 years Intermittent dysphagia and chest pressure x 2 years EGD in 2011 – Long segment Barrett’s Esophagus, Prague C10M10, without dysplasia – Eosinophilic esophagitis Symptoms resolved with twice daily Nexium

3. EGD 2013

5. Case Presentation Histology – Esophagus at 34 cm to 28 cm  Intestinal metaplasia with low grade dysplasia at multiple levels – Esophagus at 25 cm  Squamous mucosa with > 40 intraepithelial eosinophils per high power field

6. Diagnosis Eosinophilic Esophagitis And Barrett’s Esophagus with Low Grade Dysplasia

7. Clinical Questions What is the difference in recommendations for RFA in patients with LGD vs HGD? What is the efficacy and durability of RFA for Barrett’s Esophagus with LGD? Should RFA be performed for Barrett’s Esophagus with LGD? What is the relationship between Barrett’s Esophagus and Eosinophilic Esophagitis? How safe is RFA of dysplastic Barrett’s in Eosinophilic Esophagitis?

8. Carcinogenesis in BE

9. Incidence of EAC in BE Non dysplastic BE  EAC – 0.12% - 0.50% per year LGD  EAC – 1.7% per year HGD  EAC – 6.6% per year Sikkema Am J Gastroenterol 2011 Hvid-jensen NEJM 2011 Wani Am J Gastroenterol 2009

10. Inter-observer Variability in LGD 147 patients with a community diagnosis of LGD during BE surveillance – 15% with LGD confirmation by two other expert pathologists – 85 % down-staged to non dysplastic BE Incidence rate of progression to HGD/EAC – 13.4% in patients with confirmed LGD – 0.49% in patients down-staged to NDBE Curvers Am J Gastroenterol 2010

11. 2011 AGA Guidelines “We recommend endoscopic eradication therapy with radiofrequency ablation (RFA) … rather than surveillance for treatment of patients with confirmed high-grade dysplasia”

12. 2011 AGA Guidelines “Endoscopic eradication therapy with RFA should also be a therapeutic option for treatment of patients with confirmed low-grade dysplasia in Barrett’s esophagus.” “In the absence of long-term studies showing efficacy, it is not clear that the potential benefit of ablation in reducing cancer risk for patients who have Barrett’s esophagus with low-grade dysplasia warrants the risks and substantial expense of the ablative procedures.”

13. AIM Dysplasia Trial Multicenter RCT of RFA vs Sham procedure in dysplastic Barrett’s Esophagus N = 127 – randomized in 2:1 ratio Primary outcomes – Complete eradication of LGD @ 12 mos – Complete eradication of HGD @ 12 mos – Complete eradication of IM @ 12 mos Shaheen NEJM 2009

14. AIM Dysplasia Trial Eradication of HGD (N=43) @ 12 mos Shaheen NEJM 2009

15. AIM Dysplasia Trial Eradication of LGD (N=58) @ 12 mos Shaheen NEJM 2009

16. AIM Dysplasia Trial Progression of Dysplasia Shaheen NEJM 2009

17. AIM Dysplasia Extension Shaheen Gastro 2011 Eradication @ 24 mos Allowed for 1 session of “touch up” RFA @ 15 mos

18. AIM Dysplasia Extension Shaheen Gastro 2011 Durability of CE-D

19. AIM Dysplasia Extension Shaheen Gastro 2011 Wani Am J Gastroenterol 2009 Incidence of Progression to EAC [per year]

20. RFA Meta-analysis Shaheen Gastroenterology 2011 Shaheen Gastrointest Endosc 2012 Orman Clin Gastroenterol Hepatol 2013 Eradication of Dysplasia

21. RFA Meta-analysis Adverse Events Shaheen Gastroenterology 2011 Orman Clin Gastroenterol Hepatol 2013

22. AIM Dysplasia Extension Shaheen Gastro 2011 Orman Clin Gastroenterol Hepatol 2013 Wani Am J Gastroenterol 2009 Incidence of Progression to EAC

23. SURF Trial Phoa Gastroenterology 2013 European multicenter RCT of RFA vs Surveillance in LGD N = 136 randomized in 1:1 Primary outcome – Neoplastic progression (HGD or EAC) at 3 years after randomization Interim results at median 21 mos follow up presented at DDW 2013

24. SURF Trial Phoa Gastroenterology 2013 Efficacy of RFA @ 12 mos

25. SURF Trial Phoa Gastroenterology 2013 Incidence Rate of Progression to ECA

26. Cost Effectiveness of RFA Hur Gastroenterology 2012 Computer model RFA and surveillance strategies of 50 year old “patients” followed until age 80 or death. Possible causes of death – Age related all cause mortality – RFA complications – Surgical esophagectomy mortality – Esophageal adenocarcinoma

27. Cost Effectiveness of RFA Hur Gastroenterology 2012 LGD cohort – Confirmed  assume no initial diagnostic error – Stable  LGD found on more than one EGD at least 6 months apart Management – Endoscopic surveillance q 6 months x 1 year, then yearly – RFA at 0, 2, 4, 9 mos, then “touch up” RFA as needed

28. Cost Effectiveness of RFA Hur Gastroenterology 2012 RFA Outcomes – Residual dysplasia – CE-D – CE-IM – Recurrence of IM – Sub squamous intestinal metaplasia Incremental cost effective ratio (ICER) Willingness to pay (WTP) set at $100,000/QALY

29. Cost Effectiveness of RFA Hur Gastroenterology 2012 Surgery RFA

30. Cost Effectiveness of RFA Hur Gastroenterology 2012 Willingness to Pay < $ 100,000 per QALY

31. Barrett’s Esophagus and EoE Ravi Am J Gastroenterol 2011 Cross sectional study of 200 patients with BE 14 of 200 patients with BE (7%) found to have > 15 eosinophils/hpf on squamous biopsy

32. Post RFA Esophageal Eosinophilia Villa Dis Esophagus 2013 Retrospective review of 148 patients with pre and post RFA esophageal biopsies 4 of 148 patients (2.7%) developed esophageal eosinophilia at 12 months – All four had LGD – None had clinical or endoscopic findings suggestive of EoE – No pre RFA biopsies of squamous epithelium – Adverse events not reported

33. Safety of Esophageal Dilation in EoE Jung GIE 2011 Cohen Clin Gastroenterol Hepatol 2007 Retrospective single center study N = 293 dilations in 161 patients – 9.2% mucosal tear – 0.3% major bleeding – 1% immediate perforation All treated without surgery Prior study of 36 patients with complication rate of 31% and perforation rate of 8%

34. Thank you Dr. Marcelo Vela Dr. Nicolas Villa

35. Prasad G, Talley N, Romero Y, et al. Prevalence and predictive factors of eosinophilic esophagitis in patients presenting with dysphagia: a prospective study. The American journal of gastroenterology 2007;102:2627-2632. Wolfsen H, Hemminger L, Achem S. Eosinophilic esophagitis and Barrett's esophagus with dysplasia. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2007;5. Rodrigo S, Abboud G, Oh D, et al. High intraepithelial eosinophil counts in esophageal squamous epithelium are not specific for eosinophilic esophagitis in adults. The American journal of gastroenterology 2008;103:435-442. Shaheen N, Sharma P, Overholt B, et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. The New England journal of medicine 2009;360:2277-2288. Wani S, Puli S, Shaheen N, et al. Esophageal adenocarcinoma in Barrett's esophagus after endoscopic ablative therapy: a meta-analysis and systematic review. The American journal of gastroenterology 2009;104:502-513. Jacobs J, Spechler S. A systematic review of the risk of perforation during esophageal dilation for patients with eosinophilic esophagitis. Digestive diseases and sciences 2010;55:1512-1515. American Gastroenterological A, Spechler S, Sharma P, et al. American Gastroenterological Association medical position statement on the management of Barrett's esophagus. Gastroenterology 2011;140:1084-1091. Hvid-Jensen F, Pedersen L, Drewes A, et al. Incidence of adenocarcinoma among patients with Barrett's esophagus. The New England journal of medicine 2011;365:1375-1383. Ravi K, Katzka D, Smyrk T, et al. Prevalence of esophageal eosinophils in patients with Barrett's esophagus. The American journal of gastroenterology 2011;106:851-857. References

36. Shaheen N, Overholt B, Sampliner R, et al. Durability of radiofrequency ablation in Barrett's esophagus with dysplasia. Gastroenterology 2011;141:460-468. Spechler S, Sharma P, Souza R, et al. American Gastroenterological Association technical review on the management of Barrett's esophagus. Gastroenterology 2011;140. Hur C, Choi S, Rubenstein J, et al. The cost effectiveness of radiofrequency ablation for Barrett's esophagus. Gastroenterology 2012;143:567-575. Dellon E, Gonsalves N, Hirano I, et al. ACG clinical guideline: Evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). The American journal of gastroenterology 2013;108:679. Orman E, Li N, Shaheen N. Efficacy and durability of radiofrequency ablation for Barrett's Esophagus: systematic review and meta-analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2013;11:1245-1255. Villa N, El-Serag H, Younes M, et al. Esophageal eosinophilia after radiofrequency ablation for Barrett's esophagus. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus / I.S.D.E 2013;26:674-677. Falk G. Update on ablation for Barrett's esophagus. Current gastroenterology reports 2014;16:368. Fitzgerald R, di Pietro M, Ragunath K, et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus. Gut 2014;63:7-42. References

37. AIM Dysplasia Trial Eradication of IM @ 12 mos Shaheen NEJM 2009

38. AIM Dysplasia Extension Shaheen Gastro 2011 2 year extension of AIM Dysplasia Original control arm offered cross over to RFA N = 119 – 106 patients completed 2 nd year of follow up 100 eligible for extension through year 5 – 56 completed 3 rd year of follow up at time of publication Durability of eradication of both dysplasia and metaplasia assessed at 2 nd and 3 rd year

39. AIM Dysplasia Extension Shaheen Gastro 2011 Durability of CE-IM

40. AIM Dysplasia Extension Shaheen Gastro 2011 Progression of Dysplasia 5 of 119 (4.3%) with progression of any type 3 LGD  HGD – 2 with eventual CE-IM – 1 with EMR of focal HGD and withdrew from study 1 LGD to EAC – Initially randomized to Sham arm x 12 mos – RFA x 3 after crossing over – Eventual EMR of focal EAC 1 HGD to EAC – EMR of focal EAC – Eventual CE-IM at 3 years

41. RFA Meta-analysis Efficacy of RFA – 3802 patients 2135 patients in RFA registry from 148 community and academic practices Durability of RFA – 540 patients Orman Clin Gastroenterol Hepatol 2013

42. RFA Meta-analysis Orman Clin Gastroenterol Hepatol 2013 IM Recurrence

43. Cost Effectiveness of RFA Hur Gastroenterology 2012 Assumptions – NDBE  EAC 0.12%, 0.33%, 0.50% – LGD  EAC 0.19%, 0.5%, 0.75%

44. Eosinophilic Esophagitis Symptoms – Dysphagia, Food impaction – Reflux – Dyspepsia Associated with atopy Requires > 15 eos per HPF on biopsy

45. Overlap of EoE and GERD Attwood Am J Gastroenterol 1993

46. Overlap of EoE and GERD Rodrigo Am J Gastroenterol 2008

47. Diagnosis of EoE Dellon Am J Gastroenterol 2013