1. CP913721- 0 The Evolving Role of Surgery in IBD John Pemberton Advances in IBD, December, 2012 The Evolving Role of Surgery in IBD John Pemberton Advances in IBD, December, 2012

2. CP913721- 1 The Evolving Role of Surgery Safety and effectiveness of strictureplasty Approach to patients with complex perineal CD When is enough medical management of patients with CUC enough? Just how well is IPAA performing? Controversies concerning IPAA How do biologics impact surgery for IBD?

3. CP913721- 2 The Evolving Role of Surgery How safe is IPAA in IC patients? In CD patients? When is colectomy indicated for patients with dysplasia? Can you do IPAA in IBD patients with CRC? What is the risk of CRC after IPAA Are enhanced recovery programs helpful?

4. CP913721- 3 The Evolving Role of Surgery Is there a potential downside to attempts to control CD or CUC medically over longer and longer periods of time?

5. CP913721- 4 Strictureplasty CP1111844-8

6. CP913721- 5 Crohn Disease Rationale for Strictureplasty CP1111844-12 Disease involves whole intestine Impossible to cure by excision All diseased bowel does not need excision If only stenotic complications are present, these can be relieved without excision Disease involves whole intestine Impossible to cure by excision All diseased bowel does not need excision If only stenotic complications are present, these can be relieved without excision

7. CP913721- 6 Evolution toward more complex strictureplasties

8. CP913721- 7 The Evolving Role of Surgery Michelassi LONG side to side strictureplasty

9. CP913721- 8 2 The Evolving Role of Surgery Strictureplasty Campbell, L; Ambe, R; Weaver, J; et al DCR 2012 55(6):714-726.

10. CP913721- 9 2 The Evolving Role of Surgery Strictureplasty Complications Bellolio, F; Cohen, Z; MacRae, H; et al DCR 55(8):864-869, August 2012.

11. CP913721- 10 2 The Evolving Role of Surgery Strictureplasty Surgery-free survival Strictureplasty in Selected Crohn's Disease Patients Bellolio F, Cohen Z, MacRae, H, et al DCR 2012 55:864-869

12. CP913721- 11 CP1043353-62 AN APPROACH TO PATIENTS WITH PERINEAL FISTULAS AND CD

13. CP913721- 12 Evolution toward upfront aggressive COMBINED medical AND surgical therapy for perineal Crohn’s Diease

14. CP913721- 13 Surgery for Crohn Disease Combination Therapy * Initial Response (%) Recurrence(%) Time to Recurrence (Months) Infliximab82793.6 EUA + Seton + Infliximab 1004413 *Regueiro M & Mardine H. Inflammatory Bowel Diseases, March 2003, 9(2):98-103

15. CP913721- 14 Response Based on Type of Fistula CP1112779-4 Regueiro M et al: Inflam Bowel Dis 9(2):98, 2003 EUA and InfliximabEUA andInfliximab infliximabaloneinfliximabalone n=3n=9Pn=6n=14P Initial response 3 9 1.000 6 10 0.026 100%100%100%71.5% Recurrence rate 150.232 3100.036 33.3% 56% 50%100% Mean time to15 5.20.00413 2.140.001 recurrence (mo) EUA and InfliximabEUA andInfliximab infliximabaloneinfliximabalone n=3n=9Pn=6n=14P Initial response 3 9 1.000 6 10 0.026 100%100%100%71.5% Recurrence rate 150.232 3100.036 33.3% 56% 50%100% Mean time to15 5.20.00413 2.140.001 recurrence (mo) Simple fistula Complex fistula

16. CP913721- 15 Surgery for Crohn Disease Infliximab & Perineal Fistula “For perianal fistulizing CD, repeat doses of Infliximab improves clinical and radiological outcomes, although complete radiologic healing occurs in a minority of patients” * “For perianal fistulizing CD, repeat doses of Infliximab improves clinical and radiological outcomes, although complete radiologic healing occurs in a minority of patients” * *Rasul I et al. Am J Gastro 2004;99:82-88 *Rasul I et al. Am J Gastro 2004;99:82-88

17. CP913721- 16 Surgery for Perineal Crohn Disease Summary Perianal fistulous disease is rarely curedPerianal fistulous disease is rarely cured Rather, fistulas are controlled by a combined approach including surgery (seton), immunosuppressives antibiotics and infliximabRather, fistulas are controlled by a combined approach including surgery (seton), immunosuppressives antibiotics and infliximab Setons are used to keep the tracts open, eliminating accumulation of pus and fostering tract quiescenceSetons are used to keep the tracts open, eliminating accumulation of pus and fostering tract quiescence

18. CP913721- 17 Surgery for Perineal Crohn Disease Summary When the tracts are dry, the setons are removedWhen the tracts are dry, the setons are removed The perineum is reexamined regularlyThe perineum is reexamined regularly Only if fecal incontinence intervenes is proctectomy discussedOnly if fecal incontinence intervenes is proctectomy discussed

19. CP913721- 18 Risk factors for Proctectomy 5 yr. Extensive fistula/abscess vs simpleExtensive fistula/abscess vs simple 26% vs. 6% Severe Proctitis vs none or mildSevere Proctitis vs none or mild 37% vs. 10% Severe proctitis and extensive fistula/abscessSevere proctitis and extensive fistula/abscess 46% proctectomy rate

20. CP913721- 19 Fecal Diversion Patients undergoing diversion for perineal CD have <20% chance of successful restoration of intestinal continuity which is NOT improved with biologic therapy Hong MK et al Colorectal Dis 2011 13 (2); 171-6However….. Fecal diversion is useful to quiet the perineum prior to repairing an R-V fistula and to promote healing postoperatively Fecal diversion is useful to quiet the perineum prior to repairing an R-V fistula and to promote healing postoperatively

21. CP913721- 20 Chronic Ulcerative Colitis

22. CP913721- 21 Evolution Toward reasonable time frames for managing aggressive disease

23. CP913721- 22 Surgery for CUC…. when is enough, enough?,For outpatients, it seems reasonable to treat with 5 ASA preparations, topical steroids, oral steroids, AZA and biologics until unable to steroid spare effectively For inpatients, reasonably aggressive treatment includes; IV steroids & IFX for 5 days [bleeding, >10 stools indicates fulminant disease] For deteriorating inpatients, GI & Surgeon need to decide together when enough is enough High grade dysplasia signifies enough is enough Low grade dysplasia probably signifies the same

24. CP913721- 23 IPAA

25. CP913721- 24 Ileal Pouch-Anal Anastomosis Evolution Straight IPAA S pouch J pouch Long cuff Short cuff Double- stapled Laparoscopic IPAA (LAP, HALS,SILS) CP998061-4

26. CP913721- 25 Evolution of the IPAA data set

27. CP913721- 26 IPAA Mayo Experience 1/8/1981 – 12/31/2011 Total : 3405 CUC : 3048 FAP : 304 “other”: 53

28. CP913721- 27 Hahnloser D, Pemberton JH, Wolff BG et al Ann Surg. 2004 Oct;240(4):615-21 1981-2001 1,885 IPAA for CUC complete annual follow-up for 15 years n=409 annual questionnaire (prospective database) – function and continence – QoL – complications (excluding pouch failure)

29. CP913721- 28 IPAA 5 10 20 50 100 Cumulative Probability of Pouch Success 92% at 21 yr Pouch Success Years after IPAA Hahnloser D, Pemberton JH, Wolff,BG et al BJS 2007;94:333-340

30. CP913721- 29 Function (n=409) years follow-up 151015 Age (years) 33384349 Stool frequency Mean Stools/day 5.55.65.66.2 p <.001 Mean Stools/night 1.11.31.52.0 p <.001 Hahnloser D, Pemberton JH, Wolff BG Ann Surg 2004;240: 615–623

31. CP913721- 30 Complications Pouchitis 100 80 60 40 20 0 0 5 10 15 Years after IPAA cumulative probability (%) Pouchitis

32. CP913721- 31 Quality of Life Social Activities improvednot affectedmildly restrictedseverly resticted 5 10 15 5 10 15 5 10 15 5 10 15 5 10 15 5 10 15 5 10 15 Years after IPAA ns

33. CP913721- 32 Quality of Life Social Work at Activities Home improvednot affectedmildly restrictedseverly resticted 5 10 15 5 10 15 5 10 15 5 10 15 5 10 15 5 10 15 5 10 15 Years after IPAA ns

34. CP913721- 33 Quality of Life Social Work at Family Activities Home Relationship improvednot affectedmildly restrictedseverly resticted 5 10 15 5 10 15 5 10 15 5 10 15 5 10 15 5 10 15 5 10 15 Years after IPAA ns

35. CP913721- 34 Quality of Life Social Work at FamilyTravel Sports Recreation Sexual Activities Home Relationship Life improvedaffectedmildly restrictedseverly resticted ns

36. CP913721- 35 Summary with ageing… good functional outcome good and stable QoL

37. CP913721- 36 Conclusion IPAA is a durable operation with a good QoL and stable predictable outcomes over time

38. CP913721- 37 Minimally Invasive Surgery and IPAA

39. CP913721- 38 Evolution toward Minimally Invasive Surgery (MIS) for IBD (Laparoscopy/Hand Assisted Laparoscopy (HALS)

40. CP913721- 39

41. CP913721- 40 HALS IPAA Wt.= 227, BMI= 35.2

42. CP913721- 41 IPAA (2007) Total performed114 Open29 Minimally Invasive85 (75%) LAP/HALS37/48 (57%)

43. CP913721- 42 Surgical Evolution Age - Age - 32pts >65 y/o matched to 32pts<65y/o Outcomes: older pts. had more readmission for volume depletion but functional results were the same over time (Pinto RA etal Colorectal Dis 2011;13;177-83)

44. CP913721- 43 Surgical Evolution Fertility - Fertility - Weighted average infertility rate during medical treatment = 15% after IPAA = 48 % (Waljee A et al. Gut 2006;55:1575-1580) - Fecundity (probability of conception) is decreased after IPAA - Fecundity (probability of conception) is decreased after IPAA (Olsen KO et al br J Surg 1999;86:493-495) - Ability to carry a pregnancy to term is not affected. - Ability to carry a pregnancy to term is not affected. ) (Hahnloser et al Dis Colon Rectum. 2004 Jul;47(7):1127-35) - Subtotal colectomy and BI or IRA is offered to young women who wish to become pregnant - Subtotal colectomy and BI or IRA is offered to young women who wish to become pregnant

45. CP913721- 44 Surgical Evolution Fewer pelvic/adnexal adhesions form after laparoscopic pelvic dissection* and Patients undergoing lap IPAA have a higher fertility rate than open patients** Laparoscopic IPAA may be the POC *Indar AA, Efron JE, Young-Fadok TM Surg. Endosc 2009: 23:174-177 **Bartels S et al Ann Surg. 2012 May 17. [Epub ahead of print]

46. CP913721- 45 Biologics and Surgery for IBD

47. CP913721- 46 The widespread use of biologics has prompted a change in the surgical management of patients with CUC

48. CP913721- 47 Surgical Challenges in IBD IFX and Surgical Complications CD only Author Complication Odds Ratio Marchal* Early Major 1.7 (.3-7.7) Belgium Late Major 1.4(.4-5.0) Colombel** Septic.9 (.4-1.9) Mayo Non septic 1.0 (.5-2.0) Nasir*** All Complic 30.3 (TNF) v 27.9% Mayo Abscess/leak 1.99 (TNF) v 3.4% Appau****30 d readmit 2.3 (1-5.3) CCF 30 d sepsis 2.6 (1.1-6.1) 30 d abscess 5.8 (1.7-19.7) * Aliment Pharmacol Ther 2004;19:749-54 ** AM J Gastroenterol 2004;99:878-83 ***J Gastrointes Surg 2010 14:1859-1866 ****J Gastrointes Surg 2008;12:1738-44

49. CP913721- 48 Surgical Challenges in IBD IFX and Surgical Complications CUC only AuthorComplicationOdds Ratio Selvasekar Pouch specific2.6 (09-7.5) Mayo Infectious 2.7 (1.1-6.7) Schluender Surgery1.9 (.6-5.9) Cedars Infectious2.4 (.6-9.6) MorSepsis13.8 (1.8-105) CCF Ferrante Pouch specific.9 (.8-.9) Belgium Infectious.3 (.07-1.4)

50. CP913721- 49 Pharmacokinetics of the Biologics Half livesHalf lives Infliximab (IFX) = 10-12 days Adalimumab = 14 days Certolizumab = 14 days Natalizumab = 11 days For all, drug is still detectable at 8 weeks with complete clearance by 12 weeks

51. CP913721- 50 Surgery and Biologics Evolution Because CUC patients are at higher risk for post-operative infectious complications when treated with a biologic, in order to maximize the chances of success of the operation Consider more liberal use of subtotal colectomy prior to IPAA (3 staged IPAA)

52. CP913721- 51 IPAA for Crohn’s Disease Evolving

53. CP913721- 52 IPAA for CD Among 20 CD patients in whom IPAA was intentionally performed:* Pouch in place-85% Fistula-19 % Pouch/vag. Fistula-13% Stricture -17% Sepsis – 12% Urgency-30% Incontin.- 28% No. stools – 7 Mean F/U = 5yr Melton GB Fazio VW, Kiran RP et al. Ann Surgery.2008;248:608-616

54. CP913721- 53 IPAA for CD Comment Patients with an IPAA constructed for CD may have better long-term outcomes than patients with supervening CD of the pouch The number of CD patients who are candidates for primary IPAA is tiny

55. CP913721- 54 In patients in whom CD develops AFTER IPAA Aggressive combined medical/surgical management

56. CP913721- 55 Management of Crohn’s of the Pouch with Infliximab Patients treated with Infliximab for CD- related complications after IPAA – ileitis, fistulasPatients treated with Infliximab for CD- related complications after IPAA – ileitis, fistulas Follow-up No. Partial Complete No Resp. Short-term 26 23% 62% 15% Short-term 26 23% 62% 15% Long-term* 24 29 29% 42% Long-term* 24 29 29% 42% *21 months Colombel, Sandborn, Dozois et al. Am J Gastro. 2003;98:2239 67% with functioning pouch

57. CP913721- 56 Management of dysplasia in patients with CUC Surgery

58. CP913721- 57 Management Scheme for Patients With CUC Undergoing Surveillance No dysplasia Continue surveillance Indefinite dysplasia Continue surveillance LGD (flat or sessile polyp) Colectomy HGD Colectomy CRC Colectomy

59. CP913721- 58 CRC in IBD Between 1-9% of patients presenting for IPAA will have CRC Surgery is based on established oncologic principles Colon cancer IPAA Rectal Cancer (mid-high Stage I and II)  IPAA Otherwise, TPC +BI

60. CP913721- 59 Dysplasia and Cancer IPAA Dysplasia and Cancer after IPAA

61. CP913721- 60 Dysplasia and Cancer IPAA Dysplasia and Cancer after IPAA Dysplasia in the ATZ : 7/210 (3%)* Associated with dysplasia or ACA in the colon or rectum at IPAA Dysplasia in the pouch : 0/37** (bx’d yearly x 7) Total number of patients with cancer in the pouch or anal canal reported as of May 2011= 36 Incidence = 0.0015%*** (3/2198) *O’Riordan MG, et al: DCR, 2000;43:1660-1665 **Ettorre GM. DCR, 2000; 43:1743-1748 (Rome) ***O’Riordan JM. Int J Colorectal Dis 2011 (Toronto) on-line publication ahead of print

62. CP913721- 61 ATZ and Pouch Surveillance Patients considered for post op surveillance : Pre op ACA or Dysplasia Ongoing severe pouchitis Pouches in place 15 yrs and longer

63. CP913721- 62 Enhanced Recovery Protocol (ERP) LOS = 2-5 days after IPAA

64. CP913721- 63 Surgical Evolution in IBD I Strictureplasty safe and efficacious Surgical drainage and IFX is TOC for perineal CD Role for fecal diversion=? If steroid sparing not achieved-colectomy IPAA is maturing Fertility issues prompt consideration of family first/BI/IRA

65. CP913721- 64 Surgical Challenges in IBD II Biologics affect recovery from IPAA adversely prompting consideration of 3 rather 2 staged IPAA Biologics not cleared for ~12 weeks IPAA not OK for CD HGD AND LGD prompt colectomy IPAA not contraindicated for all IBD pts. with CRC Incidence of CRC after IPAA= 0.0015% Enhanced recovery protocols are effective

66. CP913721- 65 Ongoing Surgical Challenges in IBD Quantifying patient centered/reported outcomes between medical and surgical treatment for IBD. Identify the optimal time for surgical intervention in CUC Identify high risk patients requiring alternate surgical planing to avoid complications Determine best follow-up regimen after IPAA Determine those most at risk for pouchitis preop and develop better management regimens. Identify the pertinent issues concerning fecundity in patients requiring IPAA Increasing utility of MIS in IBD (NOTES, SILS)

67. CP913721- 66 Thank-you