Preventing post-operative recurrence Dr Oliver Brain Oxford - - PowerPoint PPT Presentation

Oxford Inflammatory Bowel Disease MasterClass

Preventing post-operative recurrence

Dr Oliver Brain Oxford

Disclosures

 Presented at IEE, Oxford 2013 AbbVie sponsored meeting

Talk Outline

 Risk factors for recurrence  Diagnosis of recurrence (briefly)  Evidence for recurrence prevention

Preventing post-op recurrence in CD

 An important question  Goes to the heart of our understanding (or lack) of the biology of this disease  Recurrence in the absence of macro or microscopic disease  Why at the anastomosis?1-3

• 1. Rutgeerts P et al Gut 1984;25:665-672. 2. Rutgeerts P et al Gastroenterology 1990;99:956-963. 3.Olaison G et al Gut 1992;33:331-335

Pre-OP

Paneth Cell T Cell Macrophage DC Mucus Fibroblast

Post-OP

Paneth Cell T Cell Macrophage Mucus DC DC Fibroblast

Crohn‟s phenotype over time

Cosnes J et al Inflamm Bowel Dis 2002;8(4):244

Factors that may affect recurrence

 Patient-related  Disease-related  Surgery-related

• Smoking (at least doubles recurrence rate)1,2*
• Family history
• Genetics
• Age of onset*
• Disease duration
• Disease location – perianal disease3*
• Disease behaviour – penetrating disease4*
• Granulomas
• Myenteric plexitis
• Prior resection5*
• Extensive SB resection5,6*
• Resection margins
• Anastomosis type
• Strictureplasty
• Laparoscopic vs open

* ‘Reliable’ predictors

• Mutable
• Potentially mutable
• Immutable
• 1. Reese GE et al Int J Colorectal Dis 2008;23:1213-1221. 2. Ryan WR et al Am J Surg 2004;187:219-25 3. Hofer B et al Hepatogastoenterology 2001;48:152-5 4.

Simillis et al Am J Gastroenterol 2008;103:196-205 5. Bernell O et al Br J Surg 2000;87:1697. 6. Welsch T et al Int J Colorectal Dis 2007;22:1043-9

Approach to Treatment

Immediate Delayed No treatment

Pros

• Disease behaviour

modification

• Prevention of

surgery / bowel length preservation

• Identifiable need
• Known outcomes in

absence of treatment

• No treatment risk
• Primum non nocere

Cons

• Ad hoc patient

selection and ?overtreatment

• Ltd data of disease

modification

• Limited data of

disease modification

• Disease will almost

invariably reoccur

• Disease morbidity
• When should we stop treatment?

Defining Recurrence

 Clinical  Faecal / serum markers  Endoscopic  Capsule endoscopy  Radiological – MR, CT, US, SBE  Surgical

Defining Recurrence

 Clinical – Symptoms, CDAI (or CRP) underestimate recurrence1-3

• 1. Viscido A et al Ital J Gastroenterol Hepatol 1999;31:274-279. 2. Regueiro et al Gastroenterology 2009;136:441-450e1. 3.Walters TD et al Inflamm Bowel Dis

2011;17:1547-1556. 4. Rutgeerts P et al Gut 1984;25:665-672

 Endoscopy – remains the gold standard

 New lesions can be visualised within weeks to months  Mismatch / lag between endoscopic recurrence and symptoms

 At 1 year 73% endoscopic vs 20% clinical4

Crohn‟s disease recurrence - Endoscopic

 Rutgeerts score1:

Score POR risk 0-1 <10% at 10 yr 2 40% risk at 5 yr 3-4 50-100% risk at 5 yr

• 1. Rutgeerts P et al Gut 1984;25:665-672

i0 No lesions i1 ≤5 apthous lesions i2 >5, skip lesions, anastomotic lesions i3 Diffuse apthous ileitis i4 Diffuse with larger ulcers +/- narrowing

Crohn‟s disease recurrence - Surgical

The problem:

 80% patients with Crohn’s disease require at least one resection1  Surgery rates did not decline significantly in immunomodulator era2  A small number of patients with CD develop short bowel syndrome

• 70% patients with CD require >1 resection over lifetime3-5
• 15% surgical recurrence in 5 years6

1. Caprili R et al Gut 2006;55(suppl 1):i36-58. 2. Cosnes J et al Gut 2005;54:237-241 3. Chardavoyne et ak Dis Colon Rectum 1986;29:495-502.

• 4. Lock et al NEJM 1981;304:1586-1588. 5. Landsend E et al Sand J Gastroenterol 2006;41:1204-1208. Peyrin-Biroulet L et al Am J Gastroenterol 2010;105:289-297

Medical therapies trialed

 Antibiotics  5 ASA compounds  Steroids  Enteral nutrition  Probiotics  Immunomodulators  Anti-TNF agents  Other biologics

Imidazole Antibiotics

 RCT metronidazole 20mg/kg/day vs placebo for 3 months1  RCT ornidazole 1g/day vs placebo for 1 year2

 1 yr endoscopic recurrence RR 0.44 (95% CI 0.26-0.74)3  1 yr clinical recurrence RR 0.23 (95% CI 0.09-0.57)3  NNT 4

But:

 Effect sustained only to 1 year  Higher rates adverse events RR 2.39 (95 CI 1.5-3.7) and withdrawal

• 1. D‘Haens GR et al Gastroenterology 2008;135:1123-1129. 2. Rutgeerts P et al Gastroenterology 2005;128:856-861. 3. Doherty GA et al Aliment Pharmacol Ther

2010;31:802-809

Budesonide

 Two placebo-controlled trials of 3mg and 6mg / day1,2  At 1 year post-op no improvement in:

 Endoscopic recurrence  Clinical recurrence

 In addition:

 ½ patients on steroids post-op develop dependence or resistance at 1 year3

1.Ewe K et al Eur J Gast Hep 1999;11:277-282. Hellers G et al Gastroenterology 1999;116:294-300.

• 3. Irving PM et al Aliment Pharmacol Ther 2007;26:313-329

5-ASA compounds

 Mesalazine

 3 x Meta-analyses:

 Reduced post-op recurrence by 13%1  No more effective than placebo2  Decreased clinical but not endoscopic recurrence, and inferior to Aza/ 6-MP3

 Cochrane review4

 NNT 12 to prevent clinical recurrence

 Sulfasalazine

 No benefit demonstrated4

1.Camma et al Gastroenterology 1997;113:1465-1473.2. Ford AC et al Am J Gastroenterol 2011;106:617-29 3. Doherty GA et al Gastroenterology 2009;136. 4. Doherty G et al Cochrane Data Sys Rev 2009:CD006873

Enteral Nutrition

 Evaluated in a single prospective non-randomised study1

 40 pts, post-op ileal / ileo-caecal CD  20 pts self-administered nocturnal NG enteral feed

 At 1 year:  Unlikely to be widely applicable

• 1. Yamamoto T et al Aliment Pharmacol Ther 2007;25:67-72

Control Enteral nutrition P value Clinical recurrence 35% 5% 0.048 Endoscopic recurrence 70% 30% 0.027

Probiotics

 Insufficient evidence of efficacy  Studies of: Lactobacillus johnsonii1,2

Lactobacillus rhamnosus strain GG3 Synbiotic 20004 VSL3♯5

 Metanalysis found probiotics ineffective to prevent endoscopic or clinical recurrence6

1. Marteau P et al Gut 2006;55:842-847. 2.Van Gossum A et al Inflamm Bowel Dis 2007;13:135-142. 3. Prantera C et al Gut 2002;51:385-389

• 4. Chermesh I et al Dig Dis Sci 2007;52:385-389. 5. Madsen K et al Gastroenterology 2008;134. 6. Doherty GA et al Aliment Pharmacol Ther 2010;31:802-809

Recombinant IL-10

 One placebo-controlled trial1  Tenovil given in 2 different regimens  37 Tenovil and 21 placebo patients had colonoscopy  At 12 weeks post-op no difference in:

 Endoscopic recurrence  Clinical recurrence

• 1. Colombel JF et al Gut 2001;49:42-46

Thiopurines – Inflammation

 Meta-analysis1 (inc 4 RCTs)

 Thiopurines more effective than control (placebo, antibiotics, 5ASA) at:

 2 years: mean difference 13% (95% CI 2-24%); NNT 8 (clinical)  1 year: Prevents recurrence Rutgeerts i2-i4, but not severe i3-i4

 Thiopurines more effective than placebo at:

 1 year: mean difference 23% (95% CI 9-37%); NNT 4 (endoscopic)

• 1. Peyrin-Biroulet L et al Am J Gastroenterol 2009;104:2089-2096. 2. Ardizzone et al Gastroenterology 2004;127:730-740.

Thiopurines – Further Surgery

 Retrospective review of 326 pts1

 46 pts required reoperation  > 3 years thiopurine  27% reoperation rate  < 3 months thiopurine  55% reoperation rate (p<0.004)

Papay P et al Am J Gastroenterol 2010;105:1158

Anti-TNFs and Post-Op CD

 Assumptions we might make:

 Early instigation of treatment is better1-4  Anti-TNF can maintain remission5 (in responders)  Dual immunosuppression is better6,7  We use anti-TNF in those with more severe disease8  We can prevent further surgery  Longer duration of treatment is better

1. Hanauer S et al Lancet 2002;359:1541-1549. 2. Hymas J et al Gastroenterology 2007;132:863-873. 3. Peyrin-Biroulet L et al Gastroenterology 2008;135:1420-

• 1422. 4. Colombel J-F et al Gastroenterology 2007;132:52-65. 5. Behm BW et al Cochrane Rev 2008. 6. D‘Haens G et al Lancet 2008;371:660-7. Colombel et al

NEJM 2010 ;362:1383-95

Early dual immunosuppression

D‘Haens G et al Lancet 2008;371:660-7

Infliximab – Preventative Strategy

 One published RCT1

 24 pts to IFX or placebo immediately post-op  IFX group: *more smokers 46% vs 8% *fewer immunomodulators 36% vs 54%  At 1 year endo recurrence (i2-i4):

 Other prospective open label trials2-4 are small (total 33 IFX treated patients), but are largely reflective of this response

• 1. Regueiro et al Gastroenterology 2009;136:441-550. 2. Sorrentino et al 2007 Arch Intern Med 2007;167:1804. 3. Sakuraba et al Int J Colorectal Dis 2012;27:947.
• 4. Yoshida et al Inflamm Bowel Dis 2012;18:1617

Placebo Infliximab 11/13 (85%) 1/11 (9%)

Adalimumab – Preventative Strategy

 Small prospective studies  Overall similar response rates to Infliximab

Study Control Patients Follow-up Outcome Response Rates 1 NA 8 2 yr Endoscopic remission 75% 2 NA 29 (high risk) 1 yr Endoscopic remission 79%

• 1. Papamichael et al J Crohn‘s Colitis 2012;6:924-931. 2. Aguas et al World J Gastroenterol 2012;18:4391-4398. 3.

High risk = 2 or more of: smokers, penetrating disease, extensive resection, ≥2 resections

Anti-TNF agents – Reactive strategy

St u d y Drug Control Patie nts Time since surgery Follow-up Outcome Response rates 1 Ifx 5ASA or Aza 8 6 months 6 months Mucosal healing 38% 2 Ifx NA 6 1 year 1 year Endoscopic remission 50% 3 Ifx 5ASA 13 6 months 1 year Endoscopic remission 54% 4 Ifx or Ada NA 28 6 – 12 months NA Mucosal healing 50% 5 Ada NA 15 6 months 2 years Endoscopic remission 60%

• 1. Yamamoto et al 2009. 2 Regueiro et al 2010. 3 Sorrentino et al 2012. 4 Boueyre et al 2012. 5 Papamichal et al 2012.

Anti-TNF agents – Reactive strategy

St u d y Drug Control Patie nts Time since surgery Follow-up Outcome Response rates 1 Ifx 5ASA or Aza 8 6 months 6 months Mucosal healing 38% 2 Ifx NA 6 1 year 1 year Endoscopic remission 50% 3 Ifx 5ASA 13 6 months 1 year Endoscopic remission 54% 4 Ifx or Ada NA 28 6 – 12 months NA Mucosal healing 50% 5 Ada NA 15 6 months 2 years Endoscopic remission 60%

• 1. Yamamoto et al 2009. 2 Regueiro et al 2010. 3 Sorrentino et al 2012. 4 Boueyre et al 2012. 5 Papamichal et al 2012.

Anti-TNF– High risk phenotype

 11 patients with multiple operations (≥2). Median 4.

 3 smokers, 9 perianal disease, 9 previous 6-MP

 IFX 5mg/kg started 2-4 weeks post-op, not randomised

 Clinical remission at 2 years: 60%  Endoscopic remission at 2 years: 40%

Sakuraba et al Int J Colorectal Dis 2012;27:947.

Anti-TNF or Thiopurine?

• High risk pts

 Open-label pilot. Prospective, randomised1.  22 patients – high risk, post-ileocaecal resection  After 1 year:

• 1. Armuzzi et al JCC 2013 (Epub)

Infliximab Azathioprine P value Endoscopic recurrence 9% 40% 0.14 Histological recurrence (severe) 18% 80% 0.008 ‘High risk’ = 2 or more of: age < 30 at diagnosis; penetrating disease; previous surgery.

Anti-TNF– Preventing further surgery?

 Pair-matched study

 100 post-op patients who received IFX  Matched by gender, Vienna classification, age at operation  Median follow-up:  Surgical recurrence:

Araki T et al Surg Today 2013 Mar 6 (Epub)

IFX Control 36 months 51 months IFX Control 3/100 34/100 HR 0.22 (95% CI 0.11-0.44)

How long should we treat?

 Small study, not controlled1  12 patients in endoscopic and clinical remission after 3 years IFX therapy (post-op)  Re-scoped 4 months later 10/12 (83%) developed endoscopic recurrence Re-introduction IFX at 3mg/kg restored response

• 1. Sorentino et al Clin Gastroenterol Hepatol 2010;8:591-599

Summary 1 – Effective Therapies

 5 ASA – minimal efficacy  Imidazole antibiotics  Enteral nutrition  Thiopurines – Most effective of non-biologic therapies  Anti-TNF – most effective, and ?better if used early

 No data on dual immunosuppression in this setting

} Tolerance problems / not widely applicable

Summary 2 – General Approach

 Start with a good surgeon  Individualised approach  Consider risk factors for severe disease  Bowel length preservation

• No medication for low risk disease, colonoscopy 6-12 months
• Thiopurines for moderate risk disease / i2-?i3 disease
• Anti-TNF +/- thiopurines high risk disease / i3-4 disease

 Stop smoking  Endoscopic follow-up 6- 12 months

Examples of my approach

Patient 1 Patient 2 Patient 3

• 26 yr old man
• 1st presentation.
• Smoker
• Stenosing isolated TI

disease.

• Ileo-caecal resection
• Stops smoking post-op
• 28 yr old woman
• CD diagnosed age 19
• Non-smoker
• Age 21 Rt

hemicolectomy for ileo- caecal disease (stenosis)

• 5ASA 1 year post-op
• Ileal resection (stenosis)
• 34 yr old man
• CD diagnosed 29
• Non-smoker
• Appendectomy age 27
• Azathioprine for 4 years
• 30cm TI resection plus 6

SB strictureplasties

• At resection has entero-

enteric fistula

• No treatment
• Colonoscopy 6 months
• Thiopurine
• Colonoscope 6-12

months

• Anti-TNF +/- thiopurine
• Colonoscope and MRI SB

at 6-12 months year