1. CCEB Thinking About Cancer Advances 2014 James D. Lewis, MD, MSCE Fernando Velayos, MD, MPH

2. Case #1 35 y.o. male recently diagnosed with ileocolonic CD35 y.o. male recently diagnosed with ileocolonic CD Now steroid dependentNow steroid dependent Treating physician recommends infliximab + azathioprineTreating physician recommends infliximab + azathioprine Patient is concerned about risk of cancer, and particularly lymphomaPatient is concerned about risk of cancer, and particularly lymphoma

3. Questions Does immunosuppressant therapy increase the risk of lymphoma?Does immunosuppressant therapy increase the risk of lymphoma? Do the benefits outweigh the risks?Do the benefits outweigh the risks? Is there a way to minimize the risk?Is there a way to minimize the risk?

4. AZA/6-MP & Lymphoma: Meta-analysis AuthorObservedExpected Connell00.52 Kinlen20.24 Farrell20.05 Lewis10.64 Fraser30.65 Korelitz30.61 Total112.71 SIR = 4.06, 95% CI 2.01 – 7.28 Kandiel A et al. Gut. 2005:54:1121-25 CCEB

5. CESAME - Lymphoma At cohort entry N# Lymphomas HR (95% CI) Never exposed to thiopurines 10,8106Reference On therapy with thiopurines 5,867165.3 (2.0 – 13.9) Previously discontinued thiopurines 2,80921.0 (0.2 – 5.1) Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7 CCEB

6. Anti-TNF Therapy and Any Cancer Accumulate d doses Person- years CasesAdjusted Rate Ratio (95% CI) Any19,559811.07 (0.85-1.36) 1-36694311.02 (0.71-1.47) 4-74664180.89 (0.55-1.42) 8+7083321.29 (0.90-1.85) Anderson NN. JAMA 2014;311:2406-13

7. Combination Therapy and Risk of Lymphoma Therapy# Lymph SIR95% CI Never thiopurine or TNF (1)61.50.5 – 3.2 Never thiopurine or TNF (2)331.00.96 – 1.1 Current thiopurine w/out TNF (1)136.53.5 – 11.2 Current thiopurine w/out TNF (2)41.41.2 – 1.7 Current TNF w/out thiopurine (2)00-- Current TNF + prior thiopurine (2)15.23.5 – 6.8 Current thiopurine + TNF (1)210.21.2 – 36.9 Current thiopurine + TNF (2)16.64.4 – 8.8 (1)Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7 (2)Herrinton L. Am J Gastroenterol 25 October 2011; doi: 10.1038/ajg.2011.283

8. Contribution of Thiopurines and TNF to Cancer Risk Osterman MT et al. Gastroenterology 2014;146: 941-9

9. Clinical Questions Does immunosuppressant therapy increase the risk of lymphoma?Does immunosuppressant therapy increase the risk of lymphoma? –Thiopurines – yes, but risk may revert after discontinuation –TNF – Possibly but appearing less likely with more data –Combination – Yes and possibly more than thiopurine monotherapy Do the benefits outweigh the risks?Do the benefits outweigh the risks?

10. Relationship of Age and Outcome with Azathioprine Therapy Lewis et al. Gastroenterology 2000;118(6): 1018-24 CCEB

11. Combination versus Anti-TNF Monotherapy Modeled across age ranges from 25 to 75 and across duration of therapy from 1 to 9 yearsModeled across age ranges from 25 to 75 and across duration of therapy from 1 to 9 years Assumes naïve to both drugsAssumes naïve to both drugs Allows for second anti-TNF in case of LORAllows for second anti-TNF in case of LOR Key effectiveness assumptions derived from SONIC, GAIN and CHARMKey effectiveness assumptions derived from SONIC, GAIN and CHARM Key lymphoma assumptions derived from CESAMEKey lymphoma assumptions derived from CESAME Scott FI. CGH 2014

12. One Year Outcomes Scott FI. CGH 2014

13. Age-Dependent Incidence of Lymphoma Scott FI. CGH 2014

14. Age and Duration Influence Preferred Strategy ***HSTCL (or HLH due to acute EBV infection) - Monotherapy becomes the preferred strategy if incidence in 25 year old male exceeds 36 per 100,000 per year *** Scott FI. CGH 2014

15. Clinical Questions Does immunosuppressant therapy increase the risk of lymphoma?Does immunosuppressant therapy increase the risk of lymphoma? –Thiopurines – yes, but risk may revert after discontinuation –TNF – Possibly but appearing less likely with more data –Combination – Yes and possibly more than thiopurine monotherapy Do the benefits outweigh the risks?Do the benefits outweigh the risks? –In most scenarios Is there a way to minimize risk?Is there a way to minimize risk?

16. Prevalence of EBV 20% to 40% of college freshmen20% to 40% of college freshmen >60% of recent college graduates>60% of recent college graduates >70% of young adults>70% of young adults Possibly even higher rates in other countriesPossibly even higher rates in other countries Niederman JC et al. NEJM 1970:282:361-5

17. Prevention of Immunosuppression Related Lymphoma Avoiding treatment in EBV infected often not feasibleAvoiding treatment in EBV infected often not feasible Consider avoiding thiopurines in young, EBV-negative patients to avoid fulminant infection and HLHConsider avoiding thiopurines in young, EBV-negative patients to avoid fulminant infection and HLH Consider discontinuation of medications that are not effective for IBD, particularly in young males and elderlyConsider discontinuation of medications that are not effective for IBD, particularly in young males and elderly

18. Case #2 50 year old male50 year old male 30 year history of small bowel Crohn’s30 year history of small bowel Crohn’s 1 prior bowel resection1 prior bowel resection Current meds – 6MP + AdalimumabCurrent meds – 6MP + Adalimumab 3 BM per day3 BM per day Colonoscopy – few scattered aphthous ulcers in the neo-TIColonoscopy – few scattered aphthous ulcers in the neo-TI

19. Clinical Scenario (cont) 2 years prior diagnosed with NMSC (BCC)2 years prior diagnosed with NMSC (BCC) 2 weeks ago newly diagnosed with SCC2 weeks ago newly diagnosed with SCC QuestionsQuestions –Is skin cancer risk increased by therapy? –If so, does the risk of continuing therapy outweigh the benefits?

20. Non-melanoma Skin Cancer Increased incidence in immunosuppressedIncreased incidence in immunosuppressed –Transplant patients – 65-250 x increase in SCC65-250 x increase in SCC 10 x increase in BCC10 x increase in BCC –HIV/AIDS –Proportional to degree of immunosuppression Increased severity of SCC in immunosuppressedIncreased severity of SCC in immunosuppressed Euvrard S. N Eng J Med 2003;348:1681-91 Maddox JS. Inflamm Bowel Dis 2008;14:1425–1431

21. Immunosuppression & Skin Cancer Ultraviolet lightImmunosuppressive Medications Inhibition of Antigen Presenting Cells P53 and other mutations Systemic Immunosuppression HPVSkin Cancer Adapted from Euvrard S. N Eng J Med 2003;348:1681-91

22. Thiopurines and Skin Cancer NMSCMELANOMA Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20 Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8 Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181

23. Anti-TNF and Skin Cancer NMSCMELANOMA Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20 Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8 Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181 NR

24. Duration of Immunosuppressant Therapy for IBD and NMSC Long M et al. CGH 2010;8 268-74 Pharmetrics Database - Nested case-control study Odds Ratio and 95% CI Recent and long term are not mutually exclusive

25. Timing of Thiopurines and NMSC: Conflicting Results CESAME Cohort VA UC Cohort Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8 Khan N. Am J Gastroenterol 2014: doi: 10.1038/ajg.2014.298 SIR and 95% CI

26. Clinical Questions Is skin cancer risk increased by therapy?Is skin cancer risk increased by therapy? –Thiopurines – yes –Biologics - probably If so, does the risk of continuing therapy outweigh the benefits?If so, does the risk of continuing therapy outweigh the benefits?

27. Maintenance of Remission After Withdrawal of Thiopurine Adapted from Van Assche et al. Gastroenterology 2008;134:1861–1868. CCEB

28. Continuation of Infliximab After Withdrawal of Thiopurine Adapted from Van Assche et al. Gastroenterology 2008;134:1861–1868. CCEB

29. Risk of Second NMSC 2751 Medicare Beneficiaries with 1 st NMSC 376 with 2 nd NMSC Thiopurines HR (95% CI) Anti-TNF HR (95% CI) Never useReference Recent use 0.72 (0.31-1.70)0.96 (0.34-2.70) <1 year current use 1.55 (0.88-2.75)1.32 (0.63-2.78) >1 year current use 1.41 (0.92-2.16)1.32 (0.74-2.34) Adjusted for other drug class, age, sex, median latitude, cumulative steroid exposure, and number of dermatology encounters in the year following surgery for the incident NMSC Scott FI. ACG 2014

30. Clinical Questions Is skin cancer risk increased by therapy?Is skin cancer risk increased by therapy? –Thiopurines – yes –Biologics - probably If so, does the risk of continuing therapy outweigh the benefits?If so, does the risk of continuing therapy outweigh the benefits? –In this case – consider stopping thiopurine Uncertain if risk will declineUncertain if risk will decline –Annual skin exam and regular use of sunscreen and hat

31. Case #3 28 y.o. female with small bowel CD has been managed with azathioprine for the last 8 years suddenly develops abdominal pain and dysuria28 y.o. female with small bowel CD has been managed with azathioprine for the last 8 years suddenly develops abdominal pain and dysuria CT demonstrates new inflammation of the jejunum that is abutting the bladder and pulmonary nodulesCT demonstrates new inflammation of the jejunum that is abutting the bladder and pulmonary nodules At surgery she is found to have a B cell non-Hodgkin lymphomaAt surgery she is found to have a B cell non-Hodgkin lymphoma

32. Questions How would you manage her CD during therapy for NHL?How would you manage her CD during therapy for NHL? What is the prognosis of IBD during and following chemotherapy?What is the prognosis of IBD during and following chemotherapy? How will you manage her disease if she has a relapse after completing chemotherapy?How will you manage her disease if she has a relapse after completing chemotherapy?

33. Treatment of Lymphoma EBV associated lymphoma can be initially managed with reduction in immunosuppressionEBV associated lymphoma can be initially managed with reduction in immunosuppression Rituximab monotherapy is effective but with relatively high relapse rateRituximab monotherapy is effective but with relatively high relapse rate R-CHOP (rituximab, often employedR-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) often employed Trappe R. Lancet Oncology 2012 Feb;13(2):196-206. Saha A. Clin Cancer Res May 15, 2011 17; 3056 Murukesan V. Drugs. 2012 Aug 20;72(12):1631-43.

34. Course of Crohn’s Disease Following Treatment of Lymhoma 9 Patients Treated for NHL Chemo (n=7) Ritux (n=1)No Rx (n=1) Pred / Bud (n=3) 6/9 Relapse (2 w/in 1 year) 1/9 New Dx 9 years later 2/9 No Relapse AZA / 6MP (n=2) MTX (n=1) Unk (n=1) SSA (n=1) No Rx (n=1) Mourabet MA. Inflamm Bowel Dis 2011;17:1265-9

35. Clinical Course During Chemotherapy for Cancer 15 Patients with Active IBD at Time of Cancer Diagnosis Cytotoxic Chemo Cytotoxic + Hormonal Chemo Hormonal Chemo 5/5 IBD in Remission 4/4 IBD in Remission 1/6 IBD in Remission Axelrod JE. Clin Gastroenterol Hepatol 2012:10:1021-7

36. Course of IBD Following Chemotherapy for Cancer 69 patients in remission at time of initiation of therapy Axelrod JE. Clin Gastroenterol Hepatol 2012:10:1021-7

37. Questions How would you manage her CD during therapy for NHL?How would you manage her CD during therapy for NHL? –Stop immunosuppression if possible –Antibiotics, prednisone or budesonide if needed, in discussion with oncologist What is the prognosis of IBD during and following chemotherapy?What is the prognosis of IBD during and following chemotherapy? –Fairly favorable, particularly if receiving cytotoxic chemotherapy

38. Questions How will you manage her disease if she has a relapse after completing chemotherapy?How will you manage her disease if she has a relapse after completing chemotherapy?

39. CESAME Cancer diagnosed >2 years prior to cohort entry Cancer diagnosed <2 years prior to cohort entry Total with cancer prior to cohort entry Colorectal504090 Breast592685 Uterine191332 Prostate16925 NMSC12921 All sites268153421 Beaugerie L. Gut 2014;63:1416–1423.

40. CEESAME Incident Cancer Incidence per 1000-p-y Incidence among 405 patients with history of cancer HR = 1.7 (1.3 – 2.1)HR NR (P>.05) Beaugerie L. Gut 2014;63:1416–1423.

41. Anti-TNF Therapy for RA after Curative Breast Cancer Treatment Biologic naïve (n=120) Anti-TNF exposed (n=120) Total person-years550592 Individuals with recurrent breast cancer 99 Rate/1000 p-y16 (7-31)15 (7-29) HR of recurrence cancerRef0.8 (0.3 – 2.1) Adjusted HRRef1.1 (0.4 – 2.8) Raaschou P. Ann Rheumatol Dis. 2014:205745 Cohorts matched on age at diagnosis, county of residence, stage at diagnosis Adjusted for nodal status, surgery type, chemothrapy, comorbidities

42. Questions How will you manage her disease if she has a relapse after completing chemotherapy?How will you manage her disease if she has a relapse after completing chemotherapy? –Limited data on which to base recommendations –Intuition tells us to avoid chronic immunosuppression if possible –Role of vedolizumab to be determined

43. Case #4 20 y.o. female was diagnosed with Crohn’s disease of the ileum. Presents to your ED complaining of increasing discomfort in the RLQ that is worse with meals. Mild bloating with meals. No fever. Mild-moderate RLQ tenderness. Prior colonoscopy had stenotic IC valve.20 y.o. female was diagnosed with Crohn’s disease of the ileum. Presents to your ED complaining of increasing discomfort in the RLQ that is worse with meals. Mild bloating with meals. No fever. Mild-moderate RLQ tenderness. Prior colonoscopy had stenotic IC valve.

44. Questions Would you recommend an imaging test and if so, which test?Would you recommend an imaging test and if so, which test? Does the risk of cancer influence your decision?Does the risk of cancer influence your decision? Would your decision be different if the patient was 60 y.o. rather than 20 y.o.?Would your decision be different if the patient was 60 y.o. rather than 20 y.o.?

45. Comparison of sensitivity/specificity of imaging tests in IBD Herfarth H and Palmer L. Dig Dis 2009; 27: 278 Horsthuis K et al. Radiology 2008; 247: 64

46. Radiation dose associated with common medical imaging tests Herfarth H and Palmer L. Dig Dis 2009; 27: 278

47. Diagnostic Medical Radiation and Cancer Risk CT is major source of diagnostic ionizing radiationCT is major source of diagnostic ionizing radiation –63 million CT performed in USA in 2006 Effects of radiationEffects of radiation –DNA breaks, point mutations, chromosomal translocations CT’s estimated to be responsible for 0.5-2% all cancers in USACT’s estimated to be responsible for 0.5-2% all cancers in USA Brenner DJ et al NEJM 2007; 357: 2277 Doll R et al. J Natl Cancer Inst 1981; 66: 1191

48. Radiation and IBD Levi Z, et al. DDW 2008: #119; Desmond AN, et al. DDW 2008: #120; Panes J et al DDW 2008#121 271 male, 280 female pts UC/CD271 male, 280 female pts UC/CD –13.6% CD, 4.5%UC > 40 mSV radiation –70% radiation due to abdominal CT –Increased risk men, CD, IBD related surgery 399 patients with CD399 patients with CD –High exposure defined as CED >75 millisieverts (mSv) – an exposure level which has been reported to increase lifetime cancer mortality by 7.5% 2 –CED >75 mSv is equivalent to 3750 standard X-rays –Number of CTs per patient increased from 0.3 CTs/pt (1992– 1995) to 1.3 CTs/pt (2005–2007) –15.5% > 75 mSv radiation –Pts ileocolonic disease, steroids, infliximab, surgery at greatest risk

49. Estimated Lifetime Radiation- Induced Risk of Cancer on Age at Exposure Brenner DJ et al NEJM 2007; 357: 2277

50. Findings on APCTs in the ED Kerner C et al. Clin Gastroenterol Hepatol 2012;10(1):52-7

51. Questions Would you recommend an imaging test and if so, which test?Would you recommend an imaging test and if so, which test? –In ED, patient will almost always will get CT. Always good to ask if CT needed Does the risk of cancer influence your decision?Does the risk of cancer influence your decision? –Yes-goal is to minimize long-term medical radiation exposure Would your decision be different if the patient was 60 y.o. rather than 20 y.o.?Would your decision be different if the patient was 60 y.o. rather than 20 y.o.? –Same principles are relevant in both age groups (minimize medical radiation exposure), however risk of cancer is greater for the 20 year-old