1. 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 CD
Now steroid dependent
Treating physician recommends infliximab + azathioprine
Patient is concerned about risk of cancer, and particularly lymphoma

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

4. AZA/6-MP & Lymphoma: Meta-analysis
Author
Observed
Expected
Connell
0.52
Kinlen 2
0.24
Farrell
0.05
Lewis 1
0.64
Fraser 3
0.65
Korelitz
0.61
Total 11
2.71
CCEB
SIR = 4.06, 95% CI 2.01 – 7.28
Kandiel A et al. Gut. 2005:54: 4

5. CESAME - Lymphoma At cohort entry N # Lymphomas HR (95% CI)
Never exposed to thiopurines
10,810 6
Reference
On therapy with thiopurines
5,867 16
5.3
(2.0 – 13.9)
Previously discontinued thiopurines
2,809 2
1.0
(0.2 – 5.1)
CCEB
Beaugerie L. Lancet 2009 DOI: /S (09)

6. Anti-TNF Therapy and Any Cancer
Accumulated doses
Person-years
Cases
Adjusted Rate Ratio (95% CI)
Any
19,559 81
1.07 ( )
1-3
6694 31
1.02 ( )
4-7
4664 18
0.89 ( ) 8+
7083 32
1.29 ( )
Anderson NN. JAMA 2014;311:

7. Combination Therapy and Risk of Lymphoma
SIR
95% CI
Never thiopurine or TNF (1) 6
1.5
0.5 – 3.2
Never thiopurine or TNF (2) 33
1.0
0.96 – 1.1
Current thiopurine w/out TNF (1) 13
6.5
3.5 – 11.2
Current thiopurine w/out TNF (2) 4
1.4
1.2 – 1.7
Current TNF w/out thiopurine (2) --
Current TNF + prior thiopurine (2) 1
5.2
3.5 – 6.8
Current thiopurine + TNF (1) 2
10.2
1.2 – 36.9
Current thiopurine + TNF (2)
6.6
4.4 – 8.8
Beaugerie L. Lancet 2009 DOI: /S (09)
Herrinton L. Am J Gastroenterol 25 October 2011; doi: /ajg

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?
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?

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

11. Combination versus Anti-TNF Monotherapy
Modeled across age ranges from 25 to 75 and across duration of therapy from 1 to 9 years
Assumes naïve to both drugs
Allows for second anti-TNF in case of LOR
Key effectiveness assumptions derived from SONIC, GAIN and CHARM
Key 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?
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?
In most scenarios
Is there a way to minimize risk?

16. Prevalence of EBV 20% to 40% of college freshmen
>60% of recent college graduates
>70% of young adults
Possibly 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 feasible
Consider 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 elderly

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

19. Clinical Scenario (cont)
2 years prior diagnosed with NMSC (BCC)
2 weeks ago newly diagnosed with SCC
Questions
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 immunosuppressed
Transplant patients –
x increase in SCC
10 x increase in BCC
HIV/AIDS
Proportional to degree of immunosuppression
Increased severity of SCC in immunosuppressed
Euvrard S. N Eng J Med 2003;348:
Maddox JS. Inflamm Bowel Dis 2008;14:1425–1431

21. Immunosuppression & Skin Cancer
Ultraviolet light
Immunosuppressive Medications
P53 and other mutations
Inhibition of Antigen Presenting Cells
Systemic Immunosuppression
Skin Cancer
HPV
Adapted from Euvrard S. N Eng J Med 2003;348:

22. Thiopurines and Skin Cancer
NMSC
MELANOMA
Long M. Gastroenterology 2012:143: Singh H Gastroenterology 2011:141:
Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8
Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: /ajg

23. Anti-TNF and Skin Cancer
NMSC
MELANOMA NR
Long M. Gastroenterology 2012:143: Singh H Gastroenterology 2011:141:
Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8
Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: /ajg

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

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

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

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

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

29. Risk of Second NMSC 2751 Medicare Beneficiaries with 1st NMSC 376 with 2nd NMSC
Thiopurines
HR (95% CI)
Anti-TNF
Never use
Reference
Recent use
0.72 ( )
0.96 ( )
<1 year current use
1.55 ( )
1.32 ( )
>1 year current use
1.41 ( )
1.32 ( )
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?
Thiopurines – yes
Biologics - probably
If so, does the risk of continuing therapy outweigh the benefits?
In this case – consider stopping thiopurine
Uncertain 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 dysuria
CT 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 lymphoma

32. Questions How would you manage her CD during therapy for NHL?
What is the prognosis of IBD during and following 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 immunosuppression
Rituximab monotherapy is effective but with relatively high relapse rate
R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) often employed
Trappe R. Lancet Oncology 2012 Feb;13(2):
Saha A. Clin Cancer Res May 15, 2011 17; 3056
Murukesan V. Drugs Aug 20;72(12):

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)
AZA / 6MP
(n=2)
MTX
(n=1)
Unk
(n=1)
SSA
(n=1)
No Rx
(n=1)
6/9 Relapse (2 w/in 1 year)
1/9 New Dx 9 years later
2/9 No Relapse
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?
Stop immunosuppression if possible
Antibiotics, prednisone or budesonide if needed, in discussion with oncologist
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?

39. CESAME Cancer diagnosed >2 years prior to cohort entry
Total with cancer prior to cohort entry
Colorectal 50 40 90
Breast 59 26 85
Uterine 19 13 32
Prostate 16 9 25
NMSC 12 21
All sites
268
153
421
Beaugerie L. Gut 2014;63:1416–1423.

40. CEESAME Incident Cancer
Incidence among 405 patients with history of cancer
Incidence per 1000-p-y
Incidence per 1000-p-y
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-years
550
592
Individuals with recurrent breast cancer 9
Rate/1000 p-y
16 (7-31)
15 (7-29)
HR of recurrence cancer
Ref
0.8 (0.3 – 2.1)
Adjusted HR
1.1 (0.4 – 2.8)
Cohorts matched on age at diagnosis, county of residence, stage at diagnosis
Adjusted for nodal status, surgery type, chemothrapy, comorbidities
Raaschou P. Ann Rheumatol Dis. 2014:205745

42. Questions
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.

44. Questions Would you recommend an imaging test and if so, which test?
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.?

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 radiation
63 million CT performed in USA in 2006
Effects of radiation
DNA breaks, point mutations, chromosomal translocations
CT’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 271 male, 280 female pts UC/CD 399 patients with 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 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
Levi Z, et al. DDW 2008: #119; Desmond AN, et al. DDW 2008:
#120; Panes J et al DDW 2008#121

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?
In ED, patient will almost always will get CT. Always good to ask if CT needed
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.?
Same principles are relevant in both age groups (minimize medical radiation exposure), however risk of cancer is greater for the 20 year-old