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Transcript of 1 Pro: An IBD patient on a biologic and/or an immunomodulator, who develops a malignancy: skin...
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Pro: An IBD patient on a biologic and/or an immunomodulator, who develops a
malignancy:skin cancersolid tumorlymphoma
may continue or restart these medications, if needed to treat IBD
Miguel Regueiro, MD, FACG, AGAFProfessor of MedicineClinical Head, IBD CenterUniversity of Pittsburgh Medical Ctr
Do I really have a chance of winning a debate when my side is to continue meds when CA develops?
Thank you for slides
• Jim Lewis
• Jean Fred Colombel
• Corey Siegel (also for photos of Tom!)
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Important questions in pts who develops cancer on IBD meds:
1. Did the medicine cause the cancer?
2. What is the risk of:
- continuing the med in terms of worsening cancer or
- discontinuing the med in terms of worsening IBD?
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Let’s consider three types of cancer:
-Skin Cancer
-Lymphoma
- Solid Tumors
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Case
• 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 (i1) in the neo-TI
Case (cont)
• 2 years prior diagnosed with Non Melanoma Skin Cancer (Basal Cell Ca)
• 2 weeks ago newly diagnosed with Squamous Cell Cancer
Is skin cancer caused by or are patients at increased risk from…
-azathioprine/6MP
-Methotrexate
-antiTNFs
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Thiopurines and Skin Cancer
NMSC MELANOMA
Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181
Timing of Thiopurines and NMSC (esp. older ages)
Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8
CESAME
Anti-TNF and Skin Cancer (IBD data)
NMSC MELANOMA
Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181
NR
Clinical Questions
• Is skin cancer risk increased by therapy?– Thiopurines – yes
– Methotrexate – don’t know, probably not
– Biologics – no NMSC, maybe melanoma
• 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 hats
Skin: Stop or Continue? What I do-Consult with Dermatology and then.….
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NMSC – Basal Cell Squamous Cell Melanoma
Thiopurine
antiTNF
Skin: Stop or Continue? What I do-Consult with Dermatology and then.….
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NMSC – Basal Cell Squamous Cell Melanoma
Thiopurine Continue or start:Active or Past, as long as Dermatology monitoringMTX prob ok
Stop:Only if significant recurrence or potential for disfiguring sequelae
antiTNF
Skin: Stop or Continue? What I do-Consult with Dermatology and then.….
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NMSC – Basal Cell Squamous Cell Melanoma
Thiopurine
antiTNF Continue or start:Active or Past, as long as Dermatology monitoring
Stop:NO, rarely necessary to stop
Skin: Stop or Continue? What I do-Consult with Dermatology and then.….
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NMSC – Basal Cell Squamous Cell
Melanoma
Thiopurine Start:-eradicated/resected/no mets-melanoma free for > 1 yrStop/Restart: -Hold for new onset?-Maybe ok to continue -Restart if melanoma free-Stop for metastatic ds
antiTNF
Skin: Stop or Continue? What I do-Consult with Dermatology and then.….
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NMSC – Basal Cell Squamous Cell
Melanoma
Thiopurine
antiTNF Start:-eradicated/resected/no mets-melanoma free for > 1 yrStop: -New Onset-?Restart if melanoma free > 1 yr-Do not restart <1yr or mets
Lymphoma
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Questions
Does immunosuppressant therapy increase the risk of lymphoma?
Do the benefits outweigh the risks? What do you do when a lymphoma
develops in the setting of IBD meds?
AZA/6-MP are probably related to Lymphoma (Meta-analysis): SIR 4.06
AuthorAuthor ObservedObserved ExpectedExpected
ConnellConnell 00 0.520.52
KinlenKinlen 22 0.240.24
FarrellFarrell 22 0.050.05
LewisLewis 11 0.640.64
FraserFraser 33 0.650.65
KorelitzKorelitz 33 0.610.61
TotalTotal 1111 2.712.71
SIR = 4.06, 95% CI 2.01 – 7.28Kandiel A et al. Gut. 2005:54:1121-25
CESAME – 6MP/AZA OnlyLymphoma: HR 5.3
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)
Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7
• 8905 patients representing 20,602 pt-years of exposure
• 13 Non-Hodgkin’s lymphomas
• Mean age 52, 62% male
• 10/13 exposed to IM* (really a study of combo Rx)
Risk of NH Lymphoma with anti-TNF + IM treatment for Crohn’s Disease: A Meta-Analysis
NHL rate per 10,000
SIR 95% CI
SEER all ages 1.9 - -
IM alone 3.6 - -
Anti-TNF + IM vs SEER 6.1 3.23 1.5-6.9
Anti-TNF+ IM vs IM alone 6.1 1.7 0.5-7.1
Siegel et al, CGH 2009;7:874. *not reported in 2
6.1 per 10,000 pt-years
CESAME – Combo 6MP/AZA and antiTNF: SIR = 10.2
Therapy Patients # Lymph SIR 95% CI
Never thiopurine or TNF
22,706 6 1.5 0.5 – 3.2
Current thiopurine without TNF
14,729 13 6.5 3.5 – 11.2
Current thiopurine + TNF
1,929 2 10.2 1.2 – 36.9
Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7
Clinical Questions
• Does immunosuppressant therapy increase the risk of lymphoma?– Thiopurines – yes, but risk may revert after
discontinuation
– antiTNFs – Probably not
– Combination – Yes and probably more than monotherapy
Risk:Benefit Ratio
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Hepatosplenic T Cell Lymphoma
• 41 cases from FDA AERS among patients with IBD1
– Thiopurine alone 17– Anti-TNF alone 1– Combination therapy 23
• Characteristics2
– Median age 22.5 (12 – 58)– 93% male– Median time since initiation of thiopurines ~6 years
1. Deepak P. Am J Gastroenterol 2013; 108:99–1052. Kotlyar D. Clin Gastroenterol Hepatol 2011;9:36–41
Lymphoma - Number Needed to Harm
Males Only 15-19 y.o. M(per 105)
20-24 y.o. M (per 105)
Lymphoma other than HSTCL
Annual incidence NHL + HD USA 5.2 7.0
Annual incidence NHL + HD with thiopurines (x4‡) 20.8 28.0
Annual mortality from lymphoma without thiopurines* 1.3 1.75
Annual mortality from lymphoma with thiopurines* 5.2 7.0
Excess deaths from thiopurine induced lymphoma 3.9 5.25
NNT to cause one death / year 25,641 19,074
‡ Kandiel A et al. Gut. 2005:54:1121-25* 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example
‡ Kandiel A et al. Gut. 2005:54:1121-25* 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example
What to do if lymphoma develops while taking IMM/antiTNF?
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Case – Stop or Continue?
• 39 yo male CD in remission on 6MP/IFX for 8 yrs.
• Now with weight loss, sweats, and low grade fevers
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Crohn’s ds case: NHL while taking 6MP/IFX.
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After consulting with the oncologist….
…we stopped the 6MP/antiTNF, but after 3 months of chemorx, the
antiTNF was resumed. We did not restart the 6MP.
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On CT: Hepatosplenic T cell lymphoma – enlarged spleen, otherwise nonspecific.
Thiopurine must be stopped!
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Solid Tumors
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Case Continue or Stop?
• 58 yo female with severe UC who has been on IFX/6MP (50mg/d) for past 1yr
• Just diagnosed with intraductal breast CA (T1N0MX)
• Strong FHx breast CA, pt opts for bilateral mastectomy
• After consultation with oncology, the decision is to cont meds
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No clear association between thiopurines/antiTNFs and solid tumors
in IBD
Study Types of cancer
Number of patients
Statistically significant
Armstrong 2010 lung, breast 1955 NO
Fraser 2002breast,
bronchial, renal6262 NO
Connell 1994gastric, lung,
breast, cervical755 NO
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
Thiopurine
antiTNF
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
Thiopurine Young Males
Extremely rare (<.0001%)
Usually in combo with anti-TNFs
Not with MTX/antiTNF
Fatal
antiTNF
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
Thiopurine Young males
Hemophagocytic lymphohistiocytosis Very rare (<.001%)
Should we check EBV prior to starting in our young males?
antiTNF
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
Thiopurine Older pts, long duration of 6MP
Rare (<.01%)
Males > Females
antiTNF
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
ThiopurineStop
Never Restart
antiTNF
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
ThiopurineStop, lymphoma may regress
Never Restart
antiTNF
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
ThiopurineStop, lymphoma may resolve
Never Restart
antiTNF
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
Thiopurine
antiTNFStop, probably never restart
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
Thiopurine
antiTNFStop, but restart once lymphoma resolves
Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….
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Hepatosplenic TCNo relation to EBV
After acute EBVInitially EBV -
PTLD-likeInitially EBV +
Thiopurine
antiTNFContinue, only stop if progression of lymphoma
Solid Tumor: Stop or Continue? Consult with Oncology and then.….
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Solid Tumors, e.g. Breast, Lung, Renal Probably no relationship to IBD meds
Thiopurine -Continue if curative resection, no need to stop
antiTNF -Continue if curative resection, no need to stop
Solid Tumor: Stop or Continue? Consult with Oncology and then.….
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Solid Tumors, e.g. Breast, Lung, Renal Probably no relationship to IBD meds
Thiopurine-Stop if metastatic ds and/or chemotherapy
antiTNF-Stop if metastatic ds and/or chemotherapy
Solid Tumor: Stop or Continue? Consult with Oncology and then.….
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Solid Tumors, e.g. Breast, Lung, Renal Probably no relationship to IBD meds
Thiopurine-Restart once chemo done and no active cancer (? > 1 yr)
antiTNF-Restart once chemo done and no active cancer (? > 1 yr)
Should we continue or stop IBD meds if a cancer develops?
Depends on IBD
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Deep Remission
If in deep remission, maybe stopping IBD meds is ok and not
restarting them
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Not in deep remission or disabling IBDSkin Cancer
• Basal or Squamous Cell• Resected/Controlled
– CONTINUE all meds• Not controlled and/or disfiguring
– STOP azathioprine/6MP– CONTINUE anti-TNFs
• Melanoma• Resected/Eradicated > 1 year
– CONTINUE all meds• Multiple Skin Sites/Rapid Recurrence/Mets
– STOP anti-TNFs– CONTINUE – 6MP/AZA/MTX?
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Not in deep remission or disabling IBDLymphoma
• Acute EBV and lymphoma: • STOP AZA/6MP
• CONTINUE anti-TNF, after lymphoma resolved (may not even need to stop?)
• Hepatosplenic T Cell lymphoma:• STOP AZA/6MP and anti-TNF
• PTLD-like lymphoma (likely EBV):• STOP AZA/6MP
• CONTINUE anti-TNF, after lymphoma resolved (may not even need to stop?)
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Not in deep remission or disabling IBDSolid Tumors
6MP/AZA:- CONTINUE 6MP/AZA/MTX - Stop during chemo
Anti-TNFs- CONTINUE if tumor resected/eradicated
- STOP if metastatic ds or chemorx
- RESTART once cancer eradicated/chemorx stopped
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When you vote on who will win this debate
make sure you consider both halves of the debate, but also the
2 sides of TOM ULLMAN
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Which half will you see today?…..
….the honest, kind, thoughtful, Tom Ullman?
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Or ??????
…maybe that dazed look wasn’t because Tom just ran a race,
but…..
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Playboy Ullman starring in American Hustle
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