Pro: An IBD patient on a biologic
and/or an immunomodulator, who
develops a malignancy:
skin cancer
solid tumor
lymphoma
may continue or restart these
medications, if needed to treat IBD
Miguel Regueiro, MD, FACG, AGAF
Professor of Medicine
Clinical Head, IBD Center
University of Pittsburgh Medical Ctr
1
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!)
3
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?
4
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
8
Thiopurines and Skin Cancer
NMSC
MELANOMA
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
Timing of Thiopurines and NMSC (esp. older ages)
SIR and 95% CI
CESAME
Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8
Anti-TNF and Skin Cancer (IBD data)
NMSC
MELANOMA
NR
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
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 doConsult with Dermatology and then.….
NMSC – Basal Cell Squamous Cell
Melanoma
Thiopurine
antiTNF
13
Skin: Stop or Continue? What I doConsult with Dermatology and then.….
NMSC – Basal Cell Squamous Cell
Thiopurine
Melanoma
Continue or start:
Active or Past, as long as Dermatology
monitoring
MTX prob ok
Stop:
Only if significant recurrence or potential
for disfiguring sequelae
antiTNF
14
Skin: Stop or Continue? What I doConsult with Dermatology and then.….
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
15
Skin: Stop or Continue? What I doConsult with Dermatology and then.….
NMSC – Basal Cell
Squamous Cell
Thiopurine
Melanoma
Start:
-eradicated/resected/no mets
-melanoma free for > 1 yr
Stop/Restart:
-Hold for new onset?
-Maybe ok to continue
-Restart if melanoma free
-Stop for metastatic ds
antiTNF
16
Skin: Stop or Continue? What I doConsult with Dermatology and then.….
NMSC – Basal Cell
Squamous Cell
Melanoma
Thiopurine
antiTNF
Start:
-eradicated/resected/no mets
-melanoma free for > 1 yr
Stop:
-New Onset
-?Restart if melanoma free > 1 yr
-Do not restart <1yr or mets
17
Lymphoma
18
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
Author
Observed
Expected
Connell
0
0.52
Kinlen
2
0.24
Farrell
2
0.05
Lewis
1
0.64
Fraser
3
0.65
Korelitz
3
0.61
Total
11
2.71
SIR = 4.06, 95% CI 2.01 – 7.28
Kandiel A et al. Gut. 2005:54:1121-25
CESAME – 6MP/AZA Only
Lymphoma: HR 5.3
At cohort
entry
N
#
HR (95% CI)
Lymphomas
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
Risk of NH Lymphoma with anti-TNF + IM
treatment for Crohn’s Disease: A Meta-Analysis
•
•
•
•
8905 patients representing 20,602 pt-years of exposure
13 Non-Hodgkin’s lymphomas  6.1 per 10,000 pt-years
Mean age 52, 62% male
10/13 exposed to IM* (really a study of combo Rx)
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
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
25
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; 108:99–105
2. 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
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
25,641
19,074
Annual incidence NHL + HD with thiopurines (x4‡)
NNT to cause one death / year
‡ Kandiel A et al. Gut. 2005:54:1121-25
* 5 yearAsurvival
= 68%
for NHL, 85% for HD, estimated at 75% for this example
‡ Kandiel
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?
28
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
29
Crohn’s ds case: NHL while taking
6MP/IFX.
30
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.
31
On CT: Hepatosplenic T cell lymphoma –
enlarged spleen, otherwise nonspecific.
Thiopurine must be stopped!
32
Solid Tumors
33
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
34
No clear association between
thiopurines/antiTNFs and solid tumors
in IBD
Study
Types of
cancer
Number of
patients
Statistically
significant
lung, breast
1955
NO
Fraser 2002
breast,
bronchial, renal
6262
NO
Connell 1994
gastric, lung,
breast, cervical
755
NO
Armstrong 2010
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Thiopurine
antiTNF
36
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
Thiopurine
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Young Males
Extremely rare (<.0001%)
Usually in combo with
anti-TNFs
Not with MTX/antiTNF
Fatal
antiTNF
37
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
Thiopurine
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Young males
Hemophagocytic
lymphohistiocytosis
Very rare (<.001%)
Should we check
EBV prior to starting
in our young males?
antiTNF
38
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
Thiopurine
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Older pts, long
duration of 6MP
Rare (<.01%)
Males > Females
antiTNF
39
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Thiopurine
Stop
Never Restart
antiTNF
40
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Thiopurine
Stop, lymphoma
may regress
Never Restart
antiTNF
41
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Thiopurine
Stop, lymphoma
may resolve
Never Restart
antiTNF
42
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Thiopurine
antiTNF
Stop, probably
never restart
43
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Thiopurine
antiTNF
Stop, but restart
once lymphoma
resolves
44
Lymphoma: Stop or Continue? 3 types,
Consult with Oncology and then.….
Hepatosplenic TC
No relation to EBV
After acute EBV
Initially EBV -
PTLD-like
Initially EBV +
Thiopurine
antiTNF
Continue, only stop
if progression of
lymphoma
45
Solid Tumor: Stop or Continue?
Consult with Oncology and then.….
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
46
Solid Tumor: Stop or Continue?
Consult with Oncology and then.….
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
47
Solid Tumor: Stop or Continue?
Consult with Oncology and then.….
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)
48
Should we continue or stop IBD
meds if a cancer develops?
Depends on IBD
49
Deep Remission
If in deep remission, maybe
stopping IBD meds is ok and not
restarting them
50
Not in deep remission or disabling IBD
Skin 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?
51
Not in deep remission or disabling IBD
Lymphoma
• 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?)
52
Not in deep remission or disabling IBD
Solid 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
53
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?
56
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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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