Transcript Presentation title Times New Roman Bold 45/48 points

Con: An IBD patient on a biologic and/or
an immunomodulator, who develops a
malignancy (solid tumor, lymphoma or
skin cancer), must stop and never
restart these medications
Thomas A. Ullman, M.D.
Chief Medical Officer
Mount Sinai Doctors Faculty Practice
Associate Professor of Medicine
Icahn School of Medicine at Mount Sinai
Disclosures
Consulting/Advisory Board/Research Work and Support
Pfizer
Janssen
CDx
AbbVie
Genentech
What we are not asking
•
•
Efficacy in IBD
Safety in general IBD patient population
Stage at
Diagnosis
Immunomodulators
Anti-TNF
Combination Therapy
IBD
Cancer
Chemotherapy
Radiotherapy
Hormone Therapy
Treatment
Survival
Drugs
Cancer
IBD/Flare
Cancer Recurrence/Incidence
1. Does medical therapy for IBD predispose to developing cancer?
2. Once cancer develops in an IBD patient, is the cancer outcome different?
3. In an IBD patient with a history of cancer, does IBD therapy impact cancer
recurrence?
4. In the IBD patient with active cancer does the cancer therapy affect IBD
outcomes?
5. If a malignancy develops on IBD therapy, is it ever safe to re-start that agent?
Renal Transplant Pts with History of Cancer:
High Risk of Recurrent Cancer due to
immunosuppression
• 823 pts with history of cancer
treated prior to renal
transplant:
• 185 with cancer recurrence
(22%)
Penn I. Transplantation 1993. 55; 742-7
Guidelines in IBD Patients with Hx of Cancer
ECCO (2010):
Anti-TNF therapy is contraindicated in patients with
a history of lymphoma, and “careful consideration
should be given to initiating anti-TNF therapy” in
those with a history of non-haematopoietic cancer.
Dignass et al J Crohns Colitis 4:28, 2010
ACG (2009) & WGO (2009):
No recommendations regarding management of
IBD in patients with a history of cancer.
Lichtenstein et al Am J Gastro 104:465, 2009
Bernstein et al. Inflamm Bowel Dis 16:112, 2009
Imuran Black Box Warning
•
WARNING - MALIGNANCY Chronic
immunosuppression with IMURAN, a purine
antimetabolite increases risk of malignancy in
humans. Reports of malignancy include post-transplant
lymphoma and hepatosplenic T-cell lymphoma (HSTCL)
in patients with inflammatory bowel disease. Physicians
using this drug should be very familiar with this risk as
well as with the mutagenic potential to both men and
women and with possible hematologic toxicities.
Physicians should inform patients of the risk of
malignancy with IMURAN. See WARNINGS.
Imuran, Prescribing Information
Thiopurines: Contraindications
•
Patients with rheumatoid arthritis previously
treated with alkylating agents
(cyclophosphamide, chlorambucil, melphalan, or
others) may have a prohibitive risk of
malignancy if treated with IMURAN.
Imuran, Prescribing Information
Important Caveat:
•
Malignancy within 5 years of study entry and
exclusion criterion for EVERY study involved in
the meta-analysis
Infliximab Prescribing Information
•
“The potential role of TNF-blocking therapy in the
development of malignancies is not known [see Adverse
Reactions (6.1)]. Rates in clinical trials for INFLIXIMAB
cannot be compared to rates in clinical trials of other TNFblockers and may not predict rates observed in a broader
patient population. Caution should be exercised in
considering INFLIXIMAB treatment in patients with a
history of malignancy or in continuing treatment in patients
who develop malignancy while receiving INFLIXIMAB.”
Remicade, Prescribing Information
Adalimumab Prescribing Information
•
“The risks and benefits of TNF-blocker treatment including
Adalimumab should be considered prior to initiating therapy
in patients with a known malignancy other than a
successfully treated non-melanoma skin cancer or when
considering continuing anti-TNF therapy in patients who
develop a malignancy.”
Adalimumab Prescribing Information 2011
Certolizumab Prescribing Information
“The potential role of TNF blocker therapy in the development
of malignancies in adults is not known”
Certolizumab Prescribing Information
Limitations of Existing Studies
•
•
•
•
Lack of randomized prospective data
– Most data come from observational registries
History of cancer = exclusion criterion in clinical trials
– Based on theoretical risk of immunosuppression
Most “Guidelines” advised practitioners to avoid using
immunosuppressive IBD meds in patients who have a history of
cancer
– MDs are more likely to treat only patients with lower risk of
cancer recurrence with immunosuppressive regimens
Sample sizes too small to ask about specific malignancies
– Immunosuppression vs. inflammation
– Common cancers: Breast, Prostate, Lung etc.
IBD pts with history of cancer:
Thiopurine Exposure - No Increased Risk of Subsequent
Cancer (CESAME)
•
•
19,486 pts with IBD:
–
–
Enrolled May 2004-June 2005, followed through December 2007
405 with personal history of cancer with at least one follow up visit
Compared risk of developing new/recurrent cancer:
–
93 pts exposed to IT (thiopurine):
–
312 not exposed to IT
o 6 new cancers
o 1 recurrence of meningioma
o 12 new cancers
o 4 recurrent cancers (lymphoma, breast, prostate, small bowel)
IT Naïve at
IT at Entry
Entry n=312
n=93
New Cancer (NS)
14.4/1000 PY
23.1/1000 PY
Recurrent Cancer
(NS)
6.8/1000 PY
3.9/1000 PY
P=0.98
P=0.26
L Beaugerie et al. Abstract DDW 2012.
RA Patients with History of Cancer:
Anti-TNF Treatment Did Not Increase Risk of New
or Recurrent Cancer (British Registry)
•
Over 14,000 pts with RA
–
•
Dixon et al., Arthritis Care & Research 2010. 62;755-63.
293 with prior malignancy
o 177 anti-TNF treated
o 117 DMARD treated (no anti-TNF)
Rates of incident malignancy compared
–
–
–
25.3/1000 PY in anti-TNF
38.3/1000 PY in DMARD
Prior Melanoma:
o 3/17 (18%) in anti-TNF developed incident malignancy
o 0/10 (0%) in DMARD developed incident malignancy
• BSR Guidelines at time of study read:
•
•
“Caution should be exercised….in pts with previous malignancy”
“If pts have been free of any recurrence of their malignancy for 10 yrs there is no
evidence for a contraindication to anti-TNF therapy”
DMARD
Anti-TNF
RA Patients with History of Cancer:
Anti-TNF Treatment Did Not Significantly Increase Risk
of New or Recurrent Cancer (German Registry)
• Biologic or conventional DMARD therapy between May 2001
•
and December 2006
Prior malignancy in 122 out of 5,120 pts
– 58 pts received anti-TNF
– 55 conventional DMARDs
– 14 pts exposed to anti-TNF with 15 recurrent cancers
– Crude recurrence rates:
o 45.5/1000 PY in anti-TNF exposed
o 31.4/1000 PY in DMARD exposed
o Incidence rate ratio 1.4 (P=0.6)
Strangfeld et al. Arthritis Research &Therapy 2010.
IBD &
Cancer
Cancer controlled
per oncologist?
Gut 2013. E-pub ahead of print
Yes
Within 2 years
No
Beyond 2 years
Treat severe
flares with
steroids
Favor step-up
approach*
Follow course
IBD controlled?
Yes
IBD controlled?
Yes
Hold IS
No
No
Consider cytotoxic
chemotherapy
Follow course**
IBD controlled
after
chemotherapy?
Consider
anti-TNF
*Avoid IS associated with the risk of prior cancer. The longer the IS is held,
the lower the risk of cancer recurrence.
Yes
No
**Hormonal therapy is associated with IBD flare
First line: Steroids
Follow course
Second line: Anti-TNF
Recommendations:
•
Multidisciplinary approach to the safety of using
immunosuppression based on:
– Cancer type
– Overall risk of recurrence
– Risk of IBD activity
Conclusions
•
•
•
•
•
Managing IBD patients with past or current
malignancy is an increasingly common problem.
Few studies done in patients with IBD.
Caution using thiopurines if cancer therapy will
produce bone marrow suppression.
Fear of using anti-TNFs in patients with current
cancer may not be well-founded.
Decisions need to be made on case-by-case basis
with oncologist, taking patient’s awareness and
preferences into consideration.
I’m No Perry Mason
•
•
Rubin 6, Ullman 0
Mercy?
Thank You