Transcript Advances 2012

Thinking About Cancer
Advances 2014
James D. Lewis, MD, MSCE
Fernando Velayos, MD, MPH
CCEB
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
Questions
• Does immunosuppressant therapy
increase the risk of lymphoma?
• Do the benefits outweigh the risks?
• Is there a way to minimize the risk?
AZA/6-MP & Lymphoma:
Meta-analysis
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
CCEB
Kandiel A et al. Gut. 2005:54:1121-25
CESAME - Lymphoma
At cohort
entry
N
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
#
HR (95% CI)
Lymphomas
Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7
Anti-TNF Therapy and Any
Cancer
Accumulate
d doses
Any
1-3
Personyears
19,559
6694
Cases
81
31
Adjusted Rate
Ratio (95% CI)
1.07 (0.85-1.36)
1.02 (0.71-1.47)
4-7
8+
4664
7083
18
32
0.89 (0.55-1.42)
1.29 (0.90-1.85)
Anderson NN. JAMA 2014;311:2406-13
Combination Therapy and
Risk of Lymphoma
Therapy
#
Lymph
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)
0
0
--
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)
1
6.6
4.4 – 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
Contribution of Thiopurines and TNF to Cancer Risk
Osterman MT et al. Gastroenterology 2014;146: 941-9
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?
Relationship of Age and Outcome
with Azathioprine Therapy
Gain in Quality Adjusted Years
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
-0.01 0
20
40
60
80
Age (years)
CCEB
Lewis et al. Gastroenterology 2000;118(6): 1018-24
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
One Year Outcomes
100%
90%
24.4%
26.3%
80%
Active
70%
60%
25.5%
30.1%
50%
40%
26.8%
30%
22.5%
Post-operative
remission
Response
Remission
20%
10%
22.9%
20.7%
Combination Therapy
IFX Alone
0%
Scott FI. CGH 2014
Age-Dependent Incidence of
Lymphoma
Scott FI. CGH 2014
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
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?
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
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
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
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?
Non-melanoma Skin Cancer
• Increased incidence in immunosuppressed
– Transplant patients –
• 65-250 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;348:1681-91
Maddox JS. Inflamm Bowel Dis 2008;14:1425–1431
Immunosuppression & Skin Cancer
Ultraviolet light
P53 and other
mutations
Immunosuppressive
Medications
Inhibition of Antigen
Presenting Cells
Skin Cancer
Systemic
Immunosuppression
HPV
Adapted from Euvrard S. N Eng J Med 2003;348:1681-91
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
Anti-TNF and Skin Cancer
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
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;8 268-74
SIR and 95% CI
Timing of Thiopurines and NMSC:
Conflicting Results
CESAME Cohort
VA UC Cohort
12
12
10
10
8
8
7.06
6
6
5.19
4
4
2
2
0.76
0
Current
Former
Never
Thiopurine Thiopurine Thiopurine
0
2.1
0.7
Current
Former
Thiopurine
Thiopurine
Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8
Khan N. Am J Gastroenterol 2014: doi: 10.1038/ajg.2014.298
Clinical Questions
• Is skin cancer risk increased by
therapy?
– Thiopurines – yes
– Biologics - probably
• If so, does the risk of continuing therapy
outweigh the benefits?
Maintenance of Remission After
Withdrawal of Thiopurine
Percent in Remission
Continue
Discontinue
100
80
60
40
20
0
0
24
48
72
96
Week
Adapted from Van Assche et al. Gastroenterology 2008;134:1861–1868.
CCEB
Percent Continuing Infliximab
Continuation of Infliximab After
Withdrawal of Thiopurine
Continue
Discontinue
100
80
60
40
20
0
0
24
48
72
96
Week
Adapted from Van Assche et al. Gastroenterology 2008;134:1861–1868.
CCEB
Risk of Second NMSC
2751 Medicare Beneficiaries with 1st NMSC
376 with 2nd NMSC
Never use
Thiopurines
HR (95% CI)
Reference
0.72 (0.31-1.70)
Recent use
<1 year current use 1.55 (0.88-2.75)
>1 year current use 1.41 (0.92-2.16)
Anti-TNF
HR (95% CI)
Reference
0.96 (0.34-2.70)
1.32 (0.63-2.78)
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
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
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
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?
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):196-206.
Saha A. Clin Cancer Res May 15, 2011 17; 3056
Murukesan V. Drugs. 2012 Aug 20;72(12):1631-43.
Course of Crohn’s Disease
Following Treatment of Lymhoma
9 Patients Treated for NHL
Chemo (n=7)
Pred /
Bud
(n=3)
AZA /
6MP
(n=2)
Ritux (n=1)
MTX
(n=1)
Unk
(n=1)
6/9 Relapse (2 w/in 1 year)
1/9 New Dx 9 years later
SSA
(n=1)
No Rx (n=1)
No Rx
(n=1)
2/9 No
Relapse
Mourabet MA. Inflamm Bowel Dis 2011;17:1265-9
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
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
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
Questions
• How will you manage her disease if she
has a relapse after completing
chemotherapy?
CESAME
Cancer
diagnosed
>2 years
prior to
cohort entry
50
59
Cancer
diagnosed
<2 years
prior to
cohort entry
40
26
Total with
cancer prior
to cohort
entry
Uterine
Prostate
NMSC
19
16
12
13
9
9
32
25
21
All sites
268
153
421
Colorectal
Breast
90
85
Beaugerie L. Gut 2014;63:1416–1423.
CEESAME Incident Cancer
No immunosupressant
Immunosuppressant
40
40.0
Incidence among
405 patients with
history of cancer
30.0
19.4
20.0
16.3
9.3
10.0
4.8
3.1
0.0
Incidence per 1000-p-y
Incidence per 1000-p-y
34.0
30
3.9
20
6
10
23.1
Recurrent
cancer
New
cancer
13.2
0
<50
50-65
>65
HR = 1.7 (1.3 – 2.1)
Any IS
No IS
(N=93) (N=312)
HR NR (P>.05)
Beaugerie L. Gut 2014;63:1416–1423.
Anti-TNF Therapy for RA
after Curative Breast Cancer Treatment
Biologic
Anti-TNF
naïve (n=120) exposed (n=120)
Total person-years
Individuals with recurrent
breast cancer
550
9
592
9
Rate/1000 p-y
HR of recurrence cancer
Adjusted HR
16 (7-31)
Ref
Ref
15 (7-29)
0.8 (0.3 – 2.1)
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
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
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.
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.?
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
Radiation dose associated with
common medical imaging tests
Herfarth H and Palmer L. Dig Dis 2009; 27: 278
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
Radiation and IBD
• 271 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 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
Estimated Lifetime RadiationInduced Risk of Cancer on Age
at Exposure
Brenner DJ et al NEJM 2007; 357: 2277
Findings on APCTs in the ED
Kerner C et al. Clin Gastroenterol Hepatol 2012;10(1):52-7
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