Transcript Cancer - Pitt Pharmacy Portfolio

Malignancies Post-Transplant
Pamela J. Lyons
PharmD Candidate 2014
University of Pittsburgh School of Pharmacy
Pharmacotherapy Scholars Program
Objectives
• Describe the proposed reasons for increased
malignancy after transplant
• Understand the prevalence of cancer after
transplant and list the databases that estimate
prevalence
• Describe the role of immunosuppressants in
increasing malignancy
• Explain the anti-proliferative effects of mTOR
inhibitors
• Make changes to a patient’s immunosuppression
after development of cancer
Objectives
• Describe the proposed reasons for increased
malignancy after transplant
• Understand the prevalence of cancer after
transplant and list the databases that estimate
prevalence
• Describe the role of immunosuppressants in
increasing malignancy
• Explain the anti-proliferative effects of mTOR
inhibitors
• Make changes to a patient’s immunosuppression
after development of cancer
Why an increased risk?
• Proposed mechanisms
– Inability to fight off infections that cause cancer
– Decreased cancer surveillance
– Cancer present pre-transplant
– Cancer present in allograft
– Toxic effects of immunosuppressants
Engels EA. JAMA. 2011;306(17):1891-1901
Objectives
• Describe the proposed reasons for increased
malignancy after transplant
• Understand the prevalence of cancer after
transplant and list the databases that estimate
prevalence
• Describe the role of immunosuppressants in
increasing malignancy
• Explain the anti-proliferative effects of mTOR
inhibitors
• Make changes to a patient’s immunosuppression
after development of cancer
Risk of Cancer
Years after
transplant
3
10
20
30
Cumulative risk
of cancer
3.9-14.9%
3.9-39%
13.9-50%
~80%
Reported by databases:
• Israel Penn International Transplant Tumor Registry (IPITTR)
• US Renal Data System (USRDS)
• Australian and New Zealand Data Registry (ANZDATA)
• Collaborative Transplant Registry (CTS)
• Organ Procurement and Transplantation Network/United Network
for Organ Sharing (OPTN/UNOS)
Gutierrez-Dalmau et al. Drugs. 2007;67(8):1167-1198
Limitations of the databases
•
•
•
•
Follow up time variable and short
Volunteer reporting
Missing data
May exclude types of cancer
– Ex: non-melanoma skin cancers
• Only 1st cancer cases included
Gutierrez-Dalmau et al. Drugs. 2007;67(8):1167-1198
Determining the Risk – Engels et al
• Data from the Scientific Registry of Transplant
Recipients (SRTR)
– Updated monthly from OPTN
– Data on every transplanted recipient since 1987
– Linkage with US social security death master file
• Linked data with 13 cancer registries
Engels EA. JAMA. 2011;306(17):1891-1901
Engels et al - Population
458,834 solid organ
transplants
442,629 transplanted
after cancer registries
available
176,974 patients with
complete data
175,732 patients in 4
major ethnic groups
Engels EA. JAMA. 2011;306(17):1891-1901
Engels et al
• Cancer type:
– Related to infections
– Not related to infections
• Data stratified by:
– Sex
– Age
– Race
– Calendar year
– Cancer registry area
Engels EA. JAMA. 2011;306(17):1891-1901
Infectious Cancers
Type of Cancer
Non-Hodgkin lymphoma
Hodgkin lymphoma
Nasopharyngeal cancer
Infectious Cause
EBV
Cancers of cervix, vulva, vagina, penis,
anus, oropharynx
Human Papilloma Viruses
Liver cancer
Hepatitis B and C
Karposi sarcoma
Human herpesvirus 8
Stomach
Helicobacter
Engels EA. JAMA. 2011;306(17):1891-1901
Engles et al – Determination of Risk
• Relative Risk
– Standardized incidence ratio (SIR)
• Observed cases/expected cases
• Absolute Risk
– Excess absolute risk (EAR)
• Observed cases – expected cases
• Analysis of the 4 most common cancers
– NHL, lung, liver, and kidney cancer
Engels EA. JAMA. 2011;306(17):1891-1901
Engles et al – Overall risk
• 10,656 malignancies reported
– SIR = 2.1 (CI, 2.06-2.14)
– EAR = 719/100,000 person years (CI, 693-745)
Engels EA. JAMA. 2011;306(17):1891-1901
Increase in Cancer due to Infection
Cancer
SIR (95% CI)
EAR/100,000 person
years (95% CI)
Non-Hodgkin
Lymphoma
7.54 (7.17-7.93)
168.3 (158-178)
Liver
11.56 (10.8-12.3)
109 (102-118)
Kaposi Sarcoma
61.5 (50.95-73.5)
15.2 (12.6-18.3)
Hodgkin
Lymphoma
3.58 (2.86-4.43)
7.9 (5.7-10.5)
Total
2.10 (2.06-2.14)
719 (693.3-745.6)
Engels EA. JAMA. 2011;306(17):1891-1901
Increase in Non-Infection-Related Cancer
Cancer
SIR (95% CI)
EAR (95% CI)
Lung
Kidney
Melanoma
Lip
1.97 (1.86-2.08)
4.65 (4.32-4.99)
2.38 (2.14-2.63)
16.78 (14.02-19.92)
85.3 (76.2-94.8)
76.1 (69.3-83.3)
28.5 (23.7-33.7)
15.8 (13.0-18.9)
Chronic myeloid
leukemia
Thyroid
3.47 (2.46-4.77)
3.5 (2.1-5.3)
2.95 (2.58-3.34)
20.3 (16.5-24.4)
Total
2.1 (2.06-2.14)
719.3 (6.93-745.6)
Engels EA. JAMA. 2011;306(17):1891-1901
Most Common Cancers Stratified by Transplant Type
NHL
Lung Cancer
Liver Cancer
Kidney
Cancer
Kidney Txp
6.05
(5.59-6.54)
1.46
(1.34-1.59)
1.08
(0.8-1.43)
6.66
c
(6.12-7.23)
Liver Txp
7.77
(6.99-8.61)
1.95
(1.74-2.19)
43.83
c
(40.9-46-91)
1.80
(1.4-2.29)
Heart Txp
7.79
(6.89-8.79)
2.67
(2.4-2.95)
1.02
(0.54-1.74)
2.90
(2.32-3.59)
Lung Txp
18.73
c
(15.59-22.32)
6.13
c
(5.18-7.21)
2.04
(0.56-5.22)
1.49
(0.64-2.94)
Engels EA. JAMA. 2011;306(17):1891-1901
Implications of Engels et al
• Rate of cancer post transplant not as high as
estimated by other data bases
• Both infection and non-infection related
cancers increase post transplant
• Type of cancer related to type of transplant
– Directed surveillence
Objectives
• Describe the proposed reasons for increased
malignancy after transplant
• Understand the prevalence of cancer after
transplant and list the databases that estimate
prevalence
• Describe the role of immunosuppressants in
increasing malignancy
• Explain the anti-proliferative effects of mTOR
inhibitors
• Make changes to a patient’s immunosuppression
after development of cancer
Corticosteriods
• Non-transplanted patients have increased risk
of cancer
• Proposed Mechanism
– Anti-apoptotic, proliferation-promoting effects in
carcinoma cells
– Inactivate T and B cells
– Lower MHCI expression
Gutierrez-Dalmau et al. Drugs. 2007;67(8):1167-1198
Azathioprine
• Proposed mechanism:
– Accumulation of 6-thioguanine in DNA 
synergism with UV radiation
– Enhanced mutation by diminished DNA repair
• Higher incidences of acute myeloid leukemia
and myelodysplastic syndrome
Gutierrez-Dalmau et al. Drugs. 2007;67(8):1167-1198
Valantine. J Hrt Lung Transplant. 2007;26(6)557-64
Mycophenolate Mofetil
• Conflicting in vitro data
• Systematic review of RTCs found no difference
in skin cancer compared to Azathioprine
• Case controlled studies show no increased
cancer risk with MMF
Gutierrez-Dalmau et al. Drugs. 2007;67(8):1167-1198
Calcineurin Inhibitors
• Mechanisms
– Increase TGFβ-1
• High levels present in aggressive tumors
• Enhance angiogenesis
• Impair host anti-tumor response
– Suppress p53-dependent apoptosis after UV
irradiation
• More malignancy with cyclosporine than
azathioprine
• Conflicting data comparing cyclosporine and
tacrolimus
Gutierrez-Dalmau et al. Drugs. 2007;67(8):1167-1198.
Kauffman MH et al. Transplantation. 2005;80(7):883-9.
Valantine. J Hrt Lung Transplant. 2007;26(6)557-64
Summary
• Corticosteroids, Azathioprine, and Calcineurin
inhibitors may increase the risk of cancer
• MMF does not seem to increase cancer risk
Objectives
• Describe the proposed reasons for increased
malignancy after transplant
• Understand the prevalence of cancer after
transplant and list the databases that estimate
prevalence
• Describe the role of immunosuppressants in
increasing malignancy
• Explain the anti-proliferative effects of mTOR
inhibitors
• Make changes to a patient’s immunosuppression
after development of cancer
mTOR inhibitors
• Decrease the incidence of post-transplant
malignancies
• Proposed mechanisms
– Reduce the CNI needed
– Interrupt PI3K pathway
– Sensitize tumor cells to DNA damage
• Shown to inhibit primary and metastatic
tumor growth in mice
Valantine. J Hrt Lung Transplant. 2007;26(6)557-64
Kauffman MH et al. Transplantation. 2005;80(7):883-9
Kauffman et al
Deceased renal
transplant patients in
OPTN/UNOS 19962001
30,424 treated with
CNI +/- Azathioprine
or MMF
2,825 treated with
mTOR +/Azathioprine or MMF
Primary end point: development of any de novo malignancy
Kauffman MH et al. Transplantation. 2005;80(7):883-9
Kauffman et al - Results
Incidence of cancer
Everolimus/sirolimus
Cyclosporine/tacrolimus
0.6%
1.81%
p<0.001
• mTOR inhibitors associated with a 60% reduced risk of
developing any de novo malignancy
Kauffman MH et al. Transplantation. 2005;80(7):883-9
Kauffman et al - Results
• Significant risk factors for the development of cancer post
transplant:
Risk Factor
% Increased Risk of
Cancer
Males
Adults
White patients
Previous Malignancy
60
275
243
142
Kauffman MH et al. Transplantation. 2005;80(7):883-9
mTOR Use During Active Cancer
Case Study: Campistol et al
2 pts develop Kaposi
Sarcoma
Converted to
sirolimus from CNI
Complete regression
of Kaposi Sarcoma, no
loss of graft
Case Study: Sierka D et al
13 pts develop
malignancies
Converted to
sirolimus from CNI
12 of 13 pts cancer
free at 2.3 years
Summary
• mTOR inhibitor based therapies may help
prevent de novo cancers compared to CNI post
transplant
• Conversion of a CNI to an mTOR inhibitor after
development of cancer may help cause cancer
remission
Are more intense
immunosuppression regimens
associated with cancer?
Cancer rates based on organ
Valantine. J Hrt Lung Transplant. 2007;26(6)557-64
.
Intensity of immunosuppression and transplant type
• Cancer risk estimated in national cohort study
in Sweden
– In kidney transplant, SIR = 3.9 (CI, 3.6-4.2)
– In Non-kidney transplant, SIR = 4.9 (CI, 3.7-6.4)
Gutierrez-Dalmau et al. Drugs. 2007;67(8):1167-1198
Dantal et al
231 pts 1 yr after
kidney transplant
Low dose
cyclosporine = goal
trough: 75-125ng/ml
Normal dose
cyclosporine = goal
trough: 150-250
ng/ml
Primary Endpoint: Graft function
Secondary Endpoint: Cancer, survival, rejection
Dantal et al - Results
• No difference in graft function
• 60 patients developed cancer
– 37 in the normal dosing group
– 23 in the low dose group
• P<0.034
• 66% of the cancers were skin cancer
– P<0.05
Should we decrease
immunosuppression in transplant
patients once cancer develops?
Moloney et al
Pt
Change in Therapy
Outcome
1
No
Died at 7 months from metastatic disease
2
No
Died at 7 months from metastatic disease
3
No
Died at 11 months from metastatic disease
4
No
Died at 10 months from metastatic disease
5
No
Died at 18 months from metastatic disease
6
CyA stopped
Died at 16 months from metastatic disease
7
Aza stopped and CyA
changed to tacrolimus
Alive with no reoccurrence or graft loss at 17
months
8
Aza stopped
Alive with no reoccurrence or graft loss at 27
months
9
CyA and Aza stopped
Restarted dialysis at 24 months, no reoccurance
Maloney et al. Dermatol Surg. 2004;30:674-8.
Summary
• Transplanted organs that need more intense
immunosuppression are associated with
higher cancer risks
• Higher doses of CNI are associated with higher
cancer risk
• Lowering immunosuppression may be
associated with longer survival
Objectives
• Describe the proposed reasons for increased
malignancy after transplant
• Understand the prevalence of cancer after transplant
and list the databases that estimate prevalence
• Describe the role of immunosuppressants in increasing
malignancy
• Explain the anti-proliferative effects of mTOR inhibitors
• Make changes to a patient’s immunosuppression
after development of cancer
Patient Case: KC
• 60 yo male
• Admitted 6/14/13 for DLTxp 2/2 IPF/PH
– Done on VA ECMO
• Alemtuzumab induction
• CMV: D-/R• Recovery complicated by Afib, Volume
overload, CHF requiring reintubation on 6/27
– Electrical caridoversion on 7/5
Patient Case: KC
• PMH:
– IPF, GERD, gout, CAD, stent in LAD, anxiety, basal
cell cancer
• Immunosuppression:
– Prednisone 5 mg daily
– Tacrolimus 0.5 mg BID
• Goal 10-12
– Mycophenolate Mofetil 750 mg BID
Patient Case: KC
Prophylaxis:
• Valganciclovir 500 mg BID
• Bactrim DS q MWF
• Voriconazole 200 mg BID
Other Medications:
• ASA 81 mg daily
• Heparin 5000 sq q 8h
• paroxetine 20mg QAM
• lansoprazole 30mg Daily
• levalbuterol 0.63mg QID
• metoclopramide 5mg IV Q8H
• Miralax 17gm Daily
• docusate 200mg Daily
Patient Case: KC
• Pathology results of explanted lung:
– Multifocal, multilobular, invasive adenocarcinoma
– hilar lymph node involvement
– visceral pleural invasion
– T4N1
– To be treated with crizotinib
What should we do?