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The janus face of immunosuppression -
de novo
malignancy after renal transplantation:
the experience of the Transplantation Center
Munich
Kidney International (2007) 71, 1271–1278
C D Wimmer, M Rentsch, A Crispin, W D Illner,
H Arbogast, C Graeb, K-W Jauch and M Guba
R3 陳泓丞
Background
a leading cause expected of late
death post renal transplantation.
Occurrence of cancers in immunosuppressed
organ transplant
recipients. Penn I.
Clin Transpl 1998; 147–158: 147–158
• immunosuppressed organ allograft recipients
three- to four-fold increased risk of developing
cancer in general
up to 500-fold higher incidence of certain types
of cancer
Post-transplant malignancy-
Etiology
• Multifactorial in nature
---impaired immunosurveillance of
neoplastic cells
--depressed antiviral immune activity
Etiology--
* immunosuppressive agents
-DNA damage
-interfere with normal DNA repair mechanisms
-promote tumor progression
upregulation of various cytokines
transforming growth factor-b1
IL-10
vascular endothelial growth factor
Guba M, Graeb C, Jauch KW, Geissler EK. Pro- and
anti-cancer effects of
immunosuppressive agents used in organ
transplantation.
Transplantation 2004; 77: 1777–1782
Dantal J, Hourmant M, Cantarovich D et al.
Effect of long-term immunosuppression in kidney-graft
recipients on cancer incidence:
randomised comparison of two cyclosporin regimens.
Lancet 1998; 351:623–628.
• The incidence :
increases with time and the intensity of
immunosuppression
• Tumor:
differ from those seen in the general
population
Occurrence of cancers in
immunosuppressedorgan transplant
recipients. Penn I.
Clin Transpl 1998; 147–158: 147–158
• during immunosuppressive therapy
more aggressive than those that occur in
the general population
Materials and Methods
• Cohort observational study
- reviewed for the development of cancer after
successful renal transplantation ( graft function
>90days)
• Assess the relative tumor risk
- compared with a standard, age- and sex-matched
population from the greater Munich area
• Initial immunosuppression
- post-transplant treatment at the time of discharge
Immunosuppression Regimen
• 1978 ~1982 AZA + prednisolone
• 1984~low-dose cyclosporine(150–200
ng/ml)+ AZA + prednisolone
azathioprine (AZA)
• 1996 ~
induction therapy: ATG(Fresenius) and/or
basiliximab
• >50 years: calcineurin-inhibitor-free regime with
MMF (2–3 g/day; 2–4 mg/ml) + prednisolone,
• < 50 y/o: cyclosporine low-dose (100–150
ng/ml)+ MMF (2 g/day) + prednisolone,
• With preformed antibodies >20%: TAC (8–10
ng/ml) + MMF (2 g/day) + prednisolone.
ATG: anti-thymocyte globulin TAC: tacrolimus
MMF: mycophenolate mofetil
Statistics
• Results: the mean ± s.d. when not
indicated otherwise.
• The λ2 test
raw estimations of related variables on
tumor incidence after transplantation.
• Comparisons between the groups were
calculated : log-rank test.
• Cumulative tumor incidence probability
estimations:
the Kaplan–Meier method.
• Cox-regression analysis
the influence of different variables on
relative risk for the development of
different malignancies.
• All calculations were performed with SPSS
version14.0 (SPSS Inc., Chicago, IL, USA).
Results
Cancer incidence after renal transplantation
Cancer incidence after renal transplantation
Distribution of tumors and relative
tumor risk in renal transplant
recipients
Absolute numbers of tumors detected in
2419 renal transplant recipients
Distribution of tumors and relative tumor
risk in renal transplant recipients
the most frequent tumors in the
transplant situation
• non-melanotic skin cancers (20.5%)
• renal cell carcinomas (12.0%)
• cancers of the pharynx, larynx, and the oral
cavity (8.2%).
• Within the non-melanotic skin cancers, basal cell
carcinomas (11.5%)
Effect of the initial
immunosuppressive regime on
de novo tumor development
• With the introduction of more powerful
immunosuppressive regimes
the tumor incidence over time increased:
azathioprine (AZA)<cyclosporine
(CsA)<CsA/AZA<tacrolimus
(TAC)<TAC/mycophenolate mofetil
(MMF)<CsA/MMF.
Effect of the initial immunosuppressive
regime on de novo tumor development
• Significance (P<0.05)
• 1vs MMF;
• 2vs CsA, CsA/AZA,
CsA/MMF, TAC, TAC/MMF,
MMF;
• 3vs AZA, CsA/AZA,
CsA/MMF, TAC/MMF, MMF;
• 4vs AZA, CsA, MMF,
• 5vs AZA, CsA, SRLt-
MMF/CsA;
• 6vs AZA, MMF;
• 7vs AZA, CsA;
• 8vs AZA, CsA, CsA/AZA,
Effect of the initial immunosuppression on total tumor development . SRLt-MMF/CsA
AZA < CsA < CsA/AZA < TAC <TAC/MMF < CsA/MMF
• mTOR-inhibitor (sirolimus (SRL))-based
therapies :
--lower tumor risk than all other therapy
groups.
--No significant : relatively low number of
patients and the short observation period.
• MMF-based therapy:
a significantly older patient population
(60.4±10.1 versus 43.5±12.8) than the
other protocols and therefore confounds
the interpretation.
• the addition of MMF increased the tumor
development than the corresponding
calcineurin inhibitor (CNI)-based therapies
Effect of the initial immunosuppressive
regime on de novo tumor development
• Significance (P<0.05)
• 1not significant;
• 2vs CsA, CsA/AZA,
CsA/MMF, TAC,
TAC/MMF, MMF;
• 3vs AZA, CsA/MMF, TAC,
TAC/MMF, MMF;
• 4vs AZA,
• 5vs AZA, CsA;
• 6vs AZA, CsA;
• 7vs AZA, CsA;
• 8vs AZA, CsA
Effect of the initial immunosuppression on skin cancer episodes.
• a significant impact of TAC and TAC/MMF on
the recurrence of basal cell carcinomas(BCCs)
and squamous cell carcinomas (SCCs).
• All other immunosuppressive agents showed no
difference,
except the above-mentioned potential protective
effect of SRL on skin cancer development
Effect of induction treatment
on overall tumor development
Effect of induction treatment on overall tumor development Effect of induction treatment on PTLD development
Independent risk factors for de novo
malignancies after renal transplantation
Discussion
Discussion
• Limitations
- no control over the completeness or detail of
the malignancy data recorded in registries
- high number of unreported tumor cases
- underestimation of the real problem
• Reassessing
- 3275 renal transplant recipients
- patients with incomplete follow-up : excluded
- ended up with population of 2419 patients
Discussion
• Increase of incidence of malignancies after
transplantation
- immediately after transplantation
- 50% of all de novo malignancies within the first
5 years after transplantation
- direct impact of immunosuppression :
infections with oncogenic viruses or carcinogenic effects
- immunosuppression antedates tumor
Discussion-oncogenic viruses
• human papilloma viruses:
cervix carcinomas and carcinomas of the
skin
• Epstein-Barr –viruses
PTLD
• human herpes virus 8,11
Kaposi sarcomas
Discussion
• Selection bias
1. Skin cancers and cancers of the pharynx,
larynx, or oral cavity : transplant related
2. Kidney cancers:
patients with an underlying kidney disease
• Colon, lung, prostate, and breast
cancer
- only slightly increased
Discussion
• The kind of immunosuppressive agent
- potentially affect the development of cancers
• The cautious conclusion of these data
- CNIs :increase in cancer
- TAC : enhance the recurrence of non-
melanoma skin cancer
• mTOR inhibitor-based immunosuppressive
- tendency for lower malignancy rates
• Use of IL-2-receptor antagonists
- reduced the tumor risk of transplant recipients
Conclusion
Tailored immunosuppressive therapy
• Individual's risk of allograft rejection
• Risk of cancer
• Appropriate renal population-screening
strategies
• Early treatment programs
impact on mortality and morbidity
Thanks for your attention~
特別感謝
指導醫師 李文欽 簡玉樹醫師
