Nephrology Dialysis Transplantation 2007 22(Supplement 1):i23-i26; doi:10.1093/ndt/gfm086
© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Use of proliferation signal inhibitors in non-melanoma skin cancer following renal transplantation
J. W. de Fijter
Department of Nephrology, Leiden University Medical Center, NL-2333ZA Leiden, The Netherlands
Correspondence and offprint requests to: Prof Dr J. W. de Fijter, MD, PhD, Department of Nephrology, C3-P22, Leiden University Medical Center, Albinusdreef 2, NL-2333 ZA Leiden, The Netherlands. Tel: +31 71 526 2218; Fax: +31 71 526 6868; Email: jwdefijter{at}lumc.nl
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Abstract
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Non-melanoma skin cancer (NMSC) affects a large proportion of
renal transplant recipients, with estimates suggesting that
at least half of white-skinned transplant recipients will develop
NMSC following transplantation. Squamous-cell carcinoma is the
most frequent NMSC following transplantation occurring at a
100-times greater risk than in the general population, while
the incidence of basal cell carcinoma is increased 10-fold over
the general population. The most important risk factor for the
development of NMSC in renal transplant recipients is prior
exposure to ultraviolet radiation, therefore, geographical location
and skin type highly influence the risk of NMSC. However, both
the intensity and type of immuno-suppressive therapy have been
associated with an increased risk of NMSC. Given the potential
anti-cancer actions of the proliferation signal inhibitors (PSIs),
everolimus and sirolimus, demonstrated in both pre-clinical
and clinical studies, we have analysed the effect of conversion
to PSIs in 53 renal transplant recipients developing NMSC after
transplantation. Remission of NMSC was observed in 37 patients
and was generally well tolerated with minimal adverse events
reported. Fifteen patients developed new lesions following conversion,
two of these were receiving low-dose calcineurin inhibitors
(CNIs) as part of their immuno-suppressive regimen suggesting
that there was insufficient reduction of CNIs. PSI blood levels
did not seem to affect the outcomes of conversion. These data,
along with published clinical trial data suggest that conversion
from CNIs to PSIs may be useful in the management of NMSC following
renal transplantation.
Keywords: non-melanoma skin cancer; post-transplant malignancy; proliferation signal inhibitors/mammalian target of rapamycin inhibitors; renal transplant recipients
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Introduction
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Non-melanoma skin cancer (NMSC) is a significant clinical problem
in organ transplant recipients, and is likely to increase in
importance as patients and graft survival times continue to
lengthen. Overall, basal-cell (BCCs) and squamous-cell carcinomas
(SCCs) account for >90% of all NMSC occurring in transplant
recipients [
1]. The tumours are often associated with multiple
warts or pre-malignant
in situ conditions, such as Bowen's disease
and actinic keratoses. No patient has been reported to die from
BCCs and SCCs occurring in transplant recipients, although tumours
in these patients are generally more aggressive than those appearing
in other populations [
2]. Older age, those with multiple extracutaneous
or cephalic tumours and high sun exposure also contribute to
a worse prognosis [
1]. This review discusses the increased risk
and pathogenesis of NMSC post-transplantation, specifically
highlighting the impact of immuno-suppressive regimens on the
incidence of NMSC in renal transplant recipients.
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Pathogenesis
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Skin carcinomas have a multifactorial pathogenesis, with both
intrinsic and extrinsic factors [
1]. There are many types of
NMSC, with SCCs and BCCs, originating from epidermal and hair-follicle
keratinocytes being the most frequent tumours. [
1]. Life-long
immuno-suppression [with calcineurin inhibitors (CNIs) or anti-metabolites]
is the most important risk factor for the development of NMSC.
In addition, environmental (UV-exposure, human papilloma virus
infections) and genetic factors (fair skin, genetic polymorphisms)
are suspected to play a role in the early stages of SCC development,
in which certain mutations in tumour suppressor (p53) and proto-oncogenes
may occur [
1]. Other, less common skin cancers include Kaposi's
sarcoma, originating from endothelial cells; Merkel cell carcinoma,
originating from neuroendocrine cells; primary cutaneous lymphomas
and sarcomas [
1].
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Epidemiology
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Skin carcinoma is the most common cancer in white populations,
with >15 000 new cases annually in The Netherlands alone,
a number that is still rising [
3]. It is estimated that at least
half of all white-skinned transplant recipients will develop
at least one NMSC after receiving a transplant. Overall, the
cumulative incidence of NMSC after transplantation ranges from
2–24% after 5 years to 7–33% after 10 years [
4].
SCC in particular is the most common form of skin cancer in
transplant recipients, occurring at an incidence 65–250
times greater than in the general population, while the incidence
of BCC is increased 10-fold after transplantation [
1]. This
means that the normal ratio of 4:1 BCC to SCC is reversed in
transplant recipients [
1,
5].
There is considerable evidence to suggest that the most important risk factor for the development of NMSC in immuno-compromised individuals is prior exposure to ultraviolet radiation, which, in addition to its role as a mutagen, also has immunosuppressive properties in the skin [1,4]. The tumours tend to develop on areas of the skin that are regularly exposed to the sun, such as the face and forearms, and the risk of developing a tumour is significantly increased in patients with a high lifetime sun exposure, particularly exposure occurring before the age of 30 years [6,7]. In addition, Caucasian transplant recipients with fair skin and a tendency to sunburn are at a higher risk of NMSC after transplantation than those with darker skin that tans on sun exposure [7]. Evidence of the role for ultraviolet light comes from the increased incidence of NMSC in fair-skinned populations living in countries with a hot climate and high ultraviolet exposure compared with those living in more temperate regions. For example, the 10-year incidence of NMSC in renal transplant recipients varies from 7% in Norway to 9–10% in Italy and UK, and 
33% in Australia [4]. Indeed, the highest global risk of post-transplant NMSC occurs in Caucasian patients living in the northern states of Australia [8]. When the incidence of post-transplant NMSC in Queensland was compared with that in The Netherlands, patients in the Australian cohort were around four times more likely to develop NMSC, even after adjustment for sex and age at first transplantation (Figure 1) [9]. The adjusted relative risk was greater for BCC (5.1) than for SCC (3.6).
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Fig. 1. Cumulative incidence (± 95% confidence intervals) of skin cancer in patients from Australia and The Netherlands [8] (Reprinted with permission from Lippincott, Williams and Wilkins). BCC NL, basal-cell carcinoma in The Netherlands; BCC QU, basal-cell carcinoma in Queensland; CA NL, all skin cancer in The Netherlands; CA QU, all skin cancer in Queensland; SCC NL, squamous cell carcinoma in The Netherlands; SCC QU, squamous cell carcinoma in Queensland.
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In addition to sun exposure, a number of other risk factors
for post-transplant NMSC have been identified. A UK study in
renal transplant recipients found that older age at transplantation,
presence of pre-malignant lesions such as actinic keratoses,
and male sex were associated with the development of BCC and
SCC, while a history of cigarette smoking was also associated
with development of SCC [
5]. A study of heart transplant recipients
in Spain, however, found that total sun burden and skin type
were the only significant risk factors after multivariate analysis,
with age at transplantation significant only in the crude analysis,
and no relationship detected between NMSC and sex, incident
warts or history of smoking [
7].
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Immunosuppressive regimens and NMSC
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As with all post-transplant malignancies, immuno-suppression
is a critical component of the increased risk, although the
contribution of individual agents is less clear. A study carried
out in Queensland showed no difference in the risk of developing
skin cancer between patients receiving ciclosporin (CsA) or
azathioprine and those receiving combination therapy with both
agents [
9]. Support for the role of the total level of immuno-suppression
in the development of NMSC came from a study by Dantal
et al.
[
10], in which patients were randomized to normal- or low-dose
CsA therapy (trough blood levels of 150–250 ng/ml and
75–125 ng/ml, respectively). The results showed that both
the overall risk of cancer and the risk of skin cancers were
significantly decreased in the low-dose CsA group (
P < 0.05)
(
Table 1). The low-dose regimen was, however, associated with
a significant increase in the risk of acute rejection. Studies
of newer immunosuppressive agents are limited, although a study
in renal transplant recipients showed that tacrolimus was associated
with a significantly lower incidence of NMSC compared with CsA
[
11]. A study in liver transplant recipients showed that mycophenolate
mofetil (MMF) was associated with an increased risk of NMSC,
although this risk did not remain after multivariate analysis
[
12].
In addition to the level of immunosuppression, the duration
of immuno suppression also appears to play a role in the development
of NMSC. A study carried out in Queensland showed that the cumulative
incidence of skin cancer increased progressively, from 7% after
1 year of immunosuppression to 45% after 11 years and 70% after
20 years [
9]. A more recent study in a similar population showed
that the overall incidence of NMSC increased from 19% at fewer
than 5 years to 47% after more than 20 years of immuno-suppressive
therapy [
13].
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Conversion to proliferation signal inhibitors (PSIs)
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Following on from promising experimental models demonstrating
the anti-neoplastic potential of sirolimus, the rates of malignancy
at 2 years after renal transplantation were reviewed in patients
receiving sirolimus therapy in combination with CsA, sirolimus
as base therapy or sirolimus maintenance therapy after early
withdrawal of CsA. At 2 years post-transplant, patients receiving
a combination of sirolimus and CsA had a lower incidence of
NMSC compared with patients who received placebo. The incidence
of malignancy was significantly lower in patients receiving
sirolimus with early CsA elimination than in patients who remained
on sirolimus and CsA therapy [
14]. Compared with a 5% incidence
in CsA-treated patients, no malignancies were observed in patients
receiving sirolimus as base therapy [
14]. The potential anti-tumour
benefits of CsA elimination from a sirolimus-based therapy were
further examined in a
post hoc analysis of 430 renal transplant
recipients [
15] randomly assigned at 3 months post-transplantation
to remain on sirolimus, CsA and steroids or to have CsA withdrawn
from the regimen and sirolimus trough levels increased by twofold.
At 5-year follow-up, the median time to a first skin carcinoma
was longer and the mean annualized rate was significantly lower
in the sirolimus group than in the CsA/sirolimus group [
15].
The relative risks for both BCC and SCC were significantly reduced,
indicating that a CsA-free, sirolimus-based immuno-suppressive
regimen may reduce the incidence of post-transplant skin malignancies.
To gain a better understanding of current clinical experience of conversion to a PSI in patients with NMSC, patient data from eight transplant centres across Europe were pooled. This analysis only included renal transplant recipients who were converted to PSIs following the development of NMSC. In total, 53 renal transplant recipients who developed NMSC were converted to PSIs, of these, eight patients received everolimus and 45 patients received sirolimus; CNIs were withdrawn in 51 patients and minimized in two patients (Table 2). Sirolimus blood levels ranged from 5 to 11 ng/ml and everolimus blood levels ranged from 2 to 8 ng/ml. Remission of NMSC occurred in 37 patients and was generally well tolerated; reported adverse events included acneiform skin eruptions (n = 9), aphtous ulceration (n = 2), pneumonitis (n = 1), anaemia (n = 1), oedema (n = 3) and proteinuria (n = 2). Relapse of cancer occurred in 15 patients, of those, two patients were receiving a CNI-minimization protocol although for the remaining patients the analysis suggests that a relapse of cancer is not related to PSI blood levels. One patient was lost to follow-up, one patient with previously advanced chronic allograft nephropathy returned to dialysis and five died. These data suggest that whilst PSIs might aid the management of NMSC, patient history is also likely to influence the outcome following conversion.
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Summary
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The incidence of NMSC is higher in patients receiving kidney
transplants compared with those in the general population. Although
BCCs and SCCs are not usually life-threatening, they have an
impact on patient quality of life and require treatment. Although
standard surgical treatments for skin cancer are usually effective,
reducing the risk for multiple new primary skin cancers remains
a challenging problem. The potential for PSIs in reducing the
impact of NMSC following renal transplantation has been observed
in a number of clinical studies, and increasing clinical experience
with this regimen may provide further insights into management
of the disease. At present several multi-centre studies are
underway that should provide evidence-based guidance on the
role of PSI's in the management of NMSC.
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Acknowledgements
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Data on NMSC was collected from the following centres:
Division of Nephrology and Dialysis, Internal Medicine III, Medizinische Universität Wien, Vienna, Austria; Hôpital Hotel Dieu, CHU de Nantes, Service du Pr Soulillou, Nantes, France; Cologne General Hospital, Merheim Medical Center, Germany; Universitatsklinikum Charite, Abeteilung fur Nephrologie, Berlin, Germany; Renal Unit, Kidney Transplantation Center, ‘Leonardo Sciascia’ Civic Hospital, Palermo, Italy; Nephrology Department, Hospital Universitario de Bellvitge, Barcelona, Spain; Servicio de Nefrología, Hospital Ramón y Cajal, Madrid, Spain; Renal Unit, Department of Nephrology, Hospital Clínic, University of Barcelona, Spain
Editorial assistance was provided by Ogilvy 4D.
Conflict of interest statement. The author received an honorarium from Novartis Pharma AG for participation in the workshop in Rome, March 2006, on the role of everolimus in the management of post-transplant malignancies in renal transplantation.
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Abstract
Introduction