1. health and fitness
2. therapy

STUDY
Low-Dose Retinoids in the Prevention
of Cutaneous Squamous Cell Carcinomas
in Organ Transplant Recipients
A 16-Year Retrospective Study
Catherine A. Harwood, MA, PhD, MRCP; Mary Leedham-Green, MA;
Irene M. Leigh, FRCP, DSc; Charlotte M. Proby, MA, FRCP
Objective: To evaluate the long-term efficacy of sys-
temic retinoids in reducing the incidence of cutaneous
squamous cell carcinomas (SCCs) in organ transplant recipients (OTRs), who are at greatly increased risk of SCCs.
Design: A retrospective before-after study of OTRs who
had received low-dose systemic retinoids during 1 to 16
years for prevention of SCCs.
Setting: A specialist dermatology clinic for organ trans-
plant recipients at St Bartholomew’s and the Royal London Hospital, University of London, London, England.
retinoid treatment and the number during the 12month pretreatment interval.
Results: In 28 continuously treated individuals, the mean
number of SCCs in the 12-month pretreatment interval
was 2.9. The number of SCCs was significantly reduced,
with a mean difference of 1.46 in the first year of treatment (P=.006), 2.20 in the second (P⬍.001), and 2.14
in the third (P=.02). The numbers of SCCs were also reduced in subsequent years, but this effect was no longer
significant because of smaller patient numbers. Six patients in whom retinoid treatment was interrupted subsequently had a significant increase in SCCs.
Patients: Thirty-two OTRs with at least 1 histologi-
cally proved SCC.
Interventions: Continuous systemic retinoids at dosages of 0.2 to 0.4 mg/kg per day for a minimum of 12
months.
Main Outcome Measures: The mean difference between the number of SCCs developing annually during
I
Author Affiliations: Centre for
Cutaneous Research, St
Bartholomew’s and the Royal
London School of Medicine and
Dentistry; Queen Mary,
University of London, London,
England.
Financial Disclosure: None.
Conclusions: Low-dose systemic retinoids significantly
reduce SCC development in OTRs for the first 3 years of
treatment, and this effect may be sustained for at least 8
years, with a generally well-tolerated side-effect profile.
Studies are now required to further optimize their use as
a chemopreventive strategy in high-risk OTRs.
Arch Dermatol. 2005;141:456-464
MMUNOSUPPRESSED ORGAN TRANS-
plant recipients (OTRs) have an
increased risk of a diverse range
of malignancies, of which nonmelanoma skin cancers are the
most frequently reported.1,2 A cumulative risk of nonmelanoma skin cancer of
more than 40% by 20 years after transplantation is reported in temperate climates,3 rising to more than 80% in Australia.4 Squamous cell carcinoma (SCC)
and its precursors (actinic keratoses and
carcinomas in situ [CIS] or Bowen’s disease) pose an enormous and escalating
clinical problem, since rates are 50 to 100
times that of the general population and
tumors tend to behave more aggressively
and are frequently multiple.5
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456
Prevention and management of transplant-associated skin cancer requires intensive surveillance in dedicated clinics,
education regarding photoprotection and
self-surveillance, prompt treatment of cancers and premalignancies (with, for example, surgery, cryotherapy, and topical
chemotherapeutic agents such as fluorouracil), and, in some circumstances, elective surgical resurfacing of high-risk sites
such as forehead and dorsum of hands.3
The use of systemic retinoids in prevention of transplant-related skin malignancy was first described more than 15
years ago.6 Retinoids are vitamin A analogues that interact with 2 groups of
nuclear receptors, the retinoic acid receptors and retinoid X receptors, to influ-
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ence transcription of specific genes, with a consequent
wide range of biological activities.7 Possible mechanisms by which they prevent or reduce development of
skin cancer include induction of growth arrest or apoptosis of tumor cells with resultant inhibition of tumor differentiation and promotion, induction of normal cellular differentiation, and immunomodulation, including
increased density of Langerhans cells.8-10 Preferential retinoid-induced growth inhibition of human papillomavirus 16–immortalized keratinocytes compared with noninfected cells11 may also be relevant, since SCCs from
OTRs are associated with a high prevalence of human papillomavirus DNA.12
Although systemic retinoids have been commonly used
for prevention of SCCs in high-risk OTRs, there are surprisingly few clinical studies examining this (reviewed
by De Graaf et al13). Shuttleworth and colleagues6 first
reported a preventive effect from etretinate given during 6 months in 5 of 6 renal transplant recipients. Similar beneficial effects have been documented in a number of uncontrolled series of between 4 and 16 patients
treated for less than 6 months to 5 years.8,10,14-17 In the
only randomized, placebo-controlled trial, 19 patients received acitretin for 6 months and had significantly fewer
SCCs during this time than did 19 placebo-treated patients.18 Eleven patients completed a randomized crossover trial in which acitretin produced a significant reduction in SCCs compared with no treatment during 12
months.19 In a third trial of 26 patients randomized to
treatment with 2 dosages of acitretin (0.2 vs 0.4 mg/kg
per day) during 12 months, a significant reduction was
seen in actinic keratoses but not SCCs in both groups.20
Retinoids are effective only during treatment, such that
lifelong administration is potentially required for prevention of SCCs in OTRs. However, publications to date
have reported treatment for only 2 years or less, with the
exception of 1 study in which responses at 5 years in 7
patients were documented.15 In addition, the adverse effects of systemic retinoids, including mucocutaneous xerosis, alopecia, musculoskeletal complications, increased plasma triglyceride and cholesterol levels, and
abnormalities of liver function, may limit their longterm use in OTRs, but this has rarely been examined in
patients treated for more than 5 years. In this study we
present data concerning the chemopreventive efficacy and
side-effects profile of systemic retinoids in a series of 33
OTRs treated for up to 16 years.
METHODS
PATIENTS AND TUMORS
Our institution established a dedicated dermatology clinic for
OTRs in the late 1980s and has a cohort of more than 800 OTRs
under longitudinal study, with data on almost 8000 patientyears at risk. All OTRs are seen within 6 to 12 months of transplantation and at least annually thereafter.3 Since 1988 we have
documented the use of systemic retinoids (initially etretinate
and, since 1993, its active metabolite, acitretin) in patients who
have developed at least 1 histologically proved SCC, who are
predicted to be at high risk for further tumor formation (in terms
of age, duration of transplantation, previous UV radiation ex-
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posure, and skin type3), in whom the renal physicians consider there are no specific contraindications, and in women who
are postmenopausal. A low-dosage protocol is used, starting at
approximately 0.2 mg of acitretin per kilogram per day and increasing to a maximum of 0.4 mg/kg per day according to clinical response and side-effect profile. Patients are examined every 3 months, when potential adverse effects are documented
and fasting lipid levels, renal and liver function, and full blood
count are monitored. Routine radiographic skeletal monitoring is not performed. At each follow-up visit, advice regarding
photoprotection and self-surveillance is reinforced; dysplastic
lesions are treated with cryotherapy, topical fluorouracil, curettage, and cautery; and all suspicious lesions are excised.
For the purposes of this study, we included individuals who
had received retinoids for at least 12 months between January 1, 1988, and December 31, 2003. Only patients in whom a
complete skin cancer history was available with histologic confirmation of each tumor were studied. Patients in whom there
had been an interruption in treatment for any reason during the
first year were excluded from the main analysis and were analyzed separately. Patients who had received at least 12 months
of treatment, but had then had an interruption in therapy, were
also analyzed separately for the period after this interruption. For
each individual, therapeutic benefit was assessed by comparing
the numbers of SCCs before starting retinoids with annual SCC
burden thereafter. The mean of this difference was calculated for
all patients treated for that time interval. Information on the mean
number of SCCs per year for each year after transplantation were
also available. Histologically proved CIS were analyzed separately. Basal cell carcinomas, appendageal tumors, and melanomas were not included in the analysis.
During the course of this retrospective study, it was our policy
to reduce immunosuppression only in the presence of metastatic disease. However, immunosuppression may be altered by
transplant physicians for a number of other reasons, eg, coincident posttransplant lymphoproliferative disease, Kaposi sarcoma, or gout (azathioprine is greatly reduced or stopped if allopurinol sodium therapy is started). The medical records of
all patients included were carefully scrutinized for evidence of
any coincident reduction in immunosuppression that may have
influenced the development of cutaneous SCC.
STATISTICAL ANALYSIS
The differences in numbers of SCCs between the pretreatment
period and each year after the start of treatment were calculated
for each patient. Confidence intervals (CIs) and P values for the
mean of the differences were determined by 1-sample t tests. When
the responses to acitretin of the 2 age groups at transplantation
and the 2 age groups at start of retinoid treatment were compared, independent-sample t tests were used. The statistical package used was SPSS 11.00 (SPSS Inc, Chicago, Ill).
RESULTS
Forty-two patients received systemic retinoids for chemoprevention of skin cancer at our institute between 1988
and 2003. Ten individuals were excluded from further
analysis, as they did not fulfill all study criteria (4 were
treated for less than 1 year in total; 2 were transferred
from other hospitals and skin cancer data were incomplete; 2 were treated for vulval intraepeithelial neoplasia only; 2 started treatment with retinoids for viral warts
or acne rather than skin cancers, but subsequently developed SCCs while taking retinoids). Four patients had
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Table 1. Clinical Details of Patients Receiving Continuous Retinoid Therapy
Patient No./
Sex/Age at
Transplantation, y
Immunosuppressive
Drugs
1/M/23
2/M/67
3/M/42
4/M/17
5/M/46‡
6/M/32
7/M/58
8/M/43
9/M/64§
10/M/31
11/M/54§
12/M/55
13/M/53
14/M/45
15/M/56
16/M/42
17/F/62
18/M/40§
19/M/38
20/M/60
21/M/51§
22/M/34
23/M/35
24/M/54㛳
25/M/31
26/M/50㛳
27/M/22
28/F/43
P, A
P, A, C
P, A, C
P, C
A, C
P, A, C
P, A, C
P, A, C
P, A, C
P, A
P, A, C
P, A, C
P, A, C
P, A
P, A
P, A, C
P, A, C
P, A
P, A, C
P, A, C
P, A, C
P, A, C
P, A, C
P, A, C
P, A, C
P, A, C
P, A
P, A
Time Between
Transplant and
1st SCC, y
17
5
9
10
10
14
3
10
5
17
7
2 (CIS)
3
11
4
8
4
7
10
4
7
3
7
3
6
8
11
6
Time Between
1st SCC and
Retinoids, y
Duration
of Retinoid
Treatment, mo*
Total No. of
SCCs Before
Retinoid
Treatment
No. of SCCs
1 y Before
Retinoid
Treatment
No. of SCCs in Each Year
After Retinoid Treatment†
2
1
5
6
1
3
1
1
1
4
1
0
3
5
6
6
5
2
1
1
1
1
4
2
5
1
9
1
19
98
27
24
32
36
75
31
56
24
36
114
36
51
13
30
32
180
54
30
71
33
25
48
31
16
58
100
2
4
12
6
2
11
2
3
9
4
4
0
11
5
3
4
12
2
1
4
4
3
4
6
9
4
11
3
2
4
2
3
1
6
2
3
9
0
4
0
6
2
1
1
7
0
1
4
4
3
3
3
4
2
2
2
0
1, 2, 1, 1, 0, 0, 0, 0
1, 1
0, 0
3, 1
2, 1, 0
0, 0, 0, 0, 2, 0
1, 2
1, 3, 0, 0
0, 0
5, 0, 2
7, 2, 3, 0, 0, 2, 0, 0, 4
1, 1, 3
1, 0, 0, 0
1
0. 1
5, 2
0, 0, 0, 0, 0, 0, 0, 2, 0, 0, 0, 1, 0, 2, 0, 4
2, 0, 1, 0
0, 0
1, 0, 1, 3, 5, 6
0, 0
2, 1
2, 3, 4, 6
4, 1
0
0, 0, 0, 1
0, 0, 0, 0, 0, 0, 0, 0
Abbreviations: A, azathioprine; C, cyclosporine; CIS, carcinomas in situ; P, prednisolone; SCC, squamous cell carcinoma.
*All patients received acitretin with the exception of patients 1, 8, and 22, who were initially treated with an equivalent dose of etretinate; patients 8 and 22 were
subsequently changed to therapy with acitretin.
†Data are presented in years relative to the start of retinoid treatment, whereas the data in Figures 2 through 4 are presented in calendar years.
‡Patient 5 was a cardiac transplant recipient; all other patients were renal transplant recipients.
§These 4 patients had either lymph node only (patients 11 and 21) or lymph node and distant (patients 9 and 18) metastases. In patients 9 and 11, these metastases
occurred before the start of retinoid therapy, and in patients 18 and 21 the metastases occurred during therapy.
㛳Patients 24 and 26 received retinoids for longer than the period stated. However, both had interruption in treatment of 3 months or more, and so only data before this
interruption are included. These patients were also included in the series of 6 patients in whom the effects of interruptions of treatment were evaluated (Table 4).
ruptions in treatment within the first 12 months, leaving 28 patients who had received continuous treatment
(Table 1). Two patients (patients 24 and 26) were included in both the series of 28 patients receiving continuous treatment and the analysis of effects of interruptions in treatment, as they received treatment for longer
than 1 year but then experienced an interruption in treatment. Patient 1 also discontinued treatment (because of
alopecia) after 19 months but did not experience a rebound in SCC numbers in the first 2 months after stopping treatment; he was then lost to further follow-up and
was not included in the analysis of interruptions.
One of the 28 OTRs had received a cardiac transplant, and the remainder were renal transplant recipients. Their mean age at transplantation was 44.6 years
(range, 17-67 years), and 26 were male. Immunosuppressive drug regimens consisted of azathioprine and prednisolone (n=7); azathioprine, prednisolone, and cyclosporine (n=19); prednisolone and cyclosporine (n=1);
and azathioprine and cyclosporine (n = 1). All had had
at least 1 documented SCC before retinoid therapy, with
the exception of patient 12 (Table 1). This individual had
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had 3 severe CIS lesions with probable microinvasion and
was considered very high risk (he had already had a basal
cell carcinoma before transplantation, was skin type I,
and had spent many years as an outdoor worker in the
Middle East, and his older brother [patient 13] had had
multiple SCCs). He therefore started treatment with retinoids before a frankly invasive SCC occurred. The mean
number of years from transplantation to first SCC was
7.5 (range, 3-17 years), and the mean number of SCCs
before the start of treatment with retinoids was 5.37
(range, 1-12). In the 12-month pretreatment interval, the
mean number of SCCs was 2.9 (range, 0-9). Acitretin was
used in 25 patients, but 3 patients treated before 1993
started treatment with equivalent doses of etretinate, and
2 were subsequently changed to acitretin.
EFFECT OF RETINOIDS ON THE NUMBER
OF SCCS PER YEAR
Twenty-eight patients received continuous retinoids for
at least 1 year (Table 1). The mean of the differences in
numbers of SCCs in the pretreatment compared with the
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Table 2. Effects of Retinoid Treatment on SCC Development
Years After Starting
Retinoid Treatment
No. of Patients
Mean Difference, Pretreatment
and Posttreatment SCCs
95% Confidence
Interval
P Value
1
2
3
4
5
6
7
8
28
25
14
11
6
6
4
4
–1.46
–2.20
–2.14
–1.63
–0.83
–0.67
–1.50
–1.00
–0.45 to –2.47
–1.37 to –3.03
–0.47 to –3.82
0.32 to –3.59
1.09 to –2.76
1.88 to –3.21
1.54 to –4.55
3.12 to –5.11
.006
⬍.001
.02
.09
.32
.53
.22
.50
Abbreviation: SCC, squamous cell carcinoma.
Retinoid Therapy Start
3.5
3.0
n = 28
Mean No. of SCCs/y
2.5
2.0
n = 28
1.5
n=6
n=6
n = 14
n = 11
1.0
n = 25
n = 28
0.5
n = 25
n = 27
–4
–3
n = 21
n=4
n = 23
n = 16
n = 18
–10
–9
n = 19
n = 20
–8
–7
n=4
0
–6
–5
–2
–1
1
2
3
4
5
6
7
8
Year Relative to Start of Retinoid Therapy
Figure 1. Annual numbers of squamous cell carcinomas (SCCs) before and after the start of systemic retinoid treatment. Only patients in whom there had been
continuous retinoid treatment are included.
posttreatment 12-month intervals confirmed a mean reduction of 1.46 SCCs per year (P= .006; 95% CI, −0.45
to −2.47). A total of 25 patients received retinoid therapy
for at least 2 complete years, with a mean reduction of
2.20 SCCs per year (P⬍.001; 95% CI, −1.37 to −3.03).
Fourteen patients received 3 complete years of treatment, with a mean reduction of 2.14 SCCs (P=.02; 95%
CI, −0.47 to −3.82). Eleven patients were treated for at
least 4 years, and although the mean reduction was still
1.63 SCCs, this did not quite achieve statistical significance (P=.09; 95% CI, 0.32 to −3.59). For individuals
who had received at least 5, 6, 7, 8, 9, and 16 years of
continuous treatment (n = 6, 6, 4, 4, 2, and 1, respectively), the mean difference in SCCs continued to show
an overall reduction, but this was no longer statistically
significant (Table 2, Figure 1). Responses for selected individual patients are shown in Figure 2.
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The mean number of SCCs per year after transplantation and before the start of retinoid treatment was also
calculated. There was a gradual increase in the annual
SCC number each year after transplantation, reaching a
maximum in the 12-month interval immediately before
retinoid therapy was started. As expected, there was a
strong correlation between the number of SCCs in the
12 months preceding acitretin treatment and the total
number of SCCs from time of transplantation to start of
acitretin therapy (Figure 1).
EFFECT OF INTERRUPTION
IN RETINOID THERAPY
Six patients received retinoids for more than 18 months
but had experienced an interruption in therapy, in all cases
inadvertently rather than as the result of adverse effects.
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Etretinate
10 mg 20 mg
8
Acitretin
10 mg Died
Acitretin
Dosage
5
A
10 mg
Died
B
7
No. of SCCs and CIS
No. of SCCs and CIS
4
SCC
CIS
6
5
4
3
3
2
2
1
1
0
0
1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996
1992
1993
1994
1995
1996
Year
Acitretin
Dosage
20 mg
25 mg
1998
1999
2000
2001
2002
Year
30 mg
Acitretin
Dosage
25 mg
3.5
C
3.0
3.0
2.5
2.5
No. of SCCs and CIS
No. of SCCs and CIS
3.5
10 mg
1997
2.0
1.5
1.0
0.5
10 mg
20 mg
D
2.0
1.5
1.0
0.5
0
0
1995
1996
1997
1998
1999
2000
2001
2002
2003
1997
1998
1999
Year
2000
2001
2002
2003
Year
Figure 2. Examples of individual patient responses to systemic retinoids. A-C, Skin cancer history of individuals (patients 27, 14, and 2, respectively) who had a
beneficial response to systemic retinoids. D, Data from patient 5, who failed to demonstrate a response to low-dose retinoids.
In 2 cases (patients 24 and 26, Table 1) this interruption did not occur during the first 12 months of retinoid
therapy, and these individuals were therefore also included in the analysis of continuous treatment up until
the time at which this interruption occurred. The remaining 4 cases were not included in the main analysis
because an interruption had occurred within the first year
of treatment. There was a significant difference in SCC
numbers in the 12-month interval before and after an interruption in treatment, with a mean increase of 4.67 SCCs
(95% CI, 1.3-8.03; P= .02). This “rebound” increase in
SCCs was most marked in patients taking retinoids for
longer than 12 months (Table 3). Individual data for
patient 24 are given in Figure 3.
METASTATIC SCC AND RETINOID THERAPY
Metastases from cutaneous SCC were recorded in 4 of
the 28 patients receiving continuous retinoid treatment. Two patients (cases 9 and 11) were diagnosed as
having metastatic SCC in the 2 weeks before treatment
started, and 2 patients (cases 18 and 21) developed metastatic disease while already taking retinoids. Patient 9 had
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local lymph node metastases from a spindle cell SCC arising on the right cheek, as well as bony metastases to ribs
and sacrum, and was treated with radical surgery and radiotherapy. He survived for 57 months without further metastases and died of unrelated causes (Figure 4A). Patient 11 had right axillary lymph node metastases presumed
to have originated in a primary SCC on the dorsum of the
hand, despite complete histological resection 6 months previously. He was treated with surgery and radiotherapy and
had no further metastases in 36 months of follow-up. Patient 21 had lymph node metastases from a recurrent SCC
situated on the dorsum of the left hand 66 months after
starting acitretin. In the preceding 2 years his annual number of SCCs had increased above pretreatment levels, despite an increase in acitretin dose (Figure 4B). He was
treated with surgery but died 6 months later of apparently unrelated causes. Patient 18 had a rather similar
course in that his annual SCC numbers were well controlled with acitretin treatment for 14 years, but this control appeared to be lost in the year before development of
metastases. He had both local lymph node involvement
and pulmonary metastases from poorly differentiated SCC
arising on the scalp and remained under follow-up.
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Table 3. Effects of Interruptions in Retinoid Therapy on SCC Numbers
No. of SCCs
Patient
No.*
Duration of Retinoid Treatment
Before Interruption, mo
Duration of
Interruption, mo
12-mo Preinterruption
Interval
12-mo Postinterruption
Interval
Difference
24
26
29
30
31
32
48
16
12
32†
5
2
5
3
6
6
6
6
6
0
0
1
1
0
16
4
7
4
3
2
10
4
7
3
2
2
Abbreviation: SCC, squamous cell carcinoma.
*Patients 24 and 26 were also included in the series of 28 patients receiving continuous treatment (Table 1) up to the time at which there was an interruption in
treatment. Patients 29 to 33 were not included in that series, as the interruptions occurred within the first 12 months of treatment. All patients subsequently had at
least 18 months of total retinoid therapy and were therefore taking retinoids in the postinterruption 12-month interval. Patient 1 (Table 1) also discontinued
treatment (because of alopecia) after 19 months but did not experience a rebound in SCC numbers in the first 2 months after stopping treatment; he was then lost
to further follow-up in our department and is not included in this analysis.
†Patient 30 was not included in the main analysis, as he had had an interruption in retinoid therapy within the first 12 months, although this was for just 1
month. He continued with therapy but had a longer interruption after 32 months of therapy, and it is the effect of this interruption that is recorded here.
EFFECT OF RETINOIDS ON CIS
COINCIDENT ALTERATIONS
IN IMMUNOSUPPRESSION
Immunosuppression was reduced at the time systemic
retinoid treatment was started in the 2 patients (patients 9 and 11) in whom it was being administered as
part of treatment for metastatic SCC. Careful examination of the medical records of all patients revealed no other
changes in immunosuppression in the 12 months before or after starting retinoid therapy, with the exception of patient 2, in whom a posttransplant lymphoproliferative disorder was diagnosed 8 months after acitretin
was started, and azathioprine therapy was gradually reduced and stopped during the subsequent 2 years.
30 mg 20 mg
X
25 mg
30
SCC
CIS
25
No. of SCCs and CIS
When histologically proved CIS were included in the
analysis, the reduction in annual lesion numbers remained significant in years 1 to 3 of retinoid therapy. Although similarly reduced in year 4 and later, this was no
longer significant. Many patients treated with retinoids
also had widespread epidermal dysplasia and/or viral
warts. Most experienced considerable subjective and objective improvement in these lesions, although such effects were not specifically quantified in this study.
Etretinate Acitretin
20 mg 20 mg
20
15
10
5
0
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Year
Figure 3. Effect of interruption in retinoid treatment in patient 24. There was
a significant increase in numbers of squamous cell carcinomas (SCCs) in the
12-month interval after the interruption. CIS indicates carcinomas in situ; X,
cessation of acitretin therapy.
and those younger than 55 years. There was no significant difference between these 2 groups in mean reduction of SCCs during the first 2 years of treatment.
EFFECT OF AGE AT TRANSPLANTATION AND
AGE AT STARTING RETINOID TREATMENT
EFFECT OF TIME AND CUMULATIVE
TUMOR NUMBERS BEFORE THE START
OF RETINOID TREATMENTS
For the 25 patients who had been treated for at least 2 years,
the influence of age at transplantation on response to retinoids was analyzed. Patients were divided into 2 groups:
those who underwent transplantation before 45 years of
age and those who were at or above 45 years. There was
no significant difference between these groups in mean reduction of SCCs in either the first or second years of treatment. The mean age at which retinoids were started was
55.3 years. The influence of age at start of treatment on
efficacy was analyzed by dividing patients into 2
approximately equal groups: those 55 years or older
Retinoid treatments were started a mean of 2.82 years
(range, 1-9 years) after first SCC. The effect of this time
interval on efficacy of treatment was assessed by considering patients in 2 groups: those in whom retinoids were
started less than 3 years and 3 or more years after the first
SCC. This time interval had no significant influence on
subsequent efficacy of retinoids in reducing SCCs. A mean
of 5.37 SCCs were diagnosed before retinoid therapy was
started; there was no difference in reduction of SCCs in
individuals with fewer than 5 and those with 5 or more
SCCs before starting treatment.
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Acitretin
Dosage
7
10 mg 20 mg 30 mg 10 mg 20 mg
Acitretin
Dosage
Died
9
A
SCC
CIS
B
7
No. of SCCs and CIS
No. of SCCs and CIS
Metastases
30 mg Died
20 mg 15 mg 20 mg
8
6
5
10 mg
4
3
2
6
5
4
3
2
1
1
0
0
1992
1993
1994
1995
1996
1997
1998
1999
2000
1993
1994
1995
1996
Year
1997
1998
1999
2000
2001
Year
Figure 4. Effects of systemic retinoids on the course of metastatic cutaneous squamous cell carcinoma (SCC). A, Patient 9. Retinoid treatment was started at the
time of diagnosis; no further metastases occurred and SCC development was significantly reduced. B, Patient 21. Metastases developed during retinoid treatment;
the annual number of SCCs and carcinomas in situ (CIS) increased shortly before the diagnosis of metastases.
ADVERSE EFFECTS OF RETINOIDS
Among the subjective side effects reported, dry lips, dry
skin, and palmoplantar desquamation were common and
dose limiting in 5 patients (18%) (Table 4 ). Hair loss
occurred in 2 patients and led to discontinuation of treatment by 1 patient. Arthralgia was reported by 2 individuals; in 1 patient a dose reduction was required, but
in the other, arthralgia was transient and not clearly related to treatment, and in neither case were there accompanying radiographic abnormalities. Other symptomatic side effects included dry eyes (n=3), headache (n=1),
epistaxis (n = 1), nail fragility (n = 2), and pseudoporphyria (n = 1). Elevated serum triglyceride and cholesterol levels had been present in 15 (54%) of the 28 patients before starting treatment, of whom 9 were already
taking lipid-lowering drugs. Overall, 10 (36%) of the 28
patients had an increase in lipid levels above pretreatment values while taking retinoids; 3 were already taking lipid-lowering drugs, and the dose was increased. In
6 patients, elevation of lipid levels during treatment necessitated introduction of lipid-lowering drugs, but lipid
levels had been elevated in 4 of these patients before retinoid treatment was started. Only 2 patients with normal pretreatment lipid levels had to start taking lipidlowering drugs during treatment. In 2 patients with
chronic renal impairment before the start of treatment,
renal function slowly deteriorated, but this deterioration was not considered to be due to retinoids. Results
of hematologic and liver function tests were not adversely affected in any patient.
COMMENT
This is, to our knowledge, the first study to provide information on both short-term (ⱕ5 years) and long-term
(⬎5-16 years) use of systemic retinoids in the prevention of cutaneous SCCs in OTRs. Of 28 OTRs receiving
continuous retinoid treatment, a significant mean reduction of 1.46 SCCs occurred in the first year of treatment,
(REPRINTED) ARCH DERMATOL/ VOL 141, APR 2005
462
2.24 SCCs by the second year, and 2.14 SCCs in year 3.
This reduction was sustained, but nonsignificant, at years
4 and later. In 2 patients, retinoids appeared to halt progression of documented metastatic disease. In 2 other individuals, metastases developed during treatment and,
in both cases, loss of chemopreventive efficacy had already been noted in the preceding 12 months. Most adverse effects were mild, and treatment was discontinued
in only 1 patient because of these. In 6 patients, interruption of therapy was associated with a significant rebound increase in tumors.
RETINOID CHEMOPREVENTIVE EFFICACY
Although we demonstrated a significant annual reduction in SCCs after introduction of retinoids by comparison with the 12-month pretreatment interval, it is likely
that this approach may have underestimated the true chemopreventive efficacy of retinoids. Data on the mean numbers of SCCs before retinoid treatment confirmed a steady
annual increase for each year after transplantation. Thus,
the projected tumor numbers for each year after treatment might have been expected to far exceed the baseline taken in the 12-month pretreatment interval. In these
circumstances, the annual reduction in tumor numbers
with retinoid treatment may well have been even greater
and may also have continued to be highly significant at
years 4 and above. A carefully designed case-control study
would be necessary to investigate such a possibility. A
possible confounding factor in interpreting these data is
that more frequent monitoring and intensive treatment
of premalignant lesions may have accounted for some of
the reduction in SCC numbers during retinoid treatment. However, all of these patients had been under regular surveillance since the time of their transplantation and
had received regular advice concerning photoprotection, and all of them had been treated for dysplastic lesions before starting retinoid therapy.
In a previous study, retinoids appeared to have a significantly better chemopreventive effect in patients with
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Table 4. Adverse Effects of Retinoids
Lipid Elevation
Patient
No.
Mucocutaneous
Effects
1
2
Xerosis, alopecia
Cheilitis, xerosis, pruritus,
PPD, dry eyes
Cheilitis, xerosis, epistaxis
Cheilitis, xerosis
None
Cheilitis, xerosis, PPD
None
None
Cheilitis, xerosis, PPD
Cheilitis, xerosis
Cheilitis, xerosis, PPD,
nail fragility
Cheilitis, xerosis, pruritus,
PPD, alopecia
None
Cheilitis
None
Cheilitis
Cheilitis
Cheilitis, xerosis, PPD,
dry eyes
Cheilitis, xerosis, PPD
Cheilitis
Cheilitis, dry eyes
None
Cheilitis
Cheilitis, xerosis, pruritus,
PPD, nail fragility
Cheilitis
Cheilitis, PPD
Cheilitis, PPD
Cheilitis
3
4
5
6
7
8
9
10
11
12
13
14
15
16†
17
18
19
20†
21
22
23
24
25
26
27
28
Pretreatment
Posttreatment
Lipid-Lowering
Drug*
Retinoid Treatment
Stopped or Reduced
None
None
Yes
No
No
No
None
None
Stopped
No
Alopecia
NA
Arthralgia
None
None
None
None
None
None
None
None
Yes
Yes
Yes
Yes
No
No
No
No
Yes
No
No
Yes
No
No
No
No
No
No
Pre
Pre
Pre
Pre
None
None
None
None
Pre
Reduced
No
No
Reduced
No
No
No
No
No
Arthralgia
NA
NA
Xerosis
NA
NA
NA
NA
NA
None
No
Yes
Post
Reduced
Itch
None
None
None
Pseudoporphyria
None
None
No
Yes
No
Yes
Yes
No
Yes
No
No
No
Yes
No
Post
Pre
None
Pre
Pre
None
No
No
No
Reduced
Reduced
No
NA
NA
NA
Pseudoporphyria
Lipids
NA
None
None
None
None
None
None
No
No
Yes
Yes
No
No
No
No
Yes
Yes
No
No
None
None
Pre
Diet
None
None
Reduced
No
No
No
No
Reduced
Xerosis
NA
NA
NA
NA
Xerosis
None
None
None
None
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Post
Post
Post
Post
Reduced
No
Reduced
No
Lipids
NA
Xerosis
NA
Other Effects
Reason
Abbreviations: NA, not applicable; PPD, palmoplantar desquamation.
*For patients who were receiving lipid-lowering drugs (usually a statin), the timing of initiation of this drug was recorded in terms of whether it was before (pre)
or after (post) initiation of retinoid therapy. In patient 22, the increase in the lipid level was managed by dietary control.
†During retinoid therapy, renal function deteriorated to end stage in these patients. In both cases, renal function was progressively deteriorating before initiation
of retinoid therapy, and the cause and/or rate of this deterioration was not considered to be related to retinoid therapy.
5 or more tumors before starting treatment, although only
2 cases were followed up for 5 years.15 In contrast, we
found no difference in the benefits of retinoids in patients with fewer than 5 SCCs or 5 or more SCCs before
treatment, both groups showing a significant response.
There was also no major effect of age, duration of transplantation, and interval between first SCC and starting
retinoid therapy on their efficacy. These data would appear to indicate a possible beneficial role for retinoids
whatever the burden of skin malignancy, age, and time
since transplantation.
Four (14%) of 28 patients had SCC metastases, highlighting the potentially aggressive nature of SCCs in these
high-risk patients. In 2 patients, metastases arose just before the introduction of retinoid treatment, and in both
cases no further metastases were detected after follow-up of 57 and 36 months. While this may have resulted from radical surgery and radiotherapy as well as
reduction in immunosuppression, it is possible that retinoids also had a significant therapeutic effect. The 2 patients who developed metastases while receiving treatment both followed a similar pattern of prolonged control
(REPRINTED) ARCH DERMATOL/ VOL 141, APR 2005
463
of SCCs over several years while taking retinoids, and then
apparent loss of this control in the year before metastasis occurred. It is possible that the chemopreventive efficacy of retinoids is only partial and temporary in such
high-risk individuals, and that a sudden increase in SCCs
may herald imminent metastatic disease. In a recent multicenter study, 6 of 8 similar patients with SCC metastases before or after starting retinoid treatment had to stop
because of adverse side effects.21 Martinez et al21 suggested that such patients are less able to tolerate systemic retinoid therapy, but this was not our experience
in that all 4 patients continued treatment, and 2 appeared to benefit significantly in terms of subsequent disease progression.
ADVERSE EFFECTS OF RETINOIDS
In patients without metastatic disease, low-dose retinoids appeared to be well tolerated and adverse effects
were easily managed. Only 1 patient discontinued treatment because of symptomatic side effects. In an additional 7 patients (25%), retinoid dose was limited by sympWWW.ARCHDERMATOL.COM
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tomatic side effects, usually mucocutaneous. A similarly
high level of mucocutaneous side effects has been reported in other studies.15,18-20 More than half of all patients had increased lipid levels before starting retinoids, and most were already receiving treatment for this,
reflecting the rigorous optimization of lipid levels required in these individuals, given their increased risk of
cardiovascular disease. Only 2 individuals with normal
lipid levels before retinoid therapy had an increase in lipid
levels while taking retinoids that required the introduction of lipid-lowering drugs. Retinoid dose was limited
in an additional 2 individuals to control elevated lipid
levels. Two patients with chronic renal failure and graft
rejection documented before the start of retinoid treatment progressed to end-stage renal failure (after 24 and
33 months). Despite the theoretical possibility of allograft rejection associated with their immunopotentiating effects, it was considered unlikely that retinoids significantly contributed to this progression. No deterioration
in renal function was observed in any other patient. Previous studies have also failed to demonstrate an adverse
effect of retinoids on renal function.13
“REBOUND” SCC DEVELOPMENT
DURING INTERRUPTION OF THERAPY
A significant increase in SCCs was seen in the 12 months
after interruption of treatment in 6 patients. Previous studies have also shown such a relapse in tumor development,6,15,18,19,22 such that continuous treatment appears
to be required to maintain a chemopreventive effect. It
therefore seems most appropriate to regard retinoid chemoprevention as a potentially lifelong treatment in OTRs,
and this must be considered before the patient embarks
on such treatment. However, an alternative strategy of
intermittent retinoid treatment coupled with periods of
intensive surgery during the subsequent rebound remains a possibility that has not yet been investigated.
In conclusion, low-dose retinoids significantly reduce
SCC development in high-risk OTRs for at least 3 years and
probably as long as 9 years, with an acceptable side-effect
profile. Case-control studies over extended periods, including investigation of appropriate timing of intervention and dosing regimens, are now required to optimize
use of this important chemopreventive strategy in the management of skin cancer after organ transplantation.
Accepted for Publication: November 4, 2004.
Correspondence: Catherine A. Harwood, MA, PhD, MRCP,
Centre for Cutaneous Research, St Bartholomew’s and the
Royal London School of Medicine and Dentistry, Queen
Mary, University of London, 2 Newark St, London E1 2AT,
England ([email protected]).
Funding/Support: Drs Harwood and Proby are supported by Cancer Research UK, London, England. Dr Harwood is also supported by grant RAC 404 from Barts and
the London Research Advisory Board, London.
(REPRINTED) ARCH DERMATOL/ VOL 141, APR 2005
464
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