Author

(year of publication)

Level of evi-dence

Study design

Patients (N)

Inclusion criteria

Follow-up

Outcome measures

Results

Lost to follow-up

Comments

Berg (2002)

C

Review

In the United States more than 100,000 people are living with solid organ transplants. The intense

immunosuppressive regimens necessary for prolonged survival of allografts significantly increase the rates

of both internal and cutaneous malignancies in recipients of solid organ transplants. Skin cancer is the most common cancer in patients after transplantation. Because of the early onset and high tumor burden in transplant recipients, dermatologists have significant challenges in managing the treatment of these patients. This article describes the epidemiology and clinical presentation of skin cancer during posttransplantation

immunosuppression, discusses pathogenic cofactors, and reviews the optimal management for mild and severe skin cancer in transplant recipients.

Campbell (2012)

B

Open-label RCT

86

Patients who developed NMSC (i.e. SCC or BCC) within 3 years

and who underwent kidney transplant at least 1 year before enrollment. Patients were 18 years or older, on CNI-based regimens with cyclosporine

or tacrolimus for at least 1 year prior, and on consistent immunosuppressive

regimens for at least 1 month, with calculated Nankivell glomerular

filtration rate (GFR) of at least 40 mL/min and proteinuria 500 mg or less

per day

Mean length of follow-up for the intent-to-treat population

(i.e. on- and off-therapy periods) was 1.68 and 1.74 years

for the sirolimus and CNI groups, respectively (p = 0.127)

The number of new biopsy-confirmed NMSC lesions

per patient per year, time to first new biopsy-confirmed

NMSC lesion and number of lesions recurring at the site of a previously

treated lesion

Yearly NMSC rate

was significantly lower with sirolimus (1.31 vs. 2.48

lesions/patient-year; p = 0.022). Squamous cell carcinoma

occurred at a lower rate in the sirolimus versus CNI group (p = 0.038); basal cell carcinoma rate

was similar in both. A lower proportion of patients receiving

sirolimus developed new or recurrent NMSC (56.4% vs. 80.9%; p = 0.015) or new squamous cell carcinoma

(41.0% vs. 70.2%; p = 0.006). No sirolimus patients and one CNI continuation patient experienced acute rejection. Discontinuation rates related to adverse events were

significantly higher with sirolimus (46.2% vs. 0%;

p < 0.001

54 patients (62.8%)

discontinued treatment prior to 2 years: 31 (79.5%) receiving

sirolimus and 23 (48.9%) on CNIs (p = 0.004).

The most common reason for discontinuation was AEs in the sirolimus group (46.2% vs. 0% in the CNI group; p <

0.001).

Underpowered study.

The trial was sponsored by Wyeth Pharmaceuticals, which was acquired

by Pfizer Inc. in October 2009. The authors and Wyeth representatives designed

the study.

Wyeth monitored the conduct of the study, performed statistical

analyses, and held the data. The authors interpreted the data and

collaborated in the preparation of the manuscript, supported by a professional

medical writer provided by Pfizer Inc.

Campistol (2006)

B

randomized, open-label, multicenter trial

430 renal transplant patients

randomly assigned to either

Sirolimus-cyclosporine-steroid (215) or have Cyclosporine eliminated (SRL-ST, 215)

NS

All patients were followed on an intent-to-treat (ITT)

basis through 5 yr after transplantation

Mean annualized rates of skin malignancy, Malignancy-free survival rates, Median times to first skin and nonskin malignancies

At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P= 0.007), and

the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence

interval 0.227 to 0.526; P= 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas

were significantly reduced.

.

Rates of loss to follow-up for patient survival and malignancy

were 2.8 versus 2.3% at 3 yr and 21.4 versus 12.1% at 5 yr, SRL-CsA-ST versus SRL-ST, respectively

It should be emphasized that both treatment groups contained

SRL; the difference was that SRL-CsA-ST patients also

received standard- or near-standard-dose CsA therapy and the SRL-ST patients had approximately two-fold higher SRL trough levels.

Chen (2005)*

A2

Systematic review

93 subjects from 3 trials.

Randomized or quasi-randomized controlled clinical trials on participants of any age or ethnic background who had

received a solid organ transplant (cardiac, renal, liver, pancreas, lung, multiorgan) were evaluated)

Electronic databases were searched for eligible studies using these criteria:

allocation concealment, blinding, completeness of follow-up

and withdrawals, and intention-to-treat analysis.

6 months- 2 years

The primary outcome measure of interest was the effect on

number of skin cancers (mainly SCC, BCC or melanoma).

Other outcome measures of interest included: reduction of

premalignant lesions (actinic keratoses), or reduction in number

of skin biopsies or excisions. Adverse outcomes of interest

included the number of participants experiencing cheilitis,

asteatosis, alopecia, paronychia, nocturnal visual impairment,

myalgia, headaches, hypercholesterolaemia, liver impairment

and bony abnormalities.

One crossover trial involving 23 subjects treated with acitretin 25 mg daily for 12 months reported 46 squamous cell carcinomas (SCCs) developing in six subjects during

acitretin treatment vs. 65 SCCs developing in 15 subjects during the drug-free period. Another trial involving 44 subjects treated with acitretin 30 mg daily or placebo for 6 months reported two of 19 subjects developing two SCCs in the treatment group vs. nine of 19 subjects developing 18 new skin cancers (15 SCCs, one Bowen’s disease, two basal cell carcinomas) in the placebo group.

One dose comparison trial involving 26 renal transplant recipients treated with acitretin did not find a significant difference in numbers of skin cancers developing

at the doses examined.

NS

*This study was already included in the previous 2010 guideline.

Dantal (1998)

B

RCT

normal-dose (n=116) or low-dose (n=115)cyclosporin

231 recipients of a first allograft with at most one

previous rejection episode were randomised 1 year after

transplantation

Patients who underwent first-time kidney

transplantation, were older than 18 years, and who gave informed

consent.

The mean duration of follow-up after

transplantation was 66 (SD 18) months for both groups (range

36–96; median 68).

The primary

endpoint was graft function; secondary endpoints: survival and occurrence of cancer ( particular attention was paid to skin lesions) and rejection

60 patients developed

cancers, 37 in the normal-dose group and 23 in the low-dose

group (p<0·034); 66% were skin cancers (26 vs 17;

p<0·05).

Skin cancers (normal-vs- low dose)

Squamous-cell carcinoma 15-vs- 8

Bowen’s disease 2-vs- 5

Basal-cell carcinoma 9 -vs-4

All skin cancers* 26 -vs- 17

NS

Both investigators and participating patients were aware of

treatment allocation.

The low-dose regimen was

associated with fewer malignant disorders but more frequent

rejection. (9 in low-dose -vs- 1 in the normal dose).

De Graaf (2006)

B

RCT

40 organ-transplant recipients.

-21: PDT left forearm+hand

-19: PDT right forearm+hand

-

2 years (3-monthly intervals)

Primary objective: occurrence of new SCC in OTR in the treated arm (compared with the control arm) following PDT.

Second objectives:

-to evaluate the difference in (re)occurrence of keratotic skin lesions in the arm treated with PDT compared to the control arm.

-difference in efficacy between regimen with 1 or 2 PDT treatments with a 6-month period in between the treatments

No statistically significant difference was found in the occurrence of new squamous-cell carcinomas

between the treated and untreated arms: after 2 years of follow-up, we observed 15 squamous-cell carcinomas

in nine out of 40 PDT-treated arms and 10 squamous-cell carcinomas in nine out of 40 control arms. The number

of keratotic skin lesions increased in both arms, but was less pronounced in the PDT-treated arm. After 1 year of follow-up, a trend in favor of the PDT-treated arm was observed, but statistical significance was not reached. Nearly 80% of the patients reported mild to severe adverse effects consisting of pain and a burning sensation, immediately after the treatment. No long-term adverse events were noted.

7

De Heer (2008)

C

Case series

-

-

-

Follow-up frequency

No consensus (in literature) regarding the timing and number of follow-up consultations of high-risk SCC patients. In this article a follow-up period of at least 3 years is advised for high-risk patients. First year: every 2 months. Second year: every 3 months.

-

Euvrard (2012)

B

Phase 3, multicenter, randomized, open-label

trial

120 patients

transplant recipients who were taking

calcineurin inhibitors and had at least one cSCC were randomly assigned

either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients)

or to maintain their initial treatment (in 56).

Patients who had had a first cutaneous

squamous-cell carcinoma

and those with multiple

squamous-cell carcinomas.

1 and 2 year

Primary endpoint: survival

free of SCC at 2 years. Secondary endpoints: the time until the onset of new SCC, occurrence of other skin tumors,

graft function, problems with sirolimus.

Survival free of cutaneous squamous-cell carcinoma was significantly longer in the

sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median

time until onset, 15 vs. 7 months; P = 0.02), with a relative risk in the sirolimus

group of 0.56 (95% confidence interval, 0.32 to 0.98).

14 (7 in each group)

The manufacturer of Sirolimus, Pfizer (formerly

Wyeth), provided a research grant but had no role

in the trial design or in the collection, analysis,

or interpretation of the data or writing of the

report.

Ferreira (2017)

B

Case-control study

245 subjects

RTRs of

both genders who were over 18 years, living in the state of S~ao

Paulo-Brazil, and using immunosuppressive drugs were included

N/A

Different variables for NMSC in RTR’s

Multivariate analysis identified risk factors with respective OR’s and 95% CI:
males 2.5 (1.3–4.7), age over 50 years 5.4 (2.3–12.9),

Skin phototypes I–III 3.7 (1.6–8.7), occupational sun exposure 4.1 (2.1–8.1), timetable of recreational sun exposure all day 3.0 (1.4–6.1), and duration of transplantation

(80 months or more) 3.3 (1.6–6.5).

N/A

Possibly not a very relevant article for this guideline

Fortina (2004)

B

Prospective

230 patients

heart transplant (HT) recipients, ≥18 years

At least 3 years

The risk of SCC and BCC

in HT recipients and the relationship between development

of SCC and BCC and cumulative doses of different

immunosuppressive agents, controlling for other potential

risk factors (age, sex, sunlight exposure, skin type,

and presence of warts)

The cumulative immunosuppressive drug dose

3 years after transplantation (calculated by a weighted

linear combination of azathioprine, cyclosporine, and corticosteroid

cumulative doses [WLC]) was independently

associated with an increased risk of developing SCC

but not BCC. On multivariate analysis, patients receiving

a WLC higher than the 75th percentile 3 years after

HT had a 4 times higher risk of SCC than recipients of a

WLClower than the 50th percentile 3 years after HT(95%

confidence interval, 1.4-11.4; P=.008). Other significant

risk factors for SCC development were older age at

transplantation and a greater occupational sunlight exposure.

The risk of developing BCC was only associated

with older age at transplantation and skin type II.

-

Garret (2017)

B (A2)

Multicenter retrospective cohort study

10 649 adult recipients of a primary transplant

Adult (≥18 years) recipients of a primary transplant performedat

participating transplant centers eitherbetween January 1 -December 31, 2003, or between January 1 -

December 31, 2008, were eligible for inclusion.

5 and 10 years

The primary study outcome was incidence rate of skin cancer and,separately,SCC,MM,orMerkel cell carcinoma(MCC)

From the date of transplant.

the incidence ratio for posttransplant skin cancer overall was 1437 per 100 000 person-years. The specific

subtype rates for squamous cell carcinoma, malignant melanoma,

and Merkel cell carcinoma were 812, 75, and 2 per 100 000

person-years, respectively.

At the end of follow-up ,6729(63%)patients were alive,2773(26%)were

deceased, and 1147 (11%)were lost to follow-up.

Good sizeable cohort

George (2002)

C

Prospective open randomized crossover trial

23 patients

Previous history of NMSC

2 years

The difference between the number of SCCs and BCCs developing during treatment and in the drug-free period

The number of squamous cell carcinomas

(SCC) observed in patients while on acitretin

was significantly lower than that in the drug-free

period (P = 0.002). A similar trend was observed in

patients with basal cell carcinomas, but this was not significant and the numbers were small. Side-effects were a major limiting factor. A severe rebound

increase in SCC occurred in one patient after the

acitretin was ceased.

12

Harwood (2005)

C

Retrospective

28

With at least 1 histologically proved SCC

1-16 years

The mean difference between the number of cSCCs developing annually during retinoid treatment and the number during the 12-month pretreatment trial

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.

Hofbauer (2009)

C

Review

-

-

-

-

Recommended dermatological consultations in SOTR:

-pre-transplant: once

-post-transplant: yearly

-in-situ SCC: every 6 months

-early cutaneous carcinogenesis: every 4-6 months

-moderate cutaneous carcinogenesis: every 2-4 months

-severe cutaneous carcinogenesis: every 1-3 months

-

Hoogendijk (2013)

B

RCT

155 renal transplant patients with at least one biopsy-confirmed SCC

First or second

kidney transplantation with one biopsy-confirmed cutaneous invasive SCC, age18 years,12 months posttransplantation, stable graftfunction (estimated glomerular filtration rate 20 mL/min), receiving maintenance calcineurin

inhibitor, azathioprine, mycophenolate, and/or steroids for at least 12

weeks before random assignment, and no acute rejection episode within 12

weeks before random assignment.

2 years

Development of a new SCC within 2

years

The risk reduction of new SCCs in the multivariable analysis was not

significant, with a hazard ratio (HR) of 0.76 (95% CI, 0.48 to 1.2; P .255), compared with a

non–sirolimus-based regimen.

After the first year, there was a significant 50% risk reduction, with

an HR of 0.50 (95% CI, 0.28 to 0.90; P .021) for all patients together and an HR of 0.11 (95%

CI, 0.01 to 0.94; P .044) for patients with only one previous SCC. The tumor burden of SCC was

reduced during the 2-year follow-up period in those receiving sirolimus (0.82 v 1.38 per year; HR,

0.51; 95% CI, 0.32 to 0.82; P .006) if adjusted for the number of previous SCCs and age.

ITT analysis ( 39 dropouts in sirolimus group, 14 dropouts in conventional immunosuppression group).

Small study population

Hortlund (2017)

B (A2)

Cohort study

24,698 individuals

Both solid organ transplant recipients (OTRs, n=12420) and long-term dialysis patients (LDPs)) .

Patients that received solid organ transplantation

Solid organ transplant recipients were observed for a mean of 8.6 years and 9

years, respectively, from the transplantation (if followed until

any type of cancer diagnosis).

Cancer risk (overall cancer and NMSC skin card) expressed in standardized incidence ratio.

The standardized incidence ratio for NMSC among OTRs was 44.7 [n5994,

95% CI, 42–47.5] in Sweden and 41.5 [n5445, 95% CI, 37.8–45.5] in Denmark.

NS

Good sizeable cohort.

Kidney recipients constituted the majority of all patients

(9,427 in Sweden and 4,428 in Denmark).

It was not clearly specified whether this was a prospective or retrospective study. We assumed it was prospective.

Knoll (2014)

A1

Systematic review and meta-analysis

21 trials;

individual patient data of 5876 patients

To be eligible, trials needed to collect data on

malignancy after transplantation and have a planned follow-up

period of at least three months

Minimal follow-up of 3 months.

Development of any new

malignancy after randomization (This outcome included any

type of cancer (such as basal cell skin cancer, lymphoma, etc).

Secondary outcomes included non-melanoma skin cancer, other

cancer, and death.

Sirolimus was associated with a 56% reduction in the risk of non-melanoma skin cancer (adjusted HR 0.44, 95% CI 0.30 to 0.63 p<0.001) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive

regimen, resulting in a reduction in risk of NMSC (0.32, 0.24 to 0.42).

Sirolimus was associated with an increased risk of

death (adjusted HR 1.43, CI 1.21 to 1.71, p<0.001) compared with controls. There was a higher proportion of death from infection (0.58% v 0.15%) and cardiovascular

disease (1.28% v 0.54%) in the sirolimus group compared with the control group.

-

“For every 1000 patients

converted to sirolimus and treated for two years, there would

be 95 fewer cases of non-melanoma skin cancer and 23 fewer

cases of other cancers, but 10 additional deaths.”

Subgroups might be imbalanced with respect to other factors that could influence occurrence of cancer or death.

This study was

funded by the manufacturer of sirolimus.

Lim (2016)

B

Cohort study to study long term patient and graft outcome of a clinical trial A2309.

( RCT= A2309 Study
Of 95 recipients, 66 were

randomized to everolimus (1.5 mg or 3 mg) with reduced

cyclosporine and 29 received mycophenolate sodium and

standard exposure cyclosporine.)

95

Kidney transplant recipients in Australia and New Zealand who had

participated in the A2309 Study were linked to ANZDATA registry

with the availability of 7 years of follow-up data.

Median 7.3 years

The primary outcome of interest was the first NMSC (i.e., basal cell

carcinoma [BCC] or squamous cell carcinoma [SCC] of the skin) or

any non-skin cancers diagnosed after transplantation.

Compared to

mycophenolate sodium and standard exposure

cyclosporine, everolimus treatment was associated with

unadjusted hazard ratios of 0.28 (95% confidence interval

0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively

for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34

(0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71),

respectively

There were no missing data in this cohort.

The small sample size and limited number of events

could lead to erroneous inference and may limit the confidence

we placed in the treatment effects between treatment

groups and outcome measures.

Unclear whether this was a prospective or retrospective cohort. We had reasons to assume the latter.

Marcil (2000)

A2

Systematic review

5 studies discussing SCC .

17 studies selected; 5 studies about SCC. N= 2709 enrolled patients.

Selection of articles was based on a checklist derived from the search question. Only articles published in English were included.

Mean follow-up 2.8 till 4.7 years.

Cumulative 3-year risk of new SCC developing after an index SCC.

Cumulative 3-year risk of a new SCC is less than 25% in all 5 studies, ranging from 9% to 23% (mean risk 18%).

NS

Ramsay (2007)

B

Prospective

269 renal transplant recipients (RTRs) with skin type I-IV

-

7 years

Incidence of NMSC

A total of 244

(91% enrolled) RTRs were screened on at least one occasion. The mean incidence per year of NMSC was 7.82% (SD:

1.84), comprising a mean (SD) incidence per year of squamous cell carcinoma 3.45% (1.36), basal cell carcinoma 3.58%

(1.17), and Bowen’s disease 2.52% (0.91). The risk of developing NMSC increased with duration posttransplantation:

the mean incidence per year of NMSC was 3.27% (0.53) in RTRs <5 years posttransplantation, 5.86% (3.1) in RTRs

5–10 years posttransplant, and 11.1% (1.85) in those >10 years posttransplant.

25

Salgo (2010)

B

RCT

44 renal transplant recipients

Stable renal function, age between 18 and 75 years, existence of keratotic dysplasia such as history of NMSC, AK, verruca vulgaris or lesions sharing

clinical aspects of both, transplantation for more than 1 year, no signs of

graft rejection during the last 6 months.

1 year

The primary endpoint was the improvement in the clinical assessment of

premalignant skin dysplasia (AK, verruca vulgaris etc.) from baseline to month 12.

The secondary endpoint was

the occurrence of histologically confirmed new NMSC during the 1 year

study-period.

number of rejections, transplant function,

cholesterol and urinary protein levels

In the sirolimus group, no patient had worsening of the skin at the 6-month and 12 month assessment compared to baseline findings and compared to standardtherapy (p=0.0005 and p=0.0001)

.

Nine patients developed histologically confirmed NMSC: one in the sirolimus group, 8 in the control group, p = 0.0176.

11 (1 lost to follow up, 8 AE, 2 withdrawn consent)

Fairly high lost to follow-up (25%).

Stasko (2004)

C

Review – guidelines for the management of SCC in OTR

>300 (retrospective) articles were reviewed

-

-

To develop useful clinical guidelines for the treatment of skin cancer in OTR

Guidelines developed for the treatment of skin

cancer in OTRs, supported by the best available data and

collective clinical experience.

-

Urwin (2009)

B

Retrospective

363 patients

RTRs

Total NMSC

Stepwise selection identified age, outdoor UVR exposure, living in a hot climate, pretransplant NMSC, childhood

sunburning, and skin type as predictors. The predictive index (PI) generated was used to allocate patients into three screening groups

(6 months, 2 years, and 5 years). The survival curves of these groups were significantly different (P<0.0001).

Veness (2007)

C

Review

-

-

-

-

High-risk factors include size (> 2 cm), thickness/depth of invasion

(> 4mm), recurrent lesions, the presence of perineural invasion, location near the parotid gland, and immunosuppression. These

patients have a higher risk (> 10–20%) of developing metastases to regional lymph nodes (often parotid nodes), and in some cases

also of experiencing local morbidity (perineural invasion), based on unfavourable primary lesion and patient factors.

-

Willey (2009)

C

Open-label pilot study

12 patients

High-risk SOTRs

2 years (4-8-week intervals)

Development of new SCCs (invasive and in situ) performed 12 and 24 months after the start of cyclic PDT compared with the number of SCCs developed during the year before initiation of cyclic PDT

The median reduction in the 12- and 24-month post-treatment counts from the 1-month pretreatment

counts was 79.0% (73.3–81.8%) and 95.0% (87.5–100.0%), respectively. Treatments were well

tolerated.

-

Williams (2014)

C

Review

-

-

-

-

Case reports describing skin cancer associated with voriconazole exposure emerged shortly after US Food and Drug Administration approval of the drug, and it is now established that voriconazole is an independent risk factor for the development of cutaneous malignancy in lung transplant recipients. The mechanism of voriconazole-induced skin cancer is still unknown and may involve its primary metabolite, voriconazole N-oxide.

-

Zwald Part II (2011)

C

Review

-

-

-

-

Follow-up intervals for total body skin examinations for solid organ transplant recipients:

-no skin cancer/field disease: 12 months

-field disease/1 NMSC: 3-6 months

-multiple NMSC: 3 months

-high-risk SCC: 3 months

-metastatic SCC: 1-3 months

-