Skin cancer chemoprophylaxis in renal transplant recipients:5 years of experience using low-dose acitretin

D.B.MCKENNA AND G.M.MURPHYDepartment of Dermatology, Beaumont Hospital, Dublin 9, Ireland

Accepted for publication 30 October 1998

Summary Renal transplant recipients have an increased risk of developing skin cancers, which are oftenmultiple and aggressive. Frequently, these tumours develop on a background of widespreadepidermal dysplasia. Systemic retinoids are known inhibitors of skin cancer but reports of theiruse in renal transplant patients are limited. We describe our experience using 0·3 mg/kg daily ofacitretin in 16 patients over a 5-year period. Overall, there was a significant reduction in the numberof new tumours excised in 12 of 16 patients during treatment compared with the same pretreatmentinterval. A significant chemoprophylactic effect was shown for up to 4 years of treatment. Patientswith five or more tumours prior to acitretin benefited most. Two patients discontinued treatmentbecause of side-effects and two patients developed hyperlipidaemia. Two patients with end-stage graftfailure proceeded to haemodialysis. The introduction of low-dose acitretin proved to be a usefulstrategy in the long-term reduction of skin cancer in renal transplant recipients with multiple skincancers and extensive epidermal dysplasia.

Key words: acitretin, non-melanoma skin cancer, renal transplant recipients, skin cancerchemoprophylaxis.

The retinoids have been shown to have potent anti-neoplastic effects against many malignant cell typesincluding non-melanoma skin cancer (NMSC). Becauseof predictable dose-related side-effects, use of retinoids inskin cancer prophylaxis has been largely restricted topatients at high risk of developing NMSC as in xero-derma pigmentosum1 and the basal cell naevus syn-drome.2 Renal transplant recipients have up to 500times the risk of developing NMSC compared with thenon-immunosuppressed population.3 Risk factorsinclude immunosuppressive drugs, duration of trans-plantation, exposure to ultraviolet radiation and thefrequent occurrence of warts containing potentiallyoncogenic types of the human papilloma virus (HPV).4

Experience with oral retinoids in renal transplant reci-pients has been limited because of theoretical immuno-potentiating effects of the drug and concerns regardinggraft rejection.5 Two small uncontrolled studies usingetretinate6,7 and an anecdotal report of a single patienttreated with acitretin8 suggest a preventative effect onNMSC development in renal transplant recipients withno adverse effects on graft function. A more recent

double-blind, placebo controlled study using acitretinadministered over 6 months showed a significant reduc-tion in the number of new NMSC in the retinoid treatedgroup.9 As relapse is common on discontinuation oftherapy, patients with recurring NMSC should receivecontinuous treatment in order to sustain the therapeuticbenefit.

Subjects and methods

The study design was open, and each patient served ashis/her own control. Approval was obtained from thehospital’s medical ethics committee and patients gaveinformed consent. To be eligible, each patient had tohave had at least two NMSC excised before treatmentwas instituted, be tumour-free at time of entry and haveno gross impairment of baseline fasting lipids or liverfunction. Females had to be infertile. Patients received0·3 mg/kg daily of acitretin and advice regarding sunprotection was reinforced. Cryotherapy of dysplasticlesions and surgical excision of any new tumours wascarried out at each follow-up review. The therapeuticbenefit was judged by comparing the number of newskin cancers excised during the period of treatment with

British Journal of Dermatology 1999; 140: 656–660.

656 q 1999 British Association of Dermatologists

Correspondence: Dr. D.B.McKenna, Department of Dermatology, RoyalInfirmary, Edinburgh EH3 9YW, U.K.

that observed over the equivalent immediate pre-treatment interval. The response of warts and actinickeratoses to treatment was also noted. Statisticalcomparison was made using the Mann–Whitney test.

Side-effects were monitored by monthly clinicalassessments and measurement of serum creatinine,fasting cholesterol and triglycerides as well as liverfunction. Specific enquiry was made in relation to theusual retinoid side-effects at each visit including xerosis,dryness of mucous membranes, epistaxis, muscle ache,arthralgia and hair loss. Treatment was discontinued ifthe drug was not tolerated symptomatically or if therewas significant impairment of laboratory findings. After6 months patients were assessed at 3 monthly intervalsprovided that the drug was tolerated.

Results

The group consisted of 16 renal transplant recipients,12 male and four female, aged 36–67 years (mean 52)with a transplant duration of between 2 and 25 years(mean 14) before commencement of acitretin. Immuno-suppressive regimens consisted of various combinationsof prednisolone, cyclosporin and azathioprine prescribedat conventional dosages (Table 1).

Of the 16 patients, seven had been on the drug for 5years, mean 38 months (range 6–60). The total

number of invasive tumours excised from all subjectsfrom the time of transplantation to the commencementof therapy was 111, range 2–25 (mean 6·9), compris-ing 100 squamous cell carcinomas (SCC) and 11 basalcell carcinomas (BCC). Intraepithelial carcinomas,although excised, were not included in the statisticalassessment. Taking the group as a whole there was asignificant reduction in the total number of tumoursexcised during the period of acitretin therapy comparedwith an equivalent immediate pretreatment interval, 21(18 SCC, 3 BCC) compared with 77 (64 SCC, 13 BCC),P ¼ 0·007. Fifty per cent of the patients remainedtumour-free while on the drug and 12 of 16 hadfewer tumours excised during this time compared withthe same pretreatment interval. Eight patients had 21NMSC excised while on acitretin therapy and four of thisgroup had an identical or greater number of tumoursdetected compared with their corresponding pretreat-ment period. The greatest reduction of new NMSC wasapparent in six patients with five or more tumours priorto commencement of treatment (56 vs 10, P ¼ 0·004).One patient on acitretin for 3 years died of metastaticSCC of the ear.

The therapeutic effect of the drug was also assessedtemporally by comparing the cumulative number ofNMSC that developed annually in each patient imme-diately before and during acitretin therapy for up to 5

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Table 1. Patient characteristics including numbers of non-melanoma skin cancers (NMSC) excised over an equal time interval immediately beforeand during treatment with acitretin

Patient age Transplant duration No. NMSC transplant Treatment duration No. NMSC during No. NMSC over equal(years) Immunosuppressant (years) to treatment (months) acitretin treatment pretreatment interval

56 A, P 22 2 60 0 256 C 20 2 60 0 260 A, P, C 2 2 40 3 263 A, P, C 12 4 60 2 454 A, P 11 9 38 1 947 A, P 22 8 60 1 853a A, P, C 4 5 6 0 250a A, P, C 20 16 12 2 756 A, P, C 4 3 60 4 336 A, P 13 4 12 0 067 A, P, C 6 25 60 5 2544 C 20 21 28 0 546 A, P 18 2 60 3 256 A, P 25 2 38 0 251b C 10 3 6 0 244b A, P 17 3 12 0 2

Totals 111 21 77

NMSC ¼ non-melanoma skin cancer; A ¼ azathioprine; P ¼ prednisolone; C ¼ cyclosporin. aAcitretin discontinued because of side-effects.bImmunossuppression withdrawn and acitretin discontinued.

years (Fig. 1). There was a significant reduction in thenumber of new NMSC occurring in patients at 1 year(n ¼ 16, P ¼ 0·003), 2 years (n ¼ 11, P ¼ 0·01), 3 years(n ¼ 11, P ¼ 0·02) and 4 years (n ¼ 10, P ¼ 0·04) timepoints during treatment compared with the equivalentpretreatment period. Fewer tumours were also excisedin the treatment group at 5 years but this did not reachstatistical significance possibly due to the small numberof patients on the drug for this length of time (n ¼ 7,P ¼ 0·10).

All patients had multiple viral warts and actinickeratoses typical of this patient group. In general,there was a considerable clinical improvement in bothof these lesions following treatment with acitretin. Thiswas difficult to quantify numerically due to the oftenwidespread extent of skin involvement but hyperkera-totic warts and dysplastic lesions became flatter and lessobvious.

Mucocutaneous side-effects of acitretin therapyoccurred in all patients but these were generally welltolerated. All patients complained of xerosis while otherreported side-effects in decreasing order of frequencyincluded cheilitis, desquamation, mild alopecia, head-aches, epistaxis and sweating. Two patients discontin-ued treatment after a period of 6 and 12 monthsbecause of symptoms of nausea, headache, sweatingand epistaxis. The former patient developed two SCCsover the next 6 months having been tumour-free onacitretin. The other patient has developed one BCC andtwo SCCs since discontinuing treatment.

Haematological and liver function tests remainedunchanged during acitretin therapy in all patients. Atthe start of treatment three patients had raised fastingtriglycerides, range 1·92–5·00 (normal <1·9 mmol/L),

rising in one patient to 6·4 mmol/L during acitretintreatment. Commencement of a low fat diet resulted in afall in triglyceride levels to below baseline levels in theseindividuals. The remaining patients had no increase intheir serum triglycerides while taking acitretin. Twelvepatients had elevated pretreatment cholesterol levels,range 5·34–9·10 (normal <5·20 mmol/L), increasingin one individual from 5·55 to 7·14 mmol/L duringtreatment. These patients were treated with a low fatdiet, which controlled cholesterol levels in all but twopatients, who required the cholesterol lowering agentpravastatin. This produced a fall in the cholesterol levelsin these patients to just above the normal range. Serumcholesterol was unaltered in the remaining patients.

Seven renal transplant recipients had normal renalfunction prior to commencement of acitretin as deter-mined by a normal serum creatinine and nine hadraised creatinine levels, range 134–430 (normal 50–120 mol/L). Two of these nine patients had significantgraft rejection confirmed on biopsy before acitretin wasintroduced and the serum creatinine continued todeteriorate while on the drug. Immunosuppressionwas withdrawn after 6 and 12 months and acitretinwas also discontinued. The latter patient developed anSCC 12 months later. No impairment of renal functionor significant alteration of the immunosuppressiveregimen was observed in any of the other patients.

Discussion

This study shows that 0·3 mg/kg daily of acitretinsignificantly reduces the development of new NMSC(both SCC and BCC) in renal transplant recipientswith a previous history of skin cancer and, for the first

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Figure 1. Number of new non-melanoma skin cancers before andduring acitretin therapy. n ¼ numbers of patients.

Figure 2. A squamous cell carcinoma (arrow) occurring on a back-ground of widespread epidermal dysplasia on the forehead of a renaltransplant patient.

time, that this chemoprophylactic effect is sustainedover at least a 4 year period. Previous studies haveshown a relapse in tumour development on disconti-nuation of retinoids administered over a short period oftime1,6,9 and this also occurred in two of our patientswho stopped acitretin because of symptomatic side-effects. It appears therefore that continuous treatmentis required to maintain a protective effect. The mostsignificant reduction in new tumours occurred in renaltransplant recipients with five or more NMSC prior tocommencement of the drug. These patients had exten-sive areas of epidermal dysplasia on sun-exposed skinwith multiple invasive and in situ SCCs (Fig. 2). Eightrenal transplant recipients had 21 NMSC excised whileon the drug, suggesting that acitretin at this dose wasonly partially effective in preventing the development ofnew skin cancers. Acceptance of a partial prophylacticeffect using a well tolerated low dose of acitretin may bepreferable compared with a higher dosage and thelikelihood of inducing toxic side-effects that patientswould not tolerate long-term. One patient died of meta-static SCC of the ear despite intensive clinical surveil-lance, treatment with acitretin, early and repeatedsurgical excision of the affected area and adjuvantradiotherapy.10 This patient highlights the aggressivenature of SCC in renal transplant recipients, which hasan increased metastatic potential and a 10-fold greatermortality compared with non-immunosuppressedpatients.

Bias may have operated both for and against atherapeutic effect of acitretin in this study. Most of thepatients were monitored more intensively while on thedrug compared with the pretreatment period withadvice given regarding sun protection and cryotherapyadministered to warts and dysplastic lesions. This could,theoretically at least, have accounted for some of thereduction in tumour numbers observed during thistime. Conversely, however, this more intensive surveil-lance may have allowed more rapid detection of skincancers, especially during the early treatment phase ofthe study resulting in bias against any protective affectof the drug.

This study suggests that acitretin at this dose is welltolerated in the majority of patients with only twodiscontinuing treatment because of symptomatic side-effects. Two other patients with gross impairment ofrenal function and advanced graft rejection documentedprior to commencement of acitretin progressed to end-stage renal failure and withdrawal of immunosuppres-sion after 6 and 12 months of treatment. It would beunlikely that acitretin contributed to this as no

deterioration in renal function was observed in any ofthe other patients, including those with a mildly ele-vated serum creatinine before acitretin was introduced.Despite the theoretical concerns about possible allograftrejection associated with the immunopotentiatingeffects of oral retinoid therapy, this has not beenshown to be the case to date where retinoids havebeen used in transplant recipients. McKerrow et al.5

showed that natural killer cells were reduced in numberand activity in non-immunosuppressed patients treatedwith isotretinoin and increased in those treated withetretinate. Shuttleworth et al.6 demonstrated no changein cell-mediated immunity in renal transplant recipientsgiven etretinate. It is possible that any weak immunos-timulatory affect of systemic retinoid therapy would beovercome by the immunosuppressive regimens used inrenal transplant recipients.

Serum lipids are frequently raised either as part of theunderlying renal disease or as a result of cyclosporintherapy leading to increased cardiovascular disease inrenal transplant recipients. In this study, pretreatmentcholesterol and triglyceride levels rose with acitretintherapy in two patients. A low fat diet and the additionof pravastatin in two patients resulted in a reduction ofserum lipids allowing continuation of acitretin.

Skeletal toxicity associated with chronic use of oralretinoids includes demineralization, hyperostosis andspinal ligament calcification similar to diffuse idiopathicskeletal hyperostosis (DISH). DISH, which may be linkedto abnormal metabolism of vitamin A, is more commonin males, the elderly, the obese and patients with type IIdiabetes. Its incidence in renal transplant recipientswho commonly have abnormal bone metabolism isunknown. Radiographic skeletal monitoring was notperformed in this study and no patient complained ofmuscoskeletal symptoms on direct questioning.

Possible mechanisms by which retinoids may hinderthe development of skin cancer include inhibition oftumour initiation and promotion, induction of normalcell differentiation and immunomodulation.11 The highprevalence of HPV in SCCs of renal transplant recipi-ents12 and the fact that retinoic acid is more effective ininhibiting the growth of HPV type 16 immortalizedhuman keratinocytes compared with non-infectedcells13 may provide a further explanation of its chemo-prophylactic role observed in these patients.

The introduction of a well tolerated, low-dose acitre-tin (0·3 mg/kg daily) has proven to be a useful chemo-preventative strategy in the management of renaltransplant recipients with widespread epidermal dyspla-sia and multiple NMSC.

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Acknowledgment

D. B. M. was supported by a grant from the EuropeanUnion Environment Program, grant number EV5V-CT94-0564.

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