Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
Solid organ transplant recipients (OTRs) have an increased incidence of skin cancer, resulting in significant morbidity and mortality post-transplantation. Chemoprevention strategies are focused on reducing and delaying the development of skin cancer in these patients. Although systemic retinoids are widely used in OTRs, few randomized controlled trials have been performed. Limited data suggest that acitretin may have a beneficial role in high-risk OTRs. Since rebound flares occur upon discontinuation of retinoids, chemoprevention should be viewed as a lifelong therapy. Further studies are required to establish the efficacy and long-term safety of systemic retinoids as chemopreventive agents for high-risk transplant recipients.
basal cell carcinoma, BCC, chemoprevention, organ transplantation, SCC, squamous cell carcinoma, skin cancer, systemic retinoids
Non-melanoma skin cancers (NMSC) are the most common human cancers worldwide. In Canada, the estimated incidence of NMSC is approximately 75,000 cases annually.1 Though basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) represent the two major types of NMSC, the term also encompasses Merkel cell carcinomas, cutaneous lymphomas, adnexal tumors, and other primary cutaneous neoplasms. Risk factors for the development of NMSC include ultraviolet radiation, immunosuppression, and chronic inflammation, thus supporting the interplay of the immune system in cancer development.2,3 Chemical carcinogens, other forms of radiation, infection with oncogenic strains of the human papilloma virus, and certain genodermatoses are additional known risk factors.2,3 Several complex genotypic, phenotypic, and environmental factors contribute to the pathogenesis of NMSC. Although cumulative sun exposure is the main risk factor for skin cancer development, further studies are required to fully understand the process of cutaneous oncogenesis.4,5
The high incidence of skin cancer after solid organ transplantation is well recognized. In organ transplant recipients (OTRs), the risk of SCC development is 64 to 250 times greater than in the general population.6-8 While the overall metastatic rates for SCCs range from 2% to 10%, rates of up to 47% have been reported.9 Further, the incidence of SCCs to BCCs is inverted in OTRs at a ratio of 4:1.10 Skin cancers occur at a younger age of onset, often three to five years after transplantation.10
Surgical excision with predetermined margins remains the mainstay of therapy for most NMSCs. Of the non-invasive treatment options, only imiquimod and photodynamic therapy have established efficacy in the treatment of select NMSC subtypes. Given the high incidence of NMSC in OTRs, chemopreventive therapies have been used to reduce and delay the development of skin cancer.10-12 Herein, we review the literature on retinoid chemoprevention in organ transplant recipients.
Mechanisms of Action
Retinoids, natural and synthetic derivatives of vitamin A, are protective against a variety of cancers.13 They exert their physiologic effects by binding specific nuclear receptors.14 These receptors belong to a superfamily of glucocorticosteroid, thyroid hormone, vitamin D and peroxisome proliferator-activated receptors.15 There are two classes of retinoid nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs).15 Each receptor family has three isoforms (α, β, and γ) which are encoded by separate genes.15 While RARs form heterodimers with RXRs, RXRs may form homodimers with RXRs or heterodimers with RARs, vitamin D3receptors or thyroid hormone receptors.15 In turn, these dimers act as ligand-dependent transcription factors for genes containing a retinoic acid response element (RARE).16 To date, over 500 genes have been reported to be regulatory targets of retinoids.17
The mechanism by which retinoids have a chemopreventive effect for skin cancer remains largely unknown. Several different mechanisms may be involved, including: immunomodulation, induction of apoptosis, effects on cell cycle control, inhibition of ornithine decarboxylase, inhibition of cellular proliferation and keratinization, and promotion of cellular differentiation.18 Experimental data suggest that retinoids exert their effects during the promotion and progression stages of carcinogenesis.19 The pharmacology of specific retinoids is reviewed in Table 1.20
The role of systemic retinoids in skin cancer chemoprevention was first established in patients with xeroderma pigmentosum.21,22 By the late 1980s, Shuttleworth et al. studied the efficacy of etretinate in preventing skin cancer in renal transplant recipients.23 Although systemic retinoids are widely used in OTRs, few randomized controlled trials have been performed. Each trial has varying limitations, including small sample sizes. To date, the majority of studies on retinoid chemoprevention consist of case series.
While several case series support the efficacy of etretinate in the chemoprevention of NMSCs in OTRs, there are no clinical trials to validate these findings.23-26 Similarly, only a single case report supports the use of isotretinoin.27 The best available evidence suggests that acitretin may be beneficial for high-risk OTRs.
In a prospective, open, randomized, cross-over trial, George et al. evaluated the efficacy of acitretin, a second generation retinoid, on NMSC development in renal transplant recipients.28 Acitretin (25 mg per day) was administered to 14 patients, while nine patients received no therapy. Cross-over occurred at one year, and only 47.8% of patients completed the two-year trial. The number of SCCs observed in patients on acitretin was significantly lower than that in the drug-free period (p = 0.002). A similar, yet not significant, trend was observed for BCCs. In one patient, a severe rebound in SCC development occurred upon discontinuation of acitretin. Poor drug tolerability resulted in a high withdrawal rate.
Bouwes Bavinck et al. carried out a randomized, double- blind, placebo-controlled trial to study the effect of acitretin (30 mg per day) on NMSC development in renal transplant recipients.29 All patients had ten or more keratotic skin lesions on the hands and forearms. During the six-month treatment period, two of 19 patients (11%) in the acitretin group reported a total of two new SCCs. In the placebo group, nine of 19 patients (47%) developed a total of 18 new SCCs (p = 0.01). The relative decrease in the number of keratotic skin lesions in the acitretin group was 13.4%, as compared to a relative increase of 28.2% (p < 0.01) in the placebo group. A relapse in keratotic skin lesions and skin cancers was noted upon discontinuation of therapy.
In a randomized, controlled, open-label trial, 26 renal transplant recipients were assigned randomly to two different one-year treatment protocols with acitretin.30 Thirteen patients were treated with acitretin 0.4 mg/kg/day and 13 patients received acitretin 0.4 mg/kg/day during the first three months followed by 0.2 mg/kg/day for the remaining nine months. At nine different time points, the number of actinic keratoses and tumors were counted. The erythema and thickness of the lesions, as well as the severity of side-effects, were scored. In both groups, the number of actinic keratoses decreased by nearly 50%, but the number of new malignant tumors during the study year was similar to the pre-treatment period. Thickness of the keratoses decreased significantly in both groups. The frequency of mucocutaneous side-effects, such as cheilitis, excessive peeling of the skin, and hair disorders, resulted in significant dose reductions (only three of the 14 patients maintained acitretin at a dose of 0.4 mg/kg/day).
In a retrospective before-after study, Harwood et al. evaluated the efficacy of acitretin in the chemoprevention of SCCs.31 A total of 32 OTRs received acitretin (0.2 mg to 0.4 mg/kg/day) for one to 16 years. The number of SCCs developing annually during retinoid therapy was compared to the number of SCCs during the 12-month pre-treatment period. A statistically significant reduction in SCCs was noted in the first (p = 0.006), second (p < 0.001), and third (p = 0.02) years post-treatment.
The major limitation to the use of retinoids is poor tolerability.11 In OTRs, mucocutaneous side-effects (i.e., cheilitis, xerosis, skin peeling, photosensitivity, and alopecia), headaches, and dyslipidemia frequently result in dose reductions.10,11,18 As dyslipidemia has been associated with accelerated cardiovascular disease post-transplantation, cholesterol and triglyceride levels warrant close monitoring.
|Absorption & Bioavailability||Elimination|
|Isotretinoin||10, 20, 40||3||25||10-20 hr||Hepatic||Fecal, renal|
|Tretinoin||10||1-2||–||0-60 min||Hepatic||Fecal, renal|
|Etretinate||10, 25||4||44||80-160 days||Hepatic||Fecal, renal|
|Acitretin||10, 25||4||60||50 hr||Hepatic||Fecal, renal|
|Bexarotene||75||2||Not known||7 hr||Hepatic||Hepatobiliary|
|Table 1. Pharmacology of systemic retinoids20|
|Reduction in serum levels of retinoids (via CYP3A4 induction)|
|Risk of pseudotumor cerebri potentially increased|
|Anticonvulsants||Phenytoin||Reduction in serum levels of retinoids (via CYP3A4 induction); may decrease protein binding of phenytoin and increase free fraction|
|Phenobarbital||Reduction in serum levels of retinoids (via CYP3A4 induction)|
|Carbamazepine||Reduction in serum levels of retinoids (via CYP3A4 induction); possible reduction in carbamazepine efficacy (unknown mechanism)|
|Immunosuppressive agent||Cyclosporine||Increase in serum levels via competition with retinoids for CYP3A4 metabolism|
|Hormonal contraceptive||Progestin only “minipill”||Possible reduction in serum levels of minipill, resulting in contraceptive failure|
|Folate antagonist||Methotrexate||Risk of hepatotoxicity potentially increased|
|Nutritional||Vitamin A||Hypervitaminosis A-like toxicities|
|Corticosteroids||Various||Potential for increased risk of bone loss|
|Habits||Ethanol intake (significant)||Acitretin may â€œreverse metabolizeâ€ to etretinate|
|Topical acne therapies||Benzoyl
|May increase risk of irritancy|
|Table 2. Drug interactions with systemic retinoids20|
Other known adverse effects include: ocular (i.e., reduced night vision, dry eyes), skeletal (i.e., diffuse skeletal hyperostosis, osteophyte formation, premature epiphyseal closure), gastrointestinal (i.e., nausea, diarrhea, pancreatitis), hepatic (i.e., transaminitis, toxic hepatitis), hematologic (i.e., leukopenia, agranulocytosis), neurologic (i.e., pseudotumor cerebri, depression, suicidal ideation) and muscle (i.e., myalgias, myopathy) involvement.10,11,18 Because of the risk of teratogenicity, retinoids are classified as US FDA Pregnancy Category X.
|Table 3. Systemic retinoids – laboratory monitoring guidelines20
Abbreviations: AST = aspartate aminotransferase; ALT = alanine transaminase; ALP = alkaline phosphatase; LDL = low-density lipoproteins; HDL = high-density lipoproteins.
While it has been postulated that retinoids induce immunostimulation, thereby potentiating graft rejection, these concerns have not been validated.10 In all studies to date, there have been no significant liver or renal alterations during the treatment or follow-up periods.23-31 The potential drug interactions with systemic retinoids and monitoring guidelines are reviewed in Tables 2 and 3.20
Over the years, it has been well recognized that solid organ transplant recipients are at an increased risk of developing skin cancers. Data from a small number of randomized, controlled trials suggest that acitretin may have a beneficial role in high-risk OTRs. While appropriate patient selection (i.e., patients with multiple SCCs) may improve the risk-benefit ratio, indications for use and optimal dosing regimens have yet to be established.
Given the theoretical risk of allograft rejection with systemic retinoids, low starting doses of acitretin (i.e., 10 mg per day) have been recommended. The dose of acitretin may be increased to 30 mg per day, depending on clinical response and drug tolerability. Since rebound flares occur upon discontinuation of retinoids, chemoprevention should be viewed as a lifelong therapy in OTRs. Further studies are ultimately required to establish the efficacy and long-term safety of systemic retinoids as chemopreventive agents for high-risk transplant recipients.
- Canadian Cancer Statistics. 2009. Available at: http://www.cancer.ca/Canada-wide/About%20cancer/Cancer%20statistics/Canadian%20Cancer%20Statistics.aspx?sc_lang=en. Accessed May 25, 2010.
- Foote JA, Harris RB, Giuliano AR, et al. Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults. Int J Cancer 95(1):7-11 (2001 Jan 20).
- Marks R. An overview of skin cancers. Incidence and causation. Cancer 75(2 Suppl):607-12 (1995 Jan 15).
- Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA 294(6):681-90 (2005 Aug 10).
- Demers AA, Nugent Z, Mihalcioiu C, et al. Trends of nonmelanoma skin cancer from 1960 through 2000 in a Canadian population. J Am Acad Dermatol 53(2):320-8 (2005 Aug).
- Hartevelt MM, Bavinck JN, Kootte AM, et al. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 49(3):506-9 (1990 Mar).
- Harwood CA, Surentheran T, McGregor JM, et al. Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 61(3):289-97 (2000 Jul).
- Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 40(2 Pt 1):177-86 (1999 Feb).
- Rowe DE, Carroll RJ, Day CL, Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol 26(6):976-90 (1992 Jun).
- Kovach BT, Sams HH, Stasko T. Systemic strategies for chemoprevention of skin cancers in transplant recipients. Clin Transplant 19(6):726-34 (2005 Dec).
- Chen K, Craig JC, Shumack S. Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials. Br J Dermatol 152(3):518-23 (2005 Mar).
- Lansbury L, Leonardi-Bee J, Perkins W, et al. Interventions for non-metastatic squamous cell carcinoma of the skin. Cochrane Database Syst Rev 4:CD007869.
- Niles RM. Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition 16(11-12):1084-9 (2000 Nov-Dec).
- Chambon P. The nuclear receptor superfamily: a personal retrospect on the first two decades. Mol Endocrinol 19(6):1418-28 (2005 Jun).
- Germain P, Chambon P, Eichele G, et al. International Union of Pharmacology. LX. Retinoic acid receptors. Pharmacol Rev 58(4):712-25 (2006 Dec).
- Xiao JH, Durand B, Chambon P, et al. Endogenous retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers are the major functional forms regulating retinoid-responsive elements in adult human keratinocytes. Binding of ligands to RAR only is sufficient for RAR-RXR heterodimers to confer ligand-dependent activation of hRAR beta 2/RARE (DR5). J Biol Chem 270(7):3001-11 (1995 Feb 17).
- Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res 43(11):1773-808 (2002 Nov).
- Lens M, Medenica L. Systemic retinoids in chemoprevention of non-melanoma skin cancer. Expert Opin Pharmacother 9(8):1363-74 (2008 Jun).
- Cheepala SB, Syed Z, Trutschl M, et al. Retinoids and skin: microarrays shed new light on chemopreventive action of all-trans retinoic acid. Mol Carcinog 46(8):634-9 (2007 Aug).
- Patton TJ, Zirwas MJ, Wolverton SE. Systemic retinoids. In: Wolverton SE (ed.). Comprehensive dermatologic drug therapy. 2nd ed. Philadelphia: Saunders-Elsevier, p275-300 (2007).
- DiGiovanna JJ. Retinoid chemoprevention in patients at high risk for skin cancer. Med Pediatr Oncol 36(5):564-7 (2001 May).
- Kraemer KH, DiGiovanna JJ, Moshell AN, et al. Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 318(25):1633-7 (1988 Jun 23).
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- Gibson GE, OÂ’Grady A, Kay EW, et al. Low-dose retinoid therapy for chemoprophylaxis of skin cancer in renal transplant recipients. J Eur Acad Dermatol Venereol 10(1):42-7 (1998 Jan).
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- Rook AH, Jaworsky C, Nguyen T, et al. Beneficial effect of low-dose systemic retinoid in combination with topical tretinoin for the treatment and prophylaxis of premalignant and malignant skin lesions in renal transplant recipients. Transplantation 59(5):714-9 (1995 Mar 15).
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- George R, Weightman W, Russ GR, et al. Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients. Australas J Dermatol 43(4):269-73 (2002 Nov).
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- de Sevaux RG, Smit JV, de Jong EM, et al. Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin. J Am Acad Dermatol 49(3):407-12 (2003 Sep).
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