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Systemic Retinoids: Chemoprevention of Skin Cancer in Transplant Recipients

J. Hardin, BSc, MSc and P. R. Mydlarski, MD, FRCPC
Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT

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.

Key Words: 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

Efficacy

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.

Adverse Effects

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
Retinoid Tablet/capsule
strength (mg)
Peak levels
(hr)
Bioavailability
(%)
Half-life Metabolism Excretion
First-generation retinoids
Isotretinoin 10, 20, 40 3 25 10-20 hr Hepatic Fecal, renal
Tretinoin 10 1-2 - 0-60 min Hepatic Fecal, renal
Second-generation retinoids
Etretinate 10, 25 4 44 80-160 days Hepatic Fecal, renal
Acitretin 10, 25 4 60 50 hr Hepatic Fecal, renal
Third-generation retinoids
Bexarotene 75 2 Not known 7 hr Hepatic Hepatobiliary
Table 1. Pharmacology of systemic retinoids20


Drug Group Examples Effects
Antibiotics Rifampin
Rifabutin
Reduction in serum levels of retinoids (via CYP3A4 induction)
Doxycycline
Minocycline
Tetracycline
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 “reverse metabolize” to etretinate
Topical acne therapies Benzoyl
peroxide Tretinoin
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.

Baseline Follow-up
  • Serum or urine pregnancy test (in women of childbearing years)
  • Complete blood count (CBC)
  • Liver function (AST, ALT, ALP, bilirubin)
  • Fasting lipid profile (triglycerides, total cholesterol, LDL and HDL cholesterol)
  • Renal function (blood urea nitrogen, creatinine)
  • Monthly for 3 months, then every 3 months
  • Complete blood count (CBC)
  • Liver function (AST, ALT)
  • Fasting lipid profile
  • Renal function
  • Serum or urine pregnancy test monthly (in women of childbearing years)
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

Conclusion

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.

References

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In this issue:

  1. Systemic Retinoids: Chemoprevention of Skin Cancer in Transplant Recipients
  2. Chemotherapy-Induced Hair Loss
  3. Update on Drugs and Drug News: July-August 2010