The main classes of agents used in the chemoprevention of keratinocyte cancer (KC) for individuals at extreme skin cancer risk are synthetic retinoids and nicotinamide.
Whilst large numbers of skin cancers can occur in immune competent individuals, chronically immunosuppressed organ transplant recipients (including heart/lung, hepatic and renal transplant recipients) have a greatly increased risk of developing skin cancer and are a major target population for chemoprevention (see: Organ transplantation and immunosuppression). For example, 25% of Australian renal transplant recipients will develop a KC by 5 years post transplantation and 44% by 9 years. The most dramatic increase in incidence is seen in cutaneous squamous cell carcinoma (cSCC), though there is also an increase in the incidences of basal cell carcinoma (BCC) and melanoma. A greater proportion of the cSCCs and BCCs occurring in this context show aggressive growth patterns and poor prognostic features. Aggressive cSCCs contribute to substantial numbers of deaths in the Australian organ transplant population.
Other causes of chronic immune suppression, such as chronic leukaemias and lymphomas, are associated with increased risk and aggressiveness of skin cancer, and chemoprevention may sometimes be needed in this context.
Overview of evidence (non-systematic literature review)
Four studies of retinoid chemoprophylaxis of skin cancer have been undertaken in renal transplant recipients. All have shown a significant reduction in rates of cSCCs during treatment. In one study, suppression of the incidence of KC was not maintained following cessation of retinoid chemoprophylaxis, suggesting that these agents act at a late stage in tumour development.Due to the need for long-term therapy, it is recommended that retinoid treatment be instituted for transplant recipients and also for severely affected immune competent patients only when patients begin to suffer from numbers of cSCCs that are causing significant morbidity or are life-threatening. The long-term benefits must be weighed against the short- and long-term adverse effects of retinoids. The major long-term adverse effects are calcification of tendons and ligaments and spinal hyperostoses.
Xeroderma pigmentosuma rare hereditary disorder associated with multiple early-onset SCCs and increased risk of other cancersA trial using high dose isotretinoin in seven patients showed a 63% reduction in KCs, compared with the 2-year period before treatment.
Naevoid basal cell carcinoma syndromeSmall trials of retinoids have demonstrated effective chemoprophylaxis of BCC in patients with naevoid BCC syndrome (Gorlin's syndrome).
Betacarotene supplementationTrials of betacarotene in the chemoprevention of KC have failed to demonstrate a beneficial effect.
Nicotinamide is an amide form of vitamin B3 which enhances DNA repair after ultraviolet (UV) irradiation, and reduces the immune suppressive effects of sunlight on the skin.
Oral nicotinamide reduced numbers of actinic (solar) keratoses (AKs) in phase II studies and has been shown in one phase III randomised trial to reduce the incidence of KC in high-risk immune-competent individuals with multiple previous skin cancers. Nicotinamide 500mg twice daily over 12 months reduced numbers of new KCs by 23% compared with placebo, with similar magnitudes of reduction observed for BCC and cSCC. The rate of AKs was also reduced by approximately 15%. The chemopreventive effect was lost during a 6-month post-intervention follow-up period, suggesting that nicotinamide’s mechanisms of action relate to the promotion rather than initiation stages of carcinogenesis.
Nicotinamide lacks the vasodilatory effects of nicotinic acid and was well tolerated. At very high doses (approximately 8g daily), nicotinamide has been associated with reversible liver function abnormalities. These side effects are not seen at lower doses. There is a potential drug interaction with carbamazepine.
Small phase II studies suggest that nicotinamide may be useful for the chemoprevention of KC in organ transplant recipients, but as yet there have been no large trials of its safety and efficacy in this population. Its effects on chemoprevention of melanoma are currently unknown.
Nicotinamide may be a useful chemopreventive adjunct to sun protection and sunscreen use in high risk, immune-competent individuals with a history of multiple keratinocyte cancers. It should not be recommended for lower-risk individuals without a history of skin cancer.
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