Chemoprevention can be defined as the use of natural or pharmacologic agents to prevent or reverse skin cancer genesis. These medications target pathways brought upon by UV-radiation induced tumorigenesis and intervene in the period following damaging UVR exposure and before the development of skin cancers. Molecular targets include inflammatory cytokines, cyclooxygenase-2 (COX-2), prostanoids, melanocortin one receptors and oxidative stress contributors.

Chemoprevention is indicated for the following patient populations:

Category	Details
Excessive UV light exposure	Severe photodamage Numerous precancerous lesions e.g. actinic keratoses (Aks)
History of NMSC	More than 5-10 NMSCs per year Accelerating frequency of NMSCs Multiple NMSCs in high-risk locations (head and neck) Metastatic NMSC Eruptive keratoacanthomas
Immunosuppression	Organ transplant recipients Chronic immunosuppressive therapies Haematologic malignancies (chronic lymphocytic leukaemia, non-Hodgkin lymphoma) HIV
Genetic syndromes	Xeroderma pigmentosum Recessive dystrophic epidermolysis bullosa (RDEB) Albinism Naevoid BCC syndrome Epidermodysplasia verruciformis Bazex syndrome Rombo syndrome
Other exposures	History of PUVA Chronic radiation dermatitis Chronic arsenic exposure Trauma and/or extensive burns

NMSC, non-melanoma skin cancer; BCC, basal cell carcinoma, PUVA, psoralen and ultraviolet A

The various categories of chemoprevention may include:

Retinoids

The mechanisms of action of retinoids include:

• Arresting growth and apoptosis in rapidly dividing tumour cells by acting at the nuclear level
• Promoting immune surveillance
• Keratinocyte maturation
• Thickening of the skin (topical administration)
• Topical treatment of actinic keratosis

Acitretin is the most used retinoid for chemoprevention. Indications include:

• 5 cutaneous squamous cell carcinomas (SCC) over 2-3 years
• one T2b or T3 cutaneous SCC (based on the Brigham and Women’s Hospital tumour staging) plus field photodamage
• field cancerisation not controlled with topical 5-fluorouracil or photodynamic therapy
• Xeroderma pigmentosum
• Organ transplant (those with multiple invasive low-risk cutaneous SCC and/or a high-risk cutaneous SCC)

The dose of acitretin in studies ranges from 10 mg daily, 0.2-0.4 mg/kg to 25-30 mg daily. One approach is to start with 10 mg alternate day and increasing every 4 weeks to reach a final dose of approximately 20 mg daily.

For patients on acitretin, laboratory monitoring is required:

• At baseline: full blood count, creatinine, lipid panel, liver function test
• Repeat the lipid panel and liver function test every month as the dose is increased and every 3 months when on a stable dose
• Creatinine in patients with renal dysfunction or kidney transplant

However, patients need to be informed that acitretin is a long-term medication as baseline squamous cell carcinoma formation reverts to baseline once acitretin is discontinued. Safety issues include teratogenicity, mucositis and skin toxicities.

Nicotinamide (or niacinamide)

Nicotinamide is the amide form of vitamin B3 and a precursor of nicotinamide adenine dinucleotide. It reduces the decline in cellular ATP after exposure to UV radiation, enhances the energy-dependent process of DNA repair and prevents UV radiation-induced immunosuppression. It can be prescribed for patients with field cancerisation and more than 1 previous cutaneous SCC. The dose of nicotinamide is 500 mg twice daily. Although some studies did not show a benefit in patients taking nicotinamide, this could be attributed to the small sample size due to slow recruitment, paucity of tumours detected, the short intervention period and the existing use of nicotinamide supplementation among immunosuppressed patients.

Although side effects are minimal, high doses (3g per day) may result in liver failure. Patients need to check labels and avoid purchasing nicotinic acid or niacin as adverse effects such as flushing may occur with those agents.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs work by depleting growth-stimulating hormones, generating reactive oxygen species harmful to cancer cells and inhibit COX-2 linked to cancer prorgression. In immunosuppressed organ transplant recipients, there may be negative effects on kidney graft and cardiovascular function thus the use of topical preparations such as diclofenac 1% gel can be considered particularly for the treatment of actinic keratoses.

Although one study in patients with actinic keratoses found lower numbers of NMSCs, BCCs and SCCs among those on celecoxib, another study (ASPREE) found no significant effect of aspirin on incident melanoma.

Difluoromethylornithine (DFMO)

DFMO is an ornithine decarboxylase (ODC) inhibitor. ODC is an enzyme involved in polyamine biosynthesis and production of amino acids. Polyamines are involved in cell growth, proliferation and tumour promotion. DFMO also reduces mRNA expression of sonic hedgehog and glioma-associated transcription factors which are involved in basal cell carcinoma pathogenesis. However, the adverse effect of DFMO is dose-dependent hearing loss.

Although a phase II trial of oral DFMO 500mg/m2 did not find reduction in new NMSC formation, there was a reduction in new BCCs. Another study found that topical DFMO was able to reduce the total number of actinic keratoses.

5-Fluorouracil (5-FU)

5-FU is an antimetabolite which inhibits thymidylate synthase and incorporation of metabolites into RNA and DNA. It can be used for the treatment of actinic keratoses and certain types of BCCs as well as prevent the development of SCCs.

Application of 5% fluorouracil cream twice daily to the face and ears for 2-4 weeks was found to reduce the risk of SCC requiring surgery at one year after use in a high-risk population. Oral capecitabine (a prodrug of 5-FU) can also be used as adjuvant prevention for SCCs. Common adverse effects to capecitabine include fatigue, nausea, hand-and-foot syndrome, gout and poor renal function.

Photodynamic therapy

Photodynamic therapy with 5-aminolevulinic acid (5-ALA) has been found to reduce SCCs in patients with solid organ transplants. Adverse effects include erythema, oedema, desquamation, crusting and pain.

Green tea polyphenols: epigallocatechin-3-gallate (EGCG)

EGCG is an antioxidant which is anti-inflammatory and inhibits tumour cell growth. Topical formulations may work better than oral although the evidence does not support efficacy.

References

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