Table 2.

A summary of the clinical evidence for chemopreventive agents.

Chemopreventive Agent	Proposed Mechanism of Action	Clinical Data	Evidence for Clinical Efficacy
Nicotinamide (oral)	Antioxidant, antiproliferative, reduces photoimmunosuppression	Chen et al., 2015—No change in incidence of melanomas. Decreased number of keratinocytic carcinomas (23% fewer) and actinic keratoses (13% fewer) than the placebo group.	Efficacy limited to keratinocyte carcinomas
Myristyl Nicotinate (topical)	Enhances skin cell turnover and epidermal differentiation	NCT00619060—Did not achieve safety endpoint in phase I clinical trial.	No demonstrable clinical efficacy
Celecoxib (oral)	Decrease potentially oncogenic prostaglandin synthesis and release	Elmets et al., 2010—43% lower risk of developing keratinocyte carcinomas in patients treated with celecoxib versus placebo. Tang et al., 2010—20% increase in annual basal cell carcinoma burden in treated patients versus 50% increase in placebo for patients with basal cell nevus syndrome.	Efficacy limited to keratinocyte carcinomas
Sulindac (oral)	Decrease potentially oncogenic prostaglandin synthesis and release	Lewandrowski et al., 2012—Sulindac metabolites were detected in atypical nevi; however, no significant changes in apoptosis or vascular endothelial growth factor A expression were noted.	No demonstrable clinical efficacy
Diclofenac (topical)	Decrease potentially oncogenic prostaglandin synthesis and release	Jeter et al., 2016—Diclofenac with or without DFMO increased markers of cutaneous inflammation (karyometric average nuclear abnormality (ANA)).	No demonstrable clinical efficacy
Aspirin (oral)	Decrease potentially oncogenic prostaglandin synthesis and release	Varedi et al., 2020—Dose reduction in prostaglandin E2 levels in melanocytic nevi after administration of aspirin for one week (50–70% decrease for 325mg cohort, 35–50% decrease for 81 mg cohorts).	Early clinical evidence of molecular effect
Isotretinoin (oral)	Anti-inflammatory and antiproliferative	Kraemer et al., 1988—Daily oral isotretinoin for two years reduced the incidence of new skin cancers in patients with xeroderma pigmentosum by 63%. Levine et al., 1997—Daily isotretinoin for three years resulted in no difference in keratinocyte carcinoma incidence compared to placebo in patients with a history of multiple keratinocyte carcinomas.	Efficacy limited to keratinocyte carcinomas
Acitretin (oral)	Anti-inflammatory and antiproliferative	Kadakia et al., 2012—Acitretin 25 mg orally 5 days per week for two years produced no significant difference in keratinocyte carcinoma incidence in the treatment arm versus placebo.	No demonstrable clinical efficacy
Tretinoin (topical)	Anti-inflammatory and antiproliferative	Weinstock et al., 2012—Tretinoin twice daily for 1.5-5.5 years produced no significant difference in keratinocyte incidence compared to placebo.	No demonstrable clinical efficacy
N-acetylcysteine (NAC) (oral)	Antioxidant	Cassidy et al., 2017—No significant difference in markers of UV-induced oxidative stress between NAC-treated and placebo groups.	No demonstrable clinical efficacy
Vitamin D (oral)	Antiapoptotic, photoprotective, reduces photoimmunosuppression	Scott et al., 2017—Patients treated with Vitamin D had decreased inflammatory changes following experimental sunburn.	Early clinical evidence of molecular effect
Statins (oral)	Antiproliferative, inhibition of the Ras signaling pathway	Linden et al., 2014—Lovastatin 40mg daily produced no significant differences in histopathologic markers of atypia, clinical atypia, nevus number, or molecular biomarkers of oncogenesis in atypical nevi between the treatment arm and placebo.	No demonstrable clinical efficacy
T4 endonucleases (topical)	Enables repair of dipyrimidine photo-mutations	Yarosh et al., 2001—T4N5 liposome lotion decreased the annual incidence rate of actinic keratoses and basal cell carcinomas in patients with xeroderma pigmentosa. Stoddard et al., 2017- Significant reduction in the number of new actinic keratoses observed in treated patients, persisting 12 weeks after treatment.	Efficacy limited to keratinocyte carcinomas
Difluoromethylornithine (DFMO) (oral)	Decreases epithelial polyamine levels (potentially tumorigenic)	Bailey et al., 2010—Orally dosed DFMO (500 mg/m2/day) produced no significant difference in total new keratinocyte carcinomas versus placebo over 4 to 5 years.	No demonstrable clinical efficacy
Grape Polyphenols (oral)	Photoprotective	Oak et al., 2021—California table grape powder (25 g, 3x per day) for two weeks significantly increased MED from baseline levels.	Early clinical efficacy in experimental sunburn models
Lycopene (oral)	Antioxidant	Rizwan et al., 2011—16-mg lycopene daily for 12 weeks versus control produced a significant increase in MED compared to placebo, as well as a reduction in matrix metalloprotease-1 expression and mtDNA 3895-bp deletions, as well as an increase in procollagen deposition.	Early clinical efficacy in experimental sunburn models
Selenium and Vitamin E (oral)	Antioxidant	Argos et al., 2017—Selenium and vitamin E supplementation (alpha-tocopherol (100 mg daily) and L-selenomethionine (200 μg daily) did not significantly reduce the incidence of keratinocyte carcinoma development over six years.	No demonstrable clinical efficacy
Vitamins E and C and Zinc (oral)	Antioxidant	Lloret et al., 2015—Supplementation with vitamin C 500 mg, vitamin E 400 IU, and zinc 50 mg per day did not significantly reduce levels of oxidative stress biomarkers between groups.	No demonstrable clinical efficacy
Omega-3 Polyunsaturated Fatty Acids (PUFA) (oral)	Reduces photoimmunosuppression	Pilkington et al., 2013—5-g omega-3 PUFA or a control lipid daily for 3 months did not produce a significant difference in measures of photoimmunosuppression in experimentally irradiated patients versus controls.	No demonstrable clinical efficacy