Chen et al34 conducted the ONTRAC study, a phase 3, double-blind, randomized controlled trial (RCT) looking at 386 participants with a history of at least 2 NMSCs in the preceding 5 years. At 12 months, those treated with 500 mg of nicotinamide twice daily demonstrated a statistically significant decreased rate of SCC formation (P=.05). A decreased incidence of BCC development was noted; however, this trend did not reach statistical significance (P=.12). Precancerous skin lesions also were found to be decreased in the treatment group, with 20% lower incidence of actinic keratoses (AKs) after 9 months of treatment (P<.001).34 Drago et al35 specifically studied the incidence of AKs in 38 transplant recipients—8 liver and 30 kidney—and found that previously noted AKs had decreased in size for 18 of 19 patients taking 500 mg of nicotinamide daily when originally photographed AKs were remeasured at 6-month follow-up, with 7 of these 18 patients demonstrating complete clinical regression. Of those on nicotinamide supplementation, no new AKs developed compared to the control group, which demonstrated increased size of AKs or development of new AKs in 91% of patients, with 7 AKs progressing into SCC.35
Nicotinamide has been demonstrated to be useful in preventing skin cancer in high-risk populations, such as transplant patients or those with a high incidence of NMSC.34,36 Despite promising results within the laboratory setting, nicotinamide’s effects on melanoma in humans remains less clear.31,37 Studies suggest that nicotinamide enhances tumor-infiltrating lymphocytes and DNA repair mechanisms in melanocytes, which may translate into nicotinamide, providing chemoprevention for melanoma, but research in human patients is limited.31,37
Vitamin B9—Folate, the natural form of vitamin B9, is a water-soluble compound that is found in many foods, especially green leafy vegetables, and often is supplemented because of its health benefits.38,39 In the skin, folic acid plays a key role in cellular replication and proliferation.38 Controversy exists regarding folate’s effects on cellular growth and turnover with respect to cancer incidence.38,40 Donnenfeld et al41 conducted a prospective study assessing dietary folic acid intake and development of NMSC. A total of 5880 participants completed dietary records throughout the first 2 years of the study. After an average follow-up period of 12.6 years, there was an overall increased incidence of skin cancer in those with increased dietary folate (P=.03). Furthermore, when striating by skin cancer type, there was an increased incidence of NMSC overall as well as BCC when analyzing by type of NMSC (P=.03 for NMSC; P=.05 for BCC). However, when stratifying by gender, these findings only held true for women.41 Similar effects were observed by Fung et al,42 who prospectively studied the intake of various vitamins in relationship to the development of BCC in women. During 12 years of follow-up, a positive association was observed between folate intake and BCC development (OR, 1.2; 95% CI, 1.10-1.31).42 Fung et al43 also investigated the role of several vitamins in the development of SCC and found that folate showed a negative association, which did not reach statistical significance (RR, 0.79; 95% CI, 0.56-1.11). Furthermore, Vollset et al40 conducted a meta-analysis comparing folic acid to placebo in the incidence of various types of cancer. The study excluded NMSC but reported no significant association between the development of melanoma and folic acid supplementation.40 In summary, the effects of folate have diverse consequences, potentially promoting the formation of NMSC, but studies suggest that an individual’s gender and other genetic and environmental factors also may play a role.
Vitamin C—Vitamin C (also known as ascorbic acid) is a water-soluble vitamin with antioxidant immune-mediating effects. It is found in various fruits and vegetables and serves as a cofactor for enzymes within the body playing a key role in immune function and collagen formation.44,45 It has been postulated that ascorbic acid can provide protection from UV radiation damage via its intracellular activity but conversely can contribute to oxidative damage.44 Multiple in vitro laboratory studies and animal models have demonstrated photoprotective effects of ascorbic acid.46-48 Despite these findings, minimal photoprotective effects have been found in the human population.
Kune et al49 performed a case-control study of 88 males with previously diagnosed NMSC undergoing surgical removal and investigated patients’ prior dietary habits. Patients with NMSC had a statistically significantly lower level of vitamin C–containing food in their diet than those without NMSC (P=.004).49 In addition, Vural et al50 analyzed plasma samples and blood cells of patients with AK and BCC and found a significant decrease in ascorbic acid levels in both the AK (P<.001) and BCC (P<.001) groups compared with controls. However, studies have found that consumption of certain dietary compounds can rapidly increase plasma concentration levels, which may serve as a major confounding variable in this study. Plasma concentrations of ascorbic acid and beta carotene were found to be significantly increased following consumption of a high-antioxidant diet for as short a duration as 2 weeks (P<.05).51 More recently, Heinen et al52 performed a prospective study on 1001 adults. In patients without a history of skin cancer, they found that vitamin C from food sources plus dietary supplements was positively associated with the development of BCC (P=.03).52 Similarly, Fung et al42 performed a study in women and found a positive association between vitamin C intake and the development of BCC (OR, 1.13; 95% CI, 1.03-1.23).