By Seema Gupta, MD, MSPH
Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV
Dr. Gupta reports no financial relationships relevant to this field of study.
SYNOPSIS: In a Phase III, double-blind, randomized, placebo-controlled trial, oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients.
SOURCE: Chen AC, et al. A phase 3, randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med 2015;373:1618-1626.
As its incidence continues to increase worldwide, nonmelanoma skin cancers, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), remain the most common types of cancer in fair-skinned populations. While there are several similarities between these two types, there remain significant differences in etiology and incidence rates. SCC may originate from premalignant actinic keratosis and infrequently metastasize to regional lymph nodes or more distant sites, whereas BCC rarely metastasizes but is much more commonly spread locally and may cause disfiguration.
The primary risk factors contributing to the development of nonmelanoma skin cancer are likely a combination of increased exposure to ultraviolet (UV) radiation or sun light, increased outdoor activities, use of tanning beds, increased longevity, ozone depletion, genetics, certain photosensitizing medications, and, in some cases, immune suppressive conditions.1 People who live at high altitudes or in areas with bright sunlight year round have a higher risk of developing skin cancer, as do those who spend significant amounts of time outside during the midday hours. Exposure to ultraviolet B (UVB) radiation appears to be more closely linked with skin cancer, but newer research suggests that ultraviolet A (UVA) may also play a role in the development of skin cancers.2 UV radiation increases the risk of skin cancer by causing inflammation, gene mutation, and immunosuppression.3 Specifically, along with DNA damage, UV radiation inhibits the DNA repair by depleting cellular adenosine triphosphate (ATP). An over-the-counter dietary supplement, nicotinamide (vitamin B3), is a precursor of nicotinamide adenine dinucleotide (NAD+), an essential cofactor for ATP production. Nicotinamide prevents the decline in cellular energy observed after UV exposure and may maintain efficient DNA repair. It is also highly immune protective in humans and may reduce the level of immunosuppression induced by UV radiation, which is triggered by DNA damage.4 Previous research in a small number of patients has demonstrated the benefit of the use of oral nicotinamide in preventing skin cancers and subclinical lesions.5
In their multicenter, randomized, placebo-controlled, Phase III trial, Chen et al aimed to assess the efficacy of oral nicotinamide for the chemoprevention of nonmelanoma skin cancer. A total of 386 Australian participants with a history of at least two diagnosed nonmelanoma skin cancers in the past 5 years were randomly assigned to receive 500 mg of oral nicotinamide twice daily or a placebo for 12 months. The participants had dermatological assessments at 3-month intervals for 18 months. The primary endpoint was the number of new nonmelanoma skin cancers during the 12-month intervention period.
Researchers found a 23% decrease in the rate of new nonmelanoma skin cancers in the nicotinamide group at 12 months compared with the placebo group (95% confidence interval [CI], 4-38; P = 0.02). The number of cases of actinic keratoses in the nicotinamide group was lower by 11% at 3 months (P = 0.01), 14% at 6 months (P < 0.001), 20% at 9 months (P < 0.001), and 13% at 12 months (P = 0.001) compared with the placebo group. Researchers also found a 20% (95% CI, -6 to 39) lower rate of new BCC and a 30% (95% CI, 0-51) lower rate of SCC with nicotinamide compared with placebo (P = 0.12 and 0.05, respectively).
Of note, the benefit from nicotinamide only lasted as long as the administration of nicotinamide continued. No significant differences in adverse event frequency or type were reported between the nicotinamide or placebo group during the 12-month intervention period.
COMMENTARY
Nicotinamide is widely available over-the-counter and is generally considered a safe and affordable supplement. At the doses studied, it is also very well tolerated, with patients showing no signs of adverse events. The study by Chen et al shows an impressive 23% decrease in the rate of new nonmelanoma skin cancers in participants taking 500 mg of oral nicotinamide twice daily when compared with placebo in a population of patients who have a history of having at least two diagnosed nonmelanoma skin cancers in the past 5 years. In the United States, the annual total cost of treating nonmelanoma skin cancers is estimated to be $4.8 billion. With rising incidence, these findings have the potential to decrease the health and economic burden of skin cancer. Practically speaking, for patients who already have a history of nonmelanoma skin cancers and are at high risk of developing future skin cancers, nicotinamide can be recommended as an additional means of chemoprevention in the appropriate patients. However, the use of nicotinamide in limited circumstances does not obviate the need for other skin cancer prevention measures, such as use of hats, protective clothing, sunscreens, and regular check-ups, for all patients at risk of skin cancer. The benefits of those measures, in turn, may be even more substantial.
REFERENCES
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Miyamura Y1, et al. The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin. Pigment Cell Melanoma Res 2011;24:136-147.
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Halliday GM. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis. Mutat Res 2005;571:107-120.
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Kim B, et al. Oral nicotinamide and actinic keratosis: A supplement success story. Curr Probl Dermatol 2015;46:143-149.
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Surjana D, et al. Oral nicotinamide reduces actinic keratoses in phase II double-blinded randomized controlled trials. J Invest Dermatol 2012;132:1497-1500.
