Beyond Slip, Slop, Slap, and Wrap: Vitamin B3 for Skin Cancer Prevention

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Written By

Jihane Chaieb, PharmD, BCPS
Beth Phillips, PharmD, BCPS

Reviewed By

Martin Bishop, Pharm.D., BCACP
Dawn Fuke, Pharm.D., BCPS

Citation

Chen AC, Martin AJ, Choy B, et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. N Engl J Med 2015;373:1618-26.

“Slip! Slop! Slap! And Wrap!®”, the slogan created by the American Cancer Society is a catchphrase intended to attract the public’s attention, raise awareness of the dangers of ultraviolet (UV) radiation, and promote prevention against skin cancer.1 By slipping on a shirt, slopping on sunscreen, slapping on a hat, and wrapping on sunglasses, the organization reminds the public to take measures to protect themselves against all types of skin cancer. The National Council on Skin Cancer Prevention has officially designated every Friday before Memorial Day, “Don’t Fry Day” TM, as an initiative to further support the American Cancer Society’s fight against skin cancer.1 Despite these initiatives, the incident of non-melanoma skin cancer (NMSC), including both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), continues to climb — quite rapidly. They are the most common cancers in the United States with an estimated 3.5 million cases of NMSC treated in 2006.1-4 The cost of treating NMSC in the United States imposes an enormous economic burden with a total expenditure over $4.75 billion within the last decade.4  NMSC is associated with significant morbidity, including significant local destruction and disfigurement of soft tissue, cartilage, and bone. If SCC or preceding actinic keratosis (AK) – a precancerous lesion caused by UV damage – is left undetected and untreated, SCC can metastasize — and some patients die.2

 

Risk factors for the development of skin cancer include UV exposure, pale skin, environmental factors, personal or family history of skin cancer, previous sun burns, and immunosuppression (e.g. organ transplant).1 Given the significant and growing morbidity, mortality, and economic burden of NMSC, finding effective preventative measures are of great interest. Broad-spectrum sunscreen reduces the risk and incidence of NMSC, but only about one in five patients reports regular sunscreen use.5 Adherence with sunscreen use may even be lower in high risk populations.6 The use of oral retinoids has been studied in moderate to high risk individuals with mixed results, with relapse after discontinuation and adverse effects a major problem.7, 8

 

Nicotinamide is the amide metabolite of nicotinic acid (aka niacin).  It has anti-inflammatory effects but does not impact lipids or cause vasodilation. It is found in meats, dairy products, beans, seeds, some vegetables, and nuts, and is readily available and sold as a nutritional supplement. Nicotinamide has been used in the treatment of  several dermatological conditions including bullous pemphigoid and pemphigus.9,10 Although its exact mechanism of action is not clear, nicotinamide appears to have photoprotective and anticarcinogenic effects.9,11 In two phase II double-blind studies in patients with AK lesions, the use of nicotinamide for 4 months significantly reduced the rate of new AK lesions and NMSC when compared to placebo (p<0.05 for both studies).12  However, given the small number of participants in these studies (n = 74) and the short observation period, a phase III trial was needed to confirm the benefits of nicotinamide use in a larger, high-risk population.

 

The Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) was a randomized, double-blind, placebo-controlled, multicenter, phase III trial funded by the National Health and Medical Research Council of Australia.13 The trial evaluated the role of nicotinamide to prevent NMSC in immunocompetent adult patients with at least two confirmed NMSC in the last 5 years. The authors excluded patients with a history of invasive melanoma or other cancers in the previous 5 years, AK in the previous 4 weeks, previous myocardial infarction, hypotension, nicotinamide supplementation, or retinoid use. Patients (n=386) were randomized 1:1 to receive nicotinamide 500 mg twice daily or placebo for 12 months. Skin cancer checks were completed at baseline and every three months for a total of 18 months. An intention-to-treat analysis was utilized. Baseline characteristics were similar in both groups.  However, patients in the nicotinamide group were more likely to have a history of asthma (p=0.03). The primary end point was new diagnosis of NMSC during the 12-month treatment period. Secondary endpoints included new diagnosis of BCC, SCC, and AK (individually); diagnosis of NMSC up to 6 months following the treatment period; and adverse events.13

 

Nicotinamide use was associated with fewer new NMSC lesions per person, 1.8 compared to 2.4 in the placebo group  after 12 months of treatment (p=0.02).  See Table 1. The rate of BCC, SCC, and AK were all lower in the treatment group but only the reduction in AK lesions was statistically significant (p=0.001). Six months following treatment discontinuation, the chemopreventive benefit of nicotinamide was not maintained. Sunscreen use ranged between 47 to 59% in the two groups, but the placebo group was more likely to use sunscreen at six and nine months (p<0.05).  See Table 2. There was no difference in the number and type of adverse events in the two study groups, including development of melanoma (4 new invasive and 6 in situ).13

 

Table 1. Incidence of NMSC, BCC, and SCC

 

Placebo

Nicotinamide

Relative difference, % (95% CI)

P value

Mean number of lesions/person

12-month treatment period

    NMSC

2.4

1.8

23 ( 4 to 38)

0.02

    BCC

1.7

1.3

20 (-6 to 39)

0.12

    SCC

0.7

0.5

30 (0 to 51)

0.05

6-month post-treatment period

    NMSC

0.8

0.8

-17 (-59 to 14)

0.33

     BCC

0.6

0.5

- 6 (-53 to 26)

0.73

     SCC

0.3

0.3

-59 (-163 to 4)

0.07

 

Table 2. Sunscreen use

Time point

Placebo

Nicotinamide

P value

6 months

111/190 (58%)

87/187 (47%)

0.02

9 months

110/185 (59%)

89/184 (48%)

0.03

12 months

112/189 (59%)

92/183 (50%)

0.08

 

In patients with a history of NMSC, the use of nicotinamide led to an impressive reduction in the rate of new NMSC lesions, with a number needed to treat of 7 to prevent one new NMSC lesion in 12 months. However, this reduction did not persist after treatment was discontinued. The results of this study mirror the findings from the previous phase II studies.12

 

There are several points to consider when evaluating the merits of this study. Strengths include randomization, double blinding, appropriate comparator group, low dropout rates, and adequate power. Adherence to sunscreen was much higher in this study than in the general or high risk populations — however, the authors did not report whether adherence to sunscreen use was maintained year-round. Given that sunscreen use was higher in the placebo group, the benefits of nicotinamide use are perhaps even more impressive.  However, the effects of nicotinamide were not sustained beyond the treatment period, suggesting there is no lasting benefit. Thus the optimal duration of therapy for nicotinamide is unclear – but continuous, indefinite treatment may be necessary. Patients may find it easier to take an oral medication every day rather than use a topical cream that can be messy, transferring to clothes and other surfaces. It should be noted that patients in ONTRAC were instructed to use nicotinamide in combination with sunscreen – so we can not rule out the possibility that the combination is perhaps required or synergistic.

 

Nicotinamide use was associated with a non-significant reduction in new superficial BCC. Further investigation of nicotinamide in patients with a history of BCC especially with the aggressive micronodular, infiltrating, and morpheic type lesions is needed. These lesions are more likely to recur than superficial and nodular BCC.2 While more patients in the nicotinamide group had asthma at baseline, it seems unlikely this affected the study results. Lastly, this study excluded patients receiving immunosuppression (e.g. organ transplant recipients), a group who might derive benefit from this treatment given their very high risk of developing NMSC. Further study in immunosuppressed patients is warranted.

 

The ONTRAC trial offers strong evidence to support the use of nicotinamide to reduce NMSC and AK in immunocompetent patients with a previous history of NMSC. Moreover, patients experienced relatively few adverse effects. However, the optimal duration of therapy is currently unknown and the benefit of nicotinamide dissipated within six months after discontinuation. Clearly, we need more long term efficacy and safety data. However, given the high treatment cost of NMSC, an oral agent with a favorable safety profile and significant efficacy is an attractive option to prevent NMSC in patients with a history of NMSC. One could argue that continued efforts should be directed to maximizing adherence to sunscreen. However, patients who are at high risk of skin cancer exhibit poor sunscreen use behaviors.14-17  While we aren’t ready to declare nicotinamide the standard of care, we believe it should be offered to patients with a history of NMSC. What do you think?  Would you recommend indefinite nicotinamide use to prevent new NMSC to your patients or family members?