Proposed: Clinical Trial of Vitamin Derivative to Prevent Melanoma

Nick Mulcahy

August 16, 2017

It's time to run a randomized clinical trial to see whether the vitamin B3 derivative nicotinamide can prevent melanoma in high-risk individuals, conclude the authors of a new review published online August 8 in Photodermatology, Photoimmunology and Photomedicine.

That idea is based on a variety of evidence, they say.

Most importantly, nicotinamide was shown to reduce the incidence of nonmelanoma skin cancer (NMSC) in high-risk individuals in a phase 3 trial, said senior author Gary Halliday, MD, a dermatologist at the University of Sydney in Australia, in a press statement.

"It would be worthwhile to determine whether it would also be useful for high-risk melanoma patients," he said.

The earlier phase 3 findings in NMSC come from the Australian ONTRAC (Oral Nicotinamide to Reduce Actinic Cancer) study, which was first presented at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting and was subsequently published in the New England Journal of Medicine.

In ONTRAC, nicotinamide was shown to reduce significantly the risk of developing further skin cancers among 386 patients who had been diagnosed with NMSC.

Specifically, for patients who took nicotinamide 500 mg twice daily for 1 year, there was a 23% reduction in new diagnoses of NMSC, compared with those who took placebo (P = .02). New diagnoses of basal cell carcinoma were reduced by 20%, squamous cell carcinoma by 30%, and actinic keratosis by 13%.

During the year-long study, the patients in the placebo group developed a median of 2.5 new skin cancers, whereas those in the nicotinamide group developed a median of 1.77 new cancers.

At the 2015 ASCO meeting, an ONTRAC investigator said nicotinamide was "ready for the clinic."

This week, Dr Halliday told Medscape Medical News: "Nicotinamide is now widely prescribed by dermatologists in Australia."

Nicotinamide is now widely prescribed by dermatologists in Australia. Dr Gary Halliday

The supplement is inexpensive; the recommended dose of 1 g/day costs approximately $10 per month.

When asked whether there was a downside to taking nicotinamide, Dr Halliday said, "Not that I know of."

However, other experts have raised questions about using nicotinamide as chemoprevention for skin cancer on the basis of the ONTRAC data alone.

"The level of evidence is not high enough," said Aleksandar Sekulic, MD, PhD, from the Mayo Clinic–Phoenix, Arizona, in 2015. "This is just the first study, and it was a small number of patients for a prevention study."

Also in 2015, another commentator said the Australian high-risk population might not be representative of skin cancer populations elsewhere, particularly in less sunny climates.

If in their review Dr Halliday and his coauthors were aware of these criticisms, then they did not acknowledge them in their new article.

Instead, they emphasized the need to prevent not just NMSCs but melanoma too.

"Chemopreventive strategies for skin carcinogenesis are extremely important, especially in the face of aging populations and increasing rates of melanoma and NMSC worldwide," they write.

The essay authors cite a litany of statistics to illustrate melanoma's prominence.

Melanoma is the fourth most common cancer in the Australian population. In the United States, it is the fifth leading cancer in males and the seventh leading cancer in females. In 2009, among Americans, the lifetime risk of developing melanoma (invasive or in situ) was 1 in 58 and 1 in 78, respectively. In 2016, the lifetime risk increased to 1 in 54 and 1 in 58.

The authors also cite evidence that nicotinamide can help reduce or reverse DNA damage and immunosuppression caused by ultraviolet radiation. Both of these biological mechanisms are "important in melanoma induction," they say.

"Nicotinamide's photoprotective effects and its efficacy in chemoprevention of NMSCs suggest similar potential for efficacy in melanoma prevention," say the Australian authors.

They note that nicotinamide has been used in the treatment of a range of skin disorders, such as rosacea, acne, and various bullous dermatoses. And although the anti-inflammatory effects of the agent are not fully understood, several studies (Clin Exp Immunol. 2003;131:48‐52; Mol Cell Biochem. 1999;193:119‐125) support an anti-inflammatory role of nicotinamide by way of the inhibition of PARP-1, say the review authors.

A large amount of research of potential chemopreventative agents for skin cancer has been conducted, the authors also say. Such agents include statins and vitamin D.

"However the other agents either have unacceptable side effects, are too expensive to be useful, or have not been proven to work in clinical trials," said Dr Halliday.

No chemoprevention is fully proven, he acknowledged. "The best proven approach is to reduce sun exposure," said Dr Halliday.

The authors and commentators have disclosed no relevant financial relationships.

Photodermatol Photoimmunol Photomed. Published online August 8, 2017. Abstract

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