Vitamin Prevents Skin Cancer: Only in Australia?

Nick Mulcahy

October 23, 2015Australia is the skin cancer capital of the world, and clinicians worldwide often look to the sunny continent for guidance on prevention and treatment in their locales.
However, the conclusion of an Australian chemoprevention study of nonmelanoma skin cancer — that nicotinamide is associated with a lower rate of new nonmelanoma skin cancers — has been met with caution by some experts.
Findings from the ONTRAC (Oral Nicotinamide to Reduce Actinic Cancer) trial were published in the October 22 issue of the New England Journal of Medicine.
In the phase 3 trial, nicotinamide — an over-the-counter form of vitamin B₃ — taken twice daily at a dose of 500 mg for 12 months, was compared with placebo.
All 386 study patients had had at least two nonmelanoma skin cancers in the previous 5 years, so were at high risk for more basal cell and squamous cell carcinomas. All were Australian residents.
At 12 months, the rate of new nonmelanoma skin cancers was 23% lower in the nicotinamide group than in the placebo group (P = .02).
The median number of new skin cancers developed during the year-long study was lower in the nicotinamide group than in the placebo group (2.4 vs 1.8).
Go ahead and use nicotinamide in high-risk patients, the ONTRAC team concludes.
Nicotinamide “presents a new opportunity for the chemoprevention of nonmelanoma skin cancers that is readily translatable into clinical practice,” write the investigators, led by Andrew Chen, MBBS, from the Royal Prince Alfred Hospital at the University of Sydney in Australia.
A similar statement was made when the data were first presented in May at the American Society of Clinical Oncology (ASCO) Annual Meeting.
“It is safe and…inexpensive, and this one is ready to go into the clinic,” senior investigator Diona Damian, MBBS, PhD, from the Dermatology University of Sydney, said at that time.
Some outsiders have hesitations.
“The level of evidence is not high enough,” said Aleksandar Sekulic, MD, PhD, from the Mayo Clinic Arizona in Scottsdale. “This is just the first study, and it was a small number of patients for a prevention study.”
For those reasons, the data are “not sufficient” for broader populations, such as, for example, Germans or Arizonians, whose genetic make-up might be very different than Australians, Dr Sekulic told Medscape Medical News this week.

At the ASCO meeting, a European echoed some of these comments. There was a relatively small number of study patients, and the Australian high-risk population might not be representative of skin cancer populations elsewhere, particularly in less sunny climates, said John Lear, MD, from Manchester University in the United Kingdom.
Nonetheless, Dr Lear said that this is “very exciting and promising research to prevent skin cancer using a simple therapy which could easily be translated into clinical practice quickly, with a large clinically meaningful reduction in skin cancers and actinic keratoses.”
At the time, he told Medscape Medical News that it was “surprising” to see a treatment effect in “such a short period,” given that skin cancers “develop many years after the ultraviolet exposure that caused them.”
Dr Sekulic agrees. “It’s a somewhat short time to see this preventive effect.”
Nicotinamide is not in use routinely at the Mayo Clinic, he said, unless it is being ingested as part of a patient’s multivitamin. Nonetheless, he believes “many people” in the United States will read about the study and start using the supplement.
Another American was a bit more enthusiastic.
“I have not used nicotinamide in our practice, but would consider discussing it for high-risk patients with our dermatologists in our multidisciplinary cutaneous tumor board,” said Jeffrey Farma, MD, from the Fox Chase Cancer Center in Philadelphia.
Still, Dr Farma said he wonders about “ongoing unanswered questions,” like length of use (beyond the 12 months assessed in the study) and possible changes over time in adverse events, which were comparable to placebo in the study.
When the Drug Stopped, the Effect Stopped
The study population reflects a typical skin cancer clinic population, the investigators note. The average age was 66 years, two-thirds of the patients were men, and many patients had ongoing concomitant disease, such as heart disease, arthritis, hypertension, and chronic lung disease.
The reduction in nonmelanoma skin cancer in the study patients was not limited to one cancer subtype. New diagnoses of basal cell carcinoma were reduced by 20% (P = .12), squamous cell carcinoma by 30% (P = .05), and actinic keratoses (a precursor to squamous cell disease) by 13% (P = .001).
Notably, the benefit stopped when the daily supplement stopped.
That is, the effect of nicotinamide on nonmelanoma skin cancers was not maintained after it was discontinued. A 6-month follow-up, the relative difference between the nicotinamide and placebo groups was –17% (P = .33). The benefits were not modified by age, baseline actinic keratosis count, sex, smoking status, nonsteroidal anti-inflammatory drug use, or statin use.
Patients in both groups used sun screen regularly during the study period, at about the same rate. Only half the patients had used sunscreen in the week before baseline — a fact that reinforces the results. “Hence, potential exists for oral chemopreventive agents to become an effective component in the prevention of skin cancers,” Dr Chen and his colleagues note.
Nonmelanoma skin cancer is the most common cancer in the world, and four times more common than any other cancer in Australia, they report.
Just how nicotinamide works has not been established. It is possible that nicotinamide acts by “boosting cellular energy and enhancing DNA repair,” and that the vitamin “reduces the level of immunosuppression induced by UV radiation,” the investigators write.
The study received funding from Australia’s National Health and Medical Research Council. Two study coauthors report consulting agreements with several pharmaceutical companies.
N Engl J Med. 2015;373:1618-1626. Abstract