The article was published in the April 2018 issue of Medical Observer, under the title “Does vit B3 prevent skin cancer” (PDF).
Clinical scenario
Greg, an Anglo-Australian 75-year-old retiree, presented with a nodular basal cell carcinoma on his shoulder, which I excised. Greg had been an avid surfer in his youth – a lot of sun exposure with no sunscreen. Afterwards, I read in an online GP discussion forum that oral vitamin B3 (nicotinamide) might prevent further skin cancers in people like Greg. What is the evidence?
Clinical question
What is the effect of nicotinamide, used as preventive therapy, on the incidence of skins cancers?
What does the research evidence say?
Step 1: The Cochrane Library
No Cochrane systematic review exists for this question, though the search engine identified several papers.
Step 2: TripDatabase
I conducted a search using the TripDatabase PICO search tool (Participant: “adults”, Intervention: “nicotinamide”, Comparator: “placebo”, Outcomes: “skin cancer”). The TRIP search engine also identified no systematic reviews. The primary study, a randomised trial by Chen and colleagues published in the New England Journal of Medicine in 2015, was the first result [1].
Critical appraisal
I will use the randomised controlled trial appraisal sheet from the Centre for Evidence Based Medicine [2].
PICO
Participants: who was studied?
386 adults from Sydney Australia, recruited through two tertiary teaching hospitals, who had at least two histologically confirmed non-melanoma skin cancers in the previous 5 years.
Important exclusions: immunosuppression, pregnancy or breastfeeding, cancer (metastatic cancer, invasive melanoma, or internal malignancy) in the previous 5 years, a genetic skin-cancer syndrome, large areas of confluent skin cancer (where individual lesions could not be counted), and had used several therapies (nicotinamide containing supplements, oral retinoids, field therapies for actinic keratosis) in the previous 4 weeks.
The mean age was 66-years-old, 63% were male, and about half had never smoked. The mean number of non-melanoma skin cancers in the previous five years was 8.
Intervention: what was the exposure?
nicotinamide 500 mg twice daily × 12 months
Comparator: what was the control/alternative?
placebo, identical looking coated tablets
Outcomes: what was measured?
Primary outcome: number of new, histologically confirmed non-melanoma skin cancers (basal and squamous cell carcinomas).
Other outcomes: number of new BCCs, SCCs, and actinic keratoses
Internal validity: are the trial results valid?
Randomised patient assignment?
Yes. The randomisation method is described in the supplemental protocol document available from the NEJM website. Randomisation was performed centrally by the NHMRC Clinical Trials Centre, and participants were allocated to groups, stratified by baseline skin cancer count, gender, and study site.
Groups similar at the start?
Yes. The groups were very similar (see Table 1 from the paper) [1].
Groups treated equally apart from assigned treatment?
Yes.
All patients accounted for?
Yes. Relatively few participants who dropped out and the analysis was conducted on an intention-to-treat basis.
Measures objective? Or patients and clinicians kept blinded?
Yes/Probably. This primary outcome measure (histologically confirmed skin cancers) is arguably objective. Both clinicians and participants were blinded, though the effectiveness of this blinding was not reported.
What were the results?
Primary outcomes:
- Mean number of non-melanoma skin lesions per participant at 12 months (nicotinamide vs placebo):
- 1.8 vs 2.4, which is a relative difference of 23% (95% CI 4 to 38), p = 0.02
- The result favours the nicotinamide group.
Other outcomes:
- Actinic keratosis: 13% fewer at 12 months (nicotinamide vs placebo)
- Adverse events: no clinically significant differences
Discussion and conclusion
This was a well conducted study of a common condition in Australia. That nicotinamide may have a beneficial effect on non-melanoma skin cancers is well established in prior bench and phase 2 trials (see Stat Facts), and thus, a plausible hypothesis. However, there is imprecision in the estimate in the primary outcome. The confidence interval of the relative difference between groups ranged over an order of magnitude from 4% to 38%.
We need to consider questions about external validity [2]:
- Is my patient so different to those in the study that the results cannot apply?
- Is the treatment feasible in my setting?
- Will the potential benefits of treatment outweigh the potential harms of treatment for my patient?
Thinking back to Greg, the participants in this study had many more prior skin cancers. This could be expected as a difference between patients in primary care as compared to an academic dermatology clinic. Moreover, one of the analyses in the appendix to this paper (available from the NEJM website) seems to suggest that participants who had less than 6 skin cancers in the preceding five years had little effect from nicotinamide.
Oral nicotinamide therapy is simple, appears safe, and is relatively inexpensive – 60 tablets of nicotinamide 500 mg (1 month supply) was less than $15 when I did a price check at a local Australian pharmacy.
My conclusion is that this treatment has a small-modest effect as prophylaxis against future non-melanoma skin cancers and may benefit patients with a history of many skin cancers (roughly one or more a year) the most. UV protection remains a must. The benefit to patients with a lesser history of skin cancers, which is common in general practice, is unclear. A shared-decision making process that balances the potential benefit with the financial cost and pill burden might be appropriate.
Stat Facts
Clinical trial phases
Clinical trials are conducted in phases – with each looking at difference scales of efficacy and safety. Phase 1 – these are used to test a new intervention in small group of people to evaluate safety (e.g., dose range, and side-effects). Phase 2 – these are used to determine efficacy in a small group (e.g., does/can the intervention work). Phase 3 – these are used to test the efficacy in larger groups (e.g., how does the intervention compare to usual therapy). Phase 4 – these evaluate the drug after it has been marketed (e.g., effectiveness and adverse effects in populations).
References
- Chen AC, Martin AJ, Choy B, et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention. The New England journal of medicine 2015 Oct 22;373(17):1618-26.
- Centre for Evidence-Based Medicine. Critical Appraisal tools. 2014; Available from: http://www.cebm.net/critical-appraisal/
- NHMRC – Australian Clinical Trials. Phases of clinical trials [website]. 2015 Feb 19; Available from: https://www.australianclinicaltrials.gov.au/what-clinical-trial/phases-clinical-trials
