Highlights
- Oral nicotinamide reduces the incidence of keratinocyte carcinoma (KC) among high-risk populations, notably those with prior KC history.
- Economic evaluations demonstrate nicotinamide’s preventive use results in net healthcare cost savings, driven by avoided treatment expenses.
- Quality-adjusted life-years (QALYs) gained from KC prevention justify nicotinamide as a cost-effective intervention under multiple sensitivity analyses.
- These findings support incorporation of oral nicotinamide in clinical practice guidelines for KC prevention in appropriate patient subsets.
Background
Keratinocyte carcinoma (KC), encompassing basal cell carcinoma and squamous cell carcinoma, is the most prevalent form of skin cancer in the United States. The disease imposes substantial clinical burdens due to frequent occurrence, potential for disfigurement, and risk of progression, alongside significant economic costs related to diagnosis, treatment, and long-term management. High-risk individuals, such as those with a history of prior KC or immunosuppression, face elevated incidence of multiple primary tumors. Preventive strategies are thus paramount to reduce incidence, morbidity, and healthcare expenditure.
Nicotinamide, a form of vitamin B3, has garnered attention as a chemopreventive agent for KC, with randomized controlled trials demonstrating its efficacy in reducing new KC formation by enhancing DNA repair and modulating inflammation induced by ultraviolet radiation. Despite accumulating clinical interest in nicotinamide, its economic value in real-world populations required formal evaluation to inform health policy and clinical decision-making.
Key Content
Chronological Development of Evidence
Early preclinical studies elucidated nicotinamide’s role in enhancing cellular energy metabolism and UV-induced DNA repair. Subsequently, a pivotal randomized controlled trial published in 2015 (NEJM, Chen et al.) demonstrated that daily nicotinamide (500 mg twice daily) reduced new KC occurrence by approximately 23% over 12 months in high-risk individuals. These results prompted further investigations and adoption by dermatologic societies into preventive recommendations.
Building on efficacy data, recent economic evaluations, notably the 2026 Perez et al. JAMA Dermatology study, explored cost-effectiveness in a large veterans’ cohort utilising real-world data from the Veterans Health Administration (VHA). This study compared oral nicotinamide users against matched controls with no nicotinamide exposure over an extended follow-up.
Clinical and Economic Findings from Perez et al. (2026)
The cohort comprised 33,822 individuals with 78,726 person-years of follow-up, predominantly older males with mean ages ~77 years. Nicotinamide exposure was defined as use for 30 days or more. KC incidence among exposed individuals was 0.204 per person-year compared to 0.255 among unexposed, resulting in an absolute risk reduction of 0.051 and approximately 624 KCs prevented annually among 12,287 nicotinamide users.
From a cost perspective, total nicotinamide expenditures amounted to $161,451 annually, whereas KC treatment costs saved due to reduced incidence totaled $526,032, yielding net savings exceeding $360,000. Incorporating a conservative quality-of-life decrement of 0.01 QALYs per KC, the intervention conferred 6.24 additional QALYs annually in the cohort, with a negative incremental cost-effectiveness ratio (ICER) of -$58,426 per QALY gained, positioning nicotinamide as not only cost-effective but cost-saving.
Sensitivity analyses, including probabilistic and one-way methodologies, confirmed robustness of findings despite variations in treatment costs, nicotinamide pricing, and QALY loss assumptions. Analyses modeling civilian healthcare costs versus Veterans Affairs system also supported favorable cost-effectiveness, albeit with some variation in magnitude.
Additionally, preservation of patient-reported skin symptom scores (Skindex-16) was demonstrated, underscoring the patient-centered benefits of KC prevention with nicotinamide.
Mechanistic Insights and Translational Implications
Nicotinamide enhances keratinocyte DNA repair mechanisms impaired by UV radiation, reduces immunosuppression, and mitigates inflammatory signaling pathways contributing to carcinogenesis. These mechanisms underpin the observed clinically meaningful reduction in KC incidence.
Clinically, nicotinamide is advantageous given oral administration, favorable safety profile, and low cost, making it amenable for long-term preventive use in high-risk populations. Such translational benefits expand preventive dermatology’s armamentarium beyond traditional sun avoidance and topical agents.
Expert Commentary
The compelling cost-effectiveness data from large real-world cohorts affirm nicotinamide’s preventive utility in clinical practice, particularly for individuals with prior KC history, where risk of multiple primary tumors drives clinical burden and healthcare costs.
Current guidelines (e.g., Cancer Council Australia, various dermatology consensus statements) increasingly acknowledge nicotinamide as an adjunct in KC chemoprevention. However, broader integration remains limited by variability in clinician awareness, patient adherence uncertainties, and regional reimbursement policies.
Potential limitations of available data include predominance of a male veteran population in key analyses, which may constrain generalizability to females and non-veteran populations. Long-term effects beyond one year require further study, though existing data suggest sustained benefits.
Additionally, optimal duration of nicotinamide use and comparative effectiveness against other preventive modalities warrant further investigation.
Conclusion
Oral nicotinamide offers a clinically effective, patient-centered, and cost-effective strategy for the prevention of keratinocyte carcinoma in high-risk individuals. Evidence synthesized from randomized trials and large real-world cohorts supports its adoption as a standard preventive measure, with substantial potential to reduce disease burden and healthcare costs.
Future directions include elucidation of long-term benefits, strategies to optimize adherence, and evaluation in broader demographic contexts. Integration into clinical guidelines and reimbursement frameworks will be critical to maximize healthcare impact.
References
- 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(17):1618-1626. PMID: 26465994
- Perez D, Breglio KF, Knox KM, et al. Cost-Effectiveness of Oral Nicotinamide for Keratinocyte Carcinoma Prevention. JAMA Dermatol. 2026;162(7):731-735. PMID: 42268603
- O’Neill CM, et al. Chemoprevention of Skin Cancer and its Clinical Implications. J Eur Acad Dermatol Venereol. 2023;37(3):453-462. PMID: 35512344
- Cancer Council Australia. Clinical Practice Guidelines for Basal Cell Carcinoma and Squamous Cell Carcinoma Prevention. 2023. Available at: https://wiki.cancer.org.au/australia/Guidelines
