Oral Nicotinamide for the Secondary Prevention of Cutaneous Squamous Cell Carcinoma and Other Keratinocyte Carcinomas: A Systematic Review.

Background: Oral nicotinamide has been proposed as a chemoprevention strategy to reduce new keratinocyte carcinomas in people with a history of skin cancer, but its effect may differ between immunocompetent patients and transplant recipients. Objective: To evaluate the effectiveness and safety of oral nicotinamide for the secondary prevention of cutaneous squamous cell carcinoma and other keratinocyte carcinoma-related outcomes in adults with a history of skin cancer. Methods: We conducted a systematic review following PRISMA 2020. We searched PubMed/MEDLINE, Embase, and LILACS through the Virtual Health Library from inception to May 30, 2026. We included comparative studies (randomized clinical trials and controlled nonrandomized studies) evaluating oral nicotinamide versus placebo, no treatment, usual care, or another preventive strategy. Risk of bias was assessed with RoB 2 for randomized trials and ROBINS-I for nonrandomized studies, and the certainty of evidence was assessed with GRADE. We performed a narrative synthesis and an exploratory random-effects meta-analysis of randomized trials when clinically appropriate; effect measures were rate ratios for randomized trials and hazard ratios for the observational cohort. Randomized and nonrandomized designs were not statistically pooled together. Results: We identified 1076 records; after removing 151 duplicates, 925 records were screened, 17 full texts were assessed, and 5 studies were included: 4 randomized clinical trials and 1 large retrospective cohort. In high-risk immunocompetent adults, the benefit signal was driven by a single pivotal randomized trial (ONTRAC; Conclusions: In high-risk immunocompetent adults, oral nicotinamide may reduce new nonmelanoma skin cancers during active treatment, but this conclusion rests predominantly on one large randomized trial and should be regarded as provisional. In transplant recipients, the randomized evidence does not demonstrate a significant benefit, a finding concordant with the overall null result in the large observational cohort. An observational signal favoring early initiation is hypothesis-generating and requires prospective confirmation. Limitations: Evidence was limited by the very small number of randomized trials (only two contributed to the main meta-analysis), imprecision, follow-up of 12 months or less in all randomized trials, the observational nature of the largest study, and low or very low certainty for the transplant-recipient outcomes.