Clinical Pearls & Morning Reports
Published March 1, 2023
Allen et al. conducted a phase 3, multicenter, double-blind, randomized, placebo-controlled trial to assess the role of oral nicotinamide in the chemoprevention of keratinocyte cancers in solid-organ-transplant recipients. Read the NEJM Original Article here.
Q: How do keratinocyte cancers in solid-organ-transplant recipients differ from such cancers in the general population?
A: Keratinocyte cancers, comprising mainly basal-cell carcinoma and cutaneous squamous-cell carcinoma, are the most common cancers in White populations. The immune suppression that is required for solid-organ transplantation confers a risk of keratinocyte cancer that is 50 times as high as that in the general population. Immunosuppression results in a substantial relative increase in the incidence of squamous-cell carcinoma, with the ratio of basal-cell carcinomas to squamous-cell carcinomas reversed among transplant recipients as compared with the immune-competent population. Cutaneous cancers are also more frequent, aggressive, and prone to metastasis and local recurrence than those in immunocompetent persons.
Q: How does nicotinamide reduce the development of actinic keratoses and keratinocyte cancers?
A: Nicotinamide, the amide form of vitamin B3, prevents cutaneous cancer and ultraviolet (UV) radiation–induced immune suppression in animals. Nicotinamide is a precursor of nicotinamide adenine dinucleotide and reduces the decline in cellular ATP that occurs after exposure to UV radiation. Consequently, nicotinamide enhances the energy-dependent process of DNA repair after exposure to UV radiation and prevents UV radiation–induced immunosuppression, which is triggered by DNA damage. Nicotinamide has been shown to reduce the development of actinic keratoses and keratinocyte cancers in immunocompetent persons, but its effects in transplant recipients are unclear.
A: This trial did not show a significant effect of nicotinamide therapy on the primary end point of the number of keratinocyte cancers at 12 months. The numbers of basal-cell carcinomas, squamous-cell carcinomas, and actinic keratoses were similar in the two trial groups. The mean (±SD) number of keratinocyte cancers per participant during the 12-month intervention period was 2.6±3.2 in the nicotinamide group and 2.7±3.4 in the placebo group. The rate ratio of keratinocyte cancers per participant (with adjustment for previous keratinocyte cancers) was 1.0 (95% confidence interval [CI], 0.8 to 1.3; P = 0.96). The numbers of squamous-cell carcinomas and basal-cell carcinomas alone were similar in the two groups at 12 months. The rate ratio was estimated at 1.4 (95% CI, 0.8 to 2.3) for basal-cell carcinomas and 0.9 (95% CI, 0.6 to 1.2) for squamous-cell carcinomas.
A: Mycophenolate mofetil, azathioprine, cyclosporine, and tacrolimus impede DNA repair and have carcinogenic effects beyond immunosuppression. Nicotinamide may be unable to overcome this pharmacologic suppression of both antitumor immunity and DNA-repair enzymes, despite its ability to reduce UV radiation–induced immunosuppression and enhance DNA repair in the absence of these agents. Future studies, such as international collaborations that are able to enroll a larger patient population or to focus on patients taking mTOR inhibitors, which do not have the same effect on DNA repair, could be designed to address the effect of nicotinamide on the chemoprevention of keratinocyte cancers.