Preventing Skin Cancer in Post-Transplant Patients: Review of the ONTRANS Phase 3 Clinical Trial
Author: Caden Carver, BS. Published: September 24, 2023
Allen et al aimed to evaluate the role of nicotinamide in preventing nonmelanoma skin cancer (NMSC) in patients following organ transplantation. The phase 3, randomized clinical trial was published in the New England Journal of Medicine in March of 2023. Researchers enrolled 158 adults who had received a solid-organ transplant (kidney, liver, heart, or lung) and had two or more keratinocyte cancers, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), in the previous five years. Exclusion criteria were patients with large areas of skin cancer or invasive melanoma, and patients receiving field therapy for actinic keratoses (AK) or mTOR inhibitor therapy within the previous four weeks. Patients were randomized based on sex assigned at birth, type of transplant, number or keratinocyte cancers within the previous five years, use of oral retinoids, and use of mTOR inhibitors. Participants were assigned in a 1:1 ratio to receive either oral nicotinamide 500 mg twice daily or a matched placebo twice daily for a total of 12 months. Skin cancer screenings were conducted by blinded dermatologists, first prior to initiation and then quarterly for the duration of the trial. Number of actinic keratoses, histologically-diagnosed NMSCs, routine laboratory monitoring, and adverse events were monitored throughout the trial. Sunscreen use was self-reported by participants. Additionally, participant quality of life was monitored using the Skin Cancer Index and the 36-Item Short-Form Health Survey, both administered at baseline and then repeated following conclusion of the trial. Main study endpoints were the number of new NMSC after 12 months. Secondary trial endpoints included histologic subtypes and differentiation of squamous and basal-cell carcinomas, number of AKs, cancer recurrence, quality of life, and safety. It was reported that a sample size of 254 would yield an 80% power, with a bimodal 5% significance level for detecting differences in NMSC cancer count between groups at 12 months. Researchers utilized a modified intention-to-treat approach for their analysis. A primary analysis was performed for the number of new NMSCs per patient compared between those treated with nicotinamide versus placebo. Covariate analysis for the number of previous NMSCs was conducted using a negative regression model.
Following the trial, researchers reported treatment adherence of 78% in both groups. Patients receiving nicotinamide therapy developed 2.6+/-3.2 new keratinocyte cancers over the trial period, compared to 2.7+/-3.4 in the placebo group. P-values were not reported by researchers. Researchers reported a rate ratio of NMSCs per study participant of 1.0 (95% CI 0.8-1.3, p=0.96). No significant differences in rates of basal (1.4, 95% CI 0.8-2.3) or squamous cell carcinomas (0.9, 95% CI 0.6-1.2) were noted between treatment groups. Transplantation type, sex, age, or number of previous NMSCs did not influence the number of new NMSCs developed between treatment groups. The mean number of AKs was 13.1 in the nicotinamide group, compared to 12.8 in the placebo group (difference 0.4, 95% CI -3.0-3.7). No significant differences in quality of life scales and sunscreen use were reported between groups. Notably, the percentage of study participants using sunscreen remained less than 50% for both groups throughout the course of the trial. The number of adverse events was also comparable between patients treated with nicotinamide versus placebo, with most common being infections of the skin, respiratory tract, and urinary tract. Three systemic neoplasms were observed in the placebo group, compared to one in the group treated with nicotinamide.
Reported limitations of the trial included a relatively small sample size, which was less than the target sample size of 254 needed to yield of power of 80%. The study ultimately was stopped prematurely at the one-year mark due to similar rates of NMSCs at the 12 month mark. Researchers postulated that high proportions of concomitant immunosuppressant use by patients may have contributed to high levels of suppression of antitumor immunity and DNA-repair, overpowering the ability of nicotinamide to reduce the formation of NMSCs.
Following the study, researchers concluded that additional studies were needed to assess the efficacy of nicotinamide for reducing NMSCs in post-transplant patients, despite an excellent safety profile. Authors recommended studies with larger sample sizes that focus solely on patients receiving therapy with mTOR inhibitors, in order to avoid the excessive suppression of DNA repair seen with traditional immunosuppressants commonly used in post-transplantation patients.
This article is a review of: Allen NC, Martin AJ, Snaidr VA, et al. Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients. N Engl J Med. 2023;388(9):804-812. doi:10.1056/NEJMoa2203086
