A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients

DEAR EDITOR, Immunosuppressed organ transplant recipients have an 80-fold increased risk of squamous cell carcinoma (SCC) and a 16-fold increased risk of basal cell carcinoma (BCC); SCCs are more aggressive and more likely to metastasize in these pat... show more

DEAR EDITOR, Immunosuppressed organ transplant recipients have an 80-fold increased risk of squamous cell carcinoma (SCC) and a 16-fold increased risk of basal cell carcinoma (BCC); SCCs are more aggressive and more likely to metastasize in these patients. While mammalian target of rapamycin (mTOR) inhibitors may help reduce the incidence of SCC, the current mainstay of nonmelanoma skin cancer (NMSC) chemoprevention post-transplant is oral retinoids, which have side-effects, including liver and lipid abnormalities, mucocutaneous dryness and teratogenicity. Nicotinamide (vitamin B3) enhances repair of photodamaged DNA and prevents the inhibitory effects of ultraviolet radiation on the immune system without altering baseline immune reponses. In 386 immunocompetent participants at high risk of having skin cancer, nicotinamide 500 mg twice daily reduced new NMSCs by 23% (P = 0 02), with 20% fewer BCCs and 30% fewer SCCs compared with placebo. Actinic keratoses (AKs) were also significantly reduced by nicotinamide in the same phase III randomized controlled trial. However, it is unknown whether nicotinamide prevents NMSCs and is safe in immunosuppressed renal transplant recipients. Eligible adult immunosuppressed participants included those who had received a renal transplant ≥ 12 months ago, had stable renal function and a history of ≥ 2 NMSCs in the previous 12 months. Participants were ineligible if they commenced retinoids or mTOR inhibitors within 6 months, or used nicotinamide supplements or AK field treatments within the 4 weeks prior to enrolment. This double-blind study was conducted at the Royal Prince Alfred Hospital (Sydney, Australia; Australian New Zealand Clinical Trials Registry ACTRN12612000628842) after ethical approval was received. All participants provided written informed consent. Participants were enrolled (by A.C.C. and R.A.D.) and randomized 1:1 to receive either nicotinamide 500 mg twice daily or matched placebo (Insolar; Blackmores, Warriewood, Australia) by centralized randomization (permuted blocks; National Health and Medical Research Council Clinical Trials Centre) stratified by lifetime NMSC history (< 6 or ≥ 6 NMSCs), oral retinoid use and mTOR inhibitor use. Compliance was monitored by tablet counts at each visit (A.C.C). Skin cancer checks were performed at baseline and twice monthly up to 6 months by dermatologists blinded to treatment allocation (D.L.D., P.M.L.). AKs on the face, scalp, forearms and hands were counted at baseline and twice monthly up to 6 months by a dermatology Fellow blinded to allocation (A.C.C). All squamous lesions were reviewed by a single (blinded) histopathologist (C.A.M.) to ensure consistent reporting of SCC differentiation. Blood and urine samples were taken at baseline, 2 and 4 weeks, and 2, 4 and 6 months for full blood count, electrolytes, renal and liver function tests, drug levels and urine microalbumin/creatinine ratio. Blood pressure and weight were measured at baseline and twice monthly for 6 months. The primary end point was the number of new NMSCs (BCC + SCC, including invasive and in situ SCC) up to 6 months. Secondary end points included new BCCs, new SCCs, AK counts up to 6 months and safety. The planned sample size was 80 participants, in order to provide 80% power to detect a 50% reduction in the 6-month NMSC rate at the 5% level of significance, assuming that NMSC counts followed a Poisson distribution with a mean of 1 5 for the placebo group, allowing for ≤ 10% noncompliance. However, owing to slow recruitment because of an overestimation of the eligible participant population at our site, the study was stopped early; 22 participants were recruited over 1 5 years. Analyses were by intention to treat. As per the provision specified in the statistical analysis plan, a negative binomial model was used to analyse NMSC, SCC and BCC data, owing to overdispersion that rendered the Poisson model inappropriate. Models included an offset term to account for variation in follow-up duration. The 2-monthly postbaseline AK data were analysed using a mixed model for repeated measures, including treatment group, baseline value, time point and a time-by-treatment group interaction as covariates. From August 2012 to March 2014, 25 participants were assessed for eligibility and 22 were randomized [11 in each group; Figure S1 (see Supporting Information)]. The groups had similar baseline characteristics (Table 1). Follow-up was from August 2012 to August 2014. Median compliance was 93% and 98% for the placebo and nicotinamide groups, respectively. The 6-month NMSC rate was not significantly lower for the nicotinamide group [mean 2 7, 95% confidence interval (CI) 1 4–5 3; total 30 cancers] compared with placebo (mean 4 2, 95% CI 2 2–7 8; total 45 cancers); however, the numeric trend was dominated by one patient in the placebo group show less