Effect Modification by Serum Vitamin A Levels on the Association Between Vitamin D and Relapse or Death in Patients with Digestive Tract Cancer

Abstract Background:Vitamin D interacts with vitamin A through receptor heterodimerization. This post hoc analysis of the AMATERASU randomized clinical trial (RCT) of vitamin D₃ supplementation examined whether serum vitamin A levels modify the association of vitamin D with relapse or death in patients with digestive tract cancer. Methods:The primary outcome was relapse or death. Relapse-free survival was evaluated using Nelson–Aalen cumulative hazard functions and Cox proportional hazards models. Serum vitamin A levels were categorized stepwise using clinical reference ranges and quantile cutoffs (halves, tertiles, quartiles, quintiles, and deciles), with post hoc grouping of the most coherent quantiles for analysis. Results:Among 363 patients (mean age, 66 years; 67.8% male), serum vitamin A ranged from 0.15–4.30 µmol/L (median IQR, 1.38 1.05–1.74) and correlated positively with 25(OH)D (ρ = 0.31; P 0.0001). Patients in the lowest decile had higher relapse or death risk (HR, 2.05; 95% CI, 1.10–3.84; P =0.03) than those in deciles 2–10. In the middle range (deciles 6–8), 5-year relapse-free survival was greater with vitamin D vs placebo (81.4% vs 54.9%; HR, 0.31; 95% CI, 0.14–0.69; P =0.004), with no effect in lower (deciles 1–5) or higher (deciles 9–10) ranges (Pinteraction =0.008). Conclusions:Vitamin D supplementation may reduce relapse and death among patients with middle-to-upper range serum vitamin A levels. Impact:These exploratory findings provide the first RCT evidence that serum vitamin A levels modify the effect of vitamin D supplementation on relapse or death among patients with digestive tract cancer.