Effect of Vitamin D Supplements on Relapse of Digestive Tract Cancer with Tumor Stromal Immune Response: A Secondary Analysis of the AMATERASU Randomized Clinical Trial

SIMPLE SUMMARY: Clinical evidence suggesting the beneficial effects of vitamin D supplementation on survival of patients with cancer has been accumulating. More tumoral immune cells have been shown to be associated with a longer survival time; however, interactions among vitamin D supplementation, intratumoral immune cells, and cancer relapse have not yet been elucidated. The aim was to assess the effects of vitamin D supplementation on relapse in patients with digestive tract cancer showing an immune response in the tumor. A secondary analysis of a randomized clinical trial including 372 patients was performed. In the higher half subgroup of CD56+ immune cells infiltrating in tumor stroma, the relapse ratio was significantly lower in the vitamin D group (7.4%), than in the placebo group (20.5%), whereas in the lower half subgroup, relapse ratio was not different. Vitamin D supplementation may reduce the risk of relapse in patients who already had adequate infiltration of immune cells in their tumor stroma. ABSTRACT: The aim was to examine whether vitamin D supplementation (2000 IU/day) reduces the risk of relapse in a subgroup of patients with digestive tract cancer, showing a sufficient immune response in tumor stroma by conducting secondary subgroup analyses of the AMATERASU randomized, double-blind, placebo-controlled trial (UMIN000001977). A total of 372 patients were divided into two subgroups stratified by the median density of immune cells infiltrating in tumor stroma into higher and lower halves. In the higher-half subgroup of CD56+ cells, the relapse ratio was significantly lower in the vitamin D group (7.4%) than in the placebo group (20.5%) (subdistribution hazard ratio (SHR), 0.35; 95% confidence interval (CI), 0.15–0.82), but it was equivalent (25.2% vs. 22.7%) in the lower-half subgroup of CD56+ cells (SHR, 1.21; 95% CI, 0.68–2.19) with a significant interaction (P(interaction) = 0.02). Although there were no significant differences, the risk of relapse was lower in the vitamin D group than in the placebo group in the higher half of CD45RO+ memory T cells (8.9% vs. 19.2%), and of CD8+ cytotoxic T cells (11.3% vs. 22.5%). In patients with digestive tract cancer, vitamin D supplementation was hypothesized to reduce the risk of relapse in the subgroup of patients who already have an adequate infiltration of immune cells in their tumor stroma.