Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers
Authors: Mitsuyoshi Urashima, Hironori Ohdaira, Taisuke Akutsu, Shinya Okada, Masashi Yoshida, Masaki Kitajima, Yutaka Suzuki
Journal: JAMA (2019)

<h3>Importance</h3> Randomized clinical trials of vitamin D supplementation for secondary prevention in patients with cancer are needed, given positive results of observational studies. <h3>Objective</h3> To determine whether postoperative vitamin D<sub>3</sub>supplementation can improve survival of patients with digestive tract cancers overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. <h3>Design, Setting, and Participants</h3> The AMATERASU trial, a randomized, double-blind, placebo-controlled trial conducted at a single university hospital in Japan. Enrollment began in January 2010 and follow-up was completed in February 2018. Patients aged 30 to 90 years with cancers of the digestive tract from the esophagus to the rectum, stages I to III, were recruited. Of 439 eligible patients, 15 declined and 7 were excluded after operation. <h3>Interventions</h3> Patients were randomized to receive oral supplemental capsules of vitamin D (2000 IU/d; n = 251) or placebo (n = 166) from the first postoperative outpatient visit to until the end of the trial. <h3>Main Outcomes and Measures</h3> The primary outcome was relapse-free survival time to relapse or death. The secondary outcome was overall survival time to death due to any cause. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/mL, and greater than 40 ng/mL; because of small sample size for the highest-baseline-level group, interactions were tested only between the low- and middle-baseline-level groups. <h3>Results</h3> All 417 randomized patients (mean age, 66 years; male, 66%; esophageal cancer, 10%; gastric cancer, 42%; colorectal cancer, 48%) were included in the analyses. There was 99.8% follow-up over a median 3.5 (interquartile range, 2.3-5.3) years, with maximal follow-up of 7.6 years. Relapse or death occurred in 50 patients (20%) randomized to vitamin D and 43 patients (26%) randomized to placebo. Death occurred in 37 (15%) in the vitamin D group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77% with vitamin D vs 69% with placebo (hazard ratio [HR] for relapse or death, 0.76; 95% CI, 0.50-1.14;<i>P</i> = .18). The 5-year overall survival in the vitamin D vs placebo groups was 82% vs 81% (HR for death, 0.95; 95% CI, 0.57-1.57;<i>P</i> = .83). In the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL, the 5-year relapse-free survival was 85% with vitamin D vs 71% with placebo (HR for relapse or death, 0.46; 95% CI, 0.24-0.86;<i>P</i> = .02;<i>P</i> = .04 for interaction). Fractures occurred in 3 patients (1.3%) in the vitamin D group and 5 (3.4%) in the placebo group. Urinary stones occurred in 2 patients (0.9%) in the vitamin D group and 0 in the placebo group. <h3>Conclusions and Relevance</h3> Among patients with digestive tract cancer, vitamin D supplementation, compared with placebo, did not result in significant improvement in relapse-free survival at 5 years. <h3>Trial Registration</h3> UMIN Identifier:UMIN000001977