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Original Investigation
April 9, 2019

Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers: The AMATERASU Randomized Clinical Trial

Author Affiliations
  • 1Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan
  • 2Department of Surgery, International University of Health and Welfare Hospital, Tochigi, Japan
  • 3Department of Pathology, International University of Health and Welfare Hospital, Tochigi, Japan
JAMA. 2019;321(14):1361-1369. doi:10.1001/jama.2019.2210
Visual Abstract.
Visual Abstract.
Effect of Vitamin D Supplementation on Relapse-Free Survival in Digestive Tract Cancers
Effect of Vitamin D Supplementation on Relapse-Free Survival in Digestive Tract Cancers
Key Points

Question  Does vitamin D supplementation improve survival among patients with digestive tract cancers?

Findings  In this randomized clinical trial that included 417 patients with digestive tract cancers (from esophagus to rectum), the 5-year relapse-free survival rate for those randomized to vitamin D, 2000 IU/d, vs placebo was 77% vs 69%, a difference that was not statistically significant.

Meaning  Vitamin D supplementation did not improve relapse-free survival among patients with digestive tract cancer.

Abstract

Importance  Randomized clinical trials of vitamin D supplementation for secondary prevention in patients with cancer are needed, given positive results of observational studies.

Objective  To determine whether postoperative vitamin D3 supplementation can improve survival of patients with digestive tract cancers overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels.

Design, Setting, and Participants  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.

Interventions  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.

Main Outcomes and Measures  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.

Results  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; P = .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; P = .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; P = .02; P = .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.

Conclusions and Relevance  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.

Trial Registration  UMIN Identifier: UMIN000001977

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