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

Educational Objective
To learn whether postoperative vitamin D3 supplementation can improve survival of patients with digestive tract cancers.
1 Credit CME
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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Article Information

Corresponding Author: Mitsuyoshi Urashima, MD, Division of Molecular Epidemiology, Jikei University School of Medicine, Nishi-shimbashi 3-25-8, Minato-ku, Tokyo 105-8461, Japan (urashima@jikei.ac.jp).

Accepted for Publication: February 18, 2019.

Author Contributions: Dr Urashima had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Urashima, Ohdaira, Yoshida, Kitajima, Suzuki.

Acquisition, analysis, or interpretation of data: Urashima, Akutsu, Okada, Yoshida.

Drafting of the manuscript: Urashima, Ohdaira, Yoshida, Kitajima.

Critical revision of the manuscript for important intellectual content: Akutsu, Okada, Suzuki.

Statistical analysis: Urashima, Yoshida.

Obtained funding: Urashima, Yoshida.

Administrative, technical, or material support: Ohdaira, Akutsu, Okada, Suzuki.

Supervision: Okada, Kitajima.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research was supported by the Ministry of Education, Culture, Sports, Science, and Technology in the Japan-Supported Program for the Strategic Research Foundation at Private Universities, funding from the International University of Health and Welfare Hospital, and Jikei University School of Medicine.

Role of the Funder/Sponsor: None of the funding organizations had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

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