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

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.

Figure 1.. Patient Flow Through the AMATERASU Trial

Figure 2.. Effect of Vitamin D Supplementation on Outcomes

Nelson-Aalen cumulative hazard curves are shown for (A) relapse or death and (B) total deaths. In panel C, the cumulative incidence of relapse is compared between the vitamin D and placebo groups by considering patient deaths due to causes other than relapse as the competing risk. Median observation times for relapse or death were, for placebo, 3.0 (interquartile range [IQR], 1.9-4.5) years, and for vitamin D, 3.3 (IQR, 1.9-5.3) years; for total deaths, for placebo, 3.5 (IQR, 2.3-5.0) years, and for vitamin D, 3.5 (IQR, 2.3-5.4) years; and for relapse by competing-risk analysis, for placebo, 3.0 (IQR, 1.9-4.5) years, and for vitamin D, 3.3 (IQR, 1.9-5.3) years.

Figure 3.. Subgroup Analysis

Nelson-Aalen cumulative hazard curves are shown for relapse or death in the subgroups of (A) middle (20-40 ng/mL) and (B) low (<20 ng/mL) serum hydroxyvitamin D (25[OH]D) baseline levels and for total deaths in the subgroups of (C) middle and (D) low serum 25(OH)D baseline levels. There were only 5 patients with high (>40 ng/mL) 25(OH)D baseline levels; this group was not evaluated. Numbers at risk for panel C are not given because of weighting. Median observation times for relapse or death in the middle 25(OH)D subgroup were, for placebo, 3.4 (interquartile range [IQR], 1.9-4.5) years, and for vitamin D, 3.8 (IQR, 2.4-5.3) years; and in the low 25(OH)D subgroup, for placebo, 2.8 (IQR, 1.8-4.4) years, and for vitamin D, 2.5 (IQR, 1.6-5.2) years. Median observation times for total deaths in the middle 25(OH)D subgroup were, for placebo, 3.5 (IQR, 2.3-5.0) years, and for vitamin D, 3.8 (IQR, 2.5-5.4) years; and in the low 25(OH)D subgroup, for placebo, 3.4 (IQR, 2.1-5.0 years), and for vitamin D, 3.3 (IQR, 1.9-5.4) years.