Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers

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 D 3 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-baselinelevel 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.

Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3

“…Vitamin D has been found to have antitumour effects, suggesting that it might inhibit the progression of rectal cancer 10 , breast cancer 11 , pancreatic cancer 12,13 , head and neck cancers 14 and other cancers. Urashima 15 suggested that the higher the serum level of vitamin D is, the better is the prognosis of rectal cancer patients. However, the effects of vitamin D in chemotherapy remain unknown.…”

Serum Bioavailable, Rather Than Total, 25‐hydroxyvitamin D Levels Are Associated With Hepatocellular Carcinoma Survival

“…(9) In addition, two recent RCTs suggest that patients with digestive tract cancers, especially colorectal cancer, may benefit from vitamin D supplementation. (47,48) Our findings indicate that the assessment of vitamin D status using bioavailable instead of total 25OHD levels would aid in the identification of individuals who are most likely to benefit from vitamin D supplementation.…”

Effect of Vitamin D Supplementation on Survival of Digestive Tract Cancer Patients with Low Bioavailable 25-Hydroxyvitamin D Levels: A Post Hoc Analysis of the AMATERASU Randomized Clinical Trial

“…In this post hoc analysis using residual serum samples and clinical data from the AMATERASU trial, we aimed to explore whether vitamin D supplementation improved survival in a subgroup of patients with lower than median levels of bioavailable 25(OH)D. Table 1 shows the characteristics of the participants analyzed in this post hoc study. The distribution of variables was similar to the original trial [5]. All patients were Japanese.…”

“…A meta-analysis of 16 prospective cohort studies including more than 100,000 patients showed that higher total 25(OH)D levels in serum were significantly associated with decreased cancer-specific mortality [4] independent of cancer site or pathological subtype. However, contrary to expectations, recent randomized clinical trials (RCTs) have demonstrated that vitamin D supplementation, compared with placebo, did not result in significant improvement of relapse or progression-free survival among the total study population or a subgroup of patients with low total 25(OH)D levels (<20 ng/mL) in digestive tract cancer [5] and advanced or metastatic colorectal cancer [6].…”

“…We previously conducted the AMATERASU randomized, double-blind, placebo-controlled trial of postoperative oral vitamin D3 supplementation (2000 IU/day) in 417 patients with stage I to III digestive tract cancer from the esophagus to the rectum who underwent curative surgery (UMIN000001977) [5]. In this post hoc analysis using residual serum samples and clinical data from the AMATERASU trial, we aimed to explore whether vitamin D supplementation improved survival in a subgroup of patients with lower than median levels of bioavailable 25(OH)D. Table 1 shows the characteristics of the participants analyzed in this post hoc study.…”