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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.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan.

    ,

    Department of Surgery, International University of Health and Welfare Hospital, Tochigi, Japan.

    ,

    Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan.

    ,

    Department of Pathology, International University of Health and Welfare Hospital, Tochigi, Japan.

    ,

    Department of Surgery, International University of Health and Welfare Hospital, Tochigi, Japan.

    ,

    Department of Surgery, International University of Health and Welfare Hospital, Tochigi, Japan.

    Department of Surgery, International University of Health and Welfare Hospital, Tochigi, Japan.

    Source

    JAMA 321:14 2019 04 09 pg 1361-1369

    MeSH

    Administration, Oral
    Adult
    Aged
    Aged, 80 and over
    Cholecalciferol
    Dietary Supplements
    Disease-Free Survival
    Double-Blind Method
    Female
    Gastrointestinal Neoplasms
    Humans
    Male
    Middle Aged
    Neoplasm Recurrence, Local
    Polymorphism, Single Nucleotide
    Postoperative Care
    Proportional Hazards Models
    Survival Analysis
    Treatment Outcome
    Vitamin D
    Vitamins

    Pub Type(s)

    Comparative Study
    Journal Article
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    30964526

    Citation

    Urashima, Mitsuyoshi, et al. "Effect of Vitamin D Supplementation On Relapse-Free Survival Among Patients With Digestive Tract Cancers: the AMATERASU Randomized Clinical Trial." JAMA, vol. 321, no. 14, 2019, pp. 1361-1369.
    Urashima M, Ohdaira H, Akutsu T, et al. Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers: The AMATERASU Randomized Clinical Trial. JAMA. 2019;321(14):1361-1369.
    Urashima, M., Ohdaira, H., Akutsu, T., Okada, S., Yoshida, M., Kitajima, M., & Suzuki, Y. (2019). Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers: The AMATERASU Randomized Clinical Trial. JAMA, 321(14), pp. 1361-1369. doi:10.1001/jama.2019.2210.
    Urashima M, et al. Effect of Vitamin D Supplementation On Relapse-Free Survival Among Patients With Digestive Tract Cancers: the AMATERASU Randomized Clinical Trial. JAMA. 2019 04 9;321(14):1361-1369. PubMed PMID: 30964526.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract Cancers: The AMATERASU Randomized Clinical Trial. AU - Urashima,Mitsuyoshi, AU - Ohdaira,Hironori, AU - Akutsu,Taisuke, AU - Okada,Shinya, AU - Yoshida,Masashi, AU - Kitajima,Masaki, AU - Suzuki,Yutaka, PY - 2019/10/09/pmc-release PY - 2019/4/10/entrez PY - 2019/4/10/pubmed PY - 2019/4/23/medline SP - 1361 EP - 1369 JF - JAMA JO - JAMA VL - 321 IS - 14 N2 - 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. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/30964526/Effect_of_Vitamin_D_Supplementation_on_Relapse_Free_Survival_Among_Patients_With_Digestive_Tract_Cancers:_The_AMATERASU_Randomized_Clinical_Trial_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2019.2210 DB - PRIME DP - Unbound Medicine ER -