Does Vitamin D Supplementation Impact Relapse-Free Survival in GI Cancers? Interview with:
Mitsuyoshi Urashima MD, PhD, MPH
Professor of Molecular Epidemiology
Jikei University School of Medicine
Tokyo, JAPAN What is the background for this study?  

Response: Serum levels of vitamin D, increase in response to exposure to sunlight, a vitamin D-rich diet, or vitamin D supplementation. In 1989, the risk of colon cancer was estimated to be 70% lower in people with serum vitamin D levels ≥ 20 ng/mL, compared with those < 20 ng/mL.

In a cohort study, higher vitamin D levels were associated with lower total cancer incidence and lower total cancer mortality, particularly digestive system cancer mortality. However, because of the studies’ observational nature, whether lower levels of vitamin D is merely a precursor to relapse and death or causally related to shorter survival cannot be determined.

To clarify this, a randomized, double-blind, placebo-controlled trial using vitamin D supplement was performed in patients with digestive tract cancer from esophagus to rectum; this is the first trial designed to evaluate the effect of vitamin D on survival of these patients. What are the main findings? 

Response: The 417 patients were randomized to receive oral supplemental capsules of vitamin D (2000 IU/day, n=251) or placebo (n=166) from the first postoperative outpatient visit to until the end of the trial. The 5-year relapse-free survival was 77% vs 69%; hazard ratio for relapse or death, 0.76; 95% CI, 0.50 -1.14; P = 0.18. In a subgroup of patients with serum 25(OH)D levels between 20 and 40 ng/mL at baseline, the 5-year relapse-free survival was 85% vs 71%; Hazard ratio for relapse or death, 0.46; 95%CI, 0.24-0.86; P=0.02; Pinteraction=0.04. The relatively high dose vitamin D did not appear to be associated with frequent adverse events. What should readers take away from your report?

Response: 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 in total study population. What recommendations do you have for future research as a result of this work?

Response: Although main conclusion was null as described above, a significant interaction was detected in a subgroup of patients with middle serum vitamin D levels at baseline. Moreover, the cumulative hazard rate of relapse or death was significantly less for the vitamin D group compared with the placebo group in adjustment with age, because patients allocated into vitamin D group were significantly older than placebo by chance.

Since it seemed hard for participants to continue taking supplements during years, decreased adherence may have caused a bias toward null results. In addition, survival curves were overlapped for first 18 months, which may imply that vitamin D is needed to take for at least the first 18 months to exert anti-tumor effects. Thus, we should not totally deny improving effects of vitamin D supplementation on prognosis of patients with cancers, but should keep this type of randomized trials by a greater number of patients with high adherence. Is there anything else you would like to add?

Amaterasu emerging from the cave, Ama-no-Iwato, to which she once retreated (painted by Kunisada)- Wikipedia image.jpg
AMATERASU is the name of famous Japanese sun god, described in Japanese myths. When she was hided inside of rock door, the entire world turned to dark. Because vitamin D is produced under the skin by exposing to sunshine and this is a trial performed in Japan, we named this trial as AMATERASU project.

Any disclosures? The authors do not have any potential conflicts of interests to declare. Both vitamin D and placebo supplements were purchased from Zenyaku Pharmaceutical Co., Ltd., Tokyo, Japan. We have performed this trial without any supports by pharmaceutical or supplemental companies. 


Urashima M, Ohdaira H, Akutsu T, et al. Effect of Vitamin D Supplementation on Relapse-Free Survival Among Patients With Digestive Tract CancersThe AMATERASU Randomized Clinical TrialJAMA.2019;321(14):1361–1369. doi:10.1001/jama.2019.2210 

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Last Updated on April 9, 2019 by Marie Benz MD FAAD