May 03, 2019
8 min read

Vitamin D supplementation shows limited benefit in patients with gastrointestinal cancers

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Vitamin D3 supplementation moderately prolonged PFS and, to a limited extent, RFS among patients with certain gastrointestinal cancers, according to results of two separate studies published in JAMA.

The randomized phase 2 SUNSHINE trial examined the impact of high-dose vs. standard-dose vitamin D3 supplementation during chemotherapy on PFS among patients with advanced or metastatic colorectal cancer. The researchers found no statistically significant difference in PFS when comparing groups treated with either dose; however, multivariate analysis revealed a statistically significant lower risk for disease progression or death among patients in the high-dose vitamin D3 group.

The randomized, single-center AMATERASU trial evaluated RFS among patients with stage I to stage III digestive tract cancers who received vitamin D3 supplementation or placebo. The study showed a slight, albeit not statistically significant, increase in 5-year RFS among those who received vitamin D3.

Kimmie Ng, MD, MPH
Kimmie Ng

“Vitamin D has demonstrated antiproliferative, antiangiogenic, proapoptotic, anti-inflammatory and immunomodulatory effects in cell lines and animal models of colon cancer. Epidemiologic studies in patients have also shown an association between higher plasma levels of vitamin D and improved survival in colorectal cancer and, in particular, in metastatic colorectal cancer,” Kimmie Ng, MD, MPH, director of clinical research at Dana-Farber Cancer Institute and lead author of the SUNSHINE study, told HemOnc Today.


In the double-blind, multicenter SUNSHINE trial, Ng and colleagues randomly assigned 139 patients (mean age 56 years; 43% women) with advanced or metastatic colorectal cancer in a 1:1 ratio to receive high-dose vitamin D3 (loading dose of 8,000 IU/day for the first cycle, followed by 4,000 IU/day for subsequent chemotherapy cycles) or standard-dose vitamin D3 (400 IU/day) plus concurrent chemotherapy.

Median follow-up was 22.9 months (interquartile range [IQR], 11.8-34.5).

Results showed median PFS of 13 months (95% CI, 10.1-14.7; 49 PFS events) for those who received high-dose vitamin D3 compared with 11 months (95% CI, 9.5 to 14; 62 PFS events) for those in the standard-dose group. Multivariable HR for PFS or death was 0.64 (1-sided 95% CI, 0-0.9).

Researchers observed no significant differences between the high-dose and standard-dose groups in tumor objective response rate (58% vs. 63%) or median OS (24.3 months for both groups).

“High-dose vitamin D3 supplementation improved PFS when added to standard chemotherapy for patients with previously untreated, metastatic colorectal cancer,” Ng told HemOnc Today. “Even after controlling for potentially confounding variables, high-dose vitamin D3 led to a significant 36% improvement in PFS.”



The double-blind, placebo-controlled AMATERASU trial included 417 participants (mean age, 66 years; 66% men) randomly assigned in a 3:2 ratio to receive either 2,000 IU/day vitamin D3 or placebo after undergoing surgical resection for a digestive tract cancer (esophageal, 10%; gastric, 42%; colorectal, 48%).

Researchers followed patients for a median of 3.5 years (IQR, 2.3-5.3 years), with a maximum follow-up period of 7.6 years.

Results showed 5-year RFS of 77% for those in the vitamin D3 group compared with 69% in the placebo group (HR for relapse or death = 0.76; 95% CI, 0.5-1.14). Relapse or death occurred among 50 patients (20%) in the vitamin D3 group compared with 43 patients (26%) in the placebo group. The death rate of 15% was identical in both groups (n = 37 in vitamin D3 group vs. n = 25 in placebo group).

Five-year OS was 82% in the vitamin D3 group compared with 81% in the placebo group (HR for death = 0.95; 95% CI, 0.57-1.57).

Although the differences in OS and RFS did not reach statistical significance, there was a significant increase in 5-year RFS when broken down by patients’ baseline serum 25(OH)D levels. Five-year RFS for patients with a serum 25(OH)D level between 20 ng/mL and 40 ng/mL was 85% in the vitamin D3 group compared with 71% in the placebo group (HR for relapse or death = 0.46; 95% CI, 0.24-0.86).

Mitsuyoshi Urashima MD, PhD, MPH, professor of molecular epidemiology at Jikei University School of Medicine in Tokyo and lead author of the AMATERASU study, told HemOnc Today that the overall eight percentage-point difference in RFS, although not statistically significant, suggests there is a role for vitamin D3 supplementation in the treatment of gastrointestinal cancers.

“Vitamin D is not effective in all patients with cancer, but [it] may improve the prognosis [for some] patients with cancer,” Urashima said.

Clinical impact

Ng told HemOnc Today that her group’s results need confirmation from the larger randomized phase 3 SOLARIS trial that will begin later this year through the Alliance for Clinical Trials in Oncology cooperative group.

“In the current era of very expensive and often quite toxic chemotherapy and targeted drugs, vitamin D represents a potentially important addition to the armamentarium of treatment options for [patients with] colorectal cancer, particularly with respect to safety and cost,” she said. “Consequently, if our results are confirmed in the upcoming large phase 3 randomized trial opening later this year, then this research will have a global impact on the care of patients with colorectal cancer.”


Urashima touted vitamin D3’s low cost, safety and availability as reasons why it should be considered as a supplement to cancer therapies, despite the limited association with RFS seen in his group’s study.

“In contrast to adjuvant chemotherapy and molecular targeting medicine, vitamin D is a natural compound that is essentially nontoxic and cost-effective to produce. By simply being exposed to sunlight (eg, exercising outside), patients can increase their 25-hydroxyvitamin D levels at no cost and may potentially decrease the risk for relapse and improve survival,” he told HemOnc Today. “Because vitamin D has few side effects, prescribing vitamin D3 for patients may be a good choice even if the effect of vitamin D on the survival of patients with cancer [is] not significant.”

In an editorial accompanying the studies, Elizabeth L. Barry, PhD, associate professor of epidemiology at Geisel School of Medicine at Dartmouth, and colleagues found the results of both studies to be similar with respect to PFS and RFS, with null results for OS.

“It may be tempting to interpret the preliminary findings regarding recurrence- and progression-free survival as specific antineoplastic effects of vitamin D3 supplementation,” Barry and colleagues wrote. “However, higher vitamin D levels have been associated with substantially decreased mortality and morbidity among hospitalized patients with a range of non-neoplastic diseases as well as with cancer. Thus, the findings of the two trials may reflect relatively broad biological effects of vitamin D.”

Barry and colleagues said further trials with longer follow-up and biological measurements “to clarify underlying mechanisms” are needed to evaluate and confirm the findings of both studies. – by Drew Amorosi


For more information:

Kimmie Ng, MD, MPH, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email:

Mitsuyoshi Urashima MD, PhD, MPH, can be reached at Division of Molecular Epidemiology, Jikei University School of Medicine, Nishi-shimbashi 3-25-8, Minato-ku, Tokyo 105-8461, Japan; email:

Disclosure: Ng reports grants from Celgene, Consano, Genentech, Gilead Sciences, NCI, Pharmavite, Tarrex Biopharma and Trovagene; and personal fees from Bayer, Eli Lilly, Genentech, Seattle Genetics and Tarrex Biopharma. Urashima reports no relevant financial disclosures. Please see the studies for all other authors’ relevant financial disclosures. Barry and the other editorial authors report no relevant financial disclosures.



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