VITAL Trial Suggests Vitamin D Supplementation Reduces Incidence of Advanced Cancer

A secondary analysis of the randomized, double-blind, placebo-controlled, 2 x 2 factorial VITAL clinical trial of daily high-dose vitamin D supplementation for 5 years suggested that supplementation with vitamin D reduced the incidence of advanced cancer in the overall study population of adults without a diagnosis of cancer at baseline, with the strongest risk reduction seen in individuals with normal weight.¹

Even if the observed effects of vitamin D were modest, the researchers suggested that vitamin D supplementation at the studied levels are much less toxic and lower cost than many current cancer therapies.

"These findings suggest that vitamin D may reduce the risk of developing advanced cancers," corresponding author Paulette Chandler, MD, MPH, a primary care physician and epidemiologist in the Brigham's Division of Preventive Medicine, said in a press release.² "Vitamin D is a supplement that's readily available, cheap and has been used and studied for decades. Our findings, especially the strong risk reduction seen in individuals with normal weight, provide new information about the relationship between vitamin D and advanced cancer."

The multicenter VITAL clinical trial was conducted in the US and participants included men aged 50 years or older and women aged 55 years or older who were free of cancer and cardiovascular disease at baseline. To test the independent effects of vitamin D and omega-3 supplements as well as to test for synergy between the 2, participants were divided into 4 groups: vitamin D (2000 IU/day) plus omega-3s; vitamin D plus placebo; omega-3s plus placebo; and placebos for both. Primary end points were major adverse cardiovascular events and incidence of cancer.

The primary end point for the secondary analysis was a composite incidence of metastatic and fatal invasive total cancer, because the main VITAL study showed a possible reduction in fatal cancer with vitamin D supplementation and effect modification by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) for total cancer incidence reduction for individuals with normal BMI, but not for individuals who were overweight or obese.

Among a total of 25,871 randomized participants (51% female; mean [SD] age, 67.1 [7.1] years), 1617 were diagnosed with invasive cancer over a median intervention period of 5.3 years (range, 3.8-6.1 years). Overall, 12,927 were randomized to receive vitamin D and 12,944 were assigned to placebo. As previously observed, no significant differences for cancer incidence by treatment arm were reported.

However, researchers found a significant reduction in advanced cancers for those who were randomized to vitamin D compared with placebo (226 assigned to vitamin D [1.7%] and 274 to placebo [2.1%]; HR, 0.83; 95% CI, 0.69-0.99; P = .04). Moreover, when stratified by BMI, there was a significant reduction observed for the vitamin D arm regarding the incidence of metastatic or fatal cancer among those with normal BMI (BMI 24-<30: HR, 0.89; 95% CI, 0.68-1.17; BMI ≥30: HR, 1.05; 95% CI, 0.74-1.49) (P = .03 for interaction by BMI).

"Our findings, along with results from previous studies, support the ongoing evaluation of vitamin D supplementation for preventing metastatic cancer – a connection that is biologically plausible," added Chandler. "Additional studies focusing on cancer patients and investigating the role of BMI are warranted."

In an editorial written by Lina Zgaga, PhD, of the Department of Public Health and Primary Care at the Institute of Population Health at Trinity College Dublin in the Republic of Ireland, Zgaga suggested that because it is difficult to eliminate the possibility that in some cases carcinogenesis began before the trial commenced, it could be argued that vitamin D affected cancer progression and not necessarily occurrence.³ Thus, further investigation is necessary.

However, Zgaga also indicated that very large differences in vitamin D status can be found in any population. A range of lifestyle, personal, and genetic factors affect vitamin D status, and these together drive the heterogeneity of treatment effects primarily by determining baseline levels and the 25-hydroxyvitamin D response to supplementation. Therefore, it is difficult to provide conclusive evidence of the benefit of vitamin D.

“The purpose of an [randomized clinical trial; RCT] is to provide conclusive evidence of the effect of a treatment,” Zgaga concluded. “Given the expected variability of treatment effects, how can an RCT using fixed-dose vitamin D supplementation provide definitive evidence of the benefit? Maybe it is time to consider a study design that can accommodate heterogeneity of treatment effects without compromising the strength of evidence.”

References:

1. Chandler PD, Chen WY, Ajala ON, et al. Effect of Vitamin D3 Supplements on Development of Advanced Cancer. JAMA Network Open. doi: 10.1001/jamanetworkopen.2020.25850

2. Vitamin D supplements may reduce risk of developing advanced cancer [news release]. Brigham and Women’s Hospital. Published November 18, 2020. Accessed November 30, 2020. https://www.newswise.com/articles/vitamin-d-supplements-may-reduce-risk-of-developing-advanced-cancer?sc=mwhr&xy=10019792

3. Zgaga L. Heterogeneity of the Effect of Vitamin D Supplementation in Randomized Controlled Trials on Cancer Prevention. JAMA Network Open. doi: 10.1001/jamanetworkopen.2020.27176