Daily supplementation with vitamin D3 and/or an omega-3 fatty acid supplement containing both EPA and DHA, along with a simple home exercise program, may cumulatively reduce the risk of all types of cancer, according to a study recently published in Frontiers in Nutrition.

Known as DO-HEALTH, this three-year, multicenter, double-blind, randomized-controlled clinical trial recruited 2,157 community-dwelling older adults. The authors specifically focused on older adults within an age range in which cancer incidences markedly increase, and examined the outcomes of supplementation with these two nutrients along with exercise both separately and in combination, as very few studies have taken this multi-pronged approach to date.

The participants were randomized into several groups, in order to investigate the role that daily supplementation with standard dosages of 1,000 IU vitamin D or 1 g of omega3s (which contained 500 g of EPA and DHA in a ratio of 1:2) could play on their own, or together, both with and without engagement in an exercise program. These six supplementation groups were compared against one control group which was not assigned to an exercise program and took a placebo.

At baseline, 40.7% of the participants had serum vitamin D concentrations below 20 ng/mL, which is considered insufficient. About 83% of the participants in the study were at least moderately physically active.

Study Results

Following the three-year intervention period, the authors of the study reported that there were 81 verified invasive cancer incidences (along with 29 unverified cases) among the participants. Cancer mortality was not a predefined endpoint, and only eight cases among the population were deadly. At this point, the authors of the study were able to calculate adjusted hazard ratios against the control groups which were taking placebos and not exercising.

According to the authors, there were very low numbers of site-specific cancers, and this data may not be reliable. None of the treatments individually or in combination reduced gastrointestinal cancers, or breast cancer in women. However, it was suggested that omega-3s alone or in combination with exercise may reduce prostate cancer risk, but these numbers were low and should be interpreted with caution.

For single-treatment groups, those who took vitamin D3 were 24% less likely to receive a cancer diagnosis; those who took omega-3s saw a 30% reduced cancer risk; and those who simply exercised were 26% less likely to receive a cancer diagnosis.

The results indicated that any combination of multiple treatments being investigated had a cumulative effect on cancer risk in the study population.

Those who took both omega-3s and vitamin D3 were 47% less likely to receive a cancer diagnosis compared to the control group. For those who had a combined regimen of vitamin D3 and exercise, they were 44% less likely to receive a cancer diagnosis. For those who took omega-3s and exercised, a 48% risk reduction in cancer diagnosis was observed. However, aside from the omega-3s and exercise combination group, any single or dual treatment group did not have numbers high enough to reach clinical significance.

Finally, compared to placebo, a participant who took both vitamin D and omega-3 in conjunction with an exercise program was 61% less likely than a participant in the control group to receive a cancer diagnosis.

“In this multicenter clinical trial among generally healthy and active older adults at their peak of age-related cancer risk, high-dose daily vitamin D3, supplemental marine omega-3s, and a simple home exercise program had cumulative benefits on the risk of any invasive cancer,” the authors of the study concluded. “This benefit was consistent in sensitivity analyses that excluded adults with a history of cancer, reflecting primary prevention, and when also unverified reported cancer cases were included. Assessing the effect of both the individual and combined benefit of interventions in the prevention of cancer in a large clinical trial is a rather novel approach.

The authors of the study concluded that these findings might encourage further clinical studies evaluating multi-modal treatment options for cancer prevention. “Future studies should verify the benefit of combined treatments in the prevention of cancer, also extending to longer follow-ups beyond the three-year duration assessed in this trial,” they said. 

The Broader Context

Harry Rice, vice president of regulatory and scientific affairs for the Global Organization for EPA and DHA Omega-3s (GOED) discussed the implications of these findings, and the broader context in which this trial exists.

“While the results cannot be generalized to other populations without additional research, that doesn’t discount how impressive they are in this population,” Rice told Nutraceuticals World. “Let’s put the current results into clinical perspective. The number of subjects needed to treat in order to prevent one incident case (occurrence of new cases) of cancer at the three-year follow-up with the three treatments was 35.”

Combination treatments of vitamin D and omega-3s have rarely been studied in this capacity, Rice noted. “When it comes to large-scale trials, the only other study that comes to mind is Vitamin D and Omega-3 Trial (VITAL). While DO-HEALTH was designed as a complementary trial to VITAL for two of the three interventions tested, VITAL did not test the combination of EPA/DHA and vitamin D on reducing the risk of cancer.”

In these two trials thus far, when looking at vitamin D or omega-3s separately, no single treatment has demonstrated clinically-significant cancer prevention benefits, Rice said, noting that future studies should increase both sample size to have more power and extend the duration of the intervention in order to have more cases of cancer and potentially greater impact.

When it comes to potential mechanisms of action, the insight we have today is still “speculative at best,” according to Rice. “When it comes to cancer, inflammation is thought to be a key step in cancer initiation. I would have to say that in vitro and animal studies are going to offer the most insight into the mechanism(s) of action associated with carcinogenesis.”

From the study on the DO-HEALTH group, Rice pointed to three other publications made thus far evaluating the benefits of vitamin D and EPA/DHA supplementation.

One study evaluated the prevalence of healthy aging among community-dwelling, older individuals from five European countries, and offered data on the prevalence of healthy aging as defined by chronic diseases, disabilities, cognitive impairment, or mental health limitation. This study found that 41.8% of DO-HEALTH participants were defined as healthy agers, with significant variability by country.

Another study, published in February, found an association between high baseline levels of EPA and DHA and subjects was associated with a reduced likelihood of experiencing a fall at baseline, suggesting a protective benefit. “Also, supplemental EPA/DHA versus placebo reduced the incidence rate of total falls by 10%,” Rice said, “with a subgroup analysis revealing that participants with higher EPA/DHA levels at baseline had an even lower incidence rate of falls of 17%. This suggests that achieving the best results requires one to focus on increasing EPA/DHA intake earlier, rather than later, in life.”

The first publication on the DO-HEALTH group, published in 2020, initially found no significant results when looking at these three interventions in the context of clinical outcomes including blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function.

“It’s also worth mentioning that DO-HEALTH is going to assess the three interventions’ cost-benefit in a health economic model based on documented health care utilization and observed incidence of chronic disease,” Rice said.