Despite enticing data, future of vitamin D in cancer therapy remains unknown

 Observational studies show a potential role in prevention and treatment, but many experts say more evidence is needed.

The attention paid to vitamin D by the general public and the medical research community has grown substantially in the past decade.

This is due in part to the plethora of observational research studies and clinical laboratory studies that have suggested vitamin D may have health benefits for a variety of diseases, including cancer.

If researchers ultimately prove vitamin D effectively treats and prevents cancer, the medical community would have a readily available and relatively inexpensive wonder “drug.”

“The general appeal of vitamins is that they are thought to be safe, they are seductively simple and they are emotionally appealing,” said Donald L. Trump, MD, president, CEO and professor of oncology at Roswell Park Cancer Institute in Buffalo, N.Y., and a HemOnc Today Editorial Board member.

Still, Trump said some in the oncology community remain hesitant to embark on large studies of vitamin D because they have been disappointed by studying vitamins in the past, most recently by vitamin E. Early research showed it might reduce prostate cancer risk, but a subsequent major trial showed it actually may increase the risk for prostate cancer by as much as 17% among healthy men.

Both the supporters and skeptics who spoke to HemOnc Today agreed that laboratory and clinical studies show vitamin D could have great potential as a cancer treatment and chemopreventive agent. However, they said more evidence is needed from large randomized controlled studies, adding that there is significant disagreement in the field regarding when it should be measured, what levels are normal and what doses should be tested.

Preclinical, observational evidence

Vitamin D traditionally is recognized as an important player in the maintenance of bone health. Over time, research results have led to an expanded view of its possible roles and mechanisms.

“It became increasingly clear that signaling through the vitamin D receptor with either vitamin D analogues or native hormones can influence the growth of cells,” Trump told HemOnc Today. “It is also very clear that the vitamin D receptor is present in many different tissues and influences processes that are likely to be important to cancer.”

More specifically, vitamin D is not just a vitamin but the precursor to a potent steroid hormone that regulates the expression of hundreds of target genes in most tissues of the body, according to David Feldman, MD, professor emeritus in the division of endocrinology at Stanford University School of Medicine.

Among vitamin D’s characteristics are an antiproliferative action, the promotion of differentiation or the normal development of cells, and an immunomodulatory action.

“It is also anti-inflammatory, anti-invasive and anti-angiogenic,” Feldman said. “If you look at all of those activities together, you would think that it would be a terrific drug for cancer.”

However, much of the evidence that proves these actions is derived from clinical and laboratory studies in cells or in mice, and much of the evidence that shows an influence on cancer and cancer outcomes in people is from observational studies or randomized controlled studies in which cancer was not the primary outcome.

The more thought-provoking early studies of vitamin D included those that linked sunlight exposure, a surrogate for vitamin D levels, to cancer mortality. A study published in 1980 revealed that colon cancer mortality rates were highest in locations in the United States that were exposed to the least amount of natural sunlight. In 1992, Hanchette and Schwartz published a study in Cancer that included maps that quantified the amount of ultraviolet light exposure across the country and showed it was inversely related to prostate cancer death among white men.

Current state of research

Because much of the early research into vitamin D is from clinical or observational studies, the NCI has labeled the evidence as “limited and inconsistent.” Most evidence that exists is in the areas of breast, prostate and colorectal cancers.

In breast cancer, epidemiologic studies have conflicting results. Some show an inverse association between vitamin D and breast cancer, whereas others — such as the large Women’s Health Initiative (WHI) trial and a substudy of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial — show no association.

“However, advocates of vitamin D use claim that the WHI trial had too low a dose of vitamin D and did not have long enough follow-up,” said Rowan T. Chlebowski, MD, PhD, medical oncologist at Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, and a self-proclaimed contrarian on the use of vitamin D.

Vitamin D’s association with prostate cancer is similar in that results have been mixed, according to Trump, a genitourinary oncologist.

“There are a large number of preclinical studies that show you can slow growth of prostate cancer cells by treating with the most active forms of vitamin D (1,25-dihydroxyvitamin D3 or calcitriol), and there are studies that show outcome of men with prostate cancer is associated with vitamin D levels at diagnosis,” he said.

However, more research is needed in the clinical arena, an area into which no pharmaceutical company seems willing to invest resources, Trump said.

Research continues to try to elucidate the relationship between colorectal cancer and vitamin D. Again, the results are mixed.

“Right now, there is a lot of epidemiologic data that support an association between higher vitamin D status and lower risk for developing colorectal cancer,” said Kimmie Ng, MD, MPH, assistant professor of medicine at Harvard Medical School.

Ng and colleagues have an interest in the role of vitamin D in the survival of patients who are already diagnosed with colon cancer. In several of their observational studies, they found that higher levels of vitamin D — about 33 ng/mL or higher — seem to be associated with an approximately 50% improvement in survival.

Also, a meta-analysis of five prospective observational studies showed higher plasma levels of vitamin D are associated with a lower risk of colorectal cancer.

“For right now, I do not think that we can recommend vitamin D as a treatment for colon cancer without a randomized controlled trial,” Ng said.

Researchers currently are enrolling patients onto such a trial, which is open at Dana-Farber/Harvard Cancer Center-associated hospitals and soon will expand to several other academic centers nationwide, Ng said.

The trial will randomize 120 patients with previously untreated metastatic colorectal cancer to standard chemotherapy plus a standard dose of vitamin D (400 IU/day) vs. standard chemotherapy plus a higher dose of vitamin D (8,000 IU/day for 14 days as a loading dose, then 4,000 IU/day as a maintenance dose). The primary aim of the trial is to see if higher doses of vitamin D combined with standard treatment can delay progression or growth of cancer and prolong survival.

IOM report

In 2010, the Institute of Medicine (IOM) published its “Dietary Reference Intakes for Calcium and Vitamin D” report, which was meant to clarify the health benefits of calcium and vitamin D. The IOM was tasked with examining the existing evidence and updating the Dietary Reference Intakes.

“We reviewed the evidence comprehensively and rigorously, looking at more than 1,000 studies of vitamin D and health outcomes related to bone health, cancer, cardiovascular disease, diabetes, autoimmune diseases and more,” said JoAnn E. Manson, MD, DrPH, chief of the division of preventive medicine at Brigham and Women’s Hospital and a member of the IOM committee.

The committee concluded in the report that although scientific evidence supports a key role for vitamin D and calcium in skeletal health, a causal role in nonskeletal conditions such as cancer is not currently supported.

“The concern of the IOM committee was that the evidence was inconsistent and inconclusive that vitamin D prevents cancer, cardiovascular disease or other nonskeletal outcomes, and that there was not yet evidence for a cause-and-effect relationship,” Manson said.

Therefore, the committee issued recommended dietary allowances (RDA) based on the evidence of what is needed for bone health. The committee said those aged 1 to 70 years should have an RDA of 600 IU a day, and those aged 71 years or older should have 800 IU a day. These intakes corresponded with a 25-hydroxyvitamin D level of at least 20 ng/mL.

Definition of ‘normal’

“There were a lot of advocates saying that the IOM was going to find that you have to give higher doses, and instead they only made a modest increase in the RDA,” Chlebowski said. “The people who were advocates, who believed in the observational studies, were disappointed by the decision.”

Ng, who is part of a group studying higher doses, does not disagree with the IOM, but said she isolates its decision on RDA to only bone health.

“If you look at bone health, you do only need a vitamin D level of around 20 ng/mL to maintain it,” Ng said. “However, in studying colon cancer, our studies seem to suggest that much higher doses are needed for protective effect against colon cancer. We think that those recommendations for the daily intake of vitamin D are much lower than what would be needed to potentially be effective for cancer treatment and prevention.”

In clinical and laboratory studies, scientists are examining much higher doses of vitamin D supplementation.

Feldman recently completed a mouse study that compared a placebo group of mice receiving a basal (normal) diet to mice receiving a fivefold vitamin D supplemented diet. The mice had human cancer cells placed in their breast fat pads, and time was spent allowing the cancer to grow. Feldman subsequently started treatment with vitamin D in the diet as a supplement — or continuing the basal diet (the placebo) — or injected the mice with the active hormone calcitriol.

“Once we started the vitamin D supplemented diet or calcitriol, we saw the cancer starting to shrink within 1 week,” Feldman said. “By 4 weeks, the cancer was half the size compared with the mice receiving the basal diet. Interestingly, the tumor shrinkage caused by the vitamin D supplemented diet was equivalent to the calcitriol injections, indicating the potency of dietary vitamin D. Although this is a study in mice, when you see that dramatic effect on the growth of a human breast cancer, how can you not be optimistic that this would be of benefit to patients?”

In human studies, a meta-analysis of nine large randomized controlled trials that included more than 57,000 participants found that only a moderate dose of vitamin D may be needed to have an effect on cancer mortality. In the trials, participants assigned to vitamin D supplementation received a modest median dose of 528 IU per day. Mortality was 8% lower among the supplementation group.

To further complicate the debate, many in the medical community disagree about what level of 25-hydroxyvitamin D is considered “normal.”

In its 2010 report, the IOM advocated an RDA of vitamin D that would maintain a 25-hydroxyvitamin D level of more than 20 ng/mL. In response, The Endocrine Society published an opinion stating that a 25-hydroxyvitamin D level of less than 20 ng/mL should be defined as deficient, whereas a range from 20 ng/mL to 30 ng/mL should be defined as insufficient. The Endocrine Society opinion defined the normal range as at least 30 ng/mL.

Public supplementation

The multitude of studies suggesting beneficial health effects has led to an enthusiasm for possible changes to public policy, increasing intake among a broad population and attempting to bring everyone within the normal range, Chlebowski said.

“In the United States, we like to give stuff, such as folate,” he said. “But you have to start asking: In the case of vitamin D, should observational studies be defining public policy?”

Trump said, “There is still concern that if you recommend that a whole population or large numbers of individuals take vitamin D, you will see side effects.”

Excessive vitamin D increases calcium levels in the body, which can lead to calcium deposits in the major organs and hypercalcemia. Although there are those who are uncommitted, the course of action should be clear, according to Trump, who said he believes in the potential of vitamin D.

“In contrast to what many might argue, that we know the answer about vitamin D and that we could create a favorable health effect by recommending everyone take more vitamin D, there are no definitive data to recommend that you should take more than you get in the normal course of daily living,” he said.

More answers needed

Although Trump supports the association between 25-hydroxyvitamin D and cancer, he said there is little evidence that vitamin D supplementation is an effective treatment, a view with which Chlebowski said he agrees.

In the Women’s Health Initiative cohort, Chlebowski and colleagues compared total vitamin D intake (diet plus supplementation) with subsequent 25-hydroxyvitamin D blood levels. They found that only 3% of women in the highest 25-hydroxyvitamin D quintile had vitamin D intakes of more than 1,000 IU per day.

“This means that genetic determinations of 25-hydroxyvitamin D levels may have something to do with the disease, and that means you may not be able to alter it by giving vitamin D to try to change the levels,” Chlebowski said.

One study that may shed some light on the topic is the Vitamin D and Omega-3 Trial, or VITAL, a randomized controlled trial of 20,000 participants that will examine whether vitamin D and marine omega-3 fatty acids reduce risk for cancer, heart disease and stroke in those who have no prior history of those illnesses. Recruitment began in 2010 and will continue through 2012.

“We have never said that the VITAL trial will provide all of the answers about vitamin D and the prevention of cancer, but it will be a critically important piece of evidence,” said Manson, who is the principal investigator. “In VITAL, the vast majority of participants will reach a blood level of 25-hydroxyvitamin D that is above 30 ng/mL by taking 2,000 IU of vitamin D3 a day, which we consider to be an optimal dose of supplementation to test at this time.”

This dose, which avoids exceeding the upper safety limit suggested by the IOM, provides the best balance of safety and efficacy, Manson said. However, there is some concern among others that the dose may not be high enough because both the placebo and active treatment groups are allowed to have background intake of vitamin D up to the RDA.

The delta between the background intake up to 800 IU and an additional 2,000 IU in the treated group is not as big as you would like, Feldman said.

Manson said no single trial can provide a conclusive answer to the question of vitamin D’s potential to treat or prevent cancer.

“Answering these clinical and public health questions require a convergence of evidence from several sources from basic science to animal research to epidemiologic and observational research to randomized clinical trials,” she said. “However, this study will help to answer an enormous number of clinical and public health questions.”

It also will, at a minimum, begin to provide some of the randomized controlled evidence that is needed to begin to draw conclusions.

“The epidemiologic and preclinical data about vitamin D’s role in cancer are enticing and highly suggestive of important biologic effects,” Trump said. “There is definitely something there that merits careful and continued exploration.” – by Leah Lawrence

References:

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• Manson JE. Contemp Clin Trials. 2012;33:159-171.
• National Cancer Institute. Vitamin D and cancer prevention: strengths and limits of evidence. Available at: www.cancer.gov/cancertopics/factsheet/prevention/vitamin-D.
• National Research Council. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press, 2011.
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Disclosures:

• Drs. Chlebowski, Feldman, Manson, Ng and Trump report no relevant financial disclosures.

Should studies examining the relationship between vitamin D and cancer focus on high-dose or recommended dose regimens?

Recommended dose regimens should be used for the general public, and high-dose regimens should be used for research.

The most objective measure of a patient’s overall vitamin D status is 25-hydroxyvitamin D, or 25(OH)D, blood levels. Although there are varying definitions about what is considered a normal level of 25(OH)D, there is a general consensus that having a value of less than 20 ng/mL is in the deficient range, and having a value greater than 32 ng/mL is considered sufficient for bone health.

There is some observational data to suggest that vitamin D levels greater than 40 ng/mL to 50 ng/mL range are associated with a lower risk of certain types of cancers, such as breast cancer and colorectal cancer. High levels also have been tied to improved survival from those diseases. However, to raise a patient’s 25(OH)D by 10 ng/mL, you would need to supplement with about 1,000 IU of vitamin D daily.

In its guidelines, the Institute of Medicine (IOM) was on the conservative side regarding the vitamin D recommended dose, but it was based on the current evidence that we have. It did increase the current recommended dietary allowance from 400 IU to 600 IU a day, and it increased the upper safety limit from 2,000 IU to 4,000 IU daily. However, there is still of a lot of uncertainty about what the optimal dose of vitamin D should be.

The largest vitamin D intervention trial to date was the Women’s Health Initiative, which used calcium and 400 IU daily of vitamin D in postmenopausal women. Essentially all of the results from that trial have come back negative with respect to breast and colorectal cancer incidence and bone fractures. The feeling in terms of the research community is that if there is a beneficial effect of vitamin D, a 400-IU dose is probably way too low.

We have been studying much higher doses of vitamin D, anywhere from 2,000 IU to 4,000 IU daily. Given that there is a high prevalence of vitamin D deficiency in the general public, it may mean we need to supplement with higher doses in our research to reach a higher target level of 25(OH)D.

In terms of making widespread recommendations to the general public, for the most part the data are still very limited. That is why we need clinical trials to rigorously test what the optimal dose of vitamin D should be.

Many of the theories surrounding vitamin D are based on observational studies. We do not know if the higher vitamin D level is what caused the lowering of cancer risk or the improvement in survival. Until we can prove that in a randomized controlled trial, the IOM was probably correct in recommending a more conservative dose to the general public.

Katherine D. Crew, MD, MS, is the Florence Irving Assistant Professor of Medicine and Epidemiology in the division of oncology at Columbia University. Disclosure: Dr. Crew reports no relevant financial disclosures.

It is important that we follow evidence-based recommendations when providing advice to the healthy public and in our personalized care for individual patients.

It is well established that vitamin D plays a critical role in maintaining optimal serum calcium and bone health. The recent IOM report defining new public health Dietary Reference Intakes (DRIs) determined that sufficient dose-dependent data existed to support revision of the previous guidelines.

The process of defining DRIs is neither “conservative” nor “liberal”; rather, it is an evidence-based approach. The latest DRIs were established based upon data regarding bone health, as evidence for dose-response relationships between vitamin D status and any other outcome, including cancer, was neither sufficient nor convincing.

DRIs were established for specific age groups, from infancy to the elderly, and defined as the amount of dietary vitamin D necessary to meet the needs of 95% of North Americans. Most importantly, these values assume no exposure to sunlight, which has the potential to contribute significantly to vitamin D status.

The DRIs serve the interests of a healthy population in many ways in addition to providing dietary guidelines for individuals, for example, in defining standards for school lunch programs and food labeling.

The role of vitamin D status in cancer risk, either for the overall cancer burden or specific malignancies, is far from clear. On one hand, provocative studies from laboratory experimentation and human epidemiology have emerged. Yet, data regarding cancer are heterogeneous and often conflicting, suggesting that specific types of cancer may be more or less responsive to vitamin D status.

Important questions regarding the stages of the life cycle when vitamin D may impact risk of a certain cancer and the dose-response relationships remain to be elucidated. Unfortunately, scientifically sound randomized clinical trials with a cancer outcome are exceedingly rare and studies evaluating a range of vitamin D exposures are needed.

The prevalence of vitamin D deficiency in North America has been overstated. The IOM committee suggests that serum 25-hydroxy vitamin D, a biomarker of vitamin D status, of less than 20 ng/mL represents the “at risk” population for bone disease. Attempts to further increase serum vitamin D by pharmacologic supplementation in otherwise healthy individuals to prevent cancer or a wide number of other disease processes has not demonstrated clear benefit and certainly does not reflect an evidence-based approach. Most certainly, there are clinical conditions where the pharmacologic management of vitamin D status is supported by research and necessary for optimal personalized care.

Large studies such as those from the National Health and Nutrition Examination Survey suggesting that overall mortality demonstrates a “U-shaped” curve with risk increasing for high vitamin D exposure, and several epidemiologic studies reporting a greater risk of certain cancers associated with higher vitamin D status, should be a sobering concern.

It is clear that future public health as well as clinical practice guidelines focusing upon high-risk individuals or those suffering from disease require rigorous testing of the multitude of hypotheses regarding a role for vitamin D. Dose-response studies over a wide range of exposures are recommended for future investigations.

Steven K. Clinton, MD, PhD, is a professor of medicine and medical oncology at The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital. Disclosure: Dr. Clinton reports no relevant financial disclosures.