Should clinicians recommend vitamin D supplementation to patients with cancer to improve their outcomes?

Click here to read the Cover Story, “Despite potential, data on vitamin D’s benefits for cancer remain inconclusive.”

Yes.

I recommend to my patients that they measure their vitamin D levels, and that they take enough vitamin D to ensure their levels are within the normal range.

There is a considerable body of epidemiologic data that strongly suggests the association between low vitamin D levels and unfavorable outcomes in many diseases, including autoimmune diseases, infectious diseases, cardiovascular disease and many kinds of cancer. The limitation of those studies is that they only show association and do not prove that the unfavorable outcomes are related to low vitamin D.

In addition, there is an increasing body of evidence that the level of vitamin D influences the outcome of a diagnosed cancer. The limitation of those studies is much like the epidemiologic studies: They are looking at one factor and then drawing an association. Although that doesn’t prove causation, it again is consistent with the fact vitamin D levels in the normal range may improve outcomes.

One of the most interesting studies in this regard is an analysis of a large randomized study of the use of rituximab (Rituxan; Genentech, Biogen) among patients with lymphoma. Investigators noted that patients with low vitamin D levels had an inferior response to CHOP and rituximab compared with those who had normal vitamin D levels. Inferiority appeared limited to the group who received rituximab.

These investigators then conducted a laboratory-based study of 12 normal volunteers with low vitamin D levels. Using the volunteers’ monocytes or lymphocytes mixed with tumor cells and rituximab, researchers assessed the ability of rituximab to kill lymphoma cells in vitro.

Researchers then added vitamin D supplementation to each of those individuals and repeated the analysis 3 months later. They found a striking enhancement of rituximab-mediated killing of lymphoma cells in vitro in the same patients after they had been repleted with vitamin D. Those factors suggest the level of vitamin D is important, and the final determining factor is vitamin D supplementation.

Most agree a normal vitamin D level is in the range of 30 ng/mL to 100 ng/mL and achieving a 25(OH)D3 level in that range with a dose of up to 4,000 IU is safe.

I am very comfortable recommending my patients have their vitamin D level measured and they take enough supplementation to ensure their level is in normal range because of the indication — not proof — that normal vitamin D levels reduce risk for cancer and improve outcomes after diagnosis; based on the considerable laboratory data that vitamin D and its analogs can be important in impeding the growth of cancer cells; and the fact vitamin D supplementation is safe.

References:

Akiba T, et al. Clin Cancer Res. 2018;doi:10.1158/1078-0432.CCR-18-0483.

Bittenbring JT, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.53.4537.

Fuchs MA, et al. Ann Oncol. 2017;doi:10.1093/annonc/mdx109.

Kelly JL, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.57.5092.

Liu J, et al. Oncotarget. 2017;doi:10.18632/oncotarget.18766.

Maalmi H, et al. Eur J Epidemiol. 2017;doi:10.1007/s10654-017-0298-z.

Maalmi H, et a. Nutrients. 2018;doi: 10.3390/nu10070896.

Timerman D, et al. Oncotarget. 2017;doi:10.18632/oncotarget.14316.

Vaughan-Shaw PG, et al. Br J Cancer. 2017;doi:10.1038/bjc.2017.44.

Wu Y, et al. Cancers (Basel). 2017;doi:10.3390/cancers9100144.

Yao S, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2016.4188.

Donald L. “Skip” Trump, MD, FACP, is CEO and executive director of Inova Schar Cancer Institute. He also is HemOnc Today’s Associate Editor for Medical Oncology. He can be reached at donald.trump@inova.org. Disclosure: Trump reports no relevant financial disclosures.

No.

Low levels of 25-hydroxyvitamin D — the easily measured serum storage level of vitamin D — has been statistically associated in large populations with a higher-than-average risk for cancer, autoimmune disease, cardiovascular disease and other chronic diseases. This has led to the speculation that low levels of vitamin D may predispose individuals to these diseases, and that supplementation is warranted as a preventive measure.

Unfortunately, these studies fail to account for possible confounding factors — such as obesity, inactivity and generally poor diet — that are known to be risk factors for many of these disorders. No properly controlled study has established a causal relationship between low vitamin D levels and the diseases of concern.

The randomized, double-blind, placebo-controlled Women’s Health Initiative studies of more than 36,000 women followed for more than 7 years failed to demonstrate a reduction in colorectal cancer incidence, morbidity or mortality with vitamin D supplementation. Additional analyses of this population showed no significant impact on overall mortality, coronary or other cardiovascular death, cerebrovascular death or total cancer deaths. Although these studies have been criticized for using a “small” vitamin D dose (400 IU daily), they remain the largest and best controlled efforts to evaluate the role of vitamin D in health outcomes. Further, even this dose of vitamin D statistically increased the incidence of kidney stones among those receiving vitamin D.

The Institute of Medicine (IOM) 2011 report on vitamin D and calcium concluded there was no proven benefit of vitamin D supplementation and that a “normal” American diet provided adequate vitamin D for 97.8% of the population — even assuming no sun exposure, which, for most people, is a major source of vitamin D. Further, the report noted that very high levels of supplementation, including levels recommended by some enthusiasts, may lead to health problems and toxic effects.

The fact that UVB exposure produces vitamin D has been advocated inappropriately to promote UV exposure as a means of reducing cancer risk, a message that fails to mention that UV irradiation is well established as causing most skin cancers, including melanoma. Vitamin D can be obtained more reliably and safely from diet or supplementation than from UV exposure. As well, many people make maximal daily amounts of vitamin D during casual sun exposure, in season, while wearing sunscreen, because sunscreens are far less than 100% effective at blocking the vitamin D-producing wavelengths. A further confusion is the now widely used and misleading term “vitamin D insufficiency.” Many people, when tested, are told they have this condition and need a supplement to become “sufficient.” In fact, “insufficiency” is loosely defined as a vitamin D level below an arbitrary value, usually 30 ng/mL. However, this cutoff assigns half or more of many apparently healthy adults to the “insufficient” category. There is no evidence that increasing the vitamin D level in such people improves their health. The IOM report notes that 97.5% of people with a level of 20 ng/mL have adequate vitamin D stores, and many with lower levels do, also.

I have no objection to patients taking up to 1,000 IU a day if this reassures them or makes them feel they are actively preventing or combating disease. However, I strongly advise against sunbathing, tanning salon use or mega-supplements to increase vitamin D levels.

References:

Freedman DM, et al. J Natl Cancer Inst. 2007;99:1594-1602.

Freedman DM, et al. Cancer Epidemiol Biomarkers Prev. 2009;doi:10.1158/1055-9965.EPI-08-0633.

Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Available at: www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Vitamin%20D%20and%20Calcium%202010%20Report%20Brief.pdf. Accessed on Sept. 19, 2018.

LaCroix AZ, et al. J Gerontol A Biol Sci Med Sci. 2009;doi:10.1093/gerona/glp006.

Wactawski-Wende J, et al. N Engl J Med. 2006;354:684-696.

Barbara A. Gilchrest, MD, is senior lecturer on dermatology at Massachusetts General Hospital, as well as chair emeritus of dermatology at Boston University School of Medicine. She can be reached at bgilchrest@mgh.harvard.edu. Disclosure: Gilchrest reports no relevant financial disclosures.