Vitamin D

Vitamin D-the so-called “sunshine vitamin”-is a fat-soluble substance and is classified more as a pro-hormone or steroid by some.[1,2] There are two forms, D2 (ergocalciferol) and D3 (cholecalciferol). The primary source is from the sun, where ultraviolet B (UV-B) rays in sunlight prompt the conversion of cholesterol to D3 in the skin in humans. Sources of naturally occurring vitamin D3 are cod liver oil; herring, sardines, mackerel, and other fatty fish; beef, pork, and chicken liver; and egg yolks. Other sources of vitamin D3 are fortified foods such as cereal, juice, and milk. Vitamin D2 (called ergocalciferol) is made in mushrooms and yeast.

Vitamin D is not biologically active until it is converted to 1,25(OH)2D by both the liver and kidneys. The vitamin D levels that are measured in the serum (25(OH)D) are protein-bound and have low biologic properties but are, by consensus, the best indicator of vitamin D status.[3] The regulation of vitamin D is very tightly controlled by the parathyroid hormone, calcium, and phosphorous.[1,2] Six biological systems have receptors for vitamin D.[1] These include immune cells (T cells, antigen-presenting, dendritic cells, and macrophages), the pancreas, cardiovascular system, muscle, brain, and the cell cycle. The biologic function of vitamin D is based on these systems and includes the regulation of calcium and ability for calcium to be absorbed, insulin secretion, inhibition of cell proliferation, promotion of cell differentiation, and involvement in immune activities.

How Is It Currently Used?
Vitamin D is used in conjunction with calcium for the prevention and treatment of osteoporosis, including that related to cancer therapies.[4–7] It is also used to treat psoriasis, osteomalacia, and rickets, among other conditions. Supplementation with vitamin D plus calcium has been found to increase bone mineral density in postmenopausal women and may also reduce their risk of fracture and falls (and that of older men, as well).[1,4,5,8].
In general, individuals are considered to have inadequate status if their serum concentration of 25(OH)D is less than 20 ng/mL (50 nmol/L), however, more experts today are recommending a concentration of at least 30 ng/mL (75 nmol/L).[4,5,7,9]

The current recommended vitamin D intake for adults ranges from 200–600 IU/day for achieving adequate nutritional status[4] to 800–1,000 IU/day for treating osteoporosis and preventing it in patients at elevated risk.[4,5,7] National Comprehensive Cancer Network (NCCN) guidelines advise that thyroid cancer patients with low levels of thyroid stimulating hormone may benefit from daily vitamin D intake of 800 IU (and a daily calcium intake of 1,200 mg).[10] Some groups are calling for higher dosing recommendations,[9] and recent, compelling data suggest the value of higher dosing,[11,12] but this issue remains controversial.

The upper limit for daily intake of vitamin D3 is considered to be 2,000 IU, according to the Institute of Medicine (IOM). The IOM is currently meeting to evaluate the evidence and make any recommended changes. It is anticipated that their report will be available in May 2010.[13] Monitoring serum 25(OH)D levels may help healthcare providers to determine the appropriate intake for individual patients.[14] Most studies published about the serum concentrations of vitamin D3 in the US population report that a majority fall below recommended levels.[3,15,16] In fact, two recent reports based on data from the National Health and Nutrition Examination Survey (NHANES) 2001–2004 report that 70% or more of the adult population have levels below the recommended 30 ng/mL (75 nmol/L).[15,16]

For people with cancer, risk factors can make vitamin D insufficiency an even greater reality. An
abstract presented at ASCO 2009 reports 69% of patients who were tested had serum concentrations less than 30 ng/mL and 10% had concentrations less than 12 ng/mL.[17] A second abstract reported 88% of patients with colorectal cancer were vitamin D–deficient.[18]

Risk factors that can contribute to low vitamin D in cancer include inactivity from fatigue, weight gain, endocrine changes, nutritional deficits, changes in phosphorous due to chemotherapy, and bone loss due to hormone deficiency.

What Is the Evidence Related to Vitamin D and Cancer?

The plethora of research on vitamin D and various outcomes, including all-cause and cancer-specific mortality, prompted a new review by government-sponsored agencies to evaluate whether sufficient evidence exists to change the recommended dose. The Agency for Health Care Research and Quality is one such group who recently published a review of the evidence related to numerous outcomes with vitamin D, calcium, and their combination.[1]

The review covered 165 studies and 11 systematic reviews from 1969 to September 2008. Overall, the group concluded that the data were inconsistent. With respect to cancer, most of the evidence comes from association studies and not all of the associations are positive with respect to all cancers. For example, in pancreatic cancer, higher concentrations of vitamin D were associated with an increased risk of cancer.[19,20]

There are only three randomized, controlled trials, all of which looked at cancer mortality as a secondary outcome. These studies were not designed to primarily look at cancer outcomes. The Women's Health Initiative Study was negative with respect to impacting deaths due to cancer, having used 400 IU of vitamin D3 with 1,000 mg of calcium carbonate supplementation daily.[21,22]

A British study (by researchers from the University of Cambridge School of Clinical Medicine, England) used 100,000 IU of vitamin D orally every 4 months over 5 years without calcium supplementation and also did not find a significant difference in cancer mortality.[23] Another study, done in the United States (Nebraska), however, found reduction in cancer mortality with daily supplementation of 1,000 IU of vitamin D3 with 1,500 mg of calcium carbonate.[24] Based on the fact that these three studies used very different doses, the results cannot be equally compared.

Clearly, randomized placebo controlled trials (RCTs) are needed that are designed to answer specific questions about cancer prevention and reduction in cancer mortality. Association studies provide insufficient evidence for practice changes and results from RCTs are often contrary to the hypotheses generated from these types of studies. Given that the literature to date indicates vitamin D has biologic activity consistent with health benefits related to cancer, to move this area of science forward, research is needed to clarify the role of vitamin D, with and without calcium; its optimal dose and serum concentrations; and short and long term toxicity associated with use of vitamin D.

Of note, a new randomized trial, VITAL (VITamin D and omegA-3 triaL), will test vitamin D for cancer prevention as well as heart disease and stroke among older adults (women over 65, men over 60)[25] and may help to clarify some of the benefits as well as risks. This trial will assess doses of 2,000 IU of vitamin D and 1 gram of fish oil daily and is expected to begin in 2010.

What Are the Potential Risks? There are potential risks associated with use of vitamin D. The greatest risk is hypercalcemia, which is more likely to occur at extremely high serum concentrations of 150 ng/mL (374 nmol/L).[3] At toxic levels, excess vitamin D accumulates in both adipose tissue and muscles. Hypercalcemia, besides posing a subsequent increased risk of kidney stones, can be fatal due to dehydration resulting from polyuria, and it can cause suppression of heart and brain function. Excess vitamin D intake can cause nausea, vomiting, and constipation. In patients taking digoxin, it can also cause arrhythmias.[4,6,22]

It is not definitively known what dose or duration of vitamin D would be likely to cause unwanted gastrointestinal side effects, and it is probably somewhat individual based on physiologic and genetic differences. Some argue that there are no data to suggest that doses up to 2,000 IU per day confer any risk.[9,12] One interesting observation is that excessive exposure to sunlight does not result in vitamin D intoxification. (It only increases one's risk of skin cancer.)

Vitamin D supplements are not strictly regulated by the Food and Drug Administration; as a result, their safety, effectiveness, purity, and potential interactions have often not been well tested.[6]

What's the Bottom-Line Message?

There is not enough evidence at this time to recommend an aggressive dose of vitamin D supplements for patients with cancer. However, it would be prudent to evaluate 25(OH)D concentrations in cancer survivors. Further research is needed to more precisely determine how vitamin D impacts one's risk of cancer,[1,14] and what serum levels are necessary to achieve benefits with respect to specific cancers, if such benefits exist.

In the meantime, oncology nurses should stay informed about the latest research published in the area of vitamin D and cancer and any guidelines that are developed or revised about this area of supplementation. Nurses can inform patients that studies of vitamin D are ongoing, encourage them to maintain at least an adequate nutritional intake of this vitamin (and calcium), and counsel them about the potential benefits and harms of supplements.[4–6,14]

Additional Resources
• Institute of Medicine-Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Available at: http://tiny.cc/0MvVt.
• American Cancer Society-Vitamin D. Available at: http://tiny.cc/NeRft.
• American Society of Clinical Oncology-Vitamin D Supplementation: Does It Have a Role in Cancer Treatment and Prevention? Available at: http://tiny.cc/s4nKX.
• National Institutes of Health-US clinical trials on vitamin D and cancer. Available at: http://tiny.cc/d9hTI

References:

References
1. Chung M, Balk EM, Brendel M, et al. Vitamin D and Calcium: A Systematic Review of Health Outcomes. Evidence Report No. 183. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ), 2009. AHRQ Publication No. 09-E015. Available at: http://www.ahrq.gov/downloads/pub/evidence/pdf/vitadcal/vitadcal.pdf. Accessed on August 18, 2009.

2. Dixon KM, Mason RS: Vitamin D. Int

J Biochem Cell Biol

41:982–985, 2009.
3. Holick MF: Vitamin D deficiency.

N Engl J Med

357(3):266–281, 2007.
4. National Institutes of Health, Office of Dietary Supplements: Dietary Supplement Fact Sheet: Vitamin D. Updated December 11, 2008. Available at:

http://tiny.cc/3WH75

. Accessed on August 27, 2009.
5. Gralow JR, Biermann S, Farooki A, et al: NCCN task force report: Bone health in cancer care. J Natl Compr Cancer Netw 7(suppl 3):S1–S36, 2009. Available at:

www.nccn.org/JNCCN/PDF/2009_Bone_Health_TF.pdf

. Accessed on August 18, 2009.
6. MedlinePlus Supplements. Vitamin D. Last updated on January 30, 2009. Available at:

www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitamind.html

. Accessed on August 18, 2009.
7. National Osteoporosis Foundation: Clinician's Guide to the Prevention and Treatment of Osteoporosis. Washington, DC, National Osteoporosis Foundation, 2008. Available at: www.nof.org/professionals/Clinicians_Guide.htm.
8. Dawson Hughes B: Serum 25-hydroxyvitamin D and functional outcomes in the elderly.

Am J Clin Nutr

88(suppl):537s–540s, 2008.
9. Garland CF, Gorham ED, Mohr SB, et al: Vitamin D for cancer prevention: Global perspective.

Ann Epidemiol

19(7):468–483, 2009.
10. National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. V.1.2009. Available at:

http://www.nccn.org

.
11. Cashman KD, Wallace JM, Horigan G, et al: Estimation of the dietary requirement for vitamin D in free-living adults >=64 y of age.

Am J Clin Nutr

89(5):1366–1374, 2009.
12. Vieth R: Vitamin D and cancer mini-symposium: The risk of additional vitamin D.

Ann Epidemiol

19(7):441–445, 2009.
13. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Washington, D.C., National Academies Press, 1997, p. 282.
14. Goodwin PJ: Vitamin D in cancer patients: Above all, do no harm. J Clin Oncol 27:2117–2119, 2009. Available at:

http://jco.ascopubs.org/cgi/content/full/27/13/2117

. Accessed on August 18, 2009.
15. Yetley EA: Assessing the vitamin D status of the US population.

Am J Clin Nutr

88(2):558S-564S, 2008
16. Ginde AA, Liu MC, Camargo CA Jr.: Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med 169(6):626–632, 2009.
17. Hauser KA, Karafa M, Seyidova-Khoshknabi D et al: Prevalence and risk factors of vitamin D insufficiency in cancer.

J Clin Oncol

27(suppl; abstr 9581):15s, 2009.
18. Gilmore C, James J, Zubal B, et al: Vitamin D deficiency, incidence, and response to oral supplementation among various gastrointestinal malignancies.

J Clin Oncol

27:15s(suppl; abstr 9586), 2009.
19. Stolzenberg-Solomon RZ, Hayes RB, Horst RL, et al: Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial.

Cancer Res

69(4):1439–1447, 2009.
20. Stolzenberg-Solomon RZ, Vieth R, Azad A, et al: A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers.

Cancer

Res 66(20):10213–10219, 2006
21. Wactawski-Wende J, Kotchen JM, Anderson GL, et al: Calcium plus vitamin D supplementation and the risk of colorectal cancer.

N Engl J Med

354(7):684–696, 2006.
22. Chlebowski RT, Johnson KC, Kooperberg C, et al: Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 100(22):1581–1591, 2008.
23. Trivedi DP, Doll R, Khaw KT: Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: Randomised double blind controlled trial.

BMJ

326(7387):469, 2003).
24. Lappe JM, Travers-Gustafson D, Davies KM, et al: Vitamin D and calcium supplementation reduces cancer risk: Results of a Randomized trial.

Am J Clin Nutr

85(6):1586–1591, 2007.
25. The VITamin D and omegA 3 triaL (VITAL). Last updated June 29, 2009. Available at:

http://www.vitalstudy.org/

. Accessed on August 29, 2009.