Abstract ED07-03: Role of Vitamin D in prevention of cancer: dose-response relationships
Authors: Garland Cedric , Gorham Edward , Mohr Sharif , Baggerly Carole , Garland Frank 
Published: May 2012

Abstract
ED07-03
Vitamin D insufficiency is now known to be the principal controllable cause of cancer of the colon, breast, and kidney, and is associated with higher incidence of cancer of the ovary, endometrium, several other malignancies, and all cancers as a group, except those mainly due to smoking, alcohol abuse, or long-term complications of viral infection. Insufficiency of vitamin D in childhood is associated with higher risk of prostate cancer. Consistent with this, low serum levels of the principal circulating vitamin D metabolite, 25-hydroxyvitamin D (25(OH)D), are associated with higher incidence and mortality rates from colon, breast, and ovarian cancer. There is a linear, inverse dose-response gradient between 25(OH)D and these cancers (serum levels in ng/ml may be multiplied by 2.5 to obtain nmol/L).
Dose-response relationships for cancers of the kidney, endometrium, and other solid tumors have been estimated from observational studies, a clinical trial, and natural experiments (ecological studies) of the 177 countries that report cancer incidence to the International Agency for Research in Cancer, states and counties of the US, and states or provinces of several other countries. These studies include 70 supportive epidemiological studies of human populations and 2,480 supportive laboratory research studies, according to a PubMed literature search and review performed in September, 2008. Most epidemiological studies have found that higher serum 25(OH)D levels are associated with lower cancer rates, and a clinical trial of 1100 IU/day of vitamin D3 and 1450 mg/day of calcium has detected a 72% reduction in incidence of all cancers combined. Other studies have reported favorable associations with total oral intake of vitamin D. The main question in the vitamin D-cancer field is no longer whether vitamin D can help prevent these cancers, since this has been established to a reasonable degree of certainty. They key task now is specifying the optimal serum 25(OH)D levels, or vitamin D dose, for preventing these cancers.
The best approach to this question is to determine the optimal serum level of 25(OH)D, and use it as a target for selection of the appropriate dose of vitamin D, when feasible. The commonly encountered baseline range of serum 25(OH)D is from undetectable to 100 ng/ml. Brief but regular sunlight exposure near the equator is capable of raising serum 25(OH)D to approximately 90 ng/ml, if a reasonably large area of skin (&gt; 40%) is exposed. However a mean of 60 ng/ml has been reported in US lifeguards, probably due to the relatively high latitude of the US, whose population lives, on average, approximately 37 degrees north of the equator. Hypercalcemia due to abnormally high 25(OH)D does not occur below a serum level of approximately 90 ng/ml. The median serum 25(OH)D in US adults is 20-25 ng/ml, according the National Health and Nutrition Examination Survey III.
There is considerable variation among individuals in the daily oral dose of vitamin D that is required to achieve a particular serum level of 25(OH)D. Therefore it is wisest to aim for a serum 25(OH)D target level, when possible, rather than to designate a universally optimal oral dose of vitamin D. This serum targeting approach is feasible due to the availability of laboratory tests for serum 25(OH)D, including a mail-in test using a drop of blood from a finger stick.
Meta-analyses and systematic reviews of all studies of serum 25(OH)D levels with regard to cancer incidence have revealed that the dose response relationship for prevention of cancer is linear, beginning at approximately 20 ng/ml. Reduction by half in incidence of colon cancer can be achieved by maintaining a year-around serum 25(OH)D level of &gt; 32 ng/ml; reduction by half in incidence of breast cancer would require a year around serum 25(OH)D level of &gt; 44 ng/ml. Reductions by approximately half in incidence of cancers of the kidney, endometrium, and ovary would probably require maintenance of &gt; 50 ng/ml. Based on limited data, it appears that substantial reduction in incidence of prostate cancer would require maintaining a serum 25(OH)D &gt; 40 ng/ml beginning in early childhood.
According to linear extrapolation from known dose-response curves, colon cancer would be essentially eradicated by maintaining serum 25(OH)D level &gt; 60 ng/ml. Virtual eradication of breast cancer, except for some familial cases, could be achieved with
&gt; 85 ng/ml, according to similar linear extrapolation. While it is not yet possible to state eradication levels for cancers of the kidney and endometrium, the available ecological data suggest that a reduction by 67% in kidney and endometrial cancer might be possible with serum 25(OH)D &gt; 75 ng/ml. All serum levels assume there is adequate oral intake of calcium. (This varies with the individual, but is generally approximately 1000 mg/day in males and 1500 mg/day in females, mainly from food. This may be supplemented, if necessary, by intake of calcium carbonate or other calcium compounds commonly present in substantial amounts in food, while ensuring adequate hydration with fluids.) Linear extrapolation has a degree of uncertainty, as it assumes that the linear relationship that begins at 20 ng/ml remains linear through the stated level. However, this underlying assumption appears to be reasonable, based on data from natural experiments suggesting that there is a virtually linear inverse association of vitamin D status with cancer risk through at least 70 ng/ml.
Based on the above targets, 50% reductions in incidence could be achieved by mean daily vitamin D3 supplementation of approximately 1500 IU for colon cancer, 2400 IU for breast cancer, and 3000 IU for cancers of the kidney and endometrium. Virtual eradication of colon cancer is predicted with mean daily vitamin D supplementation of 4000 IU and virtual eradication of breast cancer is predicted with 6500 IU. Doses below 2400 IU per day have no known adverse health effects, according to a National Academy of Sciences (NAS) 1996 monograph, and serious adverse health effects are unlikely below 10,000 IU per day, based on existing meta-analyses of vitamin D toxicity studies. Unless the NAS upper limit and no adverse health effect levels of vitamin D intake are revised upward, individuals taking oral vitamin D doses above 2400 IU/day should be monitored on a regular basis for serum 25(OH)D, total and ionized calcium. Individuals with sarcoidosis, or other hypercalcemic conditions that result in excess levels of 1,25-dihydroxyvitamin D, should not be supplemented with vitamin D. When serum testing of 25(OH)D is unavailable, the minimal intake of vitamin D3 should be 2000 IU per day, according to a Call to Action consensus statement on vitamin D intake for disease prevention signed by 16 prominent scientists and physicians in the vitamin D field.
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Vitamin D also plays a role in reducing mortality from breast and colon cancer. According to recent research in the US and Canada, a serum 25(OH)D level &gt; 36 ng/ml is associated with reduction by approximately half in 10-year case fatality rates of colon and breast cancer. Patients with breast, colon, ovarian, kidney, endometrial, and lung cancer should receive the amount of vitamin D supplementation needed to raise serum 25(OH)D to 60-90 ng/ml. This may require 4000-7000 IU/day of vitamin D3, depending on the individual, and should be done with regular monitoring of serum 25(OH)D, ionized and total calcium levels on a regular basis. This would, of course, not apply to the occasional patient with baseline hypercalcemia, determined by screening before initiation of increased vitamin D intake.
Oral vitamin D intake may be supplemented or replaced with prudent, measured exposure to noontime sunlight, when climate and season allow. Patients should wear a hat whenever in the sun, but &gt; 40% of body surface area should be exposed to sunlight for not to exceed 10-15 minutes per day, with a shorter interval if needed to avoid erythema.
Sunscreens should not be used during this interval, as they prevent all vitamin D photosynthesis. (If sunscreens are used after this period, they should contain an adequate concentration of titanium dioxide, zinc oxide or other inert clay compounds, to reduce total UV exposure by a factor of &gt; 8, regardless of SPF.) Such exposures can produce &gt; 10,000 IU/day of vitamin D3 by cutaneous photosynthesis on clear summer days at temperate latitudes. Individuals with a history of skin cancer, or who are taking photosensitizing medications, should receive their vitamin D solely by oral supplementation.
No known compound offers greater ability to prevent and arrest invasive cancers than vitamin D. Universal use of vitamin D for prevention could eliminate 50-75% of cancer overall with 5-10 years, and could virtually eradicate breast, colon, and kidney cancer. It is hard to understand why vitamin D is not being used throughout the US to prevent these painful, costly cancers that produce great suffering and premature mortality. Immediate action is needed by the medical community, voluntary agencies, and responsible government institutions to prevent these needless cancers by ensuring that adequate serum levels of vitamin D metabolites are maintained at all ages in the population. This includes issuing detailed recommendations by voluntary and government agencies, providing consensus statements to the medical community, population and school education, public relations, public service advertising, easy availability of population finger-stick 25(OH)D screening and periodic monitoring of serum 25(OH)D and calcium levels at little or no charge, and universal, inexpensive provision of vitamin D3 supplements.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED07-03.