To the Editor: A recent article concluded that evidence of a beneficial role of vitamin D in reducing the risk of cancer incidence and mortality is not impressive, in part because of a lack of good randomized controlled trials (RCTs).
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Randomized controlled trials are appropriate for studying pharmaceutical drugs but not necessarily for vitamin D. Most vitamin D is produced from solar UVB irradiance and confounds oral intake in RCTs of vitamin D. Nested case-control studies are less reliable than case-control studies because the relation of a single serum 25-hydroxyvitamin D [25(OH)D] level measurement to subsequent serum 25(OH) D levels declines with the passage of time, and undetectable cancers can grow rapidly in the absence of adequate serum 25(OH)D levels. This could explain why the results of Helzlsouer
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and Harbour and Miller3
showed no beneficial effect of vitamin D.The strongest evidence to date for a beneficial effect of vitamin D in reducing the risk of cancer comes from ecological studies using solar UVB dose indices. A review of such ecological studies found evidence from 3 continents for 13 types of cancer and from 1 or 2 continents for 5 types.
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Many of the recent ecological studies included a number of other cancer risk–modifying factors in the analysis, such as smoking, alcohol consumption, socioeconomic status, diet, and ethnic background. The fact that similar results have been found in diverse geographic locations, including Australia, China, Europe, France, Japan, and the United States, as well as in several multinational studies involving up to 175 countries, strongly supports the role of solar UVB. Although some ecological studies can be faulted for using latitude as the index, summertime solar UVB doses in the United States are strongly asymmetric because of variations in surface elevation and stratospheric ozone layer thickness, with highest doses in the southwest and lowest doses in the northeast, a pattern that correlates well with about 15 types of cancer.5
No mechanism other than vitamin D production has been proposed to explain the correlation with or effect of UVB doses on cancer risk in well-conducted ecological studies.Further support for the beneficial role of vitamin D in reducing the risk of cancer is that an individual and group index of high solar UVB irradiance and incidence or mortality rate of non-melanoma skin cancer is often inversely correlated with the incidence or mortality rates for other forms of cancer. In an ecological study in Spain, the mortality rate of non-melanoma skin cancer inversely correlated with mortality rates for 15 types of cancer after adjusting for the smoking index.
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A comprehensive method to evaluate the evidence for a natural compound such as vitamin D is by applying Hill's criteria for causality in a biological system. The primary criteria are strength of association, consistency, biological gradient, plausibility (mechanisms), experimental verification (eg, RCTs), and accounting for confounding factors. These criteria were evaluated for cancer and found to apply well for breast and colorectal cancer and reasonably well for 9 other types of cancer.
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Although additional evaluation linking UVB irradiation, vitamin D, and cancer risk is warranted, evidence is sufficient to recommend increasing serum 25(OH)D levels to reduce the risk of cancer incidence and death.
REFERENCES
- Vitamin D insufficiency.Mayo Clin Proc. 2011; 86: 50-60
- Overview of the cohort consortium vitamin D pooling project of rarer cancers.Am J Epidemiol. 2010; 172: 4-9
- A new system for grading recommendations in evidence based guidelines.BMJ. 2001; 323: 334-336
- Ecological studies of ultraviolet B, vitamin D and cancer since 2000.Ann Epidemiol. 2009; 19: 446-454
- The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates.Anticancer Res. 2006; 26: 2687-2699
- An ecologic study of cancer mortality rates in Spain with respect to indices of solar UV irradiance and smoking.Int J Cancer. 2007; 120: 1123-1127
- How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill's criteria for causality.Dermatoendocrinol. 2009; 1: 17-24
Article Info
Footnotes
Dr Grant receives or has received funding from the UV Foundation (McLean, VA), the Sunlight Research Forum (Veldhoven), Bio-Tech-Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Danish Sunbed Federation (Middelfart).
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Copyright
© 2011 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
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- Weighing the Evidence Linking UVB Irradiance, Vitamin D, and Cancer Risk–reply–IMayo Clinic ProceedingsVol. 86Issue 4
- PreviewIn reply: We agree with Dr Grant that evidence from ecological studies suggests that vitamin D may reduce cancer risk. Increasing distance from the equator is associated with increased risk of several cancers at a population level. However, one of the major limitations of ecological studies is referred to as the ecological fallacy, which is the error of making inferences at an individual level on the basis of aggregate population level data. It is entirely possible that a disease association found by comparing populations is absent, or even in the opposite direction, when individual level data are examined.
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