DÄ internationalArchive37/2010The Role of Vitamin D in Cancer Prevention

Review article

The Role of Vitamin D in Cancer Prevention

Does UV Protection Conflict With the Need to Raise Low Levels of Vitamin D?

Dtsch Arztebl Int 2010; 107(37): 638-43. DOI: 10.3238/arztebl.2010.0638

Zeeb, H; Greinert, R

Background: Vitamin D is essential for life. Part of the body´s supply of vitamin D is ingested in food, but UV induced vitamin D synthesis in the body plays an even more important role. UV irradiation is a cause for the currently rising incidence of skin cancer in many countries; on the other hand, Vitamin D might be protective against some cancers. In this paper we summarize the current data on vitamin D and cancer and on the vitamin D status of populations in Europe and discuss whether current recommendations on UV protection require changes.

Methods: In 2008, the International Agency for Research on Cancer (IARC) published a systematic review on vitamin D and cancer. We describe its main findings and review additional publications retrieved by a selective literature search on vitamin D, UV light, and skin cancer. In addition, we systematically review the current recommendations on vitamin D supplementation.

Results: Higher vitamin D levels are associated with a lower risk of colon cancer. For breast cancer, the situation is less clear. In general, higher vitamin D levels are associated with lower overall mortality. Concerning optimal Vitamin D levels, serum values ≥ 50 nmol/L (ie.. ≥ 20 ng/mL) are frequently discussed, and a few authors favor markedly higher values. Brief UV exposures are usually adequate for endogenous vitamin D synthesis.

Conclusion: More research is needed into the possible protective effects of vitamin D against cancer. Brief, daily UV exposure stimulates vitamin D production and causes negligible skin damage. Raising the vitamin D level even further by extended solar UV exposure or irradiation in a
solarium is inadvisable because of the risk of skin cancer. Oral vitamin D supplementation can be considered as an alternative, particularly for persons at high risk, such as the elderly and members of certain ethnic groups.

LNSLNS

Vitamin D is a necessary substance for life whose synthesis in the skin is induced by ultraviolet radiation. It is also contained in various types of food, including fish and eggs. Generally, however, the dietary intake of vitamin D has no more than a moderate influence on the vitamin D level, which is measured as the serum concentration of 25-hydroxyvitamin D (1, 2) (eBox 1 gif ppt).

Vitamin D is known to have beneficial effects on bone formation and on the neuromuscular system. In recent years, scientific attention has been devoted to its potential preventive effects against chronic diseases of various types, particularly cancer. Currently, there are active research efforts, as well as scientific debate, about a number of mechanisms, including antiproliferative effects and potential influences on cell differentiation and angiogenesis (3). Observational epidemiological studies are providing more plentiful evidence that high levels of vitamin D might protect against certain types of cancer, such as cancer of the bowel (4) and breast (5). Yet the reality of such preventive effects remains an open question, nor is there any scientific consensus about the optimal serum vitamin D concentration at which they are supposed to take place. Further controversy surrounds the issue of how adequate vitamin D levels should be achieved in the population at large.

Sunlight is the main source of UV light for vitamin D photosynthesis in man, but it is also the main risk factor for both melanocytic and non-melanocytic skin cancer (6). On the basis of statistics from the Schleswig-Holstein Cancer Registry for the year 2002 (7), it is estimated that, in Germany alone, some 140 000 people develop basal cell carcinoma, squamous cell carcinoma, and malignant melanoma each year. The high and, in some cases, rising incidence of these types of cancer is considered a public health problem in many countries where light-skinned persons make up a large percentage of the population. Therefore, many groups have issued recommendations, including the World Health Organization (WHO), the International Commission on Non-Ionizing Radiation Protection (ICNIRP), and the European Society of Skin Cancer Prevention (EUROSKIN), and many prevention campaigns have been initiated, such as those of the German Task Force on Dermatological Prevention (Arbeitsgemeinschaft Dermatologische Prävention, ADP) and the German Cancer Aid Society (Deutsche Krebshilfe, DKH). The recommendations specify that UV protection should not be performed in such a way as to endanger the formation of adequate amounts of vitamin D, but they also advise against excessive UV exposure in the pursuit of higher vitamin D levels. This advice concerns exposure to the sun as well as artificial UV radiation in solaria.

This article provides an overview of the epidemiological data on vitamin D and a discussion of the available studies on the link between vitamin D and cancer, along with the recommendations for daily vitamin D intake in various countries around the world. In view of the known carcinogenic effect of UV radiation on the skin, alternative means of achieving an adequate vitamin D level are critically discussed.

Methods

The International Agency for Research on Cancer (IARC) recently published an extensive documentation and systematic review of the link between vitamin D and cancer (6). In this paper, we present the main conclusions of the IARC report and supplement them with the findings of a selective review of relevant literature from the years 2000 to 2009. We retrieved this literature by searching the PubMed database for publications on the etiology and prevention of chronic diseases with vitamin D, serum vitamin D levels in the general population, and on ultraviolet light and cancer; the search terms were “vitamin D,” “cholecalciferol,” “ultraviolet light,” “sunlight,” “cancer,” “skin cancer,” and “prevention.”

For the international recommendations on vitamin D intake, we systematically searched the websites of the international medical societies and made use of cross-references from the other publications that were available to us.

Results

Vitamin D levels in the general population

Population-based data on vitamin D status are available from a large number of epidemiological studies that have been performed in many countries. In Europe, evidence of vitamin D deficiency has not just been found in previously known risk groups, such as the elderly (8), persons from an immigrant background, persons with dark skin, and persons who cover most or all of their skin for religious or cultural reasons (9) Note: I have added “or cultural” because it is debatable whether the near-complete veiling of some Muslim women is actually a religious requirement; middle-aged persons in the general population also commonly have vitamin D deficiency, which is defined as a concentration of 25(OH)vitamin D that is below 50 nmol/L, or marked vitamin D deficiency (a concentration below 25 nmol/L) (10). Persons who frequently expose themselves to sunlight in the summer can achieve values in the vicinity of 120 nmol/L, with markedly lower levels in winter (11). Different studies of vitamin D status are often difficult to compare with one another because of the lack of standardized measuring techniques, in addition to varying definitions of normal and low serum levels.

The German Federal Health Survey (Bundesgesundheitssurvey) for 1998 revealed vitamin D concentrations below 50 nmol/L in over half of all participants (58% of men and 57% of women), as well as a marked seasonal fluctuation, with much lower levels in winter (12). Among premenopausal women serving as normal controls in a case-control study on breast cancer in the Rhine-Neckar area, 16% had vitamin D levels below 30 nmol/L, while only 21.5% had levels of 75 nmol/L or higher (13).

According to the German Health Interview and Examination Survey for Children and Adolescents (Kinder- und Jugendgesundheitssurvey) of the Robert Koch Institute (Germany’s equivalent of the Centers for Disease Control and Prevention), 30% of children aged 3 to 17 with an immigrant background have a vitamin D level below 25 nmol/L, as compared to 18% among children in the same age group without an immigrant background. 7% of these children had high vitamin D levels above 75 nmol/L, as compared to 13% in the comparison group (14).

The influence of vitamin D on cancer and overall mortality

The findings of geographical correlation studies (ecological studies) provided a major part of the motivation for the hypothesis that UV radiation affects the incidence of cancer (15). Many such studies, including some that were published only recently, suffer from basic methodological deficiencies that render it difficult to draw firm conclusions, despite the attempts that were made to control for certain confounding factors (e.g., urbanization, various measures of socioeconomic status, the rate of lung cancer as a surrogate for smoking behavior) (16). A finding that cancer incidence or mortality declines as one approaches the equator (i.e., as the amount of UV radiation increases) cannot suffice to establish an association between UV radiation, vitamin D, and cancer.

The available observational studies regarding the potential association between vitamin D and cancer were subjected to multiple meta-analyses for the 2008 IARC report (6). Pooled analyses of the published risk estimators indicated an inverse relationship between 25-hydroxyvitamin D levels and carcinoma and adenoma of the bowel. For carcinoma of the bowel, a pooled analysis of nine case-control and cohort studies revealed a relative risk (RR) of 0.85 (95% confidence interval [95% CI], 0.79–0.91) for each 25 nmol/L rise in the serum vitamin D level. For adenoma (seven case-control and cohort studies), the relative risk was 0.93 (95% CI, 0.88–0.99). For breast cancer, a pooled analysis of four case-control studies and one cohort study revealed a protective effect with a relative risk of 0.85 (95% CI, 0.71–1.02) for each 25 nmol/L rise in the serum vitamin D level. For prostate cancer, however, no protective effect could be determined from the six case-control studies and one cohort study that were analyzed (RR 0.98; 95% CI 0.92–1.05). Moreover, two interventional trials that were performed in the framework of the randomized, double-blind, placebo-controlled Women’s Health Initiative (WHI) Study in the USA, which involved 36 282 women aged 50 to 79 (e1, e2), as well as a British randomized, controlled trial (RCT) with 2686 participants aged 65 to 84 (e3), did not reveal any effect on the incidence of bowel or breast cancer through vitamin D supplementation (10 µg [400 IU]/day in the WHI trials, 41 µg [1640 IU]/day in the British trial). Very recently, a clinical trial involving 1,179 women in Nebraska showed that the incidence of breast cancer was lowered by daily supplementation with 27.5 µg (1100 IU) of vitamin D, given in combination with calcium (e4). The main methodological problems of these clinical trials were uncertain compliance and lack of information about vitamin D levels before the intervention. Extensive further documentation of each of these studies can be found in the IARC report.

A meta-analysis of 18 RCTs led to the conclusion that vitamin D supplementation (12 to 15 µg/day) lowers overall mortality (17). An analysis by the American National Health and Nutrition Examination Survey (NHANES III) revealed elevated mortality among persons with low vitamin D levels but did not identify any specific cause of death that could account for this finding (www.cdc.gov/nchs/nhanes/nhanes_questionnaires.htm). The Cochrane is currently initiating systematic reviews on vitamin D, cancer prevention, and mortality (e5, e6).

A recent multinational prospective study on the potential link between vitamin D serum levels and cancers of seven different, less common types (cancer of the endometrium, ovary, esophagus, stomach, kidney, and pancreas, and non-Hodgkin’s lymphoma) did not reveal an association with any of these types of cancer (18).

What level of vitamin D is best?

This question probably has a different answer depending on the particular health effect that is sought. A review published in 2006 (19) addressed the question of the optimal serum levels of vitamin D with regard to bone density, lower extremity function, dental health, and the risk of falling. Although the medical societies in many countries consider values of 50 nmol/L or above to be adequate, some current publications quote optimal levels above 75 nmol/L (e7, e8). The proponents of high vitamin D levels point out that protective effects against cancer are presumed to be achievable mainly with relatively high vitamin D levels (i.e., levels of 75 nmol/L or above) (e9). The therapeutic window for vitamin D is very wide: a toxic effect (hypercalcemia) is thought to arise only when the serum level exceeds 500 nmol/L (20). The European Union has set a blood level of 200 nmol/L, corresponding to a daily intake of 100 µg (4000 IU) of vitamin D, as the upper limit of the range in which no deleterious effects are observed. If one incorporates an additional safety margin, one arrives at a recommendation to take no more than 50 µg (2000 IU) of vitamin D by mouth each day (e10). When the UV index is 6, as on a summer’s day in Germany, a light-skinned person with skin type II has to spend about 16 minutes in the sun (with 6% of the skin surface exposed) to synthesize 400 IU of vitamin D (Table 1 gif ppt).

Recommendations from various countries

Recommendations on the daily intake of vitamin D have been issued in many countries. Most are risk-adapted, i.e., higher daily doses are generally recommended for pregnant women, nursing mothers, infants, and the elderly than for children, adolescents, and young and middle-aged adults (Table 2 gif ppt). The Canadian Paediatric Society recommends a daily intake of at least 5 µg (200 IU) and at most 50 µg (2000 IU) of vitamin D for pregnant women and nursing mothers. In the German-speaking countries, the medical societies recommend daily doses varying from 5 to 10 µg, depending on the risk group. The German S3 guideline on the prevention, diagnosis, and treatment of osteoporosis in adulthood contains information on vitamin D intake (see www.dv-osteologie.de) (Table 2).

According to the IARC report (6), the following two questions will need to be answered before it can be determined what vitamin D level is best for the health of any particular individual (with a large degree of variation expected from one person to another):

  • Does a low vitamin D level increase the risk of cancer?
  • Does a low vitamin D level itself reflect poor health (i.e., could it be an effect, rather than a cause)?

The IARC favors the performance of further randomized trials, including trials of oral vitamin D supplementation, to answer these questions of causation. Although such trials are the only way to obtain therapeutically useful information on the possible influence of vitamin D on cancer incidence and mortality, they would probably yield results only after many years. Furthermore, difficulties may be anticipated with issues such as compliance and the quantification of individual UV exposure over time, given the period of the study.

The prevention of skin cancer

Solar UVA and UVB rays reach the earth’s surface. UVB has a much stronger biological effect than UVA with respect to the induction of erythema and the generation of damage to DNA, but UVB is also responsible for the induction of vitamin D synthesis. The spectra of activity for vitamin D production and for DNA damage overlap to a large extent (eBox 2 gif ppt).

In view of the high prevalence of skin cancer, primary prevention campaigns against high UV exposure have been carried out in many countries. Their main goal is to lower the morbidity and mortality due to skin cancer (21). In Germany, for example, a campaign of this type has long been a component of the Life Phases Program (Lebensphasenprogramm) (22) of the Task Force on Dermatological Prevention (Arbeitsgemeinschaft Dermatologische Prävention, ADP) and the German Cancer Aid Society (Deutsche Krebshilfe, DKH): Persons at different stages of life, mainly adolescents, are given specific information about the health risks of UV radiation. Skin cancer screening was introduced in Germany in July 2008 with the goal of improving the early detection (i.e., secondary prevention) of skin cancer in older persons (aged 35 and above). In Germany and around the world, programs of this type are being carried out in view of the clear demonstration, by a large number of scientific studies, that UV radiation (UVA and UVB, either singly or in combination) acts as a carcinogen in and of itself and is causally linked to the induction, promotion, and progression of skin cancer (e11e16). With respect to malignant melanoma, it has been found that sunburns and intermittent UV exposures increase the risk of melanoma, but a low level of chronic exposure to the sun does not. On the other hand, non-melanocytic types of skin cancer are associated with the cumulative lifetime exposure to UV light (23). In a recent re-evaluation of the available data, the IARC has listed both solar UV radiation and artificial UV radiation (from solaria) as group 1 carcinogens (24).

Summary

Although there is already evidence for a protective effect of vitamin D against some types of cancer, much research still needs to be done. The high, and increasing, incidence of skin cancer among older and younger persons alike implies that comprehensive UV protection will remain indispensable in the future. The medical societies’ recommendations in Germany and elsewhere emphasize the importance of avoiding sunburn, and exposure to the sun, at times when the UV intensity is highest, i.e., around midday. In the summer months, short UV exposures of up to 15 minutes per day on parts of the body not covered by clothing, such as the face, hands, and arms, are considered to suffice for adequate vitamin D synthesis and are recommended, in particular, to persons in certain risk groups in order to ensure that physiological amounts of vitamin D are produced. The risk of skin cancer arising from such brief exposure to the sun seems negligible compared to its benefits. One must recall, however, that solar UV light may not be intense enough to ensure adequate vitamin D synthesis in the fall and winter months, particularly at higher latitudes. There are, theoretically, three further options for the elevation of low vitamin D levels among the population subgroups at risk:

  • artificial UV exposure in solaria and the like;
  • increased dietary intake of vitamin D as part of the ordinary diet;
  • vitamin D supplementation and medical treatment of persons with low vitamin D levels.

Exposure to artificial UV rays in solaria is, like solar UV exposure, a proven risk factor for skin cancer. The UV intensity in solaria commonly reaches, or exceeds, that of the midday sun at the equator, and there is thus a risk that the minimal erythema dose will also be exceeded, with resulting damage to health (25). Furthermore, typical solarium users do not belong to any of the risk groups for vitamin D deficiency (e.g., children, the elderly, immigrants); they also generally have light skin and thus belong precisely to the group of people in whom UV exposure most increases the risk of skin cancer. Thus, solaria and prolonged exposures (more than 15 minutes daily) seem to carry excessive risk compared to solar UV and are, therefore, not recommended as a means of raising vitamin D levels.

The dietary intake of vitamin D is coupled to particular foods; thus, it can probably be raised only in exceptional cases, e.g., by the regular consumption of fish oil. Among old women in Japan, regular fish consumption (4 or more times per week) is associated with high levels of vitamin D (e17). In view of the price and less than universal availability of fish as food, elevating fish consumption would not seem to be a practical strategy for broadly improving vitamin D status across the world.

A moderate increase in individual exposure to sunlight, with observance of the basic guidelines for protection against excessive UV exposure, should be considered as a basic measure for use in clinical practice. This can be achieved, for example, by more outdoor exercise. Vitamin D supplementation can be given in addition, or as an alternative, and might also have further beneficial effects on health, e.g., antihypertensive effects, as the current literature suggests (e18). In particular, oral vitamin D supplementation is an indicated treatment for persons with clinically relevant vitamin D deficiency. In the light of current views about optimal vitamin D levels, it would seem appropriate to give higher doses of vitamin D to some patients, depending on their individual vitamin D status, their membership in a risk group, and/or the time of year. We are convinced that the twin goals of preventing skin cancer and improving vitamin D status can be met by preventive intervention, and that neither goal must be sacrificed to achieve the other.

Conflict of Interest Statement

The authors declare that they have no conflict of interest as defined by the guidelines of the International Committee of Medical Journal Editors.

Manuscript submitted on 4 May 2009; revised version accepted on 17 November 2009.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Hajo Zeeb
Bremer Institut für Präventionsforschung und Sozialmedizin (BIPS)
Universität Bremen
Linzer Straße 10
28359 Bremen, Germany
zeeb@bips.uni-bremen.de

@For eReferences please refer to:
www.aerzteblatt-international.de/ref3710

eBoxes available at:
www.aerzteblatt-international.de/article10m0638

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Institut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Universitätsmedizin der Johannes Gutenberg-Universität Mainz; Bremer Institut für Präventionsforschung und Sozialmedizin, Universität Bremen: Prof. Dr. med. Zeeb
Molekulare Zellbiologie, Dermatologisches Zentrum, Elbe Kliniken, Klinikum Buxtehude: Dr. rer. nat. Greinert
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