New study says more Vitamin D cuts risk of cancer

April 6, 2006

A new study led by led by Giovannucci from Harvard School of

Public Health, and published yesterday in the Journal of the National

Cancer Institute, claims raising the RDA of vitamin D from 400 IU to

1500 IU could cut the number of deaths from cancer by 30 per cent.

3 articles with links and full text below:

+++++++++++++++++++++

http://jncicancerspectrum.oxfordjournals.org/cgi/content/abstract/jnci;98/7/451

ARTICLE

Prospective Study of Predictors of Vitamin D Status and Cancer

Incidence and Mortality in Men

Giovannucci, Yan Liu, B. Rimm, Bruce W. Hollis, S.

Fuchs, Meir J. Stampfer, Walter C. Willett

Affiliations of authors: Channing Laboratory, Department of Medicine,

Harvard Medical School and Brigham and Women's Hospital, Boston, MA

(EG, EBR, CSF, MJS, WCW); Department of Nutrition (EG, YL, EBR, MJS,

WCW), Department of Epidemiology (EG, EBR, MJS, WCW), Harvard School

of Public Health, Boston, MA; Department of Pediatrics, Medical

University of South Carolina, ton, SC (BWH); Department of

Adult Oncology, Dana-Farber Cancer Institute, Boston, MA (CSF)

Correspondence to: Giovannucci, MD, ScD, Harvard School of

Public Health, 665 Huntington Ave., Boston, MA 02115 (e-mail:

edward.giovannucci@...).

Background: Vitamin D has potent anticancer properties, especially

against digestive-system cancers. Many human studies have used

geographic residence as a marker of solar ultraviolet B and hence

vitamin D exposure. Here, we considered multiple determinants of

vitamin D exposure (dietary and supplementary vitamin D, skin

pigmentation, adiposity, geographic residence, and leisure-time

physical activity—to estimate sunlight exposure) in relation to cancer

risk in the Health Professionals Follow-Up Study. Methods: Among 1095

men of this cohort, we quantified the relation of these six

determinants to plasma 25-hydroxy-vitamin D [25(OH)D] level by use of

a multiple linear regression model. We used results from the model to

compute a predicted 25(OH)D level for each of 47 800 men in the cohort

based on these characteristics. We then prospectively examined this

variable in relation to cancer risk with multivariable

proportional hazards models. Results: From 1986 through January 31,

2000, we documented 4286 incident cancers (excluding organ-confined

prostate cancer and nonmelanoma skin cancer) and 2025 deaths from

cancer. From multivariable models, an increment of 25 nmol/L in

predicted 25(OH)D level was associated with a 17% reduction in total

cancer incidence (multivariable relative risk [RR] = 0.83, 95%

confidence interval [CI] = 0.74 to 0.92), a 29% reduction in total

cancer mortality (RR = 0.71, 95% CI = 0.60 to 0.83), and a 45%

reduction in digestive-system cancer mortality (RR = 0.55, 95% CI =

0.41 to 0.74). The absolute annual rate of total cancer was 758 per

100 000 men in the bottom decile of predicted 25(OH)D and 674 per 100

000 men for the top decile; these respective rates were 326 per 100

000 and 277 per 100 000 for total cancer mortality and 128 per 100 000

and 78 per 100 000 for digestive-system cancer mortality. Results were

similar when we controlled further for body mass index or physical

activity level. Conclusions: Low levels of vitamin D may be associated

with increased cancer incidence and mortality in men, particularly for

digestive-system cancers. The vitamin D supplementation necessary to

achieve a 25(OH)D increment of 25 nmol/L may be at least 1500 IU/day.

+++++++++++++++++++++

http://jncicancerspectrum.oxfordjournals.org/cgi/content/full/jnci;98/7/428

EDITORIAL

Vitamin D Status and Cancer Incidence and Mortality: Something New

Under the Sun

G. Schwartz, J. Blot

Affiliations of authors: Comprehensive Cancer Center of Wake Forest

University, Winston-Salem, NC (GGS); International Epidemiology

Institute, Rockville, MD, and Vanderbilt-Ingram Cancer Center,

Vanderbilt University Medical Center, Nashville, TN (WJB)

Correspondence to: G. Schwartz, MPH, PhD, Departments of Cancer

Biology and Epidemiology, Wake Forest University, School of Medicine,

Winston-Salem, NC 27157 (e-mail: gschwart@...).

In this era of tumor genomics, proteomics, and metabolomics, the idea

that fundamental insights about cancer could emerge from observations

of the gross characteristics of individual persons (i.e., from

classical epidemiology) seems almost anachronistic. Surely the era of

discovery of common exposures with broad effects on cancer is over. Or

is it?

In this issue of the Journal, Giovannucci et al. (1) report that

estimates of vitamin D status derived from the Health Professionals

Follow-up Study were associated with statistically significant

reductions in total cancer incidence and mortality. Most of the

protective effect for vitamin D status comes from an exposure that is

common indeed—sunlight. Because many persons think of sunlight only as

a cause of cancer (especially melanoma), some perspective may be helpful.

In 1941, Apperly (2), a pathologist, demonstrated an inverse

correlation between levels of ultraviolet radiation in North America

and mortality rates from cancers in nonskin sites and proposed that

sunlight somehow conferred " a relative cancer immunity " to nonskin

cancers. Although Apperly's paper attracted little attention in its

day, epidemiologists rediscovered his fundamental insight half a

century later. Many common cancers, such as cancers of the colon and

prostate, display fascinating north–south gradients, with rates that

increase systematically with increasing geographic latitude, and show

an increased risk among African Americans (3). The increased risk with

residence at northern latitudes and greater incidence and mortality in

persons with dark pigmentation recall the descriptive epidemiology of

rickets, the classic disease of vitamin D deficiency. These

considerations led several epidemiologists, including Garland and

Garland (4) for the colon in 1980, and Schwartz and Hulka (5) for the

prostate in 1990, to propose that vitamin D deficiency increased the

risk for these cancers. Similar claims later were made for cancers at

other sites, e.g., breast, ovary, and pancreas, so that vitamin D has

become a prime candidate for cancer prevention (6,7).

Understanding how vitamin D could influence cancer risk requires an

understanding of vitamin D synthesis. The synthesis of vitamin D

begins with the production of vitamin D3 (cholecalciferol) after

7-dehydrocholesterol in the skin is exposed to ultraviolet B radiation

(wavelength = 290–315 nm). Because melanin is an effective sunscreen,

given the same ultraviolet exposure, blacks synthesize less vitamin D

than whites, accounting for the far higher prevalence of vitamin D

deficiency among blacks (8). Vitamin D can also be obtained from the

diet, although the quantity of vitamin D in Western diets is generally

small. To become biologically active, vitamin D undergoes two

hydroxylations: The first occurs in the liver at the 25th carbon

position, forming 25-hydroxyvitamin D [25(OH)D or calcidiol], the

prohormone and major circulating form of vitamin D; the second occurs

at the 1{alpha} position, forming 1,25(OH)2D (calcitriol), the

hormonal form of vitamin D. Most of the biological effects of

1,25(OH)2D are mediated by specific hormone receptors (vitamin D

receptors, or VDRs) (9).

In 1979 VDRs were identified in normal cells that were not involved in

mineral metabolism (10). In 1981, VDRs were found in malignant

melanoma cells, and 1,25(OH)2D inhibited their proliferation (11);

also, myeloid leukemia cells were induced to differentiate into

macrophages by nanomolar concentrations of 1,25(OH)2D (12). These

observations led to an explosion of interest in the role of 1,25(OH)2D

in many cell types, where the pleiotropic anticancer effects of

1,25(OH)2D, including those on cell cycle, invasion, and metastasis,

were widely confirmed. These findings have now led to the exploration

of 1,25(OH)2D and its analogs as cancer therapeutic agents (13,14).

Although possible mechanisms for the anticancer effects of 1,25(OH)2D

were becoming evident, how sunlight or vitamin D could influence

cancer risk was not, because serum levels of 1,25(OH)2D are tightly

controlled by the kidney and generally do not vary with geographic

latitude or race. How, then, could vitamin D deficiency contribute to

the north–south gradients and African American excess in cancer rates?

This problem was solved by the demonstration that many nonrenal cells,

such as prostate and colon cells, can also hydroxylate 25(OH)D at the

1{alpha} position and synthesize 1,25(OH)2D locally. In these cells,

1,25(OH)2D promotes differentiation and inhibits proliferation in a

microendocrine fashion (15). The implications of the extrarenal

synthesis of 1,25(OH)2D by nonclassical cells are profound; they imply

that sunlight exposure, which produces greater serum levels of

25(OH)D, could result in a decreased risk of cancer in the sites where

1,25(OH)2D is synthesized locally (16).

The knowledge that many factors—including skin pigmentation,

geographic latitude, and outdoor exposure—contribute to plasma levels

of 25(OH)D enabled Giovannucci et al. (1) to attempt an assessment of

the contribution of these factors to cancer risk. They assayed plasma

25(OH)D among a subset of 1095 men in the Health Professionals

Follow-Up Study and used a linear regression model incorporating six

personal characteristics (dietary and supplemental vitamin D, race,

adiposity, geographic residence, and leisure-time physical activity)

as predictors of the plasma levels of 25(OH)D. They then used this

statistical model to compute predicted 25(OH)D levels for all 47 800

men in the cohort and examined whether the 25(OH)D index was related

to subsequent cancer risk. They report that an increment of 25 nmol/L

(10 ng/ml) in predicted 25(OH)D was associated with a 17% reduction in

total cancer incidence (relative risk [RR] = 0.83, 95% confidence

interval [CI] = 0.73 to 0.94) and a 29% reduction in total cancer

mortality (RR = 0.71, 95% CI = 0.60 to 0.83), with even stronger

effects for digestive cancer. The findings from this cohort study are

the latest of several (7,17,18) linking vitamin D status with reduced

cancer risk and are some of the most compelling yet. The results, with

lower risks of most (but not all) forms of cancer, are also some of

the most broad based, and they indicate that vitamin D may have a role

in most human tumors.

Although the cohort findings are likely to increase enthusiasm for the

cancer prevention potential of vitamin D, inherent limitations of

observational epidemiologic studies combined with a history of prior

disappointments with other potential chemopreventive agents suggest

caution in their interpretation. Two decades ago there was intense

interest and hope that supplementation with beta-carotene might reduce

the risk of several cancers. Epidemiologic studies have consistently

reported that men and women with the highest dietary intakes of

beta-carotene as well as with elevated blood levels experienced lower

risks of respiratory, gastrointestinal, and other cancers. The zeal

was crushed, however, when randomized trials in the United States and

Finland showed increased rather than decreased risks of lung cancer

among adults receiving beta-carotene supplements (19,20). Vitamin E

was similarly touted as an inhibitor of cancer, as well as of

cardiovascular disease, but again the " gold standard " of randomized

trials failed to confirm the preventive correlations noted in cohort

and case–control studies (21). Epidemiologic studies also strongly

indicated that hormone replacement therapy might not only relieve

menopausal symptoms but also lower the risk of heart disease and

breast and other cancers, but again, when clinical trials were

conducted, no benefit with respect to these conditions accrued to

women administered the therapy (22). In each of these examples, the

agents may have demonstrated benefit with modification of the dose,

formulation, or timing of the intervention or with longer follow-up,

but the sobering lesson is that trends observed in nonexperimental

settings, including cohort studies, are not always confirmed

experimentally when tested in randomized clinical trials. Science,

after all, is a continual process of hypothesis formulation, testing,

and refinement; ecologic (e.g., geographic correlations) and analytic

(e.g., cohort and case–control) studies provide the evidence-based

clues to cancer etiology, but randomized trials are generally needed

to confirm these leads and develop effective disease prevention

strategies.

Will a similar unrealized promise eventually befall vitamin D? We hope

not. Although ex post facto mechanistic explanations can often be

postulated to explain epidemiologic observations, for vitamin D the

biologic evidence for inhibition of carcinogenesis is strong and,

often, was predicted by the prior epidemiologic findings on sunlight

exposure. Laboratory and observational epidemiologic research will

continue to further elucidate and refine hypotheses on vitamin D's

role, but the potential for cancer prevention by vitamin D (in pill

form) must now proceed to the clinical trial testing arena. Several

randomized trials have assessed the effects of vitamin D

supplementation on bone fracture (23), but few have assessed its

preventive effect on the risk of cancer or precancerous lesions

[although small trials are evaluating 1,25(OH)2D or it is analogs on

the treatment of prostate and other cancers].

We close with the recognition that heavy sun exposure can cause harm.

Because the ultraviolet radiation action spectra required for vitamin

D synthesis and the spectra that induce DNA damage are essentially the

same, there is an apparent conflict between the advantages of sunlight

exposure for vitamin D synthesis and its deleterious effects, the most

serious being malignant melanoma. Although much has been made of it in

the lay press, and by some in the dermatology community, the conflict

may be more apparent than real (24). The amount of sun needed to

produce adequate levels of vitamin D, at least for bone health, is

modest and can be obtained in a light-skinned person by a brief

afternoon summertime stroll. Although the dose–response relation

between ultraviolet exposure and the development of melanoma is not

well quantified, the limited exposure required for vitamin D synthesis

is likely at the very low end of the curve.

Sunlight generally is an effective means of generating large amounts

of vitamin D, but it may not be safe for all persons. For many

individuals, including those who are darkly pigmented or who live at

northern latitudes, sunlight exposure may also be insufficient to

generate adequate vitamin D. Conversely, vitamin D supplements are

widely available, inexpensive, and believed to be safe over a large

dosing range. As is often pointed out, the present recommended

allowance for vitamin D—400 IU—for individuals aged 50–70 years is

inadequate even to maintain skeletal health and is probably too low

for meaningful anticancer effects (25). A dose of 400 IU of vitamin D3

will raise serum levels of 25(OH)D3 only modestly, by about 7 nmol/L

or less than 3 ng/mL. The use of this low dose, in conjunction with

the relatively short duration of the trial, may explain the recent

failure of vitamin D to reduce the incidence of colorectal cancer in

the Women's Health Initiative (26).

In summary, a role for sunlight and vitamin D in cancer prevention is

strongly suggested by epidemiologic observations, including the

findings of Giovannucci et al. (1), and potential mechanisms have been

identified by experimental studies. The promising results from both

observational and laboratory studies should usher in a new era of

intervention studies of vitamin D and cancer risk. Because many public

health scientists are already clamoring for higher levels of vitamin D

supplementation for bone and other health, randomized trials of

vitamin D and cancer risk should be undertaken speedily (27). If the

promise of vitamin D holds, a brief walk in the sun may turn out to be

a step toward cancer prevention.

REFERENCES

(1) Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ,

Willett WC. Prospective study of predictors of vitamin D status and

cancer incidence and mortality in men. J Natl Cancer Inst

2006;98:451–9.[Abstract/Free Full Text]

(2) Apperly FL. The relation of solar radiation to cancer mortality in

North America. Cancer Res 1941;1:191–5.

(3) Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer

mortality: evidence for a protective effect of ultraviolet radiation.

Cancer 1992;70:2861–9.[iSI][Medline]

(4) Garland CF, Garland FC. Do sunlight and vitamin D reduce the

likelihood of colon cancer? Int J Epidemiol

1980;9:227–31.[Abstract/Free Full Text]

(5) Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor for

prostate cancer? (Hypothesis). Anticancer Res

1990;10:1307–11.[iSI][Medline]

(6) Studzinski GP, DC. Sunlight—can it prevent as well as cause

cancer? Cancer Res 1995;55:4014–22.[Abstract]

(7) Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB,

et al. The role of vitamin D in cancer prevention. Am J Public Health

2006;96:252–61.[Abstract/Free Full Text]

(8) Nesby-Odell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW,

Looker AC, et al. Hypovitaminosis D prevalence and determinants among

African American and white women of reproductive age: Third National

Health and Nutrition Examination Survey 1988–1994. Am J Clin Nutr

2002;76:187–92.[Abstract/Free Full Text]

(9) Holick MF. Vitamin D. A millennium perspective. J Cell Biochem

2003;88:296–307.[CrossRef][iSI][Medline]

(10) Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF. Target cells for

1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin,

pituitary, and parathyroid. Science 1979;20:1188–90.

(11) Colston K, Colston MJ, Feldman D. 1,25-Dihydroxyvitamin D3 and

malignant melanoma: the presence of receptors and inhibition of cell

growth in culture. Endocrinology 1981;108:1083–6.[Abstract]

(12) Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, Yamazaki T, et

al. Differentiation of mouse myeloid leukemia cells induced by 1

alpha,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A

1981;78:4990–4.[Abstract/Free Full Text]

(13) Agoston ES, Hatcher MA, Kensler TW, Posner GH. Vitamin D analogs

as anti-carcinogenic agents. Anticancer Agents Med Chem

2006;6:53–71.[Medline]

(14) Schwartz GG, Hall MC, Stindt D, Patton S, Lovato J, Torti FM.

Phase I/II trial of 19-nor-1[alpha]-25-hydroxyvitamin D2

(paricalcitol) in advanced, androgen-insensitive prostate cancer. Clin

Cancer Res 2005;11:8680–5.[Abstract/Free Full Text]

(15) Schwartz GG, Whitlach LW, Chen TC, Lokeshwar BL, Holick MF. Human

prostate cells synthesize 1,25-dihydroxyvitamin D3 from

25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev

1998;7:391–5.[Abstract/Free Full Text]

(16) Townsend K, KN, MJ, Colston KW, JS, Hewison

M. Biological actions of extra-renal 25-hydroxyvitamin

D-1-alpha-hydroxylase and implications for chemoprevention and

treatment. J Steroid Biochem Mol Biol

2005;97:103–9.[CrossRef][iSI][Medline]

(17) Liberman DA, Prindiville S, Weiss DG, Willett W, VA ative

Study Group 380. Risk factors for advanced colonic neoplasia and

hyperplastic polyps in asymptomatic individuals. JAMA

2003;22:2959–67.[CrossRef]

(18) EM, Schwartz GG, Koo J, Van den Berg D, Ingles SA. Sun

exposure, vitamin D gene polymorphisms and risk of advanced prostate

cancer. Cancer Res 2005;65:5470–9.[Abstract/Free Full Text]

(19) ATBC Study Group. The effect of vitamin E and beta carotene on

the incidence of lung cancer and other cancers in male smokers. N Engl

J Med 1994;330:1029–35.[Abstract/Free Full Text]

(20) Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass

A, et al. Effects of a combination of beta carotene and vitamin A on

lung cancer and cardiovascular disease. N Engl J Med

1996;334:1150–5.[Abstract/Free Full Text]

(21) Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker D, Manson JE, et

al. Vitamin E in the primary prevention of cardiovascular disease and

cancer: the Women's Health Study. JAMA 2005;294:56–61.[Abstract/Free

Full Text]

(22) Manson JE, Hsia J, KS, Rossouw JE, Assaf AR, Lasser NL,

et al. Estrogen plus progestin and the risk of coronary heart disease.

N Engl J Med 2003;349:523–34.[Abstract/Free Full Text]

(23) Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich

P, Dawson- B. Fracture prevention with vitamin D

supplementation: a meta-analysis of randomized controlled trials. JAMA

2005;293:2257–64.[Abstract/Free Full Text]

(24) Wolpowitz D, Gilchrist BA. The vitamin D questions: how much do

you need and how should you get it? J Am Acad Dermatol

2006;54:301–17.[CrossRef][iSI][Medline]

(25) Dawson- B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth

R. Estimates of optimal vitamin D status. Osteoporosis Int

2005;16:713–6.[CrossRef][iSI][Medline]

(26) Wactawski-Wende J, Kotchen JM, GL, Assaf AR, Brunner RL,

O'Sullivan MJ, et al. Calcium plus vitamin D supplementation and the

risk of colorectal cancer. N Engl J Med 2006;354:684–96.[Abstract/Free

Full Text]

(27) Hanley DA, on KS. Vitamin D insufficiency in North America.

J Nutr 2005;135:332–7.[Abstract/Free Full Text]

April 6, 2006

Forgot to include the 3rd article, which can be found here:

http://www.nutraingredients.com/news/ng.asp?n=66913 & m=1NIE406 & c=lqeudkujayvvlpc

++++++++++++++++++++++++++

>

> A new study led by led by Giovannucci from Harvard School of

> Public Health, and published yesterday in the Journal of the National

> Cancer Institute, claims raising the RDA of vitamin D from 400 IU to

> 1500 IU could cut the number of deaths from cancer by 30 per cent.

>

> 3 articles with links and full text below:

>

> +++++++++++++++++++++

>

http://jncicancerspectrum.oxfordjournals.org/cgi/content/abstract/jnci;98/7/451

>

> ARTICLE

> Prospective Study of Predictors of Vitamin D Status and Cancer

> Incidence and Mortality in Men

>

> Giovannucci, Yan Liu, B. Rimm, Bruce W. Hollis, S.

> Fuchs, Meir J. Stampfer, Walter C. Willett

>

> Affiliations of authors: Channing Laboratory, Department of Medicine,

> Harvard Medical School and Brigham and Women's Hospital, Boston, MA

> (EG, EBR, CSF, MJS, WCW); Department of Nutrition (EG, YL, EBR, MJS,

> WCW), Department of Epidemiology (EG, EBR, MJS, WCW), Harvard School

> of Public Health, Boston, MA; Department of Pediatrics, Medical

> University of South Carolina, ton, SC (BWH); Department of

> Adult Oncology, Dana-Farber Cancer Institute, Boston, MA (CSF)

>

> Correspondence to: Giovannucci, MD, ScD, Harvard School of

> Public Health, 665 Huntington Ave., Boston, MA 02115 (e-mail:

> edward.giovannucci@...).

>

> Background: Vitamin D has potent anticancer properties, especially

> against digestive-system cancers. Many human studies have used

> geographic residence as a marker of solar ultraviolet B and hence

> vitamin D exposure. Here, we considered multiple determinants of

> vitamin D exposure (dietary and supplementary vitamin D, skin

> pigmentation, adiposity, geographic residence, and leisure-time

> physical activity—to estimate sunlight exposure) in relation to cancer

> risk in the Health Professionals Follow-Up Study. Methods: Among 1095

> men of this cohort, we quantified the relation of these six

> determinants to plasma 25-hydroxy-vitamin D [25(OH)D] level by use of

> a multiple linear regression model. We used results from the model to

> compute a predicted 25(OH)D level for each of 47 800 men in the cohort

> based on these characteristics. We then prospectively examined this

> variable in relation to cancer risk with multivariable

> proportional hazards models. Results: From 1986 through January 31,

> 2000, we documented 4286 incident cancers (excluding organ-confined

> prostate cancer and nonmelanoma skin cancer) and 2025 deaths from

> cancer. From multivariable models, an increment of 25 nmol/L in

> predicted 25(OH)D level was associated with a 17% reduction in total

> cancer incidence (multivariable relative risk [RR] = 0.83, 95%

> confidence interval [CI] = 0.74 to 0.92), a 29% reduction in total

> cancer mortality (RR = 0.71, 95% CI = 0.60 to 0.83), and a 45%

> reduction in digestive-system cancer mortality (RR = 0.55, 95% CI =

> 0.41 to 0.74). The absolute annual rate of total cancer was 758 per

> 100 000 men in the bottom decile of predicted 25(OH)D and 674 per 100

> 000 men for the top decile; these respective rates were 326 per 100

> 000 and 277 per 100 000 for total cancer mortality and 128 per 100 000

> and 78 per 100 000 for digestive-system cancer mortality. Results were

> similar when we controlled further for body mass index or physical

> activity level. Conclusions: Low levels of vitamin D may be associated

> with increased cancer incidence and mortality in men, particularly for

> digestive-system cancers. The vitamin D supplementation necessary to

> achieve a 25(OH)D increment of 25 nmol/L may be at least 1500 IU/day.

>

> +++++++++++++++++++++

>

http://jncicancerspectrum.oxfordjournals.org/cgi/content/full/jnci;98/7/428

>

> EDITORIAL

> Vitamin D Status and Cancer Incidence and Mortality: Something New

> Under the Sun

> G. Schwartz, J. Blot

>

> Affiliations of authors: Comprehensive Cancer Center of Wake Forest

> University, Winston-Salem, NC (GGS); International Epidemiology

> Institute, Rockville, MD, and Vanderbilt-Ingram Cancer Center,

> Vanderbilt University Medical Center, Nashville, TN (WJB)

>

> Correspondence to: G. Schwartz, MPH, PhD, Departments of Cancer

> Biology and Epidemiology, Wake Forest University, School of Medicine,

> Winston-Salem, NC 27157 (e-mail: gschwart@...).

>

> In this era of tumor genomics, proteomics, and metabolomics, the idea

> that fundamental insights about cancer could emerge from observations

> of the gross characteristics of individual persons (i.e., from

> classical epidemiology) seems almost anachronistic. Surely the era of

> discovery of common exposures with broad effects on cancer is over. Or

> is it?

>

> In this issue of the Journal, Giovannucci et al. (1) report that

> estimates of vitamin D status derived from the Health Professionals

> Follow-up Study were associated with statistically significant

> reductions in total cancer incidence and mortality. Most of the

> protective effect for vitamin D status comes from an exposure that is

> common indeed—sunlight. Because many persons think of sunlight only as

> a cause of cancer (especially melanoma), some perspective may be

helpful.

>

> In 1941, Apperly (2), a pathologist, demonstrated an inverse

> correlation between levels of ultraviolet radiation in North America

> and mortality rates from cancers in nonskin sites and proposed that

> sunlight somehow conferred " a relative cancer immunity " to nonskin

> cancers. Although Apperly's paper attracted little attention in its

> day, epidemiologists rediscovered his fundamental insight half a

> century later. Many common cancers, such as cancers of the colon and

> prostate, display fascinating north–south gradients, with rates that

> increase systematically with increasing geographic latitude, and show

> an increased risk among African Americans (3). The increased risk with

> residence at northern latitudes and greater incidence and mortality in

> persons with dark pigmentation recall the descriptive epidemiology of

> rickets, the classic disease of vitamin D deficiency. These

> considerations led several epidemiologists, including Garland and

> Garland (4) for the colon in 1980, and Schwartz and Hulka (5) for the

> prostate in 1990, to propose that vitamin D deficiency increased the

> risk for these cancers. Similar claims later were made for cancers at

> other sites, e.g., breast, ovary, and pancreas, so that vitamin D has

> become a prime candidate for cancer prevention (6,7).

>

> Understanding how vitamin D could influence cancer risk requires an

> understanding of vitamin D synthesis. The synthesis of vitamin D

> begins with the production of vitamin D3 (cholecalciferol) after

> 7-dehydrocholesterol in the skin is exposed to ultraviolet B radiation

> (wavelength = 290–315 nm). Because melanin is an effective sunscreen,

> given the same ultraviolet exposure, blacks synthesize less vitamin D

> than whites, accounting for the far higher prevalence of vitamin D

> deficiency among blacks (8). Vitamin D can also be obtained from the

> diet, although the quantity of vitamin D in Western diets is generally

> small. To become biologically active, vitamin D undergoes two

> hydroxylations: The first occurs in the liver at the 25th carbon

> position, forming 25-hydroxyvitamin D [25(OH)D or calcidiol], the

> prohormone and major circulating form of vitamin D; the second occurs

> at the 1{alpha} position, forming 1,25(OH)2D (calcitriol), the

> hormonal form of vitamin D. Most of the biological effects of

> 1,25(OH)2D are mediated by specific hormone receptors (vitamin D

> receptors, or VDRs) (9).

>

> In 1979 VDRs were identified in normal cells that were not involved in

> mineral metabolism (10). In 1981, VDRs were found in malignant

> melanoma cells, and 1,25(OH)2D inhibited their proliferation (11);

> also, myeloid leukemia cells were induced to differentiate into

> macrophages by nanomolar concentrations of 1,25(OH)2D (12). These

> observations led to an explosion of interest in the role of 1,25(OH)2D

> in many cell types, where the pleiotropic anticancer effects of

> 1,25(OH)2D, including those on cell cycle, invasion, and metastasis,

> were widely confirmed. These findings have now led to the exploration

> of 1,25(OH)2D and its analogs as cancer therapeutic agents (13,14).

>

> Although possible mechanisms for the anticancer effects of 1,25(OH)2D

> were becoming evident, how sunlight or vitamin D could influence

> cancer risk was not, because serum levels of 1,25(OH)2D are tightly

> controlled by the kidney and generally do not vary with geographic

> latitude or race. How, then, could vitamin D deficiency contribute to

> the north–south gradients and African American excess in cancer rates?

> This problem was solved by the demonstration that many nonrenal cells,

> such as prostate and colon cells, can also hydroxylate 25(OH)D at the

> 1{alpha} position and synthesize 1,25(OH)2D locally. In these cells,

> 1,25(OH)2D promotes differentiation and inhibits proliferation in a

> microendocrine fashion (15). The implications of the extrarenal

> synthesis of 1,25(OH)2D by nonclassical cells are profound; they imply

> that sunlight exposure, which produces greater serum levels of

> 25(OH)D, could result in a decreased risk of cancer in the sites where

> 1,25(OH)2D is synthesized locally (16).

>

> The knowledge that many factors—including skin pigmentation,

> geographic latitude, and outdoor exposure—contribute to plasma levels

> of 25(OH)D enabled Giovannucci et al. (1) to attempt an assessment of

> the contribution of these factors to cancer risk. They assayed plasma

> 25(OH)D among a subset of 1095 men in the Health Professionals

> Follow-Up Study and used a linear regression model incorporating six

> personal characteristics (dietary and supplemental vitamin D, race,

> adiposity, geographic residence, and leisure-time physical activity)

> as predictors of the plasma levels of 25(OH)D. They then used this

> statistical model to compute predicted 25(OH)D levels for all 47 800

> men in the cohort and examined whether the 25(OH)D index was related

> to subsequent cancer risk. They report that an increment of 25 nmol/L

> (10 ng/ml) in predicted 25(OH)D was associated with a 17% reduction in

> total cancer incidence (relative risk [RR] = 0.83, 95% confidence

> interval [CI] = 0.73 to 0.94) and a 29% reduction in total cancer

> mortality (RR = 0.71, 95% CI = 0.60 to 0.83), with even stronger

> effects for digestive cancer. The findings from this cohort study are

> the latest of several (7,17,18) linking vitamin D status with reduced

> cancer risk and are some of the most compelling yet. The results, with

> lower risks of most (but not all) forms of cancer, are also some of

> the most broad based, and they indicate that vitamin D may have a role

> in most human tumors.

>

> Although the cohort findings are likely to increase enthusiasm for the

> cancer prevention potential of vitamin D, inherent limitations of

> observational epidemiologic studies combined with a history of prior

> disappointments with other potential chemopreventive agents suggest

> caution in their interpretation. Two decades ago there was intense

> interest and hope that supplementation with beta-carotene might reduce

> the risk of several cancers. Epidemiologic studies have consistently

> reported that men and women with the highest dietary intakes of

> beta-carotene as well as with elevated blood levels experienced lower

> risks of respiratory, gastrointestinal, and other cancers. The zeal

> was crushed, however, when randomized trials in the United States and

> Finland showed increased rather than decreased risks of lung cancer

> among adults receiving beta-carotene supplements (19,20). Vitamin E

> was similarly touted as an inhibitor of cancer, as well as of

> cardiovascular disease, but again the " gold standard " of randomized

> trials failed to confirm the preventive correlations noted in cohort

> and case–control studies (21). Epidemiologic studies also strongly

> indicated that hormone replacement therapy might not only relieve

> menopausal symptoms but also lower the risk of heart disease and

> breast and other cancers, but again, when clinical trials were

> conducted, no benefit with respect to these conditions accrued to

> women administered the therapy (22). In each of these examples, the

> agents may have demonstrated benefit with modification of the dose,

> formulation, or timing of the intervention or with longer follow-up,

> but the sobering lesson is that trends observed in nonexperimental

> settings, including cohort studies, are not always confirmed

> experimentally when tested in randomized clinical trials. Science,

> after all, is a continual process of hypothesis formulation, testing,

> and refinement; ecologic (e.g., geographic correlations) and analytic

> (e.g., cohort and case–control) studies provide the evidence-based

> clues to cancer etiology, but randomized trials are generally needed

> to confirm these leads and develop effective disease prevention

> strategies.

>

> Will a similar unrealized promise eventually befall vitamin D? We hope

> not. Although ex post facto mechanistic explanations can often be

> postulated to explain epidemiologic observations, for vitamin D the

> biologic evidence for inhibition of carcinogenesis is strong and,

> often, was predicted by the prior epidemiologic findings on sunlight

> exposure. Laboratory and observational epidemiologic research will

> continue to further elucidate and refine hypotheses on vitamin D's

> role, but the potential for cancer prevention by vitamin D (in pill

> form) must now proceed to the clinical trial testing arena. Several

> randomized trials have assessed the effects of vitamin D

> supplementation on bone fracture (23), but few have assessed its

> preventive effect on the risk of cancer or precancerous lesions

> [although small trials are evaluating 1,25(OH)2D or it is analogs on

> the treatment of prostate and other cancers].

>

> We close with the recognition that heavy sun exposure can cause harm.

> Because the ultraviolet radiation action spectra required for vitamin

> D synthesis and the spectra that induce DNA damage are essentially the

> same, there is an apparent conflict between the advantages of sunlight

> exposure for vitamin D synthesis and its deleterious effects, the most

> serious being malignant melanoma. Although much has been made of it in

> the lay press, and by some in the dermatology community, the conflict

> may be more apparent than real (24). The amount of sun needed to

> produce adequate levels of vitamin D, at least for bone health, is

> modest and can be obtained in a light-skinned person by a brief

> afternoon summertime stroll. Although the dose–response relation

> between ultraviolet exposure and the development of melanoma is not

> well quantified, the limited exposure required for vitamin D synthesis

> is likely at the very low end of the curve.

>

> Sunlight generally is an effective means of generating large amounts

> of vitamin D, but it may not be safe for all persons. For many

> individuals, including those who are darkly pigmented or who live at

> northern latitudes, sunlight exposure may also be insufficient to

> generate adequate vitamin D. Conversely, vitamin D supplements are

> widely available, inexpensive, and believed to be safe over a large

> dosing range. As is often pointed out, the present recommended

> allowance for vitamin D—400 IU—for individuals aged 50–70 years is

> inadequate even to maintain skeletal health and is probably too low

> for meaningful anticancer effects (25). A dose of 400 IU of vitamin D3

> will raise serum levels of 25(OH)D3 only modestly, by about 7 nmol/L

> or less than 3 ng/mL. The use of this low dose, in conjunction with

> the relatively short duration of the trial, may explain the recent

> failure of vitamin D to reduce the incidence of colorectal cancer in

> the Women's Health Initiative (26).

>

> In summary, a role for sunlight and vitamin D in cancer prevention is

> strongly suggested by epidemiologic observations, including the

> findings of Giovannucci et al. (1), and potential mechanisms have been

> identified by experimental studies. The promising results from both

> observational and laboratory studies should usher in a new era of

> intervention studies of vitamin D and cancer risk. Because many public

> health scientists are already clamoring for higher levels of vitamin D

> supplementation for bone and other health, randomized trials of

> vitamin D and cancer risk should be undertaken speedily (27). If the

> promise of vitamin D holds, a brief walk in the sun may turn out to be

> a step toward cancer prevention.

>

> REFERENCES

>

> (1) Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ,

> Willett WC. Prospective study of predictors of vitamin D status and

> cancer incidence and mortality in men. J Natl Cancer Inst

> 2006;98:451–9.[Abstract/Free Full Text]

>

> (2) Apperly FL. The relation of solar radiation to cancer mortality in

> North America. Cancer Res 1941;1:191–5.

>

> (3) Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer

> mortality: evidence for a protective effect of ultraviolet radiation.

> Cancer 1992;70:2861–9.[iSI][Medline]

>

> (4) Garland CF, Garland FC. Do sunlight and vitamin D reduce the

> likelihood of colon cancer? Int J Epidemiol

> 1980;9:227–31.[Abstract/Free Full Text]

>

> (5) Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor for

> prostate cancer? (Hypothesis). Anticancer Res

> 1990;10:1307–11.[iSI][Medline]

>

> (6) Studzinski GP, DC. Sunlight—can it prevent as well as cause

> cancer? Cancer Res 1995;55:4014–22.[Abstract]

>

> (7) Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB,

> et al. The role of vitamin D in cancer prevention. Am J Public Health

> 2006;96:252–61.[Abstract/Free Full Text]

>

> (8) Nesby-Odell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW,

> Looker AC, et al. Hypovitaminosis D prevalence and determinants among

> African American and white women of reproductive age: Third National

> Health and Nutrition Examination Survey 1988–1994. Am J Clin Nutr

> 2002;76:187–92.[Abstract/Free Full Text]

>

> (9) Holick MF. Vitamin D. A millennium perspective. J Cell Biochem

> 2003;88:296–307.[CrossRef][iSI][Medline]

>

> (10) Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF. Target cells for

> 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin,

> pituitary, and parathyroid. Science 1979;20:1188–90.

>

> (11) Colston K, Colston MJ, Feldman D. 1,25-Dihydroxyvitamin D3 and

> malignant melanoma: the presence of receptors and inhibition of cell

> growth in culture. Endocrinology 1981;108:1083–6.[Abstract]

>

> (12) Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, Yamazaki T, et

> al. Differentiation of mouse myeloid leukemia cells induced by 1

> alpha,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A

> 1981;78:4990–4.[Abstract/Free Full Text]

>

> (13) Agoston ES, Hatcher MA, Kensler TW, Posner GH. Vitamin D analogs

> as anti-carcinogenic agents. Anticancer Agents Med Chem

> 2006;6:53–71.[Medline]

>

> (14) Schwartz GG, Hall MC, Stindt D, Patton S, Lovato J, Torti FM.

> Phase I/II trial of 19-nor-1[alpha]-25-hydroxyvitamin D2

> (paricalcitol) in advanced, androgen-insensitive prostate cancer. Clin

> Cancer Res 2005;11:8680–5.[Abstract/Free Full Text]

>

> (15) Schwartz GG, Whitlach LW, Chen TC, Lokeshwar BL, Holick MF. Human

> prostate cells synthesize 1,25-dihydroxyvitamin D3 from

> 25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev

> 1998;7:391–5.[Abstract/Free Full Text]

>

> (16) Townsend K, KN, MJ, Colston KW, JS, Hewison

> M. Biological actions of extra-renal 25-hydroxyvitamin

> D-1-alpha-hydroxylase and implications for chemoprevention and

> treatment. J Steroid Biochem Mol Biol

> 2005;97:103–9.[CrossRef][iSI][Medline]

>

> (17) Liberman DA, Prindiville S, Weiss DG, Willett W, VA ative

> Study Group 380. Risk factors for advanced colonic neoplasia and

> hyperplastic polyps in asymptomatic individuals. JAMA

> 2003;22:2959–67.[CrossRef]

>

> (18) EM, Schwartz GG, Koo J, Van den Berg D, Ingles SA. Sun

> exposure, vitamin D gene polymorphisms and risk of advanced prostate

> cancer. Cancer Res 2005;65:5470–9.[Abstract/Free Full Text]

>

> (19) ATBC Study Group. The effect of vitamin E and beta carotene on

> the incidence of lung cancer and other cancers in male smokers. N Engl

> J Med 1994;330:1029–35.[Abstract/Free Full Text]

>

> (20) Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass

> A, et al. Effects of a combination of beta carotene and vitamin A on

> lung cancer and cardiovascular disease. N Engl J Med

> 1996;334:1150–5.[Abstract/Free Full Text]

>

> (21) Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker D, Manson JE, et

> al. Vitamin E in the primary prevention of cardiovascular disease and

> cancer: the Women's Health Study. JAMA 2005;294:56–61.[Abstract/Free

> Full Text]

>

> (22) Manson JE, Hsia J, KS, Rossouw JE, Assaf AR, Lasser NL,

> et al. Estrogen plus progestin and the risk of coronary heart disease.

> N Engl J Med 2003;349:523–34.[Abstract/Free Full Text]

>

> (23) Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich

> P, Dawson- B. Fracture prevention with vitamin D

> supplementation: a meta-analysis of randomized controlled trials. JAMA

> 2005;293:2257–64.[Abstract/Free Full Text]

>

> (24) Wolpowitz D, Gilchrist BA. The vitamin D questions: how much do

> you need and how should you get it? J Am Acad Dermatol

> 2006;54:301–17.[CrossRef][iSI][Medline]

>

> (25) Dawson- B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth

> R. Estimates of optimal vitamin D status. Osteoporosis Int

> 2005;16:713–6.[CrossRef][iSI][Medline]

>

> (26) Wactawski-Wende J, Kotchen JM, GL, Assaf AR, Brunner RL,

> O'Sullivan MJ, et al. Calcium plus vitamin D supplementation and the

> risk of colorectal cancer. N Engl J Med 2006;354:684–96.[Abstract/Free

> Full Text]

>

> (27) Hanley DA, on KS. Vitamin D insufficiency in North America.

> J Nutr 2005;135:332–7.[Abstract/Free Full Text]

>

April 6, 2006