A set of 15 papers reviewing the evidence that ultraviolet-B (UVB) irradiance and vitamin D reduce the risk of many types of cancer was just published in the January 2013 issue of the peer-reviewed journal Anti-Cancer Agents in Medicinal Chemistry. The issue was organized by Dr. Stefan Pilz and should be considered a “symposium in print.” All papers have open access at the journal’s website. The authors of the papers are recognized international experts on vitamin D and cancer. This blog summarizes some of the conclusions of the papers, taking issue with some of them. The papers are discussed in the order in which they appear in the issue.
The editorial by Pilz sets the stage for the special issue. It notes that the field of research started with the observation that solar UVB doses were inversely correlated with cancer rates. Observational studies of serum 25-hydroxyvitamin D [25(OH)D] concentrations and cancer outcomes are mixed. Two randomized controlled trials (RCTs) have shown a protective effect of vitamin D plus calcium supplementation on cancer risk, but strong results from RCTs for vitamin D is still lacking.
Zittermann et al. discuss the ranges of 25(OH)D from deficient to excess. The concentration at which any adverse effects might occur is still being studied. In addition, the mechanisms for adverse effects are not known, although hypercalcemia and hypercalcuria have been reported in individuals with underlying diseases and/or serum 25(OH)D concentrations above 200 ng/ml.
Giovannucci reviewed the evidence that UVB and vitamin D reduce the risk of colon and rectal cancer. These are the cancers with the strongest evidence of beneficial effects of both UVB and vitamin D. The ecological (geographical) studies strongly support that solar UVB irradiance is associated with lower incidence of many cancers, such as those of the colon and breast, with stronger effects usually found for mortality rates than incidence rates. Observational studies, both case-control and prospective, have found inverse correlations between serum 25(OH)D concentrations and colorectal cancer incidence. Studies based on dietary and supplementary vitamin D intake also show beneficial effects. Higher serum 25(OH)D concentrations have also been found associated with better survival rates after diagnosis of colorectal cancer.
An RCT reported a beneficial effect of vitamin D supplementation, and that was for 400 IU/d vitamin D3 plus calcium for those not taking either supplement prior to enrolling in the study. The paper also discussed possible confounding factors for both ecological and observational studies, noting that neither body weight nor physical activity can explain the findings since they are generally controlled for. The paper notes that the mechanisms whereby vitamin D could reduce the risk of colorectal cancer are known, but stops short of claiming that vitamin D is causal in reducing risk of colorectal cancer, pending a successful large-scale RCT.
Höbaus et al. discussed the role of vitamin D hydroxylases in converting 25(OH)D to 1,25-dihydroxyvitamin D [1,25(OH)2D], the active metabolite of vitamin D. In addition, their review described the role of the vitamin D hydroxylases in cancer pathogenesis and the cross-talk between the extra-renal autocrine/paracrine vitamin D system and calcium in cancer prevention.
Souberbielle et al. reviewed briefly the metabolism and various effects of vitamin D as well as the vitamin D assays and vitamin D treatments. They defined vitamin D deficiency/insufficiency considering separately the population and the patient level and proposed their opinion about which patients may benefit from vitamin D testing.
Schwartz discussed UVB and vitamin D and risk of prostate cancer. He proposed the UVB-vitamin D-prostate cancer hypothesis in 1990. Ecological studies generally support a role of UVB in reducing risk of prostate cancer. However, in the United States, it was noted that the geographical variation of prostate cancer mortality rates is different from other cancers strongly linked to UVB and vitamin D such as breast, colon, and rectal cancer, and that the ethnic background of white Americans largely mirrors the latitudinal gradient found in Europe, with northern Europeans at higher latitudes and southern Europeans at lower latitudes.
It was proposed that a genetic variation with ethnic background, apolipoprotein E, ApoE, the gene that controls cholesterol and insulin production, might explain the geographical variation.1 ApoE epsilon4 (ApoE4), is more prevalent at higher latitudes in Europe and twice as high among African-Americans as European-Americans. ApoE4 stimulates increased production of cholesterol, which is associated with risk of prostate cancer. Observational studies based on serum 25(OH)D concentrations have generally not found a correlation with prostate cancer incidence. Some case-control studies did find inverse correlations, but there is the possibility that the prostate cancer tumors reduced serum 25(OH)D concentrations, an effect called “reverse causality.” Perhaps some of the stronger evidence for an effect of UVB and vitamin D in reducing risk of prostate cancer comes from the studies of solar UVB doses experienced by individuals in cohort studies. These studies generally find significant inverse correlations. Additional supportive evidence comes from studies of vitamin D receptor (VDR) alleles or genetic variations. Several VDRs have been associated with increased or decreased risk of prostate cancer. This paper also discussed the finding by Schwartz that higher serum calcium concentrations are associated with poorer survival from prostate cancer.
Bischoff-Ferrari reviews the evidence that vitamin D helps strengthen bones and muscles in general, notes that cancer patients are prone to vitamin D deficiency, suggesting that they be supplemented with vitamin D. However, the effect of vitamin D concentrations above 50 ng/ml on risk of falls, fractures and weak muscles has not been studied.
Helzlsouer and Gallicchio review the evidence regarding the potentially beneficial role of vitamin D in several rarer cancers: bladder, endometrial, esophageal, gastric, kidney, ovarian, pancreatic cancer and non-Hodgkin’s lymphoma (NHL). The studies forming the basis for much of the discussion are the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP)2 and several studies from the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study in Finland. A fundamental problem in studying the rarer cancers is that since they are rare, it is difficult to obtain a sufficient number of cases to reduce the uncertainties of the risk sufficiently to find statistically significant results. In the VDPP for example, the 95% confidence intervals for any quantile of serum 25(OH)D concentration were about 30% to 50%, making it difficult to observe an effect of vitamin D.2 A problem with the ATBC series of studies is that follow-up periods up to 17 years after blood draw were used.
In one of those studies, on lymphoid cancers, an inverse correlation with respect to serum 25(OH)D concentration was found for the first seven years, while a direct correlation was found for the next ten years of follow up.3 The problem with long follow-up times is that serum 25(OH)D concentrations change with time. It was shown that this effect reduces the apparent beneficial effect of serum 25(OH)D for breast and colorectal cancer4, all-cause mortality rate5, and cardiovascular disease.6 As for the types of cancer reviewed by Helzlsouer and Galicchio, some studies did find inverse correlations of incidence with respect to serum 25(OH)D concentrations in prospective studies: bladder7; and pancreatic cancer.8, 9 In addition, a study in Norway found a significantly reduced mortality rate over a nine-year period for lymphoma for those with higher serum 25(OH)D concentration compared to the lowest concentration.10 Also, an inverse correlation was found for ovarian cancer prevalence in a cross-sectional study.11
Holick reviewed the evidence that vitamin D and sunlight reduce the risk of cancer. His review presented an historical overview as well as many diagrams, graphs, and tables from the published literature. In his conclusion, he notes that since VDRs exist in nearly every cell and that cells have the capability of producing 1,25(OH)2D provides strong support for the UVB-vitamin D-cancer hypothesis, and that 40-60 ng/ml “may reduce the risk of malignancy and improve survival rates for several cancers.” He also discusses the role of solar UVB as an important source of vitamin D as well as a risk factor for melanoma and skin cancer, but notes that occupational sun exposure has been associated with reduced risk of melanoma. He also mentions that vitamin D also protects against a number of other diseases.
Mason and Reichrath discuss sunlight, vitamin D, and skin cancer and diseases for which solar UVB and vitamin D are protective. The paper examines the “sunlight dilemma”, i.e. that there are both beneficial and harmful effects from sunlight exposure. The adverse effects include UV-induced DNA damage and immune suppression, which can lead to melanoma and non-malanom skin cancer (NMSC). They review the evidence that the vitamin D endocrine system may reduce the risk of both melanoma and NMSC. The paper is also strongly supportive of vitamin D for prevention of internal diseases, and mention that serum 25(OH)D concentrations should likely be above 30 ng/ml for optimal health. These concentrations can be achieved through careful sun exposure and/or vitamin D supplements of 1000-2000 IU/day.
Chlebowski reviewed the evidence that solar UVB and vitamin D can reduce the risk of breast cancer. He dismissed the ecological studies and UVB studies due to what he considered as variation in the findings across studies. However, ecological studies have found inverse correlations between solar UVB doses and breast cancer in the U.S., China, France, and Spain, after adjusting for confounding factors, so the findings seem to be robust. In more recent times, the apparent epidemiology of breast cancer may be shifting, perhaps due to widespread screening. Chlebowski also generally dismissed the findings based on serum 25(OH)D concentrations. The case-control studies have found the strongest inverse correlations between serum 25(OH)D concentration and breast cancer incidence. These studies were dismissed citing “reverse causality.”
The prospective studies with follow-up periods longer than three years identified some favorable trends, but did not identify statistically significant inverse correlations between serum 25(OH)D and breast cancer incidence. Breast cancer can progress rapidly from undetectable to detectable based on the fact that breast cancer diagnosis is higher in spring and fall than summer or winter; vitamin D protects against breast cancer in summer, while melatonin may perform a similar function in winter.12 When relative risk (RR) was plotted vs. follow-up time, it rose from 0.6 at zero years to 0.95 at seven years.4 For colorectal cancer, RR rose from 0.45 at zero years to 0.72 at 14 years of follow-up, and nearly all of the studies reported statistically significant inverse correlations. Colorectal cancer generally grows much more slowly than breast cancer. Based on these two graphs, the idea that “reverse causality” explains the findings for case-control studies of 25(OH)D and breast cancer seems unlikely.
There is one RCT that found a statistically significant 18% reduction of breast cancer incidence for 400 IU/d vitamin D3 supplementation for women who did not consume vitamin D or calcium supplements prior to enrolling in the study.13 This finding was disparaged by Chlebowski on the basis that it was unlikely that 400 IU/d was too low to have a beneficial effect. However, using the serum 25(OH)D concentration-odds ratio curve for breast cancer based on the five case-control studies14, and assuming that those in the Bolland reanalysis started with 16 ng/ml, then went to 20 ng/ml after supplementation15, a risk reduction of 15% would be expected, when estimated from the results of other research. This paper was overly pessimistic based on consideration of the all studies to date. For example, Mohr et al. reached an opposite conclusion.16
Pilz et al. reviewed the literature on vitamin D and mortality rates for those with cancer. The results for cancer-specific deaths were inconsistent. However, “the majority of studies in cancer patients showed that patients with higher 25(OH)D levels had a decreased risk of mortality.”
Lazzeroni et al. reviewed the status of RCTs on vitamin D supplementation and cancer risk. Results to date have been rather limited. “Findings from prospective cohort studies on colorectal cancer risk and on mortality constitute pieces of evidence strong enough to consider that previous randomized controlled trials (RCTs) of vitamin D use and cancer may not have correctly addressed the question, and that new randomized trials should be organized. The reasons are due to several unsolved issues including selection of the effective dose, varying baseline levels of subjects before randomization, compliance with the intervention, contamination of the placebo group (i.e., intake of vitamin D supplements by subjects allocated to the placebo group) and unknown effective lag time between start of the intervention and disease onset. The present review summarizes the existing knowledge on vitamin D RCTs and cancer. In addition we also briefly describe the design of some ongoing trials on vitamin D supplementation and cancer.” See, also, the review by Lappe and Heaney on why RCTs with vitamin D often fail.17
Chiang and Chen reviewed the anti-cancer actions of vitamin D. “Through VDR, 1α,25(OH)2D3regulates more than 200 genes in mammals, including those involved in the calcium and phosphorus homeostasis, immune function, reproduction, cardiovascular, central nerve system, inflammation, angiogenesis, and cellular proliferation, differentiation and apoptosis. Due to its versatile roles in maintaining and regulating normal cellular phenotypes and functions, 1α,25(OH)2D3 has been implicated as an anti-cancer agent. In fact, ecological and epidemiologic data have linked vitamin D deficiency with the incidence and mortality of many types of cancer. More importantly, in vitro and in vivo animal model studies have clearly demonstrated the anti-tumor effects of vitamin D. In this review, we describe the anti-cancer actions of vitamin D, with special emphasis on different pathways underlying the VDR-mediated genomic as well as less-defined non-genomic actions of vitamin D.”
I reviewed the evidence that solar UVB reduces the risk of cancer. I stated: “The ultraviolet-B (UVB)-vitamin D-cancer hypothesis was proposed in 198018 yet has not been fully accepted. Ecological studies based on geographical variations of cancer rates with respect to solar UVB doses have supported the hypothesis for about 20 cancers. This paper reviews the evidence from studies of personal or group UVB irradiance. Studies have associated personal UVB irradiance with reduced risk for breast, colon, endometrial, prostate, and renal cancer, as well as non-Hodgkin’s lymphoma (NHL). However, some studies have also found increased risk of NHL from UV irradiance, probably due to immunosuppression by UVA near 370 nm. Several related approaches have also been used to study the hypothesis. Studies in Norway and the UK found that diagnosis in summer or fall is associated with increased survival rates for breast, colon, lung, and prostate cancer, as well as Hodgkin’s lymphoma. Diagnosis of nonmelanoma skin cancer is associated with reduced risk of several cancers in sunny countries, but not often in high-latitude countries. Living at higher surface elevation is associated with reduced risk of some cancers. In a recent analyzed study of cancer rates for 54 occupations in Nordic countries, a UVB index based on standardized incidence ratios of lip cancer less those for lung cancer was inversely correlated with 15 types of cancer for males, but only four types for females.19 This ecological study provides additional evidence that UVB doses at high latitudes are adequate to reduce the risk of cancer, but requires considerable time outside to produce sufficient vitamin D. Because only vitamin D production has been proposed to explain the UVB-cancer link, studies reviewed in this paper should be considered strong evidence for the hypothesis.”
1. Grant WB. A multicountry ecological study of risk-modifying factors for prostate cancer: Apolipoprotein E e4 as a risk factor and cereals as a risk reduction factor. Anticancer Res. 2010 Jan.;30 189-199.
2. Helzlsouer KJ. For the VDPP Steering Committee. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epi, 2010 172: 4-9.
3. Lim U, Freedman DM, Hollis BW, Horst RL, Purdue MP, Chatterjee N, Weinstein SJ, Morton LM, Schatzkin A, Virtamo J, Linet MS, Hartge P, Albanes D. A prospective investigation of serum 25-hydroxyvitamin D and risk of lymphoid cancers. Int J Cancer. 2009 Feb 15;124(4):979-86.
4. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines. Dermato-Endocrinology. 2011;3(3):199-204.
5. Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res. 2012;32(1):223-36.
6. Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: A meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012 Nov 1;5(6):819-29.
7. Mondul AM, Weinstein SJ, Männistö S, Snyder K, Horst RL, Virtamo J, Albanes D. Serum vitamin D and risk of bladder cancer. Cancer Res. 2010;70 9218-9223
8. Skinner HG, Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Vitamin D intake and the risk of pancreatic cancer in two cohort studies. Cancer Epidemiol Biomarkers Prevention. 2006 Sept,; 15(9):1688-1695.
9. Wolpin BM, Ng K, Bao Y, Kraft P, Stampfer MJ, Michaud DS, Ma J, Buring JE, Sesso H, Lee IM, Rifai N, Cochrane BB, Wactawaski-Wende J, Chlebowski RT, Willett WC, Manson JE, Giovannucci EL, Fuchs CS. Plasma 25-hydroxyvitamin D and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2012;21(1):82-91.
10. Tretli S, Schwartz GG, Torjesen PA, Robsahm TE. Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study. Cancer Causes Control. 2012 Feb;23:363-70.
11. Bakhru A, Mallinger JB, Buckanovich RJ, Griggs JJ. Casting light on 25-hydroxyvitamin D deficiency in ovarian cancer: A study from the NHANES. Gynecol Oncol. 2010 Nov;119(2):314-8.
12. Oh EY, Ansell C, Nawaz H, Yang CH, Wood PA, Hrushesky WJ. Global breast cancer seasonality. Breast Cancer Res Treat. 2010 Aug;123(1):233-43.
13. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women’s Health Initiative (WHI) limited-access data set. Am J Clin Nutr. 2011 Oct;94(4):1144-9.
14. Grant WB. Role of solar UV irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol. 2012;4(2):203-11.
15. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011;31:617-22.
16. Mohr SB, Gorham ED, Alcara JE, Kane CJ, Macera CA, Parson JK, Wingard DL, Garland df. Serum 25-Hydroxyvitamin D and Prevention of Breast Cancer: Pooled Analysis. Anticancer Research September 2011 vol. 31 no. 9 2939-2948.
17. Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin. 2012;4(2):95-100.
18. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980 Sep;9(3):227-31. Grant WB. Role of solar UV irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol. 2012;4(2):203-11.
19. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyitamin D and all-cause mortality rate. Dermatoendocrinol. 2012;4(2):198-202.