#1 Stefan Pilz (Guest Editor)
#2 William Grant
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Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 1
Stefan Pilz (Guest Editor)
Department of Internal Medicine Division of Endocrinology and Metabolism Medical University of Graz Auenbruggerplatz 15, 8036 Graz Austria Tel: ++43 650 9103667 Fax: ++43 316 673216 E-mail: stefan.pilz at chello.at
A potential association of vitamin D and cancer is an issue of great public health interest because vitamin D deficiency is common in general populations .
Many people are well aware that sunlight exposure is on the one hand required for endogenous vitamin D synthesis but may on the other hand cause skin cancer. By contrast, the observation that ultraviolet-B (UV-B) exposure is associated with reduced risk of overall cancer mortality is not so generally known although this UV-B cancer link was a starting point for vitamin D cancer research [2-4].
Numerous experimental and observational studies have meanwhile addressed the relationship of vitamin D and cancer and have, by the majority, supported the hypothesis that vitamin D might be useful for the prevention and treatment of cancer [5-7].
When discussing clinical use of vitamin D supplementation, the attention is often guided to past experiences with other micronutrients (e.g. vitamin E) that revealed promising anti-cancer properties in cell culture and observational studies but failed to show benefits or were even harmful in the clinical application. It should be underlined that vitamin D significantly differs from other micronutrients because vitamin D has a unique metabolism with endogenous UV-B induced vitamin D synthesis in the skin. Apart from this, vitamin D metabolites can be rather regarded as hormones than as vitamins and regulate approximately three percent of the human genome by binding to the almost ubiquitously expressed vitamin D receptor (VDR) .
While there is an ongoing debate on vitamin D status classification and optimal vitamin D dosing, it is widely accepted that vitamin D supplementation exerts beneficial effects on skeletal health [8-10].
These data were the basis for dietary reference intakes for vitamin D and for recommendations to supplement vitamin D in osteoporosis patients and in children for the prevention of rickets [8-10].
At present, there is no RCT published that was specifically designed and powered to study vitamin D effects on cancer. Interpretations of data on vitamin D supplementation and cancer as a secondary outcome are therefore limited but it should be acknowledged that available RCTs have largely failed to show significant anti-cancer effects of vitamin D whereas only some RCT data support the notion that vitamin D may significantly protect against cancer [6,9-13].
Therefore, we need further vitamin D RCTs, but after decades of research this should not be the only conclusion that we can draw from thousands of publications in this field. Rather than showing that there exists universal agreement it was an aim of this special issue to document that there exist different views, conclusions and recommendations of the experts regarding vitamin D and cancer. Given that some vitamin D RCTs are already ongoing we will have significantly more data within the next few years .
These RCTs will be essential for future vitamin D guidelines but we should also critically discuss the design of these RCTs and ask the question whether they have sufficiently considered the knowledge derived from previously published epidemiological studies .
In addition to RCTs among general populations it will therefore be important to study cohorts that are likewise particularly vitamin D sensitive, i.e. individuals suffering from overt vitamin D deficiency. Nevertheless, at present we have to deal with the currently available evidence when considering vitamin D treatment or vitamin D food fortification for our patients or for the general population. In this context, it should always be noted that vitamin D signalling is, beyond skeletal health, involved in the pathogenesis of many different diseases with a potential impact even on overall mortality [1,5,7,15-20].
However, whereas many data suggest beneficial effects of vitamin D for several health outcomes we must also pay particular attention to potentially harmful effects of vitamin D overdosing when discussing a general vitamin D supplementation or food fortification. This special issue aims to provide an overview of the current status and future perspective of vitamin D and cancer and covers topics related to basic as well as clinical research in order to give some guidance for future cancer research as well as for current considerations regarding the use of vitamin D treatment.
Stefan Pilz et al. review data from prospective studies on 25-hydroxyvitamin D and cancer mortality in their work.
William B Grant highlights in his article that higher UV-B irradiance is associated with reduced risk of cancer.
Julia Hobaus et al. summarize the important role of vitamin D metabolism (i.e. vitamin D hydroxylases) and its crosstalk with calcium in cancer pathogenesis and cancer prevention.
Kun-Chun Chiang & Tai C Chen provide an overview of molecular anti-cancer actions of vitamin D in their article.
Rebecca S Mason and Jorg Reichrath summarize the existing literature on the relationship of sunlight, vitamin D and skin cancer and discuss positive and negative effects of UV exposure with regard to skin cancer and overall health.
Rowan T Chlebowski reviewed clinical data on vitamin D and breast cancer and concludes that current evidence does not support the use of high dose vitamin D supplementation in anticipation of benefit for breast cancer recurrence or breast cancer survival.
Epidemiological data on vitamin D and colorectal cancer are summarized by Edward Giovannucci who underlines that the association of vitamin D deficiency and colorectal cancer is strongly suggestive of a causal association.
Gary G Schwartz presents an overview on vitamin D, UV exposure and prostate cancer and points out that these relationships may be modulated according to the prevailing calcium intake.
Kathy J Helzlsouer & Lisa Gallicchio summarize clinical data on vitamin D and rare cancer sites and conclude that while there is little evidence that higher vitamin D status may be protective for some rare cancer sites there exist conflicting results regarding increased pancreatic cancer risk at very high vitamin D levels.
Matteo Lazzeroni et al. review RCTs on vitamin D supplementation and cancer and discuss the conclusions that can be drawn from published RCTs and what can be expected from ongoing vitamin D RCTs.
Heike Bischoff-Ferrari summarizes beneficial musculoskeletal effects of vitamin D supplementation in cancer patients.
Jean-Claude Souberbielle and Etienne Cavalier provide an overview on vitamin D status assessment and give some practical guidance for vitamin D testing and supplementation.
Armin Zittermann et al. highlight pathophysiological and clinical data regarding safety issues of vitamin D supplementation.
Finally, Michael F Holick summarizes current knowledge on the vitamin D, sunlight and cancer connection and gives some advice for clinical vitamin D treatment. In conclusion, this special issue gives an up to date overview on almost all aspects regarding vitamin D and cancer.
 Holick, M.F. Vitamin D deficiency. N. Engl. J. Med., 2007, 357(3), 266-283.
 Garland, C.F.; Garland, F.C. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int. J. Epidemiol., 1980, 9(3), 227-31.
 Apperly, F.L. The Relation of Solar Radiation to Cancer Mortality in North America. Cancer. Res., 1941, 7(3), 191-195.
 Grant, W.B.; Mohr, S.B. Ecological studies of ultraviolet B, vitamin D and cancer since 2000. Ann. Epidemiol., 2009, 19(7), 446-54.
 Deeb, K.K.; Trump, D.L.; Johnson, C.S. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat. Rev. Cancer., 2007, 7(9), 684-700.
 Pilz, S.; Tomaschitz, A.; Obermayer-Pietsch, B.; Dobnig, H.; Pieber, T.R. Epidemiology of vitamin D insufficiency and cancer mortality. Anticancer Res., 2009, 29(9), 3699-704.
 Bouillon, R.; Carmeliet, G.; Verlinden, L.; van Etten, E.; Verstuyf, A.; Luderer, H.F.; Lieben, L.; Mathieu, C.; Demay, M. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr. Rev., 2008, 29(6), 726-76.
 Bischoff-Ferrari, H.A.; Willett, W.C.; Wong, J.B.; Stuck, A.E.; Staehelin, H.B.; Orav, E.J.; Thoma, A.; Kiel, D.P.; Henschkowski, J. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch. Intern. Med., 2009, 169(6), 551-61.
 Ross, A.C.; Manson, J.E.; Abrams, S.A.; Aloia, J.F.; Brannon, P.M.; Clinton, S.K.; Durazo-Arvizu, R.A.; Gallagher, J.C.; Gallo, R.L.; Jones, G.; Kovacs, C.S.; Mayne, S.T.; Rosen, C.J.; Shapses, S.A. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J. Clin. Endocrinol. Metab., 2011, 96(1), 53-8.
 Holick, M.F.; Binkley, N.C.; Bischoff-Ferrari, H.A.; Gordon, C.M.; Hanley, D.A.; Heaney, R.P.; Murad, M.H.; Weaver, C.M.; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab., 2011, 96(7), 1911-30.
 Bolland, M.J.; Grey, A.; Gamble, G.D.; Reid, I.R. 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, 94(4), 1144-9.
 Brunner, R.L.; Wactawski-Wende, J.; Caan, B.J.; Cochrane, B.B.; Chlebowski, R.T.; Gass, M.L.; Jacobs, E.T.; LaCroix, A.Z.; Lane, D.; Larson, J.; Margolis, K.L.; Millen, A.E.; Sarto, G.E.; Vitolins, M.Z.; Wallace, R.B. The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial. Nutr. Cancer., 2011, 63(6), 827-41.
 Lappe, J.M.; Travers-Gustafson, D.; Davies, K.M.; Recker, R.R.; Heaney, R.P. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am. J. Clin. Nutr., 2007, 85(6), 1586-91.
 Manson, J.E.; Bassuk, S.S.; Lee, I.M.; Cook, N.R.; Albert, M.A.; Gordon, D.; Zaharris, E.; Macfadyen, J.G.; Danielson, E.; Lin, J.; Zhang, S.M.; Buring, J.E. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp. Clin. Trials., 2012, 33(1), 159-71.
 Pilz, S.; Tomaschitz, A.; Marz, W.; Drechsler, C.; Ritz, E.; Zittermann, A.; Cavalier, E.; Pieber, T.R.; Lappe, J.M.; Grant, W.B.; Holick, M.F.; Dekker, J.M. Vitamin D, cardiovascular disease and mortality. Clin. Endocrinol. (Oxf.), 2011, 75(5), 575-84.
 Lips, P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr. Rev., 2001, 22(4), 477-501.
 Pilz, S.; Tomaschitz, A.; Drechsler, C.; Zittermann, A.; Dekker, J.M.; Marz, W. Vitamin D supplementation: a promising approach for the prevention and treatment of strokes. Curr. Drug Targets, 2011, 12(1), 88-96.
 Zittermann, A.; Iodice, S.; Pilz, S.; Grant, W.B.; Bagnardi, V.; Gandini, S. Vitamin D deficiency and mortality risk in the general population: a metaanalysis of prospective cohort studies. Am. J. Clin. Nutr., 2012, 95(1), 91-100.
 Pilz, S.; Iodice, S.; Zittermann, A.; Grant, W.B.; Gandini, S. Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies. Am. J. Kidney Dis., 2011, 58(3), 374-82.
 Bjelakovic, G.; Gluud, L.L.; Nikolova, D.; Whitfield, K.; Wetterslev, J.; Simonetti, R.G.; Bjelakovic, M.; Gluud, C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst. Rev., 2011, (7), CD007470.
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. Every paper is authored by recognized experts on vitamin D and cancer and/or other health outcomes. Reports in the journal literature are discussed. Ecological studies based on geographical variation of cancer incidence and/or mortality rates have generally found the strongest relations between a vitamin D index and cancer risk. The advantages of the ecological approach include the large number of cases, the vitamin D index applies to a long time, and that confounding factors can be included in the analysis. No factor other than vitamin D production has been proposed to explain the findings regarding the solar UVB index in single-country studies. The evidence for vitamin D reducing the risk of colorectal cancer is very strong. Case-control studies incidence with respect to serum 25-hydroxyvitamin D [25(OH)D] concentration provide strong support for vitamin D reducing risk of breast cancer. The possibility of “reverse causality”, i.e., that the existence of a cancer tumor could reduce serum 25(OH)D concentrations, was discussed in some of the papers. However, since the measured beneficial effect of serum 25(OH)D decreases nearly linearly with increased follow-up time for breast and colorectal cancer and all-cause mortality rate, this effect is very unlikely. The evidence for a beneficial effect of UVB and vitamin D for prostate cancer is generally weaker than for many other types of cancer. For example, a meta-analysis of all prospective studies of prostate cancer incidence with respect to serum 25(OH)D concentration does not find a reduced risk. Also included in this issue is a paper discussing the trade-offs between solar UV exposure, vitamin D production, and risk of skin cancer. The conclusion from several papers is that serum 25(OH)D concentrations should be above 30-40 ng/ml for optimal protection against cancer, that it could take 1000-2000 IU/d or more of vitamin D3 to reach those concentrations, and that careful solar UVB irradiance is also a good source of vitamin D3.
Anti-Cancer Agents in Medicinal Chemistry Volume 13, Number 1, January 2013
Bischoff-Ferrari H. Relevance of vitamin D in bone and muscle health of cancer patients. . 2013;13(1):58-64.
Chiang KC, Chen TC. The anti-cancer actions of vitamin D. . 2013;13(1):126-39.
Chlebowski RT. Vitamin D and breast cancer incidence and outcome. . 2013;13(1):98-106.
Giovannucci E. Epidemiology of vitamin D And colorectal cancer. . 2013;13(1):11-9.
Grant WB. Update on evidence that support a role of solar ultraviolet-B irradiance in reducing cancer risk. . 2013;13(1):140-6.
Helzlsouer KJ, Gallicchio L. Shedding light on serum vitamin D concentrations and the risk of rarer cancers. . 2013;13(1):65-9.
Höbaus J, Thiem U, Hummel DM, Kallay E. Role of Calcium, Vitamin D, and the extrarenal vitamin D hydroxylases during carcinogenesis. . 2013;13(1):20-35.
Holick MF. Vitamin D, sunlight and cancer connection. . 2013;13(1):70-82.
Lazzeroni M, Serrano D, Pilz S, Gandini S. Vitamin D supplementation and cancer: Review of randomized controlled trials. . 2013;13(1):118-25.
Mason RS, Reichrath J. Sunlight vitamin D and skin cancer. . 2013;13(1):83-97.
Pilz S, Kienreich K, Tomaschitz A, Ritz E, Lerchbaum E, Obermayer-Pietsch B, Matzi V, Lindenmann J, März W, Gandini S, Dekker JM. Vitamin D and cancer mortality: Systematic review of prospective epidemiological studies. . 2013;13(1):107-17.
Pilz S. Vitamin D and cancer: current evidence and future perspective. . 2013;13(1):2-3.
Schwartz GG. Vitamin D, sunlight, and the epidemiology of prostate cancer. . 2013;13(1):45-57.
Souberbielle JC, Cavalier E. Supplementation, optimal status, and analytical determination of vitamin D: Where are we standing in 2012? . 2013;13(1):36-44.
Zittermann A, Prokop S, Gummert JF, Börgermann J. Safety issues of vitamin D supplementation. . 2013;13(1):4-10.
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 a that solar UVB irradiance in is associated with lower incidence of many cancers, such as those opf the colon and breast, with stronger effects usuallyfound 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 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 hydroxylases in cancer pathogenesis and the cross-talk between the extra-renal autocrine/paracrine system and calcium in cancer prevention.
Souberbielle et al. reviewed briefly the metabolism and various effects of as well as the assays and treatments. They defined deficiency/insufficiency considering separately the population and the patient level and proposed their opinion about which patients may benefit from 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 [Grant, 2010]. 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) [Helzlsouer, 2010] 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 [Helzlsouer, 2010]. 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 [Lim, 2009]. 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 cancer [Grant, 2011], all-cause mortality rate [Grant, 2012a], and cardiovascular disease [Wang et al., 2012]. 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: bladder [Mondul et al., 2010]; and pancreatic cancer [Skinner et al,. 2006; Wolpin et al., 2012]. 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 [Tretli et al., 2012]. Also, an inverse correlation was found for ovarian cancer prevalence in a cross-sectional study [Bakhru et al., 2010].
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 calls 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 mentions 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 perfor a similar function in winter [Oh, 2010]. When relative risk (RR) was plotted vs. follow-up time, it rose from 0.6 at zero years to 0.95 at seven years [Grant, 2011]. 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 [Bolland, 2010]. 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 studies [Grant, 2012c], and assuming that those in the Bolland reanalysis started with 16 ng/ml, then went to 20 ng/ml after supplementation [Garland et al., 2011], 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
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 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 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 RCTs and cancer. In addition we also briefly describe the design of some ongoing trials on supplementation and cancer.” See, also, the review by Lappe and Heaney  on why RCTs with vitamin D often fail.
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 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 . In this review, we describe the anti-cancer actions of , with special emphasis on different pathways underlying the VDR-mediated genomic as well as less-defined non-genomic actions of .”
Grant reviewed the evidence that solar UVB reduces the risk of cancer. “The ultraviolet-B (UVB)-vitamin D-cancer hypothesis was proposed in 1980 [Garland and Garland, 1980] yet has not been fully accepted. Ecological studies based on geographical variations of rates with respect to solar UVB doses have supported the hypothesis for about 15-20 cancers [Grant, 2012a]. 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 , 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 , as well as Hodgkin's lymphoma. Diagnosis of nonmelanoma skin 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 rates for 54 occupations in Nordic countries, a UVB index based on standardized incidence ratios of lip less those for lung was inversely correlated with 15 types of for males, but only four types for females [Grant, 2012c]. This ecological study provides additional evidence that UVB doses at high latitudes are adequate to reduce the risk of , but requires considerable time outside to produce sufficient vitamin D. Because only vitamin D production has been proposed to explain the UVB- link, studies reviewed in this paper should be considered strong evidence for the hypothesis.”
- 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.
- 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. . 2011 Oct;94(4):1144-9.
- 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.
- 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.
- Grant WB. (2010) A multicountry ecological study of risk-modifying factors for prostate cancer: Apolipoprotein E 4 as a risk factor and cereals as a risk reduction factor. Anticancer Res. 2010 Jan.;30 189-199.
- Grant WB. (2011) 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.
- Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res. 2012;32(1):223-36.
- Grant WB. (2012b) 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.
- Grant WB. (2012c) 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.
- Grant WB. (2012d) A review of the evidence regarding the solar ultraviolet-B–vitamin D–cancer hypothesis. Standardy Medyczne/Pediatria. 2012;9:610-9.
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