Cancer mortality rates vary inversely with geographic latitude and solar ultraviolet-B doses. This relationship may be due to an inhibitory role of vitamin D on cancer development. The relationship between vitamin D and cancer appears to be stronger for studies of cancer mortality than incidence. Because cancer mortality reflects both cancer incidence and survival, the difference may be due to effects of vitamin D on cancer survival. Here we review analytic epidemiologic studies investigating the relation between vitamin D, measured by circulating levels of 25-hydroxyvitamin D (25-OHD), and cancer survival. A relationship between low 25-OHD levels and poor survival is shown by most of the reviewed studies. This relationship is likely to be causal when viewed in light of most criteria for assessing causality (temporality, strength, exposure-response, biological plausibility and consistency). A serum level of 25-OHD around 50 nmol/L appears to be a threshold level. Conversely, there are several mechanisms whereby cancer could lower serum levels of 25-OHD. The severity of disease at the time of diagnosis and time of serum sampling are key factors to clarify the temporal aspect of these relationships. Evidence that vitamin D supplementation could retard the disease process or prolong survival time would be key evidence, but is difficult to generate. However, recent clinical trial results in prostate cancer support a role for vitamin D in this regard.
References
[1]
Apperly, F.L. The relation of solar radiation to cancer mortality in North America. Cancer Res. 1941, 1, 191–195.
[2]
Hollick, M.F. Vitamin D deficiency. N. Engl. J. Med. 2007, 357, 266–281, doi:10.1056/NEJMra070553.
[3]
Garland, C.F.; Garland, F.C. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int. J. Epidemiol. 1980, 9, 227–231, doi:10.1093/ije/9.3.227.
[4]
Schwartz, G.G.; Hulka, B.S. Is vitamin D deficiency a risk factor for prostate cancer? (Hypothesis). Anticancer Res. 1990, 10, 1307–1311.
[5]
Grant, W.B. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality. Dermato-endocrinology 2009, 1, 17–24, doi:10.4161/derm.1.1.7388.
[6]
Chen, W.; Armstrong, B.K.; Rahman, B.; Zheng, R.; Zhang, S.; Clements, M. Relationship between cancer survival and ambient ultraviolet B irradiance in China. Cancer Causes Control 2013, 24, 1323–1330, doi:10.1007/s10552-013-0210-4.
[7]
Robsahm, T.E.; Tretli, S.; Dahlback, A.; Moan, J. Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control 2004, 15, 149–158, doi:10.1023/B:CACO.0000019494.34403.09.
[8]
Porojnicu, A.C.; Robsahm, T.E.; Ree, A.H.; Moan, J. Season of diagnosis is a prognostic factor in Hodgkin’s lymphoma: A possible role of sun-induced vitamin D. Br. J. Cancer 2005, 93, 571–574, doi:10.1038/sj.bjc.6602722.
[9]
Lim, H.S.; Roychoudhuri, R.; Peto, J.; Schwartz, G.; Baade, P.; M？ller, H. Cancer survival is dependent on season of diagnosis and sunlight exposure. Int. J. Cancer 2006, 119, 1530–1536, doi:10.1002/ijc.22052.
[10]
Porojnicu, A.C.; Robsahm, T.E.; Dahlback, A.; Berg, J.P.; Christiani, D.; Bruland, O.S.; Moan, J. Seasonal and geographical variations in lung cancer prognosis in Norway. Does vitamin D from the sun play a role? Lung Cancer 2007, 55, 263–270, doi:10.1016/j.lungcan.2006.11.013.
[11]
Giovannucci, E. The epidemiology of vitamin D and cancer risk. In Vitamin D, 3rd ed.; Feldman, D., Wesley Pike, J., Adams, J.S., Eds.; Academic Press: Amsterdam, The Netherlands, 2011; pp. 1570–1591.
[12]
Gorham, E.D.; Garland, C.F.; Garland, F.C.; Grant, W.B.; Mohr, S.B.; Lipkin, M.; Newmark, H.L.; Giovannucci, E.; Wei, M.; Holick, M.F. Optimal vitamin D status for colorectal cancer prevention: A quantitative meta analysis. Am. J. Prev. Med. 2007, 32, 210–216, doi:10.1016/j.amepre.2006.11.004.
[13]
Gandini, S.; Boniol, M.; Haukka, J.; Byrnes, G.; Cox, B.; Sneyd, M.J.; Mullie, P.; Autier, P. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int. J. Cancer 2011, 128, 1414–1424, doi:10.1002/ijc.25439.
[14]
Jenab, M.; Bueno-de-Mesquita, H.B.; Ferrari, P.; van Duijnhoven, F.J.; Norat, T.; Pischon, T.; Jansen, E.H.; Slimani, N.; Byrnes, G.; Rinaldi, S.; et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. Br. Med. J. 2010, 340, doi:10.1136/bmj.b5500.
[15]
Wolcott, C.G.; Wilkens, L.R.; Nomura, A.M.; Horst, L.R.; Goodman, M.T.; Murphy, S.P.; Henderson, B.E.; Kolonel, L.N.; le Marchand, L. Plasma 25-hydroxyvitamin D levels and the risk of colorectal cancer: The multiethnic cohort study. Cancer Epidemiol. Biomarkers Prev. 2010, 19, 130–134, doi:10.1158/1055-9965.EPI-09-0475.
[16]
Helzlsouer, K.J. Overview of the cohort consortium vitamin D pooling project of rarer cancers. Am. J. Epidemiol. 2010, 172, 4–9, doi:10.1093/aje/kwq119.
[17]
Guerrieri-Gonzaga, A.; Gandini, S. Vitamin D and overall mortality. Pigment Cell Melanoma Res. 2013, 26, 16–28, doi:10.1111/pcmr.12036.
[18]
Boscoe, F.P.; Schymura, M.J. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993–2002. BMC Cancer 2006, 10, doi:10.1186/1471-2407-6-264.
[19]
Chen, W.; Clements, M.; Rahman, B.; Zhang, S.; Qiao, Y.; Armstrong, B.K. Relationship between cancer mortality/incidence and ambient ultraviolet B irradiance in China. Cancer Causes Control 2010, 21, 1701–1709, doi:10.1007/s10552-010-9599-1.
[20]
Goodwin, P.J.; Ennis, M.; Pritchard, K.I.; Koo, J.; Hood, N. Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. J. Clin. Oncol. 2009, 27, 3757–3763, doi:10.1200/JCO.2008.20.0725.
[21]
Vrieling, A.; Hein, R.; Abbas, S.; Schneeweiss, A.; Flesch-Janys, D.; Chang-Claude, J. Serum 25-hydroxyvitamin D and postmenopausal breast cancer survival: A prospective patient cohort study. Breast Cancer Res. 2011, 13, doi:10.1186/bcr2920.
[22]
Tretli, S.; Schwartz, G.G.; Torjesen, P.A.; Robsahm, T.E. 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, 23, 363–370, doi:10.1007/s10552-011-9885-6.
[23]
Hatse, S.; Lambrechts, D.; Verstuyf, A.; Smeets, A.; Brouwers, B.; Vandorpe, T.; Brouckaert, O.; Peuteman, G.; Laenen, A.; Verlinden, L.; et al. Vitamin D status at breast cancer diagnosis: Correlation with tumor characteristics, disease outcome, and genetic determinants of vitamin D insufficiency. Carcinogenesis 2012, 33, 1319–1326, doi:10.1093/carcin/bgs187.
[24]
Jacobs, E.T.; Thomson, C.A.; Flatt, S.W.; Al-Delaimy, W.K.; Hibler, E.A.; Jones, L.A.; Leroy, E.C.; Newman, V.A.; Parker, B.A.; Rock, C.L.; et al. Vitamin D and breast cancer recurrence in the Women’s Healthy Eating and Living (WHEL) Study. Am. J. Clin. Nutr. 2011, 93, 108–117, doi:10.3945/ajcn.2010.30009.
[25]
Ng, K.; Meyerhardt, J.A.; Wu, K.; Feskanich, D.; Hollis, B.W.; Giovannucci, E.L.; Fuchs, C.S. Circulating 25-hydroxyvitamin D levels and survival in patients with colorectal cancer. J. Clin. Oncol. 2008, 26, 2984–2991, doi:10.1200/JCO.2007.15.1027.
[26]
Ng, K.; Sargent, D.J.; Goldberg, R.M.; Meyerhardt, J.A.; Green, E.M.; Pitot, H.C.; Hollis, B.W.; Pollak, M.N.; Fuchs, C.S. Vitamin D status in patients with stage IV colorectal cancer: Findings from intergroup trial N9741. J. Clin. Oncol. 2011, 29, 1599–1606, doi:10.1200/JCO.2010.31.7255.
[27]
Mezawa, H.; Sugiura, T.; Watanabe, M.; Norizoe, C.; Takahashi, D.; Shimojima, A.; Tamez, S.; Tsutsumi, Y.; Yanaga, K.; Urashima, M. Serum vitamin D levels and survival of patients with colorectal cancer: Post-hoc analysis of a prospective cohort study. BMC Cancer 2010, 10, doi:10.1186/1471-2407-10-347.
[28]
Fedirko, V.; Riboli, E.; Tj？nneland, A.; Ferrari, P.; Olsen, A.; Bueno-de-Mesquita, H.B.; van Duijnhoven, F.J.; Norat, T.; Jansen, E.H.J.M.; Dahm, C.C.; et al. Prediagnostic 25-hydroxyvitamin D, VDR and CASR polymorphisms, and survival in patients with colorectal cancerin western European populations. Cancer Epidemiol. Biomarkers Prev. 2012, 21, 582–593, doi:10.1158/1055-9965.EPI-11-1065.
[29]
Fang, F.; Kasperzyk, J.L.; Shui, I.; Hendrickson, W.; Hollis, B.W.; Fall, K.; Ma, J.; Gaziano, J.M.; Stampfer, M.J.; Mucci, L.A.; Giovannucci, E. Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS One 2011, 6, e18625, doi:10.1371/journal.pone.0018625.
[30]
Tretli, S.; Hernes, E.; Berg, J.P.; Hestvik, U.E.; Robsahm, T.E. Association between serum 25(OH)D and death from prostate cancer. Br. J. Cancer 2009, 100, 450–454, doi:10.1038/sj.bjc.6604865.
[31]
Zhou, W.; Heist, R.S.; Liu, G.; Asomaning, K.; Neuberg, D.S.; Hollis, B.W.; Wain, J.C.; Lynch, T.J.; Giovannucci, E.; Su, L.; et al. Circulating 25-hydroxyvitamin D levels predict survival in early-stage non-small-cell lung cancerpatients. J. Clin. Oncol. 2007, 25, 479–485, doi:10.1200/JCO.2006.07.5358.
[32]
Heist, R.S.; Zhou, W.; Wang, Z.; Liu, G.; Neuberg, D.; Su, L.; Asomaning, K.; Hollis, B.W.; Lynch, T.J.; Wain, J.C.; et al. Circulating 25-hydroxyvitamin D, VDR polymorphisms, and survival in advanced non-small-cell lung cancer. J. Clin. Oncol. 2008, 26, 5596–5602, doi:10.1200/JCO.2008.18.0406.
[33]
Drake, M.T.; Maurer, M.J.; Link, B.K.; Habermann, T.M.; Ansell, S.M.; Micallef, I.N.; Kelly, J.L.; Macon, W.R.; Nowakowski, G.S.; Inwards, D.J.; et al. Vitamin D insufficiency and prognosis in non-Hodgkin’s lymphoma. J. Clin. Oncol. 2010, 28, 4191–4198, doi:10.1200/JCO.2010.28.6674.
[34]
Shanafelt, T.D.; Drake, M.T.; Maurer, M.J.; Allmer, C.; Rabe, K.G.; Slager, S.L.; Weiner, G.J.; Call, T.G.; Link, B.K.; Zent, C.S.; et al. Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia. Blood 2011, 117, 1492–1498, doi:10.1182/blood-2010-07-295683.
[35]
Pardanani, A.; Drake, M.T.; Finke, C.; Lasho, T.L.; Rozell, S.A.; Jimma, T.; Tefferi, A. Vitamin D insufficiency in myeloproliferative neoplasms and myelodysplastic syndromes: Clinical correlates and prognostic studies. Am. J. Hematol. 2011, 86, 1013–1016, doi:10.1002/ajh.22181.
[36]
Newton-Bishop, J.A.; Beswick, S.; Randerson-Moor, J.; Chang, Y.M.; Affleck, P.; Elliott, F.; Chan, M.; Leake, S.; Karpavicius, B.; Haynes, S.; et al. Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. J. Clin. Oncol. 2009, 27, 5439–5444, doi:10.1200/JCO.2009.22.1135.
[37]
Meyer, F.; Liu, G.; Douville, P.; Samson, E.; Xu, W.; Adjei, A.; Bairati, I. Dietary vitamin D intake and serum 25-hydroxyvitamin D level in relation to disease outcomes in head and neck cancer patients. Int. J. Cancer 2011, 128, 1741–1746.
[38]
Ren, C.; Qiu, M.Z.; Wang, D.S.; Luo, H.Y.; Zhang, D.S.; Wang, Z.Q.; Wang, F.H.; Li, Y.H.; Zhou, Z.W.; Xu, R.H. Prognostic effects of 25-hydroxyvitamin D levels in gastric cancer. J. Transl. Med. 2012, 10, doi:10.1186/1479-5876-10-16.
[39]
Hill, A.B. The environment and disease: Association or causation. Proc. R. Soc. Med. 1965, 58, 295–300.
[40]
Zemel, M.B. Calcium modulation of hypertension and obesity: Mechanisms and implications. J. Am. Coll. Nutr. 2001, 20, 428S–435S, doi:10.1080/07315724.2001.10719180.
[41]
Thaw, S.S.; Sahmoun, A.E.; Schwartz, G.G. Serum calcium, tumor size, and hormone receptor status in women with untreated breast cancer. Cancer Biol. Therapy 2012, 7, 467–471.
[42]
Schwartz, G.G.; Skinner, H.G. Prospective studies of total and ionized serum calcium in relation to incident and fatal ovarian cancer. Gyn. Oncol. 2013, 129, 169–172, doi:10.1016/j.ygyno.2012.12.046.
[43]
Schwartz, G.G. Prostate cancer, serum Parathyroid Hormone and the progression of skeletal metastases. Cancer Epidemiol. Biomarkers Prev. 2008, 17, 478–483, doi:10.1158/1055-9965.EPI-07-2747.
[44]
Fakih, M.G.; Trump, D.L.; Johnson, C.S.; Tian, L.; Muindi, J.; Sunga, A.Y. Chemotherapy is linked to severe vitamin D deficiency in patients with colorectal cancer. Int. J. Colorectal. Dis. 2009, 24, 219–224, doi:10.1007/s00384-008-0593-y.
[45]
Van Leeuwen, J.P.T.M.; van Driel, M.; Feldman, D.; Mu？oz, A. Vitamin D: Cancer and Differentiation. In Vitamin D, 3rd ed.; Feldman, D., Wesley Pike, J., Adams, J.S., Eds.; Academic Press: Amsterdam, The Netherlands, 2011; pp. 1592–1597.
[46]
Welsh, J. Vitamin D actions in mammary gland and breast cancer. In Vitamin D, 3rd ed.; Feldman, D., Wesley Pike, J., Adams, J.S., Eds.; Academic Press: Amsterdam, The Netherlands, 2011; pp. 1657–1673.
[47]
Krishnan, A.V.; Feldman, D. Vitamin D and prostate cancer. In Vitamin D, 3rd ed.; Feldman, D., Wesley Pike, J., Adams, J.S., Eds.; Academic Press: Amsterdam, The Netherlands, 2011; pp. 1675–1709.
[48]
Cross, H.S. The vitamin D system and colorectal cancer prevention. In Vitamin D, 3rd ed.; Feldman, D., Wesley Pike, J., Adams, J.S., Eds.; Academic Press: Amsterdam, The Netherlands, 2011; pp. 1711–1729.
[49]
Okamoto, R.; Koeffler, H.P. Hematological malignancy. In Vitamin D, 3rd ed.; Feldman, D., Wesley Pike, J., Adams, J.S., Eds.; Academic Press: Amsterdam, The Netherlands, 2011; pp. 1731–1750.
[50]
Trump, D.L.; Johnson, C.S. The anti-tumor effects of vitamin D in other cancers. In Vitamin D, 3rd ed.; Feldman, D., Wesley Pike, J., Adams, J.S., Eds.; Academic Press: Amsterdam, The Netherlands, 2011; pp. 1763–1773.
[51]
Jacobs, E.T.; Thomson, C.A.; Flatt, S.W.; Newman, V.A.; Rock, C.L.; Pierce, J.P. Correlates of 25-hydroxyvitamin D and breast cancer stage in the Women’s Healthy Eating and Living Study. Nutr. Cancer 2013, 65, 188–194, doi:10.1080/01635581.2013.756531.
[52]
Schwartz, G.G.; Whitlatch, L.W.; Chen, T.C.; Lokeshwar, B.L.; Holick, M.F. Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiol. Biomarkers Prev. 1998, 7, 391–395.
[53]
Bikle, D. Nonclassic actions of vitamin D. J. Clin. Endocrinol. Metab. 2009, 94, 26–34, doi:10.1210/jc.2008-1454.
[54]
Trump, D.L.; Hershberger, P.A.; Bernardi, R.J.; Ahmed, S.; Muindi, J.; Fakih, M.; Yu, W.D.; Johnson, C.S. Antitumor activity of calcitriol: Pre-clinical and clinical studies. J. Steroid Biochem. Mol. Biol. 2004, 89, 519–526.
[55]
Townsend, K.; Evans, K.N.; Campbell, M.H.; Colston, K.W.; Adams, J.S.; Hewison, M. Biological actions of extra-renal 25-hydroxyvitamin D-1-alpa-hydroxylase and implications for chemoprevention and treatment. J. Steroid Biochem. Mol. Biol. 2005, 97, 103–109, doi:10.1016/j.jsbmb.2005.06.004.
[56]
Barreto, A.; Schwartz, G.G.; Woodruff, R.; Cramer, S.D. 25-Hydroxyvitamin D3, the prohormonal form of 1,25-Dihydroxyvitamin D3, inhibits the proliferation of primary prostatic epithelial cells. Cancer Epidemiol. Biomarkers Prev. 2000, 9, 265–270.
[57]
Chen, T.C.; Schwartz, G.G.; Burnstein, K.L.; Lokeshwar, B.L.; Holick, M.F. The in vitro evaluation of 25-Hydroxyvitamin D3 and 19-nor-1,25-Dihydroxyvitamin D2 as therapeutic agents for prostate cancer. Clin. Cancer Res. 2000, 6, 901–908.
[58]
Swami, S.; Krishnan, A.V.; Wang, J.Y.; Jensen, K.; Horst, R.; Albertelli, M.A.; Feldman, D. Dietary vitamin D3 and 1,25-dihydroxyvitamin D3 (calcitril) exhibit equivalent anticancer activity in mouse xenograft models of breast and prostate cancer. Endocrinolology 2012, 153, 2576–2587, doi:10.1210/en.2011-1600.
[59]
Durup, D.; J？rgensen, H.L.; Christensen, J.; Schwartz, P.; Heegard, A.M.; Lind, B. A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: The CopD study. J. Clin. Endocriol. Metab. 2012, 97, 2644–2652, doi:10.1210/jc.2012-1176.
[60]
Wagner, D.; Trudel, D.; van der Kwast, T.; Nonn, L.; Giangreco, A.A.; Li, D.; Cardoze, M.; Laszlo, S.; Hersey, K.; Klotz, L.; et al. Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and Ki67 labeling in prostate cancer patients. J. Clin. Endocrinol. Metab. 2013, 98, 1498–1507, doi:10.1210/jc.2012-4019.
