Abstract
Abstract. Vitamin D is important in many cellular functions including cell cycling and proliferation, differentiation, and apoptosis. Via the induction of cell cycle arrest and/or apoptosis, vitamin D inhibits normal prostatic epithelial cells growth. Review the evidence of the effect of vitamin D supplementation on prostate cancer (PC) biomarkers and patient survival and assess optimal dosage, formulation and duration. Pubmed, Medline and Ebsco Host databases were systematically searched for relevant literature. 8 Randomized Controlled Trials were included in this review. All studies, besides one, were of high methodological quality. 4 studies used calcitriol (0,5-45 μg/weekly), 2 studies have used vitamin D3 (150-1000 μg/daily) and 2 other studies have used 1α-hydroxy Vitamin D2 (10 μg/ daily or weekly). Duration of supplementation varied between 28 days up to 18.3 months. Two studies had positive effects on prostate specific antigen (PSA) (p < .05), 1 study had a significant positive effect on median survival (p < .05) and 1 study showed a significant reduction of vitamin D receptor (VDR) expression (p < .05). The remaining studies showed negative or no effect on PC characteristics, clinical outcomes and/or survival. Current evidence suggests that vitamin D supplementation in conjunction with standard of care (e.g. chemotherapy, radiation therapy) may confer clinical benefits such as a decrease in serum PSA levels and VDR expression but further research is required to ascertain these results. Calcitriol supplementation in doses ranging from 250-1000 mg for 3–8 weeks or a lower dose of 45 mg for 18.3 months, appear most beneficial regarding outcomes of PC progression and survival.
Literature
Lazzeroni, M., Serrano, D., Pilz, S. & Gandini, S. (2013) Vitamin D supplementation and cancer: review of randomized controlled trials. Anticancer Agents Med Chem, 13(1), pp.118–25.
NHI Office of Dietary Supplements - Vitamin D, (2015).
Nair, R. & Maseeh, A. (2012) Vitamin D: The “sunshine” vitamin. J Pharmacol Pharmacother, Vol.3: p118–126.
NHI Office of Dietary Supplements - Vitamin D, (2014).
Feldman, D., Zhao, X.Y., Krishnan, A.V. (2000) Vitamin D and prostate cancer. Endocrinol., 141:5–9.
Blutt, S., & Weigel, N., (1999) Vitamin D and prostate cancer. Proc. Soc. Exp. Biol. Med., 221:89–98.
Konety, B.R., Johnson, C.S., Trump, D.L., Getzenberg, R.H. (1999) Vitamin D in the prevention and treatment of prostate cancer. Semin. Urol. Oncol., 17:77–84.
Beer, T.M., Lemmon, D., Lowe, B. A., Henner, W. D. (2003) High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Cancer Res, 97(5), pp.1217–1224.
Brown, A.J. (2000) Mechanisms for the selective actions of vitamin D analogues. Curr. Pharm. Des, 6(7), pp.701–16.
van den Bemd, G.J., Pols, H.A. & van Leeuwen, J.P. (2000) Anti-tumor effects of 1,25-dihydroxyvitamin D3 and vitamin D analogs. Curr. Pharm. Des, 6(7), pp.717–32.
Henner, W.D. & Beer, T.M. (2003) A new formulation of calcitriol (DN-101) for high-dose pulse administration in PC therapy. Rev Urol., 5 Suppl 3, pp.S38–S44.
WHO. WHO | Cancer. WHO (2014).
Lippi, G., Montagnana, M., Guidi, G. C. & Plebani, M. (2009) Prostate-specific antigen-based screening for PC in the third millennium: Useful or hype? Ann Acad Med, 41(7), pp.480–489.
Catalona W.J., Partin A.W., Slawin K.M., Brawer M.K., Flanigan R.C., Patel A. Richie J.P., DeKernion J.B., Walsh P.C., Scardino P.T., Lange P.H., Subong E.N., Parson R.E., Gasior G.H., Loveland, K.G., Southwick P.C. (1998) Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA, 279: 1542–7.
Mikolajczyk S.D., Marker K.M., Millar L.S., Kumar A., Saedi M.S., Payne J.K., Evans C.L., Gasior C.L., Linton H.J., Carpenter P., Rittenhouse H.G. (2001) A truncated precursor form of prostate-specific antigen is a more specific serum marker of prostate cancer. Cancer Res., 61: 6958–63.
Le B.V., Griffin C.R., Loeb S., Carvalhal G.F., Kan D., Baumann N.A., Catalona William J. (2010) [-2]Proenzyme prostate specific antigen is more accurate than total and free prostate specific antigen in differentiating prostate cancer from benign disease in a prospective prostate cancer screening study. J. Urol., 183: 1355–9.
Filella X. & Gimenez N. (2013) Evaluation of [-2] proPSA and prostate health index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin. Chem. Lab. Med., 51: 729–
Gross, C., Stamey, T., Hancock, S. & Feldman, D. (1998) Treatment of early recurrent PC with 1,25-dihydroxyvitamin D3 (calcitriol). J Urol, 159(6), pp.2035 – 9-40.
Osborn, J.L., Schwartz, G. G., Smith, D. C., Bahnson, R., Day, R. &Trump, D L. (1995) Phase II trial of oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory PC. Urol. Oncol, 1(5), pp.195–8.
Gandini, S., Boniol, M., Haukka, J., Byrnes, G., Cox, Brian, Sneyd, Mary Jane, Mullie, Patrick, & Autier, Philippe. (2011) Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and PC and colorectal adenoma. Int. J. Cancer, 128(6), pp.1414–1424.
Beer, T.M., Eilers, K.M., Garzotto, M., Egorin, M. J., Lowe, B. A. & Henner, W. David. (2003) Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent PC. J Clin Oncol, 21(1), pp.123–128.
Beer, T.M., Ryan, C.W., Venner, P.M., Petrylak, D.P., Chatta, G.S., Ruether, J Dean, Chi, Kim N, Young, James & Henner, W David. (2008) Intermittent chemotherapy in patients with metastatic androgen-independent PC: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel. Cancer Res., 112(2), pp.326–30.
Morris, M.J., Smaletz, O., Solit, D., Kelly, W. K., Slovin, S., Flombaum, Carlos, Curley, Tracy, Delacruz, Anthony & Schwartz, Lawrence. (2004) High-Dose calcitriol, zoledronate, and Dexamethasone for the treatment of progressive prostate carcinoma. Cancer Res., 100(9), pp.1868–1875.
Beer, T.M., Myrthue, A., Garzotto, M., O›hara, M. F., Chin, R., Lowe, Bruce A, Montalto, Michelle A, Corless, Christopher L & Henner, W David. (2004) Randomized study of high-dose pulse calcitriol or placebo prior to radical prostatectomy. Cancer Epidemiol Biomarkers Prev, 13(12), pp.2225–32.
Colli, E., Rigatti, P., Montorsi, F., Artibani, W., Petta, S., Mondaini, Nicola, Scarpa, Roberto, Usai, Paolo, Olivieri, Lorenza, Maggi, Mario, Rigatti, P., Artibani, W., Belgrano, E., Carini, M., Catanzaro, F., Mirone, V., Petta, S., Rizzo, M., Scarpa, R., Usai, E. & Zucconelli, R. (2006) BXL628, a novel vitamin d3 analog arrests prostate growth in patients with benign prostatic hyperplasia: A randomized clinical trial. Eur Urol, 49(1), pp.82–86.
Wagner, D., Trudel, D., Van Der Kwast, T., Nonn, L., Giangreco, A. A., Li, Doris, Dias, Andre, Cardoza, Monique, Laszlo, Sanda, Hersey, Karen, Klotz, Laurence, Finelli, Antonio, Fleshner, Neil & Vieth, Reinhold. (2013) Randomized clinical trial of vitamin D3 doses on prostatic vitamin D metabolite levels and Ki67 labeling in PC patients. J. Clin. Endocrinol. Metab., 98(4), pp.1498–1507.
Beer, T.M., Ryan, C. W., Venner, P. M., Petrylak, D. P., Chatta, G. S., Ruether, J. D., Redfern, C. H., Fehrenbacher, L., Saleh, M. N. & Waterhouse, D. M. (2007) Double-Blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent PC: A report from the ASCENT investigators. J. Clin. Oncol., 25(6), pp.669–674.
Scher, H.I., Jia, X., Chi, K., de Wit, R., Berry, W. R., Albers, Peter, Henick, Brian, Waterhouse, David, Ruether, Dean J, Rosen, Peter J, Meluch, Anthony A, Nordquist, Luke T, Venner, Peter M, Heidenreich, Axel, Chu, Luis & Heller, Glenn. (2011) Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant PC. J Clin Oncol, 29(16), pp.2191–8.
Attia, S., Eickhoff, J., Wilding, G., McNeel, D., Blank, J., Ahuja, Harish, Jumonville, Alcee, Eastman, Michael, Shevrin, Daniel, Glode, Michael, Alberti, Dona, Staab, Mary Jane, Horvath, Dottie, Straus, Jane, Marnocha, Rebecca & Liu, Glenn. (2008) Randomized, double-blinded phase II evaluation of docetaxel with or without doxercalciferol in patients with metastatic, androgen-independent PC. Clin Cancer Res, , 14(8), pp.2437–43.
Gee, J., Bailey, H., Kim, K., Kolesar, J., Havighurst, T., Tutsch, Kendra D, See, William, Cohen, Michael B, Street, Nick, Levan, Leon, Jarrard, David & Wilding, George. (2013) Phase II open label, multi-center clinical trial of modulation of intermediate endpoint biomarkers by 1α-hydroxyvitamin D2 in patients with clinically localized PC and high grade pin. The Prostate, 73(9), pp.970–8.
Van Tulder, M., Furlan, A., Bombardier, C. & Bouter, L. (2003) Updated method guidelines for systematic reviews in the cochrane collaboration back review group. Spine, 28(12), pp.1290–9.
Packianathan, S., Mehta, R. R. G., Hall, W. H., Boerner, P. S., Beckett, L. A. & Vijayakumar, Srinivasan. 2004) Designing a randomized phase I/II PC chemoprevention trial using 1alpha-hydroxy-24-ethyl-cholecalciferol, an analogue of vitamin D3. Cancer J (Sudbury, Mass.), (10(6), pp.357–67.
Beer, T.M., Myrthue, A. & Eilers, K.M. (2005) Rationale for the development and current status of calcitriol in androgen-independent PC. World J Urol, 23(1), pp.28–32.
Beer, T.M. & Myrthue, A. (2006) Calcitriol in the treatment of PC. Anticancer Res., 26(4A), pp.2647–51.
Beer, T.M. (2005) ASCENT: the androgen-independent PC study of calcitriol enhancing taxotere. BJU international, 96(4), pp.508–13.
Chandler, P.D., Giovannucci, E. L., Scott, J. B., Bennett, G. G., Ng, Kimmie., Chan, Andrew T, Hollis, Bruce W, Emmons, Karen M, Fuchs, Charles S & Drake, Bettina F. (2014) Null association between vitamin D and PSA levels among black men in a vitamin D supplementation trial. Cancer Epidemiol Biomarkers Prev, 23(9), pp.1944–7.
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med.
Taplin, M.E., & Ho, S.M. (2001) The endocrinology of prostate cancer. J. Clin. Endocrinol. Metab., 86(8), pp.3467–3477,
Nelles, J.L., Hu, W.Y. & Prins, G.S. (2011) Estrogen action and prostate cancer. Expert review of J. Clin. Endocrinol. Metab., 6(3), pp.437–451.
Shibata, A., & Minn, A.Y. (2000) Perinatal sex hormones and risk of breast and prostate cancers in adulthood. Epidemiol. Rev, 22(2), pp.239–248.],
Montgomery, B., Nelson, P.S., Vessella, R., Kalhorn, T., Hess, D., & Corey, E. (2010) Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer. BMC cancer, 10(1), p.244.
Crawford, E.D., Rove, K.O., Schally, A.V., Rick, F.G., Block, N.L., Beveridge, T.J., Dahdal, D.N. & Marshall, D.C. (2014) The role of the FSH system in the development and progression of prostate cancer. Am J Hematol Oncol., 10(6)
Petrylak, D.P., Tangen, C. M., Hussain, M. H. A., Lara, P. N., Jones, J. A., Taplin, Mary Ellen, Burch, Patrick A, Berry, Donna, Moinpour, Carol, Kohli, Manish, Benson, Mitchell C, Small, Eric J, Raghavan, Derek & Crawford, E David. (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory PC. N Engl J Med, , 351(15), pp.1513–20.
Tannock, I.F., de Wit, R., Berry, W. R., Horti, J., Pluzanska, A., Chi, Kim N, Oudard, Stephane, Théodore, Christine, James, Nicholas D, Turesson, Ingela, Rosenthal, Mark A & Eisenberger, Mario A. (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced PC. N Engl J Med, 351(15), pp.1502–12.
Sjöden, G., Smith, C., Lindgren, U. & DeLuca, H. (1985) 1 alpha-Hydroxyvitamin D2 is less toxic than 1 alpha-hydroxyvitamin D3 in the rat. Proceedings of the Society for Experimental Biology and Medicine. Exp Biol Med (New York, N.Y.), 178(3), pp.432–6.
Upton, R.A., Knutson, J. C., Bishop, C. W. & LeVan, L. W. (2003) Pharmacokinetics of doxercalciferol, a new vitamin D analogue that lowers parathyroid hormone. Nephrol Dial Transplant, 18(4), pp.750–8.
Knutson, J.C. , Hollis, B. W., LeVan, L. W., Valliere, C., Gould, K G & Bishop, C W. (1995) Metabolism of 1 alpha-hydroxyvitamin D2 to activated dihydroxyvitamin D 2 metabolites decreases endogenous 1 alpha, 25-dihydroxyvitamin D 3 in rats and monkeys. Endocrinol, 136(11), pp.4749–53.
Bailie, G.R. & Johnson, C.A. (2002) Comparative review of the pharmacokinetics of vitamin D analogues. Semin Dial, 15(5), pp.352–7.
Gallagher, J.C., Bishop, C. W., Knutson, J. C., Mazess, R. B. & DeLuca, H. F. (1994) Effects of increasing doses of 1 alpha-hydroxyvitamin D2 on calcium homeostasis in postmenopausal osteopenic women. J Bone Miner Res, 9(5), pp.607–14.
Ben-Eltriki, M., Deb, S. & Guns, E.S.T. (2016) Calcitriol in combination therapy for PC: pharmacokinetic and pharmacodynamic interactions. J. Cancer, 7(4), pp.391–407.
Krill, D., DeFlavia, P., Dhir, R., Luo, J., Becich, M. J. ,Lehman, E & Getzenberg, R H. (2001) Expression patterns of vitamin D receptor in human prostate. J. Cell. Biochem, 82(4), pp.566–72.
Trump, D.L., Deeb, K.K. & Johnson, C.S. (2002) Vitamin D: considerations in the continued development as an agent for cancer prevention and therapy. J. Cancer, 16(1), pp.1–9.
Chadha, M.K., Tian, L., Mashtare, T., Payne, V., Silliman, C., Levine, Ellis, Wong, Michael, Johnson, Candace & Trump, Donald L. (2010) Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant PC. Cancer Res., 116(9), pp.2132–9.
Marshall, D.T., Savage, S. J., Garrett-Mayer, E., Keane, T. E., Hollis, B.W., Horst, Ronald L, Ambrose, Linda H, Kindy, Mark S & Gattoni-Celli, Sebastiano. (2012) Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk PC under active surveillance. J. Clin. Endocrinol. Metab., 97(7), pp.2315–24.
Jemal A., Murray T., Samuels A., Ghafoor A., Ward E., Thun M.J. (2003) Cancer Statistics, 2003. CA Cancer J. Clin., 53(1):5–26.
Moul J.W. (1998) Treatment options for prostate cancer: Part I-stage, grade, PSA, and changes in the 1990’s. Am. J. Manag., 4:1031.
Moul J.W. (2000) Prostate specific antigen only progression of prostate cancer. J. Urol., 163(6):1632–42.
Gross C., Peehl D.M., Feldman D. (1997) Vitamin D and prostate cancer. In: Feldman D, Glorieux FH, Pike JW (eds) Vitamin D. Academic Press, San Diego, pp 1125–1139.
Miller G. (1999) Vitamin D and prostate cancer: biologic interactions and clinical potentials. Cancer Met. Rev., 17:353–360.
Zhao X.Y., Ly L.H., Peehl D.M., Feldman D. (1999) Induction of androgen receptor by 1α,25-dihydroxyvitamin D3 and 9-cis retinoic acid in LNCaP human prostate cancer cells. Endocrinol., 140:1205–1212.
Peehl D.M., Skowronski R.J., Leung G.K., Wong S.T., Stamey T.A., Feldman D. (1994) Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res., 54:805–810.
Schwartz G.G., Wang M.H., Zang M., Singh R.K., Siegal G.P. (1997) 1a,25-Dihydroxyvitamin D (calcitriol) inhibits the invasiveness of human prostate cancer cells. Cancer Epidemiol. Biomarkers Prev., 6:727–732.
Guzey M., Kitada S., Reed J.C. (2002) Apoptosis induction by 1alpha, 25- dihydroxyvitamin D3 in prostate cancer. Mol. Cancer Ther., 1:667–677.
Taylor J.A., Hirvonen A., Watson M., Pittman G., Mohler J.L., Bell D.A. (1996) Association of prostate cancer with vitamin D receptor gene polymorphism. Cancer Res., 56:4108–4110.
Ingles S.A., Ross R.K., Yu M.C., Irvine R.A., La Pera G., Haile R.W., Coetzee G.A. (1997) Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J. Natl. Cancer Inst. (Bethesda), 89:166–170.
Xu Y., Shibata A., McNeal J.E., Stamey T.A., Feldman D., Peehl D.M. (2003) Vitamin D receptor start codon polymorphism (FokI) and prostate cancer progression. Cancer Epidemiol. Biomarkers Prev.,12:23–27.
Habuchi T., Suzuki T., Sasaki R., Wang L., Sato K., Satoh S., Akao T., Tsuchiya N., Shimoda N., Wada Y., Koizumi A., Chihara J., Ogawa O., Kato T. (2000) Association of vitamin D receptor gene polymorphism with prostate cancer and benign prostatic hyperplasia in a Japanese population. Cancer Res., 60:305–308.
Cheteri M.B., Stanford J.L., Friedrichsen D.M., Peters M.A., Iwasaki L., Langlois M.C., Feng Z., Ostrander E.A. (2004) Vitamin D receptor gene polymorphisms and prostate cancer risk. Prostate, 59:409–418.
Medeiros R., Morais A., Vasconcelos A., Costa S., Pinto D., Oliveira J., Lopes C. (2002) The role of vitamin D receptor gene polymorphisms in the susceptibility to prostate cancer of a southern European population. J. Hum. Genet., 47:413–418.
John E.M., Schwartz G.G., Koo J., Den Berg., Ingles S.A. (2005) Sun Exposure, Vitamin D Receptor Gene Polymorphisms, and Risk of Advanced Prostate Cancer. Cancer Res., 65:5470–5479.
Patiyan A., & Eberhard V., Peter S. (2006) Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk. Eur. J. Cancer, 42:2833–2837.
Oakley-Girvan I., Feldman D., Eccleshall T.R., Gallagher R.P., Wu A.H., Kolonel L.N., Halpern J., Balise R.P., West D.W., Paffenbarger Jr., Whittemore A.S. (2004) Risk of early-onset prostate cancer in relation to germ line polymorphisms of the vitamin D receptor. Cancer Epidemiol. Biomarkers Prev., 13:1325–1330.
Correa-Cerro L., Berthon P., Haussler J., Bochum S., Drelon E., Mangin P., Fournier G., Paiss T., Cussenot O., Vogel W. (1999) Vitamin D receptor polymorphisms as markers in prostate cancer. Hum. Genet., 105:281–287.
Heaney, R.P. (2001) Factors influencing the measurement of bioavailability, taking calcium as a model. J. Nutr, 131(4 Suppl), p.1344S–8S.
Srinivasan, V.S. (2001) Bioavailability of nutrients: a practical approach to in vitro demonstration of the availability of nutrients in multivitamin-mineral combination products. J. Nutr, 131(4 Suppl), p.1349S–50S.
Mikhak, B., Hunter, D.J., Spiegelman, D., Platz, E.A., Hollis, B.W. &Giovannucci, E. (2007) Vitamin D receptor (VDR) gene polymorphisms and haplotypes, interactions with plasma 25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D, and prostate cancer risk. The Prostate, 67(9), pp.911–923.
Davis, C.D., & Milner, J.A. (2011) Nutrigenomics, vitamin D and cancer prevention. J Nutrigenet Nutrigenomics, 4(1), pp.1–11].
Elsamanoudy, A.Z., Neamat-Allah, M. A. M., Mohammad, F. A. H., Hassanien, M. & Nada, H. A. (2016) The role of nutrition related genes and nutrigenetics in understanding the pathogenesis of cancer. JMAU, 4(3), pp.115–122.
Yuan, Y. & Ferguson, L.R. (2011) Nutrigenetics and PC: 2011 and beyond. J Nutrigenet Nutrigenomics, 4(3), pp.121–36.
Norman, H.A., Butrum, R.R., Feldman, E., Heber, D., Nixon, D., Picciano, M.F., Rivlin, R., Simopoulos, A., Wargovich, M.J., Weisburger, E.K. & Zeisel, S.H. (2003) The role of dietary supplements during cancer therapy. J Nutr., 133(11), pp.3794S–3799S.