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==Overview==
==Overview==
The high incidence of prostate cancer, its associated morbidity and mortality, the complications associated with its treatment, and a partial understanding of its biologic basis have led to a focus on chemoprevention strategies. The most extensive data come from the use of 5-alpha reductase (5-AR) inhibitors; other classes of agents are also being explored. The rationale for chemoprevention, the results with 5-AR inhibitors, and the more limited data with other approaches are presented here. Screening for prostate cancer, an alternative approach that focuses on early detection to decrease morbidity and mortality
Effective measures for the [[primary prevention]] of prostate cancer include healthy [[diet]] and maintaining healthy weight.


==Primary Prevention==
==Primary Prevention==


===Vitamins and medication===
*The [[5α-reductase inhibitors]] such as [[finasteride]] and [[dutasteride]] improve lower urinary tract symptoms in men with [[Benign prostatic hyperplasia|benign prostatic hyperplasi]]<nowiki/>a (BPH), by blocking the conversion of [[testosterone]] to the more potent androgen [[dihydrotestosterone]].
*Two randomized trials have shown a reduced risk of prostate cancer in men receiving 5-ARIs, concerns were raised about a possible increased risk of high-grade prostate cancers.
*Swedish population-based cohort study of all men over the age of 40 who had at least one prostate-specific antigen (PSA) test in Stockholm County between 2007 and 2015, men who were prescribed a 5-ARI had a decreased risk for prostate cancer, and the effect was larger with longer duration of exposure<ref name="pmid29548030">{{cite journal |vauthors=Wallerstedt A, Strom P, Gronberg H, Nordstrom T, Eklund M |title=Risk of Prostate Cancer in Men Treated With 5α-Reductase Inhibitors-A Large Population-Based Prospective Study |journal=J. Natl. Cancer Inst. |volume=110 |issue=11 |pages=1216–1221 |date=November 2018 |pmid=29548030 |doi=10.1093/jnci/djy036 |url=}}</ref>.
*The reduction was limited to patients with prostate cancers with Gleason score 6 to 7; there was no impact on the risk of higher-grade disease (Gleason score 8 to 10). These data provide some reassurance that treatment with a 5-ARI for lower urinary tract symptoms is safe with regard to prostate cancer risk, but long-term follow-up data demonstrating improved survival are needed to determine the role of 5-ARIs as chemopreventive agents.


Evidence from epidemiological studies supports protective roles in reducing prostate cancer for dietary [[selenium]], [[vitamin E]], [[lycopene]], and [[soy]] foods.  High plasma levels of [[Vitamin D]] may also have a protective effect.<ref>{{cite journal |author=Wigle DT, Turner MC, Gomes J, Parent ME |title=Role of hormonal and other factors in human prostate cancer |journal=J Toxicol Environ Health B Crit Rev |volume=11 |issue=3-4 |pages=242–59 |year=2008 |month=March |pmid=18368555 |doi=10.1080/10937400701873548 |url=}}</ref> Estrogens from fermented [[soybeans]] and other plant sources (called [[phytoestrogen]]s) may also help prevent prostate cancer.<ref>{{cite journal| last=Strom| first= SS| coauthors=Yamamura Y, Duphorne CM, Spitz MR, Babaian RJ, Pillow PC, Hursting SD| title=Phytoestrogen intake and prostate cancer: a case-control study using a new database| journal=Nutr Cancer| year=1999| volume=33| issue=1| pages=20–5| pmid=10227039}} Erratum in: Nutr Cancer 2000;36(2):243.</ref> The [[selective estrogen receptor modulator]] drug [[toremifene]] has shown promise in early trials.<ref>{{cite journal| last=Steiner| first=MS| coauthors=Pound, CR, Gingrich, JR, et al.| title=Acapodene (GTx-006) reduces high-grade prostatic intraepithelial neoplasia in phase II clinical trial (abstract)| journal=Proc Am Soc Clin Oncol| year=2002| volume=21| pages=180a}}</ref><ref>{{cite journal| last=Price| first= D| coauthors=Stein, B, Goluboff, E, et al.| title=Double-blind, placebo-controlled trial of toremifene for the prevention of prostate cancer in men with high-grade prostatic intrapeithelial neoplasia (abstract)| journal=J Clin Oncol| year=2005| volume=23| pages=106s}}</ref> Two medications which block the conversion of [[testosterone]] to [[dihydrotestosterone]], [[finasteride]]<ref>{{cite journal| last=Thompson| first=IM| coauthors=Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr.| title=The influence of finasteride on the development of prostate cancer| journal=N Engl J Med| year=2003| month=July 17| volume=349| issue=3| pages=215–24| pmid=12824459| doi=10.1056/NEJMoa030660}}</ref>
Effective measures for the primary prevention of prostate cancer include:
and [[dutasteride]],<ref>{{cite journal| last=Andriole| first=GL| coauthors=Roehrborn C, Schulman C, Slawin KM, Somerville M, Rittmaster RS| title=Effect of dutasteride on the detection of prostate cancer in men with benign prostatic hyperplasia| journal=Urology| year=2004| month=September| volume=64| issue=3| pages=537–41; discussion 542–3| pmid=15351586| doi=10.1016/j.urology.2004.04.084}}</ref> have also shown some promise. The use of these medications for primary prevention is still in the testing phase, and they are not widely used for this purpose. The initial problem with these medications is that they may preferentially block the development of lower-grade prostate tumors, leading to a relatively greater chance of higher grade cancers, and negating any overall survival improvement.  More recent research found that [[finasteride]] did not increase the percentage of higher grade cancers. 


A 2008 study update found that finasteride reduces the incidence of prostate cancer by 30%. In the original study it turns that that the smaller prostate caused by finasteride means that a doctor is more likely to hit upon cancer nests and more likely to find aggressive-looking cells.  Most of the men in the study who had cancer — aggressive or not — chose to be treated and many had their prostates removed. A pathologist then carefully examined every one of those 500 prostates and compared the kinds of cancers found at surgery to those initially diagnosed at biopsy. Finasteride did not increase the risk of High-Grade prostate cancer.<ref>{{ cite news | author = Gine Kolata |  title = New Take on a Prostate Drug, and a New Debate  |  url = http://www.nytimes.com/2008/06/15/health/15prostate.html?ei=5087&em=&en=813eaa4e10f57756&ex=1213675200&adxnnl=1&adxnnlx=1213503418-GD4DbGjYsDxqV/xuGWnE1A | publisher = [[NY Times]] date = June 15, 2008  | accessdate = 2008-06-15 }}</ref><ref>{{cite journal  |author=Potosky A, Miller B, Albertsen P, Kramer B |title=Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer: A Bias-Adjusted Modeling Approach |  url  =  http://cancerpreventionresearch.aacrjournals.org/cgi/rapidpdf/1940-6207.CAPR-08-0092v1 |journal= Cancer Prevention Research |volume= Published Online First on May 18, 2008 as 10.1158/1940-6207.CAPR-08-0092  |year=2008 |doi=10.1158/1940-6207.CAPR-08-0092  |pages=174 }}</ref>
*Healthy [[diet]]


[[Green tea]] may be protective (due to its [[polyphenol]] content),<ref>{{cite journal |author=Lee AH, Fraser ML, Meng X, Binns CW |title=Protective effects of green tea against prostate cancer |journal=Expert Rev Anticancer Ther |volume=6 |issue=4 |pages=507–13 |year=2006 |month=April |pmid=16613539 |doi=10.1586/14737140.6.4.507 |url=}}</ref> although the most comprehensive clinical study indicates that it has no protective effect.<ref>{{cite journal |author=Kikuchi N, Ohmori K, Shimazu T, ''et al'' |title=No association between green tea and prostate cancer risk in Japanese men: the Ohsaki Cohort Study |journal=Br. J. Cancer |volume=95 |issue=3 |pages=371–3 |year=2006 |month=August |pmid=16804523 |doi=10.1038/sj.bjc.6603230 |url=}}</ref> 
:*Low-fat diet
A 2006 study of green tea derivatives demonstrated promising prostate cancer prevention in patients at high risk for the disease.<ref>{{cite journal |author=Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A |title=Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study |journal=Cancer Res |volume=66 |issue=2 |pages=1234–40 |year=2006 |pmid=16424063 | doi = 10.1158/0008-5472.CAN-05-1145}}</ref> Recent research published in the Journal of the [[National Cancer Institute]] suggests that taking [[multivitamins]] more than seven times a week can increase the risks of contracting the disease.<ref name="BBC_NEWS_Multivitamin">{{cite web | url = http://news.bbc.co.uk/1/hi/health/6657795.stm| title = Multivitamin prostate warning | author = | authorlink = | coauthors = | date = 2007-05-16 | format = | work = Health | publisher = BBC NEWS | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-04-23}}</ref><ref name="pmid17505071">{{cite journal | author = Lawson KA, Wright ME, Subar A, Mouw T, Hollenbeck A, Schatzkin A, Leitzmann MF | title = Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study | journal = J. Natl. Cancer Inst. | volume = 99 | issue = 10 | pages = 754–64 | year = 2007 | month = May | pmid = 17505071 | doi = 10.1093/jnci/djk177 | url =  }}</ref> This research was unable to highlight the exact vitamins responsible for this increase (almost double), although they suggest that vitamin A, vitamin E and beta-carotene may lie at its heart. It is advised that those taking multivitamins never exceed the stated daily dose on the label. Scientists recommend a healthy, well balanced diet rich in fiber, and to reduce intake of meat.
:*More fruits and vegetables


A 2007 study published in the Journal of the National Cancer Institute found that men eating cauliflower, [[broccoli]], or one of the other [[cruciferous vegetables]], more than once a week were 40% less likely to develop prostate cancer than men who rarely ate those vegetables.<ref name="CBS_News_Broccoli">{{cite web | url = http://www.cbsnews.com/stories/2007/07/24/health/webmd/main3094509.shtml | title = Broccoli May Help Cut Prostate Cancer, Broccoli, Cauliflower May Make Aggressive Prostate Cancer Less Likely  | author = | authorlink = | coauthors = | date = 2007-07-24 | format = | work = | publisher = CBS News | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-04-23}}</ref><ref name="pmid17652276">{{cite journal | author = Kirsh VA, Peters U, Mayne ST, Subar AF, Chatterjee N, Johnson CC, Hayes RB | title = Prospective study of fruit and vegetable intake and risk of prostate cancer | journal = J. Natl. Cancer Inst. | volume = 99 | issue = 15 | pages = 1200–9 | year = 2007 | month = August | pmid = 17652276 | doi = 10.1093/jnci/djm065 | url =  }}</ref> The [[phytochemical]]s [[indole-3-carbinol]] and [[diindolylmethane]], found in cruciferous vegetables, has [[antiandrogen]]ic and immune modulating properties.<ref>{{cite journal
*Healthy weight<ref name="pmid25281467">{{cite journal |vauthors=Cuzick J, Thorat MA, Andriole G, Brawley OW, Brown PH, Culig Z, Eeles RA, Ford LG, Hamdy FC, Holmberg L, Ilic D, Key TJ, La Vecchia C, Lilja H, Marberger M, Meyskens FL, Minasian LM, Parker C, Parnes HL, Perner S, Rittenhouse H, Schalken J, Schmid HP, Schmitz-Dräger BJ, Schröder FH, Stenzl A, Tombal B, Wilt TJ, Wolk A |title=Prevention and early detection of prostate cancer |journal=Lancet Oncol. |volume=15 |issue=11 |pages=e484–92 |date=October 2014 |pmid=25281467 |pmc=4203149 |doi=10.1016/S1470-2045(14)70211-6 |url=}}</ref>
|author=Sarkar FH, Li Y
*[[Statins]]<ref name="pmid17179483">{{cite journal |vauthors=Platz EA, Leitzmann MF, Visvanathan K, Rimm EB, Stampfer MJ, Willett WC, Giovannucci E |title=Statin drugs and risk of advanced prostate cancer |journal=J. Natl. Cancer Inst. |volume=98 |issue=24 |pages=1819–25 |date=December 2006 |pmid=17179483 |doi=10.1093/jnci/djj499 |url=}}</ref>
|title=Indole-3-carbinol and prostate cancer
*[[Metformin]]<ref name="pmid23918942">{{cite journal |vauthors=Margel D, Urbach DR, Lipscombe LL, Bell CM, Kulkarni G, Austin PC, Fleshner N |title=Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes |journal=J. Clin. Oncol. |volume=31 |issue=25 |pages=3069–75 |date=September 2013 |pmid=23918942 |doi=10.1200/JCO.2012.46.7043 |url=}}</ref>
|journal=J. Nutr.
*[[Vitamin E|Vitamin E<ref name="pmid8127329">{{cite journal |vauthors= |title=The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers |journal=N. Engl. J. Med. |volume=330 |issue=15 |pages=1029–35 |date=April 1994 |pmid=8127329 |doi=10.1056/NEJM199404143301501 |url=}}</ref>]]
|volume=134
*[[Selenium]]<ref name="pmid21537051">{{cite journal |vauthors=Fleshner NE, Kapusta L, Donnelly B, Tanguay S, Chin J, Hersey K, Farley A, Jansz K, Siemens DR, Trpkov K, Lacombe L, Gleave M, Tu D, Parulekar WR |title=Progression from high-grade prostatic intraepithelial neoplasia to cancer: a randomized trial of combination vitamin-E, soy, and selenium |journal=J. Clin. Oncol. |volume=29 |issue=17 |pages=2386–90 |date=June 2011 |pmid=21537051 |doi=10.1200/JCO.2010.32.0994 |url=}}</ref>
|issue=12 Suppl
|pages=3493S–3498S
|year=2004
|month=December
|pmid=15570059
|doi=
|url=
}}</ref><ref>{{cite journal
|author=Hsu JC, Zhang J, Dev A, Wing A, Bjeldanes LF, Firestone GL
|title=Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells
|journal=Carcinogenesis
|volume=26
|issue=11
|pages=1896–904
|year=2005
|month=November
|pmid=15958518
|doi=10.1093/carcin/bgi155
|url=http://carcin.oxfordjournals.org/cgi/content/full/26/11/1896
|accessdate=2008-09-12
}}</ref>
 
===Ejaculation frequency===
 
In 2003, an Australian research team led by Graham Giles of The Cancer Council Australia concluded that frequent [[masturbation]] by males appears to help prevent the development of prostate cancer.<ref>[http://www.blackwell-synergy.com/links/doi/10.1046%2Fj.1464-410X.2003.04319.x]Giles, et al., Sexual factors and prostate cancer, BJU International, Volume 92 Issue 3, Ausust 2003, pp. 211-216</ref><ref name="BBC_NEWS_Masturbation"/> Australian research concluded that the more men ejaculate between the ages of 20 and 50, the less likely they are to develop prostate cancer. The protective effect is greatest while men are in their twenties: those who had ejaculated more than five times per week in their twenties, for instance, were one-third less likely to develop aggressive prostate cancer later in life. The results contradict those of previous studies, which have suggested that having had many sexual partners, or a high frequency of sexual activity, increases the risk of prostate cancer by up to 40 percent. The key difference is that these earlier studies defined sexual activity as sexual intercourse, whereas this study focused on the number of ejaculations, whether or not intercourse was involved.<ref name="New_Scientist">{{cite web | url = http://www.newscientist.com/article/dn3942-masturbating-may-protect-against-prostate-cancer.html | title = Masturbating may protect against prostate cancer | author = Douglas Fox | authorlink = | coauthors = | date = 2003-07-16 | format = | work = | publisher = New Scientist | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-04-23}}</ref> Another study completed in 2004 reported that "Most categories of ejaculation frequency were unrelated to risk of prostate cancer. However, high ejaculation frequency was related to decreased risk of total prostate cancer." The report abstract concluded, "Our results suggest that ejaculation frequency is not related to increased risk of prostate cancer." <ref>{{cite journal |author=Leitzmann MF, Platz EA, Stampfer MJ, Willett WC, Giovannucci E |title=Ejaculation frequency and subsequent risk of prostate cancer |journal=JAMA |volume=291 |issue=13 |pages=1578–86 |year=2004 |month=April |pmid=15069045 |doi=10.1001/jama.291.13.1578 |url=}}</ref>
 
===More fish oil, less vegetable oil===
 
A high consumption of [[omega-6]] [[polyunsaturated fatty acids]] (PUFAs), which are found in most types of [[vegetable oil]] (e.g. [[corn oil]] - the most consumed oil in USA, [[soybean oil]], [[sunflower oil]], etc.), increased prostate tumor growth, speeded up histopathological progression, and decreased survival, while the [[omega-3]] [[fatty acids]] (e.g. in [[fish oil]]) had the opposite, beneficial effect<ref>{{cite journal |author=Yong Q. Chen, at al |title=Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids |journal=The Journal of Clinical Investigation |volume=117  |issue=7 |year=2007 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1890998 |accessdate=2008-11-30 |doi=10.1172/JCI31494 |pmid=1890998 |unused_data=|pages: 1866-1875}}</ref>.
 
===Myristic and palmitic saturated fatty acids===
Some researches have indicated that some specific saturated fatty acids ([[myristic acid]]<ref name="pmid14693732">{{cite journal | author = Männistö S, Pietinen P, Virtanen MJ, Salminen I, Albanes D, Giovannucci E, Virtamo J | title = Fatty acids and risk of prostate cancer in a nested case-control study in male smokers | journal = Cancer Epidemiol. Biomarkers Prev. | volume = 12 | issue = 12 | pages = 1422–8 | year = 2003 | month = December | pmid = 14693732 | doi = | url = http://cebp.aacrjournals.org/cgi/reprint/12/12/1422.pdf | issn = }}</ref><ref name="palmiticmyristic"/><ref name="saturated"/> and [[palmitic acid]]<ref name="palmiticmyristic">{{cite journal | author = Kurahashi N, Inoue M, Iwasaki M, Sasazuki S, Tsugane AS | title = Dairy product, saturated fatty acid, and calcium intake and prostate cancer in a prospective cohort of Japanese men | journal = Cancer Epidemiol. Biomarkers Prev. | volume = 17 | issue = 4 | pages = 930–7 | year = 2008 | month = April | pmid = 18398033 | doi = 10.1158/1055-9965.EPI-07-2681 | url = | issn = }}</ref><ref name="saturated">{{cite journal | author = Crowe FL, Allen NE, Appleby PN, Overvad K, Aardestrup IV, Johnsen NF, Tjønneland A, Linseisen J, Kaaks R, Boeing H, Kröger J, Trichopoulou A, Zavitsanou A, Trichopoulos D, Sacerdote C, Palli D, Tumino R, Agnoli C, Kiemeney LA, Bueno-de-Mesquita HB, Chirlaque MD, Ardanaz E, Larrañaga N, Quirós JR, Sánchez MJ, González CA, Stattin P, Hallmans G, Bingham S, Khaw KT, Rinaldi S, Slimani N, Jenab M, Riboli E, Key TJ | title = Fatty acid composition of plasma phospholipids and risk of prostate cancer in a case-control analysis nested within the European Prospective Investigation into Cancer and Nutrition | journal = Am. J. Clin. Nutr. | volume = 88 | issue = 5 | pages = 1353–63 | year = 2008 | month = November | pmid = 18996872 | doi = | url = http://www.ajcn.org/cgi/content/abstract/88/5/1353 | issn = }}</ref> are associated with increased risk of prostate cancer in a dose-dependent manner. Another study further investigated these and other saturated fatty acids.<ref name="saturated"/> However it's still uncertain if this association is a cause or consequence of the disease.


==References==
==References==
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Latest revision as of 17:54, 12 January 2021


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

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Overview

The high incidence of prostate cancer, its associated morbidity and mortality, the complications associated with its treatment, and a partial understanding of its biologic basis have led to a focus on chemoprevention strategies. The most extensive data come from the use of 5-alpha reductase (5-AR) inhibitors; other classes of agents are also being explored. The rationale for chemoprevention, the results with 5-AR inhibitors, and the more limited data with other approaches are presented here. Screening for prostate cancer, an alternative approach that focuses on early detection to decrease morbidity and mortality Effective measures for the primary prevention of prostate cancer include healthy diet and maintaining healthy weight.

Primary Prevention

  • The 5α-reductase inhibitors such as finasteride and dutasteride improve lower urinary tract symptoms in men with benign prostatic hyperplasia (BPH), by blocking the conversion of testosterone to the more potent androgen dihydrotestosterone.
  • Two randomized trials have shown a reduced risk of prostate cancer in men receiving 5-ARIs, concerns were raised about a possible increased risk of high-grade prostate cancers.
  • Swedish population-based cohort study of all men over the age of 40 who had at least one prostate-specific antigen (PSA) test in Stockholm County between 2007 and 2015, men who were prescribed a 5-ARI had a decreased risk for prostate cancer, and the effect was larger with longer duration of exposure[1].
  • The reduction was limited to patients with prostate cancers with Gleason score 6 to 7; there was no impact on the risk of higher-grade disease (Gleason score 8 to 10). These data provide some reassurance that treatment with a 5-ARI for lower urinary tract symptoms is safe with regard to prostate cancer risk, but long-term follow-up data demonstrating improved survival are needed to determine the role of 5-ARIs as chemopreventive agents.

Effective measures for the primary prevention of prostate cancer include:

  • Low-fat diet
  • More fruits and vegetables

References

  1. Wallerstedt A, Strom P, Gronberg H, Nordstrom T, Eklund M (November 2018). "Risk of Prostate Cancer in Men Treated With 5α-Reductase Inhibitors-A Large Population-Based Prospective Study". J. Natl. Cancer Inst. 110 (11): 1216–1221. doi:10.1093/jnci/djy036. PMID 29548030.
  2. Cuzick J, Thorat MA, Andriole G, Brawley OW, Brown PH, Culig Z, Eeles RA, Ford LG, Hamdy FC, Holmberg L, Ilic D, Key TJ, La Vecchia C, Lilja H, Marberger M, Meyskens FL, Minasian LM, Parker C, Parnes HL, Perner S, Rittenhouse H, Schalken J, Schmid HP, Schmitz-Dräger BJ, Schröder FH, Stenzl A, Tombal B, Wilt TJ, Wolk A (October 2014). "Prevention and early detection of prostate cancer". Lancet Oncol. 15 (11): e484–92. doi:10.1016/S1470-2045(14)70211-6. PMC 4203149. PMID 25281467.
  3. Platz EA, Leitzmann MF, Visvanathan K, Rimm EB, Stampfer MJ, Willett WC, Giovannucci E (December 2006). "Statin drugs and risk of advanced prostate cancer". J. Natl. Cancer Inst. 98 (24): 1819–25. doi:10.1093/jnci/djj499. PMID 17179483.
  4. Margel D, Urbach DR, Lipscombe LL, Bell CM, Kulkarni G, Austin PC, Fleshner N (September 2013). "Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes". J. Clin. Oncol. 31 (25): 3069–75. doi:10.1200/JCO.2012.46.7043. PMID 23918942.
  5. "The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers". N. Engl. J. Med. 330 (15): 1029–35. April 1994. doi:10.1056/NEJM199404143301501. PMID 8127329.
  6. Fleshner NE, Kapusta L, Donnelly B, Tanguay S, Chin J, Hersey K, Farley A, Jansz K, Siemens DR, Trpkov K, Lacombe L, Gleave M, Tu D, Parulekar WR (June 2011). "Progression from high-grade prostatic intraepithelial neoplasia to cancer: a randomized trial of combination vitamin-E, soy, and selenium". J. Clin. Oncol. 29 (17): 2386–90. doi:10.1200/JCO.2010.32.0994. PMID 21537051.

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