Table 2.

Epidemiologic and clinical intervention studies with vitamin and trace element/mineral-associated nutraceuticals in prostate cancer

Natural product	Study type	Intervention	Population/location	Outcome	Reference
Vitamin D	•Case-control cohort	•Daily oral administration vitamin D3 (4000 IU) •PCa patients scheduled for prostatectomy •Time: For 2 months prior to surgery	USA 27 cases Ethnicity:AA (n = 10) EA (n = 17)	•Reduced immune and inflammation signaling in PCA transcriptome •Increased expression of immune and inflammation-associated genes in AAs relative to EAs	Hardiman et al.54
Vitamin D	•Phase I •Open-label multi-center, non-randomized dose-escalation study	•Oral administration of inecalcitol (40–8000 µg) daily, or twice a day in combination with a 1-h intravenous infusion of docetaxel (75 mg/m2, every 3 weeks) and oral prednisone (5 mg twice a day) •Naive metastatic castrate-resistant PCa patients received up to six 21-day treatment cycles •Time: For 6 months	France 54 cases Ethnicity: French	•Reduced serum PSA levels (at 4000 µg) by ≥30 and ≥50% within the first 3 months •Increased median time of PSA progression to 169 days •Well tolerated at 4000 µg	Medioni et al.52
Vitamin D	•Phase IIa •Randomized placebo-controlled trial	•Daily oral administration of cholecalciferol (vitamin D3 200,000 IU) as one dose at study entry plus genistein [(G-2535), 600 mg daily], or placebo cholecalciferol day 1 and placebo genistein daily •Patients with early stage PCa and scheduled for radical prostatectomy •Time: For 21–28 days prior to surgery	Univ. of Wisconsin chemoprevention consortium 15 cases Ethnicity: N/A	•Non-significant increase in calcitriol serum concentrations compared to placebo (0.104 ng/mL ± 0.2 vs. 0.0013 ng/mL ± 0.08; p = 0.08); but no increase in prostate tissue •Elevated AR expression (p = 0.04) and apoptosis (p = 0.1) in prostate tumor tissues compared to placebo	Jarrad et al.51
Vitamin D	•Phase III •Multi-center •Randomized open-label study •Case cohort	•Oral administration of ASCENT [high-dose calcitriol (45 µg), docetaxel (36 mg/m2), and dexamethasone (24 mg)] for 3 out of every 4 weeks or control [prednisone (5 mg) twice daily with docetaxel (75 mg/m2), and dexamethasone (24 mg) every 3 weeks) •Patients diagnosed with metastatic castration-resistant PCa and disease progression •Time: follow-up of 48 weeks	ASCENT Study 198 hospitals [USA, Canada, Germany, Hungary, Czech Republic, Romania, Slovakia, and Serbia] 953 cases North American (722 cases), Europe (231 cases) (Years: 2006–2007)	•More deaths in ASCENT arm and trial was halted •Decreased median overall survival to 17.8 months (95% CI = 16.0–19.5) compared to 20.2 months (95% CI = 18.8–23.0) in the control arm (log-rank p = 0 .002) •Survival remained inferior after adjusting for baseline variables (HR = 1.33, p = 0.019) •No difference in serum PSA levels •Docetaxel toxicity occurred by 2-fold in ASCENT (31%) compared to control arm (15%) •Common adverse events were GI effects (75% of patients), blood and lymphatic disorders (48%)	Scher et al.117
Vitamin D	•Case-cohort design nested within SELECT	•Daily administration of selenium (200 μg of L-selenomethionine) + vitamin E (400 IU of all rac-α -tocopheryl acetate), vitamin E and placebo, selenium and placebo, and placebo •Patients (aged ≥50 years (AA) or ≥55 years) with no PCa history, PSA ≤ 4 ng/mL and non-abnormal DRE •Time: For 7–12 years, median overall follow-up of 5.46 years	Data from Selenium and Vitamin E Cancer Prevention Trial (SELECT) 427 sites (United States, Canada, and Puerto Rico) 1731 cases, 3203 cohort Ethnicity: EA [n = 1394 (80.5%) cases, n = 2213 (69.1%) cohort] AA [n = 250 (14.4%) cases, n = 802 (25%) cohort] Other [n = 87 (5%) cases, n = 188 (5.9%) cohort]	•Both low and high vitamin D concentrations were associated with increased risk of PCa, and more strongly for high-grade disease •Optimal range of circulating vitamin D for PCa prevention may be narrow; significantly reduced risks among men with moderate vitamin D concentrations (approximately 45–70 nmol/L) •Higher vitamin D levels associated with reduced risk of advanced PCa in AAs	Kristal et al.118
Vitamin D	•Phase II •Randomized, double-blind, placebo-controlled cancer	•Daily oral administration of vitamin D3 (cholecalciferol) at doses 400, 10,000, or 40,000 IU •Patients (30–85 years) with a Gleason score 6 or 7 •Time: For 3–8 weeks prior to prostatectomy	University Health Network 45 patients University of Toronto Toronto, Canada Ethnicity: N/A (Years: 2008–2012)	•Prostatic (1,25(OH)2D) concentrations showed that VDR was significantly lower in prostate tissues with the highest concentration of 1,25(OH)2D •IL-6 expression was the highest in the prostate stroma, while PTGS2 (COX2) levels were lowest in the prostate cancer tissues from men in the highest tertile of prostatic 1,25(OH)2D •TNF-α, IL-6, and IL-8 were suppressed by 1,25 (OH)2D in the primary epithelial cells, whereas TNF-α and PTGS2 were suppressed by 1,25(OH) 2D in the stromal cell	Giangreco et al.63
Vitamin E	•Randomized, double-blind, placebo-controlled cancer prevention trial	•Daily administration of α-tocopherol (all-rac-α-tocopheryl acetate 50 mg) or β-carotene (20 mg) or both α-tocopherol and β-carotene, or placebo •Patients aged 50–69 years with a smoking history •Time: For 5 years, median follow of 6.1 years, follow-up of 18 years	Alpha-Tocopherol, β-Carotene Cancer Prevention (ATBC) Study 25,563 patients in Southwestern Finland Ethnicity: Finnish (Years: 1985–1993; National Registries follow-up till 2011)	•α-tocopherol reduced post-trial PCa mortality (RR = 0.84; 95% CI = 0.70–0.99) relative to non-recipients •Daily α-tocopherol (50 mg) for a median of 6.1 years decreased the risk of PCa •No significant late effects (follow-up of 18 years) of α-tocopherol intake on PCa incidence	Virtamo et al.26
Vitamin E	•Randomized, double-blind, placebo-controlled trial •Case-control cohort	•Daily oral administration of selenomethionine (200 μg), vitamin E (all-rac-α-tocopheryl acetate, 400 IU), or both or placebo •Patients with no PCa history, PSA ≤ 4 ng/mL and non-abnormal DRE •Time: For 0–7.9 years, median follow-up of 5.5 years •The trial was stopped early due to lack of efficacy of either supplement	SELECT study 1746 PCa incident cases and sub-cohort of 3211 derived from SELECT trial 427 sites (United States, Canada, and Puerto Rico) Ethnicity: AA [n = 251(14.4%) cases, n = 735 (24.4%) ctrls] Hispanic [n = 58 (3.3%) cases, n = 139 (4.6%) ctrls] EA [n = 1406 (80.5%) cases, n = 2083 (69.2%) ctrls] Other [n = 31 (1.8%) cases, n = 51(1.7%) ctrls]	•High Pca incidence in men supplemented with high-dose α-tocopherol •Higher plasma α-tocopherol levels could interact with selenomethionine supplements to increase high-grade PCa risk •Higher PCa hazard risk (HR = 2.04, 95% CI = 1.29–3.22, p-trend = 0.005) was associated with patients who received selenomethionine supplement in combination with α-tocopherol in the fifth quintile relative to the first quintile •Plasma levels of α-tocopherol were positively associated with risk of high-grade PCa disease (HR = 1.59, 95% CI = 1.13–2.24, p-trend = 0.001, Gleason grade 7–10), in the fifth quintile •Plasma levels of α- and γ-tocopherol were not associated with PCa overall	Albanes et al.67
Vitamin E (APC-100)	•Phase I/ IIa •Open-label, non-randomized, dose-escalation study •Case cohort	•Oral administration of antioxidant moiety of vitamin E [APC-100, (900–2400 mg)] •Patients diagnosed with castrate-resistant PCa •Time: For 4–36 weeks	USA 20 cases Ethnicity: EA [n = 13 (65%)] AA [n = 5 (25%)] Asian [n = 2 (10%)]	•25% of patients receiving APC-100 treatment maintained stable disease •Median progression free survival) was 2.8 months •APC-100 undetectable in plasma at dose of 2100 mg	Kyriakopoulos et al.64
Vitamin E	•Double-blind, placebo-controlled cancer prevention trial	•Daily oral administration of α-tocopherol (all-rac-α-tocopheryl acetate 50 mg), β-carotene (20 mg), both or placebo •Patients aged 50–69 years with a smoking history •Time: For 5–8 years	Data from ATBC study 200 cases (100 aggressive) and 200 controls Southwestern Finland Ethnicity: Finnish (Years: 1985–1993)	•Serum metabolomic response to supplementation determined •Downregulated vitamin E (γ-tocopherol, β-tocopherol) and amino acid (N6-aceytllysine, β-alanine, ornithine, and glutarylcarnitine) metabolites •Upregulated vitamin E (α-tocopherol), co-factor (α-CEHC sulfate, α-CEHC glucuronide) and carbohydrate (fructose) metabolites	Mondul et al.119
Vitamin E	•Case cohort	•Daily intake/administration of vitamin E supplements (30, 100, 200, 400, 600, or 800 IU) assessed •Patients diagnosed with prostate adenocarcinoma and residing within the study catchment areas •Time: For 1 year prior to diagnosis	Data from North Carolina-Louisiana PCa project 2102 cases Ethnicity: AA [n = 1023] EA [n = 1079] (Years: 2004–2009)	•Dietary and supplemental α-tocopherol and PCa aggressiveness were inversely related in AAs (p-trend = 0.2, 0.15) •Dietary intake of α- (p-trend = 0.006) and δ-tocopherol (p-trend = 0.007) were related inversely to PCa aggressiveness among EAs	Antwi et al.66
Vitamin E	•Prospective •Randomized trial •Case cohort	•Weekly intervention of high intake of plant-based foods (whole grains, fruits, vegetables, and legumes (soybean products) and exercise) and low intake of meat and dairy products •Patients diagnosed with biochemically recurrent PCA •Time: For 6 months (3 months of active intervention followed by monthly boosters)	Midlands Region of South Carolina 39 cases Ethnicity: EA [n = 28 (72%)] AA [n = 11 (28%)]	•After adjusting for baseline PSA levels, plasma levels of α-tocopherol (p = 0.01) at 3 months were inversely related to serum PSA levels at 6 months •Lower serum PSA levels at 3 and 6 months were associated with percent increase in plasma levels of α-tocopherol relative to baseline	Antwi et al.14
Vitamin E	•Randomized trial	•Administration of vitamin E (400 IU) every other day, vitamin C (500 mg) daily, or their respective placebos •Physicians aged ≥ 50 years •Time: 10.3 years, post-trial follow-up of 2.8 years	Physicians Health Study II Total of 14,641 US Physicans enrolled 1373 PCa cases Ethnicity: N/A (Years: 1997–2007), follow-up till 2011	•Supplementation had no effect on PCA incidence	Wang et al.70
Vitamin E/lycopene	•Prospective •Randomized, double-blind, placebo-controlled trial	•Daily administration of α-tocopherol (50 mg), β-carotene (20 mg), both α-tocopherol and β-carotene, or placebo •Patients aged 50–69 years with a smoking history •Time: For 5 years, median follow of 6.1 years, follow-up of 18 years	Data from ATBC study 200 cases (100 aggressive) and 200 controls Southwestern Finland Ethnicity: Finnish (Years: 1985–1993)	•Energy and lipid-related serum metabolite levels were associated with low risk of aggressive PCa with the exception of Erucoyl-sphingomyelin and Trimethylamine N-oxide •Serum levels of other metabolite chemical classes were not associated to non-aggressive or overall PCa risk •Glycerophospholipid, long-chain fatty chain, and TCA metabolites were primarily modulated compared to other metabolites	Mondul et al.73
Vitamin E/selenium	•Randomized, placebo-controlled trial •Case-cohort	•Daily oral administration of selenomethionine (200 μg), vitamin E (all-rac-α-tocopheryl acetate, 400 IU), or both or placebo •Patients with no PCa history, PSA ≤ 4 ng/mL and non-abnormal DRE •Time: 7–12 years, median overall follow-up of 5.46 years	Data from SELECT study 1739 cases, 2922 ctrls Ethnicity: AA [13.7% cases, 24% ctrls] Hispanic [3.3% cases, 4.3% ctrls] EA [81.2% cases, 70% ctrls] Other [1.8% cases, 1.7% ctrls]	•Vitamin E supplementation increased the risk of PCa among men with low selenium status •Overall, low-grade, and high-grade PCa risk was higher among men with lower selenium status and receiving vitamin E supplements (p = 0.008) •Vitamin E supplementation (alone) had no effect in men with high selenium status (≥40th percentile of toenail selenium) (p = 0.02) •Selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status •Men should avoid selenium and vitamin E supplementation at doses that exceed recommended dietary intakes	Kristal et al.68
Vitamin E/selenium	•Case cohort study of SELECT trial participants	•Daily oral administration of selenomethionine (200 μg), vitamin E (all-rac-α-tocopheryl acetate, 400 IU), or both or placebo •Patients with no PCa history, PSA ≤ 4 ng/mL and non-abnormal DRE •Time: 7–12 years, median overall follow-up of 5.46 years	Data from SELECT study Sub-cohort: 1866 cases	•NKX3.1 rs11781886 genotypes did not significantly modify total low-grade or high-grade PCa risk •NKX3.1 rs11781886 genotypes CC (total, low grade) in the selenium arm and CT (total, high grade) in the vitamin E arm were associated with increased risk of PCa	Martinez et al.72
Vitamin E/selenium	•Case cohort study of SELECT trial participants	•Daily oral administration of selenomethionine (200 μg), vitamin E (all-rac-α-tocopheryl acetate, 400 IU), or both or placebo •Patients with no PCa history, PSA ≤ 4 ng/mL and non-abnormal DRE •Time: For 7–12 years, median overall follow-up of 5.46 years	Data from SELECT study Sub-cohort: 1434 cases	•The effect of selenium or vitamin E supplementation on high-grade PCa risk may vary by genotype •Inheritance of TTPA genetic variants (rs12679996, rs4606052) and Vitamin E supplementation were linked to increased PCa risk •SNPs in Vitamin E-associated genes, SEC14L2, SOD1, and TTPA, modified risk of developing high-grade PCa disease •Potential interactions betweenSOD2, SOD3, and TXNRD2, and selenium status and PCa risk	Chan et al.94
Selenium	•Phase III •Randomized doubled-blind placebo-controlled trial	•Daily oral administration selenium (200 µg /or 400 µg) or placebo •High-risk PCa patients (PSA > 4 ng/mL and/or abnormal DRE) with negative prostate biopsy •Time: Follow-up of 5 years	Negative Biopsy Trial (NBT)-USA and New Zealand 699 patients Ethnicity of 699 patients were N/A Ethnicity of initial participants White [n = 404 (86.7%)] AA [n = 16 (3.4%)] Asian [n = 5 (1.1%)] Hispanic [n = 38 (8.2%)] Native American [n = 3 (0.6%)]	•Intervention did not significantly modify PCa susceptibility •No changes in PSA velocity were seen in selenium treatment groups relative to placebo subjects •Mortalities occurred in the placebo (5), low (3), and high-dose selenium (2) treatment groups	Lu et al.85
Selenium	•Phase II •Randomized, double-blind, placebo-controlled trial •Case cohort	•Daily oral administration of 200/or 800 μg of selenium or placebo •Patients diagnosed with localized non-metastatic PCa (Gleason score < 8, PSA < 50 ng/mL, age < 85 years) •Time: For placebo (36.3 months, follow-up 38.4 months); selenium 200 μg (33.4 months, 33.3 months), 800 μg: (33.3 months, 33.8 months)	USA 140 cases Ethnicity: EA [n = 123 (88%)] Non-EA [n = 17 (12%)]	•No significant effects on PSA velocity and Gleason score •Increased PSA velocities in the highest quartile of patients receiving high-dose selenium (800 µg) relative to placebo (p = 0.018) •Total of four deaths in treatment groups	Lu et al.85
Selenium	•Double-blind, randomized, placebo-controlled trial	•Daily administration of selenium as selenomethionine 200 μg/day) or placebo •Men ≥40 years of age with a confirmed diagnosis of HGPIN lesions via biopsy with no evidence of PCa •Time: For 3 years •The primary endpoint was progression of HGPIN to PCa over a 3-year period	NCI Intergroup trial/Southwest Oncology Group (SWOG) 423 randomized men with HGPIN Ethnicity: N/A	•Selenium supplementation had no effect on PCa risk •No differences in Gleason scores between the two arms	Marshall et al.120
Selenium	•Phase I/II •Randomized double-blind placebo-controlled trial •Case cohort	•Daily administration of dietary supplement [selenium (55 mg), lycopene (35 mg), and green tea catechins (600 mg)] or placebo •Patients diagnosed with multi-focal high-grade prostatic intraepithelial neoplasia (mHGPIN) and/or atypical small acinar proliferation (ASAP) •Time: For 1 month (Phase I), 6 months (Phase II), mean follow-up of 37 months	Univ. of Turin, Italy 10 cases (Phase I), 60 cases (Phase II) Ethnicity: Italian (Years: 2009–2014)	•No significant change in mean serum PSA levels •Higher PCa diagnoses were in intervention group at re-biopsy compared to placebo (p = 0.053) •Upregulated miRNAs (26b-5p, let-7i-5p, let-7d-5p, 16-5p, 199a-5p, 214-3p, 15a-5p, 29b-3p, 30e-5p, and 34a-5p) and downregulated miR-494, an oncosuppressor, in PCa relative to normal tissue	Gontero et al.43
Selenium	•Randomized, double-blind, double-dummy trial •Multi-center	•Patient data from Profluss® intake 1 tablet/day [(85% of fatty acids sterols, selenium(50 µg) and lycopene (5 mg)] and control •Patients aged 55–80 years diagnosed with lower urinary tract symptoms (negative DRE for PCa, PSA < 4 ng/mL) •Time: For 1 year, follow-up of 2 years	Post hoc analysis of Procomb trial 209 patients Ethnicity: Italian (Years: 2012–2014)	•No detrimental or protective role of supplementation in increasing PCa risk •No significant differences in the mean serum PSA levels or Gleason score •No effect on PCa risk (OR = 1.07; 95% CI = 0.64–1.79; p = 0.95), incidence (HR = 1.38; 95% CI = 0.32–5.90; p = 0.67)	Morgia et al.27
Selenium	•Randomized, placebo-controlled trial	•Daily oral administration of selenium (selenized yeast, 300 µg) or placebo •Patients undergoing diagnostic prostate biopsies and radical prostatectomy •Time: For 5 weeks	Netherlands 23 cases Ethnicity: Dutch	•Downregulated genes associated with cell migration, invasion, remodeling, and immunity •Exhibited an inhibitory effect against EMT via upregulation of epithelial markers (E-cadherin and EPCAM) and downregulation of mesenchymal markers (vimentin and fibronectin)	Kok et al.90
Selenium	•Randomized, double-blind, placebo-controlled trial •Case-control cohort •(sub-study of participants within SELECT)	•Daily oral administration of selenomethionine (200 μg) or vitamin E (all-rac-α-tocopheryl acetate, 400 IU), or both selenomethionine and vitamin E or placebo •Patients with no PCa history, PSA ≤ 4 ng/mL and non-abnormal DRE •Time: For 0–7.9 years, median follow-up of 5.5 years •The trial was stopped early due to lack of efficacy of either supplement	SELECT study data 1746 PCa incident cases and sub-cohort of 3211 derived from SELECT trial 427 sites (United States, Canada, and Puerto Rico) Ethnicity: AA [n = 251(14.4%) cases, n = 735 (24.4%) ctrls] Hispanic [n = 58 (3.3%) cases, n = 139 (4.6%) ctrls] EA [n = 1406 (80.5%) cases, n = 2083 (69.2%) ctrls] Other [n = 31 (1.8%) cases, n = 51(1.7%) ctrls]	•Increased PCa risk (HR = 2.04; 95% CI = 1.29–3.22) in patients receiving selenomethionine alone or in combination with α-tocopherol in the highest quintile relative to the first quintile (p-trend = 0.005) •Positively associated with plasma levels of α-tocopherol in patients receiving selenomethionine in the fifth quintile (HR = 2.12; 95% CI = 1.32–3.40; p-trend = 0.0002) •Non-significant elevation of PCa risk associated with selenomethionine in the third tertile of plasma α-tocopherol levels relative to placebo	Albanes et al.67
Selenium	•Randomized-controlled trial •Case cohort	•Daily administration of (a) tomato products containing lycopene 30 mg per day; (b) tomato products plus ([green tea (1 cup), black tea (1 cup), pomegranate juice (330 mL), grape juice (330 mL),soy- isoflavones (200 mg), 1-selenomethionin (200 µg), omega -3 fatty acids (3.13 g n-3 fatty acids)]; (c) control (habitual) diet •Prior to curative treatment of PCa patients with non-metastatic disease •Time: For 3 weeks	Oslo University Hospital, Norway 86 cases Ethnicity: N/A (Years: 2007–2012)	•Tomato products plus therapy slightly decreased (non-significant) serum PSA levels among intermediate-risk patients post surgery •Decreased serum PSA levels with highest increases in levels of lycopene, selenium and fatty acid C20:5 n-3 •Tomato products plus therapy significantly changed fatty acid profiles (p < 0.001) and doubled plasma selenium values	Paur et al.11
Selenium	•Pilot •Randomized, double-blind, placebo-controlled trial	•Daily administration of selenium-enriched yeast (SY) (247 μg) or placebo (non-enriched yeast) •Healthy subjects (aged 19–43 years) with no smoking history •Time: For 9 months, follow-up after 12 months	American Health Foundation, New York and Penn State College of Medicine, Pennsylvania 36 healthy patients Ethnicity: AA [n = 11 (31.6% ctrl, 29.4% treatment)] EA [n = 25 (68.4% ctrl, 70.6% treatment)]	•Upregulated (clusterin isoform 1 [CLU], transthyretin, α-1Bglycoprotein, transferrin, complement component 4B proprotein, isocitrate dehydrogenase, haptoglobin, keratin 1) and downregulated (α-1 antitrypsin [AAT], angiotensin precursor and albumin precursor) several proteins •CLU and AAT are associated with PCa development •Supplementation resulted in selenium plasma levels lower in AAs relative to EAs •Levels of AAT were higher in AA men compared to EA men •Supplementation reduced AAT levels; however, after intervention AAT levels recovered in AAs at 12 months, but remained low in EA men	Sinha et al.91
Selenium/lycopene	•Multi-center •Cohort	•Daily administration of Profluss [1:1 ratio of SeR 320 mg + lycopene (5 mg) + Selenium (50 μg) (group I), control (group Ic), SeR 320 mg + Lycopene (5 mg), Selenium(50 μg), and α-blockers treatment (group II), control (group IIc)] •Patients with LUTS, PSA > 4 ng/mL, Abnormal DRE/transrectal ultrasound, chronic inflammation-associated BPH, high-grade PIN and/or ASAP •Time: For 6 months (Group I) and 3 months (Group II)	Flogosis And Profluss in Prostatic and Genital Disease (FLOG) study 9 centers (Italy) 108 patients (Group I) 60 patients (Group II) Ethnicity: Italian (Years: 2009-2010)	•Decreased serum PSA levels in Group I, but no difference in Group II •Reduced extension and grading of flogosis in treated patients •Decreased of total interstitial mononuclear cells, mancrophages, B and T lymphocytes after 6 months in group I and 3 months in group II relative to controls	Morgia et al.93
Selenium/multi-vitamins	•Prospective cohort	•Daily intake of multi-vitamins or individual supplement (such as, selenium, β-carotene, and zinc) •PCa free at enrollment. Patients with AARP memberships •Time: For 1 year, follow-up to 5 years	National Institutes of Health (NIH)-AARP Diet and Health Study 10,241 cases (8765 localized and 1476 advanced disease) Ethnicity: EA (92%), AA (4%) Other (4%) (Years 1995–1996)	•Increased risk of advanced (RR = 1.32; 95% CI = 1.04–1.67) and fatal (RR = 1.98; 95% CI = 1.07–3.66) PCa with excessive use of multi-vitamins relative to non-users •Frequent use (≥7 per week) increased risk of PCa (p-trend = 0.003) and localized disease (p-trend = 0.004) •Strongly associated with PCa risk in patients with a family history of PCa	Lawson et al.65
Zinc	•Case-control surveillance cohort	•Daily use of multi-vitamin containing zinc, vitamin E, beta-carotene, folate, and selenium •Patients with a primary diagnosis of PCa and no other malignancy except non-melanoma skin cancer •Time: For 1–10 years or more	USA hospitals located in four centers (Baltimore, Boston, New York, and Philadelphia) 1706 cases, 2404 matched ctrls Ethnicity: EA [83.9% cases, 77% ctrls] AA [16.1% cases, 23% ctrls] (Years: 1976 onwards)	•10 years or more use of zinc in a multi-vitamin or supplement was linked to 2-fold (OR = 1.9, 95% CI = 1.0–3.6) increase in PCA risk •Lower risk was associated with the use of multi-vitamin that did not contain zinc	Zhang et al.16
Zinc	•Randomized, placebo-controlled trial	•Daily intake and supplemental use of vitamin C, vitamin D, zinc, calcium, carotenoids, lycopene, EPA* plus DHA* or multi-vitamin weekly •Placebo patients, free of BPH at baseline •Time: For 1 year	Prostate Cancer Prevention Trial (PCPT) subjects 4770 patients Ethnicity: EA [n = 4460 (93.5%)] AA [n = 153 (3.2%)] Hispanic [n = 98 (2.1%)] Other [n = 59 (1.2%)]	•BPH assessed by International Prostate Symptom Score questionnaire. Diet, alcohol, and supplement use assessed by food frequency questionnaire •Supplement intake did not affect BPH risk •A diet low in fat and red meat, and high in protein and vegetables, as well as regular alcohol consumption may reduce risk of BPH	Kristal et al.17
Zinc	•Prospective •Case-control cohort	•Daily use of vitamin E, selenium, and zinc supplements •Patients with no history of PCa •Time: Average follow-up 3.5 years	VITAL study cohort (USA) 832 cases, 34,412 ctrls Ethnicity: EA [781 (94.6%) cases, 31,642 (93.2%) ctrls] AA [17 (2.1%) cases, 421 (1.2%) ctrls]	•10 year average intake of supplemental zinc was not associated with a reduced PCa risk overall •Risk of advanced PCa (regionally invasive or distant metastatic) decreased with greater intake of supplemental zinc (adjusted HR = 0.34, 95% CI = 0.13–1.09 for 10-year average intake >15 mg/day vs. non-use, p-trend = 0.04)	Gonzalez et al.77
Zinc	•Multi-stage, stratified sampling design	•Daily zinc intake and cadmium exposure in relation to recommended daily allowance •Subjects aged 50 years or more (zinc intake and cadmium exposure fit within the tolerable range limit for adults) •Time: For <1–18.1 years, average follow-up of 12.4 years	Third National Health and Nutrition Examination Survey (NHANES III) 2474 patients Ethnicity: EA, AA, and Mexican-Americans (Years: 1988–1994, follow-up to 2006)	•Cadmium exposure is a risk factor of cancer mortality in older Americans and the risk increases in those with inadequate zinc intake •Cadmium exposure was not associated with PCa risk	Lin et al.79

EA European-American, AA African-American, PCA prostate cancer, PSA prostate-specific antigen, BPH benign prostatic hyperplasia, HR hazard ratio, OR odds ratio, RR relative risk, DRE digital rectal exam, SNP single-nucleotide polymorphism, IGF-I insulin-like growth factor-I, IGFBP-3 IGF-binding protein-3, miRNA microRNA, Ctrls controls