Table 1.

Phytochemicals or plant-based interventions in PCa primary care

Phytosubstance/plant-based supplement (dosage)	Study design	Year	Study participants (n = number)	Effects/results	Adverse events of phytosubstance	Major study limitations	Ref
Plant foods (green vegetable, cruciferous vegetable, tomatoes, beans) and whole-grain breads	Data from three case–control studies	1999	Incident PCa cases (n = 617) and controls (n = 636)	Reduced PCa risk	Not available	Multiple comparisons — some findings could occur as significant by chance	[28]
Fruit (cryptoxanthin)				Enhanced PCa risk, independent of antioxidant vitamin intake
Legumes (not limited to soy) and certain vegetables	Multicentre, multiethnic, case–control study	2000	Confirmed PCa cases (n = 1619) and controls (n = 1618)	Legumes and certain categories of vegetables may protect against PCa	Not available	Not available	[29]
Fruit, vegetable, vitamin A	Follow-up on cohorts of former workers and residents of Wittenoom Gorge since 1975, to document the epidemiology of asbestos-related diseases	2008	PCa cases (n = 1985)	Decreased PCa risk with increasing intake of vegetable rich in vitamin C (bell peppers and broccoli); fruit, other vegetable, vitamin A not observed a strong factor in PCa development	Not available	Analysed ‘total fruit and vegetable’ intakes analysed may not be directly comparable to typical definitions of total fruit and vegetable intakes; Repeated assessments of dietary intake would improve the study; Required careful interpretation (some results may arise by chance)	[30]
Green tea	Case–control study (epidemiological study)	2004	Adenocarcinoma of prostate cases (n = 130) and controls (n = 274)	Declined PCa risk with increasing frequency, duration, and quantity of green tea vs controls	Not available	Not available	[33]
Polyphenon E (800 mg of EGCG and lesser amounts of other GTC, totally 1.3 g of tea polyphenols/day) administered during the interval between prostate biopsy and radical prostatectomy	Open-label, single-arm two-stage phase II clinical trial	2009	Men with positive prostate biopsies (n = 26)	Decreased PSA, VEGF, HGF with no elevation in liver enzymes	No adverse effects (only 1 patient reported mild nausea)	Not available	[34]
Green tea (6 cups/day) or water (control) prior to radical prostatectomy	Randomised exploratory, open label, phase II trial	2015	Men diagnosed with PCa (n = 113) prior to radical prostatectomy randomised into brewed green tea, black tea, or water control	Decreased NFκB in radical prostatectomy tissues, reduced urinary 8OHdG, decrease in serum PSA vs control	No serious adverse event reported	Not blinded study	[37]
Polyphenon E (800 mg of EGCG/day) or placebo for 3–6 weeks until the day before surgery	Randomised, double-blind, placebo-controlled trial	2012	Men with PCa scheduled to undergo radical prostatectomy (n = 50)	Low bioavailability and/or bioaccumulation of green tea polyphenols in prostate tissue; Insignificant changes in PSA, serum insulin-like growth factor, oxidative DNA damage in blood leukocytes	Well tolerated, minimal adverse events (nausea, diarrhoea, headache, 1 patient had a mild ALT elevation)	Short duration of intervention	[38]
Polyphenon E (400 mg of EGCG/day) for 1 year	Placebo-controlled, randomised clinical trial	2015	Men with HGPIN and/or ASAP (n = 97)	EGCG accumulated in plasma; no effects on PCa prevention	Well tolerated	Low completion rate	[39]
Quercetin and green tea (1 g of green tea extract with 800 mg of quercetin or placebo (green tea + placebo) for 4 weeks	Prospective randomised, open label, parallel two arm intervention study	2020	Men scheduled for prostatectomy (n = 31)	No significant increase in EGCG or EGC or decrease in GTP methylation in prostate tissues	No serious adverse effects	Not reported participant food intake (foods containing quercetin or green tea)	[40]
EGCG (600 mg/day) and/or fish oil or placebo	Double-blinded, randomised controlled trial	2016	Men scheduled for repeat prostate biopsy following an initial negative prostate biopsy (n = 89)	No significant changes in FAS or Ki67	No grade ≥ 3 adverse events	Limited sample size, hospital-based design among men scheduled for repeat prostate biopsy may restrict the generalizability of results	[41]
Lycopene and green tea (6 months)	ProDiet randomised controlled trial	2019	Men with raised PSA levels but PC-free (n = 128)	Lycopene lowered pyruvate levels → suggested effects on reduced PCa risk	Not available	ProDiet RCT originally designed to test the feasibility of a dietary intervention (not to detect an effect of the intervention on metabolite levels), small sample size,	[44]
Lycopene (15 mg/day) or placebo for 6 months	Randomised clinical pilot study	2008	Patients with benign prostate hyperplasia (n = 40)	Inhibited disease progression vs placebo	Well tolerated, no adverse events	Not available	[45]
Profluss® (Serenoa repens + selenium + lycopene)		2013	Patients with benign prostate hyperplasia and/or PIN/ASAP (n = 168)	Anti-inflammatory effects	Not available	Lack of placebo controlling	[46]
Red/yellow tomato paste, purified lycopene (yellow and red tomato paste 200 g/d, which provided separated by 2 weeks of washout, in a parallel design first group purified lycopene 16 mg/d for 1 week and second group placebo)	Randomised, single-blinded crossover study for tomato paste studies and a parallel study for lycopene studies, ex vivo study (incubation of LNCaP cells with sera from healthy volunteers)	2010	Healthy men (n = 30)	Upregulated IGFBP-3 and Bax/Bcl-2 ratio and decreased cyclin-D1, p53, and Nrf-2 after cell incubation with sera from health men who consumed red tomato paste	No side effects reported	Not available	[47]
Tomato consumption (canned and cooked) more than 4 times/week	Prospective study (food frequency questionnaire)	2020	Incident cases of PCa (n = 1 226)	Canned and cooked tomatoes may reduce PCa risk (more available lycopene)	Not available	Dietary habits information only from the enrolment questionnaire (repeated measures not provided), not distinguishing between molecular PCa subtypes, relatively low number of aggressive PCa limits power to evaluate risk with good precision	[48]
Tomato sauce	Prospective cohort of men from the Health Professionals Follow-Up Study (food frequency questionnaire)	2016	n = 46 719	Tomato sauce may play a role in TMPRSS2:ERG-positive PCa reduction	Not available	Possible misclassification of diet, restricting cases to men treated with radical prostatectomy rendered the entire population of men who did not develop PCa an inappropriate comparison group	[49]
Tomato-enrich diet, lycopene (15 mg capsules/day), or green tea (600 mg/day) for 6 months	Pilot, randomised-controlled trial	2019	Men with PSA between 2.0 and 2.95 ng/ml or negative biopsies (n = 266)	No effects on serum levels of IGF-I, IGF-II, IGFBP-3, or IGFBP-2	Not available	Trial not set up to investigate IGFs as a primary outcome and designed as a feasibility pilot study	[50]
Lycopene (35 mg/day), green tea catechins (600 mg/day), and selenium (55 µg/day) or placebo for 6 months	Double-blind Phase I–II randomised controlled trial	2015	Men with primary multifocal HGPIN and/or ASAP (n = 60)	Higher incidence of PCa at re-biopsy and microRNAs associated with PCa progression vs placebo	Well tolerated	Small number of patients, simultaneous use of three compounds (not allowed precise evaluation of each substance, absence of PCa family history), not performed molecular analysis	[51]
Selenium and lycopene or control for 1 year	Post-hoc analysis of the Procomb trial	2017	Patients who underwent prostate biopsy when ≥ 4 ng/ml and/or PCa suspicion (n = 209)	No detrimental effects on increasing PCa risk; no protective effects	Not available	Lack of measurement of serum levels of selenium or other micronutrients, low rate PCa diagnosed	[52]
Serum lycopene	Nested case–control study in the Prostate Cancer Prevention Trial, a placebo-controlled trial	2011	PCa cases (n = 1683) and controls (n = 1751)	No evidence on association between serum lycopene and PCa	Not available	Not available	[53]
Lycopene-rich tomato extract (30 mg/day) for 6 months	Phase II randomised, double-blind, placebo-controlled trial	2015	Men with HGPIN (n = 58)	Large differences in serum lycopene but no treatment effects	Not available	Small size and restricted statistical power, presence of HGPIN as an endpoint	[54]
Lycopene-rich tomato supplement (30 mg of lycopene/day)	Phase II trial	2007	Androgen-independent PCa patients (n = 46)	Not effective in androgen-independent PCa	Less severe — appeared more plausibly related to lycopene (diarrhoea, nausea, abdominal distension, flatulence, vomiting, anorexia, dyspepsia)	Stable PSA in several patients (unclear whether due to lycopene), PSA decline as primary endpoint	[55]
Retinol and α-carotene (serum)	Nested case–control study – data from PCPT, a multicentre, randomised, placebo-controlled SWOG-coordinated trial	2015	n = 18,880	Increased PCa risk in men with higher level of serum retinol and α-carotene	Not available	Small number of high grade cancers, limited differences by race or ethnicity	[56]
β-carotene (30 mg/day) and retinyl palmitate (25,000 IU/day) for lung cancer prevention	Randomised controlled trial	2009	CARET participants	Increased PCa risk associated with high-dose β-carotene and retinyl palmitate plus at least one other dietary supplement	Not available	Only evidence whether participants used or not supplements — inability to investigate which particular place person at a risk, underpowered to examine PCa deaths	[57]
Common circulating carotenoids and retinol	Men from the Prostate Cancer Prevention Trial placebo arm	2022	Men with negative end-of-study biopsy (n = 235)	Not useful in PCa prevention through the modulation of intraprostatic inflammation	Not available	Inability to assess whether circulating carotenoids reflect prostate tissue levels (circulating levels and tissue inflammation not measured concurrently)	[58]
Genistein (30 mg/day) or placebo for 3–6 weeks	Phase 2 placebo-controlled, randomised, double-blind clinical trial	2012	Early PCa patients before prostatectomy (n = 47)	Reduced KLK4 in tumour cells and a non-significant decrease in androgen and cell cycle-related biomarkers vs placebo	Not available	Small number of cases, short time of intervention	[62]
Soy isoflavones (27.2 mg isoflavone aglycones per tablet, 3 tablets/day) or placebo for 2 weeks	Pilot randomised double blind clinical study	2009	PCa patients (n = 25)	Decreased prostate COX-2 mRNA and increased p21 mRNA	Not available	Not available	[64]
Soy isoflavones (soy beverage protein containing 60 mg of genistein) or placebo for 12 weeks	Prospective randomised, placebo-controlled clinical trial	2004	PCa patients (n = 76)	Decreased or unchanged PSA and free testosterone vs placebo	Not available	Not available	[65]
Broccoli (400 g/week) or peas (400 g/week) for 6 months	Parallel, dietary intervention study	2008	Male volunteers with previous diagnosis of HGPIN (n = 22)	Interaction with GSTM1 genotype modulating signalling pathways associated with inflammation and carcinogenesis, changes in TGFβ, insulin signalling, and EGF (decreasing PCa risk)	Not available	Men within both arms exerted significant changes in androgen receptor pathway (but this can be associated with aging independently of diet), informative stratification of global gene expression profiles, other dietary phytochemicals could interact with plasma signalling peptides	[66]
BSE (200 µmol/day) or a placebo for 4–8 weeks	Double-blind, randomised controlled trial	2020	Men scheduled for prostate biopsy (n = 98)	Differentially expressed genes correlating with BSE treatment — AMACR and ARLNC1 (implicated in PCa development)	Bloating, headache, no grade ≥ 3 adverse events	Short treatment duration	[67]
Milk thistle — silybin-phytosome (2.5–20 g/daily in 3 divided doses)	Phase I trial	2007	PCa patients (n = 13)	13 g of oral silybin-phytosome is well tolerated and recommended to phase II dose	Hyperbilirubinemia (grade 1—2 bilirubin elevations in 9 of 13 patients), ALT elevation (grade 3 toxicity) in one patient; no grade 4 toxicity	Not available	[72]
Milk thistle – silybin-phytosome (13 g/daily in 3 divided doses)	Clinical trial	2010	PCa patients planning for prostatectomy (n = 12)	High-dose oral silybin-phytosome achieves high blood concentrations transiently, but low levels in prostate tissue	Mild (diarrhoea, hyperbilirubinemia). One patient developed grade 4 post-operative thrombo-embolic event	Short duration	[73]

Abbreviations: ALT, alanine aminotransferase; ASAP, atypical small acinar proliferation; BSE, broccoli sprout extract; CARET, The Carotene and Retinol Efficacy Trial; COX-2, cyclooxygenase-2; DNA, deoxyribonucleic acid; EGC, epigallocatechin; EGCG, epigallocatechin-3-gallate; EGF, epidermal growth factor; FAS, fatty acid synthase; GSTM, glutathione S-transferase mu 1; GTC, green tea catechins; GTP, green tea polyphenols; HGF, hepatocyte growth factor; HGPIN, high-grade prostatic intraepithelial neoplasia; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; KLK4, kallikrein-related peptide 4; mRNA, messenger RNA; NF-κB, nuclear factor-κB; PCa, prostate cancer; PIN, prostatic intraepithelial neoplasia; PSA, prostate-specific antigen; TGFβ, transforming growth factor beta; VEGF, vascular endothelial growth factor; 8-OHdG, 8-Hydroxy-2'-deoxyguanosine; g, gram; mg, milligram; μg, microgram