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indolent PSA dynamics, however, there may be a period of interventions in the management of BCR prostate cancer for
several years of observation before embarking on salvage delaying disease progression, indicated by PSA progression,
ADT [4], with its associated toxicities [5]. Substantial anxiety numbers progressing to/time to initiation of ADT or other
during this period of watchful waiting (WW) [6] often drives salvage therapies.
patients to seek non-hormonal treatments. Complementary
medicine use among men with prostate cancer ranges from Patients and Methods
8% to 90% (median 31%) with 8% to 50% (median 30%)
The following electronic databases were searched (earliest to
using it specically for cancer care [7]. For herbal medicine
May 2015): EMBASE (Ovid), MEDLINE (Ovid), AMED
use, the prevalence ranges from 1.2% to 24.5%. Evidence for
(Ovid), Cochrane Central Register of Controlled Trials
the efcacy of non-hormonal herbal treatments
(CENTRAL) and CINAHL (EBSCO).
(phytotherapies) is needed from studies in humans.
In addition, further relevant papers were identied using the
Scientic investigation of phytotherapeutic agents for
related articles function in PubMed, and by hand-searching
potential benet in prostate cancer chemoprevention is
reference lists of relevant journal articles and conference
increasing, especially for green tea (Camelia sinensis)
proceedings.
catechins, lycopene and soy (Glycine max) isoavones,
curcumin from turmeric (Curcuma longa), sulphoraphane
and indole-3-carbinol from broccoli (Brassica oleracea). Pre- Search Strategy
clinical studies and/or clinical trials also suggest benets for
resveratrol from grape skins or Japanese knotweed Search strategy in MEDLINE, adapted for other databases.
(Polygonum cuspidatum), pomegranate (Punica granatum) 1 exp Prostatic neoplasms/
extract (POMx), Silymarin (from St Marys/milk thistle, 2 prostate cancer.mp.
Silybum marianum), and mushrooms such as reishi 3 1 or 2
(Ganoderma lucidum), turkey tail (Coriolus/Trametes), and 4 (herb$ or medicinal plant$ or plant extract$ or plant drug$
shiitake (Lentinula edodes). or botanic$ or phytotherap$).mp
Potential anti-cancer mechanisms of these agents have been 5 (citrus or pomegranate or Punica granatum or indol-3-
extensively reviewed elsewhere [817]. These include carbinol or broccoli or diindolymethane or DIM or
inhibition of proliferation, induction of apoptosis, and cell glucosinolate$ or sulphoraphane or polyphenol$ or
cycle arrest. Soy isoavones, indole-3-carbinol and 3,30 - resveratrol or grape or curcumin or turmeric or Curcuma
diindolylmethane from broccoli, lycopene (predominantly longa or green tea or Camellia sinensis or catechin$ or
found in tomatoes), ()-epigallocatechin-3-gallate (green tea isoavone$ or phytoestrogen$ or genistein or daidzein or
polyphenols), and curcumin from turmeric, are known to Glycine max or soy$ or lycopene or red clover or Trifolium
downregulate the signal transductions in androgen receptor or liquorice or licorice or Glycyrrhiza or garlic or Allium
(AR), protein kinase B (Akt), nuclear factor-jB (NF-jB), sativum or pycnogenol or shitake or mushroom$ or
and other signal transduction pathways [18]. In vitro, Ganoderma or Trametes or turkey tail or PSP or PSK or
sulphoraphane can inhibit cancer cells through a variety of Coriolus or Lentinula or lentinan or Agaricus or silybin or
mechanisms including inammation, angiogenesis, and Silybum or silymarin or silybin$ or axseed or linseed or
metastasis, and in vivo, its administration inhibited prostate Linum or Viscum or mistletoe or Iscador).mp
cancer progression and metastasis in transgenic 6 4 or 5
adenocarcinoma of the mouse prostate (TRAMP) mice [11]. 7 3 and 6
Pomegranate polyphenols modulate B-cell lymphoma 2 (Bcl- 8 limit 7 to (English and clinical trials, all)
2) proteins, increase p21 and p27, and downregulate the English language restriction was imposed.
cyclin-cyclin-dependent kinase (Cdk) complex network [12].
Silymarin (St Marys/milk thistle) and its main active Study Selection
constituent, silibinin may enhance IGF-binding protein 3
(IGFBP-3) action and inhibit IGF-1-induced growth or affect Randomised clinical trials were eligible for inclusion in this
levels of AR-regulating genes [10]. Mushroom review. Trials investigating phytotherapeutic extracts in
polysaccharides stimulate T-cells, B-cells, neutrophils, and combination with mainstream treatment were excluded.
macrophage dependent immune system responses [16].
Systemic bioavailability is poor for curcumin and silibinin Types of Participants
[10,17].
Patients with BCR hormone-sensitive prostate cancer after
The objective of the present systematic review was to evaluate local therapy for histologically conrmed prostate cancer were
the evidence from randomised trials of phytotherapeutic included.
Types of Intervention sample size, duration, outcome measures, results, and AEs.
Where necessary, authors were contacted for further details.
Trials investigating phytotherapeutic extracts, isolated
phytochemicals, and plant-derived dietary components/items The quality of each study was assessed using the Cochrane
were included. Data from studies investigating herbal Collaborations risk of bias assessment tool [19]. Three
formulations containing additional vitamins or minerals were reviewers (D.v.D., K.B. and C.P.) worked independently to
excluded. Studies of PC-SPES (mixture of eight different herbs, determine selection, attrition, detection, performance, and
including chrysanthemum, liquorice and saw palmetto, plus the reporting bias. Any discrepancies were resolved by discussion
minerals selenium, calcium, magnesium, zinc and copper), between the reviewers. To supplement the quality assessment,
which has been discredited due to adulteration with synthetic additional criteria were assessed according to the proposed
drugs, and of herbs administered via non-oral routes were elaboration of Consolidated Standards Of Reporting Trials
excluded. (CONSORT) checklist item 4 for reporting randomised
controlled trials (RCTs) of herbal medicines [20].
Types of Controls
Data Analysis
Studies comparing interventions with inactive controls (e.g.
placebo, no treatment, standard care or a waiting list control) Lack of homogeneity across trials precluded any meaningful
or active control interventions (e.g. a different variant of the meta-analysis.
same intervention or a different herbal intervention) were
included.
Results
Types of Outcome Measures Description of Studies
The primary outcomes of the present review were After the removal of duplicates, 318 articles were located and
23 full-text articles were assessed, ve of which met the
1 Disease progression denoted by changes in PSA levels and selection criteria (Fig. 1). Key data extracted from the
PSA kinetics (PSA velocity, i.e. rise rate; PSA-DT). identied studies are included in Table 1 [11,2124]. Of the
ve studies, two were placebo controlled [11,22], two
Secondary Outcomes Included compared the intervention with a different herbal
intervention [23,24], and one was a variant of the same
1 Numbers progressing/time to initiation of mainstream
intervention (high-/low-dose) trial [21]. Study durations were
treatments, such as ADT or salvage therapies.
as follows: 2 months [24], three of 6 months [11,22,23], and
2 Changes to prostate symptoms.
one study of up to 18 months [21]. However in the latter,
3 Quality of life measures.
only 58% completed either 18 months or met the protocol-
4 Adverse events (AEs).
dened progression.
5 Compliance.
Details of the 18 excluded studies are given in Table 2 [4,2541].
Outcomes Excluded
1 Bioavailability/tissue levels. Patients
2 Mechanisms of action.
In all, 500 patients were randomised across these ve studies,
of which 489 were included in intention-to-treat analyses. Of
Data Extraction and Methodological Quality these, 368 were patients with BCR prostate cancer. One
Assessment placebo-controlled RCT was conducted in each of the UK
Two reviewers (D.v.D. and C.P. or K.B.) independently [22] and France [11]; the other three were conducted in the
screened the titles and abstracts of all articles returned from USA [21,23,24].
the search strategy. When necessary, full-text articles were One study (Pomi-T; Power Heath Products Ltd,
obtained to determine eligibility of the study. Any Pocklington, York, UK) included men before and after radical
disagreement between the two authors was to be resolved by therapies, on active surveillance (AS) or WW. The others
a third author (C.P. or K.B.). Data extraction from included included men after RP and/or radiotherapy (RT) for localised
studies was conducted by two investigators (D.v.D. and K.B.). prostate cancer [11,21,23,24]. One of these also included men
Excluded studies were reviewed by D.v.D. and M.P.; on hormone therapy (LHRH analogue) [23].
discrepancies were checked by K.B.
Four studies reported mean ages, which ranged from 69 to
The following data were extracted from the included articles: 75 years [11,21,23,24], and the other reported a median age
intervention, patient characteristics at baseline, trial design,
of 75 years [23]. The mean baseline Gleason scores reported least two PSA values at least 2 weeks apart [23]; rising PSA
in two studies were 6.4 [22] and 6.45 [21], respectively. The level at three or more time points at least a month apart,
baseline PSA levels were specied in four studies: means of within the year before enrolment [21].
0.76 ng/mL [11], 6.5 ng/mL [22], 5.3 ng/mL [21], and a
PSA-DT calculations were reported in three of the studies
median value of 6.5 ng/mL [23]. The baseline PSA-DT was
[11,21,24], and PSA velocity calculations described in a fourth
reported in three trials: means were 14.4 [11] and
(linear mixed-effects modelling with logarithm of PSA level
14.7 months [21]; percentages of men with slow, moderate
[23]). The PSA-DT was calculated either by tting a simple
and fast PSA velocities were 38% (<4 months), 32% (4
linear regression model, using the slope, (the natural log of 2
9 months), and 30% (>9 months), respectively [24].
divided by the slope obtained from tting a linear regression
The PSA inclusion criteria were specied in four studies: PSA of the natural log of PSA on time (months) [21], consistent
level of >0.2 and <5 ng/mL after RP EBRT [11]; no PSA with the Memorial Sloan Kettering Cancer Centre calculation
level limits [24]; a minimum PSA level of 10 ng/mL [23]; a [11]), or by using only the difference of the rst and last PSA
PSA level of 0.4 ng/mL after RP or multiple therapies, PSA values (the natural log(2) 9 time interval/log nal PSA log
level of >1.5 ng/mL after primary RT or cryotherapy; PSA initial PSA [24]).
nadir plus 2 ng/mL after EBRT with neoadjuvant hormonal
Current users of hormone therapy were included in one trial
therapy [21].
[24]. One study permitted LHRH analogue but no other
Denitions of BCR were included in four studies: increasing hormones within the previous 4 weeks [23]. Three other
PSA level at three successive measurements [11]; at least two studies included prior but not current users [11,21,22]. Two
consecutive increases in serum PSA level [24]; three allowed hormone use in conjunction with RT [11,22] and the
successive elevations at a minimum interval of 2 weeks or at other at least 1 year prior to enrolment [21]. There was no
Reference Intervention, Diagnosis and Study design, Endpoints Main results AEs Authors
and country extract and participant no. of conclusions
dosage vs characteristics participants
comparator and duration
Intervention compared with an inactive control intervention (e.g. placebo, no treatment, standard care, or a waiting list control)
Placebo controlled
Monotherapies
Cipolla et al. Sulphoraphane BCR prostate cancer rising Double-blind, Primary: Primary endpoint was not reached Only Grade I GI toxicity This stabilised SF
[11] (SF) PSA level (at three randomised, 0.012 log (ng/mL)/ using four values (months 0, 1, 3, (bloating) in the SF was shown to
France 60 mg daily vs successive measurements) placebo- month decrease 6). arm (n = 17) but not signicantly delay
placebo after RP (n = 29) or RP controlled trial, in the log PSA The adjusted median log PSA slope statistically different PSA progression
and RT (n = 39) or RP n = 81/78 ITT slopes in the SF in the SF group was 38.5% lower from placebo (n = 10) after RP RT.
and RT and HT (n = 10) population (SF, arm vs placebo than in the placebo group. The decrease in
Current or prior HT? Yes, n = 38; placebo, arm Mean PSA level change between the the PSA slope
in conjunction with RT n = 40) Secondary: end of month 6 and baseline was was most marked
(n = 10) Duration: Difference in PSA signicantly lower in the SF vs after 3 months
PSA level: >0.2 and 6 months values from placebo group at a mean (SD) of treatment
<5 ng/mL; mean baseline to the 0.099 (0.34) vs 0.62 (1.47) ng/mL
0.76 ng/mL end of month 6 (P = 0.043).
PSA-DT: >5 and PSA-DT PSA-DT was 86% longer in the SF
<36 months; mean Testosterone level vs the placebo group, at 28.9 vs
14.4 months 15.5 months.
Gleason score: 8 Testosterone levels: no difference
Age, mean (SD): 69 between arms
(6) years Very good tolerance
Multi-component interventions
Thomas et al. Pomi-T: Localised prostate cancer RCT placebo- PSA levels PSA levels were stable or lower than No statistically This study found a
[22] pomegranate managed with AS (n = controlled, Average PSA change baseline more often in the Pomi- signicant difference signicant short-
UK green tea, 121, 60%) or WW (n = n = 203/199 (136/ Number remaining T group (46% vs 14%; P < 0.001). in AEs between arms: term, favourable
broccoli 78, 40%) following a PSA 134 active; 67/ on AS In the AS sub-group (n = 121) the 34 (24%) in Pomi-T effect on the
sprouts and relapse after radical 65 placebo) Cholesterol mean PSA level dropped by and 23 (34%) in percentage rise in
turmeric all treatments (RT, n = 65; Duration: Blood glucose 0.14% (95% CI 7.57 to 7.95) in placebo group. PSA in men
300 mg/day vs RP and RT, n = 8; 6 months CRP the Pomi-T group, but rose by No Grade IIIIV managed with AS
placebo brachytherapy, n = 9). BP 46.98% in the placebo group toxicities, but one and WW after
Current or prior HT? No (95% CI 28.51 to 68.31; P = Grade II (diarrhoea) ingestion of this
current use, prior use 0.001); in the WW subgroup (n = with Pomi-T. food supplement
included. 78) the mean PSA rose by 8.78% GI events in 21 (15.5%)
Mean PSA level: 6.5 ng/mL in the Pomi-T group (95% CI in Pomi-T vs 5 (7.5%)
PSA-DT: not specied 6.32 to 26.62) vs 80.34% in the in the placebo group
Gleason score, mean: 6.4 placebo group (95% CI 50.54 to (NS).
Age, mean: 73 years 116.55; P = 0.001). No effect on INR in 30
(active); 76 years Median increase in PSA level was men on warfarin
(placebo) 63.8% lower in the Pomi-T vs the
placebo group (14.7% vs 78.5%; P
< 0.001) at 6 months.
More men in the Pomi-T group
than in the placebo group
continued on AS or WW (92% vs
72%).
No signicant differences between
groups for cholesterol, serum
glucose, CRP or BP. Compliance
was excellent (96.5% Pomi-T, and
21
Phytotherapeutic interventions in recurrent prostate cancer
22
Table 1 (continued)
van Die et al.
Reference Intervention, Diagnosis and Study design, Endpoints Main results AEs Authors
and country extract and participant no. of conclusions
dosage vs characteristics participants
comparator and duration
Reference Intervention, Diagnosis and Study design, Endpoints Main results AEs Authors
and country extract and participant no. of conclusions
dosage vs characteristics participants
comparator and duration
BP, blood pressure; CRP, C-reactive protein; GI, gastrointestinal; INF, international normalisation ratio; ITT, intention to treat; HT, hormone therapy; NS, statistically non-signicant.
Reference Intervention, Diagnosis and inclusion of ADT Study design Endpoints Results AEs
and extract and and duration
country dosage vs
van Die et al.
comparator
Reference Intervention, Diagnosis and inclusion of ADT Study design Endpoints Results AEs
and extract and and duration
country dosage vs
comparator
Twardowski White button BCR prostate cancer/PSA failure after Phase I dose- PSA progression. 11% overall PSA response rate. CR to Minimal side-effects,
et al. [29] mushroom RP or RT. PSA 0.2 ng/mL after RP, escalation study, DHT, DHEA and undetectable levels in two patients on mostly limited to
USA (Agaricus bisporus) or 2.0 ng/mL above post-RT nadir. n = 36 oestrogen. 8 and 14 g/day. PR in two patients Grade I abdominal
at six doses: Current or prior HT? Yes, prior. Up to Duration: Cytokine multiplex on 8 and 12 g/day. 13 (36%) had bloating.
4/6/8/10/12, and 9 months of neoadjuvant or adjuvant 3 months Myeloid-derived some PSA decrease below baseline One case of Grade
14 g/day treatment, completed at least suppressor cells after 3 months. III hyponatraemia
6 months before registration (MDSCs) in CR and PR demonstrated higher levels at 8 g/day dose,
Evidence of metastases? No peripheral blood of baseline interleukin 15 than non- patient was taken
PSA, median: 1.9 ng/mL mononuclear cells. responders, and associated declines off protocol
PSA-DT: not reported Toxicity in MDSCs.
Gleason score, mean: not specied PSA responses did not correlate with
Age, median: 68 years serum testosterone, DHT or DHEA
levels
Guess Modied citrus Recurrent adenocarcinoma of the Non-randomised PSA level. No decreases in absolute PSA level. Well tolerated. No
et al. [30] pectin (MCP), prostate and low but progressively phase II pilot PSA-DT An increase in PSA-DT in eight of 10 serious side-effects
USA Pecta-Sol, 14.4 rising PSA after RP, EBRT, RP and study, evaluable patients, but only seven but three patients
g/day in divided RT or cryosurgery. n = 13/10 were statistically signicant withdrew due to
doses Current or prior HT? Yes, previous. Duration: (P 0.05). side-effects (two
Evidence of metastases? No, up to stage 12 months Compliance excellent (patient with mild
3c subjective report) abdominal cramps,
PSA, mean: 1.03 ng/mL one with mild
PSA-DT, mean: 6.9 months diarrhoea) that
Gleason score, mean: 6.9 resolved soon after
Age, mean: 69.6 years stopping the MCP
Hussain Soy isoavones, Prostate cancer and rising PSA (i) Pilot study, n = 41 PSA levels. No PSA CRs (normalisation of PSA) or Very well tolerated,
et al. [31] 200 mg/day orally under WW; or (ii) after local Duration: Biomarkers (IGF and PRs (50% reduction). with no toxicity
USA therapy, or (iii) while receiving HT. 0.86 months oxidative stress PSA velocity decreased in whole group attributable to
Current or prior HT? Yes, prior. markers). (P = 0.01). Novasoy treatment.
Current LHRH analogues permitted. Toxicity No signicant change in the level of No Grade III AEs
Evidence of metastases? Yes 5-hydroxymethyl-20 -deoxyuridine or
PSA, mean: 13.3 ng/mL plasma levels of IGF-1 and IGFBP-3.
PSA-DT: not specied No observed changes in serum
Gleason score: not specied testosterone
Age, mean: 73 years
deVere White Genistein-rich Five treatment groups: failed RP; failed Open-label pilot PSA levels. One AS patient had 50% reduction in Three patients
et al. [32] extract, 5 g/day: RT; intermittent HT; combination of study, n = 52 Clinical chemistries PSA level. withdrew due to
USA 40% isoavones RP and RT; AS or WW. Duration: (ALP, AST, total Seven AS patients had PSA level AEs (diarrhoea)
(Novasoy) added Current or prior HT? Not specied. 6 months bilirubin, creatinine, reductions of <50%.
to a mushroom Evidence of metastases? Yes cholesterol, and Patients in the AS group had PSA
(G. lucidum) PSA, mean: 7 ng/mL GGT) levels on average 27% lower than
mycelia culture a PSA-DT: not specied otherwise predicted (P = 0.026).
total of 450 mg/ Gleason score, mean: not calculable Clinical chemistries were all unaltered
day of genistein, Age, mean: 74.5 years
plus an additional
450 mg/day of
other aglycone
isoavones
Reference Intervention, Diagnosis and inclusion of ADT Study design Endpoints Results AEs
and extract and and duration
country dosage vs
comparator
van Die et al.
Kwan Soy beverage, Rising PSA after curative radical RT for Phase II non- PSA level. PSA level showed a declining trend in Well tolerated.
et al. [33] 500 mL/day, prostate cancer but no clinical randomised PSA-DT. four patients (13.8%). Most common AE
Reference Intervention, Diagnosis and inclusion of ADT Study design Endpoints Results AEs
and extract and and duration
country dosage vs
comparator
Kranse Isoavones plus Hormonally untreated men with RCT crossover PSA, total and free. Free PSA decreased during verum No serious AEs; one
et al. [37] green tea extract, prostate cancer and rising PSA after study, n = 37 PSA-DT. (P = 0.02). patient withdrew
The lycopene, RP or RT or under WW. Duration: Male sex hormone Total PSA-DT unaffected, but NS due to abdominal
Netherlands antioxidants Current or prior HT? No. 1.5 month levels increase from 9.5 months during pains
including Evidence of metastases? No. treatment placebo period to 10 months during
carotenoids, PSA, median: 3.24 ng/mL. phases separated verum.
selenium, PSA-DT: not specied. by a 0.5 month In men in whom the free androgen
phytosterol, Gleason score: not specied. washout index decreased (21/32), there was a
a-tocopherol and Age, median: 70 years signicant decrease in the slopes of
margarine vs both total and free PSA (P = 0.04).
placebo Male sex hormone levels lower with
verum (P = 0.02): DHT,
0.11 nmol/L (P = 0.005);
testosterone, 1 nmol/L (P = 0.02)
Barber et al. Lycopene whole- Men with localised prostate cancer on Phase II clinical PSA velocity. Regression slopes of (log) PSA vs time Discolouration of
[38] tomato lycopene clinical surveillance (AS or within-groups PSA-DT. decreased in 26/37 (70%) of patients faeces
UK supplementation BCR/WW). pilot study, Toxicity (P < 0.001).
10 mg/day (two Current or prior HT? Yes, at least n = 37 PSA-DT: non- signicant increase
tablets of Lycoplus 1 year prior. Duration, mean: (median increase of 174 days).
each tablet Evidence of metastases? No. 10.4 months No toxicity
contains 5 mg PSA, mean: 23.3 ng/mL.
lycopene, 100 mg PSA-DT: not specied.
vitamin C, 1.25 mg Gleason score, mean: 6.
vitamin E, 0.83 mg Age, mean: 73 years
phytoene and
phytouene and
0.21 mg b-
carotene)
Dorff Prostate Health BRC, rising PSA level after RT or RP Open label pilot PSA response. No men had a PSA CR or PR. Grade I or II liver
et al. [4] Cocktail (PHC), a or both with PSA-DT between 3 and study, n = 40/39 PSA-DT. 15/39 men (38%) had a PSA decline enzyme elevations
USA supplement 36 months. Duration: 4-week Circulating tumour (1.155% maximum decrease); (transient), Grade I
containing vitamins Current or prior HT? Yes, at least cycles (113 cells. median change at 3 months was or II GI symptoms
D and E, saw 3 months prior with testosterone cycles, median DHT. 18.1%. (nine), Grade I
palmetto, lycopene, recovery. 10) Testosterone PSA-DT median 6.7 months; 12/37 weakness/
green tea and soy Evidence of metastases? No. (32%) had slower PSA-DT. dizziness/pain
extracts PSA, median: 2.8 ng/mL. Circulating tumour cells in 16/33 (ve), and Grade I
PSA-DT, median: 9.4 months. patients. fatigue (two)
Gleason score: 23% had Gleason >7. No change in testosterone or DHT
Age, median: 67 years
Risk of BCR PCa
Bosland Soy protein isolate vs Men at high risk of recurrence after RCT placebo BCR rate (dened as 28.3% developed BCR within 2 years, Trial stopped after 45
et al. [39] placebo RP. controlled, development of PSA close to the a priori predicted rate of men developed
USA Current or prior HT? Not specied. n = 177/159 (81 >0.07 ng/mL) over 30% [22 (27.2%) in the intervention BCR due to lack of
Evidence of metastases? Yes soy; 78 placebo) rst 2 years after group and 23 (29.5%) in the placebo treatment effect.
PSA level, mean before RP 7.4 ng/mL. Duration: up to randomisation. group]. Six potentially related
PSA-DT: not specied. 2 years Time to recurrence. Self-reported adherence was excellent, GI issues but no
Gleason score, mean: 7 Adherence with 152 patients (96%) reporting difference to
Age, mean: 61 years having consumed >90% of the placebo group
packets supplied
Reference Intervention, Diagnosis and inclusion of ADT Study design Endpoints Results AEs
and extract and and duration
Vidlar Silymarin [St. Marys Men with prostate cancer after RP. RCT placebo QoL. Improved QoL. No AEs reported.
et al. [40] thistle; Silybum Current or prior HT? Not specied. controlled, Haematology and Decreased LDLs and total cholesterol
Czech marianum (SM)] Evidence of metastases? Not specied. n = 37 (n = 19, basic clinical from baseline in SM-Se group
Republic 570 mg, combined PSA, mean: not specied. SM-Se group; chemistry (ALT, (P < 0.05); increase from baseline in
with selenium (Se) PSA-DT: not specied. n = 18, placebo AST and GGT, erythrocyte count and haemoglobin
240 lg as Gleason score: not specied. group) cholesterol, TAG, in SM-Se group (P < 0.05).
selenomethionine Age, mean: 63.8 years Duration: ApoA1 and ApoB). No change to testosterone or
vs placebo 6 months Oxidative stress antioxidant status
markers.
Testosterone
Advanced PrCa
Stenner- Pomegranate (Punica Early PSA rise after initial therapy, and RCT double- PSA values. No differences between groups for PSA No Grade III
Liewen granatum) juice, PSA level 5 ng/mL. blind, placebo- Pain scores. values or pain scores. toxicities.
et al. [41] 500 mL or 500 mL Current or prior HT? Yes, both. controlled phase Adherence Adherence to protocol was good, with Bowel disturbances
Switzerland placebo beverage/ Evidence of metastases? Yes IIb, 94 patients (96%) completing the (one case
day for 1 month, PSA level, mean: 74.6 ng/mL n = 103/98 rst period (days 128), and 87 obstipation and
followed by PSA-DT: not specied Duration: (89%) completing both periods (days one diarrhoea in
250 mL Gleason score: 8 in 49% 2 months 156) verum group)
pomegranate juice/ Age, mean: 72.5 years most frequently
day (both arms) reported
for a further
month
ALP, alkaline phosphatase; ALT, alanine aminotransferase; Apo, apolipoprotein AST, aspartate amino-transferase; CR, complete response; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; GI, gastrointestinal; GT,
c-glutamyltransferase; HT, hormone therapy; LDL, low-density lipoprotein; MCP, modied citrus pectin; PP, per protocol analysis; PR, partial response; QoL, quality of life; SM, Silybum marianum; TAG, trigylcerides.
Phytotherapeutic interventions in recurrent prostate cancer
signicant difference across groups for current or prior use of 50.54116.55) rise in the placebo group (P = 0.001) [22]. The
hormone/anti-androgen therapy in any of the trials including serum PSA level decreased in 25% of men administered
these baseline data [11,21,23,24]. tomato/lycopene for 1 month followed by a combination of
tomato and soy protein for a further month, compared with
Interventions 43% men administered soy protein for 1 month, followed by
the combination for a further month, (36% men overall) [24].
Three types of interventions were identied in the studies: No partial (50% PSA reduction) or complete (PSA level of
phytotherapeutic extracts, isolated phytochemicals, and plant- 4 ng/mL) responses were seen with lycopene or lycopene
derived dietary items. Interventions were delivered either as plus soy isoavones over 6 months [23]. However, 95% of
monotherapies or in combinations. Two studies investigated patients in the lycopene group and 67% of the lycopene-
lycopene: dietary lycopene (tomatoes) >25 mg/day, calculated isoavones arm achieved stabilisation of serum PSA levels.
according to a food worksheet vs a powdered soy protein Additionally, the PSA velocity signicantly declined over the
supplement 40 g/day (Solae Company, St. Louis, MO, USA; 6 months for both men with hormone-sensitive (P = 0.015)
product Number AB20 Soy 1.2; each 40 g packet contained and hormone-refractory (P = 0.017) prostate cancer.
24 mg genistein, 12 mg diadzein, and 2 mg glycitein. Lycopene-only resulted in a signicantly greater decline than
isoavones were present in the aglycone form) for 1 month the combination for the men with hormone-refractory disease
followed by the combination for a further month (both arms) (P = 0.021). In the pomegranate study (POMx), declining
[24]; lycopene 30 mg/day (Lyc-o-mato,15 mg orally twice post-baseline PSA levels were seen in 13% (six patients in the
daily) vs a combination of lycopene at the same dose plus low-dose arm and nine patients in the high-dose arm) and
isoavone capsules 80 mg daily (Solgen R 40 mg orally twice stable disease was seen in 36 (78%) patients in the low-dose
daily, LycoRed Company, Beer-Sheva, Israel) [23]. The other arm and 40 (82%) in the high-dose arm [21].
three studies investigated three different interventions: free
stabilised sulphoraphane 60 mg daily (NutrinovTM) [11]; Pomi-
T, a combination of pomegranate (Punica granatum) extract, PSA-DT
green tea (Camellia sinensis), broccoli sprouts (Brassica All three studies reporting on PSA-DT found prolongation in a
oleracea) and turmeric (Curcuma longa) all 300 mg/day; and number of men [11,21,24]. An estimated 78% PSA-DT increase
pomegranate (Punica granatum) extract 1 g or 3 g/day (POMx was seen with sulphoraphane (21.7 months) compared with
capsules, POM Wonderful LLC; 1 or 3 capsules/day, each placebo (12.2 months) [11]. The median PSA-DT extended from
containing 1 000 mg of polyphenol extract, comparable to 14.26 to 28.9 months over 6 months. With tomato or soy protein
250 mL pomegranate juice, 90% polyphenols) [21]. for 1 month followed by a combination of the two for a further
month, prolongation of the PSA-DT occurred in 58% of men,
Controls/Comparators 65% in the tomato group, and 51% in the soy group [24]. The
Two studies were placebo-controlled trials (sulphoraphane percentage of men whose PSA-DT was classied as slowest
[11] and Pomi-T [22]) of 6 months duration; the (>9 months) increased from 30% to 48% (P = 0.08), over the 2-
pomegranate (POMx) study was a high-/low-dose study of up month period. Administration of POMx capsules (1 or 3 g/day)
to 18 months duration [21]; and the remaining two resulted in a median lengthening of the PSA-DT from 11.9 to
compared lycopene with a different phytotherapeutic agent 18.5 months over the study period of up to 18 months (P <
(soy protein) for 2 months [24]/combination (lycopene plus 0.001), with no signicant difference between the dosage
soy isoavones for up to 6 months) [23]. regimens [21]. In the 1g-POMx group, 76% of patients had a
stable or lengthening PSA-DT and 46% had increases of 100%
in PSA-DT. In the 3g-POMx group, 82% of patients had stable or
Effects of Interventions
lengthening PSA-DT, and 41% had 100% increase in PSA-DT.
PSA levels
Other
With all ve interventions investigated, serum PSA levels
either stabilised, decreased, or increased less than with There was no signicant effect on testosterone levels with
placebo in a signicant number of men on verum [the active sulphoraphane, POMx or lycopene and soy protein
study substance(s)]. PSA levels rose signicantly less with [11,21,24]. With administration of POMx capsules, oestradiol
sulphoraphane than with placebo over 6 months (P = 0.03), trended higher in the high-dose group from 28.0 to 32.3 pg/
and the log PSA slope was signicantly lower between mL, but not in the low-dose group. Sex hormone-binding
baseline and the end of month 6 (P = 0.036), and particularly globulin (SHBG) increased in both groups (42.554.7 nmole/
at months 3 and 6 (P = 0.011) [11]. In the Pomi-T study, the L in the 3g-POMx group and 42.849.2 nmole/L in the 1g-
mean PSA level rose by 8.78% in the WW group on verum POMx) with no signicant difference between groups [21].
(95% CI 6.32 to 26.62), compared with an 80.34% (95% CI Lycopene plus soy resulted in reductions in serum vascular
endothelial growth factor (VEGF; P < 0.04) and total (iv)], the propriety product name or extract name and name
cholesterol, in both treatment arms [24]. of manufacturer of the product [4A.(2)], and dose and
duration of administration [4C(i) and (ii)], but none included
AEs the botanical family [4A.1(iii)], the type and concentration of
extraction solvent (where relevant); or a description of the
AEs were predominantly Grade I gastrointestinal events that practitioners (4F).
were not signicantly more frequent than with placebo in the
RCTs. As shown in Table 1, other events were minor in
nature. Discussion
There is growing interest in researching phytotherapeutic
Risk of Bias interventions for BCR prostate cancer, especially ones that do
Risk of bias analysis was conducted in accordance with the not interfere with hormone receptors. Many men who
Cochrane Collaboration guidelines for systematic reviews as experience PSA relapse after local treatment for prostate
an assessment of the validity of ndings, and is summarised cancer turn to herbal and other complementary medicines in
in Figure 2A,B [11,2124]. Most were categorised as low risk an attempt to delay the need for ADT, with its attendant
(60%) or unclear (20%). Random sequence generation was side-effects, to prolong the time to metastases, and/or reduce
only described in two of the ve studies. The two unblinded prostate cancer-specic morbidity and mortality. We have
active-comparator studies were assessed as high risk on presented the results of a systematic review of the evidence
selection, performance, and detection bias criteria [23,24]. In from randomised trials of phytotherapeutic extracts, isolated
the sulphoraphane study, it would appear the trial product phytochemicals, and plant-derived dietary items in the
manufacturer had involvement in data analysis and context of BCR prostate cancer. To our knowledge, this is the
interpretation [11]. rst review of phytotherapeutic interventions in this cohort.
Of the 23 identied clinical studies, ve met the criteria for
inclusion. No two were identical in terms of intervention and
Reporting According to Elaboration of CONSORT for
comparator, thus precluding any meaningful meta-analysis.
Trials of Herbal Interventions
Overall, the quality of the studies was good, although
All identied studies were assessed according to the generally sample sizes were small and durations short.
elaborated CONSORT statement for trials of herbal Interventions investigated were sulphoraphane; lycopene vs
interventions [20]. Generally compliance was low (Table 3). soy (Glycine max) protein; lycopene with soy isoavones;
All studies reported the common names of the plant [4A.1 Pomi-T, which is a combination of pomegranate (Punica
Fig. 2 Risk of bias summary (a) and graph (b) of included studies.
(a) (b)
Table 3 Reporting according to the proposed elaboration of CONSORT checklist Item 4 for reporting RCTs of herbal medicine.
granatum), green tea (Camellia sinensis), broccoli sprouts rather metabolism and absorption [24]. Importantly, in the
(Brassica oleracea) and turmeric (Curcuma longa); and three studies that monitored testosterone levels across the
pomegranate (Punica granatum) extract (POMx). Despite treatment phase, no signicant changes were found. With
small sample sizes, all studies found serum PSA levels to POMx [21], both dosage regimens resulted in non-signicant
stabilise, decrease, or rise more slowly in a signicant number increases in SHBG levels. Only one study measured changes
of men. Statistically signicant results were found for a in VEGF, which found signicant reductions with both
decrease in the mean PSA slope vs placebo with dietary lycopene and soy protein [24]. Safety and tolerability
sulphoraphane, the mean PSA change with Pomi-T, and PSA were very good for all interventions. However, these ndings
velocity in both hormone-sensitive and hormone-refractory should be treated with caution pending replication of results
prostate cancer with lycopene and lycopene plus soy from further adequately powered studies.
isoavones. Prolongation of the PSA-DT was seen in all three
studies reporting on this endpoint [11,21,24], and reached
statistical signicance with sulphoraphane, and POMx. In the Limitations
third, the 2-month study of tomato vs soy protein, it should Consistent with the ndings of other reviews on
be noted that PSA was not the main endpoint of interest, but phytotherapeutic interventions in prostate cancer [4244],
limitations include the number of studies identied, sample studies highlighted several barriers to comparability of
sizes, duration of follow-up, and lack of power in some ndings from phytotherapy research in this cohort; namely
studies to detect clinically meaningful changes in PSA or variations in study population, intervention, design and
other biomarkers of disease progression. One study included endpoints. As most studies do not concurrently measure
men on both AS (before local therapy) and WW (after local other markers of tumour progression in participants, the
therapy), without consistent reporting of sub-population possibility of the interventions masking PSA kinetics cannot
analysis, thereby limiting our ability to determine the impact be excluded.
on the rising PSA population after local therapy [22].
In addition, comparison of results across studies is hindered Recommendations
by the variety of ways used to report PSA endpoints: mean Greater consensus among researchers designing clinical trials
change in PSA/percentage change from baseline; percentage is needed to permit meta-analyses and meaningful
lower than control arm; percentage of men with a decrease in comparisons of studies that would assist clinicians in advising
PSA; number of/percentage of men with a partial (>50% patients of the risks and/or benets of phytotherapeutic
reduction) or complete PSA response; time to PSA interventions in BCR prostate cancer. Four areas are
progression. The PSA-DT was dened as the mean or median candidates for such consensus:
log slope; the number of men moving from one risk category
(slow, moderate or fast) to another; the median or mean 1 Denitions of BCR, and the number and frequency of PSA
number of months prolongation; and percentage change readings over time: The authors propose that researchers
from baseline. use the AUA denition of BCR after RP (PSA level of
>0.2 ng/mL measured 613 weeks after RP, followed by a
For adherence to the proposed elaboration of CONSORT conrmatory test showing a persistent PSA level of
checklist item 4 (Table 3) for trials of herbal medicine, >0.2 ng/mL [45]. Researchers should also follow the AUA
reporting was inadequate for information relating to the herb recommendation for dening BCR after RT by using the
name, characteristics of the herbal product, quantitative American Society for Radiation Oncology (ASTRO)
description, and qualitative testing. A lack of complete and denition of BCR (the midpoint between PSA nadir and
transparent reporting impacts on reproducibility of studies, as the rst of three consecutive rises in PSA level [5]).
well as translation into clinical practice. 2 Stratication: Because metastasis-free survival is strongly
Abstracts published in proceedings of professional meetings inuenced by the PSA-DT and Gleason score, it is
were searched but not included in the review. As none of important to stratify patients on these two factors (PSA-DT
these was a negative study, this is unlikely to reect of <9 vs 9 months and Gleason score 3 + 4 vs 4 + 3
publication bias. However, publication bias cannot be [2,3]).
excluded. The key issues identied with phytotherapeutic 3 Methods of calculating the PSA-DT: As recommended by
research in this area are summarised in Table 4. the Prostate-Specic Antigen Working Groups Guidelines
on PSA-DT, the calculation of PSA-DT is the natural log
The overall aim of the present review was to examine the of 2 divided by the slope obtained from tting a linear
evidence for phytotherapeutic interventions in prolonging regression of the natural log of PSA on time (months) for
metastasis-free survival in men with BCR prostate cancer. at least three values of PSA all >0.2 ng/mL and all taken
The attempt to pool or compare results from the identied within 12 months [46].
4 Reporting of results: Results should include, where
available, change in the PSA-DT, 30% and/or 50% decline
Table 4 Key limitations identied with phytotherapeutic research in this in PSA level and metastasis-free survival in accordance
area. with the Prostate Cancer Working Group denitions [47].
Small sample sizes
Short follow-up periods Endpoints
Inadequate power
Signicant variations in study populations Although the PSA-DT is probably the most important
Signicant variations in intervention prognostic factor in metastases-free survival and overall
Signicant variations in design
Signicant variations in endpoints
survival [2], further evidence is needed to conrm ndings
Publication bias cannot be excluded that changes in PSA-DT after initiation of a therapy are
Bias sometimes difcult to establish due to incomplete reporting prognostic for metastasis-free survival in patients with BCR
Some manufacture driven trial data
Type and concentration of extraction solvent used not commonly reported
disease [5,48]. Inclusion of metastases-free survival as an
Extraction methods and actual bioavailability of compounds are variable endpoint is encouraged, despite necessitating lengthy follow-
The ratio of herbal drug to extract not commonly reported up periods. To determine whether effects endure, adequate
Equivalence of product with expected bioactivity is variable
follow-up periods, and non-treatment follow-up beyond the
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