Phytonutrients and outcomes following breast cancer: a systematic review and meta-analysis of observational studies.

BACKGROUND: Phytonutrient intakes may improve outcomes following breast cancer, but the impact of postdiagnosis introduction vs established prediagnostic exposure as well as optimum doses has not been established. Evidence from observational studies for key exposures was evaluated, including dosage and intake time frames. METHODS: MEDLINE, EMBASE, CINAHL, Cochrane Library, ClinicalTrials.gov, and the ISRCTN registry were searched for prospective and retrospective observational studies investigating the impact of soybean, lignans, cruciferous (cabbage-family) vegetables, green tea, or their phytonutrients on breast cancer survival outcomes. A random-effects model was used to calculate summary hazard ratios (HRs) and 95% confidence intervals (CIs). Nonlinear dose-response analyses were conducted using restricted cubic splines. RESULTS: Thirty-two articles were included. Soy isoflavones were associated with a 26% reduced risk of recurrence (HR = 0.74, 95% CI = 0.60 to 0.92), particularly among postmenopausal (HR = 0.72, 95% CI = 0.55 to 0.94) and estrogen receptor-positive survivors (HR = 0.82, 95% CI = 0.70 to 0.97), with the greatest risk reduction at 60 mg/day. In mortality outcomes, the reduction was mostly at 20 to 40 mg/day. Soy protein and products were inversely associated with cancer-specific mortality for estrogen receptor-positive disease (HR = 0.75, 95% CI = 0.60 to 0.92). An inverse association was observed for serum or plasma enterolactone, measured prediagnosis and early postdiagnosis, with cancer-specific mortality (HR = 0.72, 95% CI = 0.58 to 0.90) and all-cause mortality (HR = 0.69, 95% CI = 0.57 to 0.83). No effects were observed for cruciferous vegetables. There was a 44% reduced risk of recurrence with prediagnostic green tea for stage I and II breast cancer (HR = 0.56, 95% CI = 0.38 to 0.83). CONCLUSIONS: Soy, enterolactone, and green tea demonstrated significant risk reductions in outcomes following breast cancer. Evidence is needed regarding the impact of postdiagnostic introduction or substantial increase of these exposures.

A Placebo-Controlled Double-Blinded Randomized Pilot Study of Combination Phytotherapy in Biochemically Recurrent Prostate Cancer.

BACKGROUND: Men with biochemical recurrence of prostate cancer following local therapies often use natural supplements in an attempt to delay metastases and/or avoid the need for more aggressive treatments with undesirable side-effects. While there is a growing body of research into phytotherapeutic agents in this cohort, with some promising results, as yet no definitive recommendations can be made. This pilot study was undertaken to assess the feasibility of a fully-powered study to examine the effects of this phytotherapeutic intervention (containing turmeric, resveratrol, green tea and broccoli sprouts) on PSA doubling time in men with biochemical recurrence with a moderate PSA rise rate. METHODS: A double blind, randomized, placebo-controlled parallel trial was conducted with 22 men with biochemically recurrent prostate cancer and a moderate rise rate (PSA doubling time of 4-15 months and no evidence of metastases from conventional imaging methods). Patients were randomized to either the active treatment arm or placebo for 12 weeks. The primary endpoints were feasibility of study recruitment and procedures, and measurement of proposed secondary endpoints (prostate symptoms, quality of life, anxiety, and depression as measured on the EORTC QLQ-C30 and PR-25, the IPSS and HADS). Data were collected to estimate PSA-log slopes and PSA-doubling times, using a mixed model, for both the pre-intervention and post-intervention periods. RESULTS: Adherence to study protocol was excellent, and the phytotherapeutic intervention was well-tolerated, with similar numbers of mild-to-moderate adverse events in the active and placebo arms. Both the intervention and data collection methods were acceptable to participants. No statistical difference between groups on clinical outcomes was expected in this pilot study. There was between-subject variation in the PSA post treatment, but on average the active treatment group experienced a non-significant increase in the log-slope of PSA (pre-treatment doubling time = 10.2 months, post-treatment doubling time = 5.5 months), and the placebo group experienced no change in the log-slope of PSA (pre-treatment doubling time = 10.8 months, post-treatment doubling time = 10.9 months). CONCLUSION: The findings suggest that a fully powered study of this combination is feasible in men with biochemically recurrent prostate cancer and a moderate PSA rise rate. Prostate 77:765-775, 2017. © 2017 Wiley Periodicals, Inc.

Phytotherapeutic interventions in the management of biochemically recurrent prostate cancer: a systematic review of randomised trials.

OBJECTIVE: To evaluate the evidence from randomised trials for the efficacy and safety of phytotherapeutic interventions in the management of biochemically recurrent (BCR) prostate cancer, indicated by prostate-specific antigen (PSA) progression, numbers progressing to/time to initiation of androgen-deprivation therapy or salvage therapy. PATIENTS AND METHODS: MEDLINE (Ovid), EMBASE (Ovid), AMED (Ovid), CINAHL (EBSCO) and the Cochrane Library databases were searched. Clinical trials investigating phytotherapeutic interventions as dietary supplements or dietary components, including multi-component herbal formulations, in men with BCR prostate cancer were located. Eight of nine authors contacted for further information responded. Methodological quality was assessed using the Cochrane Collaboration's risk of bias assessment tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews was followed. RESULTS: Of 23 full-text articles assessed for eligibility, five met the criteria for inclusion. Two studies were placebo controlled; two were active control trials; and one a high-/low-dose trial. The interventions were administered as isolated phytochemicals (sulphoraphane), phytotherapeutic extracts [Pomi-T (pomegranate, turmeric, green tea and broccoli sprout extract), soy, lycopene, and POMx (pomegranate extract)], or plant-derived dietary items (soy and lycopene). All studies found serum PSA levels to stabilise, decrease or rise more slowly in a significant number of men, and three studies reported stabilising or lengthening of PSA-doubling time. Studies were generally of good quality, but sample sizes were predominantly small, and durations short. CONCLUSIONS: High-quality studies in this area are lacking. Sulphoraphane, lycopene, soy isoflavones, POMx, and Pomi-T are safe and well tolerated. There is limited evidence that they can affect PSA dynamics. No recommendation can be made for the use of these agents in managing prostate cancer morbidity and mortality until high-quality, fully powered studies are available. Recommendations are made for improving reproducibility and translation of findings with regard to study population, study endpoints, design, and the reporting of phytotherapeutic interventions.

Soy and soy isoflavones in prostate cancer: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the evidence from randomized controlled trials (RCTs) on the efficacy and safety of soy/isoflavones in men with prostate cancer (PCa) or with a clinically identified risk of PCa. PATIENTS AND METHODS: MEDLINE, EMBASE, the Allied and Complementary Medicine (AMED), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane Library databases were searched. We identified RCTs investigating soy/soy isoflavones as dietary supplements or dietary components for the secondary prevention or treatment of PCa in men with PCa or with a clinically identified risk of developing PCa. Studies of multi-component formulations were excluded. Six authors were contacted for further information for the meta-analyses. Methodological quality was assessed using the Cochrane Collaboration's risk-of- bias tool. The PRISMA statement for reporting systematic reviews was followed. RESULTS: Of the eight RCTs that met the inclusion criteria, six restricted recruitment to men diagnosed with PCa, while two included men with clinically identified risk of PCa. A large degree of heterogeneity was found with respect to dosages and preparations of soy/isoflavones administered. Most studies had small sample sizes and were of short duration. The risk of bias was assessed as low in all assessed studies except for one, for which the risk of bias was unclear. Meta-analyses of the two studies including men with identified risk of PCa found a significant reduction in PCa diagnosis after administration of soy/soy isoflavones (risk ratio = 0.49, 95% CI 0.26, 0.95). Meta-analyses indicated no significant differences between groups for prostate-specific antigen (PSA) levels or sex steroid endpoints (sex hormone-binding globulin [SHBG], testosterone, free testosterone, oestradiol and dihydrotestosterone). CONCLUSIONS: The results of a meta-analysis of two studies suggest there may be support for epidemiological findings of a potential role for soy/soy isoflavones in PCa risk reduction; however, a clear understanding of the impact of soy/isoflavones on PSA, total testosterone, free testosterone and SHBG levels in men with, or at identified risk of, PCa could not be derived from these data, given the limitations of sample size and study duration in individual trials. A good safety profile is shown by this meta-analysis for soy/soy isoflavones supplementation.

Vitex agnus-castus extracts for female reproductive disorders: a systematic review of clinical trials.

Vitex agnus-castus L. (chaste tree; chasteberry) is a popular herbal treatment, predominantly used for a range of female reproductive conditions in Anglo-American and European practice. The objective of this systematic review was to evaluate the evidence for the efficacy and safety of Vitex extracts from randomised, controlled trials investigating women's health.Eight databases were searched using Latin and common names for Vitex and phytotherapeutic preparations of the herb as a sole agent, together with filters for randomised, controlled trials or clinical trials. Methodological quality was assessed according to the Cochrane risk of bias and Jadad scales, as well as the proposed elaboration of CONSORT for reporting trials on herbal interventions.Thirteen randomised, controlled trials were identified and twelve are included in this review, of which eight investigated premenstrual syndrome, two premenstrual dysphoric disorder, and two latent hyperprolactinaemia. For premenstrual syndrome, seven of eight trials found Vitex extracts to be superior to placebo (5 of 6 studies), pyridoxine (1), and magnesium oxide (1). In premenstrual dysphoric disorder, one study reported Vitex to be equivalent to fluoxetine, while in the other, fluoxetine outperformed Vitex. In latent hyperprolactinaemia, one trial reported it to be superior to placebo for reducing TRH-stimulated prolactin secretion, normalising a shortened luteal phase, increasing mid-luteal progesterone and 17ß-oestradiol levels, while the other found Vitex comparable to bromocriptine for reducing serum prolactin levels and ameliorating cyclic mastalgia. Adverse events with Vitex were mild and generally infrequent. The methodological quality of the included studies varied, but was generally moderate-to-high. Limitations include small sample sizes in some studies, heterogeneity of conditions being treated, and a range of reference treatments.Despite some methodological limitations, the results from randomised, controlled trials to date suggest benefits for Vitex extracts in the treatment of premenstrual syndrome, premenstrual dysphoric disorder and latent hyperprolactinaemia. Further research is recommended, and greater transparency in reporting for future trials.

Effects of a combination of Hypericum perforatum and Vitex agnus-castus on PMS-like symptoms in late-perimenopausal women: findings from a subpopulation analysis.

BACKGROUND: It has been suggested that some of the symptoms typically attributed to menopause may be more related to premenstrual syndrome (PMS) than menopause, as perimenopausal women appear to be more prone to PMS-like symptoms, or at least to tolerate them less well. OBJECTIVE: The objective of this study was to evaluate the effectiveness of a phytotherapeutic intervention comprising a combination of Hypericum perforatum (St. John's wort) and Vitex agnus-castus (chaste tree/berry) in the management of PMS-like symptoms in perimenopausal women. DESIGN: A double-blind, randomized, placebo-controlled parallel trial was conducted over 16 weeks on menopause-related symptoms. Data on PMS-like symptoms were collected at 4-weekly intervals from a small subgroup of late-perimenopausal women (n = 14) participating in this study. The primary endpoint was PMS scores measured on the Abrahams Menstrual Symptoms Questionnaire, comprising the subclusters of PMS-A (anxiety), PMS-D (depression), PMS-H (hydration), and PMS-C (cravings). Herbal combination therapy or placebo tablets were administered twice daily. RESULTS: At the end of the 16-week treatment phase, analyses of covariance showed the herbal combination to be superior to placebo for total PMS-like scores (p = 0.02), PMS-D (p = 0.006), and PMS-C clusters (p = 0.027). The active treatment group also showed significant reductions in the anxiety (p = 0.003) and hydration (p = 0.002) clusters, using paired-samples t tests. Results of trend analyses showed significant treatment group effects across the five phases for total PMS and all subscales, all in the clinically expected direction. No significant trends were evident in the placebo group. CONCLUSIONS: These results suggest a potentially significant clinical application for this phytotherapeutic combination in PMS-like symptoms among perimenopausal women. Further research is warranted through a randomized, controlled trial dedicated to investigation of these symptoms.

Vitex agnus-castus (Chaste-Tree/Berry) in the treatment of menopause-related complaints.

BACKGROUND: The origin of the current practice of administering Vitex agnus-castus in menopause-related complaints is uncertain, but appears to be relatively recent. Here we review the evidence for this application of Vitex based on evidence from pharmacological studies and clinical research. METHODS: The mechanisms of potential relevance in the context of menopause are explored with reference to the current understanding of the endocrinology and neuroendocrinology of menopause and associated symptoms. CONCLUSIONS: We conclude that, while evidence from rigorous randomized controlled trials is lacking for the individual herb in this context, emerging pharmacological evidence supports a role for V. agnus-castus in the alleviation of menopausal symptoms and suggests that further investigation may be appropriate.

Predictors of placebo response in a randomized, controlled trial of phytotherapy in menopause.

OBJECTIVE: The aim of this study was to evaluate predictors of the placebo response in a randomized, placebo-controlled, double-blind trial of a phytotherapeutic combination for the treatment of menopausal symptoms. METHODS: A post hoc analysis was conducted on data from 46 placebo participants completing the study. Variables at baseline were investigated for prediction of improvement on any of the endpoints of flushing, depression measured on the Hamilton Depression Inventory, and menopausal symptoms measured on the Greene Climacteric Scale. Hierarchical linear regression analyses were carried out on the individual endpoints, controlling for baseline scores. Multivariate linear regression analysis was also conducted on these three endpoints in combination. RESULTS: Higher anxiety at study entry predicted placebo response on all three outcome measures individually (flushing: R = 0.33, P = 0.03; depression: R = 0.34, P < 0.001; and Greene Climacteric score: R = 0.24, P = 0.04); and in combination (P = 0.002), as did total Greene Climacteric scores at study entry (R = 0.24, P = 0.005). Improvement during nontreatment run-in predicted placebo response for depression (P = 0.005), menopausal symptoms (R = 0.28, P = 0.013), and the three combined endpoints (P = 0.015). Severity of scores at baseline predicted subsequent improvement on the Greene Climacteric scores only (r = 0.038, P = 0.009). CONCLUSIONS: These findings may facilitate identification of potential placebo responders in future randomized controlled trials on menopausal symptoms and have relevance to study design in this context. Further research is required.

Are we drawing the right conclusions from randomised placebo-controlled trials? A post-hoc analysis of data from a randomised controlled trial.

BACKGROUND: Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms equally, and that treatment effects are additional to the placebo effect. However, these assumptions have recently been challenged, and different mechanisms may potentially be operating in the placebo and treatment arms. The objective of the current study was to explore the nature of placebo versus pharmacological effects by comparing predictors of the placebo response with predictors of the treatment response in a randomised, placebo-controlled trial of a phytotherapeutic combination for the treatment of menopausal symptoms. A substantial placebo response was observed but no significant difference in efficacy between the two arms. METHODS: A post hoc analysis was conducted on data from 93 participants who completed this previously published study. Variables at baseline were investigated as potential predictors of the response on any of the endpoints of flushing, overall menopausal symptoms and depression. Focused tests were conducted using hierarchical linear regression analyses. Based on these findings, analyses were conducted for both groups separately. These findings are discussed in relation to existing literature on placebo effects. RESULTS: Distinct differences in predictors were observed between the placebo and active groups. A significant difference was found for study entry anxiety, and Greene Climacteric Scale (GCS) scores, on all three endpoints. Attitude to menopause was found to differ significantly between the two groups for GCS scores. Examination of the individual arms found anxiety at study entry to predict placebo response on all three outcome measures individually. In contrast, low anxiety was significantly associated with improvement in the active treatment group. None of the variables found to predict the placebo response was relevant to the treatment arm. CONCLUSION: This study was a post hoc analysis of predictors of the placebo versus treatment response. Whilst this study does not explore neurobiological mechanisms, these observations are consistent with the hypotheses that 'drug' effects and placebo effects are not necessarily additive, and that mutually exclusive mechanisms may be operating in the two arms. The need for more research in the area of mechanisms and mediators of placebo versus active responses is supported. TRIAL REGISTRATION: International Clinical Trials Registry ISRCTN98972974.

Hypericum perforatum with Vitex agnus-castus in menopausal symptoms: a randomized, controlled trial.

OBJECTIVE: To evaluate the effectiveness of a phytotherapeutic intervention comprising a combination of Hypericum perforatum (St. John's wort) and Vitex agnus-castus (Chaste tree/berry) in the management of menopausal symptoms. DESIGN: A double-blind, randomized, placebo-controlled, parallel trial was performed over 16 weeks in 100 eligible late-perimenopausal or postmenopausal women experiencing hot flushes and other menopausal symptoms. Herbal combination therapy or placebo tablets were administered twice daily. The primary endpoint was hot flush episodes. Secondary endpoints included Greene Climacteric Scale scores, Hamilton Depression Inventory scores, and Utian Quality of Life Scale scores. RESULTS: Ninety-three women completed the study. Data analysis on an intent-to-treat basis found no significant differences between the two groups for any of the endpoints. Analyses performed at interim data time points revealed no significant differences at week 4, 8, or 12 for daily weighted flushes or scores on the Greene Climacteric Scale or Hamilton Depression Inventory. However, significant improvements across the treatment phase were observed in both the placebo and active treatment groups for these endpoints. No significant change was found for either group on quality of life. CONCLUSION: The herbal combination of H. perforatum and V. agnus-castus was not found to be superior to placebo for the treatment of menopausal symptoms. The herbal combination was well tolerated with no significant adverse events noted in the short term. Robust findings from quality studies such as this are important for informing the community, healthcare providers, and regulatory authorities.

St. John's wort and Kava in treating major depressive disorder with comorbid anxiety: a randomised double-blind placebo-controlled pilot trial.

OBJECTIVE: We report the first randomised controlled trial (RCT) using a combination of St. John's wort (SJW) and Kava for the treatment of major depressive disorder (MDD) with comorbid anxiety. METHODS: Twenty-eight adults with MDD and co-occurring anxiety were recruited for a double-blind RCT. After a placebo run-in of 2 weeks, the trial had a crossover design testing SJW and Kava against placebo over two controlled phases, each of 4 weeks. The primary analyses used intention-to-treat and completer analyses. RESULTS: On both intention-to-treat (p = 0.047) and completer analyses (p = 0.003), SJW and Kava gave a significantly greater reduction in self-reported depression on the Beck Depression Inventory (BDI-II) over placebo in the first controlled phase. However, in the crossover phase, a replication of those effects in the delayed medication group did not occur. Nor were there significant effects on anxiety or quality of life. CONCLUSION: There was some evidence of antidepressant effects using SJW and Kava in a small sample with comorbid anxiety. Possible explanations for the absence of anxiolysis may include a potential interaction with SJW, the presence of depression, or an inadequate dose of Kava.

Echinacea alkylamides modulate induced immune responses in T-cells.

The effects of Echinacea and several of its phytochemical components on NFkappaB expression by Jurkat cells (a human T-cell line) were investigated in vitro. In the absence of stimulation, Echinacea and its components exerted no significant effect on basal NFkappaB expression levels. In the presence of endotoxin (LPS), NFkappaB expression was decreased. However, this decrease was significantly reversed by treatment with cichoric acid, an Echinacea root extract (prepared from both Echinacea angustifolia and Echinacea purpurea) and the alkylamide fraction derived from this combination. For the phorbol myristate acetate stimulation of Jurkat cells, effects on NFkappaB expression were mixed. Depending on the concentration, cichoric acid and a 2,4-diene alkylamide significantly induced NFkappaB levels, whereas a 2-ene alkylamide caused a significant inhibition. In contrast, both the Echinacea and the mixed alkylamide fraction exerted no effect. The alkylamide results indicate that the two basic forms of these compounds present in Echinacea may have opposing effects. These opposing effects demonstrate the importance of a knowledge, not only of the phytochemical make-up of a herbal preparation, but also of the actions of each component and the consequences of differing relative amounts in the preparation being investigated.

Bilberry adulteration using the food dye amaranth.

Vaccinium myrtillus or bilberry fruit is a commonly used herbal product. The usual method of determining the anthocyanin content is a single-wavelength spectrophotometric assay. Using this method, anthocyanin levels of two extracts were found to be 25% as claimed by the manufacturers. When high-performance liquid chromatography (HPLC) was used, however, one extract was found to contain 9% anthocyanins probably not derived from V. myrtillus but from an adulterant. This adulterant was subsequently identified, using HPLC, mass spectroscopy, and nuclear magnetic resonance, as amaranth, that is, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7-naphthalenedisulfonic acid trisodium salt-a synthetic dark red sulfonic acid based naphthylazo dye. As described in this study, if deliberate adulteration occurs in an extract, a single-wavelength spectrophotometric assay is inadequate to accurately determine the levels of compounds such as anthocyanins. Detection of deliberate adulteration in commercial samples thus requires the use of alternative, more sophisticated, methods of analysis such as HPLC with photodiode array detection as a minimum.

RP-HPLC detection of a sulphiting-induced artefact from paeoniflorin in dried roots of Paeonia lactiflora.

Paeoniflorin is one of the bioactive ingredients of the roots of Paeonia lactiflora (Paeoniaceae). A comparative study of processed and non-processed commercial samples of dried roots of P. lactiflora indicated a very low level of paeoniflorin in the processed sample and the formation of a new more polar component, sodium paeoniflorin sulphonate, during treatment of the roots with sulphiting agents.

Bioavailability of Echinacea constituents: Caco-2 monolayers and pharmacokinetics of the alkylamides and caffeic acid conjugates.

Many studies have been done over the years to assess the effectiveness of Echinacea as an immunomodulator. We have assessed the potential bioavailability of alkyl- amides and caffeic acid conjugates using Caco-2 monolayers and compared it to their actual bioavailability in a Phase I clinical trial. The caffeic acid conjugates permeated poorly through the Caco-2 monolayers. Alkylamides were found to diffuse rapidly through Caco-2 monolayers. Differences in diffusion rates for each alkylamide correlated to structural variations, with saturation and N-terminal methylation contributing to decreases in diffusion rates. Alkylamide diffusion is not affected by the presence of other constituents and the results for a synthetic alkylamide were in line with those for alkylamides found in an ethanolic Echinacea preparation. We examined plasma from healthy volunteers for 12 hours after ingestion of Echinacea tablets manufactured from an ethanolic liquid extract. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkylamides were detected in plasma 20 minutes after tablet ingestion and for each alkylamide, pharmacokinetic profiles were devised. The data are consistent with the dosing regimen of one tablet three times daily and supports their usage as the primary markers for quality Echinacea preparations.

Modulation of macrophage immune responses by Echinacea.

Echinacea preparations are widely used herbal medicines for the prevention and treatment of colds and minor infections. There is little evidence for the individual components in Echinacea that contribute to immune regulatory activity. Activity of an ethanolic Echinacea extract and several constituents, including cichoric acid, have been examined using three in vitro measures of macrophage immune function - NF-kappaB, TNF- alpha and nitric oxide (NO). In cultured macrophages, all components except the monoene alkylamide (AA1) decreased lipopolysaccharide (LPS) stimulated NF-kappaB levels. 0.2 microg/ml cichoric acid and 2.0 microg/mL Echinacea Premium Liquid (EPL) and EPL alkylamide fraction (EPL AA) were found to significantly decrease TNF-alpha production under LPS stimulated conditions in macrophages. In macrophages, only the alkylamide mixture isolated from the ethanolic Echinacea extract decreased LPS stimulated NO production. In this study, the mixture of alkylamides in the Echinacea ethanolic liquid extract did not respond in the same manner in the assays as the individual alkylamides investigated. While cichoric acid has been shown to affect NF-kappaB, TNF-alpha and NO levels, it is unlikely to be relevant in the Echinacea alterations of the immune response in vivo due to its non- bioavailability - i.e. no demonstrated absorption across the intestinal barrier and no detectable levels in plasma. These results demonstrate that Echinacea is an effective modulator of macrophage immune responses in vitro.