domingo, 7 de julio de 2019

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)—Health Professional Version - National Cancer Institute 6/10

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)—Health Professional Version - National Cancer Institute
National Cancer Institute

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)–Health Professional Version

Soy

Overview

This section contains the following key information:
  • Soy foods (e.g., soy milk, miso, tofu, and soy flour) contain phytochemicals that may have health benefits and, among these, soy isoflavones have been the focus of most of the research.
  • Soy isoflavones are phytoestrogens. The major isoflavones in soybeans are genistein(the most abundant), daidzein, and glycitein.
  • Genistein affects components of multiple growth and proliferation -related pathways in prostate cancer cells, including the COX-2 /prostaglandin, epidermal growth factor(EGF), and insulin-like growth factor (IGF) pathways.
  • Some preclinical studies have indicated that the combined effect of multiple isoflavones may be greater than that of a single isoflavone.
  • Some animal studies have demonstrated prostate cancer prevention effects with soy and genistein; however, other animal studies have yielded conflicting results regarding beneficial effects of genistein on prostate cancer metastasis.
  • Epidemiologic studies have generally found high consumption of nonfermented soy foods to be associated with a decreased risk of prostate cancer.
  • Early-phase clinical trials with isoflavones, soy, and soy products for the prevention and treatment of prostate cancer have been limited to relatively short durations of intervention and sample sizes with low statistical power. These studies targeted heterogeneous prostate cancer patient populations (in high-risk, early- and later-stagedisease) and varying doses of isoflavones, soy, and soy products, and have not demonstrated evidence of reducing prostate cancer progression.
  • Other trials evaluating the role of isoflavones, soy, or soy products in the management of androgen deprivation therapy (ADT) side effects have found no improvement with isoflavone treatment compared with placebo.
  • Soy products are generally well tolerated in patients with prostate cancer. In clinical trials, the most commonly reported side effects were mild gastrointestinal symptoms.

General Information & History

Although records of soy use in China date back to the 11th century BC, it was not until the 18th century that the soy plant reached Europe and the United States. The soybean is an incredibly versatile plant. It can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.[1]
Soy foods contain a number of phytochemicals that may have health benefits, but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most biological activity.[2] Other isoflavones found in soy include daidzein and glycitein.[3] Many of these isoflavones are also found in other legumes and plants, such as red clover.
Isoflavones are quickly taken up by the gut and can be detected in plasma as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma concentration may be achieved by 6 hours after soy product consumption.[4] Isoflavones are phytoestrogens that bind to estrogen receptors. Prostate tissue is known to express estrogen receptor beta and it has been shown that the isoflavone genistein has greater affinity for estrogen receptor beta than for estrogen receptor alpha.[5]
A link between isoflavones and prostate cancer was first observed in epidemiological studies that demonstrated a lower risk of prostate cancer in populations consuming considerable amounts of dietary soy.[6,7] Subsequent studies evaluating the role of soy in experimental models further showed anticancer properties of soy, specifically relevant to prostate carcinogenesis. These early studies have led to a few clinical trials in humans using soy food products or supplements that targeted men with varying stages of prostate cancer. Although these studies showed modulation of intermediate endpoints or surrogate biomarkers of prostate cancer progression, the results indicating beneficial effects from soy or soy products have been mixed.

Preclinical/Animal Studies

In vitro studies

Individual isoflavones
A number of laboratory studies have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate epithelial cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 mRNA and protein levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced secretion of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin receptors EP4 and FP, suggesting that genistein may exert chemopreventive effects by inhibiting the synthesis of prostaglandins, which promote inflammation.[8] In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down regulate growth factors involved in angiogenesis (e.g., EGF and IGF-1) and the interleukin -8 gene, which is associated with cancer progression. These findings suggest that genistein and daidzein may have chemopreventive properties.[9] Both genistein and daidzein have been shown to reduce the proliferation of LNCaP and PC-3 prostate cancer cells in vitro . However, during the 72 hours of incubation, only genistein provoked effects on the dynamic phenotype and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on membrane fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells. No such effects were observed for daidzein at the same dose.[10]
Combinations of isoflavones
Some experiments have compared the effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one study, human prostate cancer cells were treated with a soy extract (containing genistin, daidzin, and glycitin), genistein, or daidzein. The soy extract induced cell cycle arrest and apoptosis in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerous benign prostatic hyperplasia (BPH) cells, but the soy extract had no effect on those cells. These findings suggested that products containing a combination of active compounds (e.g., whole foods) may be more effective in preventing cancer than individual compounds.[11] Similarly, in another study, prostate cancer cells were treated with genistein, biochanin A, quercetin, doublets of those compounds (e.g., genistein + quercetin), or with all three compounds. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.[12]
At least one study has examined the combined effect of soy isoflavones and curcumin. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the androgen receptor than were curcumin or the isoflavones individually.[13]

Animal studies

Animal models of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared with TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors EGFR and IGF-1R in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects.[14] In one study, following the appearance of spontaneous prostatic intraepithelial neoplasia lesions, TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1,000 mg genistein/kg chow). Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer.[15] In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis, but no change in primary tumor volume, than did mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment.[16] In contrast, in a study reported in 2011, there were more metastases in secondary organs in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer xenografts and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/day or 400 mg genistein/kg body weight/d) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of advanced prostate cancer.[17]
Radiation therapy is commonly used in prostate cancer, but, despite this treatment, disease recurrence is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. In one study, human prostate cancer cells were treated with soy isoflavones and/or radiation. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic molecules than cells treated with isoflavones or radiation only. Nude mice were implanted with prostate cancer cells and treated by gavage with genistein (21.5 mg/kg body weight/d), mixed isoflavones (50 mg/kg body weight/d; contained 43% genistein, 21% daidzein, and 2% glycitein) and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit lymph node metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.[18]
In the treatment of prostate cancer, bone health is a common concern in the setting of hormone deprivation therapy, which is associated with bone loss. Because of increased beta versus alpha estrogen receptor binding, soy-derived compounds are thought to be protective of bone. Animal studies have shown that genistein and daidzein can prevent or reduce bone loss in a manner similar to synthetic estrogen. Both isoflavones may modulate bone remodeling by targeting and regulating gene expression and may inhibit calcium urine excretion, which also helps to maintain bone density.[19,20]

Human Studies

Human studies evaluating isoflavones and soy for the prevention and treatment of prostate cancer have included epidemiological studies and early-phase trials. Several phase I-II randomized clinical studies have examined isoflavones and soy product for bioavailability, safety, and effectiveness in prostate cancer prevention or treatment.[21-23] These studies have included a wide range of subject populations, including high-risk men; prostate cancer patient populations (localized and later-stage disease); varying doses of isoflavones, soy, and soy products; and were limited to relatively short durations of observation or intervention and sample sizes with low statistical power.

Epidemiologic studies

In 2018, a meta-analysis of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) was significantly associated with a decrease in the risk of prostate cancer. Fermented soy food intake, total isoflavone intake, and circulating isoflavones were not associated with a reduced risk of prostate cancer.[24] However, these data from population studies must be interpreted with caution as the studies relied on self-reported data obtained using varying forms of dietary data collection instruments with recall bias, in addition to numerous forms of individual or multiple isoflavones, soy supplements, and soy foods. Additionally, these studies failed to account for other confounding genetic or behavioral variables that may affect the risk of prostate cancer.

Prevention studies

Too few randomized placebo-controlled trials have been completed to evaluate the effect of isoflavones or soy in preventing prostate cancer progression (refer to Table 3). The studies targeted men with negative prostate biopsies and elevated serum prostate-specific antigen (PSA) (2.5–10 mcg/mL at baseline). The duration of intervention was between 6 months [13] and 1 year [25,26], with varying formulations of isoflavones derived from soy [13,25] and red clover.[26] In a single trial that showed no significant changes in serum PSA after intervention with isoflavones, a reduction in prostate cancer progression at 1 year in a subgroup of men older than 65 years was demonstrated. Other than mild to moderate adverse events, no treatment-related toxicities were observed in all three trials.
Table 3. Randomized Placebo-controlled Trials of Isoflavones or Soy for Prostate Cancer Preventiona
Soy/Isoflavone Dose/dDuration of Intervention/Sample SizeToxicitiesOutcomes
ALT = alanine transaminase; AST = aspartate transaminase; N = number; PCa = prostate cancer; PSA = prostate-specific antigen.
aMen with a negative biopsy and elevated PSA max 10 mcg/mL.
Soy isoflavones (40 mg/d; comprising 66% daidzein, 24% glycitin, and 10% genistin) and curcumin (100 mg/d) versus placebo [13]6 mo; N = 85No significant adverse effects either in the placebo or supplement groups; one subject on placebo experienced severe diarrheaduring the trial and dropped out subsequentlyDecrease in serum PSA (P< .05)
60 mg/d isoflavone extract from red clover [26]12 mo; N = 20Significant increase in ALT and AST after 3 mo (P< .001)Decrease in serum PSA (P< .05)
60 mg/d isoflavones [25]12 mo; N = 158Two patients had grade 3 adverse events, one in the isoflavone group suffered iliac arterystenosis and the other in the placebo group suffered ileus; other adverse events were mild in severityDecrease in PCa incidence in men older than 65 years with isoflavones (P< .05)

Treatment of prostate cancer

Clinical trials evaluating isoflavones, soy supplements, and soy products (refer to Table 4and Table 5) for treating localized prostate cancer before radical prostatectomy have used window-of-opportunity trial designs (from biopsy to prostatectomy). These trials have primarily focused on evaluating serum and tissue biomarkers implicated in prostate cancer progression, bioavailability in plasma and prostate tissue, and toxicity at various doses. The trials are small in size and of short duration. They are useful for informing the design of well-powered larger clinical trials in the future, but they provide inadequate data to inform clinical practice.
Isoflavones
Table 4. Randomized Placebo-controlled Trials of Isoflavones Before Prostatectomy in Men With Localized Prostate Cancer
Isoflavone Dose/dDuration of Intervention/Sample SizeToxicitiesOutcomes
AR = androgen receptor; N = number; PCa = prostate cancer; PSA = prostate-specific antigen.
30 mg/d genistein [27]3–6 wk; N = 54Clinical adverse events were Grade 1 (mild); two biochemical adverse events recorded, both in the genistein group (one increase in serum lipase, one increase in serum bilirubin) potentially related to study agentDecrease in serum PSA (P < .05), decrease in total cholesterol(P < .01), increase in plasma genistein (P < .001)
Soy isoflavone capsules (total isoflavones, 80 mg/d) [28]6 wk; N = 86All adverse events were Grade 1 (mild)Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol in the isoflavone-treated group compared with men receiving placebo were not statistically significant
Supplement containing 450 mg genistein, 300 mg daidzein, and other isoflavones/d versus placebo followed by open-label [29]6 mo intervention followed by 6 mo open label (active surveillance); N = 53Not evaluatedSignificant increase in serum genistein and daidzein; no significant findings regarding serum PSA changes
Isoflavone tablets (60 mg/d) [30,31]4–12 wk; N = 60Adverse events were Grade I and II in both groups, with two events that were identified as Grade III in the treatment arm and determined to be unrelated to agent (constitutional symptoms of feverrelated to a viralinfection)Increase in plasma isoflavones (P < .001) in the isoflavone-treated group versus placebo; greater concentrations of plasma isoflavones daidzein (P = .02) and genistein (P= .01) were inversely correlated with changes in serum PSA
Isoflavone capsules 40, 60, or 80 mg [30,32]27–33 d; N = 45Adverse events were Grade I-IIIncreased plasma isoflavones at all doses; increased serum total estradiol in the 40 mg (P = .02) isoflavone-treated arm versus placebo; increased serum-free testosterone in the 60 mg isoflavone-treated arm (P = .003)
Cholecalciferol(vitamin D3) 200,000 IU + genistein (G-2535) 600 mg/d [33]21–28 d; N = 15Adverse events occurred in four patients in the placebo group and five patients in the vitamin D + genistein groupIncreased AR expression (P < .05); no other significant findings
Soy protein or whole soy products
Table 5. Randomized Placebo-controlled Trials of Soy Protein or Soy Products Before Prostatectomy in Men With Localized Prostate Cancer
Intervention Dose/dDuration of Intervention/Sample SizeToxicitiesOutcomes
COX = cyclooxygenase; GI = gastrointestinal; N = number; PSA = prostate-specific antigen.
Soy supplement with 60 mg isoflavone versus placebo supplement [34]12 wk; N = 60Nine grade I-II GI toxicities in the placebo group and eight from the isoflavone groupNo significant findings
Soy supplements (three 27.2 mg tablets/d; each tablet contained 10.6 mg genistein, 13.3 mg daidzein, and 3.2 mg glycitein) or a placebo [35]2 wk before surgery; N = 19Not evaluatedHigher isoflavone concentration (x6) in tissue than in serum following treatment with the soy supplements
Soy isoflavone supplements (total isoflavones, 160 mg/d and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) [36]12 wk; N = 33Not evaluatedNo significant difference between groups
Soy (high phytoestrogen), soy and linseed(high phytoestrogen), or wheat (low phytoestrogen) [37]8–12 wk; N = 29Not evaluatedReduction in total PSA (P = .02); percentage of change in free/total PSA ratio (P = .01); percentage of change in free androgen index (P = .04)
Soy isoflavone supplement (providing isoflavones, 81.6 mg/d) or placebo [8]2 wk before surgery (pilot); N = 25Not evaluatedDecrease in COX-2 mRNA levels (P < .01); increases in p21 mRNA levels (P < .01) in prostatectomy specimens obtained from the soy-supplemented group compared with placebo group

Isoflavones and soy products for biochemical recurrence after treatment

Other studies have examined the role of isoflavones and soy products in prostate cancer patients with biochemical recurrence after treatment. However, these early-phase studies have not demonstrated any significant changes in serum PSA or PSA-doubling time, [38-41] with one study suggesting modulation of systemic soluble and cellular biomarkers consistent with limiting inflammation and suppression of myeloid-derived suppressor cells [41] (refer to Table 6).
Table 6. Clinical Trials of Soy and Soy Products in Men on Active Surveillance or With Biochemical Recurrence After Treatment for Prostate Cancer
Intervention (Dose/d) and Trial DesignDuration of InterventionTarget Population (N)ToxicitiesOutcomes
GCP = genistein combined polysaccharide; GI = gastrointestinal; PCa = prostate cancer; PSA = prostate-specific antigen; RCT = randomized controlled trial.
Soy beverage daily (providing approximately 65–90 mg isoflavones); nonrandomized [38]6 moRising PSA after radiation for PCa diagnosis; N = 34Adverse events included minor GI side effectsNo statistically significant findings regarding PSA, PSA-doubling time
Soy milk 3x/d (isoflavones, 141 mg/d); open-label [39]12 moRising PSA after treatment for PCa; N = 20Toxicity data lacks details; GI (loose stools) toxicities were the most common complaint from a small number of men in the GCP groupNo statistically significant findings regarding serum PSA changes
Beverage powder containing soy-protein isolate (20 g protein) or calcium caseinate; RCT [40]2 yBiochemical recurrence after radical prostatectomy; N = 177All adverse events were grades I-II; there were no differences in adverse events between the two groupsNo significant findings regarding serum PSA changes
Two slices soy bread containing 68 mg/d soy isoflavones or soy bread containing almond powder; RCT [41]56 dBiochemical recurrence after radical prostatectomy N = 32Soy and soy-almond breads were without grade 2 or higher toxicitySignificant modulation of multiple plasma cytokines and chemokines

Management of androgen deprivation therapy side-effects

ADT is commonly used for locally advanced and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased quality of life, changes in cognition, and metabolic syndrome. Three studies have examined men undergoing ADT who were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; isoflavones, 160 mg/d) for 12 weeks. Two studies assessed ADT side effects. Neither study found an improvement in side effects following isoflavone treatment, compared with placebo.[42,43]
The third randomized placebo-controlled trial assessed changes in PSA level and biomarkers of energy metabolism (e.g., blood glucose level) and inflammation (e.g., blood interleukin-6 level). In this study of men undergoing ADT, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/d total isoflavones, and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or a placebo for 12 weeks. The results showed no difference between the two groups in PSA levels or in levels of metabolic and inflammatory parameters (e.g., glucose, interleukin-6).[36]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

Overall, isoflavones, soy, and soy products were well tolerated in clinical trials of high-risk prostate cancer patients.[26,29,35,39,42,44] The most commonly reported side effects were gastrointestinal symptoms.[29,38,45]
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