Name of trial (NCT No.)
Start
Subjects
Inclusion criteria
Intervention
Outcomes (primary, secondary, tertiary)
Feasibility Study on a Nordic Lifestyle Intervention Trial Among Men With Prostate Cancer (NCT01300104)
Feb 2011
24 Danish men
Biopsy-proven PC within 2 years, Gleason ≤6, PSA ≤10 ng/ml
Prescribed vigorous exercise ≥3× 45 min/week, whole grain rye (170–180 g/day)
Feasibility, PC progression (PSA and biopsy), insulin sensitivity/secretion, metabolic profile, inflammation, quality of life
Diet in Altering Disease Progression in Patients With Prostate Cancer on Active Surveillance (NCT01238172)
Jan 2011
464 men
Biopsy-proven PC within 2 years, clinical stage ≤T2a, no distant metastasis (no M1), <25% of biopsy cores with cancer
Dietary education and telephone counseling sessions for 24 months
Clinical progression, time to progression, time to treatment, anxiety (PC related), quality of life, dietary recall
Effect of Sulforaphane on Prostate CAncer PrEvention (NCT01950143)
Aug 2013
78 men
Low/intermediate PC, BMI between 19.5 and 35 kg/m2
Standard broccoli soup, Beneforté broccoli soup, or Beneforté extra broccoli soup for 12 months
Global gene expression in prostatic tissue, metabolite concentration in prostatic tissue
Active Surveillance Exercise Clinical Trial (NCT02435472)
May 2016
Estimated 150 men
Biopsy-proven localized PC, clinical stage <T3, PSA ≤10 ng/ml
4–5 home-based walking sessions/week at 55–75% individual exercise capacity
Genomic signature changes (3 a priori genomic classifiers), mRNA expression patterns, anxiety (general and PC-specific), adherence
Exercise Training as a Novel Primary Therapy for Men With Localised Prostate Cancer (NCT02409212)
May 2015
Estimated 50 men
Biopsy-proven low/intermediate PC, Gleason ≤3 + 4, PSA ≤20 ng/ml, clinical/diagnostic evaluation in past 12 months, life expectancy ≥10 years
Supervised and independent aerobic exercise sessions for 12 months with bimonthly counseling
Feasibility by rate of recruitment, adherence
Low-Fat Diet and Fish Oil in Men on Active Surveillance for Prostate Cancer (NCT02176902)
Nov 2014
Estimated 100 men
Biopsy-proven PC, clinical stage ≤T2c, Gleason <3 + 4, PSA <20 ng/ml
4 fish oil capsules/day for 1 year with dietary counseling and low-fat diet guidelines
Proliferation index (Ki67) in prostatic tissue; other tissue markers/biomarkers of proliferation/progression, cell cycle progression; serum PSA, GPR120 gene expression, adherence
Diet and Exercise Program in Promoting Weight Loss and Improving Health in Patients With Low- or Low-Intermediate-Risk Prostate Cancer (NCT02454517)
May 2016
Estimated 200 men
Biopsy-proven low/intermediate PC, Gleason ≤3 + 4, PSA <20 ng/ml, BMI ≥25 kg/m2
Diabetes prevention program intervention with specific diet and 16x 30–60 min exercise sessions over 24 weeks
Change in expression of insulin receptor (IGF-1R), fasting C-peptide, insulin, IGF-1, IGF-BP3, adiponectin levels; protein kinase B on PC epithelial cells; fasting glucose levels; sustainability of beneficial changes; adverse pathology; quality of life
Cholecalciferol Supplement in Treating Patients With Localized Prostate Cancer Undergoing Observation (NCT00887432)
April 2009
Estimated 100 men
Biopsy-proven PC, ECOG status ≤1, most recent 25(OH) D3 levels <40 ng/ml within 3 months of study, no history of PC treatment
PO cholecalciferol daily for 9 months followed by 3 month washout, then 9 months placebo; the reverse is also implemented in the second arm
PSA response, PSA dynamics/change, toxicity, relationship between CYP24, 27B1, and SNPs and serum 25-OH(D) in response to supplementation
CAPSAICIN Trial: Assessing Capsaicin as a Chemopreventive Agent for Prostate Cancer (NCT02037464)
Jan 2014
Estimated 100 men
Biopsy-proven PC, clinical stage ≤T2b, Gleason <6, PSA <10 ng/ml, recent PC biopsy
One capsaicin supplement capsule 2× daily
Biomarker changes (ki67 and p27), PSA kinetics, tumor grade, additional biomarkers of apoptosis, TRP-V1, and TRP-V6
Molecular Mechanisms of Dutasteride and Dietary Interventions to Prevent Prostate Cancer and Reduce Its Progression (NCT01653925)
Nov 2010
120 men
Low-risk PC
5 dietary consultations over 12 months to encourage omega-3 intake and low-fat diet; 6 months into trial, add 5α-reductase inhibitor for 6 months
Lipid metabolism from blood and prostatic microenvironment, gene expression profile, estrogen/androgen metabolism, utility of urine-based PC markers (PCA3)
Web-based Lifestyle Trial Among Men With Prostate Cancer: Prostate 8 (NCT02470936)
June 2015
Estimated 76 men; AS and post-RP
Biopsy-proven nonmetastatic PC with diagnosis >=2010; clinical stage ≤T3a; if treated, must be >3 months prior to enrollment; ≤4 of 8 healthy behaviors on questionnaire
Web-based, personalized lifestyle program with diet and exercise recommendations and online tools; Fitbit with online community access; and behavior-reinforcing text messages
Health behavior changes; task self-efficacy, intervention acceptability; change in physical activity, plasma vitamin E, lycopene, blood pressure, fasting glucose, cholesterol, HbA1c, CRP, waist circumference, weight, BMI, anxiety (general and PC-specific), depression, quality of life
Smoking
Accumulating evidence suggests that smoking may increase risk of aggressive prostate cancer and prostate cancer-specific mortality. The US Surgeon General found the evidence “suggestive” that smoking contributes to a higher prostate cancer mortality rate [39], in agreement with a 2014 meta-analysis of 51 articles reporting that smoking was associated with a 24% increased risk of prostate cancer death (RR = 1.24; 95% CI: 1.18, 1.31) and a statistically significant dose-response (RR = 1.20 for 20 cigarettes per day). The population attributable risk was 6.7% and 9.5% for cigarette smoking and prostate cancer death in the USA and Europe, respectively, corresponding to more than 10,000 prostate cancer-related deaths annually in the two regions combined [40]. A more recent 2015 NEJM-published, pooled analysis of five US cohort studies by Carter et al. found that current smokers experienced a 40% increased risk of death compared to those who had never smoked (RR = 1.4; 95% CI: 1.2, 1.7) [41]. Several studies reported that smoking is associated with more aggressive disease at diagnosis, defined as higher stage or tumor grade [42–44], and the relation between smoking and cancer progression, defined as biochemical recurrence [5, 45], metastasis [46], and hormone refractory prostate cancer [47], is suggestively positive. Concern remains that some or all of the observed associations may be due to delayed diagnosis and treatment among smokers.
In 2011, with 22 years of follow-up and a large number of outcomes (524 prostate cancer-specific deaths and 878 biochemical recurrences), we examined smoking at the time of prostate cancer diagnosis and prostate cancer-specific mortality and biochemical recurrence in the HPFS. Current smoking was associated with a 61% increased risk of prostate cancer-specific mortality (HR = 1.61; 95% CI: 1.11, 2.32) and a 61% increased risk of biochemical recurrence (HR = 1.61; 95% CI: 1.16, 2.22) [48]. Even after adjusting for changes in grade and stage secondary to smoking, estimates for current smoking were as follows: prostate cancer-specific mortality (HR = 1.38; 95% CI: 0.94, 2.03) and biochemical recurrence (HR = 1.47; 95% CI: 1.06, 2.04). Further adjustment for treatment did not significantly change these estimates. In a separate analysis to evaluate potential bias from any difference in screening behavior between smokers and nonsmokers, we included only men diagnosed from 1994, after PSA screening had become well established. In that analysis, we further adjusted for screening intensity as reflected in the proportion of 2-year periods in which a participant reported at least one PSA screen, dichotomizing at 50%. The estimates for smoking were even stronger after adjustment for PSA screening intensity: prostate cancer-specific mortality (HR = 2.12; 95% CI: 1.18, 3.79) and biochemical recurrence HR = 2.02; 95% CI: 1.30, 3.13). If the association between smoking and prostate cancer-specific mortality and recurrence resulted from delayed diagnosis, we would have expected to see an attenuation of the association. Thus, the observed positive associations between current smoking and risk of prostate cancer mortality or recurrence were likely not due to this potential bias.
In this same report, a greater number of pack-years were associated with an increased risk of prostate cancer-specific mortality, but not biochemical recurrence. Compared to current smokers, men who quit smoking more than 10 years ago had prostate cancer mortality risk similar to those who had never smoked. Additionally, the study by Rieken et al. supports these findings and reported a similar risk of biochemical recurrence for long-term quitters of 10 or more years compared to those who were never smokers (HR = 0.96; 95% CI: 0.68, 1.37) [49].
Overall, the literature on smoking and prostate cancer suggests that smoking may promote the development of more aggressive disease and increase prostate cancer recurrence and prostate cancer-specific mortality. Quitting smoking may reduce risk of progression or death from prostate cancer as well as lowering the risk of nearly all chronic diseases.
Dietary Factors
There are several different aspects of diet that may contribute to prostate cancer progression. Below, we review vegetables, grains, and soy; meat, fat, and animal products; coffee and tea; and nutritional supplements. For each topic, we briefly summarize the epidemiologic literature with a focus on effects of the food or nutrient after diagnosis.
Vegetables, Grains, and Soy
Vegetables are a rich source of vitamins, minerals, and phytochemicals, some of which may be beneficial in reducing risk of prostate cancer development or progression. While there are some inconsistencies, data generally suggest that lycopene/lycopene-rich foods (e.g., tomatoes) [50], cruciferous vegetables [51], and soy/soy-based foods [10] may reduce the risk of developing prostate cancer, in particular more aggressive disease.
Only limited studies have examined post-diagnostic intake of vegetables and the risk of prostate cancer progression. Our team observed that post-diagnosis intake of tomato sauce (but not fresh tomatoes) and cruciferous vegetables was associated with marked reductions in the risk of recurrence among men initially diagnosed with localized prostate cancer [10, 52, 53], although data were not entirely consistent across studies.
In a post hoc exploratory analysis of 41 men with localized prostate cancer enrolled in a randomized controlled trial in Norway, subjects receiving ~30 mg of lycopene per day for 25 days from tomato-containing products had a PSA decrease of 0.23 μg/L as compared to the control group that experienced a 0.45 μg/L increase (P = 0.02) [54]. Landberg et al. conducted a small randomized crossover trial of 24 men with untreated prostate cancer who consumed 6 weeks of a diet plentiful in rye whole grains/bran then 6 weeks of a refined wheat-based diet, with a 2-week washout period in between [55]. Seven men dropped out, leaving 17 men with complete data for analysis. The authors reported that the rye whole grain and bran diet vs. refined wheat diet were associated with lower levels of urinary C-peptide and plasma insulin and PSA [55]. While compelling, it should be noted that these types of results come from small trials, and further research is warranted to understand the biological effects of these foods and nutrients on prostate cancer etiology and progression.
In unaffected men, several studies have focused specifically on the potential protective benefits of soy on risk of developing prostate cancer. A recent meta-analysis of five cohort and nine case-control studies reported a 26% reduction of prostate cancer risk for consumption of soy food (RR = 0.74, 95% CI: 0.63, 0.89; P = 0.01), specifically for consumption of non-fermented soy food (e.g., tofu and soy milk) (RR = 0.70, 95% CI: 0.56, 0.88; P = 0.01) and not for fermented soy foods (e.g., miso and natto) (RR = 1.02, 95% CI: 0.73, 1.42; P = 0.92) [56]. Some data suggest that results may be limited to or stronger among Asian populations as opposed to Western populations [56] or may depend on genetic variants in estrogen receptor [57, 58]. In prostate cancer patients, the evidence on soy and its effect on PSA levels have been inconsistent; some studies have reported favorable effects while others reported no effects [59–61]. This heterogeneity was recently summarized in a 2015 review [62].
Several studies that examined soy among patients electing active surveillance also had mixed results [63–66]. While not directly relevant to men on active surveillance, there are some data from men initially treated for their prostate cancer showing a potential beneficial effect of soy, though data are also inconsistent. Studies have examined the relation between PSA rise and use of soy products as a supplemental therapy [67] or as a secondary treatment for recurring prostate cancer [68, 69]. Ahmad et al. conducted a randomized placebo-controlled trial observing soy supplements alone and PSA rise [67]. Patients with localized prostate cancer who were scheduled to receive radiation therapy enrolled to receive 200 mg/day soy isoflavone supplements or a placebo for 6 months in conjunction with radiation treatment [67]. After radiation treatment, the soy supplement group had a greater reduction in median PSA value than the placebo group (76% vs. 59% reduction in median PSA value, respectively). In another randomized placebo-controlled trial, soy isoflavone supplement treatment before radical prostatectomy was associated with lower inflammatory mRNA and protein expression levels and increased cell cycle progression inhibitor p21 mRNA expression levels in prostatectomy specimens [70]. In contrast to these compelling findings, in a double-blinded RCT of ~177 men with high prognostic risk prostate cancer managed by surgery, 2 years of daily supplementation with soy protein isolate led to no difference in the occurrence of biochemical failure compared to placebo (calcium caseinate) [61].
Meat , Fat , and Animal Products
Fairly consistent evidence suggests that greater intake of processed meat (including processed red meat or processed poultry) elevates the risk of developing prostate cancer [71, 72], including more advanced disease or aggressive disease [73–76]. Potential biologic mechanisms may involve fat, nitrites and nitrates contained in processed meat, or carcinogenic heterocyclic amines (HA) formed during cooking at high temperatures. The World Health Organization recently classified processed meat as a human carcinogen and red meat as a “probable” carcinogen. While one systematic review and meta-analysis reported a general null association between red meat and prostate cancer risk [71], the WHO report mentioned specifically a body of evidence indicating positive associations between red meat and risk of developing advanced prostate cancer [72]. Limited (and not entirely consistent) data suggest that fish may be a healthy alternative to red or processed meat for men with prostate cancer [52, 77, 78]. Omega-3 fatty acids, found in fish, are actively being studied for the primary prevention of cancer and cardiovascular disease (NCT01169259).
Poultry intake (prior to diagnosis) was recently shown to be inversely associated with risk of developing advanced and fatal prostate cancer in a pooled analysis of 15 cohort studies [79]; specific types of poultry or cooking methods were not specifically evaluated. Egg consumption during adulthood may increase risk of developing aggressive prostate cancer. The same pooled analysis reported that participants who ate about one half an egg or more per day had a 14% increased risk of advanced and 14% increased risk of fatal prostate cancer compared to those with very low egg intake [79]. In the HPFS, we reported a statistically significant 81% increased risk of developing lethal prostate cancer among men consuming 2.5 or greater eggs per week compared to those consuming less than half an egg per week [80].
Studies on meat or animal product intake among men on active surveillance have not been reported to the best of our knowledge. However, a few studies have focused on the associations of post-diagnostic meat (including poultry), fat, or animal product intake and risk of prostate cancer progression, and a few clinical trials are examining comprehensive lifestyle changes, including vegetarian diet, among men on active surveillance (see below, multiple lifestyle changes). Among men diagnosed with localized prostate cancer in CaPSURE™ , men with the highest intakes of poultry with skin had a 2.3-fold increased risk (HR = 2.26; 95% CI: 1.36, 3.76 comparing highest to lowest quintile) of prostate cancer recurrence/progression compared to those with the lowest intake [77]. This could be due to higher heterocyclic amine content or the cooking method used in chicken eaten with skin vs. without the skin. We observed a more modest nonsignificant increased risk of poultry intake with skin in the HPFS adjusted for pre-diagnosis intake [80]. Skinless poultry was not associated with progression in either study. In CaPSURE™, men in the highest quintile of egg intake had a twofold increased risk of prostate cancer progression compared to those in the lowest quintile (HR = 2.02; 95% CI: 1.10, 3.72) [77], while no association was observed for egg intake after diagnosis and lethal prostate cancer in the HPFS, which accounted for pre-diagnosis intake [80]. The increased risk observed in CaPSURE™ could be attributed in part to egg consumption prior to diagnosis, which could not be accounted for in this analysis. More studies are needed to substantiate these observations.
Processed red meat was associated with an elevated but nonsignificant increased risk of prostate cancer progression in both CaPSURE™ and HPFS [77, 80]. Saturated fat consumption , most often from meat, has been implicated in prostate cancer progression [81]. Strom et al. observed a twofold increase in risk of biochemical recurrence (HR = 1.95; 95% CI: 1.19, 3.19) associated with greater saturated fat consumption among 390 men who underwent radical prostatectomy for organ-confined prostate cancer at diagnosis [82]. In 2015, we analyzed data from the Physicians’ Health Study and reported that men consuming 5% more of their daily calories from saturated fat and 5% less of their daily calories from carbohydrates had a 2.8-fold increased risk of prostate cancer-specific mortality (HR 2.78; 95% CI: 1.01, 7.64, P = 0.05). Those consuming 10% more of their daily calories from vegetable fats and 10% less of their calories from carbohydrates reduced their risk of overall mortality by a third (HR = 0.67; 95% CI: 0.47, 0.96, P = 0.03) [83].
Dairy intake and higher calcium intake (greater than the recommended dietary allowance of ~1000 mg/day) have generally been associated with a small to moderate increase in the risk of developing prostate cancer [10, 84]. Data on post-diagnostic intake of dairy are limited, but suggest that higher dairy intake after diagnosis may be associated with an increased risk of developing fatal prostate cancer and that intake of high-fat dairy in particular may be detrimental. For example, among ~3900 men initially diagnosed with localized prostate cancer, consumption of whole milk (but not low-fat milk) was associated with a twofold greater risk of progression to lethal disease [85]. Among 926 men initially diagnosed with nonmetastatic prostate cancer in the Physicians’ Health Study , consuming ≥3 vs. <1 servings/day of dairy was associated with 2.4-fold increased risk of prostate cancer death; of note, in this study, while this positive association was stronger for high-fat dairy, there remained a positive association for low-fat dairy as well [86].
Coffee and Tea
A few studies have reported that pre-diagnostic coffee consumption is associated with a significant reduction in the risk of developing high-grade or lethal prostate cancer [87, 88]. One study of 47,911 men observed a 60% reduction in the risk of lethal prostate cancer for men in the highest (≥6 cups per day) vs. lowest categories of coffee consumption [88]. The results were similar for caffeinated and decaffeinated coffee and may be due to coffee’s antioxidant effects [89]. Those findings were supported by some, but not all, subsequent studies, as well as meta-analyses [90, 91]. There are no studies to date about post-diagnostic coffee intake and risk of progression of prostate cancer; however, one study by Geybels et al. among men diagnosed with prostate cancer found that drinking ≥4 cups per day of coffee vs. ≤1 cup/week (measured 2 years before diagnosis) was associated with a 59% reduced risk of prostate cancer recurrence/progression (HR = 0.41, 95% CI: 0.20–0.81; p-trend = 0.01) [92]. Because the data are limited in men with prostate cancer, the evidence is not strong enough to recommend that nondrinkers take up coffee to lower their risk of prostate cancer progression. However, coffee may improve overall health and is associated with lower risk of a number of illnesses, including gallbladder disease, diabetes, Parkinson’s disease, and overall death, so it may be beneficial to maintain intake for prevention of other health conditions if already a coffee drinker.
Several epidemiologic studies, mostly in Asian populations, suggest that tea consumption may possibly be associated with a reduced risk of prostate cancer [93]; however, a recent meta-analysis of observational studies reported no overall association for tea consumption and prostate cancer, with a suggestive benefit seen only in case-control studies, which are prone to substantial bias [94]. Another meta-analysis found green (but not black) tea consumption to be beneficial, but again, the benefit was only observed in the less reliable case-control studies [95]. Some clinical trials of tea extracts have yielded promising initial results [96, 97], but not all [98] for chemoprevention. Further studies of tea, and especially trials of tea extracts in prostate cancer patients, are warranted. Given the limited evidence, the data are insufficient to recommend taking up consumption of tea to reduce risk of prostate cancer progression.
Nutritional Supplements
Currently, several large professional bodies generally do not recommend the usage of nutritional supplements to prevent cancer or cancer progression [99, 100]. Rather, in the American Cancer Society 2012 summary on Nutrition and Physical Activity Guidelines for Cancer Survivors , Rock et al. state: “Evidence from both observational studies and clinical trials suggests that dietary supplements are unlikely to improve prognosis or overall survival after the diagnosis of cancer, and may actually increase mortality” [99].
One exception may be vitamin D, as it has recently been reported that many older adults are vitamin D deficient [101, 102]. Vitamin D is actively being studied for primary prevention of total cancer and cardiovascular disease as part of the NCI-funded VITAL trial (NCT01169259), slated to release results in late 2017. In the interim, men should have their levels checked by their doctor before taking a vitamin D supplement.
Since our last summary, further data have emerged indicating the need for tailoring when it comes to nutritional supplementation. Individuals may have different needs depending on their treatments, other conditions, or status with regard to particular nutrients. Also, there have been several cautionary tales indicating that more is not always better [103, 104], and an individual’s baseline level of a particular nutrient or his genetics may influence how his body responds to supplementation [103, 105–108] with regard to cancer outcomes. For example, in the HPFS, among ~4400 men initially diagnosed with nonmetastatic prostate cancer, those who consumed 140 or more μg/day of supplemental selenium after diagnosis had a 2.6-fold increased risk of prostate cancer death [103] compared to nonusers. An earlier placebo-controlled trial among men on active surveillance randomized to placebo, 200 ug/day or 800 ug/day of high-selenium yeast for 6 months, reported no difference in PSA velocity between groups; however, those in the highest quartile of baseline selenium and supplemented with 800 ug/day of selenium had a higher PSA velocity compared to placebo [109]. Such findings underline the need for caution when considering using vitamins or supplements, as it is possible that not all vitamin usage is benign or beneficial. Therefore, it is recommended that cancer survivors review their usage of nutritional supplements with their physicians, as individuals may require different supplements throughout the different phases of their cancer management or due to other comorbidities or conditions.
Taken together, men with prostate cancer should focus on consuming a varied diet rich in vegetables, whole grains, skinless poultry, and fish and avoid processed meats rather than focus on consuming any specific vitamins or supplement.
Multiple Lifestyle Changes
As cancer has multiple causes, it is reasonable to assume that disparate lifestyle factors may work together to reduce or delay the risk of progression. We previously investigated the combined effect of six lifestyle factors and the risk of developing metastatic or fatal prostate cancer, among ~42,000 men from the HPFS (576 lethal prostate cancer events observed). The six factors investigated were BMI <30 kg/m2, not smoking or quitted more than 10 years ago , engaging in ≥3 h of vigorous physical activity weekly or ≥7 h of brisk walking, and consuming ≥1 serving fatty fish, ≥7 servings of tomatoes, and <3 servings of processed meat per week. Men who followed five to six factors had about a 68% decreased risk of developing lethal prostate cancer compared to those following zero to one factor [110]. These results examined pre-diagnostic lifestyle habits and the risk of developing lethal prostate cancer but may still be relevant to men on active surveillance who have not received treatment or had their prostate glands removed (i.e., men who are similar to the general population aside from having received a diagnosis). We saw similar results when applying the six-factor score to the Physicians’ Health Study [110].
There are several open clinical trials examining lifestyle interventions, several of which are summarized in Table 16.1. Studies chosen for the table focused on men on active surveillance and pending published studies. Of note, the Men’s Eating and Living trial (MEAL) is a multisite national phase III randomized clinical trial testing the hypothesis that a high vegetable diet reduces the risk of disease progression in prostate cancer patients on active surveillance. MEAL is funded by the Department of Defense , the National Cancer Institute , and the Prostate Cancer Foundation . The accrual goals were met (n ~ 464), and the trial is in an active follow-up phase, with results anticipated in 2018. For further details, see NCT01238172 on clinicaltrials.gov.
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