Prostate cancer: data for foods & supplements
Introduction
Introduction
Introduction
Vitamin D
Introduction
Introduction
Green Tea
Introduction
Pomegranate
Pomegranate
Vegetable Fat
Pomegranate
Soy Products
Vegetable Fat
Vegetable Fat
Vegetable Fat
Vegetable Fat
Vegetable Fat
Lycopenes
Lycopenes
Lycopenes
Coffee
Lycopenes
Lycopenes
Prostate cancer: foods with increased risk
Omega-3 PUFA
Dairy-based Protein
Dairy-based Protein
Dairy-based Protein
Dairy-based Protein
Dairy-based Protein
Dietary Fat
Dairy-based Protein
Dietary Fat
Prostate cancer: introduction
Introduction
For the patient, among the fundamental health changes one can make is diet modification. This is also one of the few aspects of health the individual can control. There is a rapidly growing body of literature in the utilization of foods and supplements to either decrease the probability of developing prostate cancer, or to enhance a person’s ability to fight prostate cancer. Crucially, about 233,000 new cases of prostate cancer were diagnosed in the United States alone in 2014, and close to 30,000 men in the US died from prostate cancer in 2014. (15)
A number of foods, food extracts, and vitamin supplements have been explored in prostate cancer, and a large number of these are synthesized below. With this burgeoning field, we believe in being data-driven, and special attention is paid to human trials, the methodology of the individual studies, and the external generalizability of a given set of data.
Vitamin D
Vitamin D
There have been several studies of both antecedent Vitamin D concentration and the efficacy of supplementation in humans.
Study 1
In a prospectively enrolled trial of 667 men with either an elevated PSA or abnormal digital rectal examination among 5 clinics in Chicago, IL, Vitamin D (25-OH Vitamin D) levels were drawn prior to prostate biopsy. (16) Among the variables examined were race of the patient, Gleason score, and NCCN (National Comprehensive Cancer Network) risk level. The distribution of patients was varied, and included 55.9% with Gleason 6 or lower, as well as 23.8% who had cases classified as NCCN high-risk. There was not a specific regimen of Vitamin D supplementation patients had been on prior to enrollment. The study was powered to detect a statistical risk between Vitamin D deficiency and prostate cancer.
Results showed that there was a statistically significant association between Vitamin D deficiency in African-Americans and risk of prostate cancer (25-OH Vitamin D < 20 ng/mL), with an odds ratio of 2.43 (95% Confidence Interval (CI): 1.20 – 4.94; p = 0.01). In this particular study, a statistically significant risk of prostate cancer in “European-Americans” (as categorized in the publication) was not identified.
Furthermore, there was an association of even lower Vitamin D levels in African-Americans (25-OH Vitamin D < 12 ng/mL) and Gleason > 4+4 disease, with an odds ratio of 4.89 (95% CI: 1.59 – 15.07; p = 0.006). At this level of Vitamin D deficiency, an association with tumor stage at diagnosis was also found, with an odds ratio of 4.22 (95% CI: 1.52 – 11.74; p = 0.003).
Among European-Americans, a statistical link between severe Vitamin D deficiency (25-OH Vitamin D < 12 ng/mL) and both Gleason score and tumor stage at diagnosis was seen. The odds ratio for a Gleason score > 4+4 was 3.66 (95% CI: 1.41-9.50; P = 0.008), and for tumor stage >cT2b an odds ratio 2.42 (95% CI: 1.14-5.10; P = 0.008).
Study 2
A nested case control study was performed culling data from the Prostate Cancer Prevention Trial, to examine the risk of prostate cancer development and serum 25-OH Vitamin D concentrations. (17) There were 1,695 cases of prostate cancer, with 1,682 control patients. Multivariate logistic regression models were employed to assess for the risk of prostate cancer, along with Gleason score subgroups. Vitamin D deficiency was divided into quartiles, with cutoff values between quartiles being 17.9, 22.7, and 28.5 ng/mL.
Results revealed that for Gleason 8-10 score prostate cancer, there was a linear decrease in risk with increasing Vitamin D level. Comparison of quartile 4 vs. 1 had an odds ratio of 0.55 (95% CI: 0.32-0.94; P = 0.04]. Other quartile comparisons were not statistically significant.
This specific quartile result may have clinical validity, as a 25-OH Vitamin D level of 30 ng/mL is generally considered adequate.
Study 3
A prospective study of 100 men with newly-diagnosed localized prostate cancer were studied for a correlation of Vitamin D levels and adverse pathologic features. (18) These men did not carry a diagnosis of Vitamin D deficiency, and were not taking supplementation (such patients were excluded).
65% of patients had suboptimal levels of Vitamin D (< 30 ng/mL), and 32% of overall patients had a level less than 20 ng/mL. Gleason score, pathologic stage, and margin status were analyzed by logistic regression analysis. No significant correlation was found for any of these variables.
Study 4
A provocative study was published from the North Carolina-Louisiana Prostate Cancer Project suggesting the possible importance of calcium intake in understanding the relative risk of a person’s vitamin D levels. (19) 537 African-American and 663 European-American newly diagnosed prostate cancer patients were divided into tertiles based on Vitamin D level (25-OH Vit D: <20ng/mL, 20–30ng/mL, and 30ng/mL). Prostate cancer aggressiveness was defined as: high aggressive cases: Gleason sum > 8, or PSA >20 ng/ml at diagnosis, or Gleason sum = 7 and stage T3-T4. Low aggressive cases: Gleason sum <7 and diagnosed at stage T1-T2 and PSA <10 ng/ml at diagnosis; intermediate aggressive cases included all other cases.
Tertiles were compared for African-Americans and Americans of European ancestry. Very interestingly, for African-American patients with suboptimal daily calcium intake (< 1200 mg/day) there was an increased risk for prostate cancer aggressiveness with an odds ratio = 2.23 (95%CI: 1.26-3.95; p = 0.001). However, those taking calcium > 1200 mg/day, had a protective effect observed of higher Vitamin D levels with an odds ratio = 0.19 (95%CI: 0.05-0.70; p = 0.001). Thus if an African-American patient with prostate cancer had a 25-OH Vitamin D level > 30 ng/mL and a calcium intake of > 1200 mg/day, only then would they have a higher probability of lower-risk prostate cancer, per the findings of this study.
The above relationship between calcium intake and Vitamin D level was not observed for European-Americans.
Study 5
One possible explanation for people with normal or high Vitamin D levels to have an increased risk ordecreased risk of aggressive prostate cancer is suggested by an inspection of data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. (20) Using a case-control design, 950 cases and 964 matched controls had 25-OH Vitamin D levels and Vitamin D Binding Protein (DBP) concentrations measured.
Serum Vitamin D binding protein (DBP) was seen to modulate the link between serum Vitamin D levels and prostate cancer. A higher risk for prostate cancer for elevated 25-OH Vitamin D levels was observed among men having DBP concentrations above the median (OR = 1.81, 95% CI: 1.18-2.79 for highest vs. lowest quintile, p = 0.001) compared to those with DBP below the median (OR = 1.22, 95% CI: 0.81-1.84, p-trend 0.97; p-interaction = 0.04).
Green Tea
Green tea and its extracts have shown promise in the laboratory and in the clinic, and multiple human trials have been conducted both for prostate cancer prevention and for patients already diagnosed with prostate cancer.
Study 1
A precancerous state to prostate cancer is high-grade prostate intraepithelial neoplasia (HG-PIN); up to 30% of HG-PIN patients may progress to develop prostate cancer. A clinical trial of chemoprevention with green tea catechins (GTC) in 60 men with HG-PIN was conducted in Italy. (21) This was a double-blind, placebo-controlled study. Patients were treated with three GTC capsules (200 mg each) daily for 1 year. Importantly, the purity of the GTC capsules was verified by high-performance liquid chromatography.
After 1 year, only one tumor was diagnosed among the 30 GTCs-treated men (incidence = approximately 3%), whereas nine cancers were found among the 30 placebo-treated men (incidence = 30%). Interestingly, prostate-specific antigen (PSA) levels did not change significantly between the two arms. No significant side effects or adverse effects were reported in the publication.
Other observations included quality of life measurements, with improvement noted in the treatment group. There were also fewer lower urinary tract symptoms, and the International Prostate Symptom Score improved on treatment also.
This was an overall well-conducted study, with a placebo arm and utilization of a specific product and dose, with good statistical endpoints. The trial was a relatively smaller study with 60 patients.
Study 2
In a large cohort of Japanese patients, green tea was studied to see the dose-dependence with localized or advanced prostate cancer. (22) In this effort, 49,920 men between age 40-69 were prospectively enrolled. Patients completed a questionnaire with their green tea consumption frequency, and followed over time. The categories were “almost none”, 1–2 days/week, 3–4 days/week, 1–2 cups/day, 3–4 cups/day, and ≥5 cups/day.
404 men developed prostate cancer while in follow up, 114 of which were advanced. Analysis showed that green tea was not associated with localized prostate cancer. However, green tea was associated with a protective effect for advanced prostate cancer (defined as extraprostatic or metastatic cancer), with a dose-dependent decrease in risk based on consumption. The multivariate relative risk was 0.52 (95% CI: 0.28 - 0.96) for men drinking 5 or more cups/day compared with less than 1 cup/day (p = 0.01).
Competing variables included that patients who drank more green tea tended to consume more fruits, vegetables, and soy food, but were also older and smoked more. On this study it was also not known whether or not patients had any other prostate cancer screening such as PSA testing. There was no standard concentration or strength of green tea on the trial. Overall, this large prospective study does suggest a benefit of green tea, particularly in the context of other positive results.
Study 3
A small study of 20 patients in New Zealand was conducted to see the benefits of a Mediterranean diet. (23) Prostate-specific antigen, C-reactive protein and DNA damage were evaluated at baseline and after three months of following the diet. Dietary specifics and adherence was through a diet questionnaire.
Total genomic DNA was extracted from blood samples, and an electrophoresis assay was used to measure DNA damage. A significant reduction in DNA damage was observed, particularly for certain patients, among them with those with green tea consumption (p = 0.002). Higher intakes of red meat (p = 0.003) and dairy products (p = 0.008) were inversely associated with DNA damage. No significant relationship for C-reactive protein or PSA was observed.
Overall this is a small trial, and the follow up is short (3 month), with no changes in PSA seen. There is a difference in DNA damage, but it is unclear from this trial alone whether this finding translates to other meaningful outcomes.
Study 4
A fascinating pre-clinical (cell line) study tested whether prostate cancer sensitivity to cell death can be enhanced with green tea. (24) The chemotherapy used was docetaxel, in 2 cell lines either alone or in combination with green tea (epigallocatechin gallate) plus quercetin (a flavonoid from apples and onions).
A substantial improvement in prostate cancer cell death was seen with the combination treatment. In one cell line there was a 3-fold improvement, and in the other an 8-fold improvement over docetaxel chemotherapy alone.
Although this study was in cells only (and not humans), it is very provocative as to the benefit of adding a dietary product such as green tea, which several studies have shown does not carry any notable side effects or reactions.
Study 5
To assess the effect of green tea further in human patients, a randomized trial of green tea, black tea, and water was conducted among 113 men with prostate cancer. (25) Patients drank 6 cups of their assigned drink per day.
Results showed significantly decreased NF-kB staining in RP tissue (p = 0.013), antioxidant effect (p = 0.05), and PSA decrease (p = 0.04). A very nice laboratory correlate was performed, and tea polyphenols molecules were seen in prostate tissue in 32/34 men (and therefore evidence of green tea compounds penetrating into prostate tissue). Neither the black tea nor the water groups had any of these effects observed.
This trial was well-conducted, with a placebo group, randomized, and meaningful endpoints such as PSA and laboratory evidence of biological effect with the green tea compounds seen in prostate tissue.
Pomegranate
Pomegranate
Pomegranate and its extracts have been suspected to have anti-cancer properties for a number of years. It has been seen in the laboratory that the peel and fruit of pomegranate are rich in ellagitannins, which in turn are metabolized to its active form, ellagic acid, by gut flora. Ellagic acid has been shown to inhibit prostate cancer proliferation and angiogenesis via induction of hypoxic conditions, and promoting apoptosis. Compounds have been studied for several years in humans, with mixed results.
Study 1
A Phase II trial of pomegranate juice was conducted in men with prostate cancer with biochemical recurrence, following definitive local therapy (prostatectomy or radiation). (6) Patients had to have had a PSA > 0.2 ng/mL but less than 5 ng/mL, and Gleason score < 7. Participants ingested 8 ounces of pomegranate juice daily of a specific brand and dose. Treatment continued until there was progression of prostate cancer. A total of 46 patients enrolled on the trial.
The primary study endpoint showed that the mean PSA doubling time of patients increased from 15 months at baseline to 54 months post-treatment. This was a statistically significant improvement, with a p value < 0.001, and therefore slower prostate cancer growth. 35% of patients had PSA decreases observed. In terms of safety, no serious adverse events were reported.
Laboratory correlative studies included assessing patient serum both pre- and post-treatment. Comparison of these samples regarding the growth of LNCaP cells showed a 12% decrease in cell proliferation and 17% increase in apoptosis.
Overall, this study was a well-conducted single-arm US trial with good clinical endpoints (PSA doubling time) and laboratory correlates (demonstrating what effect the pomegranate juice was having). Also, a specific product, dose, and frequency were specified, strengthening the study, and with no serious adverse effects, this trial does have good external generalizability.
Study 2
A double-blind, placebo-controlled multi-institutional study of pomegranate extract was performed, recruiting patients who had biochemical recurrence after definitive local therapy for prostate cancer (either prostatectomy or radiation). (26) Initially the study was planned to have 300 subjects across 3 arms (placebo, pomegranate extract and standard pomegranate juice), but the study was converted after 1 year to just include 180 subjects over 2 arms (extract and placebo), because of slow accrual. The statistical power of the study was reported as being unchanged by this adjustment.
Patients were treated for 12 months. 41% of the patients stopped the trial early due to progression of prostate cancer. The main statistical endpoint, median PSA doubling time, increased from 11.1 months at baseline to 15.6 months in the placebo group, compared with an increase from 12.9 months at baseline to 14.5 months in the extract group. In the arm that was ended early – with pomegranate juice – PSA doubling time increased from 12.7 at baseline to 20.3 in the juice group (P=0.004).
Only 3 adverse events were judged definitely related to the pomegranate extract: these were nausea, constipation and decreased appetite. There were no serious adverse events on the trial.
Interestingly, 34 patients had a genetic factor that may influence their sensitivity for benefit from pomegranate: a MnSOD single-nucleotide polymorphism. For this particular subgroup, those taking pomegranate extract experienced a 12 month improvement in median PSADT from 13.6 at baseline to 25.6 months, whereas placebo group patients had a median PSA doubling time change of 10.9 months to 12.7 months. (p = 0.03)
This study contrasts with the other publication reviewed (6). In this current study, strengths included that it was a placebo-controlled trial, and also had a specific dose and frequency of treatment used. Based on analysis of the trials, the contrast may be due to a difference in population. In the latter study (26), 41% of patients had prostate cancer progression within 1 year, whereas in the earlier trial (6), the large majority had stable disease or improvement at the 18 month mark of follow up. Furthermore, patients were treated with the pomegranate product for a longer period of time in the positive trial (6), and with pomegranate juice, rather than the extract. It is also hypothesis-generating that among the patients with the particular genetic alteration (MnSOD single-nucleotide polymorphism), the PSA doubling time improved by 12 months.
Soy Products
Soy products are rich in protein and phytoestrogens. Multiple studies examining its role in prevention and treatment have been published.
Study 1
A randomized controlled trial was conducted spanning 13 years at 7 US facilities comparing daily consumption of a soy protein supplement vs placebo in 177 men. (27) Inclusion criteria were for men considered clinically at high risk of recurrence after radical prostatectomy for prostate cancer.
The supplement used in the intervention group was a beverage made from a powder containing 20 grams of protein in the form of soy protein isolate. Placebo patients drank a beverage with calcium caseinate. Supplementation with soy or placebo was started within 4 months after surgery and continued for up to 2 years, with prostate-specific antigen (PSA) measurements made at 2-month intervals in the first year and every 3 months thereafter. The primary endpoint was biochemical recurrence of prostate cancer – as defined by a PSA rise to over 0.07 ng/mL.
Results showed no difference between the groups. There was a slight numerical difference, but not statistically significant. The odds ratio for benefit was 0.96 (95% CI: 0.53-1.72, p = 0.89). 27.2% of patients had a recurrence in the soy protein intervention group, and 29.5% in the placebo group. Compliance to treatment was reported as over 90%. No adverse events were found that were caused by supplementation.
Study 2
Another randomized controlled trial (double-blind) was performed the University of Kansas Medical Center, and published in 2013. (1) Patients had localized prostate cancer, and the treatment group took a soy isoflavone (80 mg/d of total isoflavones, 51 mg/d aglucon units). Soy or placebo was taken for 6 weeks prior to prostatectomy.
Changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol were analyzed at baseline, mid-point, and at the time of radical prostatectomy. Genes controlling cell cycle regulation and apoptosis were analyzed by microarray technology.
Outcomes showed that there were not any significant differences in the biochemical markers assessed including PSA and testosterone. However, 12 genes involved in cell cycle control and 9 genes involved in apoptosis were down-regulated in the treatment tumor tissues versus the placebo control.
Study 3
A phase 2 randomized double-blind placebo-controlled trial was carried out involving 47 patients from Norway. (2) The isoflavone genistein (the predominant isoflavone in soybean) was studied. Patients on the study had localized prostate cancer and planned for prostatectomy.
Either 30 gm genistein or placebo was taken daily for 3-6 weeks. The primary endpoint was comparison of levels of androgen-related biomarkers and cell cycle-related genes by PCR. The biomarkers included: androgen receptor, NK3 homeobox 1, and kallikrein-related peptide 4 (KLK4).
Results showed that there was a significant reduction in mRNA level of KLK4 in prostate cancer cells (p = 0.033). Other genes had reductions as well, but non-significant in the statistical comparison.
Study 4
Genistein has also been studied in castrate-refractory prostate cancer cell lines. One very interesting study examined the expression of apoptosis markers, and also looked at a xenograft tissue model (tissue culture, not animals). (3)
With exposure to genistein, an increase in expression of pro-apoptotic proteins such as Bax was found. Furthermore in the xenograft prostate cancer model, the combination of genistein plus cabazitaxel (a FDA-approved chemotherapeutic agent used in CRPC) was compared to 3 groups: control, cabazitaxel alone, or genistein alone. The reduction in growth of CRPC cells was significantly greater in the combination of genistein + cabazitaxel.
Study 5
Data from 12,395 California Seventh-Day Adventist men was analyzed for incident cases of prostate cancer and correlated with soy milk intake. Overall 225 cases were found in this dataset. “Frequent” consumption, defined as more than one soy milk drink per day, was compared to lesser intake.
Analysis revealed that for the frequent consuming group, there was a 70% reduction in the incidence of prostate cancer. Relative risk = 0.30 (95% CI: 0.1-1.0, p = 0.03).
These studies show a few key points. Firstly, there is a biological effect of soy isoflavones observed, with the impact on apoptosis proteins (as evidenced by the studies from Kansas and Norway). Secondly, no evidence of harm has been found, either in terms of efficacy or side effects. The largest US randomized controlled trials did not find an effect on PSA or testosterone however, but interestingly the study from the California Seventh-Day Adventist dataset found a 70% reduction (though with wide confidence intervals). Thirdly, chemotherapy effectiveness (with cabazitaxel) was enhanced significantly with genistein.
Therefore there does appear to be a biological effect on apoptosis, but the clinical outcomes data is still mixed. The data for enhancement of chemotherapy effect is quite intriguing.
Vegetable Fat
Vegetable Fat
Data was culled from the 4,577 male patient prospective Health Professionals Follow-up Study, to assess if there is a difference in mortality for patients with prostate cancer, who eat predominantly animal fat vs. vegetable fat. (28) The 4,577 patients enrolled had non-metastatic prostate cancer, and 315 cases of lethal prostate cancer and 1064 deaths were found over a median follow up of 8.4 years. Data was analyzed for intake of saturated, monounsaturated, polyunsaturated, trans, animal, and vegetable fat. (all after diagnosis of prostate cancer)
Mortality rates were reported in rates per 1000 person-years for lethal prostate cancer. Comparing the highest vs. lowest quintile of intake, rates were 28.4 vs 21.4 for saturated, 20.0 vs 23.7 for monounsaturated, 17.1 vs 29.4 for polyunsaturated, 32.4 vs 17.1 for trans, 32.0 vs 17.2 for animal, and 15.4 vs 32.7 for vegetable fat.
Replacing 10% of energy intake from carbohydrate/animal fat with vegetable fat was associated with a lower risk of lethal prostate cancer (HR = 0.71; 95% CI: 0.51-0.98; P = .04) and all-cause mortality (HR = 0.74; 95% CI: 0.61-0.88; P = .001). No other fats were associated with lethal prostate cancer.
Saturated fat intake was associated with a higher all-cause mortality, with HR = 1.30 (95% CI: 1.05-1.60; p = 0.02). Trans fat intake after diagnosis was also associated with increased all-cause mortality, with HR = 1.25 (95% CI: 1.05-1.49; p = 0.01).
This study presents very compelling evidence for the benefit of vegetable fat (over animal fat) in nonmetastatic prostate cancer. This is a large prospective study, and US-based. The most intriguing analysis from the data is that replacement of 10% intake of animal fat with vegetable fat confers a statistically significant benefit for dying from prostate cancer, and for mortality in general (hazard ratio = 0.74).
Lycopenes
Data for the role of lycopenes has been gradually accumulating over several years. A number of human trials, including multiple from North America have been published.
Study 1
A meta-analysis of 34 observational studies was conducted, which in sum included 592,479 patients (who at study start did not have prostate cancer). 22 of the 34 studies were from North America. (7) The role of alpha-carotene, beta-carotene, and lycopenes was examined. Variables collected included dietary intake as well as blood concentrations.
Data revealed that blood levels of lycopenes did not correlate with risk of prostate cancer. However, dose-response analysis indicated that prostate cancer risk was reduced by 3% per 1 mg/day (95% CI: 0.94-0.99) of lycopene consumed in terms of dietary intake.
This is one of the largest analyses of the possible benefit of lycopene. These data support the benefit of lycopene consumption with increasing benefit proportional to the concentration consumed per day.
Study 2
Another large study supporting the benefit of lycopenes was the Health Professionals Follow Up Study, published in the Journal of the National Cancer Institute in 2002. (8) 47,365 patients were in this cohort, with 2,481 developing prostate cancer during follow up. Lycopene intake was reviewed, and associated with a reduced risk of prostate cancer (RR for high versus low quintiles = 0.84; 95% CI = 0.73 to 0.96; p = 0.003)
Furthermore, intake of tomato sauce was associated with a larger reduction in prostate cancer risk (RR for 2+ servings/week versus <1 serving/month = 0.77; 95% CI = 0.66 to 0.90; P < 0.001). The development of extraprostatic/metastatic prostate cancer was also decreased (RR = 0.65; 95% CI = 0.42 to 0.99).
This publication was another well-conducted analysis involving a large number of patients. As is typical for large observational studies, there was not a specific dose or formula of lycopene source utilized.
Study 3
An update to the 2002 publication was published by the same group in 2014 in the Journal of the National Cancer Institute. (9) 49,898 male health professionals had dietary patterns analyzed, and time of collection ranged from 1986 to 2010.
Overall higher lycopene intake in comparison of the top vs. bottom quintiles showed a protective effect for both total prostate cancer (HR = 0.91; 95% CI = 0.84 to 1.00; p = 0.009) and lethal prostate cancer (HR = 0.72; 95% CI = 0.56 to 0.94; p = 0.04). Review of questionnaire data suggested that early intake rather than “recent intake” correlated inversely with prostate cancer risk.
Data was also separated into the pre-PSA era and the PSA era. Very interestingly, the correlation of lycopene benefit for the top quintile remained unchanged between eras with a hazard ratio of 0.72.
Thus in this updated analysis, men with the highest intake were half as likely to develop lethal prostate cancer compared with those with the lowest intake. Data also suggested that the antineoplastic benefits of lycopene may be acting early in the disease process.
Study 4
A nested case control study of data from the Prostate Cancer Prevention Trial (which examined the benefit of finasteride for prostate cancer prevention with finasteride, compared to placebo) was performed and published in 2011. (10) There were a total 1,683 cases – men with prostate cancer - and 1,751 controls. 461 patients had a Gleason score ≥ 7, and 125 Gleason score ≥ 8. Patients had a prostate biopsy after 7 years of treatment to assess if they had developed prostate cancer during the time on study.
Nonfasting blood was collected approximately 3 months prior to randomization and annually thereafter until diagnosis or the end of the study. Lycopene concentration was measured in 0.5 mL serum samples that were collected at years 1 and 4, pooled, and refrozen at −70ºC before analysis. Total lycopene concentration was measured by high performance liquid chromatography.
From the data it was seen that there was no association in this population of patients for lycopenes in conferring a protective effect from prostate cancer. The odds ratios for a linear increase in lycopene (per 10 μg/dL) were 0.99 (95% CI: 0.94-1.04), 1.01 (0.94-1.08), and 1.02 (0.90-1.15) for Gleason 2 to 6, 7 to 10, and 8 to 10, respectively.
Therefore this was a negative study in terms of the benefit of lycopenes. There are a number of possible confounding factors in this analysis. For one, lycopene concentrations were measured at years 1 and 4, and therefore it is unclear if a given patient had a consistent lycopene blood concentration over 7 years or not (could have varied significantly). It was reported in the manuscript that the correlation of lycopene concentration and self-reported dietary consumption was very low, and perhaps either the lycopene source as well as variability of concentration over time could have impacted the results.
Study 5
A prospective analysis of data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was conducted, in a dataset with 1,338 cases of prostate cancer identified among 29,361 men. Average time of follow up was 4.2 years. A 137-item food frequency questionnaire was completed by participants at baseline.
Analysis of this dataset showed several trends for benefit of various lycopene sources, but these were not statistically significant. Trends for a protective effect were seen for pizza: in patients having > 1 serving/wk versus < 0.5 servings/month, relative risk was 0.83 (95% CI: 0.67-1.03; p = 0.06). For spaghetti or tomato sauce consumption, the relative risk for developing advanced prostate cancer was 0.81 (95% CI: 0.57-1.16; p = 0.31), in comparing > 2 servings/week vs < 1 serving/month. Lastly, there was a trend towards benefit for those with a family history of prostate cancer, but again not statistically significant.
In summary, this was a study that did not show a statistically significant association of lycopenes in protecting against prostate cancer. However, multiple trends were seen, and it is conceivable that the short follow up time of approximately 4 years may not have been long enough to achieve statistical significance.
Study 6
A small prospective trial was conducted in Italy, in which 32 patients with high-grade prostatic intraepithelial neoplasia (HGPIN) consumed a lycopene-enriched diet (20-25 mg/day of lycopene; through 30 g/day of triple concentrated tomato paste) for 6 months. (12) A prostate biopsy was then taken at the 6 month mark, to see if there was progression from HGPIN to prostate cancer.
PSA and plasma lycopene levels were assessed at baseline and after 6 months of dietary lycopene supplementation. Prostatic lycopene concentration was also assessed after the supplementation diet at the 6-month biopsy.
Based on the biopsy results at 6 months, patients were classified into 3 groups (prostate cancer, HGPIN, and prostatitis), and subsequently compared. The prostatic lycopene concentration at the end of the study was found to have a statistically significant risk for cancer. Concentrations less than 1 nanogram per milligram of prostate tissue were shown to have a higher risk for prostate cancer (p = 0.003). Furthermore, all patients who had a prostatic lycopene concentration of < 1 ng/mg developed prostate cancer during study follow up. PSA levels did not change on study.
In sum, this was a well-designed study, having a specific food source and concentration for patients to consume, a pathologic endpoint (prostate lycopene concentrations). It was a small trial, but overall builds on the body of evidence for lycopene benefit in prostate cancer.
Study 7
The potential synergy of lycopenes with prostate cancer treatment, specifically the one of the chemotherapy docetaxel, was studied in a laboratory effort at the University of California at Irvine. (13) In a DU145 xenograft tumor model, docetaxel treatment was compared to the combination of docetaxel + lycopene (in the form of the BASF product LycoVit 10%, which contains 11.45% total lycopene).
In this comparison, there was a 38% increase in antitumor activity and tumor regression compared to docetaxel alone. (p = 0.047) There was a further analysis of IGF-IR (insulin-like growth factor I receptor) on prostate cells, to see if the IGF-IR expression is high or low. Data revealed that lycopene treatment enhanced the growth-inhibitory effect of docetaxel more effectively on DU145 cells with IGF-IR high expression.
Correlative studies showed that lycopene inhibited IGF-IR activation through inhibiting IGF-I stimulation and by increasing the expression and secretion of IGF-BP3. Downstream effects include inhibition of AKT kinase activity and survivin expression, followed by apoptosis.
This study had an appropriate control arm and good laboratory investigations to explain mechanisms of action. The data showed that the combination of lycopene + chemotherapy worked better than chemotherapy alone by a 38% difference in antitumor activity. Furthermore one mechanism may be through inhibition of IGF-1 (insulin-like growth factor I), though further studies need to be done, to see if IGF-IR expression can be a predictive marker of benefit of the addition of lycopene.
Coffee
Coffee
Although in older studies there was a possible link seen between coffee intake and cancer risk, more modern studies and meta-analyses have generally seen a neutral effect. Coffee has been postulated to even possibly have a protective effect via apoptosis pathways or by reducing oxidative stress. To this point, a review article from the University of Oslo in Norway was published showing an overall neutral risk of coffee with prostate cancer. (32)
A meta-analysis conducted out of Shanghai, China analyzed 13 cohort studies, with a total of 34,105 cases and 539,577 participants included. (5) When comparing highest vs. lowest coffee intake, a protective effect in the pooled analysis was seen, with a relative risk = 0.90 (95% CI: 0.85-0.95). No significant heterogeneity was found in combining the data amongst publications.
Dose-response calculations were also performed, and found that cancer risk decreased by 2.5% (RR = 0.975; 95% CI: 0.957-0.995) for every 2 cups/day increment in coffee consumption.
These large review studies and meta-analysis reveals an overall neutral or possibly a mild protective effect. A relative risk = 0.90 for protection from prostate cancer was found in the Shanghai meta-analysis.
Omega-3 PUFA
Omega-3 PUFA (polyunsaturated fatty acids)
Study 1
The role of Omega-3 PUFA in prostate cancer has been explored in a few studies. In the National Health and Nutrition Examination Survey (NHANES), which ran from 2003-2010, tried to correlate PSA changes with omega-3 PUFA intake. (29) Fish consumption (a common source of Omega-3 PUFA) was recorded via 30-day food questionnaires, while omega-3 consumption was from 24-hour dietary recall assessment.
Data from 6,018 men was analyzed, and logistic regression did not find a correlation with either fish consumption or omega-3 PUFA intake.
Study 2
Another study was a Phase II randomized control trial to test the effect of decreasing dietary fat combined with decreasing the dietary omega-6:omega-3 ratio on prostate cancer development and progression. (30) 55 men diagnosed with prostate cancer and planned for a radical prostatectomy were randomized to either a low-fat diet with 5 grams of fish oil daily (with dietary omega-6:omega-3 ratio = 2:1), or a control group of a “Western diet”. The Western diet was reported to have a omega-6:omega-3 ratio = 15:1. The primary endpoint was change in serum insulin-like growth factor I (IGF-I).
The outcomes from the groups revealed that there was no change in the serum IFG-1 level between the two arms. Laboratory analysis showed that there was decreased prostate cancer proliferation however, in the fish oil arm. Within prostate tissue after surgery, there was a decreased ratio of omega-6:omega-3 in the fish oil group as well.
Study 3
A case-cohort analysis from the SELECT trial (Selenium and Vitamin E Cancer Prevention Trial) to examine the relation of high blood concentrations of omega-3 PUFA and risk of prostate cancer. (31) The cases of prostate cancer in the trial totaled 834 patients.
Results showed that in comparing the lowest vs. the highest quartile of blood omega-3 PUFA concentrations, the highest quartile had an increased risk for prostate cancer (HR = 1.43, 95% CI: 1.09 -1.88). Interestingly higher concentrations of linoleic acid (omega-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01).
Therefore the data suggests that although there may be a biologic effect based on Ki-67 staining (which correlates with cell proliferation), there was no effect on PSA change in the NHANES study. Furthermore, data from 834 men in the SELECT trial showed an increase risk for prostate cancer. Thus the sum of evidence is neutral risk or increased risk of omega-3 polyunsaturated fatty acids and prostate cancer.
Dairy-based protein
Dairy-based protein
A cohort study from the Physician’s Health Study was conducted to evaluate the link of milk with prostate cancer mortality. (33) A total of 21,660 patients with 2,806 incident prostate cancer cases were identified. Of these, there were 305 deaths. Total follow up was over 28 years.
Data revealed that intake of total dairy products was associated with increased prostate cancer incidence, with a hazard ratio of 1.12 (95% CI: 0.93, 1.35), when comparing those men with a dairy intake of > 2.5 servings/day vs. ≤0.5 servings/day. Whole milk intake was associated with increased risk of the development of fatal prostate cancer with a hazard ratio = 1.49 (95% CI: 0.97, 2.28); this comparison was between men who had at least 1 serving per day vs. those who “rarely consumed” whole milk. In the survival analysis, whole milk increased the risk of progression to fatal disease after diagnosis [HR = 2.17 (95% CI: 1.34, 3.51)].
For skim and low fat milk, intake was linked to a greater risk of nonaggressive prostate cancer, but not associated with fatal prostate cancer.
Study 2
A second analysis from the Physician’s Health Study, published in 2015, culled data from 926 men and explored the relation of prostate cancer mortality with dairy intake. (34) Specifically, total, high-fat, and low-fat dairy intake after diagnosis for 926 men with non-metastatic prostate cancer were included in this research. Patients completed a diet questionnaire a median of 5 years after diagnosis of prostate cancer, and were subsequently followed for a median of 10 years for mortality data acquisition.
Outcomes during follow up showed that during 8,903 person-years of follow-up, 333 men died, with 56 of these due to prostate cancer. Men consuming ≥3 servings/day of total dairy products had a 76% higher risk of total mortality for a HR = 1.76 (95% CI: 1.21 - 2.55, ptrend < 0.001), compared to those consuming less than 1 dairy product/day. For prostate cancer-specific mortality, HR = 2.41 (95% CI: 0.96 - 6.02, ptrend = 0.04).
Study 3
The mechanism for why dairy protein has been found to be associated with worse prostate cancer outcomes may have been at least partially elucidated by a New Zealand group. (35) In this study, 20 New Zealand patients with prostate cancer were enrolled to adhere to a Mediterranean diet for 3 months. There was no control group for this study.
Results from this study were reported as saying that DNA damage was promoted by dairy products, along with red meat and omega-6 polyunsaturated fatty acids.
The two analyses from the Physician’s Health Study provides compelling data that whole milk portends a serious increased risk for fatal prostate cancer development (HR = 2.17), and secondly, that men with prostate cancer consuming > 3 servings of dairy products per day had a prostate cancer-specific mortality risk with HR = 2.41. The mechanism may be DNA damage, though larger studies may be needed for fully understanding the pathobiology.
Dietary fat
Dietary fat
Study 1
Multiple research efforts have examined the risk of prostate cancer with saturated fat. The AARP Diet and Health Study was a prospective US study headed by the National Cancer Institute, with dietary habits and prostate cancer incidence followed over 9 years. (36) In total, 288,268 men were enrolled in the study, and 23,281 prostate cancer cases developed. Of these, the breakdown was 18,934 nonadvanced, and 2,930 advanced (including 725 fatal cases). Dietary intake of various fats were assessed via self-administered food-frequency questionnaires.
The data revealed that saturated fat intake was correlated with fatal prostate cancer, with HR = 1.47 (95% CI, 1.01-2.15; Ptrend = 0.04). This hazard ratio was from the statistical comparison of the highest vs. lowest quintile of saturated fat intake. α-Linolenic acid intake was related to increased risk of advanced prostate cancer (HRQ5 vs. Q1, 1.17; 95% CI, 1.04-1.31; Ptrend = 0.01). Saturated fat intake was not associated with “nonadvanced” prostate cancer.
Study 2
The relation of α-Linolenic acid with prostate cancer was further explored from data from a randomized clinical trial published by the University of Alabama at Birmingham. (37) Flaxseed is a common source of α-Linolenic acid, and was tested in a 134 patient randomized trial of flaxseed supplementation versus no supplementation for a few weeks prior to prostatectomy.
In the original study, PSA levels and post-operative measurement of α-Linolenic acid concentration within the prostate tissue was measured, and correlated to known single nucleotide polymorphisms (SNPs) that influence α-Linolenic acid metabolism. These can also be biomarkers of more aggressive prostate cancer.
Statistical calculations showed that prostatic linolenic acid concentration was associated with PSA level (p = 0.004). No association was seen between any of the SNPs studied and prostatic linolenic acid concentration however.
Study 3
A case-cohort analysis was performed from the Melbourne Collaborative Cohort Study, utilizing data from 1,717 men and 464 prostate cancer cases. Plasma phospholipids, dietary fatty acids, and the possible connection with prostate cancer risk was investigated. (38) Dietary fatty acid intake was recorded by a 121-item food frequency questionnaire.
Plasma phospholipid level did correlate with prostate cancer risk, when comparing the highest vs. lowest quintile among patients, for a hazard ratio = 1.51 (95% CI: 1.06, 2.16; p = 0.003). No statistically significant association for dietary intake was seen. The data showed that moderate intake of linoleic acid did correlate with prostate cancer risk, when comparing quintiles 2 and 3 with the lowest quintile (quintile 1). For Q2 vs. Q1, HR = 1.58 (95% CI: 1.10, 2.28) ] and for Q3 vs. Q1, the HR = 1.70 (95% CI: 1.18, 2.46). Interestingly the HR increase was not statistically significant for quintiles 4 and 5.
These 3 large data sets show an increased risk of saturated fats and α-Linolenic acid with both advanced prostate cancer and fatal prostate cancer cases. Interestingly the Australian study (38) found an association of plasma phospholipid concentration and prostate cancer risk, essentially quantifying the percentage of saturated fat intake, and therefore this could be a potential testing method. Overall these studies present a good level of evidence to reduce saturated fat from Western diets.
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