http://orcid.org/0000-0002-3107-9474
Abstract
There is an increasing evidence for a link between nutrition, lifestyle and prostate cancer (PCa) development and/or progression of disease. The objective of this study was to examine the association between dietary factors and PCa incidence and aggressiveness in a case-control study. After the analysis of the anatomic pathology, subjects were classified in patients with PCa (n = 157) and controls (n = 158). Clinical data including Gleason score, PSA values and biopsy results, were compiled. Frequencies of food consumption and sociodemographic data were also obtained. The results showed that physical activity was significantly higher in control (p < .022). It was also found that some nutritional habits offer a protective effect among studied subjects, like high nuts (p = .041) and fish (p = .041) intakes. Moreover, there was a significant reduction in risk (p = .029) in cases with a higher fruits and vegetables intakes. A decreased risk of aggressive PCa was associated with fruits, vegetables, legumes and fish intakes. However, these relationships were not statistically significant when data were adjusted for covariates. In conclusion, this study found an inverse association between PCa risk and the intake of fruits and vegetables, fish and nuts. The results suggested that a diet with higher intakes of these foods as Mediterranean diet may lower the risk of PCa in the studied population. As dietary factors are modifiable, identifying food groups or dietary patterns that modulate the risk of PCa and its aggressiveness can offer effective and practical strategies for its primary prevention.
1. Introduction
The available information in recent years shows that among various neoplasms, prostate cancer (PCa) has the highest estimated new cases in men [Citation1]. Because of the growing incidence of PCa and the low death rates, prevention of PCa and specifically aggressiveness and treatment resistances in PCa is an important issue [Citation2]. There is an increasing evidence for a link between nutrition, lifestyle and PCa development [Citation3,Citation4]. It has been showed that lifestyle modifications such as smoking cessation, exercise and weight control offer opportunities to reduce the risk of developing PCa [Citation5]. Consequently, a large body of literature endeavors to elucidate the role of lifestyle factors, including diet, in PCa risk, development of the tumor and successful survivorship. In addition, the large disparity in PCa incidence between the Eastern and the Western hemispheres, points to a key role of environmental factors, such as diet, as an etiologic factor in this disease [Citation6].
Different studies provide data about PCa and its strong associations with metabolic, hormonal and inflammatory profile. In PCa it is clear that obesity and metabolic syndrome are important risk factors [Citation3,Citation4]. It has been suggested that a higher body mass index (BMI), is positively associated with an increased risk of developing an aggressive form of prostate cancer and consequently an increase in its mortality rate. Besides, it has been proposed that obesity increases the risk of biochemical recurrence after primary treatment [Citation7]. Insulin resistance, usually related to overweight/obesity, are also associated with high PCa risk, although different factors could be responsible for this correlation. Contradictory results have also been found concerning the relationship of benign prostatic hyperplasia, with total caloric or fat intake, BMI and diabetes [Citation8]. In addition, obesity has also been shown to increase prevalence of other illnesses such as lower urinary tract symptoms, overactive bladder, erectile dysfunction and hypogonadism [Citation9–12].
In other cancer like breast cancer, the consumption of fruits and vegetables, dietary fiber intake, vitamin supplementation along with the intake of probiotic products, are the most extensively studied by a negative association to cancer risk [Citation13]. In PCa it is clear that obesity and metabolic syndrome are important risk factors [Citation3,Citation4]. Based on the epidemiological studies, several dietary factors and vitamins/supplements may be associated with PCa risk and/or progression of disease [Citation14]. Many nutrients show potential benefits in helping to slow progression and reduce recurrence, as well as complementing conventional treatment to improve quality of life [Citation15]. Nutraceuticals and supplements, particularly antioxidants, polyphenols and soy have evidence for benefit for prevention of PCa and progression of the disease [Citation3]. Comhaire and Mahmoud [Citation16] suggest food supplementation with the liposterolic extract of Serenoa repens and a combination of the antioxidants selenium, lycopene and natural vitamin E, together with fish oil to prevent or delay PCa and benign prostatis hypertrophy. Trends in the published data suggest that consumption of carbohydrates, saturated, trans and ω-6 fats and certain vitamin supplements may promote PCa risk and progression [Citation17] . Conversely, consumption of fruit, vegetables, dietary fiber and ω-3 fatty acids seem to slow the risk and progression of the disease [Citation18], even to produce a small reduction in prostate cancer risk [Citation19].
The high prevalence of “latent” PCa compared with clinically significant disease suggests that dietary factors influencing the later stages of PCa progression may be relevant to effective intervention. Epidemiological studies suggest that diet is a key factor in the etiology of aggressive PCa [Citation20]. Moreover, the WHO) reported that approximately a 30% of cancer deaths are due to five behavioural risk factors and diet, such as high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco and alcohol habits [Citation13]. For some slow growing cancers, such as PCa, presentation with a more aggressive form at diagnosis confers risk of a worse outcome than those diagnoses with less aggressive disease. There is a need to identify adjustable behaviours such as diet and exercise that may decrease not only the overall risk of cancer, but also the risk of aggressive disease within specific types of cancer [Citation21]. Because of the limited number of studies available for a secondary outcome assessment, additional studies of aggressive and fatal disease are eagerly awaited [Citation22].
Despite the information available, a common consensus on which nutrients or food groups may be beneficial and which could be harmful in PCa is lacking [Citation15]. Recently, a dietary pattern that includes rich fruits and vegetables, reduced refined carbohydrates, total and saturated fats and reduced cooked meats has been related to PCa risk reduction [Citation14]. Recent publications included that significant linear trend between the Western pattern, the carbohydrate pattern and the increment of PCa risk, moreover there are evidence suggesting that high adherence to a Mediterranean diet is associated with reduced risk of overall cancer mortality as well as a reduced risk of incidence of several cancer types including PCa [Citation23,Citation24]. Therefore more research is needed to elucidate the effects of consumption of particular food and how this relates to PCa. The objective of this study was to examine the association between dietary factors and PCa incidence and aggressiveness in a case-control study.
2. Materials and methods
2.1 Patients and data collection
Patient recruitment was carried out in the Department of Urology, University Hospital “Virgen de las Nieves”, Granada. Research protocols were approved by the Institutional Review Boards at the Hospital. All men enrolled in the study were patients with PSA levels above 4 ng/ml with a suspicion of developing PCa and upon whom a biopsy was performed. After the analysis of the anatomic pathology, subjects were classified in patients (n = 157) and controls (n = 158). All research subjects provided written informed consent. Some of the samples were not well classified at the biopsy examination and hence were lost in consequent analysis.
Consented patients were interviewed by the urologists and were asked to respond to a series of structured questionnaires that solicited information, which included back-ground characteristics, occupation and family history of PCa, comorbid conditions, PCa diagnosis and physical activity level. In addition, patients were interviewed using a food frequency structured questionnaire by trained dieticians. Food consumption was recorded according to whether an item had been consumed or not during the last year, the number of times it was consumed per week and the amount consumed each time (in household measures). At the time of interview subjects height was measured using a stadiometer and weight was measured using a floor scale. BMI was then calculated using the formula weight (Kg)/height (m)2.
2.2 Clinical parameters
PCa characteristics, which included Gleason grade and serum PSA level, were obtained by the urologists. PCa aggressiveness was classified as a function of Gleason grading system. The Gleason score grades the severity of prostate tumours according to tumour histology. PCa with a total Gleason score ≥7 was considered histologically aggressive; while those graded <7 were regarded nonaggressive [Citation25]. BMI was calculated from weight and height measurements obtained according to the standard calculation of weight (Kg) divided by height (m2).
2.3 Statistical methods
SPSS v.20.0 (SPSS Inc., Chicago, IL) [Citation26] was used for statistical analysis. Chi-square and Fisher’s test was used to evaluate the differences in distribution of categorical variables, and Mann-Whitney test or Students t-test analysis, was used to check the differences in distribution of continuous variables. Shapiro-Wilk’s test was performed to check the normality of the variables. Nutrients and food consumption variables were distributed in the approximated marginal tertiles.
Odds ratios (OR) for risk of PCa and for the Gleason index value, associated with nutrients and foods and the corresponding 95% confidence intervals (CI) for a tertile increment of intake of the respective food groups, were estimated using unconditional logistic regression model. For the risk on PCa the regression was performed with and without adjustment of four covariates: age (categorized in 3-year groups), alcohol (no/yes), diabetes (no/yes) and physical activity (no/yes). In the case of the Gleason index value, the covariates selected were: age (categorized in 3-year groups), familiar Cancer (no/yes) and smoking (smoker, ex-smoker and non-smoker).
To select the most appropriate covariates for each regression, a multiple backward stepwise logistic regression was computed. Tests for trend associated the increased of intake were performed with the test of Cochran-Armitage. For all the statistical tests, the significance level was set at 0.05.
3. Results and discussion
3.1 Patient characteristics
Physical activity was found to be a lifestyle factor significantly higher in control subjects (p < .022) (). Recently, Morote et al. showed that a sedentary lifestyle is associated with increased risk of PCa detection [Citation27]. The influence of physical activity on the risk of PCa has been analysed in several studies with contradictory results [Citation4,Citation28,Citation29]. However, a meta-analysis including 88,294 men suggests a slight association between physical activity and PCa risk [Citation30]. Body mass index (BMI) mean value in PCa patients (28.1 ± 4.1) was not statistically significant comparing with controls (28.4 ± 4.3). Epidemiological studies on the relationship between obesity and PCa are somewhat conflicting: a Italian cohort study showed a positive association between high BMI and PCa incidence [Citation31], yet the Swedish Cohort study conducted in 15,326 men over 3.5 years of follow up, found no overall association [Citation32]. Obesity may contribute to hormonal changes through the decrease of sex hormone-binding globuline levels and concomitant increase of bioavailable androgens and also by enhancing peripheral aromatization of androgens to estrogens. There are evidence that estrogens either alone or together with androgens, can induce aberrant prostatic growth and subsequent neoplastic transformation. In addition, adipose tissue produces different adipocytokines, like adiponectin, which has been evaluated in different stages of PCa, through contradictory results have also been published [Citation33,Citation34]. Whether the increase of adipocytokines and other inflammatory markers are related only to obesity or to PCa as well needs to be investigated [Citation8]. Smoking habits, alcohol and coffee consumption were similar in the two groups of the present study (Details in ).
Table 1. Sociodemographic characteristics of case and control participants.
A significant association between age and the risk of aggressive PCa was found with a mean value of 67.7 in patients with Gleason score <7 and a mean value of 71.6 in patients with a Gleason score ≥7 (). Adiposity measurement including BMI and waist circumference have been reported to be positively associated with aggressive prostate cancer [Citation35]. In this study, there were no differences in the BMI between high grade and low grade PCa patients (mean values of 28.7 ± 4.4 and 28.3 ± 4.2, respectively). Other authors have reported that aggressive cases were greater among men older at diagnosis and with greater BMI than their counterparts [Citation27,Citation36]. Recent studies reported that BMI is related to chemotherapy results such as an analysis developed in a Japanese PCa that classified for adverse pathological findings and biochemical recurrence after radical prostatectomy and others reported that BMI <25 kg/m2 are associated with reduced survival in patients with castrate resistant PCa being treated with docetaxel chemotherapy [Citation37,Citation38]. Tumour aggressiveness was not clearly associated with any of the other studied characteristic.
3.2 Food consumption
Food consumptions reported as total consumption per day in cases and control patients is shown in . In order to analyse the relation between food consumption and PCa, univariate analyses were conducted. There were not statistically significant differences in food consumption between cases and controls. shows intakes of food groups in low and high grade PCa patients. A significant association between fruit consumption and PCa aggressiveness was observed. The fruit intake mean value (g/day) in patients with Gleason score <7 was higher (389.7 ± 285.6) than the intake in cases with a Gleason score ≥7 (mean value 278.1 ± 231.8). There were not differences in intakes between the two studied groups in the other food groups.
Table 2. Food consumption of case and control participants.
Table 3. Food consumption of case participants.
gives the results of unconditional logistic regression model with and without adjustment of four covariates to study the association of food consumption with PCa risk. In individual unadjusted analyses a significant 18.6% reduction in risk was found between the highest and the lowest fruit intake categories. When data were adjusted for covariates, there was a not statistically significant 20% decrease risk for the highest intake categories. The effect of total consumption of fruit and vegetables on PCa risk was examined. There was a linear trend, with 25% reduction in risk in the highest intake category. In models adjusted for covariates, there was a significant reduction in risk (p = .029), with a 22.5% decreased risk in the highest fruit and vegetables intake category. Fruits and vegetables are rich in fibre, micronutrients and phytochemicals which may have anti-carcinogenic actions [Citation22]. Recent reports have examined the associations of fruit and vegetable intake on the incidence of PCa, but the findings are inconsistent and differ with the study design. Most cohort studies report non-significant results and several case-control studies suggest that vegetable intake may lower the risk of PCa [Citation39,Citation40]. Some authors suggested that the intakes of certain types of fruit or vegetables may be more important than others in reducing the risk of PCa, owing to the different compounds found in each [Citation22].
Table 4. Odds ratios of prostate cancer incidence associated with food intake.
Association of fish intake with PCa risk shows a statistically significant trend for reduced risk, with the >50 g category consumption in models unadjusted and adjusted for covariates (p = .043). Cross-national studies showed inverse associations between per capita consumption of fish and the incidence of and mortality rates from PCa [Citation41]. Moreover, intake of fish and marine-derived ω-3 fatty acids has been shown to be associated with decreased PCa mortality [Citation42]. A meta-analysis of fish intake and PCa [Citation43] concluded that there was an association between fish consumption and a significant 63% reduction in PCa specific mortality (four cohort studies (n = 49.661), RR: 0.37; 95% CI: 0.18–0.74).
A decreased PCa risk was associated with the highest nut intake categories. When data were adjusted for covariates, there were statistically significant protective effects for high nuts intake (p = .041). There are few studies that analyse the role of nuts intake on prostate cancer. A small clinical study in men at risk for PCa showed increased serum γ-tocopherol and a trend towards an increase in the ratio of free prostate specific antigen (PSA): total PSA after eight weeks of a diet supplemented with 75 g walnuts per day compared with a control diet [Citation44]. On the contrary, other study found no significant difference between mean PSA levels of a 6-month walnut-supplemented diet [Citation45].
One of the potential reasons for inconsistent results of case-control and cohort studies examining the association between diet and PCa may be that most of the studies had a small number of advanced tumours. Given the clinical importance of advanced PCa, it is crucial to understand which nutrients, food, or food groups significantly modulate the risk of its occurrence [Citation46]. gives association of food consumption with PCa aggressiveness using unconditional logistic regression model with and without adjustment of covariates. A decreased risk of aggressive PCa was associated with fruits and vegetables, legumes and fish intakes. However, these relationships were not statistically significant when data were adjusted for covariates. Epidemiological studies conducted to date have revealed that some dietary factors modulate the risk for advanced PCa [Citation46]. It has been shown an inconsistent association for intake of fruits and vegetables with a decrease advanced PCa risk. If these findings are confirmed by more adequately powered epidemiologic studies, the risk of advanced PCa, which is fatal and thus clinically significant, may be reduced by dietary modification and chemoprevention [Citation47].
Table 5. Odds ratios of prostate cancer aggressiveness associated with food intake.
There are some limitations of this study that must be recognized. First, although we used a validated food-frequency questionnaire for assessing the dietary intake, measurement errors that might lead to underestimation or even over estimation of associations were inevitable. In addition, PCa is a slowly growing cancer. The use of current diet as a surrogate for past diet restricts our ability to evaluate the accurate food consumption.
In conclusion, this study found an inverse association between PCa risk and the intake of fruits and vegetables, fish and nuts. The results suggested that a diet with higher intakes of these foods as Mediterranean diet may lower the risk of PCa in this population. As dietary factors are modifiable, identifying food groups or dietary patterns that modulate the risk of PCa and its aggressiveness can offer effective and practical strategies for its primary prevention.
Acknowledgements
This paper will be part of Noelia Urquiza’s doctorate, which is being completed as part of the “Nuevas Dianas Terapéuticas” at the University of Granada, Spain. The authors are grateful to all the donors and clinicians for making this project possible.
Disclosure statement
Authors have nothing to disclose.
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References
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