Abstract
BACKGROUND:
Prostate cancer (PCa) is a significant health concern, and its incidence and prevalence are influenced by various lifestyle factors, including diet. In recent years, the Mediterranean diet has gained popularity due to its potential health benefits and associations with reduced risk for various diseases. However, the impact of the Mediterranean diet on PCa remains a topic of debate.
OBJECTIVE:
The aim of this study was to test the association between adherence to the Mediterranean diet and PCa severity.
METHODS:
Background, clinical and dietary information (from food frequency questionnaires) were collected from 118 consecutive patients attending a university hospital in Southern Italy. Multivariate logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to test the associations.
RESULTS:
Patients reporting higher adherence to the Mediterranean diet were less likely to have more at risk PCa both when comparing intermediate/high vs. low risk and high vs. intermediate /low risk PCa (OR = 0.12, 95% CI: 0.02, 0.85 and OR = 0.05, 95% CI: 0.01, 0.31, respectively).
CONCLUSIONS:
In conclusion, higher adherence to the Mediterranean diet may be associated with a clinically less severe clinical PCa.
Introduction
Prostate cancer (PCa) represents one of the most common malignancies in men and the fifth leading cause of cancer-related deaths worldwide [1]. In Italy, the incidence of PCa has steadily risen over the past decades [1]. According to the latest available data, PCa remains the most commonly diagnosed cancer among Italian men, accounting for approximately 17% of all new cancer cases in men [2]. The age-standardized incidence rate for PCa is estimated to be approximately 29.4 per 100,000 men, demonstrating significant interregional variation within the country, such as northern regions generally exhibiting higher incidence rates compared to southern ones [2]. However, despite advancements in early detection and treatment strategies, PCa-related deaths continue to affect a substantial fraction of the patients, estimated to reach approximately 5.4 per 100,000 men [2].
The etiology of PCa is multifaceted, influenced by a complex interplay between genetic predisposition and environmental factors [3]. While age and family history remain the primary non-modifiable risk factors, a myriad of modifiable risk factors have been investigated in recent years, opening avenues for targeted prevention strategies. Among the modifiable risk factors, lifestyle choices, including diet, have garnered considerable attention in the context of PCa development and progression. Dietary habits are highly relevant as they offer a tangible and accessible means to potentially reduce the burden of PCa on a global scale [4]. Comprehensive evidence from the literature shows that individual dietary factors may exert a relatively low impact on PCa risk [5–13]. In contrast, a more holistic evaluation of dietary patterns has been shown to play a significant role in PCa risk and progression [14–16]. The Mediterranean diet, characterized by high consumption of fruits, vegetables, whole grains, fish, and olive oil, and low intake of red and processed meats [17], has been suggested to reduce the risk of PCa and improve the patient’s survival [18]. The aim of the present study was to assess whether adherence to the Mediterranean diet was associated with PCa severity in a sample of Italian patients.
Methods
The study followed STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines [19].
Study population
Consecutive patients attending the urology clinic at the University Hospital of Catania (Italy) between January 2015 and December 2016 were considered for inclusion after trans perineal prostate biopsy (12 cores) for suspicious PCa. Patients were included if they met the following: diagnosis of clinically localized adenocarcinoma of the prostate; undergoing radical retropubic prostatectomy. All the study procedures were carried out in accordance with the Declaration of Helsinki (1989) of the World Medical Association and participants provided written informed consent after accepting to participate. The study protocol was approved by the ethics committee of the referent health authority (Registration number: 41/2015).
Data collection
The patients’ background characteristics included demographic (such as age and educational level) and lifestyle information (such as, physical activity and smoking status). Educational level was categorized as (i) primary/ secondary and (ii) tertiary (university). Physical activity level was evaluated through the International Physical Activity Questionnaires (IPAQ) [20] and categorized as (i) low, (ii) moderate and (iii) high. Smoking status was categorized as (i) non-smoker and (ii) current/ex-smoker. Body mass index (BMI) was calculated by dividing the patient’s weight in kilograms by the square of height in meters and categorized as normal weight (BMI <25 kg/m2), overweight (BMI 25 to 29.9 kg/m2) and obese (BMI ≥30 kg/m2).
Dietary assessment
Dietary information was assessed through two food frequency questionnaires (FFQs) validated for the Italian population [21, 22]. The 110-item FFQ referred to the consumption of foodstuff and beverages over the previous six months not considering potential changes due to the diagnosis of the disease. The frequency of consumption ranged between ‘never’ and ‘4–5 times per day’ taking into account seasonality (consumption of foods such as fruit and vegetables was considered during the availability during the season and then proportionally adjusted).
Adherence to the Mediterranean diet
Adherence to the Mediterranean diet was assessed through a literature-based index [23] previously applied in Italian studies [24]. The scoring system considered the frequency consumption (based on optimal serving sizes obtained from the scientific literature) of the main foods characterizing the Mediterranean diet (positive points for olive oil, fruit, vegetable, legumes, fish, grains, and moderate intake of alcohol, and negative points for excess consumption of meat and dairy). The overall score ranged from 0 to 18 points and was then categorized in low (<8 points), medium (8–12 points), and high adherence (>12 points).
Clinical data and endpoints
Clinical data included a Gleason score sum of all prostate needle biopsies obtained before radical prostatectomy to confirm adenocarcinoma [25]. Information regarding tumor burden on the prostate biopsy included the greatest percentage of any single core involved by prostate carcinoma (GPC) and total overall percentage of carcinoma (TPC). The TPC was calculated by adding the percentage of carcinoma on all involved cores to provide an estimate of overall tumor burden. Tumors were staged using the TNM system, which includes extraprostatic extension and seminal vesicle invasion [26] and a second modified TNM staging system that also includes surgical margin status [27]. This later modified system classifies tumors as either being organ confined (pT2) or having adverse pathology defined as either pT3 disease (TNM system) and/or having positive surgical margins.
PCa severity was based on risk classification as low, intermediate, and high according to EAU guidelines [28]. This classification is based on the grouping of patients with a similar risk of biochemical recurrence after radical prostatectomy or external beam radiotherapy. Briefly, patients were grouped into the three groups based on the following parameters: (i) low risk, PSA <10 ng/mL and Gleason score <7 and cT1-2a; (ii) intermediate risk, PSA 10–20 ng/mL or Gleason score = 7 or cT2b; and high risk, PSA >20 ng/mL or Gleason score >7 or cT2c. Advanced PCa were defined as any PSA, any Gleason score, and cT3-4 or cN+.
Statistical analysis
Patients were grouped based on three groups of adherence to the Mediterranean diet. Categorical variables are presented as frequency and percentage, continuous variables are presented as mean and standard deviation. Differences of frequency between groups were calculated by Chi-square test. Mediterranean diet adherence scores distribution was tested for normality distribution with the Kolmogorov-Smirnov test, and it followed a slightly asymmetric normal distribution due to extreme values of the upper side. Mann-Whitney U test was used to compare differences in intakes between groups, as appropriate. The outcome was PCa severity dichotomized as (i) intermediate/high vs. low grade and (ii) high vs. intermediate/low grade PCas. The association between level of adherence to the Mediterranean diet and PCa severity was calculated through univariate (unadjusted) and multivariate logistic regression analyses adjusted for energy intake, age, educational level, BMI status, smoking status, and physical activity level. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated as a measure of probability. All reported P values were based on two-sided tests and compared to a significance level of 5%. SPSS 17 (SPSS Inc., Chicago, IL, USA) software was used for all the statistical calculations.
Results
Demographic background characteristics of the study sample by level of adherence to the Mediterranean diet are presented in Table 1. There was a significantly different distribution of certain variables, such as age groups, smoking status, and physical activity level in relation to the score, with older, never-smoker, and more physically active patients reporting higher scores of adherence to the Mediterranean diet (Table 1). Also concerning the clinical characteristics some differences between groups emerged (Table 2): specifically, there was a higher proportion of patients more adherent to the Mediterranean diet (meaning higher scores) among participants with lower Gleason score, PSA, staging, severity, GPC and TPC (Table 2).
Demographic characteristics of the study sample by level of adherence to the Mediterranean diet (n = 118)
Demographic characteristics of the study sample by level of adherence to the Mediterranean diet (n = 118)
Clinical characteristics of the study sample by level of adherence to the Mediterranean diet (n = 118)
Abbreviations: GPC (greatest percentage of any single core involved by prostate carcinoma); TPC (total overall percentage of prostate carcinoma).
The distribution of the main components of the Mediterranean diet by level of PCa severity is shown in Table 3. Only frequency of legume (≥1 serv/w), meat (<1 serv/d), and regular olive oil consumption was significantly differently distributed across severity groups, with a higher proportion of patients meeting these criteria for higher adherence to the Mediterranean diet among those with less severe PCa (Table 3).
Individual components of the Mediterranean diet adherence score in the study sample by severity of prostate cancer (n = 118)
AU, alcohol unit.
Finally, Table 4 presents the association between adherence to the Mediterranean diet and severity of PCa. Patients reporting higher adherence to the Mediterranean diet were less likely to have more at risk PCa both when comparing intermediate/high vs. low risk and high vs. intermediate/low risk PCa (OR = 0.12, 95% CI: 0.02, 0.85 and OR = 0.05, 95% CI: 0.01, 0.31, respectively).
Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between adherence to the Mediterranean diet and severity of prostate cancer
*Multivariate model was adjusted for energy intake (continuous, kcal/d), age (age groups, years), BMI (normal, overweight, obese), educational status (primary/secondary, tertiary), smoking status (never, current), and physical activity level (low, medium, high).
In the present study, the association between adherence to the Mediterranean diet and PCa severity has been investigated in 120 patients undergoing urology visits in a university hospital in a Mediterranean population. The findings showed that patients reporting higher adherence to the Mediterranean diet were less likely to have higher PCa severity grade. Previous evidence suggests that adoption of this dietary pattern may lower the risk of PCa [29], although an updated meta-analysis reported no significant results concerning total and advanced PCa risk [30]. Moreover, a summary of published dietary intervention trials of Mediterranean diet adoption in cancer survivors showed that adherence to the Mediterranean-type diet was associated with a lower risk of mortality also in PCa patients (among other cancer sites) [31]. Studies on the clinical severity and progression of PCa are scarce. A study specifically investigating the severity progression of 410 PCa patients on an active surveillance protocol reported that higher adherence to the Mediterranean diet was associated with a lower risk of Gleason grade group score progression [32]. However, another study testing the same variables on 564 men enrolled in the Canary Prostate Active Surveillance Study reported that higher adherence to the Mediterranean diet after diagnosis was not associated with significant reductions in the risk of grade reclassification during active surveillance [33]. In comparison with the few intervention studies in the scientific literature specifically focused on genetic markers of disease severity, a pilot dietary intervention where 20 volunteer PCa patients were advised to follow a Mediterranean-type diet for three months showed that participants showed an effect on DNA damage, demonstrating decreased DNA fragility related to higher intake of fish and olive oil, and reduction in dairy and meat [34]. Also, another pilot study conducted on 20 men diagnosed with PCa showed that an intervention based on adherence to a Mediterranean-type dietary pattern resulted in lower DNA damage related to an increase in legumes and a decrease in red meat intake [35]. Notably, both studies reported no statistically significant relationships between the adoption of a Mediterranean-type dietary model and inflammatory biomarkers (i.e., blood levels of C-reactive protein) and PSA.
Dietary factors are investigated for their capacity to influence the immune system toward anti- or pro-inflammatory effects promoting a subclinical low-grade chronic inflammation [36]. The protective effects of the Mediterranean diet are attributed to its rich antioxidant content, anti-inflammatory properties, and potential to modulate hormonal pathways involved in PCa pathogenesis [37]. Dietary components characterizing the Mediterranean diet, including fruit and vegetables, but also olive oil, red wine, legumes and whole grains, are rich in vitamins and phytochemicals, such as polyphenols, which exert antioxidant and anti-inflammatory effects in the human body [38]. Also, mono- and poly-unsaturated fatty acids (MUFA and PUFA, respectively) highly represented in olive oil [39] and fish [40], respectively, have been hypothesized to play a protective role toward the onset of cancer [41]. Among compounds of specific interest for PCa, lycopene, vitamin E, and selenium, isothiocyanates, and allyl compounds have been investigated for their potential preventive roles against such malignancy [42]. Lycopene, a carotenoid found in tomatoes and other red fruits, has been associated with a reduced risk of PCa due to its potent antioxidant and anti-inflammatory properties [43]. Similarly, vitamin E and selenium have shown promising effects in modulating oxidative stress and cellular signaling pathways implicated in PCa development [44]. Isothiocyanates and allyl compounds are derivatives from glucosinolates in cells of plants of the Brassicaceae or Cruciferae (commonly known as mustard) family (such as cabbage, kohlrabi, Brussel sprouts, cauliflower, broccoli, kale, horseradish, mustard, and turnips) which have demonstrated to potentially modulate several cellular processes implicated in tumorigenesis, such as DNA repair, growth and cell differentiation, and cell apoptosis [45]. Conversely, the Mediterranean diet is also low in processed foods, trans fats, and refined sugars, which have been linked to chronic pro-inflammatory actions, oxidative stress, and alterations in hormone metabolism, contributing to the development and progression of PCa [46]. However, despite the growing body of evidence linking diet to PCa, some studies have yielded inconclusive or conflicting results, necessitating further research to better elucidate the specific dietary components that confer protective or detrimental effects on prostate health.
The results of this study should be considered in light of some limitations. First, the study had an observational design; thus, no causal relations can be inferred from the presented findings, but only associations. Second, the participants of the study consisted of a convenient sample of consecutive patients, not necessarily representing the totality of PCa patients. Third, although adjustment for potential confounding factors was provided, unmeasured variables (i.e., unknown variables related to the time of referral) may still affect the retrieved associations. Fourth, prostate biopsy was performed as standard technique and not fusion biopsy was performed. This aspect could have underestimated the rate of prostate cancer. Finally, although the use of FFQs represents a standard for such types of studies, the self-reported measures may be affected by under- or over-estimations due to social desirability and recall bias.
In conclusion, there is some evidence suggesting that adherence to the Mediterranean diet might have a preventive effect against PCa risk. The mechanisms supporting such a hypothesis suggest that higher adherence to the Mediterranean diet might have benefits in both the pathogenetic initiation processes as well as in the progression of the disease. Future studies should take into account whether adherence to this dietary pattern might affect from the beginning of the course of the disease, being associated with lower severity. However, further studies are needed to corroborate such hypotheses.
Data Availability Statement
The data that support the findings of this study are available upon reasonable request.
Funding
This work was supported by the Distinguished Scientist Fellowship Program (DSFP) at King Saud University, Riyadh, Saudi Arabia.
Conflict of Interest
The authors have no conflict of interest to report.
Author Contributions
Conceptualization, G.I.R. and S.S.; methodology, G.I.R., S.S., A.A.A.; formal analysis, G.I.R. and S.S.; investigation, G.I.R., G.M., and A.LG.; data curation, G.I.R.; writing—original draft preparation, S.S. and A.LG.; writing—review and editing, M.G.A., S.C., A.A.A., M.F., G.M.; supervision, G.I.R. and G.M. All authors have read and agreed to the published version of the manuscript.