Impact of modifiable lifestyle risk factors for prostate cancer prevention: a review of the literature

Introduction Although prostate cancer (PCa) is one of the most common cancers among men, the impact of modifiable risk and protective factors is still being debated. This review aims to qualitatively summarize the most recent studies related to potential healthy lifestyle factors affecting the development of PCa. Methods for data acquisition The literature focusing on modifiable risk factors for prostate cancer was reviewed. Medline and Embase via the Ovid database were searched, and all relevant and inherent articles were analyzed. Non-eligible publications, such as review articles, editorials, comments, guidelines, or case reports, were excluded. Synthesis of the evidence obtained from data analysis This review confirms that there is strong evidence that being overweight or obese increases the risk of advanced prostate cancer (assessed by body mass index (BMI), waist circumference, and waist–hip ratio), particularly considering central adiposity and ethnicity as contributing factors. The possible contribution of smoking still seems not entirely clear, while alcohol seems to affect PCa prevention in patients taking 5α-reductase inhibitors (5-ARIs). Dietary fibers may have anti-inflammatory properties and improve insulin sensitivity by reducing IGF bioactivity. In particular, dietary fiber intake like insoluble and legume fibers may be inversely associated with prostate cancer risk. Also, hyperglycemia and hyperinsulinemia, with untreated diabetic fasting blood glucose levels, could be modifiable prostate cancer risk factors. In two studies, aspirin was associated with a lower risk of lethal PCa and overall mortality. Concerning the role of vitamins, despite conflicting and divergent results, serum retinol concentration seems to be associated with an increased risk of prostate cancer and high-grade prostate cancer. Some studies resulted in disagreement about the role of selenium and vitamin E. We found inconsistent and controversial findings about the association between vitamin D and prostate cancer risk. Conclusion Far from being conclusive evidence, our findings confirm some strong evidence already found in the previous literature and highlight the need to clarify the role of some risk factors whose role is not yet completely known. This effort would facilitate the cultural and social change that may allow the shift from the treatment of prostate cancer when diagnosed to the real efforts needed for systematic prevention.


Introduction
Prostate cancer (PCa) is the most common cancer among men worldwide (1), with the highest incidence and the third highest mortality rate in Europe (2). The advent of prostate-specific antigen (PSA) and its derivatives increased the number of patients being diagnosed with PCa. Non-modifiable risk factors, such as age, ethnicity, and hereditary factors, represent well-established causes underlying the etiology of PCa (3, 4). Nevertheless, the impacts of modifiable risk factors, such as diet, physical activity, obesity, and smoking, remain largely unclear (5).
In 2018, the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) presented the Continuous Update Project expert report on prostate with the aim to analyze cancer prevention through diet, nutrition, and physical activity. The recommendations of this report stated evidence on obesity, highlighting that waist circumference and waist-hip ratio are strongly associated with an increased risk of advanced prostate cancer, defined as high-grade PCa (Gleason score ≥7) or stage 3-4 on the American Joint Committee on Cancer (AJCC 1992) classification. Also, there is strong evidence that betacarotene is unlikely to have a role in the carcinogenesis of PCa. Despite this robust and strongly supported evidence, only limited and inconsistent evidence is reported in the literature about other modifiable risk factors (6,7).
Considering the impossibility to manage non-modifiable risk factors, a clear analysis of the modifiable and preventable ones appears of utmost importance. In this review, we aimed to summarize the most recent evidence about the impact of diet, habits, physical activity, and other modifiable risk factors on the carcinogenesis of PCa.
2 Methods for data acquisition 2

.1 Search strategy
The current review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (8).
The literature search was performed in February 2023. Only articles published in the last 10 years were considered. Two authors independently selected the articles for inclusion in the review. When there was no agreement between the authors for inclusion/ exclusion, a third author was involved in the definitive decision.
The literature search and the selection process are reported in Figure 1.

Study selection
There was no restriction on the type of study (retrospective or prospective), but only clinical trials and randomized controlled trials were considered, excluding non-eligible publication types, such as review articles, comments, guidelines, editorials, and case reports.
A total of 2,147 articles were identified and screened through the evaluation of the title and the abstract to exclude irrelevant studies. When the abstract clearly showed that the related article did not focus on the objective of the present review, it was excluded. In case of doubt, the article was studied for potential inclusion. Subsequently, full-text assessment was performed for all articles included. Articles were excluded when results did not achieve statistical significance and/or when statistical analysis was not robust. Duplicates (defined as articles clearly reporting the same series) and irrelevant articles, which would not contribute to the review, were excluded. Only articles in English were considered.
At the end of the selection process, 31 articles were included in the review (Table 1).

Data extraction
Two authors extracted the following data from the included articles: year of publication, type of the study, funding, patients' characteristics, and results. Dietary fiber intake can modulate the association between alcohol intake and risk of prostate cancer.
(Continued) Literature search and selection.   Evidence of an interaction between atocopherol and selenium itself or selenomethionine increasing high-grade prostate cancer risk.
(Continued) As quantitative analysis was not possible due to the very high heterogeneity among the included studies, only qualitative analysis was carried out.

Studies included
All studies included were published between 2012 and 2023. A total of 21 studies were nested case-control (NCC), three studies were observational, and seven were case-control studies.
The cohort was nested within the following trials: ◼ The Selenium and Vitamin E Cancer Prevention Trial (SELECT): a randomized placebo-controlled trial that tested the role of selenium and vitamin E in reducing prostate cancer risk (the USA, Puerto Rico, and Canada)  ◼ The NutriNet-Santéstudy was an ongoing web-based cohort launched in France in 2009 with the aim to study the association between nutrition and health (51).
In terms of geographical distribution, many studies were multicentric randomized studies including patients from the USA, the UK, Europe, Canada, and Puerto Rico, with a small contribution from Finland, France, Pakistan, Uruguay, Turkey, Korea, and Italy.
The results of the studies included are summarized in Table 1.
3 Synthesis of the evidence obtained from data analysis 3.1 Lifestyle habits

Tobacco consumption
Cigarette smoking is considered a major public health concern worldwide due to its consequences in terms of mortality and morbidity. Despite the correlation between smoking and several solid tumors, the relationship between smoking and PCa remains a matter of debate (52). The REDUCE trial offered an opportunity to evaluate the relationship between cigarette smoking and prostate cancer. Ho et al. (12) conducted a logistic regression to test the association between smoking and cancer on the first on-study biopsy in REDUCE. Among men with high PSA levels and negative biopsy in REDUCE, smoking was unrelated to overall prostate or low-grade PCa. However, smoking was found to be associated with an increased risk of high-grade PCa.

Alcohol consumption
Concerning alcohol consumption, most of the evidence in the literature confirms a correlation with the increased risk of highgrade prostate cancer, with a smaller influence on the overall risk. In particular, alcohol consumption among moderate and heavy drinkers (estimated at least 10 units/week) appears to increase the risk of high-grade PCa (9). Fowke et al. (10) confirmed that alcohol affects PCa in patients on 5a-reductase inhibitors (5-ARIs). Dutasteride was assumed to be associated with a significantly reduced risk of high-grade PCa among alcohol abstainers, suggesting that alcohol intake represents an unfavorable risk factor in those taking phosphodiesterase inhibitors. However, it is reported that the intake of a high amount of dietary fiber represents a protective factor among alcohol consumers (11).

Sexual habits/activity
The role of sexual activity as a modifiable risk factor in PCa prevention is still being debated. The main studies in the literature focused on ejaculatory frequency, number of sexual partners, and age of the first intercourse. Sexually transmitted infections (STIs) have also been investigated. However, it was not possible to unequivocally clarify the correlation with the carcinogenesis of prostate cancer (53). Spence et al. (14) carried out a case-control study, finding a reduction in the risk of overall and low-grade PCa among men with multiple female sexual partners during their lifetime (more than 20). In contrast, men with multiple male sexual partners had a slightly increased risk, with an apparent association with a higher risk of STIs. Frequent sexual intercourse may lead to a potentially increased exposure to sexually transmitted diseases (STDs) and is associated with higher androgen function and higher PCa risk (54). Indeed, Cirakoglu et al. (16) found a positive association between the number of sexual partners during a lifetime and the incidence of PCa. In addition, Rider et al. (15) supported the "prostate stagnation hypothesis", as they reported a positive role of frequent ejaculation during a lifetime (more equal than 20 per month) in preventing prostate cancer. This can be related to the decrease of carcinogenic molecules within prostatic fluid due to frequent ejaculation.

Diet and chronic inflammation
Dietary fiber intake is associated with anti-inflammatory properties through a decreased oxidation of lipids and better control of glucose serum levels, which are known for decreasing proinflammatory cytokines like plasma interleukins (55). Chronic inflammation contributes to several forms of cancers, and it is well known that this can stimulate prostate carcinogenesis (56, 57). Deschasaux et al. confirmed that high dietary fiber is inversely associated with PCa risk, especially for insoluble and legume fiber intake. However, the authors found no association between prostate cancer risk and soluble, cereal, vegetable, and fruit fiber intakes.
Phospholipid long-chain w-3 fatty acids represent serum biomarkers of fatty acid intake, whose role in prostate cancer carcinogenesis has been recently suggested (58). Brasky et al. (17) investigated the association between plasma LCw-3PUFA and PCa, confirming an increased prostate cancer risk.

Meat
The International Agency for Research on Cancer (WHO-IARC) classified processed meat intake as "carcinogenic to humans" and consumption of red meat as "probably carcinogenic to humans" (59). The carcinogenic role of processed and red meat was confirmed also in two case-control studies (19,20), in which increased consumption was directly associated with increased risk of PCa, with a significant dose-response rate. Moreover, Bashir et al. (19) found a decreased risk association with fluid, vegetable, and fruit intake. Nevertheless, Diallo et al. (21) observed no correlation between red or processed meat intake and PCa but found that meat intake is involved in carcinogen-induced tumors such as colorectal cancer.

Diabetes
Glucose metabolism and chronic inflammation may have a role in PCa development (60), modulating signaling pathways and promoting uncontrolled cell proliferation and oxidative stress (61). Murtola et al. (23) evaluated prostate cancer risk in relation to normal and elevated serum glucose levels in diabetic patients. Diabetic patients with high blood glucose levels have an increased risk of overall PCa. The use of antidiabetic drugs and glucose level normalization is reported to contribute to decreasing the risk of PCa.
Miles et al. (22) studied its relationship with concentrated dietary sugar intake. Increased consumption of added or concentrated sugar-sweetened beverages (in the highest quartile) is related to an increased risk of PCa. There is a non-linear association instead with sugar intake from juices and desserts, suggesting a role of low glycemic index food selection in the prevention.

Body mass index and metabolic syndrome
The relationship between obesity, body mass index (BMI), and PCa has been extensively investigated in literature and was confirmed by the WCRF/AICR recommendations in 2018. In particular, obesity is related to lower concentrations of free testosterone and a decreased risk of localized/low-grade PCa and with an increased risk of advanced/high-grade PCa (62, 63). In two nested case-control studies from the SELECT and REDUCE trials (26, 27), increased BMI was found to be associated with a higher risk of high-grade PCa (Gleason score ≥7) in patients uninformed about PCa.
Nemesure et al. (24), in a case-control study on the Barbados population, found that a major correlation between waist size and waist-hip ratio is a measure of central adiposity and adiposity distribution, and prostate cancer risk. These results were confirmed also in another case-control study carried out by Boehm et al. (28). This suggests that body fat distribution may be more directly related to an increased high-grade risk PCa than BMI alone.
Abdominal obesity is closely related to metabolic syndrome (MetS), including insulin resistance, hypertension, impaired glucose tolerance, and lipid profile (64). According to some authors, lateonset hypogonadism (LOH), defined as the decrease of androgen levels, should be considered part of the MetS (65, 66). Kayali et al. (25) published a case-control study on the Turkish population subdividing patients into groups according to the presence of MetS and LOH. The authors found that the group with both MetS and LOH had an increased risk of prostate cancer, especially with aggressive histologic features.
In addition, the altered hepatic metabolism in non-alcoholic fatty liver disease (NAFLD), which is associated with metabolic syndrome, determines a suppression of the hepatic glucose leading to hyperglycemia, hypertriglyceridemia, and hyperinsulinemia (27, 67). Choi et al. (29) analyzed the correlation with PCa, suggesting that NAFLD is directly associated with an increased risk of prostate cancer, especially in non-obese patients with NAFLD.
Lastly, Jamnagerwalla et al. (30) found that high total serum cholesterol and high serum HDL are associated with an increased risk of high-grade PCa, thus confirming the importance of metabolic syndrome in the predisposition to PCa.

Use of hypertensive drugs
The use of hypertensive drugs is reported to increase the risk of mortality among patients diagnosed with prostate cancer. In particular, in a Finnish cohort of patients, Siltari et al. (33) found that ACE inhibitors and ATr blockers correlate with improved survival, while diuretics correlate with decreased survival.
Similarly, in a UK longitudinal cohort, Cardwell et al. reported that ACE inhibitors and ATr blockers decreased the risk of cancerspecific mortality (68).
The mechanism related to the role of ACE inhibitors and ATr blockers is unclear but probably involves the activity of angiotensin-II in mediating cell proliferation and fibrosis (69)

Use of aspirin and NSAIDs
Whereas regular aspirin administration probably protects from some malignancies, its exact role in the carcinogenesis of overall PCa and lethal PCa is still unclear. Downer et al. (32) found out that current and previous regular aspirin use (more than 200 mg per week) is associated with a lower lethal prostate cancer risk, especially compared to never users. In this study, the administration of aspirin after diagnosis had an impact on overall mortality. In a Finnish case-control study, Veitonmäki et al. (31) tested the association between non-steroidal anti-inflammatory drugs (NSAIDs) and PCa and found that NSAID users had an increased high-grade and all-grade PCa. This was similar for all types of NSAIDs tested, except for aspirin, which acted as a protective factor for overall prostate cancer risk.

Thyroxine, thyroid-stimulating hormone, and hypothyroid status
Triiodothyronine (T3) and thyroxine (T4) are thought to promote carcinogenesis through cell differentiation and development (54, 70). Mondul et al. (34) explored the relationship between circulating thyroid hormones, thyroid status, and prostate cancer risk. Compared with euthyroid men, the patients with high thyroid-stimulating hormone (TSH) and hypothyroidism had a decreased risk of PCa.

Vitamin and micronutrients
Vitamins are essential nutrients for human metabolism, and they play an important role as coenzymes in the normal functioning of the body as well as in many vital processes. In recent years, it has become clear that vitamins are essential for health and human disease (21, 70), thanks to several studies examining this correlation. However, according to Cancer Research UK, there is no reliable evidence that dietary supplements can help prevent cancer. Evidence in the literature is inconclusive and conflicting, with positive or no reported associations.
The 2018 WCRF/AICR recommendation downgraded lycopene and selenium supplementation from "may reduce prostate cancer risk" to "limited-inconclusive" (7). In fact, Morgia et al. (39) studied the incidence of PCa in a group of patients treated with selenium and lycopene in the previous Procomb study, but the evidence did not support a significant role for supplements in affecting prostate cancer risk. Conversely, Antwi et al. (38) carried out a case-control study among African American (AA) and European-American (EA) men from North America. They observed a higher intake of lycopene among EAs and a higher intake of beta-cryptoxanthin among AAs. Dietary lycopene and beta-cryptoxanthin have an indirect relationship with the development of high-grade PCa among EAs and AAs.
Vitamin E reduces DNA damage, enhances DNA repair, affects cellular responses to oxidative stress, inhibits cell proliferation, enhances immune responses, and reduces cellular testosterone levels (71). Albanes et al. (35) investigated the role of presupplementation of plasma a-tocopherol or g-tocopherol in the development of high-grade (Gleason score 7-10) prostate cancer. Men with higher concentrations of a-tocopherol had a similar risk if compared to men with lower concentrations. Nevertheless, the authors found a strong positive association between plasma atocopherol and the risk of developing PCa in men receiving selenomethionine supplementation.
Retinol has been reported to promote cell differentiation and apoptosis. It increases the level of other antioxidants and regulates DNA transcription (63). Nash et al. (37) presented a nested casecontrol study evaluating the association of serum retinol and carotenoids with overall PCa risk. The authors found that serum retinol levels were associated with an increased risk of all grades of prostate cancer. Even in the placebo group, a-carotene was moderately positively associated with the risk of all grades of prostate cancer. In addition, Hada et al. (40), in 2015, prospectively investigated serum retinol and the overall risk of PCa as well as the role of a-tocopherol and b-carotene in overall PCa prevention. After multivariable adjustment, they concluded that high serum retinol was not associated with overall cancer risk but was associated with an increased risk of prostate cancer (72)(73)(74).
Vitamin D metabolites regulate cell growth and differentiation. The administration of vitamin D analogs suppresses prostate cancer progression in animal models and phase II studies (36,37,74). Schenk et al. (36) conducted a case-cohort study using data from the PCPT and found that high levels of serum 25(OH)-vitamin D slightly increased the risk of high-grade PCa and could reduce the risk of low-grade PCa.
Hoyt et al. (41) evaluated the relationship between dietary intake of phylloquinone, menaquinone, total vitamin K, and prostate cancer risk. The authors reported clear evidence of the role of vitamin K in the development of prostate cancer. In this study, the authors concluded that vitamin K intake affects the incidence of overall and advanced prostate cancer.

Drug use disorder
Drug use disorder (DUD) is reported to increase the risk of fatal prostate cancer. According to Dahlman et al. (13), DUD gives rise to a little increase in incident prostate cancer, but more interestingly, it is a statistically significant predictor of fatal prostate cancer. The authors hypothesize that in this group of patients, the underlying cause is the more advanced stage at diagnosis due to a delay in the diagnosis and treatment. This study is retrospective and based on the Swedish population.
In a previous study, Chhatre et al. reported that substance use disorders, including prescription drugs and recreational or nonlegal substances, are related to an increase in mortality in patients diagnosed with advanced prostate cancer, particularly in patients with mental and behavioral disorders (75).

Discussion
In accordance with the latest World Cancer Research Fund International Continuous Update Project report on prostate 2018, a systematic and global analysis of the scientific research on prostate cancer, the present review shed more light on modifiable risk factors of prostate cancer, including diet, micronutrients, obesity, and metabolic syndrome, but may topics remain a matter of debate and controversial (54).
In the last years, many articles have been published on the refinements in the diagnosis of PCa (77) as well as on the algorithms for predicting the risk of recurrence after cutting-edge techniques for the treatment of this disease (78), but no comparable effort has been made in order to implement the strategies to prevent PCa.
Although not conclusive, our review contributes to clarifying potentially modifiable risk factors for the development of PCa and focuses on the role of some biochemical mechanisms not yet fully understood in the pathogenesis of PCa.
One of the major limitations of this review is its failure to quantify the risk for each risk factor considered. Unfortunately, different studies on a specific risk factor use different statistical analyses, so the results are often not comparable. If we found many studies obtaining appreciable results, it was not possible to achieve a cumulative result. As a consequence, for many risk factors, the results of our review could not be conclusive.
In addition, as many authors have highlighted, risk factors are often correlated with each other, thus making it much more difficult, or even impossible, to quantify the role of a single risk factor in the prevention of PCa. In this respect, we argue that policies for the prevention of PCa should not be addressed to a single risk factor, even if important in public health, but to a number of risk factors together, especially when working on lifestyle, diet, and sexual habits.
Noteworthy, major risk factors, such as tobacco, alcohol consumption, and DUD, are risk factors for many other diseases, like lung, liver, and bladder cancers, with well-established evidence in the literature showing that reducing these modifiable risk factors dramatically results in a decrease of the prevalence of these tumors.
Other risk factors concerning lifestyle, diet, and sexual habits are not strictly related to a specific pathology, especially when the reduction of these risk factors is not planned in the scenario of wider prevention policies aiming to improve the general health status. A policy aiming to improve the general health status of patients, through a reduction of modifiable risk factors concerning lifestyle, diet, and sexual habits, would lead to an improvement in quality of life and general health and in turn a decrease in the risk of developing cancer and other non-tumoral pathologies. In this view, PCa would be one of the targets of this policy.
Further studies are needed to reach proper evidence in the perspective that prevention may be effective in limiting the number of patients not undergoing treatment. In this view, the prevention of PCa may improve the quality of life due to the burden of complications and side effects of active treatment, such as surgery, radiotherapy, chemotherapy, and androgen deprivation, which are known for their negative impact on the quality of life.
Last but not least, preventing men from developing prostate cancer would be much more cost-effective for the healthcare systems of the majority of countries. All the efforts to facilitate the shift from the paradigm of treatment of PCa to the paradigm of its prevention (which has been called the "paradigm shift") would be beneficial, and a deeper insight into the modifiable risk factors of this disease is of the utmost importance to plan policies for systematic prevention (77).
There is common agreement in the literature about the effectiveness of early diagnosis as a policy for cancer prevention. Although a tumor-specific marker for prostate cancer is not available as yet, the advent of PSA and its derivatives, like PSA-IgM, as well as other markers, like PCA-3, has been investigated with the aim to support the early diagnosis of prostate cancer (79)(80)(81). Multiparametric MRI has also revolutionized the detection of prostate cancer in its earliest stage (82)(83)(84)(85). Unfortunately, overtreatment remains a matter of fact, with many men needing therapy for side effects related to treatment. For this reason, the policies aiming to prevent PCa should focus not only on detecting prostate cancer as early as possible but also on more efforts to the prevention of modifiable risk factors in order to achieve a decrease in the prevalence of prostate cancer and a consequent decrease of the side effects of treatment. This is particularly important when considering the overall costs of PCa.
It goes without saying that this concept of prevention is strictly related to education and cultural environment, which may be different in different countries. In this view, the policies to prevent modifiable risk factors for PCa may be different from country to country and should be made known early to patients.
The present review shows a number of modifiable risk factors that should be known and understood for the implementation of health policies, as well as for counseling patients as regards prostate cancer, particularly those who are at risk due to non-modifiable risk factors, such as familiarity, race, or genetics.

Conclusion
Prostate cancer is a major issue in men's health, with an increased number of patients being diagnosed and treated due to the refinements in detection techniques in the last two decades. This led to overtreatment in some cases, unnecessary costs for the health systems, and the need to treat the side effects related to the treatment.
The implementation of policies of prevention may lead to less incidence of PCa. Due to the impossibility to act on non-modifiable risk factors, there is still the chance to apply policies able to decrease the impact of modifiable risk factors.
The present review of the literature showed that many risk factors are fit as targets of prevention policies. Unfortunately, we were not able to quantify the role of every single risk factor due to the fragmentation of the literature or even the presence of conflicting results in some cases. However, focusing on a wide range of risk factors allowed a deeper insight into the mechanisms of nutrients, lifestyle, habits, and drugs in preventing or facilitating PCa. This may support proper patient counseling as well as inform policies for prostate cancer prevention.