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Nutrition, physical activity, and lifestyle factors in prostate cancer prevention

Ballon-Landa, Eric; Parsons, J., Kellogg

doi: 10.1097/MOU.0000000000000460
PREVENTION IN UROLOGY: Edited by J. Kellogg Parsons and Maximilian Burger
Free

Purpose of review To review current evidence for prostate cancer prevention with nutrition, physical activity, and lifestyle interventions and identify future research directions.

Recent findings Multiple preclinical and observational studies have observed that diet, exercise, and lifestyle interventions may play a role in mitigating disease progression, mortality, and overall disease burden for high-grade and fatal prostate cancer. Increased vegetable and fruit intakes, decreased red meat and saturated fat intakes, and increased exercise are potentially associated with decreased risk of incident disease and increased progression-free, prostate cancer-specific, and overall survival. Randomized controlled trials (RCTs) have demonstrated that selenium and vitamin C supplements are ineffective in preventing incident prostate cancer and that vitamin E supplements potentially increase incident prostate cancer risk. A large RCT of a high vegetable diet intervention among prostate cancer patients on active surveillance, the Men's Eating and Living study, will soon complete analysis. An RCT for an exercise intervention among men with metastatic castrate-resistant prostate cancer is currently accruing.

Summary Although preclinical and observational studies have identified potential benefits for high vegetable, low fat, low meat diets, and increased exercise, Level I evidence is limited. To inform clinical care, future research should focus on RCTs evaluating clinical effectiveness.

Department of Urology, University of California, San Diego, California, USA

Correspondence to J. Kellogg Parsons, MD, MHS, Department of Urology, University of California, San Diego, 9500 Gilman Drive #0987, La Jolla, CA 92093, USA. Tel: +1 858 822 7874; e-mail: k0parsons@mail.ucsd.edu

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INTRODUCTION

Prostate cancer prevention seeks to contain costs and prevent morbidities associated with diagnosis and treatment. Prevention strategies target all stages of the disease process [1]. Interventions focused on primary prevention of prostate cancer aim to prevent incident disease. Secondary prevention involves screening for preclinical disease in an at-risk population. An example familiar to urologists is serum prostate-specific antigen (PSA) screening. Tertiary prevention aims to reduce disease progression or recurrence in patients with known disease. Many primary and tertiary prevention therapies focus on modifiable risk factors for disease, including nutrition, physical activity, and lifestyle.

The review summarizes the current state of clinical evidence for prostate cancer primary and tertiary prevention using diet, exercise, and lifestyle modification.

Box 1

Box 1

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DIET

Dietary recommendations for prostate cancer prevention closely mirror those for cardiovascular and overall health. They generally involve increasing vegetable and fruit intakes, whereas decreasing red meat and saturated fat intakes. Preclinical and epidemiological data support the benefits of these approaches. Randomized controlled trials (RCTs) do not support micronutrient supplementation for primary prevention; one RCT of tertiary prevention has results forthcoming.

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Primary prevention: macronutrients and energy balance

Data from preclinical studies have identified various pathways through which diet affects prostate cancer development. Investigators have linked carbohydrate resistance to prostate cancer incidence and progression. Ryan et al. [2] found that insulin growth factor-1 (IGF-1) receptor was expressed on normal prostate, localized prostate cancer, and metastatic foci; Lubik et al. [3] observed that IGF-2 was overexpressed in prostate cancer, with insulin-mediated activation leading to androgen receptor pathway activation. Taken together, these data offer a possible mechanism linking carbohydrate consumption with prostate cancer development.

Observational studies have similarly found diet to be associated with primary prostate cancer prevention. A meta-analysis evaluating the role of tomato and lycopene found a significantly reduced risk of incident prostate cancer associated with high intake of both raw [relative risk (RR) = 0.89; 95% confidence interval (CI) 0.8–1.00] and cooked (RR = 0.81; 95% CI 0.71–0.92) tomato products [4]. Similarly, in a meta-analysis of coffee intake, each three additional cups/day reduced the risk of fatal prostate cancer (RR = 0.89; 95% CI 0.82–0.97) [5]. Utilizing the Physicians’ Health Study (PHS), Yang et al. analyzed blood fatty acid levels in two patterns: polyunsaturated fatty acid metabolism and de novo lipogenesis [6]. Although the former was not significantly associated with prostate cancer risk, the latter was associated with increased incident prostate cancer [odds ratio (OR) = 1.63; 95% CI 1.04–2.55]. In 20 316 Hawaiian men, Le Marchand et al. [7] noted elevated risks of prostate cancer with higher beef (RR = 1.6; 95% CI 1.1–2.4), milk (RR = 1.4; 95% CI 1.0–2.1), and animal fat (RR = 1.6; 95% CI 1.0–2.4) consumption. Similarly, in a population-based case–control study, West et al. [8] reported a nearly three-fold increased risk for aggressive prostate cancer in men aged 68–74 years with higher dietary fat intake (OR = 2.9; 95% CI 1.0–8.4).

Cohort data also suggest that both positive energy balance and obesity as measured by BMI are associated with increased risks of aggressive disease. Among 280 000 men in the National Institutes of Health-American Association of Retired Persons Diet and Health Study (NIH-AARP), BMI more than 35 kg/m2 was positively associated with prostate cancer mortality (RR = 2.12; 95% CI 1.08–4.15, P = 0.02) [9]. Findings were similar among 141 895 men in the European Prospective Investigation into Cancer and Nutrition cohort, in which BMI was inversely associated with total prostate cancer risk but positively associated with high-grade and fatal disease [5th versus 1st quintile, hazard ratio (HR) = 1.32, 95% CI 1.01–1.72; HR = 1.35, 95% CI 1.09–1.68, respectively] [10▪]. In 2952 men from the UCSF Cancer of the Prostate Strategic Urologic Research Endeavor registry, overweight, obese, and very obese men had an increased risk of aggressive prostate cancer at time of diagnosis [11]. In the Cancer Prevention I, (n = 381 638) and II (n = 434 630) Studies, prostate cancer mortality was significantly higher for obese (BMI >30 kg/m2) than nonobese (BMI <25 kg/m2) men, and prostate cancer mortality was over 30% higher in the heaviest (BMI 18.50–22.99 kg/m2) compared with the leanest (BMI <18.50 kg/m2) men [12].

In contrast, BMI has been associated with a modestly decreased risk of incident prostate cancer. In a meta-analysis of 25 prospective studies, obesity was associated with decreased and increased risks of localized and advanced prostate cancer, respectively [13]. Higher BMI was also associated with a decreased total prostate cancer risk in the NIH-AARP and Health Professionals Follow-up Study (HPFS) cohorts [9,14]. Studies have consistently observed inverse associations of serum PSA with BMI [15–21]. Therefore, one interpretation of these data are that diminished PSA in obese men delays diagnosis relative to nonobese men, thereby leading to more advanced stages of disease and corresponding increases in prostate cancer mortality. A PSA-related delay in diagnosis would also potentially explain the decreased incidence of localized prostate cancer in obese men.

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Primary prevention: micronutrients and energy balance

Despite promising epidemiological evidence, two landmark RCTs failed to show benefit for micronutrient supplements in prostate cancer prevention [22–27]. The Selenium and Vitamin E Cancer Prevention Trial randomized 35 533 men with normal digital rectal examination and PSA less than 4 ng/ml to one of four daily interventions: placebo, selenium 200 μg, vitamin E 400 IU, or both [28]. The primary endpoint was incident prostate cancer. The study was terminated early because of futility, and extended follow-up analysis later noted a 17% increased risk of incident prostate cancer among the vitamin E alone arm (HR = 1.17, P = 0.008) [29]. In post hoc analyses, men with high baseline selenium experienced a 91% increased risk of high-grade prostate cancer with selenium supplementation (HR = 1.91; 95% CI 1.20–3.05, P = 0.008), whereas men with low baseline selenium experienced an increased risk of total and high-grade disease with vitamin E supplementation (HR = 1.63, P = 0.02; HR = 2.11, P = 0.008, respectively) [30]. The authors concluded that neither vitamin E nor selenium levels should exceed recommended daily requirements.

The Physicians’ Health Study II randomized 14 641 US male physicians into one of four arms: daily placebo, vitamin E 400 IU, vitamin C 500 mg, or both [31,32]. After 11.2 years mean follow-up, neither intervention demonstrated any effect on prostate cancer incidence.

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Tertiary prevention

Caloric intake, obesity, and energy balance may potentially affect prostate cancer progression. In an analysis of 82 men on androgen deprivation therapy (ADT) for recurrence after local therapy, the presence of metabolic syndrome upon ADT initiation – defined by modified Adult Treatment Panel-III criteria, which includes obesity defined by increased waist circumference – was associated with a 2.55-fold increased risk of PSA progression (P = 0.003) and a 2.65-fold increased risk of death (P = 0.045) after adjusting for covariates [33]. The authors also noted a 2.78-fold increased risk of PSA progression with BMI more than 30 kg/m2 (P = 0.003) – mirroring the increased risk of progression and death from high-risk disease in larger observational studies. Similarly, obesity has been associated with an increased risk of biochemical recurrence and decreased progression-free survival after radical prostatectomy [34–38] and radiation [39,40].

Dietary patterns after prostate cancer diagnosis appear to affect progression. Yang et al. stratified men in the PHS by intake of Western (high fat, meat, processed foods) and ‘prudent’ (high vegetable, fruit, fish, whole grains) diets and found that men with predominantly Western diets experienced higher prostate cancer specific (HR = 2.53; 95% CI 1.0–6.42, P = 0.02) and all-cause mortality (HR = 1.67; 95% CI 1.16–2.42, P = 0.01) compared with men with ‘prudent’ diets [41]. Similarly, Van Blarigan et al. [42] found an association of high saturated fat intake with all-cause and prostate cancer-specific mortality, whereas high vegetable fat intake was associated with decreased all-cause mortality. In 1000 men within the α-Tocopherol, β-Carotene Cancer Prevention Study, men in the highest quintile of vitamin D had a 28% reduced risk of prostate cancer death compared with the lowest quintile (HR = 0.72, 95% CI 0.52–0.99) [43].

Although there have as yet been no published RCTs of the effect of diet change on prostate cancer progression, the Men's Eating and Living Study is a multicenter RCT in which 478 men on active surveillance were randomized to a telephone-based diet intervention emphasizing high vegetable intake versus a control state [44▪▪]. The primary outcome is a composite endpoint of clinical progression as measured by total PSA, PSA doubling time, and pathology on repeat biopsy. Secondary endpoints include rates of definitive treatment, disease-related anxiety, and health-related quality of life. Follow-up completed in September 2017 and results are expected in 2018.

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PHYSICAL ACTIVITY

As with diet, physical activity recommendations for prostate cancer prevention mirror those for cardiovascular and overall health. Preclinical studies have suggested that exercise modulates tumor development through alteration of oxidative stress, whereas epidemiological and clinical data have shown improved prostate cancer outcomes with higher levels of exercise.

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Primary prevention

Preclinical studies have demonstrated a beneficial antioxidative effect of exercise on tumor development [45–49]. One model posited hydrogen peroxide as the primary regulator among numerous pathways contributing to prostate cancer proliferation (Ras, PI3-kinase, p53) [50]; exercise reduces intracellular levels of peroxide via its antioxidative effect, thus diminishing tumorigenesis [47,51,52]. Reviewing the biochemical changes after exercise, Thomas et al. [53] found direct effects of oxidative stress, IGF-1, chronic inflammation (interleukin-2, tumor necrosis factor, C-reactive protein, interleukin-6, prostaglandins), and heat shock proteins – all which have been implicated in cancer development – to be favorably modified after exercise.

Epidemiological studies have consistently demonstrated 10–30% decreased risks of incident prostate cancer with increased physical activity [54–57], including the HPFS, in which men more than 65-year old with the highest level of vigorous activity demonstrated a 67% reduced risk of advanced disease (P = 0.003) and a 74% reduced disease-specific mortality risk (RR = 0.26; 95% CI 0.11–0.66) [58].

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Tertiary prevention

Observational studies have also demonstrated a decreased risk of aggressive and fatal disease with increased physical activity. Arem et al. [59] found a pooled 11% decreased risk of overall cancer mortality among physically active patients within the NIH-AARP cohort (HR = 0.89; 95% CI 0.84–0.94, P < 0.001), but no significant difference in prostate cancer-specific mortality. In a meta-analysis, Friedenreich et al. [60▪] found a pooled 37% risk reduction in death from any cancer (RR = 0.63; 95% CI 0.54–0.73); they demonstrated a 38% prostate cancer-specific risk reduction (RR = 0.62; 95% CI 0.47–0.82). This meta-analysis drew from the HPFS, the Swedish National Prostate Cancer Register, and the Alberta Cancer Registry, each of which demonstrated an inverse association of physical activity with prostate cancer-specific mortality among men diagnosed with prostate cancer [61,62▪,63]. Among 957 prostate cancer patients followed for up to 17 years, increased postdiagnosis physical activity was associated with lower aggressive prostate cancer (HR = 0.64; 95% CI 0.43–0.95) and disease-specific mortality risk (HR = 0.67; 95% CI 0.48–0.94) [56].

Prospective interventions of physical activity for prostate cancer are limited. A pilot study to validate Fitbit as a tool to measure physical activity among men with localized prostate cancer has demonstrated this as a feasible tool [64▪▪]. Thus, a relatively low-cost intervention may be sufficient to measure physical activity, thus eliminating the confounder of self-reported activity upon which so much epidemiological data rests. A multinational RCT (Intense Exercise for Survival) is underway examining the effects of a 2-year structured exercise program in men with castrate-resistant prostate cancer, which may inform the clinical care of men with advanced disease [65▪▪].

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LIFESTYLE

Diet and exercise are inherently linked. As efforts to influence one will impact the other, it may be more appropriate to measure the impact of combined interventions. To this end, Kenfield et al. [66▪] proposed a lifestyle score for prevention of prostate cancer death, incorporating smoking cessation, physical activity, BMI less than 30 m/kg2, and a Mediterranean diet. Patients with higher scores had 68% decreased risk of death from prostate cancer (HR = 0.32; 95% CI 0.19–0.52) among HPFS men; a similar trend was observed among men in PHS.

Prospective interventions have replicated this effect. In the Prostate Cancer Lifestyle Trial, 93 men on active surveillance were randomized to an exercise, psychosocial, and nutritional intervention versus regular care; significantly fewer men in the intervention arm underwent treatment with surgery, radiation, or ADT after 2 years of follow-up [67]. The Gene Expression Modulation by Intervention with Nutrition and Lifestyle pilot study evaluated gene expression alterations of 30 men via prostate biopsy 3 months after an intensive nutritional and lifestyle (physical activity, stress management, psychosocial support) intervention [68]. Among this group, gene expression pathways with roles in tumorigenesis were significantly modulated, such that similar interventions may impact progression of prostate cancer. More studies are necessary to evaluate whether these effects can: be sustained for a longer duration, either at the gene expression level or via measureable physical and/or mental health outcomes; stand up to comparison with a control group; and be translated to measureable improvements in disease specific or overall survival.

Although affecting oncologic outcomes, lifestyle interventions may also ameliorate the physical and emotional burdens of prostate cancer. Among 440 men receiving radiotherapy for prostate cancer, increased physical activity was associated with significantly reduced side-effects (rectal symptoms, erectile, and urinary function, all P < 0.01); smokers and overweight men had significantly worse rectal symptoms (P < 0.001 and P < 0.05, respectively) [69]. Similarly, an HPFS analysis demonstrated significantly improved health-related quality of life scores among men with higher physical activity levels [70]. A trial of 121 men undergoing radiotherapy with or without ADT – randomized to 24 weeks of resistance training, aerobic exercise, or usual care – demonstrated short-term benefits of both regimens in reducing fatigue (the primary outcome), and more durable benefits for resistance training (P = 0.002) [71]. Other benefits accrued included improved quality of life (P = 0.015), strength (upper and lower body, P < 0.001), and preventing weight gain (P = 0.049).

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CONCLUSION

Despite the limited amount of high-quality data in support of diet, nutrition, and lifestyle factors in the prevention of incident, recurrent, or fatal prostate cancer, these interventions have been incorporated within clinical practice guidelines and patient-directed materials (https://www.pcf.org/) [72,73]. In part, this may reflect the limited number of modifiable factors affecting prostate cancer, as well as their minimal risks; certainly, the generalized benefits of nutrition and physical activity on cardiovascular and overall health support their inclusion within clinical practice.

Yet some aspects of the current evidence are wanting. First, numerous studies have drawn conclusions from relatively few observational studies; some of these findings may not be generalizable to the public. Second, the same data may be confounded by a reliance upon self-report, particularly because nutrition and physical activity are culturally biased toward overestimation. Third, there is a lack of high-quality level one evidence, with one completed RCT evaluating a nutrition intervention (results pending) and no RCTs of exercise. With increased utilization of active surveillance (newly recommended by updated American Urological Association guidelines), these cohorts of men could serve as a fertile ground for future investigative research [74].

Still, there are few – if any – disadvantages to encouraging healthy diets and increased exercise among patients. Urologists, and the medical community, would benefit the public health by encouraging their patients to adopt all of these choices, and thus improve their overall and prostate health Table 1.

Table 1

Table 1

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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A meta-analysis demonstrating improved survival among all cancers as well as in a substratified analysis of prostate cancer, showing a 38% decreased prostate cancer-specific mortality among men with increased physical activity.

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A prospective study with up to 17 year follow-up of 830 men with prostate cancer. The authors found a significant decrease in prostate cancer specific and overall mortality among men with increased physical activity; this was true when measuring postdiagnosis activity as well as pre and postdiagnosis physical activity.

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One of few prospective trials for physical activity and prostate cancer, this study demonstrates that the Fitbit could serve as a reliable measure of physical activity among men with prostate cancer.

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An ongoing multinational trial whose results could help to better characterize the role of exercise in advanced, aggressive prostate cancer.

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A unique composite analysis of the various lifestyle factors that can contribute to prostate cancer death. Using data from the HPFS and PHS, the authors developed a predictive score incorporating diet, physical activity, and smoking.

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Keywords:

lifestyle; nutrition; physical activity; prevention; prostate cancer

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