Can BPH and prostate cancer be prevented?

Benign prostatic hyperplasia (BPH) and prostate cancer are two of the most common and costly diseases of older men (J Urol 2005; 173:1309-13; J Urol 2005; 173:1256-61; J Urol 2011; 186:971-6; CA Cancer J Clin 2016; 66:7-30; Curr Opin Urol 2013; 23:331-6). While timely diagnosis and appropriate treatment are important strategies for mitigating morbidity and mortality, BPH and prostate cancer are also potentially preventable.

There are three basic types of disease prevention: primary, secondary, and tertiary (figure). Primary prevention refers to the prevention of incident disease in at-risk populations. A common example is childhood immunization. Secondary prevention is reducing the burden of a disease through population screening and treatment of pre-clinical conditions. Examples include prostate-specific antigen (PSA) screening for prostate cancer and blood glucose screening for type 2 diabetes. Finally, tertiary prevention focuses on diminishing the risk of recurrence or progression in patients with clinical disease. An example is bacillus Calmette–Guérin (BCG) therapy after transurethral resection in patients with high-grade, nonmuscle-invasive bladder cancer.

This review focuses on primary prevention of BPH and prostate cancer.  

Next: Prevention of BPH

Prevention of BPH

Scientific data support two strategies for BPH prevention: modulation of lifestyle factors (table 1) and pharmacologic 5α-reductase inhibition (5-ARI).

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Obesity. Increased body weight, body mass index, and waist circumference have been associated with increased prostate volume as measured by ultrasound and magnetic resonance imaging(Curr Opin Urol 2014; 24:10-4; J Clin Endocrinol Metab 2006; 91:2562-8). Obesity has also been associated with increased risks of symptomatic BPH, lower urinary tract symptoms (LUTS), and BPH surgery in studies involving thousands of U.S., Chinese, and European men (Curr Opin Urol 2014; 24:10-4).

Diabetes. Diabetes mellitus (DM), increased serum insulin, and elevated fasting plasma glucose have been associated with increased prostate volume and increased risks of prostate enlargement, BPH, BPH surgery, and LUTS in studies cumulatively including tens of thousands of men (J Clin Endocrinol Metab 2006; 91:2562-8; Curr Opin Urol 2011; 21:1-4).

Physical activity. Exercise has been associated with decreased risks of BPH surgery, clinical BPH, histologic BPH, and LUTS (Curr Opin Urol 2014; 24:10-4; Eur Urol 2011; 60:1173-80). A meta-analysis of studies involving a total of 43,083 men indicated that moderate to vigorous physical activity reduced the risk of BPH or LUTS by as much as 25% relative to a sedentary lifestyle, with the magnitude of the benefit increasing with higher levels of activity (Eur Urol 2008; 53:1228-35).

Diet. Red meat, fat, milk and dairy products, cereals, bread, poultry, and starch increase BPH and LUTS risks; vegetables, fruits, polyunsaturated fatty acids, linoleic acid, vitamin A, and vitamin D potentially decrease those risks.

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In addition, higher circulating concentrations of vitamin E, lycopene, selenium, and carotene have been associated with decreased risks of BPH, as has moderate alcohol consumption (Curr Opin Urol 2014; 24:10-4;J Urol 2009; 182:1463-8).

Next: Saw palmetto, finasteride, dutasteride

Saw palmetto. The most recent Cochrane systematic reviews of randomized clinical trials of the herb Serenoa repens (Saw palmetto) for the treatment of BPH and LUTS concluded that it does not decrease LUTS, diminish nocturia, improve urinary flow parameters, or reduce prostate size (Curr Opin Urol 2014; 24:10-4). The most common commercialized extract of Saw palmetto used in these trials was Permixon.

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Finasteride and dutasteride. Finasteride (Proscar) and dutasteride (Avodart) are 5-ARIs that block the conversion of testosterone to dihydrotestosterone (DHT). DHT is a potent androgen that promotes prostate growth and is an essential component of BPH pathogenesis (J Urol 2004; 172[4 Pt 1]:1399-403). In asymptomatic older men, high serum DHT and DHT metabolite concentrations have been associated with an increased risk of incident BPH (Am J Epidemiol 2008; 168:1416-24; J Urol 2010; 184:1040-4.).

In a secondary analysis of asymptomatic men in the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the incidence of BPH by 40%. The number needed to treat (NNT) to prevent one BPH case ranged from 58 for men aged 55-59 years to 31 for men aged 65 and older. These NNT data are comparable to published NNT guidelines for aspirin, statins, diuretics, and β-blockers for the primary prevention of cardiovascular disease (Eur Urol 2012; 62:234-41). These findings were later validated in a similar post-hoc analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, in which dutasteride was associated with a 41% reduced risk of incident BPH (BMJ 2013; 346:f2109).

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Interestingly, obesity attenuates the efficacy of both finasteride and dutasteride for preventing BPH (Eur Urol 2012; 62:234-41; European Urol 2013; 63:1115-21), possibly through epigenetic regulation of the 5α-reductase gene (J Urol 2015; 194:1031-7).

Next: Prevention of prostate cancer

Prevention of prostate cancer

Epidemiologic data suggest many of the same lifestyle factors associated with BPH risk-including obesity, exercise, and diet-also display the same risk patterns for prostate cancer (Eur Urol 2012; 61:560-70). Unlike BPH, however, there have been several randomized chemoprevention trials for prostate cancer. These trials have included two types of agents: vitamin supplements and 5-ARIs (table 2).

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Vitamin supplements have consistently proven ineffective. However, two randomized trials have demonstrated the efficacy of 5-ARIs in reducing prostate cancer risk.

Selenium and vitamin E. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a randomized, placebo-controlled trial of prostate cancer prevention in a general population. SELECT was the largest cancer prevention trial yet undertaken, involving over 35,500 men. The primary endpoint was incident prostate cancer, and there were four study arms: placebo, selenium, 200 μg alone; vitamin E, 400 IU alone; and both selenium and vitamin E.

Over a 7-year study period, there was no benefit observed from selenium, vitamin E, or the combination. Moreover, with additional follow-up, a slightly increased risk of incident prostate cancer was observed in the vitamin E alone group. These data led to the conclusion that selenium and vitamin E supplementation add no protective benefit for prostate cancer and that vitamin E may potentially increase the risk for some patients (Curr Urol Rep 2016; 17:35).

Vitamin C. Another randomized, phase III, placebo-controlled trial of micronutrients was the Physicians Health Study II (PHS II). PHS II was a study of over 14,000 male physicians older than 50 years who were randomized to vitamin E, 400 IU; vitamin C, 500 mg; or placebo. Over an 8-year study period, neither vitamin C (p=.8) nor vitamin E (p=.6) reduced the risk of incident prostate cancer (Curr Urol Rep 2016; 17:35).

Finasteride. The Prostate Cancer Prevention Trial (PCPT) was a randomized controlled trial of finasteride for the prevention of incident prostate cancer. The PCPT recruited over 18,000 men who were at least 55 years old with a normal digital rectal exam (DRE) and PSA levels ≤3 ng/mL. These men were randomized to receive finasteride, 5 mg daily, or placebo for 7 years. They underwent annual PSA/DRE screening and for-cause prostate biopsies for PSA ≥4 ng/mL or abnormal DRE; those participants who did not undergo for-cause biopsy underwent biopsy at study completion.

An independent data safety monitoring board ended the study 15 months prior to planned completion. Prostate cancer was diagnosed in 18.4% of the men on finasteride compared to 24.4% of controls, a 25% decreased risk (p<.001). Although higher grade (Gleason sum ≥7) disease occurred more frequently in the finasteride group as compared to the control group (6.4% vs 5.1%, p<.001), a post hoc analysis suggested that the increased detection of Gleason ≥7 disease in the finasteride cohort resulted from a diagnostic bias associated with finasteride-induced prostate volume reductions (Curr Urol Rep 2016; 17:35).

Dutasteride. Dutasteride inhibits 5a-reductase types 1 and 2, resulting in greater reductions in DHT than finasteride (Prostate Cancer Prostatic Dis 2007; 10:149-54), although the clinical significance of this difference remains unclear. The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study tested the efficacy of dutasteride to prevent cancer in 8,000 men at relatively high risk for it: inclusion criteria included PSA 2.5 to 10 ng/mL in men aged 50 to 60 years and prostate biopsy within 6 months of enrollment that was negative for cancer, high-grade prostatic intraepithelial neoplasia, and atypia. Participants underwent PSA screening every 6 months, for-cause prostate biopsies as clinically indicated, and planned prostate biopsies at 24 and 48 months.

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After 48 months, 19.9% of dutasteride patients had been diagnosed with prostate cancer, compared to 25.1% of placebo patients, a 22.8% relative risk reduction (p<.001). There was a significant difference in the number of high-grade tumors diagnosed (p<.003).

Next: Summary

Summary

While familiarity with these concepts is important, practical applications of these data to urologic practice currently remain unclear for at least three reasons. First, Level I (i.e. randomized controlled trial) evidence of lifestyle modulations to prevent BPH and prostate cancer are lacking. That is, although epidemiologic evidence points to links between lifestyle and prostate disease, there is no direct evidence that lifestyle changes will prevent BPH or prostate cancer.

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Second, since weight loss, diet, exercise, and other lifestyle measures do not typically fall within the purview of urologic practice, it is unlikely that urologists will oversee such interventions independent of other physicians.

Finally, although there are robust data demonstrating the efficacy of 5-ARIs to prevent clinically significant BPH and prostate cancer, routine use of 5-ARI therapy for prostate disease prevention in asymptomatic men is a controversial topic that lacks both FDA approval and consensus of opinion in the urologic community.

Still, it is perfectly reasonable to counsel patients that the same lifestyle interventions that prevent cardiovascular disease may also prevent prostate disease. It may also be worthwhile to discuss 5-ARI data with men who are concerned about and/or at higher risk for prostate cancer-namely, African-Americans and those with a strong family history.

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