Prostate cancer is a leading cause of cancer and cancer death in American men. For the year 2008, 186,000 prostate cancer cases were expected and 28,700 deaths due to this disease [1]. In the United States there is an overall 16.7% risk of developing prostate cancer [1] and early detection and treatment remain the primary focus for controlling the disease. More than 90% of men diagnosed with prostate cancer currently opt for treatment. This increasing incidence of prostate cancer, the morbidity and mortality of the disease and its treatments, combined with an improved insight into its biological basis and hormone dependency, have led to an increasing interest in chemoprevention strategies.

Chemoprevention refers to the use of agents to prevent cancer or the adverse outcomes of the disease. Multiple factors, including high incidence, long latency period between initial evidence of prostate cancer and the development of overt or lethal disease, and advanced age of onset and death [2,3], make prostate cancer an ideal target for chemoprevention strategies. Even a modest delay in development of symptomatic cancer may be sufficient to reduce the incidence of the disease, improve survival, and prevent the complications of the disease and the morbidity of its treatments.

This chapter reviews the evidence for the use of current chemopreventive agents in patients at risk for prostate cancer. We focus specifically on the risks and benefits of 5ARIs as there are no other effective agents that have undergone rigorous investigation with phase III randomized clinical trials with positive results. Grading of the quality of evidence and strengths of recommendations in this chapter are based on the guidelines proposed by the international Grading of Recommendations Assessment, Development, and Evaluation Working Group (Grade).

As our understanding of the pathogenesis of prostate cancer improves, an increasing number of risk reduction strategies are correspondingly being developed [4]. The focus of most treatment strategies for decreasing the risk of prostate cancer (primary prevention), slowing disease progression (secondary prevention) or delaying advancement in those in whom curative therapy has failed (tertiary prevention) is the androgen axis. Androgens are essential for prostatic development, growth, and function. Testosterone, after conversion to the more potent 5-alpha-dihydrotestosterone, controls prostate mitotic activity and potentially prostate carcinogenesis. Interventions that alter circulating androgen levels or inhibit 5-alpha-reductase have proven to have the most potential as preventive agents for prostate cancer.

Two 5ARIs, finasteride and dutasteride, are currently commercially available. Finasteride is selective for the type 2 isoenzyme, which reduces the level of dihydrotestosterone (DHT) by 65–70% [5]. Dutasteride inhibits both type 1 and type 2 isoenzymes and reduces the level of DHT by approximately 90% [6]. To date, one randomized trial assessing the influence of finasteride on the prevalence of biopsy-proven prostate cancer – the Prostate Cancer Prevention Trial (PCPT) – has been completed [7]. It is expected that a second phase III trial using the dual inhibitor dutasteride – the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial [8] – will report its results soon. The REDUCE trial is a multicenter, international study in which subjects are randomized to receive either dutasteride or placebo for a period of 4 years. Eligibility criteria include a serum prostate-specific antigen (PSA) of 2.5–10 ng/mL and a previous negative prostate biopsy within 6 months of randomization. The protocol requires prostate biopsies to be performed after 2 and 4 years of follow-up.

Literature search

A Medline literature search was performed to identify phase III clinical trials investigating prostate cancer chemoprevention. We used the search terms “prostate cancer,” “chemoprevention,” “prevention,” and “clinical trial.” All trials that met criteria were reviewed by the authors.

The evidence

The Prostate Cancer Prevention Trial (PCPT)

The primary objective of the PCPT was to determine if finasteride could reduce the period prevalence (defined as the sum total of prostate cancers diagnosed over a period of 7 years) of prostate cancer. A total of 18,822 men at least 55 years of age, with a normal digital rectal examination (DRE) and a baseline PSA level ≤ 3 ng/mL, were enrolled and randomly assigned to finasteride (5 mg per day) or placebo. Men were asked to continue this drug regimen for 7 years. Prostate biopsy was recommended if the subsequent annual PSA level, adjusted for the finasteride effect [9], exceeded 4 ng/mL or if a DRE was suspicious. The primary endpoint of the study was the prevalence of prostate cancer diagnosed by “for cause” biopsies or “end-of-study” biopsies during the 7-year study period. Originally, the authors of the PCPT reported that there was a 24.8% reduction in the incidence of prostate cancer from 24.4% with placebo to 18.4% in men treated with finasteride. The authors also noted that magnitude of the risk reduction did not differ according to PSA level, age, race/ethnicity or family history of prostate cancer [7].

The PCPT was closed more than a year earlier than planned because the primary study endpoint, a decrease in the prevalence of biopsy-proven prostate cancer in the finasteride arm, was achieved. However, based on the dataset frozen in March 2003, high-grade tumors of Gleason grade 7–10 were more common in the finasteride group than in the placebo group. This apparent increase in the incidence of high-grade prostate cancer prompted an intense debate within the urological community regarding the benefits of finasteride-based prevention of prostate cancer and resulted in a general lack of acceptance of finasteride for prostate cancer prevention. Subsequent analyses, which included all data through the day of the trial unblinding on 23 June 2003, yielded additional information that resulted in an observed overall risk reduction of 27% [10].

Pathological characteristics of the cancersin the PCPT

A major concern about early detection of prostate cancer by PSA and prevention by finasteride is the discovery of and responsibility to treat biologically inconsequential tumors that would not require treatment during a man’s lifetime. The commonly accepted pathological definition of a clinically insignificant tumor is an organ-confined, low-volume, and low-Gleason score tumor [11]. The most commonly used criteria for insignificant disease on biopsy proposed by Epstein are a combination of clinical factors (stage T1c and PSA density < 0.15 ng/mL/g), grade of tumor (Gleason score ≤ 6, with no Gleason 4 or 5), and extent of tumor (< 3 cores with tumor (no core with > 50% tumor) or < 3 mm cancer present in only 1 core) [11].

Lucia et al. [12] reviewed the pathological characteristics of prostate biopsies from men in the placebo and finasteride groups of the PCPT. These authors found that 75% of all cancers and 62% of Gleason score ≤ 6 cancers met the biopsy criteria for clinically significant tumors. In addition, surrogate measures for tumor volume, including volume of disease on biopsy, and risk of perineural invasion were lower in men who received finasteride. The risk of insignificant cancer at ranges of PSA were 51.7% (PSA 0–1.0 ng/mL), 33.7% (1.1–2.5 ng/mL), 17.8% (2.6– 4 ng/mL), and 11.7% (4.1–10 ng/mL). Conversely, the risks of high-grade tumors for the same PSA strata were 15.6%, 37.9%, 49.1% and 52.4%, respectively. This study revealed that only approximately 25% of detected tumors met the criteria for insignificance, a rate similar to the findings of the contemporary series of men who undergo treatment for their disease [13]. This analysis suggests that men who developed prostate cancer on finasteride had a lower tumor volume and decrease in aggressive features across all tumor grades as compared with the placebo arm. About two-thirds of all detected tumors and half of Gleason score ≤ 6, which finasteride is known to prevent, met the definition for clinical significance. Tumors among men treated with finasteride were smaller and has less extensive characteristics.

In an analysis from 2007, Lucia assessed whether the increased risk of high-grade prostate cancer associated with finasteride in the PCPT was due to an effect of finasteride on the interpretation of tumor grade as well as the impact of a change in prostate size with finasteride on accuracy of biopsy grading [14]. Prostate biopsies with Gleason score 8–10 were examined histologically for hormonal effects, and those with Gleason score 7–10 were examined for pathological surrogates of disease extent. Prostate volumes were measured at biopsy. Samples from radical prostatectomy (N 222, finasteride; N 306, placebo) were examined for tumor grade and extent. Grades at biopsy and prostatectomy were compared between the groups. The authors found that prostate volumes were lower in the finasteride group (25.1 cm3 versus 34.4 cm3) and that pathological surrogates for tumor aggressiveness were lower with finasteride than with placebo. Among patients who underwent prostatectomy, patients who received placebo had a significantly higher risk of upgrading on the prostatectomy specimen than those who received finasteride. This finding suggests (and has been supported by other similar observations) that the smaller gland size that resulted from finasteride treatment facilitated diagnosis of high-grade disease while patients who received placebo were more likely to have had a biopsy that missed the high-grade tumor. These results, in combination with the biopsy data finding less extensive tumors in patients treated with finasteride, suggested that high-grade cancer was detected earlier and was less extensive in the finasteride group than in the placebo group.

Finasteride increases sensitivity of PSA and DRE

Observations made after the PCPT suggested that the increase in high-grade disease in the finasteride group may have been secondary to detection bias rather than an actual alteration in the natural history of the disease [7]. In 2006, Thompson et al. examined the impact of finasteride on the sensitivity and area under the receiver operating characteristics curve (AUC) of PSA for detecting prostate cancer [15]. They compared the placebo and finasteride groups for sensitivity and AUC of PSA for the detection of all cancers and for high-grade cancers. The AUC of PSA for all outcomes was greater for the finasteride group than the placebo group. The sensitivity of PSA was higher for men in the finasteride group than in the placebo group at all PSA cut-offs matched by specificity.