Chemoprevention

Currently, the most promising agents for the prevention of prostate cancer are the 5-a-reductase inhibitors, finasteride and dutasteride7,10,11 These medications work by inhibiting 5-a-reductase, an enzyme that converts testosterone to its more active form, DHT, which is involved in prostate epithelial proliferation. There are two types of 5-a-reductase, type I and type II; both are implicated in the development of prostate cancer. Finasteride selectively inhibits the 5-a-reductase type-II isoenzyme, whereas dutasteride inhibits both isoenzymes.11 Both finasteride and dutasteride falsely lower the PSA in patients and this needs to be adjusted for when measuring the PSA in patients on these medications.7,11

The Prostate Cancer Prevention Trial (PCPT) compared finasteride 5 mg daily for 7 years to placebo for the prevention of prostate cancer. When compared to placebo, the point prevalence of prostate cancer was reduced for those on finasteride by 24.8% (95% confidence interval [CI] 18.6-30.6%) (hazard ratio 0.75). However, in those that did develop prostate cancer, there was an increase in the number of high-grade (Gleason grade 7-10) tumors detected at biopsy in the finasteride group. Overall, finasteride did reduce the frequency of prostate cancer; however, the prostate cancers that were diagnosed in the finasteride group were more aggressive.

The use of finasteride to prevent prostate cancer is the subject of a recent joint consensus statement. The American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) used the results from a systematic review of the literature to develop evidence-based recommendations for the use of 5-a-reductase inhibitors for prostate cancer chemoprevention. 5-a-reductase inhibitors decrease the period prevalence of for-cause prostate cancer by approximately 26% (relative risk 0.74; 95% CI, 0.67-0.83). The absolute risk reduction is about 1.4% (4.9% in controls versus 3.5% in the treatment arms), although this may vary with the age of the treated population. On the basis of these outcomes, ASCO and AUA recommend that asymptomatic men with a PSA less than or equal to 3 ng/mL, who are regularly screened with PSA, may benefit from a discussion of both the benefits of 5-a-reductase inhibitors for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer). Men who are taking 5-a-reductase inhibitors for benign conditions such as lower urinary tract symptoms may benefit from a similar discussion, understanding that the improvement of symptoms should be weighed with the potential risks of high-grade prostate cancer.

Selenium and vitamin E alone or in combination were evaluated in the ¿e/enium and Vitamin E C ancer Prevention Trial (SELECT), a clinical trial investigating their effects on the incidence of prostate cancer. The data and safety monitoring committee found that after 5 years selenium and vitamin E taken alone or together did not prevent prostate cancer. On the basis of these data and safety concerns, the trial was halted.1 Other agents, including vitamin D, lycopene, green tea, nonsteroidal anti-inflammatory agents, isoflavones, and statins, are under investigation for prostate cancer and show promise; however, none are currently recommended for routine use out-

side of a clinical trial. Screening

Early detection of potentially curable prostate cancers is the goal of prostate cancer screening. For cancer screening to be beneficial, it must reliably detect cancer at an early stage, when intervention would decrease mortality. Whether prostate cancer screening fits these criteria has generated considerable controversy.1 Digital rectal examination (DRE) has been recommended since the early 1900s for the detection of prostate cancer. The primary advantage of DRE is its specificity, reported at greater than 85%, for prostate cancer. Other advantages of DRE include low cost, safety, and ease of performance. However, DRE is relatively insensitive and is subject to interobserver variability. DRE as a single screening method has poor compliance and had little effect on preventing metastatic prostate cancer in one large case-control study.15

Pmstale-spec,f,c a,,„ge„ ,s a „sefil marker for de,ec,mg pros,ate ca„cer a, early stages, predicting outcome for localized disease, defining disease-free status, and monitoring response to androgen-deprivation therapy or chemotherapy for advanced-stage disease. PSA is used widely for prostate cancer screening in the United States, with simplicity as its major advantage and low specificity as its primary limitation.16 PSA may be elevated in men with acute urinary retention, acute prostatitis, and prostatic ischemia or infarction, as well as BPH, a nearly universal condition in men at risk for prostate cancer. PSA elevations between 4.1 ng/mL (4.1 mcg/L) and 10 ng/mL (10 mcg/L) cannot distinguish between BPH and prostate cancer, limiting the utility of PSA alone for the early detection of prostate cancer. Additionally, only

38% to 48% of men with clinically significant prostate cancer have a serum PSA out-

side the reference range.

Neither DRE nor PSA is sensitive or specific enough to be used alone as a screening test. Although the relative predictability of DRE and PSA is similar, the tumors identified by each method are different. Catalona and associates18 confirmed that the combination of a DRE plus PSA determination is a better method of detecting prostate cancer than DRE alone.

The common approach to prostate cancer screening today involves offering a baseline PSA and DRE at the age of 40 with annual evaluations beginning at the age of 50 to all men of normal risk with a 10-year or greater life expectancy. Men with an increased risk of prostate cancer, including men of African American ancestry and men with a family history of prostate cancer, may begin screening earlier, at age 40 to 45.

Despite this common practice, the benefits of prostate cancer screening are un-proven.19 PSA measurements can identify small, subclinical prostate cancers, where no intervention may be required. Detecting prostate cancer in those not needing therapy not only increases the cost of care through unnecessary screening and workups but also increases the toxicity of therapy, by subjecting some patients to unnecessary 20 21

therapy. Currently, the American College of Physicians recommends that rather than screening all men for prostate cancer as a matter of routine, physicians should describe the potential benefits and known risks of screening, diagnosis, and treatment, listen to the patient's concerns, and then decide on an individual's screening method.

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