It is important that all men are counseled about the potential risks and benefits of prostate cancer screening so that they have a full understanding of what PSA screening can and cannot do.

However, we need smarter screening strategies that can allow us to screen more proficiently and increase the likelihood that a screen-detected cancer is one that really requires treatment.

A number of new approaches may allow us to improve screening sensitivity and specificity for prostate cancers that require closer monitoring and/or treatment. These approaches include obtaining a baseline PSA measurement at younger ages than currently practiced, using PSA velocity in younger men, the use of risk calculators, and new biomarkers.

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Two large studies published last year in The New England Journal of Medicine (2009;360:1310-1319 and 1320-1328) have fueled the debate about the true value of routine PSA screening for prostate cancer. Prior nonrandomized studies demonstrated that screening could result in a substantial clinical and pathologic stage migration to more favorable disease characteristics at presentation and result in a lower biochemical failure rate for a given tumor grade,stage, and PSA level. Many clinicians believe PSA screening has helped contribute to the drop in prostate cancer-related mortality over the past 15 years in the United States.

But does PSA screening really reduce the risk of prostate cancer-related death? To examine this question, investigators in the 1990s designed two studies, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)—a study conducted in the United States—and the European Randomized Study of Screening for Prostate Cancer (ERSPC).

In the PLCO study, investigators randomly assigned 76,693 men to undergo annual digital rectal examinations (DRE) for four years and annual PSA testing for six years, with biopsies recommended for men who had a PSA level greater than 4 ng/mL. At seven years, more prostate cancers were detected in those undergoing screening. 

However, researchers observed no differences in the likelihood of dying of prostate cancer between screened and nonscreened subjects. In ERSPC, researchers randomly assigned 162,387 men to receive screening or no screening. Again, more prostate cancers were diagnosed in those who underwent screening, but unlike in PLCO, the men who were assigned to routine PSA screening had a significant 20% reduction in the risk of dying of prostate cancer.

A number of reasons could explain the opposite conclusions from the two trials. One may be that routine screening in the general population was more widespread in the United States at the time these studies began. In fact, more than 40% of the men entering PLCO had already had a PSA test at least once in their lifetime. In addition, the intervals between PSA screenings differed in the trials.

In PLCO, men were screened every year while in ERSPC the men were screened less frequently. These differences suggest that the men in PLCO were at lower risk of developing prostate cancer and were subjected to a screening interval that is more likely to detect cancers that are not lethal.

Moreover, the PLCO trial had a more notable problem. More than half (52%) of the men who were assigned to the nonscreening arm actually had at least one PSA test during the course of the trial.  This makes the comparison between death rates in the two arms less meaningful since it was not a true test of screening compared with no screening.

It is widely accepted that PSA screening identifies many cancers that are not harmful and may not need to be treated. ERSPC results showed that it was necessary to screen 1,410 men and treat 48 with prostate cancer to prevent one prostate cancer-related death.

This finding highlights the biggest challenge for screening today, distinguishing at the time of diagnosis between cancers that are potentially lethal and require treatment and those that are not lethal and consequently need no therapy. Except for the highest grade tumors (which are a minority of newly diagnosed cancers), there is currently no physical exam, X-ray, blood test, or other test that can make this distinction.

As a result of this uncertainty, more than 90% of newly diagnosed prostate cancer patients in the United States choose immediate treatment rather than initial surveillance with treatment reserved for those whose tumors progress. Consequently, we have significant treatment-related morbidity and associated costs to patients and society.

Several new markers currently in clinical testing hold promise to meet this challenge. Unlike PSA, which is prostate specific but not prostate-cancer specific, PCA3 and TMPRSS2:ERG gene fusions appear to be cancer specific. By assaying for these markers in urine and post-prostatic massage urine samples, they can potentially add to the diagnostic accuracy of PSA and other risk factors while minimizing unnecessary biopsies. They are also under study to determine if they can help distinguish indolent from biologically significant cancers to help guide decisions on surveillance or therapy.

Primary chemoprevention

Given the limitations of current PSA screening paradigms, it makes sense that primary chemoprevention strategies are optimized to reduce morbidity and mortality associated with prostate cancer. Primary chemoprevention targets the general population of healthy adults and those at elevated risk for prostate cancer. The challenge is to find an intervention that has acceptable toxicity and cost. It is also paramount to identify subsets of men for whom chemoprevention is most appropriate and cost-effective.

Due to the often slow growth of prostate cancers, the molecular pathogenesis of it lends itself to potential primary prevention strategies. Studies suggest that prostate carcinogenesis is a multi-step process induced by both genetic and epigenetic changes.

These changes disrupt molecular pathways involved in cell proliferation, differentiation, apoptosis, and senescence. There are several precursor lesions for prostate cancer that have been described, such as high-grade prostatic intraepithelial neoplasia (HGPIN), proliferative inflammatory atrophy, and atypical small acinar neoplasia. These precursor lesions possess many genetic changes that are present in prostate cancer and represent intermediate stages between normal and malignant epithelium. 

The precursor lesions may appear as much as 20 years before the appearance of clinically evident cancer, suggesting that the development of prostate cancer may occur over a protracted time interval. Theoretically, this prolonged carcinogenesis provides an ideal opportunity to intervene before malignancy is established. Researchers have reported on, or are close to reporting on, a number of primary chemoprevention trials. Some results look promising, others look disappointing. However, some consensus on the use of 5-alpha reductase inhibitors is emerging and the data are fairly strong.

Unfortunately, the Physicians’ Health Study II and the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that neither selenium nor vitamin E was beneficial in combating prostate cancer. However, both the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial showed significant benefits with two different 5-alpha reductase inhibitors. The trials showed that men who took either of these agents had a similar reduction in prostate cancer risk (22% to 25%).

Over this past year, a secondary analysis of PCPT and the primary analysis of REDUCE showed that induction of high-grade disease is no longer a concern with the use of this class of medications. Data support recommending these agents to men at higher risk for prostate cancer because of family history or elevated PSA. Use of these agents, which are generally safe and have a very tolerable adverse effect profile, are especially useful in men who require treatment for lower urinary tract symptoms due to benign prostatic hyperplasia and patients who otherwise are concerned about their risk for prostate cancer.

This year, researchers are expected to report data from three large prostate cancer prevention trials evaluating the use of selenium (Southwest Oncology Group 9917), selenium, vitamin E, and soy protein (National Cancer Institute of Canada), and the estrogen receptor blocker toremifene.

Taken together, recent developments suggest that we may be at the start of a new era in the diagnosis and primary chemoprevention of prostate cancer.

Dr. Klein is Chairman of the Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio