Prostate cancer screening with prostate‐specific antigen: Where are we going?

Stamey et al’s 1987 landmark publication correlating prostate cancer volume with prostate-specific antigen (PSA) values marked the start of the modern prostate cancer era. Stamey et al showed that PSA was elevated in men with newly diagnosed prostate cancer and that it increased with an advancing tumor stage and an increasing tumor volume. They also showed that PSA levels frequently fell to undetectable levels after radical prostatectomy and correlated with disease progression after surgery and radiation. They cautioned readers, however, that PSA was not specific for cancer and was elevated in 86% of men with benign prostate hypertrophy. Since then, PSA has become the most widely used tumor marker for prostate cancer. In 1991, Catalona et al published their analysis of 1653 healthy men aged 50 years or older who underwent testing for PSA. They concluded that PSA testing was superior to a digital rectal examination for finding prostate cancer and proposed PSA as a screening test. The underlying assumption behind their recommendation was that earlier detection of disease would allow earlier intervention, which in turn would save men from disease progression and prostate cancer mortality. Before this assumption could be tested, their recommendations were embraced by the US urologic community; this resulted in a tripling of the prostate cancer incidence in the ensuing 10 years. In 2004, Thompson et al published their extraordinary observation that low-grade prostate cancer was widely prevalent in men with PSA values less than 4.0 ng/mL, a value previously considered an appropriate cut point for justifying a prostate biopsy. In 1993, using a decision analysis similar to the technique used by de Carvalho et al, we modeled 3 treatment strategies for clinically localized prostate cancer: surgery, radiation, and active monitoring. We concluded that treatment offered limited benefit (measured as quality-adjusted life expectancy) for patients with low-grade tumors and likely harmed many patients. Patients aged 60 to 65 years with moderateor high-grade disease benefited from intervention only if the most optimistic assumptions of treatment efficacy were used. However, in most other cases, active intervention offered less than a 1-year improvement or an actual decrease in quality-adjusted life expectancy in comparison with active monitoring. Invasive treatment was harmful for men older than 70 years. These conclusions have since been validated by 3 randomized trials. Population-based case series data have helped us to understand the natural history of prostate cancer. In 2004, Johansson et al published a 21-year follow-up of a consecutive case series of 223 men presenting with clinically localized prostate cancer in 1977-1984. Most of these men presented with low-grade disease (148 men or 66%) or intermediategrade disease (66 men or 30%). Only 9 patients had high-grade disease; none were identified as a result of PSA testing. Johansson et al found that only 35 men (16%) died of prostate cancer. Most men died of competing medical hazards without evidence of disease progression. They concluded that only 8% of men, those with a potential survival longer than 15 years, would have benefitted from radical prostatectomy. In 2005, using data from the Connecticut Tumor Registry, we performed a retrospective population-based competing risk analysis of 767 men aged 55 to 74 years with presumed localized disease diagnosed in 1971-1984. We also concluded that men with low-grade cancers had minimal risk of disease progression during 20 years of follow-up and, therefore, were unlikely to benefit from treatment. More recently, reports from 2 randomized trials concerning PSA screening have provided additional insights into the PSA screening controversy. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was initiated in 1993 by the National Cancer Institute and randomized 76,683 men aged 55 to 74 years at 10 centers. The trial demonstrated