Data from the National Cancer Institute's (NCI) Prostate Cancer Prevention Trial (PCPT) published last week showed that a substantial number of men enrolled in the trial as controls were found to have prostate cancer despite consistently normal screening tests over the study period. The study results were published in the May 27 New England Journal of Medicine.

"This was the first systematic study of men with prostate-specific antigen (PSA) levels from 0 to 4.0 nanograms per milliliter (ng/ml)," said study leader Dr. Ian Thompson of the University of Texas Health Science Center in San Antonio. "It shows that cancer of the prostate can be present in men with 'normal' PSAs. The main study finding was that 15 percent of men in the PCPT control arm had a positive end-of-study biopsy despite having PSA levels below 4.0 ng/ml and normal digital rectal exams (DREs) throughout the study." Clinicians often use the value of 4.0 ng/ml or greater as the trigger for further investigation. A PSA level below 4.0 is generally considered normal.

The 2,950 men in the study were from the control arm of the PCPT, a 7-year NCI-funded trial evaluating the ability of the drug finasteride to prevent prostate cancer. The men received annual prostate screening with a PSA test and a DRE. All men entered the trial at age 50 or above, had initial PSA levels of 3.0 ng/ml or less, and a normal DRE. All were asked to undergo end-of-study prostate biopsy.

The study also found that 2.3 percent of men with PSA levels of 4.0 ng/ml or less had high-grade cancers. For men with a PSA of 2.0 or less, the chance of having a high-grade cancer was even lower - 1.4 percent. High-grade tumors often grow more quickly and may be more likely to spread than low-grade tumors.

"Although high-grade cancers are generally considered to be more aggressive, we need to remember that we really don't know the clinical significance of any of these cancers found in men with PSA levels below 4.0," said Dr. Howard Parnes, chief of the Prostate and Urologic Cancer Research Group in NCI's Division of Cancer Prevention.

Since the late 1980s, PSA tests have been widely used in the United States in an attempt to detect prostate cancer at an early stage. However, PSA testing has never been proven to reduce the risk of dying from prostate cancer. For this reason, NCI is currently funding a large clinical trial - the Prostate, Lung, Colorectal, and Ovarian Screening Trial - to determine whether early detection of prostate cancer through screening saves lives. In addition, not all prostate cancer detected by PSA screening is clinically relevant; therefore, screening carries the risk of overdiagnosing the disease, which may lead to unnecessary treatment. Thus, PSA testing is not a universally recommended screening procedure.

"This study tells us that there is no magic PSA level below which a man can be assured of having no risk of prostate cancer nor above which a biopsy should automatically be performed," says Dr. Parnes. "A man's decision to have a prostate biopsy requires a thoughtful discussion with his physician, considering not only the PSA level, but also his other risk factors, his overall health status, and how he perceives the risks and benefits of early detection."