News from the NCI

Men with low prostate specific-antigen (PSA) levels can still have prostate cancer, according to data from the Prostate Cancer Prevention Trial (PCPT), a Southwest Oncology Group (SWOG) study funded by the National Cancer Institute (NCI). In the PCPT, these prostate cancers were detected by biopsy in men with normal PSA levels. The report, published in the May 27 issue of the New England Journal of Medicine, focused on these men at low risk of having prostate cancer––the 2,950 men on the placebo arm who had normal digital rectal exams (DREs) and PSAs ≤ 4 ng/ml for the seven-year study duration.

"The good news is that the vast majority of these cancers were low and intermediate grade, which often are not clinically significant," noted Leslie Ford, MD, associate director for clinical research in NCI's Division of Cancer Prevention, who participated in the research.

"This was the first systematic study of men with PSA levels from 0 to 4 ng/ml. It shows that cancer of the prostate can be present in men with 'normal' PSAs," said Ian Thompson, MD, of the University of Texas Health Science Center at San Antonio, who led the study. A PSA level ≤ 4 ng/ml is generally considered normal; higher PSA levels are the trigger for further investigation, such as a prostate biopsy.

Since the late 1980s, PSA tests have been widely used in the US 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. Not all prostate cancer detected by PSA screening is clinically relevant and, therefore, screening carries a risk of "over-diagnosing" the disease, which could lead to unnecessary surgery or radiation therapy. Thus, PSA testing is not a universally recommended screening procedure. An ongoing NCI study is addressing the issue of whether PSA screening reduces the risk of death from prostate cancer.

Men in the control arm of the PCPT received a placebo rather than finasteride and, like the men on the finasteride arm, received annual prostate screening for seven years with a PSA test and a DRE. All men in the PCPT entered the trial at age 55 or above, had an initial PSA level ≤ 3 ng/ml and a normal DRE. All were asked to undergo an end-of-study prostate biopsy. "The main study finding was that 15% of the men in the control arm had a positive end-of study biopsy despite having PSA levels ≤ 4 ng/ml and normal DREs throughout the study," according to Dr. Thompson. Importantly, the study also found that only 2.3% of men in the control arm with PSA levels ≤ 4 ng/ml had high-grade cancers – Gleason score 7 to 10. For men with a PSA ≤ 2, the chance of having a high-grade cancer was even lower––1.4%. Gleason scores of the highest grades––8 or 9––were found in only 7 men, or 0.2% of men in the control arm. Most of the men with prostate cancer, 349 of them (78%), had Gleason scores of 5 or 6. "Most of these men would not have been diagnosed if they had not taken part in this study, since biopsies are not routinely performed in men with such low PSA levels. We need better methods to distinguish the harmless, slow-growing cancers from the more aggressive ones," emphasized Dr. Ford. "If more biopsies are performed at lower PSA levels, more cancers will be found and treated. But some men would undergo treatment, and the risks associated with it, for tumors that would never have been clinically significant."

Prostate cancer clinicians often say that men are much more likely to die with prostate cancer than from it. According to recent autopsy studies, many men over age 50 have early, undiagnosed prostate cancer. Clinicians concur that most early cancers remain harmless, though some may progress to clinically significant disease. "Lowering the PSA threshold for proceeding to prostate biopsy would increase the risks of overdiagnosing and overtreating clinically unimportant disease," noted Dr. Thompson. "There is a great need for methods, beyond tumor grade, to better predict which men have prostate cancers requiring treatment."