Men with low PSA (prostate specific antigen) levels on screening tests can still have prostate cancer, according to a study* released today by scientists from the National Cancer Institute (NCI), part of the National Institutes of Health, and the Southwest Oncology Group, an NCI-funded network of researchers. In this study, prostate cancers were detected by biopsy in men with normal PSA levels.
"The good news is that the vast majority of these cancers were low and intermediate grade, which often are not clinically significant," said Leslie Ford, M.D., 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 nanograms per milliliter (ng/ml). It shows that cancer of the prostate can be present in men with 'normal' PSAs," said Ian Thompson, M.D., University of Texas Health Science Center at San Antonio, who led the study. Doctors often use the value of 4.0 ng/ml or greater as the trigger for further investigation, such as a prostate biopsy. A PSA level below 4.0 is generally considered normal.
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.
The 2,950 men in this study were from the "control arm" of the Prostate Cancer Prevention Trial (PCPT), an NCI-funded study that found in 2003 that the drug finasteride reduced by 25 percent a man's chances of getting prostate cancer.
Men in the control arm were given a placebo, or sugar pill, instead of finasteride and, like the men on the finasteride arm, received annual prostate screening for seven years with a PSA test and a digital rectal exam (DRE). All men in PCPT entered the trial at age 55 or above, had an initial PSA level of 3 ng/ml or less, and a normal DRE. All were asked to undergo an end-of-study prostate biopsy. The report released today focused on men at low risk of having prostate cancer––the 2,950 men on the placebo arm who had normal DREs and PSAs less than or equal to 4 ng/ml for the seven-year study duration.
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. 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.
"The main study finding was that 15 percent of the men in the PCPT control arm had a positive end-of study biopsy despite having PSA levels below 4 ng/ml and normal DREs throughout the study," said Thompson.
Importantly, the study also found that only 2.3 percent of men in the PCPT control arm with PSA levels of 4 ng/ml or less had high-grade cancers. For men with a PSA of 2 or lower, the chance of having a high-grade cancer was even lower––1.4 percent. Grade was measured by Gleason score, a system that ranks tumors from 2 to 10 based on their appearance under the microscope. High-grade tumors––Gleason scores of 7 to 10––often grow more quickly and may be more likely to spread than lower-grade tumors.
Gleason scores of the highest grades––8 or 9––were found in only seven participants, or 0.2 percent of men in the PCPT control arm. Most of the men with prostate cancer, 349 of them (78 percent), 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," said Ford.
"We need better methods to distinguish the harmless, slow-growing cancers from the more aggressive ones," continued 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."
Treatment for prostate cancer can sometimes lead to impotence, urinary incontinence, and other problems, causing a substantial health burden for men.
"Lowering the PSA threshold for proceeding to prostate biopsy would increase the risks of overdiagnosing and overtreating clinically unimportant disease," said Thompson.
NCI-funded researchers are looking for ways to determine which men harbor aggressive tumors. The NCI Early Detection Research Network (EDRN) has a Prostate Collaborative Group, which is applying a variety of strategies to find ways to detect prostate cancer early. Some scientists are using the new tools of genomics and proteomics to look at how gene expression patterns and proteins in the blood may differ in men with aggressive tumors vs. those with slow-growing ones.
"There is a great need for methods, beyond tumor grade, to better predict which men have prostate cancers requiring treatment," said Thompson.
Prostate cancer is the most common cancer in men, after skin cancer. It estimated that approximately 230,110 men in the United States will be diagnosed with the disease this year, and about 30,000 men will die from it.