Men with low PSA (prostate specific antigen) levels on
screening tests can still have prostate cancer, according
to a study* 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, 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 nanograms per milliliter (ng/ml). It shows that
cancer of the prostate can be present in men with 'normal'
PSAs," said Ian Thompson, MD, 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% 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% 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% 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%. 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% of men in the PCPT
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," 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 is 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.
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* Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS,
Parnes HL, Minasian LM, Ford LG, Lippman SM, Crawford ED,
Crowley JJ, Coltman CA. Prevalence of Prostate Cancer among
Men with a Prostate-Specific Antigen Level = 4.0 ng per
Milliliter. New England Journal of Medicine, May 27,
2004; 350(22):2239-2246