U.S. Cancer Screening Trial Shows No
Early Mortality Benefit from Annual Prostate Cancer Screening
annual screenings for prostate cancer led to more diagnoses of the
disease, but no fewer prostate cancer deaths, according to a major new
report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer
Screening Trial, a 17-year project of the National Cancer Institute
(NCI), part of the National Institutes of Health. The PLCO was designed
to provide answers about the effectiveness of prostate cancer
this report tells us is that there may be some men who are diagnosed
with prostate cancerand have the side-effects of treatment, such as
impotence and incontinence, with little chance of benefit," said Dr.
John E. Niederhuber, director of the NCI. "Clearly, we need a better
way of detecting prostate cancer at its earliest stages and as
importantly, a method of determining which tumors will progress. Many
of the molecular studies we're currently sponsoring will hopefully
yield new, better ways of definitively classifying which men need
treatment and which can consider watchful waiting. Until we have
developed and verified a new test's benefits and harms, as we have done
with the PLCO, regular visits to your doctor to monitor your health are
still strongly recommended."
appear online March 18, 2009, in the New England Journal of Medicine,
to coincide with presentation of the data at the European Association
of Urology meeting in Stockholm, Sweden. The print version of the
results will appear in the March 26, 2009 issue.
does not have a recommendation about prostate cancer screening. The
U.S. Preventive Services Task Force, whose recommendations are
considered the gold standard for clinical preventive services, recently
concluded that there is insufficient evidence to assess the balance of
benefits and harms of prostate cancer screening in men younger than age
75 and recommended against prostate cancer screening in men age 75 and
were 76,693 men in the PLCO trial that was conducted at 10 centers
around the United States. Of the men in the trial, 38,343 were randomly
assigned to screening with annual prostate-specific antigen (PSA) tests
for six rounds and digital rectal exams (DRE) for four rounds. A DRE is
an exam whereby a doctor inserts a lubricated, gloved finger into the
rectum and feels for anything that is not normal. The other 38,350 men
were randomly assigned to usual care, but received no recommendations
for or against annual prostate cancer screening.
those men who were screened annually, 85 percent had PSA tests and 86
percent had DREs. Men in the usual-care arm sometimes had these tests
as well, due to the growing public acceptance of such screening.
Screening by PSA in this usual-care group increased from 40 percent at
the beginning of the study to 52 percent of men by the last screening
year, and screening with DRE ranged from 41 percent initially to 46
percent by the last screening year. Men in the screening arm were
referred to their usual health care provider for follow-up testing for
prostate cancer if their PSA level was greater than 4.0 nanograms per
milliliter (ng/mL) or if a DRE found an abnormality.
report includes data for all participants at seven years after they
joined the trial and for 67 percent of participants at 10 years after
they joined the trial. Other important findings include:
seven years, 22 percent more prostate cancers were diagnosed in the
screening arm (2,820 men vs. 2,322 in the usual-care group). This
excess is continuing to be observed in data collected up to 10 years
(currently a 17 percent excess, 3,452 men vs. 2,974 men).
vast majority of men in both groups who developed prostate cancer were
diagnosed with relatively early stage II (out of IV stages, of which IV
is late stage) disease, and the number of later-stage cases was similar
in the two groups. However, using the Gleason scoring system,which
assesses tumor aggressiveness, men in the usual-care group had more
prostate cancers that fell into the Gleason 8 to10 range, which marks
them as more aggressive. The smaller number of men with prostate cancer
with a Gleason score of 8 to10 in the intervention group may eventually
lead to a mortality difference between men in the two groups but data
analyzed so far have not shown such a difference.
in both groups who were diagnosed with prostate cancer at the same
stage received similar treatments for their disease. This reflects the
PLCO study design policy of not mandating specific therapies.
seven years, 50 deaths were attributable to prostate cancer in the
screening group and 44 deaths were attributable in the usual-care
group. Through year 10, there were 92 prostate cancer deaths in the
screening group and 82 in the usual-care group. The difference between
the numbers of deaths in the two groups was not statistically
significant. Thus there was no detectable mortality benefit for
screening vs. usual-care.
the uncertainties about the mortality benefits of PSA testing, NCI has
been pursuing many avenues to find new ways of screening for prostate
cancer, including several sets of biomarkers that are being validated
in its Early Detection Research Network (EDRN), some using specimens
from PLCO's biorepository of tissue and blood. Some examples of the
marker tests include using microstrands of RNA to detect disease,
examining changes in genes such as GSTP1, and imaging of proteins in
prostate cancer tissue.
wants to understand why some prostate cancers are lethal even when
found early by annual screening, and what approaches can be used to
identify these more aggressive cancers when they can be effectively
treated," said Dr. Christine Berg, NCI leader of the PLCO
trial and senior author of the study. "The PLCO biorepository is an
invaluable resource for such research, with nearly three million
biological samples collected from our participants. Our hope is that
through all aspects of the PLCO, we will gather the information that
tells us whom to treat aggressively and whom to avoid overtreating."
report in this same online publication of the NEJM is from the large
European Randomized Study of Screening for Prostate Cancer (ERSPC),
which shows a 20 percent reduction in the rate of death from prostate
cancer but with a high risk of overdiagnosis. In the ERSPC, unlike the
PLCO trial, men were referred for follow-up testing if their PSA level
was 3.0 ng/mL or higher and were also screened, on average, every four
years as opposed to annually in the PLCO.
such as lowering the threshold for what is considered an abnormal PSA
level to 3.0 ng/mL will diagnose more cases, but it is not at all clear
that it will identify the prostate cancers that are more likely to lead
to a man's death," said Berg.
PLCO data are being made public now because the study's Data and Safety
Monitoring Board (DSMB), an independent review committee that meets
every six months, saw a continuing lack of evidence that screening
reduces death due to prostate cancer as well as the suggestion that
screening may cause men to be treated unnecessarily. The DSMB also
supports continued follow up of all participants so that every
participant is tracked for at least 13 years from entry onto thetrial.
PLCO is a large-scale clinical trial, sponsored and run by NCI's
Division of Cancer Prevention, begun in 1992 to determine whether
certain cancer screening tests can help reduce deaths from prostate,
lung, colorectal and ovarian cancer. The underlying rationale for the
trial is that screening for cancer may enable doctors to discover and
treat the disease earlier.
155,000 women and men between the ages of 55 and 74 have joined the
PLCO trial. At entry, participants were assigned at random to one of
two study groups: One group received routine health care from their
health providers. The other received a series of exams to screen for
prostate, lung, colorectal, and ovarian cancers. Screening of
participants ended in late 2006. Follow-up of participants is
anticipated to continue for several more years.
For more information on the National Cancer Institute, visit www.cancer.gov.