U.S. Cancer Screening Trial Shows No
Early Mortality Benefit from Annual Prostate Cancer Screening
Six 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 screening.
"What this report tells us is that there may be some men
who are diagnosed with prostate cancer and have the side-effects
of treatment, such as impotence and incontinence, with little chance
of benefit," said John E. Niederhuber, M.D., 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."
Results 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.
NCI 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 older.
There 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
Of 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.
This 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
- At 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
- The 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.
- Men 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
- At 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.
Given 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.
"NCI 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 Christine Berg, M.D., 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."
Another 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
"Approaches 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.
The 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 the trial.
The 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.
Nearly 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.
A call-in teleconference will be held on Tuesday, March 17, 2009
at 12:00 p.m. (noon) EDT to discuss the implications of this finding
and to answer reporter questions about these results. This teleconference
is only for credentialed reporters who agree to abide by the embargo
policies of the NEJM. To register for the teleconference and receive
call-in information, please contact a NCI press officer at either
(301) 496-6641 or firstname.lastname@example.org by
9:00 a.m. EDT on Tuesday, March 17.
A Q&A on the prostate screening results from the PLCO is available
A new issue of NCI’s BenchMarks, related to cutting-edge prostate
cancer treatment issues, will be available March 19, 2009 at http://www.cancer.gov/newscenter/benchmarks-vol8-issue1.
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and their families, through research into prevention and cancer
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please visit the NCI Web site at http://www.cancer.gov or
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Reference: Andriole GL, Grubb RL, Buys SS, Chia
D, Church TR, Fouad MN, Gelmann EP, Kvale PA, Reding DJ, Weissfeld
JL, Yokochi LA, Crawford ED, O’Brien B, Clapp JD, Rathmell JM, Riley
TL, Hayes RB, Kramer BS, Izmirlian G, Miller AB, Pinsky PF, Prorok
PC, Gohagan JK, and Berg CD. Mortality Results from a Prostate-Cancer
Screening Trial. Online March 18, 2009. In print, March 26, 2009.
Vol. 360, No. 13. NEJM.