© The Canadian Journal of Urology™; 19(Supplement 1); October 2012
29
PSA implications and medical management of prostate cancer for the primary care physician
Controversies in prostate cancer screening
The widespread introduction of PSA testing has
led to a significant migration in the prostate cancer
stage at diagnosis—a higher proportion of men are
being diagnosed at far earlier stages of the disease.
4
Often cancers diagnosed from this type of screening
carry little risk for mortality compared with other
potential causes of death such as cardiovascular
disease. The probability of “over-diagnosis” along
with the possibility of unnecessary, aggressive “over-
treatment” has resulted in the current prostate cancer
screening controversy. Overtreatment of clinically
and pathologically insignificant cancers has likely, to
a large extent, also contributed to the conflicting data
about survival benefits from screening.
The US Preventive Services Task Force (USPSTF)
released a recommendation statement for screening
for prostate cancer that was published in July 2012.
5
Prostate cancer screening was given a grade D
recommendation and the recommendation statement
effectively discouraged its use.
5
The main position
of the USPSTF is that PSA screening results in
overdiagnosis and that the potential harms related
to prostate cancer screening outweigh the potential
benefits.
This USPSTF recommendation statement, which
updates a previous version issued in 2008, asserts that
prostate cancer screening results in the detection of
many cases of asymptomatic prostate cancer, and that a
substantial percentage of menwho have asymptomatic
cancer detected by PSA screening have a tumor that
either will not progress or will progress so slowly that
it would have posed little threat as a competing risk
for mortality. The potential benefit of PSA screening
is the reduction in prostate cancer mortality 10 to 14
years later. On the other hand, the harms of screening
include pain, fever, bleeding, infection, and transient
urinary difficulties associated with prostate biopsy;
the psychological harm of overdiagnosis of indolent
disease; and the potential harms of treatment that
include erectile dysfunction and urinary incontinence.
Finally, USPSTF asserts that the inability to reliably
distinguish tumors that will remain indolent from
those destined to become lethal results in many men
being subjected to the harms of treatment for indolent
prostate cancer.
5
Evidence from screening trials
The results from two pivotal studies of prostate cancer
screening were published in 2009. The European
Randomized Study of Screening for Prostate Cancer
(
ERSPC) and the Prostate, Lung, Colon and Ovary
(
PLCO) trial of the National Cancer Institute were
poised to elucidate the role of PSA screening.
6,7
Unfortunately, their results have led tomore confusion
rather than clarity.
In the PLCO trial, 76,693 patients from 55 to 74
years of age were randomized to receive screening
versus no screening.
7
Randomization was performed
in blocks, and men were stratified by age and center.
Men in the investigation group received annual PSA
screening tests, and those in the control groupwere not
actively screened but some received screening outside
the trial, which resulted in significant contamination.
8
The primary study endpoint was cause-specific
mortality for prostate cancer. Data on cancer incidence,
cancer stage, and patient survival were collected for
secondary study endpoints. At the 10 year follow up,
there was no difference in mortality in the screened
group versus the control group. However, there
were a number of significant drawbacks and flaws
in the study design that may explain this outcome.
Contamination was a significant problem: 44% of the
study subjects had PSA screening before the study
(
they were “pre-screened”), and 52% of the men in the
control group had PSA testing performed outside of
the study, at the discretion of their treating physicians.
The ERSPC study was a randomized, multicenter,
multinational study of 182,160men aged 50 to 74 years.
6
The men were screened at 4 year intervals, except in
Sweden where they were screened at 2 year intervals.
A PSA level ≥ 4.0 ng/mL and an abnormal DRE were
initially considered as indications for prostate biopsy in
some centers; from 1997 on, all centers recommended
a biopsy to men presenting with a PSA value ≥ 3.0
ng/mL. Biopsies were carried out within the ERSPC
screening centers. The trial reported a 20% reduction
in prostate cancer deaths. It was estimated that at 9
years of follow up, to prevent one death from cancer,
1,410
men would need to be screened (number needed
to screen, NNS) and a further 48 would need to be
treated (number needed to treat, NNT). A 2 year
follow up study
9
reported that to prevent one death
from prostate cancer, the NNS was 936 and the NNT
was 33. Like the PLCO trial, the ERSPC trial had a
number of flaws. Screening practices varied across
different study locations. The centers used different
PSA thresholds for sending men for biopsies, and
different PSA screening intervals. Many men were
screened with intervals as long as every 4 years, which
is significantly different from current practice. In
addition, an estimated 20% of the control group was
contaminated by off-protocol screening.
Athird study fromGoteborg, Swedenwas reported
in the Lancet in 2010.
10
In that study, 20,000 patients
were randomized to an intervention (screening) group
