Download PSA based screening reduces the rate of prostate cancer death by

e d i t o r i a l
PSA based screening reduces the rate
of prostate cancer death by 20%
A uthors
H. Van Poppel, C. Bangma
Key words
Prostate cancer, PSA screening
Summary
Recently The New England Journal of Medicine
recently published two original articles on
screening for prostate cancer. Both were randomized studies, one performed in the US and
Introduction
The US study, the Prostate, Lung, Colorectal, and
Ovarian (PLCO) Cancer Screening Trial ran from
1993 through 2001 in 10 US study centres. About
67,700 men were randomized to receive either annual screening or usual care and a PSA of ≥ 4.0ng/
ml indicated prostate biopsy. After 7 to 10 years of
follow up, the rate of death from prostate cancer did
not differ significantly between the 2 study arms.
The European Randomized study of Screening for
Prostate Cancer (ERSPC) randomized more than
160,000 men, aged 55 to 69 years. Prostate biopsy
was performed when the PSA was ≥ 3.0ng/ml and
the study showed a clearly reduced rate of death
from prostate cancer by 20%.
Discussion
In the same journal both articles were discussed by
Dr. M.J. Barry under the title: “Screening for prostate cancer: the controversy that refuses to die”.3
Since, many experts have attempted to bring correct information in the lay press using the stronger
or weaker points of both studies to defend or destroy the usefulness of PSA based prostate cancer
screening. This is obviously bringing more confusion to our healthy male population. On the 3rd of
April, the American Urological Association (AUA),
reacted on the internet by saying that these studies
cannot lead to the conclusion that PSA screening
should be abandoned and that PSA testing remains
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published by Andriole et al the other performed
in Europe and published by Schröder et al.1,2
Both studies yielded conflicting data concerning PSA screening and prostate cancer drugs.
(BJMO 2009;Vol 3;5:209-211)
a valuable screening tool and should be appropriately offered to men. “Prior to the use of the PSA
test, tumors were found mostly in advanced, and
less treatable, stages giving patients far fewer options for treatment. It is the opinion of the AUA
that the PSA test is a valuable screening tool that
saves lives and men with concerns about elevated
PSA scores should consult their urologist about
next steps.”
Prof. Dr. Chris Bangma, chairman of the Department of Urology at the university of Rotterdam
(successor of Prof. F.H. Schröder, first author of the
ERSPC study), therefore wrote to the general practitioners and urologists in the Netherlands about
what has become a Europe vs. US debate. In terms
of a football game one seems to be at a 1-1 draw
and this is indeed translated in the lay press as a
continuity in the doubt about reduced mortality
by PSA screening. Therefore some clarification is
needed.
What are the conditions for a good screening study
on cancer mortality? Mainly, there are four points
that are critically important to successfully run a
randomized study in the population:
1.Clean inclusion: at the start of the study the participants may not have been examined for the
disease under study.
2.Good compliance: sufficient number of participants are needed that strictly follow the complete protocol.
3.Few contamination: the participants in each
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Key messages for clinical practice
1. The ERSPC study has undoubtedly shown that PSA screening and prostate biopsy at PSA
≥ 3,0ng/ml reduces prostate cancer mortality by 20%.
2.The PLCO study, in which the rate of death from prostate cancer did not differ significantly
between patients who underwent yearly PSA screening and patients who underwent usual care
after 7 to 10 years of follow up, is qualitatively to poor to ever be able to show a difference,
even with a longer follow up time.
3.Many experts today will look at PSA velocity in younger patients and consider age related PSA
values instead of working with fixed PSA thresholds to trigger prostate biopsies.
arm need to comply with the protocol and not
switch to the other study arm.
4.Long follow up: participants need to be followed
up sufficiently long in order to reach the aimed
endpoint.
In the PLCO study, these 4 points are under considerable threat:
1.At initiation, there was no exclusion of participants that already had a PSA testing before. It is
therefore possible that the participating population was already cleaned from a number of prostate cancers or cleaned from men with a very
low PSA that found the need of a second screening superfluous. In the PCLO study 43 % of men
had already undergone 1 or more PSA testings
before inclusion in the study. In the ERSPC trial
men were not allowed to participate when they
had previously undergone PSA testing.
2.In the PCLO study, about 40% of men with a
PSA ≥ 4.0ng/ml followed the protocol and underwent a biopsy as prescribed. So there was
protocol violation in 60% of the cases. The compliance in the ERSPC protocol was about 90%.
3.In both randomized studies men in the control
arm should not undergo PSA testing. In the
PLCO study 52% of the patients in the control
arm still got PSA testing, while in the screening arm this was 85%. Understandably this
high rate of contamination in the control group,
because of an abuse of PSA testing in the US,
made it about impossible for PLCO with 77,000
participants to ever give an answer to the question whether prostate cancer mortality is reduced by PSA testing. With a difference in PSA
testing of only 33% between the 2 arms in the
PLCO study this could have been foreseen. In
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the ERSPC study this difference is about 80%.
When the European study was designed and the
power calculation was done the fact of contamination was already taken into account. Because
of a much lower PSA use in Europe in the initial
phase of the ERSPC trial, this low level of contamination had no influence on the outcome of
the trial.
4.The PLCO study has a follow up of only 7 years
and this is too short to show a difference in
mortality. The authors of the PLCO study also
acknowledge this fact. Because of larger numbers in the European study this difference could
indeed be shown after 9 years.
All the above mentioned reasons are the main
causes why the PLCO study could not come to a
positive difference but also shows that the study is
qualitatively poor to ever be able to show a difference, even with longer follow up.
For the European researchers it is clear that the
PLCO study cannot contribute to a solution of the
question whether screening can decrease prostate
cancer mortality. More importantly the analysis of
quality of life gain by the reduced cancer specific
mortality will be most important. Indeed, despite
the fact that the screening effect (prevent one cancer death by screening 1,400 men) is comparable
with effects described for screening in breast and
colon cancer, the over-diagnosis of insignificant
tumors is much higher for prostate cancer.
Over-diagnosis is not a correct wording since a
cancer that is present cannot be ‘over’diagnosed.
The real problem is that a certain amount of insignificant cancers are still treated by radical prostatectomy, external beam radiotherapy or interstitial
radiotherapy, while if they were left untreated it is
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very likely that they would never harm the patient.
If this problem of overtreatment would not exist,
nobody would continue to discuss the fact whether
PSA based prostate cancer screening is useful.
The ERSPC study has undoubtedly shown that PSA
screening and prostate biopsy at PSA ≥ 3.0ng/ml
reduces prostate cancer mortality by 1/5. Many
urologists today will not any longer use a certain
PSA cut off to trigger prostate biopsies. Many experts today will look at PSA velocity in younger
patients and consider age related PSA values. If
this would have been done in the screening study,
the reduction in prostate cancer mortality would
even have been more pronounced.
Prostate cancer research should now focus on
how to distinguish significant and insignificant
cancers, give more space to active surveillance in
order to differentiate between indolent and life
threatening cancers. Once this issue is solved, the
controversy about prostate cancer screening will
have died.
References
1. GL Andriole, RL Grubb, SS Buys, et al. Mortality results from
a randomized prostate-cancer screening trial. N Engl Med
2009;360;1310-1319.
2. FH Schröder, J Hugosson, MJ Roobol, et al. Screening and
prostate-cancer mortality in a randomized European study. N
Engl J Med 2009;360;1320-1328.
3. MJ Barry. Screening for prostate cancer – The controversy
that refuses to die. N Engl J Med 2009;360;1351-1354.
Correspondence address
Authors: H. Van Poppel 1 and C. Bangma 2
1
University Hospitals Leuven, Department of Urology,
Herestraat 49, 3000 Leuven, Belgium;
2
Erasmus MC University Medical Centre Rotterdam,
Dept. of Urology, Rotterdam, The Netherlands
Please send all correspondence to:
Prof. Dr. H. Van Poppel
Department of Urology
University hospitals Leuven
Herestraat 49
3000 Leuven
Belgium
[email protected]
Conflicts of interest: the authors have nothing to
disclose and indicate no potential conflicts of interest.
For you and your patient:
Multidisciplinary National Cancer Guidelines,
established by the College of Oncology in collaboration with the KCE are accessible at :
www.guidelinescancer.be
www.richtlijnenkanker.be
www.recommandationscancer.be
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