Screening cáncer próstata, nejm, marzo 2017

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The new engl and jour nal of medicine
n engl j med 376;13 nejm.org March 30, 2017 1285
Prostate Cancer Screening — A Perspective on the Current
State of the Evidence
Paul F. Pinsky, Ph.D., Philip C. Prorok, Ph.D., and Barnett S. Kramer, M.D., M.P.H.
After a quarter century of extensive screening for
prostate cancer with prostate-specific antigen
(PSA) in the United States, and after the comple-
tion of two major trials examining the effects of
such screening, the medical community is still
divided with regard to its effectiveness and its
benefits-to-harms ratio. Here, we review the cur-
rent status of PSA screening and examine emerg-
ing trends.
In 2012, after publication of the findings
from the major randomized trials of PSA-based
screening for prostate cancer — the European
Randomized Study of Screening for Prostate Can-
cer (ERSPC) and the Prostate, Lung, Colorectal,
and Ovarian Cancer Screening Trial (PLCO) —
the U.S. Preventive Services Task Force (USPSTF)
recommended against PSA-based screening for
prostate cancer (a recommendation that is cur-
rently undergoing routine review and updating).1
The 2012 statement applied to men in the gen-
eral U.S. population (excluding specific high-risk
groups, such as men with known BRCA muta-
tions). Over the next several years, other organi-
zations and professional societies in North Amer-
ica issued guidelines either recommending against
PSA-based screening in average-risk men or rec-
ommending some form of shared decision mak-
ing about screening2-7
(Table 1). With respect to
shared decision making, for example, the Amer-
ican College of Physicians recommended dis-
cussing the benefits and harms of screening and
ordering screening only when the patient ex-
presses a clear preference for it.
The above entities cited as the benefits of
screening a reduction in prostate-specific mor-
tality of approximately 1 death per 1000 men
screened (the USPSTF cited a range of 0 to 1 per
1000). This rate comes from the ERSPC; specifi-
cally, a difference in prostate cancer–specific
mortality of 1.3 deaths per 1000 men over 13
years of follow-up and a mean of approximately
two PSA screens among men in the screening
group.8
In contrast, the PLCO did not show a
reduction in prostate cancer–specific mortality;
in a recent update, the risk ratio was 1.04 for the
screened group versus the control group after a
Organization Recommendation Year
U.S. Preventive Services Task Force1
Recommend against routine screening at any age 2012
Canadian Task Force on Preventive Health Care2
Recommend against screening at any age 2014
American College of Preventive Medicine3
American Academy of Family Physicians4
American Urological Association5
Implement shared decision making for men 55 to 69 yr of age and
proceed on the basis of men’s values and preferences; recom-
mend against screening for other ages
2013
American College of Physicians6
Discuss benefits and harms for men 50 to 69 yr of age and order
screening only if clear preference is expressed for screening;
recommend against screening for other ages
2015
National Comprehensive Cancer Network7
Offer screening after a discussion of risks and benefits for men
45 to 75 yr of age; screening for men older than 75 yr should
be done cautiously and only in very healthy men
2016
Table 1. Recommendations on Prostate-Specific Antigen (PSA)–Based Screening for Prostate Cancer.
The New England Journal of Medicine
Downloaded from nejm.org on March 29, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.

n engl j med 376;13 nejm.org March 30, 20171286
median of 15 years of follow-up.9,10
The extent to
which the PLCO findings should be taken as
evidence against the efficacy of PSA screening
and how much its results should be “weighted”
relative to those from ERSPC are questions that
have been widely debated. Purely on the basis of
the relative number of prostate cancer deaths,
the PLCO would have roughly a one third weight
(to two thirds for ERSPC), under the assumption
that the trials were of similar quality (the 2012
USPSTF analysis rated both as “fair” quality).
The primary issue arguing for the PLCO weight
to be substantially downgraded is that of control
group “contamination” — that is, the use of PSA
testing in men in the control group. Estimates
from the PLCO show that during the course of
the trial, including the post-screening phase, ap-
proximately 85% of men in the control group
had undergone a PSA test at least once.10-12
Recently, a misconception has spread that in
the PLCO, the control group had more screening
than the intervention group. This has now been
clearly demonstrated to be untrue.10,13
Further,
the indirect evidence is compelling — specifi-
cally, a persistently higher incidence of prostate
cancer in the screened group than in the control
group, of 11% overall and 27% during the
screening phase of the trial, indicating more and
earlier screening in that group.10
In addition,
there are various metrics of intensity of PSA
screening, with men in the screened group un-
dergoing, during the screening phase, a mean of
approximately five tests, as compared with three
tests for men in the control group.11
Nonethe-
less, the level of contamination probably did
substantially reduce the statistical power of the
trial, and thus the negative trial result must be
viewed as providing only limited evidence of a
lack of a benefit of PSA screening with regard to
prostate cancer mortality, in concert with the
USPSTF assessment of strength of evidence from
the trial. An important point to note is that the
widespread promotion in the United States of PSA
screening before its effectiveness was proven
made conducting a randomized trial problematic.
This provides a cautionary lesson about embrac-
ing an unproven practice while hoping for sup-
port from future clinical trials.
Large trials like the PLCO and ERSPC are dif-
ficult undertakings, and neither trial is devoid of
flaws. The PLCO data, but not the ERSPC data,
have been made available to all researchers
through a data-sharing website.14
These data have
been used by non-PLCO researchers investigating
the contamination issue in the PLCO. An issue
that has been raised about the ERSPC and also
noted by the USPSTF is an imbalance in treat-
ments across groups, even when cancer stage is
taken into account. This has been documented
and investigated by ERSPC researchers, who as-
sert that this imbalance was unlikely to account
for the lower mortality in the screened group.15,16
Having the ERSPC data also made widely avail-
able, as a recent commentary has called for, would
allow outside researchers, for example, to per-
form their own analyses of the potential impli-
cations of treatment imbalances on the ERSPC
findings.17
When all these considerations are taken into
account, the estimate of approximately 1 prostate
cancer death averted per 1000 men screened
several times each and followed for 10 to 15 years
seems a reasonable summary of the evidence.
In any case, establishing whether there is any
benefit associated with PSA screening is only
one side of the equation. Harms associated with
the treatment of prostate cancer are common,
and the recommendations against screening
derive from the conclusion that the harms may
outweigh any likely benefits. Noted harms in-
cluded false positive tests and their downstream
sequelae, such as anxiety and complications of
diagnostic tests, including biopsy.1-6
In this re-
spect, PSA screening is similar to other cancer
screening methods. What distinguishes PSA test-
ing among cancer screening tests with respect to
harms is the extent of overdiagnosis of indolent,
nonlethal cancers combined with the frequency
and severity of side effects from the standard
therapies used to treat such cancers. As has been
well documented, the advent of PSA screening
created a pseudoepidemic of diagnoses of pros-
tate cancer. The incidence rose from approximate-
ly 135 (per 100,000) at the dawn of the PSA era
(1987 and 1988) to a mean of 220 in the period
1991 through 1993 (a 63% increase) and contin-
ued to be well above 150 through 2009.18
Data
from the ERSPC show approximately 35 over
diagnosed cases per 1000 men screened, which
amounted to 27 additional cases per prostate
cancer death averted.8
The USPSTF evidence review estimated that
radical prostatectomy was associated with a
20-percentage-point increase in the risk of uri-

Sounding Board
nary incontinence and a 30-percentage-point in-
crease in the risk of erectile dysfunction after 1 to
10 years.19
Radiation treatment was estimated to
increase the risk of erectile dysfunction by 17 per-
centage points, as well as to increase the risk of
bowel dysfunction.19
Active surveillance — also
known as active monitoring, a strategy of moni-
toring and delayed initiation of curative treat-
ment — has the potential to reduce the harms
of overdiagnosis while maintaining the benefits
of early detection.
An additional consideration in judging the
benefits-to-harms tradeoff is that many of the
harms are front-loaded, occurring much earlier
than benefits, which are delayed by years. That
raises the question of how long one must wait to
realize the benefits to counterbalance the well-
established harms. The recently completed ran-
domized Prostate Testing for Cancer and Treat-
ment (ProtecT) trial of treatment for localized
prostate cancer probably provides the most rele-
vant evidence from a population of men with
prostate cancer detected through screening. In
that trial, 1643 men who received a diagnosis of
prostate cancer after a one-time PSA screen were
randomly assigned to active monitoring (primar-
ily PSA monitoring), radical prostatectomy, or
radiation therapy.20
After a median of 10 years of
follow-up, prostate cancer–specific survival was
approximately 99% in all three study groups,
with no significant difference between groups
(although power was limited because of low event
rates). Through the 10-year follow-up period, 55%
of men in the active monitoring group received
curative treatment. A higher rate of metastatic
progression was observed in the active monitor-
ing group (6%) than in the other groups (approxi-
mately 3%), a difference that began to emerge
within 3 to 4 years. However, that difference did
not translate into a difference in prostate cancer
death rates, even after 6 to 7 more years of follow-
up. In addition, the definition of metastatic
progression included asymptomatic disease de-
fined by high PSA levels (>100 ng per milliliter)
or on the basis of imaging studies alone, so the
clinical significance of the metastatic disease
end point is unclear. Although the ProtecT trial
left some questions unanswered about the rela-
tive merits of active monitoring, it did confirm a
very high survival rate among men with local-
ized disease even without immediate curative
treatment, which suggests that any benefits of
early detection are likely to be far in the future;
in contrast, the harms tend to start early and
persist, especially in association with immediate
radical prostatectomy or radiation therapy. Pro-
tecT also highlighted the fact that a substantial
proportion of men undergoing active monitoring
still receive treatment at some point.
PSA testing rates have declined since the
USPSTF guidelines were released. The most re-
cent USPSTF recommendation was published in
May 2012, with a draft report published in Octo-
ber 2011. From 2010 to 2013, among men 50 to
59 years of age, screening rates decreased from
33.2% to 24.8%; among men 60 to 74 years of
age, rates decreased from 51.2% to 43.6%.21
An-
other study showed a decrease over the same
period from 37.8% to 30.8% among men older
than 50 years of age.22
This decrease in screening
was accompanied by a decline in prostate cancer
incidence. Data from the Surveillance, Epidemi-
ology, and End Results Program (SEER) show a
gradual decline in incidence from 2001 to 2011
of approximately 23% over the decade, followed
by a precipitous 20% decrease in 1 year from
2011 to 2012 and another small decrease (6%)
from 2012 to 2013.18
Therefore, these recommendations constitute
a “natural experiment” that reflects population-
level changes in PSA screening patterns. Because
of various gaps and delays in obtaining critical
data, however, as well as the extended time it
takes for prostate tumors to progress, the chal-
lenge is to analyze the results of this experiment
in terms of the effect of these changes on pros-
tate cancer mortality as quickly and accurately as
possible. Just as the decline of approximately
45% in U.S. prostate cancer mortality rates from
the late 1980s to the present has been analyzed
for its potential relationship to the rise in PSA
screening (with the findings equivocal because
of likely confounding by increasingly effective sys-
temic therapies), so any future trends in prostate
cancer mortality (and incidence) will be analyzed
for their relationship to decreasing PSA testing
trends.
A recent analysis of SEER data showed essen-
tially no change from 2005 to 2013 in the inci-
dence of distant-stage disease at diagnosis (among
men 50 to 74 years of age), although changes
could appear after more time has passed.23
Going
forward, rates of distant-stage disease at diagno-
sis could be an early indicator of changes in

n engl j med 376;13 nejm.org March 30, 20171288
mortality. However, early detection through PSA
screening could be resulting in the diagnosis of
prostate cancer in men at a time when they have
no evidence of distant disease but in whom,
because of micrometastases, clinically evident
distant disease will develop later, despite early
detection and treatment.24
In such a scenario,
screening would lower the incidence of distant-
stage disease but not the occurrence rate of meta-
static disease. Unfortunately, however, those data
(on cumulative occurrence rates of metastatic
disease) are not currently available in SEER.
Prostate cancer mortality remains the most reli-
able end point for which nationally representative
data are available. Note there is also a several-
year lag in incidence from SEER and in national
mortality rates, which makes analysis of real-
time trends difficult.
It is tempting to use other data sources,
which may be available sooner, to assess the ef-
fects of reduced screening. However, the poten-
tial for misinterpretation with such sources is
great. With less screening, indolent cases would
be expected to disproportionately decrease, since
those are the ones most likely to be detected
during screening. Accordingly, the proportion of
prostate cancers that are advanced would be
expected to increase, and therefore the mere fact
of such an increase is not meaningful.
That there is still no clarity about the useful-
ness and desirability of routine PSA-based screen-
ing after 25 years and two large trials suggests
that its net benefit is unlikely to be more than
marginal, whereas the harms are proven and
substantial. Under the “first do no harm” prin-
ciple, it seems reasonable to forgo mass screen-
ing as a public health policy at this point but to
continue to perform research on how to reduce
the harms of PSA screening while maintaining
any benefits. Some suggested modifications, in-
cluding screening less frequently (than annually)
and discontinuing screening for men with very
low PSA values, may decrease health care costs
and harms associated with false positive tests
while having a minimal effect on screening ben-
efits. Active monitoring may relieve some of the
burdens of overtreatment, but the required peri-
odic biopsies (if they are a component of the
surveillance strategy), the anxiety from delaying
treatment, and the high rate of eventually under-
going surgical or radiation treatment — with
their attendant side effects — are substantial
harms that are still incurred.25
There is a critical
need for strategies to reduce the burdens associ-
ated with the diagnosis of indolent disease,
through a combination of not diagnosing it in
the first place and accurately classifying it as not
needing any further follow-up or treatment, while
still maintaining any mortality benefits for men
with aggressive disease. Perhaps that is the most
pressing research challenge going forward.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the Division of Cancer Prevention, National Cancer Insti-
tute, National Institutes of Health, Bethesda, MD. Address re-
print requests to Dr. Pinsky at the National Cancer Institute,
9609 Medical Center Dr., Rm. 5E108, Bethesda, MD, 20892, or
at pp4f@nih.gov.
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DOI: 10.1056/NEJMsb1616281
Copyright © 2017 Massachusetts Medical Society.

Screening cáncer próstata, nejm, marzo 2017

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