S c re e n i n g fo r P ro s t a t e

Cancer
a,b,c d,
Sigrid V. Carlsson, MD, PhD, MPH , Andrew J. Vickers, PhD *

KEYWORDS
 Prostate cancer  Screening  Prostate-specific antigen  Biomarkers
 Magnetic resonance imaging

KEY POINTS
 Prostate-specific antigen (PSA) screening can reduce the risk of metastatic prostate can-
cer and death from the disease but is also associated with major harms, including over-
diagnosis and overtreatment, with concomitant urinary, sexual, and bowel dysfunction.
 Primary care physicians can follow 7 simple steps that will dramatically reduce the harms
of PSA screening while preserving its benefits.
 Patients need to be informed of the need for conservative management of low-grade pros-
tate cancer and referred to urologists who promote active surveillance.
 Primary care physicians need to develop relationships with urologists who advocate con-
servative approaches to biopsy and treatment.

INTRODUCTION
Epidemiology
Prostate cancer is a major public health problem across the globe. With 1.3 million
new cases and 359,000 deaths in 2018, prostate cancer is the second most com-
mon cancer and the fifth leading cause of cancer death in men worldwide. It is
the commonest cancer in men in more than half of the countries of the world
(105 of 185) and the leading cause of cancer death in men in 46 countries. The high-
est rates are seen in the Caribbean. Prostate cancer mortality has been decreasing

Funding: S.V. Carlsson’s and A.J. Vickers’s work was supported in part by funding from National
Institutes of Health/National Cancer Institute (P30 CA008748, P50 CA92629, U01 CA199338-02),
the Prevent Cancer Foundation, and Sidney Kimmel Center for Prostate and Urologic Cancers.
S.V. Carlsson is also funded by a National Institutes of Health/National Cancer Institute Transi-
tion Career Development Award (K22 CA234400).
a
Department of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New
York, NY, USA; b Department of Epidemiology and Biostatistics, Memorial Sloan Kettering
Cancer Center, New York, NY, USA; c Department of Urology, Institute of Clinical Sciences,
Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; d Department of
Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 485 Lexington
Avenue, New York, NY 10065, USA
* Corresponding author.
E-mail address: vickersa@mskcc.org

Med Clin N Am - (2020) -–-

https://doi.org/10.1016/j.mcna.2020.08.007 medical.theclinics.com
0025-7125/20/ª 2020 Published by Elsevier Inc.
2 Carlsson & Vickers

in many countries because of screening, early detection, and improved treatment

(eg, Northern America, Northern and Western Europe, Oceania, and developed
countries of Asia) but increasing in several countries (eg, Central and South America,
Central and Eastern European countries, many countries in Asia) possibly because
of changes in risk factors, a more Westernized lifestyle, and limited access to
treatment.1

Current Evidence for Prostate Cancer Screening

Localized prostate cancer is asymptomatic. By the time symptoms become present,
the disease is generally too advanced for cure. Indeed, one of the most common pre-
sentations of prostate cancer before the advent of screening was paralysis, related to
spinal cord metastasis. Therefore, the concept of screening is particularly appealing
for prostate cancer, because it provides an opportunity to identify the disease at a
curable stage. Research into a test that could detect prostate cancer earlier led to
the discoveries of the blood test prostate-specific antigen (PSA), first isolated and
defined in the 1970s.2–4 Several screening studies in the late1980s to early 1990s
showed that the PSA test could identify more prostate cancers at an organ-
confined, clinically localized stage as compared with evaluations for palpable tumors
by digital rectal examination, which set the stage for a widespread adoption of PSA
testing, particularly in the United States, resulting in a rapid surge in prostate cancer
incidence.5–10
There is level 1 evidence for PSA screening from large-scale randomized
controlled trials, comparing regular PSA screening of men aged 50 to 70 every 2
to 4 years with no invitation to screening. The European Randomized Study of
Screening for Prostate Cancer (ERSPC) reports a reduction in prostate cancer mor-
tality by 20% (rate ratio [RR] 0.80, 95% confidence interval [CI] 0.72–0.89, P<.001) at
16 years of follow-up in favor of screening.11 At this follow-up, the number needed to
invite to screening to prevent 1 prostate cancer death is reported to be 570, and the
number needed to diagnose is 18. The corresponding estimates from the Swedish
Göteborg-1 trial with 18 years of follow-up are a reduction in prostate cancer mortal-
ity of 35% (RR 0.65, 95% CI 0.49–0.87, P 5 .003). To prevent 1 death from prostate
cancer at 18 years, the number needed to invite to screening was 231, and the num-
ber needed to diagnose was 10. In contrast, at 17 years of follow-up in the US Pros-
tate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, there was no
significant difference in prostate cancer mortality between the screening arm
compared with the usual care arm (RR 0.93, 95% CI 0.81–1.08, P 5 .4).12 However,
this has been attributed to a high degree of contamination of PSA testing in the usual
care arm, with more than 50% of patients randomized to no screening nonetheless
undergoing PSA testing.13,14 Statistical models have been used to reconcile the dif-
ferences in implementation and settings and have reported that both trials provide
compatible evidence that screening reduces prostate cancer mortality: estimated
at 25%–31% in ERSPC and 27%–32% in PLCO, respectively.15 Similarly, there is
well-documented evidence from large, prospective observational studies regarding
the prognostic utility of measuring a man’s baseline PSA level in midlife to determine
subsequent risk of future life-threatening prostate cancer.16–21
The age-specific prostate cancer mortality in the United States is decreased by
50% from peak rates because of PSA screening and improvements in treatment,
but recently, this trend has been flattening because of recommendations against
PSA screening in previous years, mainly the 2012 US Preventive Services Task Force
guideline.10,22 Studies now document a recent increase in metastatic prostate
cancer.23–26
 Screening for Prostate Cancer 3

Controversies
PSA screening can have several beneficial effects. Most men have a “normal” PSA
value less than the cutoff for further evaluation, and up to 97% of men report some
reassurance with PSA screening.27 Screening can reduce a man’s risk of developing
metastatic prostate cancer and dying from the disease.11,28 For every prevented death
from prostate cancer, a life is lengthened by 8 years on average.29
However, screening can also induce many undesired effects, including anxiety from
false positive PSA tests and complications from further investigation with prostate bi-
opsy, including hospitalization for infectious complications or rectal bleeding.30 One
major harm of PSA screening is overdiagnosis, that is, the diagnosis of indolent,
slow-growing prostate cancer that would otherwise not be diagnosed during the
man’s lifetime.31–33 Indolent disease is typically defined in terms of cancer grade.
Gleason score 6, also termed grade group 1, is low-grade cancer that does not require
immediate treatment.34 High-grade disease, for which treatment should be consid-
ered, is defined as Gleason score 7 (grade group 2) or higher. Overdiagnosis turns
healthy men into patients, which may take its toll on psychological well-being and
quality of life.35,36 Most importantly, over the past 2 decades, most men with low-
risk prostate cancer in the United States underwent treatment with surgery and radi-
ation. Such overtreatment has no, or almost no, benefit in terms of mortality reduction
but leads to important and persistent side effects, most notably, urinary and erectile
dysfunction.37 In recent years, there has been a large shift in the treatment trends
with more than half of men with low-risk disease now being recommended what is
called active surveillance as the first management option, that is, careful monitoring
with repeated testing and examinations and a switch to curative treatment upon signs
of disease progression.38–40 Avoiding overtreatment of indolent prostate cancer is
crucial because active treatment with surgery, radiation, or ablative focal therapies
can have significant impact on men’s quality of life. Many years after treatment with
radical prostatectomy or radiotherapy for favorable-risk prostate cancer, significant
deterioration still persists in a substantial proportion of men in one or many functional
domains: sexual function, urinary function (incontinence), and bowel function.37,41
Modeling the lifetime effects of annual PSA screening between ages 55 and 69 versus
no screening, Heijnsdijk and colleagues29 estimated a loss of 23% of life-years gained
with screening, primarily because of impaired quality of life owing to long-term side
effects from treatment.

Current Guidelines
Table 1 gives a summary of examples of current PSA screening recommendations
from major guideline groups in the United States and Europe. The guidelines are
consistent in recommending shared decision making before starting screening and
that the age range for screening should be around 45 to 70. There is some minor vari-
ation in the starting age (45–55) and the criteria for an upper age limit. The proposal for
screening outlined in the clinical care points in later discussion is based on the Memo-
rial Sloan Kettering Cancer Center recommendations42 but are close to those of other
groups.

CLINICAL CARE POINTS

In later discussion, the authors propose 7 steps for primary care doctors42,43 (Box 1).
The authors’ proposal is based on the following principles. First, primary care is time-
pressured, and primary care physicians cannot be expected to have in-depth subspe-
cialty knowledge. Hence, the goal is to make shared decision making and the
4 Carlsson & Vickers

Table 1
Examples of current guidelines for prostate cancer screening in 2020

Guideline Group Reference, Year Age to Start Age to Stop

National Carroll et al,65 2019 40–45 75 (continue in
Comprehensive select cases)
Cancer Network
(NCCN)
Memorial Sloan Vickers et al,42 2016 45 60 for men with PSA
Kettering Cancer <1 ng/mL,
Center (MSK) otherwise 70
(continue based
on general health
and prior PSAs)
European Mottet et al,40 2020 50 <15-y life
Association of 45 if family history expectancy (stop
Urology (EAU)– or African based on life
European American expectancy and
Association of 40 if carrying BRCA2 performance
Nuclear Medicine mutations status)
(EANM)–
European Society
for Radiotherapy
& Oncology
(ESTRO)–
European Society
of Urogenital
Radiology (ESUR)–
International
Society of
Geriatric
Oncology (SIOG)
American Urological Carter et al,66 2013a 55 70 (or <10–15 y life
Association (AUA) expectancy)
US Preventive Force USPST et al,67 55 (shared decision 70 (recommends
Services Task Force 2018 making) against)
(USPSTF)
American Cancer Wolf et al,68 2010 50 (shared decision <10-y life
Society (ACS) making) expectancy

For additional examples of recommendations for PSA screening from various guideline groups,
please see recent comprehensive reviews.
a
Published 2013; Reviewed and validity confirmed 2018.
Data from Refs.69,70

subsequent screening algorithm relatively simple. Second, ensuring that PSA

screening does more good than harm is primarily a matter of making sure that it
does less harm: the recommendations reflect a “harm-reduction” approach. Third,
given that there is great variability within urology with respect to compliance with clin-
ical practice guidelines, the authors do make it incumbent upon primary care physi-
cians to check that any urologists to whom they refer patients are engaging in best
practices (described in points 5, 6, and 7).
1. Get consent for prostate cancer screening, preferably using the “Simple
Schema” decision aid.
 Screening for Prostate Cancer 5

Box 1
Key practice points for primary care physicians

1. Get consent for prostate cancer screening, preferably using the “Simple Schema” decision
aid.
2. PSA screening is only for healthy men aged 45 to 70.
3. Tailor screening frequency based on PSA level and cease screening for men older than 60
unless PSA is higher than median (1 ng/mL).
4. For men with elevated PSA (3 ng/mL), repeat PSA.
5. Use secondary tests, such as marker or imaging before biopsy, or only refer to urologists who
do so.
6. Only refer to urologists who recommend active surveillance to almost all patients with low-
grade cancer.
7. Preferably refer to urologists at major academic centers.

Prostate cancer screening is a preference-sensitive decision with important con-

sequences. As such, it is important to obtain informed consent from patients
following shared decision making. Although this only generally needs to occur
once, informed consent is required to enter into a screening regimen, not for
each and every PSA test, there are valid concerns as to the time required given
the constraints of a busy primary care practice. Some guidelines recommend
practices that are difficult to implement, such as one whereby patients are
informed about 16 separate facts on PSA and are asked 12 questions about
their preferences.44 The authors developed what is known as the “Simple
Schema”45 (Box 2) for primary care physicians, which does not require knowl-
edge above and beyond what any primary care physician would be expected
to know, is brief, and focuses on harm reduction. The critical step is to warn
patients about the risk that PSA screening will lead to the identification of
low-risk disease and the need to avoid aggressive treatment in such cases.
Early emphasis on active surveillance as the optimal management strategy
for low-risk disease is critical.
A common question among primary care physicians is whether they should more
strongly endorse PSA screening for men at higher risk, such as African Amer-
icans, or those with a family history or a genetic disposition. In brief, there is no
reason to think that the benefit-to-harm ratio of PSA screening varies suffi-
ciently for higher risk groups to mandate screening. Moreover, attempts to
tailor PSA screening based on genomic risk, what are known as “polygenic
risk scores,” have not shown clinical utility for population-based
screening.46–49
2. PSA screening is only for healthy men aged 45 to 70.
It is widely known that the introduction of PSA screening has led to widespread
overdiagnosis. What is less widely recognized is that overdiagnosis is highly
age dependent. Indeed, nearly half of the overdiagnosis associated with the
introduction of PSA testing occurred in men aged older than 70.50 Critically,
PSA testing is of doubtful value in men aged older than 70: the hazard ratio
for prostate cancer mortality for men older than 70 reported by the ERSPC
is 1.18 (95% CI 0.81–1.72), that is, likely no benefit and, at most, about a
20% reduction in the risk of death from prostate cancer.51 Hence, stopping
6 Carlsson & Vickers

Box 2
Decision aid for primary care physicians for shared decision making about prostate cancer
screening: the “Simple Schema”45

Key facts about prostate cancer and screening

 Prostate cancer is common: most men will develop it if they live long enough.
 Although only a small proportion of men with prostate cancer die of the disease, the best
evidence shows that screening reduces the risk for prostate cancer death.
 Screening detects many low-risk or “indolent” cancer cases.
 In the United States, most low-risk cancer is treated, and the treatment itself can lead to
complications, such as incontinence, erectile dysfunction, and bowel problems.
Key take-home messages
 The goal of screening is to find aggressive prostate cancer early and cure it before it spreads
beyond the prostate.
 Most cancer cases found by screening do not need to be treated and can be safely managed
by a program of careful monitoring known as “active surveillance.”
 If you choose to be screened, there is a good chance that you will be diagnosed with low-risk
cancer, and you may face pressure from your physicians or family to treat it.
Discrete decision
 If you are concerned that you would be uncomfortable knowing that you have cancer and
not treating it, screening may not be for you.
 If you are confident that you would only accept treatment for aggressive cancer and would
not be unduly worried about living with a diagnosis of low-risk disease, you are probably a
good candidate for screening.

Reproduced with permission from Vickers AJ, Edwards K, Cooperberg MR, Mushlin AI. A simple
schema for informed decision making about prostate cancer screening. Annals of Internal Med-
icine. 2014;161:441-442. https://www.acpjournals.org/doi/10.7326/M14-0151.

screening at 70 will have a large effect on overdiagnosis with little, if any, effect
on mortality. Note that by ceasing screening, it is meant that PSA tests are
generally discouraged in an asymptomatic man older than 70 with PSA levels
in the normal range (ie, <3 ng/mL). Follow-up of older men older than 70 with
PSA levels higher than 3 ng/mL is a matter of clinical judgment, taking into ac-
count the age and general health of the man (denoted “PSA surveillance”).52
Note also that it is reasonable to cease screening earlier than age 70 for
men who have important comorbidities or to continue screening in a 70 year
old in exceptional health.
As regards the starting age for screening, it has been shown at age 45, but not
before, it is possible to identify a subgroup of men who are at important risk
of prostate cancer morbidity or mortality within 10 years.21 The yield is rela-
tively low, that is, very few young men have an elevated PSA, and some com-
mentators have therefore made the reasonable suggestion that screening start
at 50 instead, based on this being the lowest age included in the ERSPC ran-
domized trial. On the other hand, because younger men have a longer life-
expectancy, they will lose a greater number of quality-adjusted life-years
from cancer-related death and are at low risk for overdiagnosis. It has also
been shown that, because PSA is a far stronger predictor of prostate
cancer–specific mortality than race or family history, age at the start of
screening should be the same for essentially all men.53
3. Tailor screening frequency based on PSA level and cease screening for men
older than 60 unless PSA is higher than median (1 ng/mL).
 Screening for Prostate Cancer 7

PSA is not only diagnostic of the current risk of prostate cancer but highly prog-
nostic of future risk.16–21 Moreover, because prostate cancer is generally slow
growing, screening intervals can safely be extended for men with low PSA.
There are clear data that men with a low PSA are highly unlikely to develop
aggressive prostate cancer within an 8- to 10-year period.20,21,54 This finding
has led to the “traffic light” algorithm as follows42:
 PSA less than 1 ng/mL: green light. Repeat PSA at a 8- to 10-year interval.
 PSA 1 to 2.99 ng/mL: amber light: Repeat PSA at a 2- to 4-year interval.
 PSA 3 ng/mL: red light. Consider further workup.
Fully 90% of prostate cancer deaths by age 85 occur in men with PSA above the
median of 1 ng/mL at age 60.20 It has also been shown that men with low PSA
who continue to get screened are at some risk of overdiagnosis but receive no
mortality benefit compared with if they had ceased screening.17,54 Hence, men
with PSA less than 1 ng/mL at age 60 should cease screening.
4. For men with elevated PSA (‡3 ng/mL), repeat PSA.
Many men will experience a temporary increase in PSA related to benign dis-
ease. For instance, in a landmark JAMA paper, 44% of men with PSA greater
than 4 and 40% of those with PSA greater than 2.5 returned to normal PSA
within 1 year.55 A typical recommendation is that PSA should be repeated 4
to 6 weeks after an abnormal PSA.
5. Use secondary tests, such as marker or imaging, before biopsy or only refer
to urologists who do so.
Only a small proportion of men with a moderately elevated PSA will have the sort
of high-grade prostate cancer that is important to identify. Typically, for every
100 men with PSA greater than 3 ng/mL, approximately 70%, 20%, and 10%,
respectively, will have benign disease, low-grade (indolent) prostate cancer,
and high-grade cancer. There are now a wide variety of secondary tests that
are available to determine which men with an elevated PSA should be subject
to prostate biopsy. These secondary tests, which include biomarkers as
shown in Table 2, as well as multiparametric MRI, have been shown to reduce
both unnecessary biopsies and overdiagnosis of indolent disease.56–58
Some of these tests can be implemented in the primary care setting. For
example, BioReference Laboratories offers a combined test for PSA, that is,
when a PSA test is selected, the blood sample is automatically checked for
the 4Kscore if PSA is elevated. However, in most cases, secondary tests,
particularly MRI, are ordered by the urologist As such, it is incumbent on the
primary care physician to develop a relationship with a urologist who takes a
conservative approach to biopsy, incorporating secondary tests and only con-
ducting biopsy on men shown to be at elevated risk of high-grade prostate
cancer.
6. Only refer to urologists who recommend active surveillance to almost all pa-
tients with low-grade cancer.
The major harm of PSA screening is overtreatment, with consequent urinary,
sexual, and bowel dysfunction.37 Guidelines suggest that treatment should
be restricted to men with high-grade disease. Men with Gleason score 6 (grade
group 1) cancer should be managed conservatively, with an approach known
as active surveillance, which involves PSA monitoring, repeat biopsies at reg-
ular intervals, and delayed intervention for men who progress to grade group 2
or higher disease. However, rates of active surveillance vary enormously be-
tween different practices: in 1 study, the proportion of low-risk men placed
on active surveillance ranged from 25% to 80%.59 As a result, the urologist
8 Carlsson & Vickers

Table 2
Reflex biomarkers recommended by the National Comprehensive Cancer Network Guidelines
v.2.2019 Prostate Cancer Early Detection

Initial Biopsy Repeat Biopsy

% free PSA % free PSA
Prostate Health Index (PHI) Prostate Health Index (PHI)
4Kscore 4Kscore
ExoDx Prostate (IntelliScore) ExoDx Prostate (IntelliScore)
PCA3
ConfirmMDx

Additional biomarkers (investigational): Michigan Prostate Score (MiPS), SelectMDx.

From Carroll P, Kellogg Parsons J, Andriole G, et al. NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines). Prostate Cancer Early Detection. V.2.2019. Available at: https://www.nccn.org/
professionals/physician_gls/pdf/prostate_detection.pdf. 2019. With permisison.

chosen by the primary care physician must take not only a conservative
approach to biopsy but also a conservative approach to treatment. The pri-
mary care physician needs to ensure that the urologist raises active surveil-
lance before biopsy and advises active surveillance to all, or nearly all, men
with Gleason score 6 (grade group 1) disease.
7. Preferably refer to urologists at major academic centers.
The volume-outcome relationship is one of the most widely replicated findings in
cancer medicine. In brief, both the chance of cure and the chance of side ef-
fects are strongly correlated with provider volume.60–63 In 1 study, the risk of
recurrence after prostate cancer was approximately half as great for surgeons
with 250 radical prostatectomies compared with those who only had experi-
ence of 10 prior cases.64 As such, primary care physicians should recommend
to patients who require treatment for their prostate cancer, patients with grade
group 2 or higher disease should be treated at a high-volume center. The
easiest way to ensure this is to refer patients to a hospital that is designated
by the National Cancer Institute as a Comprehensive Cancer Center (https://
www.cancer.gov/research/nci-role/cancer-centers).

SUMMARY

PSA screening can importantly reduce the risk of death from prostate cancer but is
also associated with major harms, overdiagnosis, and overtreatment, with attendant
urinary, sexual, and bowel dysfunction. Following a few simple steps can dramatically
reduce the risk of harm from PSA screening without materially reducing its benefits. In
particular, patients need to be informed repeatedly of the need for conservative man-
agement of low-grade prostate cancer and referred to urologists who promote active
surveillance. Primary care physicians need to develop relationships with urologists
who advocate conservative approaches to biopsy and treatment.

DISCLOSURE

A.J. Vickers is named on a patent for a statistical method to detect prostate cancer.
The patent application for the statistical model has been licensed and commercialized
as the 4Kscore by OPKO Diagnostics. A.J. Vickers receives royalties from sales of this
test and owns stock options in OPKO.
 Screening for Prostate Cancer 9

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