The New England Journal of Medicine
nengl 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 completion
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 current status of PSA screening and examine emerging 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 Cancer (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 currently undergoing routine review and updating).1 The 2012 statement applied to men in the general
U.S. population (excluding specific high-risk groups, such as men with known BRCA mutations). Over the next several years, other organizations and professional societies in North America issued guidelines either recommending against PSA-based screening in average-risk men or recommending some form of shared decision making about screening2-7 (Table 1). With respect to shared decision making, for example, the American
College of Physicians recommended discussing the benefits and harms of screening and
ordering screening only when the patient expresses a clear preference for it.
The above entities cited as the benefits of screening a reduction in prostate-specific mortality 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; specifically, 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 Force 1 Recommend against routine screening at any age 2012 Canadian Task Force on Preventive Health Care 2 Recommend against screening at any age 2014 American College of Preventive Medicine 3 Recommend against screening at any age 2016 American Academy of Family Physicians 4 Recommend against screening at any age 2012 American Urological Association 5 Implement shared decision making for men 55 to 69 yr of age and proceed on the basis of men’s values and preferences; recommend 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 by CHRIS SEMSARIAN on April 3, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
The New England Journal of Medicine
1286 n engl j med 376;13 nejm.org March 30, 2017
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, approximately
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 — specifically,
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 undergoing,
during the screening phase, a mean of
approximately five tests, as compared with three
tests for men in the control group.11 Nonetheless,
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 embracing
an unproven practice while hoping for support
from future clinical trials.
Large trials like the PLCO and ERSPC are difficult
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 treatments
across groups, even when cancer stage is
taken into account. This has been documented
and investigated by ERSPC researchers, who assert
that this imbalance was unlikely to account
for the lower mortality in the screened group.15,16
Having the ERSPC data also made widely available,
as a recent commentary has called for, would
allow outside researchers, for example, to perform
their own analyses of the potential implications
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 included
false positive tests and their downstream
sequelae, such as anxiety and complications of
diagnostic tests, including biopsy.1-6 In this respect,
PSA screening is similar to other cancer
screening methods. What distinguishes PSA testing
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 prostate
cancer. The incidence rose from approximately
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 continued
to be well above 150 through 2009.18 Data
from the ERSPC show approximately 35 overdiagnosed
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-
The New England Journal of Medicine
Downloaded from nejm.org by CHRIS SEMSARIAN on April 3, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
Sounding Board
n engl j med 376;13 nejm.org March 30, 2017 1287
nary incontinence and a 30-percentage-point increase
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 percentage
points, as well as to increase the risk of
bowel dysfunction.19 Active surveillance — also
known as active monitoring, a strategy of monitoring
and delayed initiation of curative treatment
— 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 wellestablished
harms. The recently completed randomized
Prostate Testing for Cancer and Treatment
(ProtecT) trial of treatment for localized
prostate cancer probably provides the most relevant
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 (primarily
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 monitoring
group (6%) than in the other groups (approximately
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 followup.
In addition, the definition of metastatic
progression included asymptomatic disease defined
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 relative
merits of active monitoring, it did confirm a
very high survival rate among men with localized
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. ProtecT
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 recent
USPSTF recommendation was published in
May 2012, with a draft report published in October
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 Another
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, Epidemiology,
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 populationlevel
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 challenge
is to analyze the results of this experiment
in terms of the effect of these changes on prostate
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 systemic
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 essentially
no change from 2005 to 2013 in the incidence
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 diagnosis
could be an early indicator of changes in
The New England Journal of Medicine
Downloaded from nejm.org by CHRIS SEMSARIAN on April 3, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
Th e new england journal o f medicine
1288 n engl j med 376;13 nejm.org March 30, 2017
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 distantstage
disease but not the occurrence rate of metastatic
disease. Unfortunately, however, those data
(on cumulative occurrence rates of metastatic
disease) are not currently available in SEER.
Prostate cancer mortality remains the most reliable
end point for which nationally representative
data are available. Note there is also a severalyear
lag in incidence from SEER and in national
mortality rates, which makes analysis of realtime
trends difficult.
It is tempting to use other data sources,
which may be available sooner, to assess the effects
of reduced screening. However, the potential
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 usefulness
and desirability of routine PSA-based screening
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” principle,
it seems reasonable to forgo mass screening
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, including
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 benefits.
Active monitoring may relieve some of the
burdens of overtreatment, but the required periodic
biopsies (if they are a component of the
surveillance strategy), the anxiety from delaying
treatment, and the high rate of eventually undergoing
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 associated
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 Institute,
National Institutes of Health, Bethesda, MD. Address reprint
requests to Dr. Pinsky at the National Cancer Institute,
9609 Medical Center Dr., Rm. 5E108, Bethesda, MD, 20892, or
at pp4f@
nih
.gov.
1. Moyer VA. Screening for prostate cancer: U.S. Preventive Services
Task Force recommendation statement. Ann Intern Med
2012; 157: 120-34.
2. Bell N, Connor Gorber S, Shane A, et al. Recommendations
on screening for prostate cancer with the prostate-specific antigen
test. CMAJ 2014; 186: 1225-34.
3. Livingston CJ, Freeman RJ, Mohammad A, et al. Choosing
Wisely in preventive medicine: the American College of Preventive
Medicine’s top 5 list of recommendations. Am J Prev Med
2016; 51: 141-9.
4. American Academy of Family Physicians. Prostate cancer:
clinical preventive service recommendation. 2012 (http://www
.aafp .org/ patient-care/ clinical-recommendations/ all/ prostate
-cancer .html).
5. American Urological Association. Early detection of prostate
cancer: AUA guideline, 2013 (https:/ / www .auanet .org/ education/
guidelines/ prostate-cancer-detection .cfm).
6. Wilt TJ, Harris RP, Qaseem A. Screening for cancer: advice
for high-value care from the American College of Physicians.
Ann Intern Med 2015; 162: 718-25.
7. National Comprehensive Cancer Network. NCCN clinical
practice guidelines in oncology: prostate cancer early detection,
version 2.2016 (https:/ / www .nccn .org/ professionals/ physician_gls/
pdf/ prostate_detection .pdf).
8. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and
prostate cancer mortality: results of the European Randomised
Study of Screening for Prostate Cancer (ERSPC) at 13 years of
follow-up. Lancet 2014; 384: 2027-35.
9. Andriole GL, Crawford ED, Grubb RL III, et al. Prostate cancer
screening in the randomized Prostate, Lung, Colorectal, and
Ovarian Cancer Screening Trial: mortality results after 13 years
of follow-up. J Natl Cancer Inst 2012; 104: 125-32.
10. Pinsky PF, Prorok PC, Yu K, et al. Extended mortality results
for prostate cancer screening in the PLCO trial with median
follow-up of 15 years. Cancer 2017; 123: 592-9.
11. Pinsky PF, Blacka A, Kramer BS, Miller A, Prorok PC, Berg C.
Assessing contamination and compliance in the prostate component
of the Prostate, Lung, Colorectal, and Ovarian (PLCO)
Cancer Screening Trial. Clin Trials 2010; 7: 303-11.
12. Shoag JE, Mittal S, Hu JC. Reevaluating PSA testing rates in
the PLCO trial. N Engl J Med 2016; 374: 1795-6.
13. Pinsky P, Prorok P. More on reevaluating PSA testing rates in
the PLCO trial. N Engl J Med 2016; 375: 1500-1.
14. Cancer Data Access System (CDAS) home page (https:/ /
biometry .nci .nih .gov/ cdas).
15. Bokhorst LP, Venderbos LD, Schröder FH, Bangma CH, Steyer-
The New England Journal of Medicine
Downloaded from nejm.org by CHRIS SEMSARIAN on April 3, 2017. For personal use only. No other uses without permission.
Copyright © 2017 Massachusetts Medical Society. All rights reserved.
Sounding Board
n engl j med 376;13 nejm.org March 30, 2017 1289
berg EW, Roobol MJ. Do treatment differences between arms
affect the main outcome of ERSPC Rotterdam. J Urol 2015; 194:
336-42.
16. Wolters T, Roobol MJ, Steyerberg EW, et al. The effect of
study arm on prostate cancer treatment in the large screening
trial ERSPC. Int J Cancer 2010; 126: 2387-93.
17. Haines IE, Ablin RJ, Miklos GL. Screening for prostate cancer:
time to put all the data on the table. BMJ 2016; 353: i2574.
18. Surveillance, Epidemiology, and End Results (SEER). Cancer
Statistics Review (CSR) 1975–2013 (http://seer .cancer .gov/ csr/
1975_2013/ ).
19. Chou R, Croswell JM, Dana T, et al. Screening for prostate
cancer: a review of the evidence for the U.S. Preventive Services
Task Force. Ann Intern Med 2011; 155: 762-71.
20. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year outcomes
after monitoring, surgery, or radiotherapy for localized prostate
cancer. N Engl J Med 2016; 375: 1415-24.
21. Drazer MW, Huo D, Eggener SE. National prostate cancer
screening rates after the 2012 US Preventive Services Task Force
recommendation discouraging prostate-specific antigen-based
screening. J Clin Oncol 2015; 33: 2416-23.
22. Jemal A, Fedewa SA, Ma J, et al. Prostate cancer incidence
and PSA testing patterns in relation to USPSTF screening recommendations.
JAMA 2015; 314: 2054-61.
23. Jemal A, Ma J, Siegel R, Fedewa S, Brawley O, Ward EM.
Prostate cancer incidence rates 2 years after the US Preventive
Services Task Force recommendations against screening. JAMA
Oncol 2016; 2: 1657-60.
24. Welch HG, Gorski DH, Albertsen PC. Trends in metastatic
breast and prostate cancer — lessons in cancer dynamics. N Engl
J Med 2015; 373: 1685-7.
25. Ruane-McAteer E, Porter S, O’Sullivan JM, Santin O, Prue G.
Active surveillance for favorable-risk prostate cancer: is there a
greater psychological impact than previously thought? A systematic,
mixed studies literature review. Psychooncology 2016 November
15 (Epub ahead of print).
DOI: 10.1056/NEJMsb1616281
Copyright © 2017 Massachusetts Medical Society.

Visit:

https://www.sophirisbio.com/patients/clinical-trials/

Clinical Trials

We have completed eight clinical trials of topsalysin (PRX302) – including a Phase 2a trial for the treatment of localized prostate cancer (PRX302-2-07) and a Phase 3 trial for the treatment of the lower urinary tract symptoms of BPH. In March 2017, we initiated a second Phase 2 clinical trial (PRX302-2-08) to confirm the dose and optimize the delivery of topsalysin for the treatment of clinically significant localized prostate cancer. We reported safety and biopsy findings from our Phase 2b clinical trial following a single administration of topsalysin. A single administration of topsalysin continues to appear to be safe and well-tolerated and demonstrated an ability to ablate prostate cancer tumor cells with 10/37 patients (27%) demonstrating a clinical response of which 6 were complete ablations. See additional details about this study below. In our completed PRX302-2-07 PCA trial, the one-time administration of topsalysin was well tolerated with no serious adverse events and no new safety signals being reported. Topsalysin demonstrated an ability to ablate tumor cells in over 60 percent six months after treatment in a patient population with pre-identified, clinically significant prostate cancer. In the PLUS-1 study, PRX302 demonstrated a favorable safety profile, with no evidence of any treatment related sexual or cardiovascular side effects. The Phase 3 trial achieved its primary endpoint — a single treatment with topsalysin demonstrated a statistically significant improvement in BPH symptoms over a 12 month period.

On-going Clinical Trials

Study	Phase	Trial Design
PRX302-2-08	Phase 2b – 38 patients	Phase 2b 6 to 12 month trial with topsalysin in patients who have histologically proven, clinically significant localized prostate cancer to confirm the dose and optimize the delivery of a single and potentially a second transperineal intraprostatic treatment of topsalysin

PRX302-2-08

In March 2017, we initiated a second Phase 2 clinical trial to confirm the dose and optimize the delivery of topsalysin for the treatment of clinically significant localized prostate cancer. This study utilizes previously obtained MRI images of each patient’s prostate mapped to real time 3D ultrasound to target the delivery of topsalysin directly into and around a pre-identified clinically significant tumor. The primary objective of the study is safety and tolerability of an injection of topsalysin and the key efficacy variable is focal ablation of a clinically significant lesion on biopsy after six months.

We have reported safety and biopsy findings from our Phase 2b clinical trial following a single administration of topsalysin. A single administration of topsalysin continues to be safe and well-tolerated and demonstrated an ability to ablate prostate cancer tumor cells with 10/37 patients (27%) demonstrating a clinical response of which 6 were complete ablations.

The Phase 2b prostate cancer clinical trial represents the first trial designed to allow qualified patients to receive a second administration of topsalysin six months after initial treatment. On December 17, 2018 we announced top-line safety and biopsy results from the ten patients who received a second administration of study drug, which appeared to be safe and generally well-tolerated. Additional benefit was not observed on targeted biopsy six months after re-treatment with a second administration of topsalysin. The decision to include a second administration of topsalysin in any future clinical studies is under review by the Company.

View Press Release »

In June, we were notified that a patient death occurred following administration of a second dose of topsalysin. In August, we announced that following a comprehensive review of the recently received autopsy report, together with hospital records and the negative serology results for acute hypersensitivity, the investigator and the Company believe that the cause of death is consistent with the autopsy finding of Sudden Cardiac Death (SCD) probably due to an arrhythmia. The autopsy found that the patient had multiple risk factors for SCD. The investigator and the Company concur that the event is unlikely related to the topsalysin or the procedure.

View Press Release »

Completed Clinical Trials

Localized Prostate Cancer

We have completed three clinical trials of PRX302 – including a Phase 2a trial for the treatment of localized prostate cancer (PRX302-2-07). Learn more about our completed clinical development in Localized Prostate Cancer and their trial designs below:

PRX302-2-07 | PCa

PRX302-1-02 | PCa

PRX302-1-01 | PCa

BPH

We have completed five clinical trials of PRX302 for the treatment of the lower urinary tract symptoms of BPH – including a Phase 3 trial l for the treatment of the lower urinary tract symptoms of BPH. Learn more about our completed clinical development in BPH and their trial designs below:

PLUS-1 | PRX302-3-01 | BPH

TRIUMPH | PRX302-2-03 | BPH

PRX302-2-06 | BPH

PRX302-2-01 | BPH & PRX302-2-02 | BPH

© Sophiris Bio Corp. 2019 All rights reserved

• Terms and Conditions