EUROPEAN UROLOGY 68 (2015) 179–182

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Platinum Priority – Brief Correspondence

Editorial by Sigrid V. Carlsson and Peter C. Albertsen on pp. 183–184 of this issue

Differences in Treatment and Outcome After Treatment with

Curative Intent in the Screening and Control Arms of the
ERSPC Rotterdam

Leonard P. Bokhorst a,*, Ries Kranse b, Lionne D.F. Venderbos a, Jolanda W. Salman a,
Geert J.L.H. van Leenders c, Fritz H. Schröder a, Chris H. Bangma a, Monique J. Roobol a,
for the ERSPC Rotterdam Study Group
a b
Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands; Netherlands Comprehensive Cancer Organization, Utrecht,
The Netherlands; c Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands

Article info Abstract

Article history: Screening for prostate cancer (PCa) results in a favorable stage shift. However, even if
Accepted October 4, 2014 screening did not result in a clinically apparent lower stage or grade, it might still lead to
less disease recurrence after treatment with curative intent (radical prostatectomy [RP]
and radiation therapy [RT]) because the tumor had less time to develop outside the
Keywords: prostate. The outcome after treatment could also differ because of variations in treat-
Prostatic neoplasms ment quality (eg, radiation dosage/adjuvant hormonal therapy). To test these hypothe-
Prostate-specific antigen ses, we compared differences in the treatment quality of the screening and control arms
of the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam
Screening
and disease-free survival (DFS) after curative treatment in PCa patients with similar
Radical prostatectomy stage and grade. A total of 2595 men were initially treated with RP or RT. In the control
Radiotherapy arm, RT was more often combined with hormonal therapy; treatment dosage was often
Cure rates 69 Gy. This most likely resulted from changes over time in treatment that coincided
with the later detection in the control arm. DFS was higher in the screening arm in all risk
groups. After correction for lead time, these differences were minimal, however. We
concluded that treatment quality differed between the screening and control arms of the
ERSPC Rotterdam. RT quality was especially superior in the control arm with higher
dosages and more often RT in combination with hormonal therapy. Despite these
differences favoring the control arm, DFS differences were minimal.
Patient summary: We looked at differences in prostate cancer (PCa) treatment and
outcome after PCa treatment in men diagnosed after screening and men diagnosed after
normal clinical practice. Treatment differed with superior treatment given to men
diagnosed in normal clinical practice. We propose a likely explanation for this appar-
ently counterintuitive finding (progressive insight combined with, on average, a later
detection of tumors in unscreened men). Although unscreened men received better
treatment, this advantage seemed to be outweighed by the advantage associated with
the earlier detection, on average, of the tumor in screened men.
Trial registration: ISRCTN49127736
# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Erasmus University Medical Centre, Department of Urology, Room NA-1710,
P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel. +31 10 703 2243; Fax: +31 10 703 5315.
E-mail address: l.bokhorst@erasmusmc.nl (L.P. Bokhorst).

http://dx.doi.org/10.1016/j.eururo.2014.10.008
0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
180 EUROPEAN UROLOGY 68 (2015) 179–182
Screening as done in the Rotterdam section of the European
Randomized Study of Screening for Prostate Cancer (ERSPC)
was shown to reduce prostate cancer (PCa)-specific mortality
in 32% of men after 13 yr of follow-up and up to 51% after
correction for nonattendance and contamination [1,2].
PCa screening may achieve this positive effect in multiple
ways. Most likely it is a result of the favorable stage shift in
the screening arm, resulting, for example, in fewer men with
advanced and metastatic disease and thus more curative
rather than palliative treatment [1,3]. But even if screening
did not result in a clinically noticeable lower stage or grade
for an individual patient, earlier detection with its associated
earlier treatment could still have prevented micro-meta-
static tumor development outside the prostate, resulting in
higher cure rates after treatment in men with screening-
detected PCa compared with men with clinically detected
cancer with a similar clinical stage and grade. Figure 1 shows
this principle graphically. In addition, treatment between
arms could differ including variations in treatment modality
(eg, radical prostatectomy [RP] vs radiation therapy [RT])
but also differences in the quality of similar treatment
modalities (eg, radiation dosage/adjuvant hormonal therapy
in men receiving RT). We therefore aimed to compare
differences in treatment quality between the screening and
control arms of the ERSPC Rotterdam and to compare the
outcome of curative treatment in PCa patients within similar
prognostic groups, based on stage and grade at time of
diagnosis, to test the hypothesis that screen-detected and
clinically detected men with similar characteristics might
still have a different prognosis.
The screening protocol and study population of the
ERSPC Rotterdam were previously described in detail
[4,5]. For this analysis all men receiving RP or RT as initial
treatment were compared. Characteristics of treatment
quality were studied. For comparison, men were divided
by clinical characteristics into four risk groups: low-,
intermediate- and high-risk PCa, based on the D’Amico
et al criteria [6], and a separate group for men with
metastatic PCa (M1 and/or prostate-specific antigen [PSA]
100 ng/ml). The last group was not assessed further in
[(Fig._1)TD$IG]
Fig. 1 – Model showing how screening could result in better outcomes.
1 = Screening could result in a stage shift, resulting in better prognosis.
2 = If screening did not result in a clinically apparent stage shift, earlier diagnosis and treatment in time could still have resulted in a better prognosis,
for instance, because of less time for the tumor to develop outside the prostate.
the current analysis because treatment was not with
curative intent. Disease-free survival (DFS), defined
as no biochemical recurrence (ie, a PSA value two times
>0.2 ng/ml after RP or a PSA value 2.0 ng/ml above the
PSA nadir after RT), no local progression, no distant
metastasis, no PCa death, and no additional treatment
during follow-up, was compared between the arms using
the Kaplan-Meier method. The between-arm survival
curve comparisons were done for equal clinical parame-
ters and most importantly treatment quality character-
istics because these could affect results. The comparison
was certainly affected by lead time in the screening arm
(notably for low- and intermediate-risk disease). For PCa,
this lead time was estimated to range from 12.2 to 2.9 yr
depending on tumor characteristics [7]. Therefore, a
method described by Duffy et al [8] was used to correct
survival times in the screening arm for lead times related
to specific tumor characteristics.
Of all the PCa cases in ERSPC Rotterdam, 2595 (62.6%)
were initially treated with RP or RT (Supplementary Table 1).
Within the predefined groups, tumor characteristics at RP
such as extracapsular extension were less favorable in the
control arm (Supplemental Table 2a). Surgical margins were
more often positive in the control arm in the low- and
intermediate-risk groups. These differences indicate that
even within similar risk groups, tumors were more advanced
in the control arm that were most likely due to the later
detection in time.
1. Treatment comparison
If treatment itself was looked at, especially in men receiving
RT, treatment was superior in the control arm. In the high-
risk group of the control arm, more men received hormonal
therapy (HT) in addition to RT (50.4% vs 12.0%) (Supplemen-
tary Table 2b). The addition of HT to RT for men with higher
risk tumors was proven to increase overall survival in a
randomized trial first published in 2002 [9]. Most of the men
in the screening arm were diagnosed and treated before the
first publication of this trial, resulting in very low rates of men
 EUROPEAN UROLOGY 68 (2015) 179–182 181

receiving HT in addition to RT in the screening arm. In the
control arm, diagnosis was more often after 2002, meaning
these men could benefit from the improved treatment (RT
and HT). In addition to the combination of HT and RT,
radiation dosages given in the control arm were significantly
higher than in the screening arm (Supplementary Table 2b).
This again is most likely a result of the later diagnosis of men
in the control arm because treatment dosages gradually
increased during the course of the trial. The superior RT in the
control arm could have improved PCa-specific survival in the
control arm.
[(Fig._2)TD$IG]
In the RP group, surgical technique (eg, open or
laparoscopic) and individual surgeon caseload/hospital vol-
ume could have differed between the screening and control
arm, but neither was available for analysis. It could be
expected that surgical technique might have changed over
time in favor of the control arm, as with RT. Individual
surgeon caseload/hospital volume could have affected surgi-
cal margin status. In the Netherlands, however, differences
between hospitals are smaller than in some other counties,
with the largest hospital performing 240 RPs in 2010 [10].
It might therefore be expected that its effect is small.

Fig. 2 – Disease-free survival after radical prostatectomy for men with T1–T2 disease, stratified by pathologic Gleason score (=6, 7, I8), surgical margin
(positive or negative), and arm, after correction for lead time in the screening arm. Time in the screening arm was corrected for lead time using a
method described previously [8].
pGleason = pathologic Gleason score; SM = surgical margin.
182 EUROPEAN UROLOGY 68 (2015) 179–182
2. Disease-free survival comparison
Without correction for lead time, DFS rates were higher in
the screening arm in both men receiving RP and RT. After
correcting the screening arm for lead time, differences
were less apparent, however (Fig. 2; Supplementary Fig. 1).
Correction (based on an assumed exponential model [8])
seems imperfect because it resulted in lower DFS rates in the
screening arm directly after diagnosis. At the end of the
survival curves, DFS in the screening arm (corrected for lead
time) was higher than in the control arm. Point estimate
comparison (z test) at the end of the survival curves only
resulted in significant differences in the Gleason score
7 group in men receiving RP with positive surgical margins
(DFS 38% in the screening arm vs 13% in the control arm at
9.8 yr; p = 0.046) and in men receiving RT with a dosage
<69 Gy (DFS 47% in the screening arm vs 9% in the control
arm at 7.9 yr; p < 0.001). This corroborates the hypothesis
that early detection and treatment reduces PCa development
outside the prostate and therefore increases DFS. Supple-
mentary Table 3 provides more detailed data on outcome
after treatment and additional treatment.
The current analysis was further limited by overdiagnosis
[11]. Overdiagnosed cancers could have resulted in more
favorable outcomes in the screening arm, especially in the
group of men with low-risk PCa. This makes interpretation of
the difference between the screening and control arms in the
low-risk PCa group especially difficult.
3. Conclusions
The fact that the ERSPC is a randomized study does not
imply that treatments in both study arms are comparable.
Therefore this study aimed to compare differences in
treatment quality in men receiving treatment with curative
intent in the screening and control arms of the ERSPC
Rotterdam, as well as comparing the outcome of men with
clinically similar tumor characteristics. We found a differ-
ence in the quality of similar treatments between the
screening and control arms of the ERSPC Rotterdam. RT
quality was especially superior in the control arm with
higher dosages and more often RT in combination with HT.
We provided a reasonable explanation (progressive insight
combined with later detection in the control arm). Despite
these quality differences in treatment that favored the
control arm, DFS in men with similar treatment and tumor
characteristics was marginally better in the screening arm.
Author contributions: Leonard P. Bokhorst had full access to all the data
in the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Bokhorst, Roobol.
Acquisition of data: Bokhorst, Roobol.
Analysis and interpretation of data: Bokhorst, Roobol, Kranse, Venderbos.
Drafting of the manuscript: Bokhorst.
Critical revision of the manuscript for important intellectual content:
Bokhorst, Venderbos, Salman, Kranse, van Leenders, Schröder, Bangma,
Roobol.
Statistical analysis: Bokhorst, Roobol, Kranse.
Obtaining funding: Schröder, Roobol.
Administrative, technical, or material support: None.
Supervision: Roobol, Bangma, Schröder.
Other (specify): None.
Financial disclosures: Leonard P. Bokhorst certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: Data referred to in this report
are derived explicitly from the ERSPC Section Rotterdam, which is
supported by grants from the Dutch Cancer Society, the Netherlands
Organisation for Health Research and Development, and the Abe
Bonnema Foundation, as well as by many private donations.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.eururo.2014.10.008.
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