- Email: [email protected]
Differences in Treatment and Outcome After Treatment with Curative Intent in the Screening and Control Arms of the ERSPC Rotterdam
EUROPEAN UROLOGY 68 (2015) 179–182
available at www.sciencedirect.com journal homepage: www.europeanurology.com
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. Schro¨der a, Chris H. Bangma a, Monique J. Roobol a, for the ERSPC Rotterdam Study Group a
Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands;
b
Netherlands Comprehensive Cancer Organization, Utrecht,
The Netherlands; c Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
Article info
Abstract
Article history: Accepted October 4, 2014
Screening for prostate cancer (PCa) results in a favorable stage shift. However, even if 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 prostate. The outcome after treatment could also differ because of variations in treatment quality (eg, radiation dosage/adjuvant hormonal therapy). To test these hypotheses, 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 and disease-free survival (DFS) after curative treatment in PCa patients with similar stage and grade. A total of 2595 men were initially treated with RP or RT. In the control arm, RT was more often combined with hormonal therapy; treatment dosage was often 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 apparently 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.
Keywords: Prostatic neoplasms Prostate-specific antigen Screening Radical prostatectomy Radiotherapy Cure rates
* 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: [email protected] (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
[(Fig._1)TD$IG]
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-metastatic tumor development outside the prostate, resulting in higher cure rates after treatment in men with screeningdetected 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
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 parameters and most importantly treatment quality characteristics 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 highrisk group of the control arm, more men received hormonal therapy (HT) in addition to RT (50.4% vs 12.0%) (Supplementary 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
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.
EUROPEAN UROLOGY 68 (2015) 179–182
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.
181
In the RP group, surgical technique (eg, open or laparoscopic) and individual surgeon caseload/hospital volume 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 surgical 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)TD$IG]
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
2.
EUROPEAN UROLOGY 68 (2015) 179–182
Disease-free survival comparison
Obtaining funding: Schro¨der, Roobol. Administrative, technical, or material support: None.
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. Supplementary 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.
Supervision: Roobol, Bangma, Schro¨der. 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, consultancies, 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. References [1] Roobol MJ, Kranse R, Bangma CH, et al. Screening for prostate cancer: results of the Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer. Eur Urol 2013;64:530–9. [2] Bokhorst LP, Bangma CH, van Leenders GJ, et al. Prostate-specific antigen-based prostate cancer screening: reduction of prostate cancer mortality after correction for nonattendance and contami-
3.
Conclusions
nation in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Eur Urol 2014;65:329–36.
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 difference 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.
[3] Schroder FH, Hugosson J, Carlsson S, et al. Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol 2012;62:745–52. [4] Roobol MJ, Kirkels WJ, Schro¨der FH. Features and preliminary results of the Dutch centre of the ERSPC (Rotterdam, the Netherlands). BJU Int 2003;92(Suppl 2):48–54. [5] Roobol MJ, Schro¨der FH. European Randomized Study of Screening for Prostate Cancer (ERSPC): rationale, structure and preliminary results. BJU Int 2003;92(Suppl 2):1–122. [6] D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–74. [7] Wever EM, Heijnsdijk EA, Draisma G, et al. Treatment of localregional prostate cancer detected by PSA screening: benefits and harms according to prognostic factors. Br J Cancer 2013;108:1971–7. [8] Duffy SW, Nagtegaal ID, Wallis M, et al. Correcting for lead time and length bias in estimating the effect of screen detection on cancer survival. Am J Epidemiol 2008;168:98–104. [9] Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103–6. [10] Rapportage prostaatkanker SCK rapport 2014. Integraal kankercentrum Nederland Web site. www.iknl.nl.
Critical revision of the manuscript for important intellectual content:
[11] Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due
Bokhorst, Venderbos, Salman, Kranse, van Leenders, Schro¨der, Bangma,
to prostate-specific antigen screening: estimates from the Europe-
Roobol.
an Randomized Study of Screening for Prostate Cancer. J Natl
Statistical analysis: Bokhorst, Roobol, Kranse.
Cancer Inst 2003;95:868–78.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
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. Schro¨der a, Chris H. Bangma a, Monique J. Roobol a, for the ERSPC Rotterdam Study Group a
Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands;
b
Netherlands Comprehensive Cancer Organization, Utrecht,
The Netherlands; c Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
Article info
Abstract
Article history: Accepted October 4, 2014
Screening for prostate cancer (PCa) results in a favorable stage shift. However, even if 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 prostate. The outcome after treatment could also differ because of variations in treatment quality (eg, radiation dosage/adjuvant hormonal therapy). To test these hypotheses, 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 and disease-free survival (DFS) after curative treatment in PCa patients with similar stage and grade. A total of 2595 men were initially treated with RP or RT. In the control arm, RT was more often combined with hormonal therapy; treatment dosage was often 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 apparently 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.
Keywords: Prostatic neoplasms Prostate-specific antigen Screening Radical prostatectomy Radiotherapy Cure rates
* 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: [email protected] (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
[(Fig._1)TD$IG]
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-metastatic tumor development outside the prostate, resulting in higher cure rates after treatment in men with screeningdetected 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
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 parameters and most importantly treatment quality characteristics 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 highrisk group of the control arm, more men received hormonal therapy (HT) in addition to RT (50.4% vs 12.0%) (Supplementary 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
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.
EUROPEAN UROLOGY 68 (2015) 179–182
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.
181
In the RP group, surgical technique (eg, open or laparoscopic) and individual surgeon caseload/hospital volume 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 surgical 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)TD$IG]
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
2.
EUROPEAN UROLOGY 68 (2015) 179–182
Disease-free survival comparison
Obtaining funding: Schro¨der, Roobol. Administrative, technical, or material support: None.
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. Supplementary 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.
Supervision: Roobol, Bangma, Schro¨der. 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, consultancies, 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. References [1] Roobol MJ, Kranse R, Bangma CH, et al. Screening for prostate cancer: results of the Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer. Eur Urol 2013;64:530–9. [2] Bokhorst LP, Bangma CH, van Leenders GJ, et al. Prostate-specific antigen-based prostate cancer screening: reduction of prostate cancer mortality after correction for nonattendance and contami-
3.
Conclusions
nation in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Eur Urol 2014;65:329–36.
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 difference 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.
[3] Schroder FH, Hugosson J, Carlsson S, et al. Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol 2012;62:745–52. [4] Roobol MJ, Kirkels WJ, Schro¨der FH. Features and preliminary results of the Dutch centre of the ERSPC (Rotterdam, the Netherlands). BJU Int 2003;92(Suppl 2):48–54. [5] Roobol MJ, Schro¨der FH. European Randomized Study of Screening for Prostate Cancer (ERSPC): rationale, structure and preliminary results. BJU Int 2003;92(Suppl 2):1–122. [6] D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–74. [7] Wever EM, Heijnsdijk EA, Draisma G, et al. Treatment of localregional prostate cancer detected by PSA screening: benefits and harms according to prognostic factors. Br J Cancer 2013;108:1971–7. [8] Duffy SW, Nagtegaal ID, Wallis M, et al. Correcting for lead time and length bias in estimating the effect of screen detection on cancer survival. Am J Epidemiol 2008;168:98–104. [9] Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103–6. [10] Rapportage prostaatkanker SCK rapport 2014. Integraal kankercentrum Nederland Web site. www.iknl.nl.
Critical revision of the manuscript for important intellectual content:
[11] Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due
Bokhorst, Venderbos, Salman, Kranse, van Leenders, Schro¨der, Bangma,
to prostate-specific antigen screening: estimates from the Europe-
Roobol.
an Randomized Study of Screening for Prostate Cancer. J Natl
Statistical analysis: Bokhorst, Roobol, Kranse.
Cancer Inst 2003;95:868–78.