Definition of high-risk prostate cancer impacts oncological outcomes after radical prostatectomy

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Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−7

Clinical-Prostate cancer

Definition of high-risk prostate cancer impacts oncological outcomes after radical prostatectomy Sophie Knipper, M.D.a,b,*, Pierre I. Karakiewicz, M.D.b, Alexander Heinze, M.D.a, Felix Preisser, M.D.a,c, Thomas Steuber, M.D.a,d, Hartwig Huland, M.D.a, Markus Graefen, M.D.a, Derya Tilki, M.D.a,d b

a Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada c Department of Urology, University Hospital Frankfurt, Frankfurt am Main, Germany d Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Received 25 July 2019; received in revised form 24 November 2019; accepted 16 December 2019

Abstract Background: To examine the impact of different pretreatment definitions on biochemical recurrence (BCR)-free survival, metastasisfree survival, and cancer-specific survival after radical prostatectomy. Methods: Overall, 26,364 patients with clinically localized disease who underwent radical prostatectomy at a single institution (1992 −2017) were retrospectively analyzed. Seven pretreatment definitions of high-risk CaP (prostate-specific antigen [PSA] ≥20 ng/ml, clinical stage ≥T2c, clinical stage T3 [cT3], biopsy Gleason score [GS] 8−10 [Grade Group {GG} IV−V], biopsy GS 9 to 10 [GG V], D’Amico risk definition, National Comprehensive Cancer Network risk definition) were evaluated. Kaplan-Meier, as well as multivariable Cox regression analyses were used. Results: Depending on the definition, patients with high-risk CaP comprised between 0.9% (cT3) and 20.3% (D’Amico high-risk) of the population. Ten-year BCR-free survival rates varied from 36.0% (≥cT2c) to 47.4% (National Comprehensive Cancer Network high-risk). Ten-year metastasis-free survival rates varied from 56.6% (GS 9−10/GG V) to 77.5% (PSA ≥ 20 ng/ml). Ten-year cancer-specific survival rates varied from 86.6% (cT3) to 94.5% (PSA ≥ 20 ng/ml). In multivariable analysis, all high-risk definitions were associated with significantly higher risk of BCR (hazard ratio [HR]: 3.4−3.9), metastatic progression (HR: 3.9−8.8), and cancer-specific mortality (HR: 2.8-11.2). Conclusions: Variety in outcomes exists, depending on the pretreatment definition of high-risk CaP. Among the tested, GS 9 to 10 (GG V), cT2c, and cT3 were the strongest predictor for higher BCR risk, cT3 was the strongest predictor for higher metastatic progression risk and GS 9 to 10 (GG V) was the strongest predictor for higher cancer-specific mortality risk in multivariable analyses. Ó 2019 Elsevier Inc. All rights reserved.

Keywords: Prostate cancer; High-risk definition; Survival outcomes

1. Introduction Prostate cancer (CaP) is one of the most common male malignancies worldwide. However, depending on the tumour characteristics, oncological outcomes after initial treatment, Funding: There was no external financial support for this study. *Corresponding author. Tel.: +49 (0)40 7410-51300; fax: +49 (0)40 7410-51323. E-mail address: [email protected] (S. Knipper). https://doi.org/10.1016/j.urolonc.2019.12.014 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.

such as radical prostatectomy (RP), vary widely. Specifically, patients with high-risk CaP are at higher risk of biochemical recurrence (BCR) after initial treatment, as well as at higher risk of metastatic progression and cancer-specific mortality (CSM) in comparison to low- or intermediate-risk CaP [1−4]. Indeed, several definitions of high-risk CaP exist [5−7]. Recently, Mossanen et al. described major heterogeneity in oncological outcomes after RP, depending on the pretreatment definition of high-risk CaP [6]. They suggested clinical

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stage T3 and Gleason score 8 to 10 to be the strongest predictors regarding CSM with an 18- to 20-fold higher risk of CaP death compared to patients who did not meet the criteria. Unfortunately, none of the earlier cancer-control outcomes, such as BCR or metastatic progression were assessed. However, due to the long natural history of the disease, these outcome measurements appear particularly important. To address this unmet need, we examined the impact of different pretreatment definitions on BCR-free survival, metastasis-free survival (MFS), and cancer-specific survival (CSS) after RP. We hypothesized that a high variability in earlier oncological outcomes exists between the different high-risk definitions. This may have implications on patient counselling prior to treatment choices.

2.3. Statistical analyses

A total of 27,161 consecutive patients treated with RP for clinically localized CaP in a single high-volume European center between 1992 and 2017 were evaluated for this study. Of these, 797 were excluded because of missing data on follow-up, leading to a final cohort of 26,364 patients. The study was approved by the institutional review board in Hamburg, Germany. In accordance with federal and institutional guidelines, all men signed an institutional review board-approved, protocol-specific informed consent form before study entry. This permits collection of deidentified patient data at baseline and follow-up, which were entered into a secure, password-protected database for subsequent analysis. Questionnaires and death reports of the national cancer registry were used annually for follow-up. All data were prospectively stored in an institutional database (FileMaker Pro 10; FileMaker, Inc., Santa Clara, CA).

Descriptive statistics included frequencies and proportions for categorical variables (biopsy GS, clinical T-stage, neoadjuvant hormonal therapy, and high-risk definitions). Means, medians, and ranges were reported for continuously coded variables (age, year of surgery, and PSA). The chi-square tested the statistical significance in proportions differences. The t test and Kruskal-Wallis test examined the statistical significance of means and median differences. We performed 7 sets of analyses that focused on oncological outcomes depending on risk definition as defined above. Kaplan-Meier plots graphically depicted BCR-free survival, MFS, and CSS. Univariable and multivariable Cox regression models tested the relationship between oncological outcomes (BCR, metastatic progression, and CSM) and the 7 different high-risk definitions. Additional adjustment was made for age and year of surgery. The discrimination of the multivariable models was tested using the Heagerty’s concordance index (c-index), which is similar to an area under the receiver operating characteristics curve and applicable to time to event data [12]. It describes the probability that, given 2 randomly drawn patients, the patient who experienced an event (e.g., BCR, metastatic progression, and CSM) had a higher risk score than a patient who had not experienced the event. The maximum c-index value is 1.0, which indicates perfect prediction, while 0.5 indicates the probability of correctly predicting the outcomes by random chance, i.e., tossing a coin. For all statistical analyses R software environment for statistical computing and graphics (version 3.4.3) was used. All tests were 2 sided with a level of significance set at P < 0.05.

2.2. Covariates and endpoints

3. Results

Seven common high-risk definitions were examined: (1) Prostate-specific antigen (PSA) ≥20 ng/ml, (2) ≥cT2cstage, (3) cT3-stage, (4) biopsy Gleason score (GS) 8 to 10 (Grade Group [GG] IV−V), (5) biopsy GS 9 to 10 (GG V), (6) D’Amico risk classification (high-risk: PSA ≥ 20 ng/ml and/or ≥cT2c-stage and/or biopsy GS 8−10), and (7) NCCN risk classification (high-risk: PSA ≥ 20 ng/ml or cT3-stage or biopsy GS 8−10) [8−10]. Patient follow-up consisted of periodical PSA testing and postoperative imaging studies, which were performed according to PSA level and further symptoms by the referring urologists [11]. Initial BCR was defined as PSA ≥ 0.2 ng/ml and rising after RP only or after RP with adjuvant RT. MFS was defined as no radiological sign of metastases in further performed imaging studies. CSM was defined as death attributable to CaP. Follow-up time was defined as time (months) between surgery and BCR/metastatic progression/CSM, or last follow-up.

Clinicopathologic characteristics of the overall cohort (n = 26,364) are described in Table 1. Median age was 64 years with a median preoperative PSA of 6.9 ng/ml. Depending on the definition, patients with high-risk CaP comprised between 0.9% and 20.3% of the population. Specifically, 7.3% of patients (n = 1,929) presented with PSA ≥ 20 ng/ml, 2.4% of patients (n = 635) presented with ≥cT2cstage, 0.9% of patients (n = 241) presented with cT3-stage, 13.9% of patients (n = 3,668) harbored biopsy GS 8 to 10 (GG IV−V), 5.8% of patients (n = 1,535) harbored biopsy GS 9 to 10 (GG V), 20.3% of patients (n = 5,345) were classified within D’Amico high-risk group and 19.3% of patients (n = 5,082) were classified within NCCN high-risk group. Median follow-up was 61.1 months. BCR was recorded in 5,130 (19.5%) patients, metastases occurred in 924 (3.5%) patients, cancer-specific death was observed in 315 (1.2%) patients and overall 1,323 (5.0%) patients died within the study period.

2. Patients and methods 2.1. Patient population

ARTICLE IN PRESS S. Knipper et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−7 Table 1 Descriptive characteristics of 26,364 radical prostatectomy patients, treated between 1992 and 2017 in a tertiary referral center, stratified according to different high-risk criteria (prostate-specific antigen [PSA] ≥20 ng/ml; biopsy Gleason score [GS] ≥8 [Grade Group {GG} IV−V]; biopsy GS ≥ 9 [GG V]; clinical ≥T2-stage; clinical T3-stage; D’Amico high risk; National Comprehensive Cancer Network [NCCN] high risk) Variables Age at surgery (y) Median (interquartile range) Year of surgery Median (interquartile range) Preoperative PSA (ng/ml) Median (interquartile range) Neoadjuvant hormonal therapy (n, %) No Yes Biopsy Gleason score (n, %) ≤6 (GG I) 3 + 4 (GG II) 4 + 3 (GG III) 4 + 4 (GG IV) 3 + 5 (GG IV) 5 + 3 (GG IV) 4 + 5 (GG V) 5 + 4 (GG V) 5 + 5 (GG V) Unknown Clinical T-stage (n, %) T1c T2a T2b T2c T3a Unknown Risk categories PSA (n, %) ≥20 ng/ml Clinical T-stage (n, %) ≥cT2c cT3 Biopsy Gleason score (GS) (n, %) ≥GS 8 (GG IV−V) ≥GS 9 (GG V) D’Amico risk groups (n, %) High risk NCCN risk groups (n, %) High risk

Overall (n = 26,364)

Table 2 Kaplan-Meier analyses predicting biochemical recurrence (BCR)-free survival, metastasis-free survival (MFS) and cancer-specific survival (CSS) in 26,364 radical prostatectomy patients treated between 1992 and 2017 in a tertiary referral center, stratified according to different high-risk criteria (prostate-specific antigen [PSA] ≥20 ng/ml; clinical ≥T2-stage; clinical T3-stage; biopsy Gleason score [GS] ≥8 [Grade Group {GG} IV−V]; biopsy GS ≥9 [GG V]; D’Amico high risk; National Comprehensive Cancer Network [NCCN] high risk)

64.3 (59.1−68.6) 2011 (2007−2014) 6.9 (4.8−10.6) 25,197 (95.6) 1,167 (4.4) 11,059 (41.9) 7,809 (29.6) 3,425 (13.0) 1,839 (7.0) 241 (0.9) 53 (0.2) 1,030 (3.9) 332 (1.3) 173 (0.7) 403 (1.5) 19,909 (75.5) 3,797 (14.4) 1,687 (6.4) 394 (1.5) 241 (0.9) 336 (1.3)

1,929 (7.3) 635 (2.4) 241 (0.9) 3,668 (13.9) 1,535 (5.8) 5,345 (20.3) 5,082 (19.3)

3.1. Oncological outcomes Survival estimates are shown in Table 2. In KaplanMeier analyses within the overall cohort, after stratification of 10-year BCR-free survival by each of the 7 high-risk criterions and their nonhigh-risk counterparts, 10-year BCRfree survival rates varied from 36.0 and 37.5 (≥cT2c and GS 9−10/GG V) to 47.4% (NCCN high risk) (Fig. 1). In Kaplan-Meier analyses within the overall cohort, after stratification of 10-year MFS by each of the 7 high-risk criterions and their nonhigh-risk counterparts, 10-year MFS rates varied from 56.6 (GS 9−10/GG V) to 77.5% (PSA ≥

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PSA* <20 ng/ml ≥20 ng/ml Clinical T-stage* ≤T2b ≥T2c Clinical T-stage* ≤T2c T3 Biopsy Gleason score* ≤GS 7 (GG I−III) ≥GS 8 (GG IV−V) Biopsy Gleason score* ≤GS 8 (GG I-IV) ≥GS 9 (GG V) D’Amico risk groups* Low/intermediate High NCCN risk groups* Low/intermediate High

10-y BCR-free survival rates (%)

10-y MFS rates (%)

10-y CSS rates (%)

75.3 44.3

93.8 77.5

98.3 94.5

74.1 36.0

93.0 75.5

98.3 88.3

73.5 39.0

92.8 69.5

98.1 86.6

76.8 45.4

95.1 69.2

98.5 92.9

74.9 37.5

94.0 56.6

98.3 89.0

78.7 47.2

95.8 75.7

98.7 93.7

78.5 47.4

95.8 75.2

98.6 94.1

* Significantly different between the groups.

20 ng/ml) (Fig. 2). In Kaplan-Meier analyses within the overall cohort, after stratification of 10-year CSS by each of the 7 high-risk criterions and their nonhigh-risk counterparts, 10-year CSS rates varied from 86.6 (cT3) to 94.5% (PSA ≥ 20 ng/ml). In multivariable analysis, all high-risk definitions were associated with a higher risk of BCR, metastatic progression, and CSM compared to patients who did not meet the specific definition of high-risk CaP, respectively (Table 3). Hazard ratios (HR) for BCR ranged from 3.4 (PSA ≥ 20 ng/ml) to 3.9 (GS 9−10/GG V, ≥cT2c and cT3), for metastatic progression from 3.9 (PSA ≥ 20 ng/ml) to 8.8 (cT3) and for CSM from 2.8 (PSA ≥ 20 ng/ml) to 11.2 (GS 9−10/ GG V). In discrimination analyses, the c-index on receiver operator characteristics analysis ranged between 0.540 (cT3) and 0.681 (NCCN high risk) for predicting 10-year BCR, between 0.712 (cT3) and 0.758 (D’Amico high risk) for predicting 10-year metastatic progression and between 0.795 (PSA ≥ 20 ng/ml) and 0.833 (GS 8−10/GG IV−V) for predicting 10-year CSM (Supplementary table 1). 4. Discussion Oncological outcomes after RP vary widely depending on the disease characteristics. Specifically, patients with

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Fig. 1. Kaplan-Meier analyses depicting biochemical recurrence (BCR)- free survival rates in 26,364 radical prostatectomy patients, treated between 1992 and 2017 in a tertiary referral center, stratified according to different high-risk criteria (prostate-specific antigen [PSA] ≥20 ng/ml; biopsy Gleason score (GS) ≥8 [Grade Group {GG} IV−V]; biopsy GS ≥ 9 [GG V]; clinical ≥T2-stage; clinical T3-stage; D’Amico high risk; National Comprehensive Cancer Network [NCCN] high risk). Data of non high-risk counterpart are not shown.

high-risk CaP are at higher risk of recurrence after initial treatment, as well as at higher risk of metastatic progression, CSM in comparison to low- or intermediate-risk CaP [1−4]. However, several definitions of high-risk CaP exist [5−7]. Recently, Mossanen et al. described major heterogeneity in oncological outcomes after RP, depending on the pretreatment definition of high-risk CaP [6]. They suggested clinical stage T3 and GS 8 to 10 to be the strongest predictors regarding CSM with an 18- to 20-fold higher risk of CaP death. Unfortunately, their cohort was limited in sample size (i.e., n = 44 cT3 patients), as evidenced by wide confidence intervals of their HR (CI: 10.6−37.4). Moreover, none of the earlier cancer-control outcomes, such as BCR or metastatic progression were assessed. However, due to the long natural history of the disease, these outcome measurements appear particularly important. Indeed, 2 studies reported on BCR and MFS after RP depending on various pretreatment definitions [5,13]. Specifically, Yossepowitch et al. reported within 2 different studies on high variability of BCR and metastatic progression risk, depending on the high-risk definition [5,14]. In contrast, Nguyen et al. did not observe substantial variation in BCR risk

based on the specific high-risk definition [13]. However, all 3 studies only included patients who were treated until 2004 [5], 2005 [14], and 2007 [13]. Additionally, they did not address long-term oncological outcome, such as CSM [5,13]. Based on these considerations, we examined the impact of different pretreatment definitions on BCR-free survival, MFS, and CSS after RP in a contemporary cohort. We hypothesized that a high variability in earlier oncological outcomes exists between the different high-risk definitions. Our analyses demonstrated several noteworthy observations. First, the rate of high-risk patients varied according to definition between 0.9% (241 patients, cT3) and 20.3% (5,345 patients, D’Amico high-risk) within our population. Previous reports also observed high variability in rates between different definitions. Specifically, Mossanen et al. reported on rates between 0.7 (44 patients, cT3) and 8.2% (529 patients, D’Amico high-risk) within their cohort of 6,477 patients (years 1995−2007) [6]. Yossepowitch et al. described high-risk rates between 3.0 (144 patients, cT3) and 20.0% (957 patients, D’Amico high-risk) in their cohort (1985−2004) of 4,708 patients [5]. Moreover, also Nguyen et al. reported on high-risk rates between 3.2 (105 patients,

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Fig. 2. Kaplan-Meier analyses depicting metastases-free survival rates in 26,364 radical prostatectomy patients, treated between 1992 and 2017 in a tertiary referral center, stratified according to different high-risk criteria (prostate-specific antigen [PSA] ≥20 ng/ml; biopsy Gleason score [GS] ≥8 [Grade Group {GG} IV−V]; biopsy GS ≥ 9 [GG V]; clinical ≥T2-stage; clinical T3-stage; D’Amico high risk; National Comprehensive Cancer Network [NCCN] high risk). Data of non high-risk counterpart are not shown.

PSA ≥ 20 ng/ml) and 16.0% (519 patients, NCCN highrisk) in their contemporary cohort including patients between 1996 and 2007 [13]. In consequence, variability in high-risk rates is widely documented and our results from a large European cohort are in agreement with NorthAmerican reports. Second, survival rates also varied widely depending on the definition within our cohort, as evidenced by 10-year BCR-free survival rates between 36.0 and 37.5 (≥cT2c and GS 9−10/GG V) to 47.4% (NCCN high risk), 10-year MFS rates between 56.6 (GS 9−10/GG V) and 77.5% (PSA ≥ 20 ng/ml) and 10-year CSS rates between 86.6 (cT3) and 94.5% (PSA ≥ 20 ng/ml). This is corroborating previous results who also showed high variability in survival rates. Specifically, Yossepowitch et al. reported on 10-year BCRfree survival rates between 41.0 (cT3) and 59.0% (D’Amico high-risk). Moreover, Nguyen et al. described 10-year BCR-free survival rates between 31.0 (PSA ≥ 20 ng/ml) and 43.0% (GS 8−10/GG IV−V) in their patient cohort [5,13]. Furthermore, Mossanen et al. reported on 10-year CSS rates between 69.7 (cT3) and 89.7% (PSA ≥ 20 ng/ml) [6]. In consequence, high variability has been shown. However, to the best of our knowledge, we are the first to report

on both short- and long-term oncological outcomes for different high-risk definitions within a large European cohort. It is of note that irrespective of the definition, less than 15% of patients experienced CSM at 10 years which is in agreement with the literature [4,7,15]. However, the majority of patients suffered from BCR within 10 years and up to 43.4% of patients (GS 9−10/GG V) experienced metastatic progression. Thus, close monitoring and follow-up, as well as careful consideration of adjuvant treatment is warranted within these patients [10]. Third, in multivariable analysis, all high-risk definitions were associated with significantly higher risk of BCR (HR: 3.4−3.9), metastatic progression (HR: 3.9−8.8), and CSM (HR: 2.8−11.2) in comparison to their nonhigh-risk counterparts. This is only partly in agreement with the literature. Specifically, Yossepowitch et al. described a significantly higher risk of BCR (HR: 3.3−4.4) throughout their highrisk definitions, as well as Nguyen et al., who demonstrated increased risk of BCR in univariable analyses (HR: 4.9 −5.3). Moreover, Yossepowitch et al. described a significantly higher risk of metastatic progression in their highrisk definitions compared to the nonhigh-risk counterparts (HR: 3.2−6.5). Likewise, Mossanen et al. reported on

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Table 3 Seven multivariable Cox regression models predicting biochemical recurrence (BCR), metastatic progression (MET), and cancer-specific mortality (CSM) at 10 years in 26,364 radical prostatectomy patients treated between 1992 and 2017 in a tertiary referral center, stratified according to different high-risk criteria (prostate-specific antigen [PSA] ≥20 ng/ml; clinical ≥T2-stage; clinical T3-stage; biopsy Gleason score [GS] ≥8 [Grade Group {GG} IV−V]; biopsy GS ≥ 9 [GG V]; D’Amico high risk; National Comprehensive Cancer Network [NCCN] high risk). All models were adjusted for age at diagnosis and year of surgery Multivariable HR (95% CI) for BCR PSA <20 ng/ml ≥20 ng/ml Clinical T-stage ≤T2b ≥T2c Clinical T-stage ≤T2c T3 Biopsy Gleason score ≤GS 7 (GG I−III) ≥GS 8 (GG IV−V) Biopsy Gleason score ≤GS 8 (GG I-IV) ≥GS 9 (GG V) D’Amico risk groups Low/intermediate High NCCN risk groups Low/intermediate High

P value

Multivariable HR (95% CI) for MET

P value

Multivariable HR (95% CI) for CSM

P value

Ref. 3.4 (3.1−3.6)

<0.001

Ref. 3.9 (3.4−4.6)

<0.001

Ref. 2.8 (2.1−3.7)

<0.001

Ref. 3.9 (3.5−4.3)

<0.001

Ref. 6.8 (5.3−8.5)

<0.001

Ref. 3.6 (2.5−5.0)

<0.001

Ref. 3.9 (3.3−4.8)

<0.001

Ref. 8.8 (6.3−12.4)

<0.001

Ref. 4.1 (2.5−6.7)

<0.001

Ref. 3.6 (3.4−3.9)

<0.001

Ref. 5.7 (5.0−6.6)

<0.001

Ref. 6.8 (5.3−8.9)

<0.001

Ref. 3.9 (3.5−4.3)

<0.001

Ref. 6.3 (5.3−7.5)

<0.001

Ref. 11.2 (8.0−15.8)

<0.001

Ref. 3.7 (3.5−3.9)

<0.001

Ref. 6.0 (5.3−6.8)

<0.001

Ref. 4.8 (3.8−6.0)

<0.001

Ref. 3.7 (3.5−4.0)

<0.001

Ref. 5.8 (5.1−6.7)

<0.001

Ref. 4.7 (3.7−5.8)

<0.001

CI = confidence interval; HR = hazard ratio.

higher risk of CSM for all high-risk definitions. However, their analyses showed a very wide variability according to the specific high-risk definition, with a 4- to 20-fold higher risk of CSM in comparison to the nonhigh-risk counterparts [6]. This is in contrast to our results (CSM HR: 2.8−11.2), as well as to the results of Yossepowitch et al. (CSM HR: 3.5−5.1) [14]. Taken together, variability in predicting higher risk of BCR, metastatic progression, and CSM between the specific high-risk definitions exists, but varies within small ranges for BCR and metastatic progression, as well as for most definitions in CSM. The only accentuated predictor for higher CSM risk is GS 9 to 10/GG V which has not been examined in any of the above mentioned studies. In general, closer follow-up and distinct consideration of adjuvant treatment is warranted in these patients [10]. Several limitations of our study need to be mentioned. First and foremost are the limitations inherent to retrospective analyses. However, these limitations are shared with all previous studies addressing the comparison of different high-risk definitions [5,6,13,14]. Second, our follow-up period was moderate concerning the long natural history of CaP. Moreover, we lack PSA velocity data which have also been used to define high-risk CaP [5]. 5. Conclusions Variety in outcomes exists, depending on the pretreatment definition of high-risk CaP. Among the tested, GS 9 to

10 (GG V), cT2c, and cT3 were the strongest predictor for higher risk of BCR, cT3 was the strongest predictor for higher risk of metastatic progression and GS 9 to 10 (GG V) was the strongest predictor for higher risk of CSM in multivariable analyses. Conflict of Interest The authors declare that they have no conflict of interest. Supplementary materials Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j. urolonc.2019.12.014. References [1] Nepple KG, Stephenson AJ, Kallogjeri D, Michalski J, Grubb RL, Strope SA, et al. Mortality after prostate cancer treatment with radical prostatectomy, external-beam radiation therapy, or brachytherapy in men without comorbidity. Eur Urol 2013;64(3):372–8. [2] Boehm K, Leyh-Bannurah S-R, Rosenbaum C, Brandi LS, Bud€aus L, Graefen M, et al. Impact of preoperative risk on metastatic progression and cancer-specific mortality in patients with adverse pathology at radical prostatectomy. BJU Int 2017;120(5):666–72. [3] D’Amico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen M-H. Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-

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