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Review – Prostrate Cancer

Benefits and Risks of Primary Treatments for High-risk Localizedand Locally Advanced Prostate Cancer: An InternationalMultidisciplinary Systematic Review

Lisa Moris a,b,y,*, Marcus G. Cumberbatch c,y, Thomas Van den Broeck a, Giorgio Gandaglia d,Nicola Fossati d, Brian Kelly e, Raj Pal f, Erik Briers g, Philip Cornford h, Maria De Santis i,Stefano Fanti j, Silke Gillessen k,l, Jeremy P. Grummetm, Ann M. Henry n, Thomas B.L. Lamo,p,Michael Lardas q, Matthew Liew r, Malcolm D. Mason s, Muhammad Imran Omar p,Olivier Rouviere t,u, Ivo G. Schoots v, Derya Tilki w,x, Roderick C.N. van den Bergh y,Theodorus H. van Der Kwast z, Henk G. van Der Poel aa, Peter-Paul M. Willemse bb,Cathy Y. Yuan cc, Badrinath Konety dd, Tanya Dorff ee,ff, Suneil Jain gg,hh, Nicolas Mottet ii,Thomas Wiegel jj

aDepartment of Urology, University Hospitals Leuven, Leuven, Belgium; b Laboratory of Molecular Endocrinology, KU Leuven, Leuven, Belgium; cAcademic

Urology Unit, University of Sheffield, Sheffield, UK; dUnit of Urology, Division of Oncology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan,

Italy; eDepartment of Urology, Austin Health, Heidelberg, VIC, Australia; fBristol Urological Institute, Southmead Hospital, Bristol, UK; g Patient Advocate,

Hasselt, Belgium; hRoyal Liverpool and Broadgreen Hospitals NHS Trust, Liverpool, UK; iDepartment of Urology, Charité University Hospital, Berlin, Germany;jDepartment of Nuclear Medicine, Policlinico S. Orsola, University of Bologna, Italy; kDepartment of Medical Oncology and Haematology, Cantonal Hospital

St. Gallen, University of Bern, Bern, Switzerland; lDivision of Cancer Sciences, University of Manchester and The Christie, Manchester, UK; mDepartment of

Surgery, Central Clinical School, Monash University, Australia; n Leeds Cancer Centre, St. James's University Hospital and University of Leeds, Leeds, UK;oDepartment of Urology, Aberdeen Royal Infirmary, Aberdeen, UK; pAcademic Urology Unit, University of Aberdeen, Aberdeen, UK; qDepartment of Urology,

Leto Hospital, Athens, Greece; rDepartment of Urology, Wrightington, Wigan and Leigh NHS Foundation Trust, Wigan, UK; sDivision of Cancer & Genetics,

School of Medicine Cardiff University, Velindre Cancer Centre, Cardiff, UK; tHospices Civils de Lyon, Department of Urinary and Vascular Imaging, Hôpital

Edouard Herriot, Lyon, France; u Faculté de Médecine Lyon Est, Université Lyon 1, Université de Lyon, Lyon, France; v Department of Radiology & Nuclear

Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands; w Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-

Eppendorf, Hamburg, Germany; x Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany; y Department of Urology, Antonius

Hospital, Utrecht, The Netherlands; z Department of Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; aa Department of

Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands; bb Department of Oncological Urology, University Medical Center, Utrecht Cancer

Center, Utrecht, The Netherlands; cc Department of Medicine, Health Science Centre, McMaster University, Hamilton, ON, Canada; dd University of

Minnesota, Minneapolis, MN, USA; ee Department of Medical Oncology and Developmental Therapeutics, City of Hope, Duarte, CA, USA; ff Department of

Medicine, University of Southern California (USC) Keck School of Medicine and Norris Comprehensive Cancer Center (NCCC), Los Angeles, CA, USA; gg Centre

for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK; hh Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast,

UK; ii Department of Urology, University Hospital, St. Etienne, France; jj Department of Radiation Oncology, University Hospital Ulm, Ulm, Germany

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ava i lable at www.sc iencedirect .com

journa l homepage: www.europea nurology.com

y These authors shared first authorship.* Corresponding author.E-mail address: lisa.moris1506@gmail.com (L. Moris).

Please cite this article in press as: Moris L, et al. Benefits and Risks of Primary Treatments for High-risk Localized and LocallyAdvanced Prostate Cancer: An International Multidisciplinary Systematic Review. Eur Urol (2020), https://doi.org/10.1016/j.eururo.2020.01.033

https://doi.org/10.1016/j.eururo.2020.01.0330302-2838/© 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Article info

Article history:

Accepted January 30, 2020

Associate Editor:

James Catto

Keywords:

Prostate cancerLocalizedLocally advancedPrimary therapyRadical prostatectomyExternal beam radiotherapyBrachytherapyModality treatmentSystemic treatmentSystematic review

Abstract

Context: The optimal treatment for men with high-risk localized or locally advancedprostate cancer (PCa) remains unknown.Objective: To perform a systematic review of the existing literature on the effectivenessof the different primary treatment modalities for high-risk localized and locally ad-vanced PCa. The primary oncological outcome is the development of distant metastasesat �5 yr of follow-up. Secondary oncological outcomes are PCa-specific mortality, overallmortality, biochemical recurrence, and need for salvage treatment with �5 yr of follow-up. Nononcological outcomes are quality of life (QoL), functional outcomes, and treat-ment-related side effects reported.Evidence acquisition: Medline, Medline In-Process, Embase, and the Cochrane CentralRegister of Randomized Controlled Trials were searched. All comparative (randomizedand nonrandomized) studies published between January 2000 and May 2019 with atleast 50 participants in each arm were included. Studies reporting on high-risk localizedPCa (International Society of Urologic Pathologists [ISUP] grade 4–5 [Gleason score {GS}8–10] or prostate-specific antigen [PSA] >20 ng/ml or � cT2c) and/or locally advancedPCa (any PSA, cT3–4 or cN+, any ISUP grade/GS) or where subanalyses were performedon either group were included. The following primary local treatments were mandated:radical prostatectomy (RP), external beam radiotherapy (EBRT) (�64 Gy), brachytherapy(BT), or multimodality treatment combining any of the local treatments above (�anysystemic treatment). Risk of bias (RoB) and confounding factors were assessed for eachstudy. A narrative synthesis was performed.Evidence synthesis: Overall, 90 studies met the inclusion criteria. RoB and confoundingfactors revealed high RoB for selection, performance, and detection bias, and low RoB forcorrection of initial PSA and biopsy GS. When comparing RP with EBRT, retrospective seriessuggested an advantage for RP, although with a low level of evidence. Both RT and RPshould be seen as part of a multimodal treatment plan with possible addition of (postop-erative) RT and/or androgen deprivation therapy (ADT), respectively. High levels ofevidence exist for EBRT treatment, with several randomized clinical trials showingsuperior outcome for adding long-term ADT or BT to EBRT. No clear cutoff can be proposedfor RT dose, but higher RT doses by means of dose escalation schemes result in an improvedbiochemical control. Twenty studies reported data on QoL, with RP resulting mainly ingenitourinary toxicity and sexual dysfunction, and EBRT in bowel problems.Conclusions: Based on the results of this systematic review, both RP as part of multi-modal treatment and EBRT + long-term ADT can be recommended as primary treatmentin high-risk and locally advanced PCa. For high-risk PCa, EBRT + BT can also be offereddespite more grade 3 toxicity. Interestingly, for selected patients, for example, those withhigher comorbidity, a shorter duration of ADT might be an option. For locally advancedPCa, EBRT + BT shows promising result but still needs further validation. In this setting, itis important that patients are aware that the offered therapy will most likely be in thecontext a multimodality treatment plan. In particular, if radiation is used, the combina-tion of local with systemic treatment provides the best outcome, provided the patient isfit enough to receive both. Until the results of the SPCG15 trial are known, the optimallocal treatment remains a matter of debate. Patients should at all times be fully informedabout all available options, and the likelihood of a multimodal approach including thepotential side effects of both local and systemic treatment.Patient summary: We reviewed the literature to see whether the evidence from clinicalstudies would tell us the best way of curing men with aggressive prostate cancer that hadnot spread to other parts of the body such as lymph glands or bones. Based on the resultsof this systematic review, there is good evidence that both surgery and radiation therapyare good treatment options, in terms of prolonging life and preserving quality of life,provided they are combined with other treatments. In the case of surgery this meansincluding radiotherapy (RT), and in the case of RT this means either hormonal therapy orcombined RT and brachytherapy.© 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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1. Introduction

Following the introduction of prostate cancer (PCa)screening, there has been a rise in the number of mendiagnosed with clinically nonmetastatic PCa. Nevertheless,17–31% of these men present with high-risk localized or

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locally advanced disease, and need curative treatment [1]since 10- and 15-yr PCa-specific mortality rates, if untreat-ed, remain 28.8% and 35.5%, respectively [2]. Althoughcurative treatment provides a survival benefit [3], there isstill no consensus regarding the optimal treatment option.In general, different strategies combining local with

ks of Primary Treatments for High-risk Localized and Locallyystematic Review. Eur Urol (2020), https://doi.org/10.1016/j.

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systemic treatment seem to have the best result in thispatient cohort. Extensive evidence on the benefit of localcurative treatment to improve survival already exists, andtherefore, androgen deprivation therapy (ADT) alone shouldnot be considered a valid treatment option in the setting ofhigh-risk and locally advanced PCa [4–6]. Currently, theEuropean Association of Urology (EAU) PCa guidelinesrecommend radical prostatectomy (RP) with extended pelviclymph node dissection in a multimodal approach (withpossible postoperative radiotherapy [RT] � ADT), or externalbeam radiation therapy (EBRT) at a dose of 76–78 Gy, or EBRTwith brachytherapy (BT) boost with long-term ADT in menwith life expectancy of �10 yr [3]. Evidence on whichtreatment modality is based is still lacking and has led toexperience- rather than evidence-based management ofpatients. The aim of this systematic review (SR) is to comparethe available primary local curative treatment options forhigh-risk localized and locally advanced PCa at diagnosis.

2. Evidence acquisition

The review was conjointly commissioned and undertakenby the EAU Prostate Cancer Guideline Panel and theAmerican Society of Clinical Oncology (ASCO). The protocolfor this review has been published online (http://www.crd.york.ac.uk/PROSPERO; CRD42017078862) [7].

Briefly, the review was performed according to thePreferred Reporting Items for Systematic Reviews andMeta-analyses (PRISMA) guidelines [8] and methodology asdetailed in the Cochrane handbook [9] (Supplementarymaterial). The study population comprised male patientswith histologically proven high-risk localized PCa (Interna-tional Society of Urologic Pathologists [ISUP] grade 4–5[Gleason score {GS} 8–10] or prostate-specific antigen [PSA]>20 ng/ml or � cT2c) or locally advanced PCa (any PSA, cT3–4 or cN+, any ISUP grade/GS) [3]. The treatment options ofinterest included any primary local treatment with curativeintent: RP, EBRT (�64 Gy), BT, or multimodality treatment(defined as a combination of primary local treatments �systemic treatment). The primary outcome was distantmetastasis-free survival (DMFS) [10]; secondary oncologicaloutcomes included PCa-specific mortality (PCSM), overallmortality (OM), biochemical failure (BF), and need forsalvage treatment. Secondary nononcological outcomeswere quality of life (QoL), functional outcomes, and adverseevents. Abstracts and full-text screening, and data extrac-tion were independently performed in duplicate (L.M., M.C.,G.G., N.F., B.K., and R.P.) and disagreement was resolved bydiscussion or reference to an independent third party (T.V.D.B.). Owing to the anticipated heterogeneity across studies,only a narrative synthesis was planned.

3. Evidence synthesis

3.1. Quantity of evidence identified

The study selection process is outlined in the PRISMA flowdiagram (Fig. 1). Ninety studies met the inclusion criteria,

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recruiting 367 347 patients with a total of 24 randomizedclinical trials (RCTs) [11–34] and 66 nonrandomized studies(NRSs; four prospective and 62 retrospective studies).

3.2. Characteristics of the included studies

Four major comparisons could be categorized: (1) com-parison of RP and RT (258 809 patients, all NRSs), (2)comparisons of RT with or without ADT and ADT duration(21 353 patients, 12 RCTs, six NRSs), (3) comparisons ofdifferent schedules of RT (77 152 patients, 11 RCTs,24 NRSs), and (4) comparison of RP with or withoutadditional therapies (10 033 patients, one RCT, sevenNRSs). Both baseline study characteristics (SupplementaryTables 1–4) and corresponding outcome data (Supplemen-tary Tables 5–8) are presented. SupplementaryTables 1 and 5 summarize studies comparing RT with RP[35–64]. Supplementary Tables 2 and 6 report onstudies comparing RT with or without ADT and ADTduration [13–18,23,26,27,29,30,32,65–69]. SupplementaryTables 3 and 7 compare different RT modalities (includingBT) [11,12,19–22,24,25,28,33,34,69–92], and Supplementa-ry Tables 4 and 8 compare different RP modalities[16,31,93–98]. Four studies reported on RT doses below70 Gy [37,41,55,57]. Since this does not reflect currenttreatment, a separate table was created for these studies,excluding them from any further recommendation (Sup-plementary Tables 9 and 10).

3.3. Risk of bias and confounding assessment

Figs. 2 and 3 summarize the risk of bias (RoB) assessment ofall studies individually. In total, 24 RCTs were included, butin most RCTs, adequate blinding was not feasible. Therefore,as with all studies of this sort, selection, performance, anddetection bias overall are judged to be high on purelytechnical grounds. Attrition and reporting bias were judgedto be low. Most confounding factors, such as clinical Tcategory, biopsy GS, and initial PSA, were adequatelyconsidered through statistical adjustments in a largeproportion of studies, while the correction for biopsystrategy remained unclear.

3.4. RP versus RT

Thirty studies compared RP with EBRT (�ADT) [35–64]. Allwere NRSs and no full-text RCTs were available. There wasonly one prospective observational study [53]. Therefore,data quality in all these reports is low. RT was delivered asmonotherapy (or the use of ADT was not documented) in11 of 30 studies, and doses were <70 Gy in four of 30 studies[38,41,43–45,49,53,54,59,61,63]. Therefore, many of thestudies in this category do not reflect contemporary practiceand were not taken into account for the final recommenda-tions.

3.4.1. Oncological outcomes

Four NRSs reported on DMFS [35,36,46,55] with nostatistical difference between RP and EBRT + ADT. Twen-

ks of Primary Treatments for High-risk Localized and Locallyystematic Review. Eur Urol (2020), https://doi.org/10.1016/j.

Records identified throughdatabase searching

(n =16000)

Records after duplicates removed(n = 13983)

Records screened(n = 13983)

Full-text articles assessedfor eligibility

(n = 782)

Studies included inqualitative synthesis

(n = 90)

Oncological outcomes Functional outcomes

Full-text articles excluded (n = 692), withreasons:- Conference abstract (n = 335)- Wrong study design (n = 128)- Insufficient follow-up (n = 58)- Not population of interest (n = 59)- Small sample size (<50/arm; n = 38)- Wrong intervention (n = 33)- Duplicate paper (n = 15)- Not retrieved (n = 13)- No outcome of interest (n = 9)- Other language (n = 4)

Identification

Screening

Eligibility

Included

Fig. 1 – PRISMA flow chart. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-analyses.

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ty-seven out of 30 NRSs described data on OM or PSCM,with the majority of the studies favoring RP[35,36,43,44,47,49,51,55,59,60,64]. When comparing RPwith the combination of EBRT + ADT, the reported benefitin OS and cancer-specific survival (CSS) ranged from 10%to 28% [35,55,60] and from 4% to 8% [35,47,51,55],respectively, at 10 yr, favoring RP even when comparedwith recommended EBRT doses of 76–78 Gy [47,48,51]. Ofinterest is the NRS by Tilki et al [40] evaluating RP in amultimodal setting. This study showed that RP withoutadditional treatment, compared with maxRT (EBRT + BT +ADT), resulted in higher PCSM and OM rates (PCSM:hazard ratio [HR]: 2.80 [95% confidence interval {CI},1.26–6.22], and all-cause mortality: HR 1.65 [95% CI, 0.94–2.91]). However, when compared with RP + adjuvant RTand/or maxRP (RP + RT + ADT), no differences in outcomeswere observed.

3.4.2. Nononcological outcomes

Regarding toxicity after RP or RT, two studies for locallyadvanced [49,62] and three for high-risk PCa [47,53,56]reported on genitourinary (GU) toxicity (ie, need for

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catheterization, GU infection, hematuria, strictures, andlower urinary tract symptoms), sexual dysfunction, andgastrointestinal (GI) toxicity (ie, diarrhea, bleeding, andproctitis). Despite very heterogeneous methods ofreporting, studies showed generally more sexual dys-function and urinary incontinence in patients after RP[53,56] and more GI toxicity after RT [47], whichresembles the conclusions of the PROTECT trial [99].

3.5. RP—with or without additional therapy

Eight studies compared different RP modalities [16,31,93–98], of which only one was a RCT [31], comparing salvagewith adjuvant RT after RP in a high-risk PCa population.

3.5.1. Oncological outcomes

Two of the included studies evaluated the effect of adjuvantRT (vs salvage RT) on survival outcomes [31,97]. The RCT byBolla et al [31] only demonstrated an improvement inbiochemical failure–free survival (BFFS) after adjuvant RT,with no difference in overall survival (OS) or PCa-specificsurvival (PCSS).

ks of Primary Treatments for High-risk Localized and Locallyystematic Review. Eur Urol (2020), https://doi.org/10.1016/j.

Fig. 2 – Risk of bias summary graph. PSA = prostate-specific antigen.

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Four studies reported on the combination of RP withsystemic therapy [16,93,94,96]. One RCT reported onadjuvant bicalutamide after RP, but did not show an OSor CSS benefit after a median follow-up (FU) of 11.2 yr[16]. Two studies investigated the effect of neoadjuvantsystemic treatments [93,94]. One NRS reported an addi-tional benefit of both BFFS and OS after 10 yr of FU withneoadjuvant ADT [94]. The second NRS compared neoadju-vant luteinizing hormone-releasing hormone (LHRH) ana-log plus chemotherapy (estramustine, oral etoposide, andpaclitaxel [EEP]) before RP, showing improved OM and BFFS[93]. However, FU of the combination arm was only 48.8 mocompared with 111 mo in the RP arm.

3.5.2. Nononcological outcomes

Only two studies reported functional outcome data. The RCTreported an increase in the 10-yr cumulative incidence ofsevere (grade 3) toxicity (p = 0.052) and late grade �2 GUtoxicity (p = 0.003) with adjuvant RT, compared withsalvage RT, while late GI toxicity did not differ between thetwo groups [31]. Sooriakumaran et al [98] compared theeffect of open versus robotic RP on erectile functionrecovery in high-risk PCa patients, showing no statisticallysignificant difference after 24 mo of FU.

3.6. EBRT with or without ADT and comparison of ADT duration

3.6.1. EBRT alone versus EBRT + ADT

Nine studies compared EBRT alone with EBRT + ADT,including four RCTs and the updated results of EORTC22863 trial [14,16,26,30,32] and three NRSs [65,66,68], plusone subanalysis of two RCTs, the RTOG 85-31 and RTOG 86-10 [67]. The EORTC 22863 and TROG 96.01 trials used LHRH

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agonists with an AR antagonist for flare prevention[14,30,32]. Two other RCTs compared EBRT �adjuvantbicalutamide [16,26].

There was fairly consistent evidence from the RCTs ofbenefits with combined EBRT + ADT, compared with EBRTalone. Although different RCTs reported on different out-comes, oncological outcomes were uniformly in favor of thecombination EBRT + ADT. Three RCTs showed improve-ments in OS [16,26,30,32], two studies showed improve-ments in PCSS [14,30,32], and one study showedimprovement in DMFS [32]. The subanalysis by Horwitzet al [67] of both RTOG 85-31 and RTOG 86-10 trials,excluding post-RP and cN1 patients, confirmed thesebeneficial findings for PCSS and DFMS.

Iversen et al [16] evaluated side effects associated withbicalutamide treatment in patients treated with RP or RT.Most frequently reported side effects were gynecomastia(68.8% vs 8.3%) and mastalgia (73.7% vs 7.6%) in thebicalutamide group, which were similar to previouslyreported data. There were no differences in other non-oncological outcomes between the randomized groups.

3.6.2. Studies of duration of ADT in the context of EBRT

Eight studies evaluated the impact of ADT duration ononcological outcomes. For the comparison of short-term (4–6 mo) versus long-term (24–36 mo) ADT, seven RCTs[13,15,17,18,23,27,29] and one NRS [69] were identified.Intermediate-term ADT was defined as ADT for 18 mo.

An advantage of long-term ADT over short-term ADT wasfound in four RCTs with improvements in OM, PCSM, and BF[15,17,27,29]. Two RCTs reported on the development of DM,both showing a significant advantage for long-term ADT[13,17]. Of interest is the RCT by Nabid et al [18], showing no

ks of Primary Treatments for High-risk Localized and Locallyystematic Review. Eur Urol (2020), https://doi.org/10.1016/j.

Fig. 3 – Risk of bias assessment for individual studies.NRS = nonrandomized study; RCT = randomized clinical trial.

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differences in OS, CSS, and DFS between long-term (36 mo)and intermediate-term ADT.

Only two studies reported on functional outcomes[17,18]. Nabid et al [18] showed no statistical difference inglobal QoL; however, a clear difference in favor ofintermediate-term ADT was observed for physical QoL (p <

0.001), fatigue (p = 0.003), nausea and vomiting (p = 0.04),constipation (p = 0.03), sexual activity and function (p <

0.001 and p = 0.03), and specific treatment-related QoL (p <

0.001). Lawton et al [17] reported no differences in late GUand GI toxicity comparing 4 and 24 mo of ADT.

3.7. RT—different intertreatment modalities

Thirty-five studies performed comparisons of differentschedules, or combinations of modalities in the contextof RT as the principal curative therapy [11,12,19–22,24,25,28,33,34,70–92,100,101]. The categories wereEBRT versus EBRT + BT, EBRT/BT dose/fractionation/fieldsize comparisons, and the addition of chemotherapy to RTas multimodality therapy.

3.7.1. EBRT versus BT (monotherapy or BT boost + EBRT; �ADT)

There were 17 studies comparing EBRT with BT (mono-therapy or as boost to EBRT; �ADT) [20–22,70–72,74,76,77,82–87,92,100]. Of these, there was one RCT[20–22], two prospective comparative studies [70,84], and14 NRSs. For monotherapy, EBRT doses ranged from 70 to81 Gy and low-dose rate BT (LDR-BT) ranged from 140 to145 Gy [71,74,77,84,100]. When combined with BT, EBRTdoses varied between 40 and 50.4 Gy, with BT doses for LDR-BT ranging from 90 to 115 Gy [20–22,76,82,83,87,92] andfrom 6.5 Gy in three fractions to 10 Gy in 2 Gy fractions forhigh-dose rate BT (HDR-BT) [70,72,85,86].

Studies comparing EBRT with EBRT + BT boost showed animprovement in oncological outcomes in favor of combina-tion therapy. The RCT (ASCENDE-RT) reported improvedBFFS for EBRT + ADT with BT boost (83%) compared withEBRT + ADT (73%, p = 0.048) at 6.5-yr FU [22]. In the NRSs,EBRT + BT boost (�ADT) resulted in improved DMFS in onlyone study [83], improved OS in five studies [72,76,82,87,92],improved CSS in four studies [72,76,83,86], and improvedBFFS in three studies [76,82,83].

Five NRSs compared BT alone (�ADT) with EBRT (�ADT)[71,74,77,84,100]. Three studies suggested improved BFFSand PCSM with BTcompared with EBRT [71,74,77]. However,information on the administration of ADT or EBRT doses wasoften missing, and patients receiving BT/EBRT tended to beyounger and had a lower T category. Of interest is the studyby D’Amico et al [100] comparing BT (�ADT) with EBRT + BT(�ADT), showing that trimodality treatment (EBRT + BT +ADT), but not treatment with EBRT alone or ADT alonecompared with BT, resulted in an improved PCSM.

Contrary to the superior oncological results for EBRT + BT(�ADT), data on QoL and side effects are less favorable.Three studies reported on higher GU toxicity after EBRT + BTboost [20,21,85]. In the ASCENDE-RT trial by Rodda et al[20,21], 5-yr grade 3 GU toxicity was worse when treatedwith EBRT + LDR-BT boost + ADT compared with dose-

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escalated EBRT + ADT (5 yr: 18.3% vs 5.2%). The NRS by Khoret al [85] showed more grade 3 strictures (as GU toxicitysurrogate) in the combination group (5 yr: 11.8% vs 0.3%).

3.7.2. EBRT—trials of dose, fractionation, and field size

Seven RCTs [11,12,19,24,25,34,88] and 11 NRSs [28,73,75,78–81,89–91,101] compared different EBRT modalities.

Four studies (two different RCTs and one update of thetrial by Arcangeli et al [11,12], and one NRS) comparedhypofractionation and conventional fractionation[11,12,79,88], comparing conventional EBRT (78–80 Gy)with moderate hypofractionation (3.1 Gy fractions to a totaldose of 62 Gy and 3.4 Gy fractions to a total dose of 64.6 Gy)[11,12,88]. There were no differences in DMFS, OM, PCSM, orBFFS in any of these studies. Both RCTs reported onfunctional outcomes with no difference in the incidenceand severity of late GI or GU toxicity [11], but an increase inoverall grade 3 or worse late GU toxic effects (19% vs 13%)[88] after moderate hypofractionation compared withconventional EBRT was observed.

Eight studies compared different conventional EBRTdoses ranging from 68 to >80 Gy [34,73,75,80,81,89,90,101],with increasing doses over the years due to the introductionof conformal and then intensity-modulated RT (IMRT). OneNRS compared three-dimensional conformal RT (70–74 Gy)with IMRT (78–82 Gy), showing better survival outcomes inthe IMRT group for BFFS, OS, and CSS [90].

Three studies evaluated the effect of pelvic irradiation inaddition to EBRT, BT, or both [19,78,91]. One RCT reported asignificant improvement in progression-free survival (PFS)and BF for neoadjuvant ADT + whole-pelvis RT whencompared with neoadjuvant ADT + prostate-only RT orwhole-pelvis RT + adjuvant EBRT [19]. A second RCTreported whole-pelvis RT to be associated with a significantimprovement in BFFS in the EBRT + BT group but withoutimpact on OS or PCSS [78].

3.7.3. EBRT �chemotherapy

Three studies reported on the addition of chemotherapy[24,25,33], with EEP in the RTOG 9902 trial and docetaxel inthe QRT-SOGUG phase 2b and RTOG 0521 trial [25,33]. TheRTOG 0521 RCT showed improvement in OS with docetaxelcompared with EBRT + ADT [24]. All trials reported asignificantly higher rate of chemotherapy-related toxicities,especially in the RTOG 9902 trial, which was closed earlydue to excess toxicity and treatment-related mortality.

3.8. Locally advanced PCa

Twelve studies reported specifically on locally advanced PCa(according to the EAU PCa guidelines definition), with fiveRCTs [17,26,29,30,32] and seven NRSs[43,49,56,57,62,65,67]. Five NRSs compared RP with EBRT� BT [43,49,56,57,62], showing better survival outcomes forRP compared with EBRT � ADT in well-selected patients.Four RCTs compared EBRT + ADT versus EBRT alone withoutcomes in favor of the combination therapies (DMFS, OM,PCSM, and/or BFFS) [19,26,30,32]. One NRS reportedreduced PCSM in patients treated with RT alone; however,

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RT dose and ADT duration were not reported [65]. Finally,two RCTs compared EBRT + short-term ADT with EBRT +long-term ADT and showed superior DMFS for long-termADT [17,29].

3.9. Discussion

3.9.1. Principal findings

3.9.1.1. RP versus EBRT and RP intergroup comparison. Historically,men with high-risk PCa have been managed most com-monly with EBRT, ADT, or both [1,102], while RP has beendiscouraged in this setting, due to concerns about sideeffects and inadequate disease control [102–105]. Theincluded retrospective studies report encouraging resultsfor RP over EBRT with the advantage of avoiding ADT inmany patients. However, no randomized data are availableto evaluate RP versus EBRT � ADT in terms of survivaloutcomes and/or toxicity, but the ongoing randomizedSPCG-15 trial will provide us with valuable information onthis matter [106]. Clearly, the reported retrospective studiesshould be interpreted with extreme caution, as patientswith good performance status and limited or no comorbid-ity may be more commonly considered for RP. Indeed,patients treated with RP in the included studies are youngerwith a less advanced tumor classification. Out of the30 studies, 11 performed a propensity score matching fortumor and patient characteristics [38–40,43,49,51,56,59–62]. However, even this cannot completely correct for theinherent selection bias due to unmeasured confoundingvariables [107]. It is noteworthy that in several studies, RPwas compared with EBRT alone [38,41,43–45,49,53,54,59,61,64] or EBRT < 70 Gy [37,41,55,57], whichshould be regarded as suboptimal treatment in a contem-porary high-risk setting and no recommendations shouldbe based on these observations. The same applies to RPmonotherapy, which fails to be a definitive cure in manypatients. Therefore, patients must be informed about thepossible need for combination therapy (RP with RT aloneand/or ADT). However, it remains unclear which therapeu-tic approach after RP is superior [108].

We can make the following conclusions:

� No curative primary treatment modality (as part ofmultimodality therapy) has shown superiority over anyother curative treatment option in terms of survival.

� RP (including the option for [postoperative] RT and/orADT) or EBRT + ADT may be offered to patients with high-risk localized and locally advanced PCa as long as it is partof a multimodal treatment scheme.

� Although too soon to make recommendations, the use of(neo)adjuvant chemotherapy with RP is currently beingtested as part of the multimodality treatment of high-riskor locally advanced PCa [109]. Future analysis and longerFU of these trials will provide valuable information.

3.9.1.2. Studies in the context of primary RT. RT represents a validtreatment option but, like RP, as part of a multimodalstrategy in most cases [14,16,26,30,32,67,68]. Many of theincluded studies were performed in the era before dose-

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escalated RT and should be interpreted cautiously since theyused RT doses far below the recommended 76–78 Gy;indeed, four studies reported doses below 70 Gy[14,17,26,66]. Extrapolation of the findings of these studiesto contemporary practice therefore requires much caution.

Five RCTs have confirmed the benefit of combining EBRTwith ADT, and this is a very-well-established treatmentoption in current practice. However, the optimal duration ofADT (from 18 mo to indefinite) remains undefined. In ahigh-risk setting, long-term ADT (18–36 mo) has shownclear benefits over short-term ADT [17,29]. This is notmerely an effect of ADT compensating for lower doses of RT,since the RCT by Zapatero et al [27] confirmed that evenwith dose-escalated RT doses (median dose of 78 Gy), long-term ADT (24 mo) results in longer BFFS and OS than 4 mo ofADT. Owing to significant side effects, reducing ADT lengthseems desirable as long as it will not affect efficacy. Nabidet al [18] designed a superiority study comparing long-termADT (36 mo) with intermediate-term ADT of 18 mo,showing no difference in DM, OS, and CSS after 9.4 yr ofFU, but confirmed improvements of certain QoL aspects(physical, emotional, and social functioning and fatigue).Although the authors suggest that intermediate-term ADTmight be noninferior to 36 mo of ADT for OS, propernoninferiority trials have to be performed before finalrecommendations can be made. In addition, the use of RTdoses of only 70 Gy and the low compliance of 53% to long-term ADT (vs 88% for intermediate-term ADT) complicatesinterpretation of this study.

The combination of EBRT + BT boost aims to increasedoses to the prostate while minimizing radiation to thesurrounding organs. Only the ASCENDE-RT trial randomizedpatients to 46 Gy + EBRT boost to a total of 78 Gy or to pelvic46 Gy + LDR-BT boost, and reported superior 9-yr BFFS ratesof 62% and 83% respectively, despite a general increase inlate GU toxicity [20–22]. In multiple retrospective series,this combination demonstrated excellent results withbetter local tumor control compared with EBRT alone.However, in most studies, patient and tumor characteristicswere more favorable in the combination group withyounger patients and lower clinical T categories.

Hypofractionation has been developed to deliver equiv-alent biologically effective doses to the tumor with a higherdose per fraction, based on the fact that PCa cells are moresensitive to large-dose fractions than the surroundingnormal tissue. Both HDR-BT and EBRT schemes have triedto implement this, but controversy remains. The RCTs byArcangeli et al [11,12] and Incrocci et al [88] showedconflicting results in late complications, but equivalence inPCa deaths with moderate hypofractionation (62–64.6 Gy,with 3.1–3.4 Gy per fraction) in high-risk PCa. From aneconomical and patient-friendly point of view, bothmoderate and extreme hypofractionation can offer greatadvantage with fewer fractions, but further well-designednoninferiority trials are needed to confirm their role.

Data on the use of irradiation of the lymph nodes arelimited in this SR, and studies mostly report data for mixedpatient groups (cN0-X) [19,78,91]. The RTOG 9413 trialshowed a benefit of whole-pelvis RT with neoadjuvant ADT

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in high-risk PCa patients compared with prostate-only RT,highlighting the benefit of prophylactic pelvic RT and theinteraction with hormonal therapy [19]. Two RCTs, RTOG0924 and PIVOTAL-boost, are in progress, which willcompare whole-pelvis versus prostate-only RT and providemore information on hard clinical endpoints (such as OS)and the toxicity profile of whole-pelvis RT.

Finally, different trials evaluated the benefit of addingchemotherapy to curative local treatments with the aim oftreating micrometastatic disease. Optimization of chemo-therapy regimens and time of delivery (neoadjuvant oradjuvant) remains investigational. The GETUG-12 trialsuggested improved relapse-free survival with docetaxel +ADT versus ADT alone [110]. The phase 2b trial by Carleset al [33] reported good tolerability of low weekly doses ofdocetaxel, but without benefits in 5-yr BFFS, PFS, and OS. Itssuccessor, the RTOG 0512 trial, revised treatment scheduleswith adapted RT schemes and docetaxel instead of EEP[24]. In a population with 84% GS 8–10 patients, animprovement in OS was observed with adjuvant docetaxelfollowing RT after 5.7 yr of FU. In contrast, the recentlypresented long-term results for M0 high-risk PCa patients inthe STAMPEDE trial did not show improved OS withdocetaxel before RT + long-term ADT [111]. However, up-front docetaxel improved PFS and failure-free survival inthis patient population without excess in late toxicity,which might influence future treatment decision making.An improved insight into patient profiles will be needed toidentify those patients who will likely benefit from adjuvantchemotherapy. Other additional systemic therapies includ-ing novel endocrine agents (such as abiraterone acetate,apalutamide, and enzalutamide) are currently being testedin clinical trials, combining systemic with local treatmentfor increased disease control, which is discussed to a greaterextent in an SR by Tosco et al [112].

We can conclude that the following:

� In patients with localized high-risk or locally advanceddisease, EBRT with long-term ADT (24–36 mo) � BT boost(HDR or LDR) are valid treatment options. ADT mostlyconsisted of an LHRH analog combined with a 1-moantiandrogen for flare prevention.

� Adjuvant ADT should be continued for at least 24 mo;however, for all high-risk patients, there is insufficientevidence to support prolonging of ADT for another year.Comorbidity at the time of diagnoses and treatment-related side effects must be taken into account whendeciding on ADT duration.

� Although results are promising, there are not enoughmature data to encourage the general use of adjuvantchemotherapy in the multimodality treatment of high-risk or locally advanced PCa. The recently presented datafrom the MRC STAMPEDE trial in high-risk M0 patientswill add greatly to the current knowledge [111].

Finally, our SR evaluated the effects of local treatment onQoL. In general, both radical and systemic treatments resultin significant side effects, which affect QoL of patients and

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their families who are confronted with the diagnosis. Wecan conclude that patients treated with RP experiencemainly GU toxicity and sexual dysfunction, while EBRT canresult in GI problems. Attention should be drawn to theseside effects and proper support should be organized.

3.9.2. Implications for clinical practice and further research

Patients with high-risk localized or locally advanced PCafrequently have recurrence driven by subclinical metasta-ses and microscopic local tumor extension. Furtheroptimization of treatment will therefore rely on improve-ment of multimodality treatment and development ofnovel therapeutic strategies. Numerous trials with (neo)adjuvant chemotherapy and new AR-targeted therapies aspart of the multimodal approach are currently tested andwill likely change the treatment landscape. However, notonly treatment, but also classification of patients intoprognostic groups is the key to optimal treatment. A recentSR on the impact of biochemical recurrence (BCR) aftertreatment with curative intent proposed additional riskstratification (EAU high-risk BCR and EAU low-risk BCR)based on risk factors for clinical progression and worsesurvival (short PSA doubling time and a high final GS afterRP, and a high biopsy GS and a short interval to BCR afterRT). Such a classification system can guide clinicaldecisions to initiate salvage treatment. A first validationof this classification system was performed in a large seriesof patients with BCR after RP, showing its potential andapplicability in daily practice [113]. However, furthervalidation is still mandatory in both post-RP and post-RTsettings. Another rapidly evolving area is the use of (non)genomic biomarkers and molecular imaging [114–117]. Such prognostic and predictive tools offer analternative way of patient stratification supplementaryto our clinical system and may guide clinicians in thedecision whether to intensify FU and treatment schemes.Our SR did not report on the use of focal therapy in thissetting. Until now, data on ablative therapies are relativelynew and fail to provide long-term outcome data. Especiallyin the high-risk and locally advanced setting, there is apaucity of comparative studies with sufficient FU time.Therefore, it cannot be recommended in today’s practice[118,119]. However, we want to stress that the treatmentlandscape of PCa is a dynamic field with constantprogression and change. The recommendation of todaymight be outdated the next year. It is our responsibility tokeep up to date within a highly changing field.

3.9.3. Limitations and strengths of this SR

This study represents the first SR comparing bothoncological effectiveness and functional outcomes focus-ing on local treatment in high-risk and locally advancedPCa. This review was performed based on robust method-ological standards and as a collaborative project involvingtwo multidisciplinary panels of experts (EAU ProstateCancer Guidelines Panel and ASCO) including a patientrepresentative [8,9,120]. Limitations include the retrospec-tive nature of the majority of studies, and the overallclinical and methodological differences between studies,

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contributing to the heterogeneity of data. Variation wasapparent in baseline patient characteristics, type, duration,and correct administration of ADT, as well as the variety inRT doses. To overcome the problem of RT studies reportingon doses <70 Gy, we created a separate table and excludedthe studies from interpretation of the results. Theseinterstudy differences limit direct comparison of dataand preclude further strong or new recommendations.Ongoing big data projects, such as PIONEER and ICECaP,will define validated core outcome sets for both localizedand metastatic PCa, which should be used in future clinicaltrials [121]. Finally, clinical staging and stratificationdepended on standard imaging techniques with chestradiograph, abdominal computed tomography (CT), andisotope bone scan in all included RCTs. However, the fieldof imaging and staging is rapidly evolving, with promisingdata for multiparametric magnetic resonance imaging(mpMRI), positron emission tomography (PET)/CT, andprostate-specific membrane antigen PET/CT for localstaging and detection of lymph node and bone metastases.Results from current trials will enlighten us on the use andbenefit of these new modalities for the management ofhigh-risk and locally advanced PCa. It should be acknowl-edged that the recommended use of MRI for local stagingand subsequent MRI fusion targeted biopsies resulted inupgrading of the PCa identified [122]. However, mpMRIfusion biopsies are a recent development, and therefore,studies using this technique were not included as these donot have sufficient FU.

4. Conclusions

In this collaborative SR performed under the auspices ofthe EAU Prostate Cancer Guideline Panel and ASCO, weevaluated current evidence on the effectiveness of localprimary therapy in high-risk and locally advanced PCa.Based on the results of this SR, both RP as part ofmultimodal treatment and EBRT + long-term ADT can berecommended as primary treatment in high-risk andlocally advanced PCa. For high-risk PCa, EBRT + BT can alsobe offered despite more grade 3 toxicity. Interestingly, forselected patients, for example, those with higher comor-bidity, a shorter duration of ADT might be an option. Forlocally advanced PCa, EBRT + BT shows promising resultbut still needs further validation. In this setting, it isimportant for patients to be aware that the offered therapywill most likely be in the context of a multimodalitytreatment plan. In particular, if radiation is used, thecombination of local and systemic treatment provides thebest outcome, provided that the patient is fit enough toreceive both. Until the results of the SPCG15 trial areknown, the optimal local treatment remains a matter ofdebate. Patients should at all times be fully informedabout all available options and the likelihood of amultimodal approach, including the potential side effectsof both local and systemic treatment.

This SR was performed under the auspices of the EAUGuidelines Office Board, the EAU Prostate Cancer GuidelinePanel, and the American Society of Clinical Oncology.

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Author contributions: Lisa Moris had full access to all the data in thestudy and takes responsibility for the integrity of the data and theaccuracy of the data analysis.Study concept and design: Moris, Van den Broeck, De Santis, Mason,Willemse, Lam, Cornford, Mottet, Konety, Dorff, Jain, Wiegel.Acquisition of data: Moris, Cumberbatch, Gandaglia, Fossati, Kelly, Pal,Van den Broeck, van den Bergh, Willemse, Yuan.Analysis and interpretation of data: Moris, Van den Broeck, van den Bergh,Tilki, Briers, Gillessen, Grummet, Henry, De Santis, Mason, Cornford,Mottet, Konety, Dorff, Jain, Wiegel.Drafting of the manuscript: Moris, Van den Broeck, Cornford.Critical revision of the manuscript for important intellectual content: Moris,Cumberbatch, Gandaglia, Fossati, Kelly, Pal, Van den Broeck, van denBergh, Omar, Tilki, Briers, Gillessen, Grummet, Henry, Lardas, Liew,Rouvière, De Santis, Mason, Schoots, van Der Kwast, van der Poel, Fanti,Willemse, Yuan, Lam, Cornford, Mottet, Konety, Dorff, Jain, Wiegel.Statistical analysis: None.Obtaining funding: None.Administrative, technical, or material support: None.Supervision: Wiegel, Mottet, Cornford, Van den Broeck, Moris.Other: None.

Financial disclosures: Lisa Moris certifies that all conflicts of interest,including specific financial interests and relationships and affiliationsrelevant to the subject matter or materials discussed in the manuscript (eg,employment/affiliation, grants or funding, consultancies, honoraria, stockownership or options, expert testimony, royalties, or patents filed,received, or pending), are the following: Professor Dr. D. Tilki receivedspeaker honorarium from Astellas and a travel grant from Janssen. Dr. E.Briers has received grant and research support from IPSEN, the EuropeanAssociation of Urology, and Bayer; is an ex officio board member for EuropaUOMO; is an ethics committee and advisory group member for REQUITE; isa patient advisory board member for PAGMI; and is a member of SCA andEMA PCWP. Professor Gillessen has served on advisory boards for Orion,Innocrin, Clovis, Bayer, AAA International, Roche, Menarini, Sanofi, andProteoMedix; receives company speaker honorarium from Janssen; andhas served on the IDMC for Janssen. Professor Dr. J.P. Grummet receivedspeaker honorarium from Mundipharma, a travel grant from Astellas, anda research grant from Cancer Australia; and is the owner of MRI PRO PtyLtd., an online training platform. Professor Dr. A.M. Henry participates intrials by Cancer Research UK and the National Institute of Health Research;her department receives research grants from Cancer research UK, TheMedical Research Council, and the National Institute of Health. ProfessorDr. M. De Santis is a company consultant for Amgen, Astellas, AstraZeneca,Bayer, Bristol-Myers Squibb, Celgene, Dendreon, Eisai Inc., ESSA, Ferring,GSK, Incyte, IPSEN, Janssen Cilag, Merck, MSD, Novartis, Pfizer, Pierre FabreOncologie, Roche, Sanofi Aventis, SeaGen, Shionogi, Synthon, Takeda, Teva,OncoGenex, and Sandoz; receives speaker honoraria from Amgen, Astellas,AstraZeneca, Bayer, Bristol-Myers Squibb, Ferring, GSK, IPSEN, JanssenCilag, Merck, MSD, Novartis, Pfizer, Pierre Fabre Oncologie, Roche, SanofiAventis, Synthon, and Takeda; participates in trials run by the TechnicalUniversity Munich, Amgen, Astellas, AstraZeneca, Bayer, Bristol-MyersSquibb, Celgene, Dendreon, Eisai Inc., Ferring, GSK, IPSEN, Incyte, JanssenCilag, Merck, MSD, Novartis, Pfizer, Pierre Fabre Oncologie, Roche, SanofiAventis, SOTIO, and Cancer Research UK; participates in various trials as amember of the EORTC GU group; and has received research grants fromPierre Fabre Oncologie, and travel grants from Amgen, Astellas,AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Dendreaon, Ferring,GSK, IPSEN, Incyte, Janssen Cilag, Merck, MSD, Novartis, Pfizer, Pierre FabreOncologie, Roche, Sanofi Aventis, SeaGen, Shionogi, Synthon, Takeda, andTeva/OncoGenex. Professor Dr. M.D. Mason is a company consultant forEllipses Pharma and Oncotherics. Professor Dr. H.G. van der Poel is acompany consultant for Intuitive Surgical; has participated in trials for

Please cite this article in press as: Moris L, et al. Benefits and RisAdvanced Prostate Cancer: An International Multidisciplinary Seururo.2020.01.033

Astellas and Steba Biotech; and has received grant and research supportfrom Astellas. Professor Dr. S. Fanti is a company consultant for Bayer andANMI; has received speaker honorarium from Bayer, Genzyme, ANMI, andGE Healthcare; and participates in trials by Amgen, Bayer, BMS, Genzyme,Janssen, Merck, and Novartis. Dr. T.B.L. Lam is a company consultant for andhas received company speaker honoraria from Pfizer, GSK, Astellas, andIPSEN. Professor Dr. P. Cornford is a company consultant for Astellas, IPSEN,and Ferring; receives company speaker honoraria from Astellas, Janssen,IPSEN, and Pfizer; participates in trials run by Ferring; and receivesfellowships and travel grants from Astellas and Janssen. Professor Dr. N.Mottet is a company consultant for Janssen, GE, BMS, Sanofi, and Astellas;has received speaker honoraria from Astellas, Pierre Fabre, Steba, Janssen,and Ferring; and has received fellowships and travel grants from Astellas,IPSEN, Sanofi, Janssen, and Roche. Professor Dr. T. Wiegel is an advisoryboard member for IPSEN; receives company speaker honoraria from IPSENand Hexal; is a member of the Janssen Steering Committee; and hasparticipated in the ATLAS/AUO trial. Dr. L. Moris, Dr. M.G. Cumberbatch, Dr.G. Gandaglia, Dr. N. Fossati, Dr. B. Kelly, Dr. R. Pal, Dr. T. Van den Broeck, Dr. R.C.N. van den Bergh, Dr. M.I. Omar, Dr. M. Lardas, Dr. M. Liew, Professor Dr. O.Rouvière, Dr. I.G. Schoots, Professor Dr. T.H. van Der Kwast, Dr. P-P. M.Willemse, Dr. C.Y. Yuan, Professor Dr. B. Konety, Professor Dr. T. Dorff, andProfessor Dr. S. Jain have nothing to declare.

Funding/Support and role of the sponsor: None.

Appendix A. Supplementary data

Supplementary material related to this article can befound, in the online version, at doi:https://doi.org/10.1016/j.eururo.2020.01.033.

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