Systematic Review and Meta-analysis of Perioperative Outcomes and Complications After Robot-assisted Radical Prostatectomy

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1 EUROPEAN UROLOGY 62 (2012) available at journal homepage: Platinum Priority Review Prostate Cancer Editorial by Peter C. Albertsen on pp of this issue Systematic Review and Meta-analysis of Perioperative Outcomes and Complications After Robot-assisted Radical Prostatectomy Giacomo Novara a, *, Vincenzo Ficarra a,b, Raymond C. Rosen c, Walter Artibani d, Anthony Costello e, James A. Eastham f, Markus Graefen g, Giorgio Guazzoni h, Shahrokh F. Shariat i, Jens-Uwe Stolzenburg j, Hendrik Van Poppel k, Filiberto Zattoni a, Francesco Montorsi l, Alexandre Mottrie b, Timothy G. Wilson m a University of Padua, Padua, Italy; b O.L.V. Robotic Surgery Institute, Aalst, Belgium; c Department of Epidemiology, New England Research Institutes, Inc., Watertown, MA, USA; d University of Verona, Verona, Italy; e Royal Melbourne Hospital, Grattan Street, Melbourne, Australia; f Memorial Sloan-Kettering Cancer Center, New York, NY, USA; g Martini-Clinic, Prostate Cancer Centre, University Hamburg-Eppendorf, Hamburg, Germany; h University Vita-Salute San Raffaele, H. San Raffaele-Turro, Milan, Italy; i Weill Medical College of Cornell University, New York, NY, USA; j University of Leipzig, Leipzig, Germany; k University Hospital, Katholieke Universiteit Leuven, Leuven, Belgium; l University Vita-Salute San Raffaele, H. San Raffaele, Milan, Italy; m City of Hope National Cancer Center, Duarte, CA, USA Article info Article history: Accepted May 22, 2012 Published online ahead of print on June 2, 2012 Keywords: Prostatic neoplasms Prostatectomy Laparoscopy Robotics Abstract Context: Perioperative complications are a major surgical outcome for radical prostatectomy (RP). Objective: Evaluate complication rates following robot-assisted RP (RARP), risk factors for complications after RARP, and surgical techniques to improve complication rates after RARP. We also performed a cumulative analysis of all studies comparing RARP with retropubic RP (RRP) or laparoscopic RP (LRP) in terms of perioperative complications. Evidence acquisition: A systematic review of the literature was performed in August 2011, searching Medline, Embase, and Web of Science databases. A free-text protocol using the term radical prostatectomy was applied. The following limits were used: humans; gender (male); and publications dating from January 1, A cumulative analysis was conducted using Review Manager software v.4.2 (Cochrane Collaboration, Oxford, UK). Evidence synthesis: We retrieved 110 papers evaluating oncologic outcomes following RARP. Overall mean operative time is 152 min; mean blood loss is 166 ml; mean transfusion rate is 2; mean catheterization time is 6.3 d; and mean in-hospital stay is 1.9 d. The mean complication rate was 9, with most of the complications being of low grade. Lymphocele/lymphorrea (3.1), urine leak (1.8), and reoperation (1.6) are the most prevalent surgical complications. Blood loss (weighted mean difference: ; p < ) and transfusion rate (odds ratio [OR]: 7.55; p < ) were lower in RARP than in RRP, whereas only transfusion rate (OR: 2.56; p = 0.005) was lower in RARP than in LRP. All the other analyzed parameters were similar, regardless of the surgical approach. Conclusions: RARP can be performed routinely with a relatively small risk of complications. Surgical experience, clinical patient characteristics, and cancer characteristics may affect the risk of complications. Cumulative analyses demonstrated that blood loss and transfusion rates were significantly lower with RARP than with RRP, and transfusion rates were lower with RARP than with LRP, although all other features were similar regardless of the surgical approach. # 2012 Published by Elsevier B.V. on behalf of European Association of Urology. * Corresponding author. Department of Surgical and Oncological Sciences, Urologic Unit, Via Giustiniani 2, Padua, Italy. Tel ; Fax: address: giacomonovara@gmail.com, giacomo.novara@unipd.it (G. Novara) /$ see back matter # 2012 Published by Elsevier B.V. on behalf of European Association of Urology.

2 432 EUROPEAN UROLOGY 62 (2012) Introduction Radical prostatectomy (RP) is a standard surgical treatment for clinically localized prostate cancer [1]. Robot-assisted RP (RARP) has become a very popular procedure in both the United States and Europe, and it has been estimated that >75 of RPs are performed using the da Vinci platform (Intuitive Surgical Inc., Sunnyvale, CA, USA) [2,3]. As for every surgical procedure, perioperative complications are a major surgical outcome for RP. Some recent populationbased studies evaluated prevalence of complications in large cohort of patients who received retropubic RP (RRP) or minimally invasive RP (MIRP; mainly RARP in the United States) and demonstrated lower risk of complications in patients having robotic surgery [4,5]. However, data from population-based studies might be limited by inaccuracies in data collection that may lead to underreporting of complications and heterogeneity in surgical techniques. We previously reported a systematic review of the literature on RARP demonstrating complication rates ranging from 1.5 to 20 in surgical series published up to 2007 and including the very first cases performed with the da Vinci platform [6]. Moreover, in another systematic review of the literature limited to papers published up to 2008, we demonstrated that prevalence of perioperative complications following RRP, laparoscopic RP (LRP), and RARP was similar [7]. In 2002, Martin et al. proposed a standardized method for reporting complications from surgical procedures. The method was based on 10 criteria, including methods of data accrual, duration of follow-up, presence of outpatient information, definitions of complications, mortality and morbidity rates, procedure-specific complications, severity grading, length of in-hospital stay, and analysis of risk factors [8]. Although such criteria are not routinely applied, some studies evaluated complications following RRP [9],LRP[10],orRARP[11 14] using such standardized criteria. Because of the increasing use of RARP as well as the mounting literature in the field on perioperative complications of RARP, we elected to update our previous systematic reviews. Specifically, we aimed to evaluate complication rates following RARP, risk factors for complications after RARP, and surgical techniques to improve complication rates after RARP. We also performed a cumulative analysis of all studies comparing RARP with RRP or LRP in terms of perioperative complications. 2. Evidence acquisition To update our previous systematic review [6,7], we performed a literature search in August 2011 using the Medline, Embase, and Web of Science databases. The Medline search included only a free-text protocol using the term radical prostatectomy in the title and the abstract fields of the records. The following limits were used: humans; gender (male); and publications dating from January 1, The searches of the Embase and Web of Science databases used the same free-text protocol, keyword, and publication dates. Two authors (G.N. and V.F.) separately reviewed the records to select RARP as well as studies that compared RRP with LRP, RRP with RARP, and LRP with RARP, and discrepancies were resolved by open discussion. Other significant studies cited in the reference lists of the selected papers were evaluated as well as studies published after the systematic search. All noncomparative studies reporting the outcome of RARP for >100 cases were collected. The present review included only studies reporting perioperative complications (excluding functional sequelae such as urinary incontinence or erectile dysfunction). Studies published only as abstracts and reports from meetings were not included in the review. All of the data retrieved from the selected studies were recorded in an electronic database. Quality control of the electronic data recording was performed on a random sample of papers (accounting for about 15 of the articles). All of the papers were categorized according to the 2011 level of evidence for therapy studies: systematic review of randomized trials or n-of-1 trials (level 1); randomized trial or observational study with dramatic effect (level 2); nonrandomized controlled cohort/follow-up study (level 3);, case control study, or historically controlled study (level 4); or mechanism-based reasoning (level 5) [15]. Methodological reporting of complications was evaluated according to the Martin criteria [8] Statistical analysis Cumulative analysis was conducted using Review Manager v.4.2 software designed for composing Cochrane Reviews (Cochrane Collaboration, Oxford, UK). Statistical heterogeneity was tested using the chi-square test. A p value <0.10 was used to indicate heterogeneity. Where there was a lack of heterogeneity, fixed effects models were used for the cumulative analysis. Random effects models were used in case of heterogeneity. For continuous outcomes, the results were expressed as weighted mean differences (WMDs) and standard deviations (SDs); for dichotomous variables, results were given as odds ratios (ORs) and 95 confidence intervals (CIs). Due to limitations in the Review Manager v.4.2 software, meta-analysis of continuous variables was possible only when rough data were presented as mean SD. For all statistical analyses, a two-sided p < 0.05 was considered statistically significant. 3. Evidence synthesis 3.1. Quality of the studies and level of evidence Figure 1 shows the flowchart of this systematic review of the literature. We selected 110 records reporting oncologic outcomes after RARP. One further study (level 2) published during the realization of the systematic review was also added [16]. Thirty-six abstracts or meeting reports and three duplicate publications were excluded. The remaining studies were 21 (level 4), 32 studies comparing different techniques in the context of RARP (5 studies, level 2;

3 EUROPEAN UROLOGY 62 (2012) Fig. 1 Flow chart of the systematic review. LRP = laparoscopic radical prostatectomy; RARP = robot-assisted radical prostatectomy; RRP = retropubic radical prostatectomy. 18 studies, level 3; 9 studies, level 4); 12 studies comparing RARP with RRP (5 studies, level 3; 7 studies, level 4); and 7 studies comparing RARP with LRP (1 study, level 2; 6 studies, level 4) Perioperative outcomes after robot-assisted radical prostatectomy Table 1 summarizes operative time, blood loss, transfusion rate, catheterization time, and in-hospital stay in the RARP surgical series. Overall mean operative time is 152 min (range: min), mean blood loss is 166 ml (range: ml), mean transfusion rate is 2 (range: 0.5 5), mean catheterization time is 6.3 d (range: d), and mean in-hospital stay is 1.9 d (range: 1 6 d) Perioperative outcomes after robot-assisted radical prostatectomy in difficult cases Table 2 summarizes the studies assessing the effects of particular patient characteristics on perioperative outcomes. Specifically, three studies evaluated the impact of patients body mass index (BMI) [32 34], one study evaluated prior abdominal surgery [35], five studies evaluated prostate volume [36 40], one study evaluated clinical tumor stage [41], and one study evaluated prior surgery for benign prostatic hyperplasia (BPH) [40] and presence of median lobe [40]. Higher patient BMI was associated with longer operative time in all of the studies but failed to be associated with the other perioperative outcomes. Similarly, higher prostate volume was associated with longer operative time, higher blood loss, longer catheterization time, and slightly longer in-hospital stay in virtually all studies. Prior BPH surgery was associated with longer operative time, and presence of median lobe was associated with longer operative time and higher blood loss [40] Aspects of surgery influencing perioperative outcomes after robot-assisted radical prostatectomy Table 3 summarizes the studies that evaluated the association of surgeon experience with perioperative outcomes. Zorn et al. compared operative time and estimated blood loss for the first 700 RARPs performed in a high-volume institution. They stratified patients into three consecutive groups (cases 1 300, cases , and cases ) and demonstrated significant improvements in both parameters based on surgical experience [42]. Two other studies compared the performance of surgeons who had fellowship training in RARP and surgeons without RARP training [43,44]. Kwon et al. demonstrated that fellowship-trained surgeons outperformed surgeons who had previously performed >25 LRPs only in terms of mean operative time (205 min vs 229 min, p = ), whereas no differences were observed for the other

4 434 Table 1 Perioperative outcomes in robot-assisted radical prostatectomy series (all level 4 evidence) First author Institution Cases Study design Operative time, min, median/mean Blood loss, ml, median/mean Transfusion Catheterization duration, d (range) In-hospital stay, d (range) Patel, 2008 [17] Global Robotic Institute, 1500 Prospective 105 (55 300) 111 (50 500) (4 28) 1 Celebration, FL, USA Tewari, 2008 [18] Weill Cornell Medical 215 Prospective (4 14) College, NY, USA Carlucci, 2009 [19] Mount Sinai Medical Center, 700 Prospective 124 (48 266) 69 (5 400) 0 7 (4 30) 1 NY, USA Greco, 2009 [20] Northwesterm University, 180 Prospective Chicago, IL, USA Jaffe, 2009 [21] Montsuris, Paris, France 293 Prospective Martin, 2009 [22] Mayo Clinic Arizona, Phoenix, 509 Retrospective AZ, USA Murphy, 2009 [23] Melbourne, Australia 400 Prospective Coelho, 2010 [12] Global Robotic Institute, 2500 Prospective 90 (75 100) 100 ( ) (4 6) 1 Celebration, FL, USA Davis, 2010 [24] University of Texas MD 178 Prospective 246 ( ) 200 (35 850) Anderson Cancer Center, Houston, TX, USA Jeong, 2010 [25] Robert Wood Johnson 200 Retrospective 212 ( ) 189 (50 800) Medical School, NJ, USA Lasser, 2010 [26] Warren Alpert Medical 239 Prospective ( ) (1 23) School at Brown University, Providence, RI, USA Lee, 2010 [27] Yonsei University College of 307 Unclear Medicine, Seoul, Korea Novara, 2010 [11] University of Padua, Italy 415 Prospective ( ) 5 5 (4 7) 6 (5 7) Ploussard, 2010 [28] Creteil, Paris, France 206 Prospective Bolenz, 2011 [29] University of Texas 264 Retrospective 235 ( ) 5 1 (1 2) Southwestern Medical Center, Dallas, TX, USA Heldt, 2011 [30] Loma Linda University, Loma Linda, CA, USA 418 Retrospective Jayram, 2011 [31] University of Chicago, Chicago, IL, USA 148 (D Amico high risk) Prospective 150 ( ) 3 6 (5 8) Mean (range) 152 (90 291) 166 (69 534) 2 (0.5 5) 6.3 (5 8.6) 1.9 (1 6) EUROPEAN UROLOGY 62 (2012)

5 Table 2 Perioperative outcomes in robot-assisted radical prostatectomy series stratified by patient characteristics First author Institution Cases Study design and level of evidence Operative time, min, median/mean Blood loss, ml, median/mean Transfusion Catheterization duration, d In-hospital stay, d Patient s BMI Wiltz, 2009 [32] University of Chicago, IL, USA BMI <25: 216 Prospective comparative * BMI 25 30: 464 study, level * BMI >30: * Moskovic, 2010 [33] Mount Sinai Medical Center, BMI <25: 270 Prospective comparative 121 * * New York, NY, USA BMI 25 30: 600 study, level * * BMI >30: * * Zilberman, 2011 [34] Duke University Medical BMI <25: 100 Prospective comparative 159 ( ) * 150 ( ) Center, Durham, NC, USA BMI : 286 study, level ( ) * 150 ( ) BMI : ( ) * 150 ( ) BMI >35: ( ) * 150 ( ) Ginzburg, 2010 [35] Connecticut Health Center, Farmington, CT, USA Prior abdominal surgery Prior abdominal surgery: 251 Prospective comparative No prior abdominal surgery: 588 study, level Prostate volume or size Link, 2008 [36] City of Hope, Duarte, CA, USA Prostate volume <30 cm 3 : 69 Prospective comparative * 200 ( ) * (6 8) * Prostate volume cm 3 : 883 study, level * 200 ( ) * (6 8) * Prostate volume cm 3 : * 200 ( ) * (6 8) * Prostate volume 70 cm 3 : * 250 ( ) * (7 8) * Allaparthi, 2010 [37] Turfts University, Brighton, Prostate volume <30 cm 3 : 10 Prospective comparative ( ) 1 MS, USA Prostate volume cm 3 : 182 study, level ( ) (1 12) Prostate volume cm 3 : ( ) (1 2) Prostate volume 80 cm 3 : (50 550) 1.4 (1 5) Martinez, 2010 [38] Skolarus, 2010 [39] Huang, 2011 [40] Ham, 2009 [41] Huang, 2011 [40] Huang, 2011 [40] University of Western Ontario, London, Ontario, Canada University of Michigan Health System, Ann Arbor, MI, USA Harvard Medical School, Boston, MA, USA Yonsei University College of Medicine, Seoul, Korea Harvard Medical School, Boston, MA, USA Harvard Medical School, Boston, MA, USA BMI = body mass index; BPH = benign prostatic hyperplasia. * Statistically significant. Prostate volume <40 cm 3 : 75 Prospective comparative * Prostate volume cm 3 : 51 study, level * Prostate volume >60 cm 3 : * Prostate volume <50 cm 3 : 582 Retrospective comparative 232 * 155 * Prostate volume cm 3 : 279 study, level * 169 * Prostate volume >100 cm 3 : * 250 * Prostate size: g: 221 Prospective * * 0.5 * * * Prostate size: g: * * 0 * * * Prostate size: 51 62:g: * * 0 * * * Prostate size: >62 g: * * 2 * * * ct stage ct1 2: 200 Retrospective comparative ct3: 121 study, level Prior BPH surgery Prior BPH surgery: 59 Prospective comparative * No prior BPH surgery: 892 study, level * Presence of median lobe Median lobe: 42 Prospective comparative * * No median lobe: 909 study, level * * EUROPEAN UROLOGY 62 (2012)

6 436 EUROPEAN UROLOGY 62 (2012) Table 3 Perioperative outcomes in robot-assisted radical prostatectomy series stratified by surgical experience In-hospital stay, d (range) Catheterization duration, d Transfusion Blood loss, ml, median/mean (range) First author Institution Cases Study design Operative time, min, median/mean (range) Zorn, 2009 [42] University of Chicago, IL, USA Cases Prospective comparative 286 ( ) * 266 ( ) * Cases study, level ( ) * 190 ( ) * Cases (94 400) * 169 ( ) * 205 (63 551) * 100 (25 700) (1 5) Prospective comparative study, level RARP by 4 fellowship-trained surgeons 229 ( ) * 100 (5 500) (0 7) Kwon, 2010 [43] Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA 165 RARP by 8 robotically naïve LRP surgeons 2 Prospective comparative study, level 3 60 RARP by 2 fellowship-trained urologists Leroy, 2010 [44] Mayo Clinic Florida, Jacksonville, FL, USA 3 90 RARP by 3 open surgeons moving to RARP LRP = laparoscopic radical prostatectomy; RARP = robot-assisted radical prostatectomy. Statistically significant. * parameters [43]. Similarly, Leroy et al. demonstrated similar performances in terms of perioperative parameters for fellowship-trained RARP surgeons and RRP surgeons moving to RARP [44]. Table 4 summarizes all of the studies evaluating the impact of different modifications in RARP technique on perioperative outcomes. Technical details for virtually all RARP steps were addressed. Perioperative outcomes were not affected by the adoption of the transperitoneal approach compared with the extraperitoneal approach [45], by preservation of the bladder neck [46], orbythe adoption of interfascial dissection of the neurovascular bundle [47]. Statistically significant but not clinically relevant impact on operative time and blood loss was observed in one study comparing nerve-sparing approach without countertraction and the standard technique [48]. Three studies evaluated the effect of specific techniques for control of the dorsal venous complex (DVC) on perioperative outcomes. Guru et al. [49] and Lei et al. [51] demonstrated that incision of the DVC without ligation was followed by significantly shorter operative time and higher blood loss compared with incision after ligation. However, incision of the DVC without ligation was associated with a significantly lower apical positive surgical margin rate [49] and better early continence rates [51]. Meta-analysis of rates for operative time (WMD: 51.2; 95 CI, to 20.29; p = 0.16), blood loss (WMD: 10.2; 95 CI, 3.1 to 23.6; p = 0.13), and transfusion (OR: 3.54; 95 CI, ; p = 0.27) did not demonstrate any significant difference between the two techniques (Fig. 2A 2C). Wu et al. compared zero-polyglactin suture of the DVC with staple ligation and found that staple ligation was followed by significantly lower blood loss [50]. Eight studies evaluated the impact of anterior [52,54,57,58], posterior [53,55], or complete anterior and posterior [16,56,57] reconstruction of the vesicourethral junction. Most of the studies failed to demonstrate any significant impact on the main perioperative outcomes. Only Sammon et al. demonstrated, in a small randomized controlled trial (RCT), a significant decrease in catheterization time for patients receiving a double-layer urethrovesical anastomosis ( d vs d, p = 0.03) [56]. Meta-analysis of catheterization time was possible only for anterior reconstruction versus standard vesicourethral anastomosis and did not demonstrate any significant difference between the two techniques (WMD: 0.01; 95 CI, 0.21 to 0.22; p = 0.96) (Fig. 3). Finally, two small RCTs compared the use of barbed and standard monofilament suture for vesicourethral anastomosis [59,60]. Williams et al. demonstrated a significantly lower catheterization time for those patients having anastomosis with barbed suture [59], whereas Sammons et al. failed to detect any statistically significant difference [60]. A meta-analysis of the catheterization time in the two studies did not demonstrate any significant difference between barbed and standard suture (WMD: 0.73; 95 CI, 2.76 to 4.22; p = 0.68) (Fig. 4).

7 Table 4 Perioperative outcomes in robot-assisted radical prostatectomy (RARP) series with different RARP surgical techniques First author Institution Cases Study design and level of evidence Operative time, min, median/mean Blood loss, ml, median/mean Transfusion Catheterization duration, d In-hospital stay, d Chung, 2011 [45] Freire, 2009 [46] Yonsei University College of Medicine, Seoul, Korea Harvard Medical School, Boston, MA, USA Transperitoneal vs extraperitoneal approach Extraperineal: 155 Retrospective Transperineal: 105 comparative study with historical control, level 4 Bladder neck preservation Bladder neck preservation: 348 Prospective comparative Standard: 271 study, level Shikanov, 2009 [47] Kowalczyk, 2011 [48] Guru, 2009 [49] Wu, 2010 [50] Lei, 2011 [51] University of Chicago, IL, USA Harvard Medical School, Boston, MA, USA Roswell Park Cancer Institute, Buffalo, NY, USA Northwestern University, Chicago, IL, USA Harvard Medical School, Boston, MA, USA Neurovascular bundles dissection Extrafascial NS: 110 Prospective comparative 180 ( ) 150 ( ) Interfascial clipless NS: 703 study, level (85 520) 150 ( ) NS without countertraction: 342 Prospective comparative 130 ( ) * 175 ( ) * 1 NS with countertraction: 268 study with historical 135 ( ) * 150 ( ) * 0 control series, level 4 Dorsal venous complex control Incision of the DVC without ligation: 145 Prospective comparative * * 1 Ligation of the DVC before apex dissection: 158 study, level * * 0 DVC suture: 67 Prospective comparative * DVC staple ligation: 95 study with historical * control series, level 4 Division and selective suturing of the DVC: 240 Prospective comparative * * Standard: 303 study, level * * Anterior and posterior reconstruction Patel, 2009 [52] Global Robotic Institute, Periurethral suspension stitch: 237 Prospective comparative Celebration, FL, USA Standard: 94 study, level Kim, 2010 [53] Ewka Womans University, Posterior reconstruction: 25 Retrospective Seoul, Korea Standard: 25 comparative study, level Koliakos, 2010 [54] OLV Hospital, Aalst, Belgium Anterior and posterior reconstruction: 24 Prospective randomized Standard: 26 study, level Joshi, 2010 [55] Netherlands Cancer Institute, Posterior reconstruction: 53 Prospective comparative Amsterdam, The Netherlands Standard: 54 study, level Sammon, 2010 [56] Vattikuti Urology Institute, Single layer urethrovesical anastomosis: 50 Prospective randomized * Detroit, MI, USA Double-layer urethrovesical anastomosis: 46 study, level * Tan, 2010 [57] Weill Cornell Medical Standard: 214 Prospective 187 ( ) 150 ( ) College, New York, NY, USA Anterior reconstruction: 303 with historical control, 185 ( ) 150 ( ) Total anatomic restoration: 1383 level ( ) 140 ( ) Johnson, 2011 [58] University of Michigan Anterior reconstruction: 87 Prospective * Health System, Ann Standard: 142 with historical control, * Arbor, MI, USA level 4 Hurtes, 2012 [16] Multicenter Anterior and posterior reconstruction: 39 Prospective randomized 200 ( ) 300 ( ) 6 (5 40) 6 (2 11) Standard: 33 study, level ( ) 300 ( ) 7 (5 20) 6 (2 18) Williams, 2010 [59] Sammon, 2011 [60] Harvard Medical School, Boston, MA, USA Vattikuti Urology Institute, Detroit, MI, USA DVC = dorsal venous complex; NS = nerve sparing. * Statistically significant. Barbed suture for anastomosis Barbed monofilament suture: 45 Prospective randomized * Standard monofilament suture: 36 study, level * Barbed monofilament suture: 33 Prospective randomized 184 ( ) 150 (75 150) Standard monofilament suture: 31 study, level ( ) 100 (50 150) EUROPEAN UROLOGY 62 (2012)

8 438 EUROPEAN UROLOGY 62 (2012) Fig. 2 Comparison of (A) operative time, (B) blood loss, and (C) transfusion rates in robot-assisted radical prostatectomy following incision of the dorsal venous complex without ligation and incision after ligation. CI = confidence interval; DVC = dorsal venous complex; lig = ligation; SD = standard deviation; WMD = weighted mean difference. Fig. 3 Catheterization time in robot-assisted radical prostatectomy following anterior reconstruction or standard vesico-urethral anastomosis. CI = confidence interval; SD = standard deviation; WMD = weighted mean difference.

9 EUROPEAN UROLOGY 62 (2012) Fig. 4 Catheterization time in robot-assisted radical prostatectomy following vesico-urethral anastomosis with barbed monofilament suture or standard monofilament. CI = confidence interval; RARP = robot-assisted radical prostatectomy; SD = standard deviation; WMD = weighted mean difference Overall complication rates after robot-assisted radical prostatectomy Table 5 summarizes overall complication rates in RARP published between 2008 and The mean complication rate was 9 (range: 3 26). Specifically, the mean complication rates by grade were as follows: grade 1, 4 (range: ); grade 2, 3 (range: 2 9); grade 3, 2 (range: 0.5 7); grade 4, 0.4 (range: 0 1.5); grade 5, 0.02 (range: 0 0.5). Only three studies complied with at least 9 of the Martin criteria [11 13], and only one complied with all 10 [11]. Table 6 summarizes prevalence of specific complications in RARP published between 2008 and Lymphocele/ lymphorrea (mean 3.1; range ), urine leak (mean 1.8; range ), and reoperation (mean 1.6; range 0.5 7) were the most prevalent surgical complications Aspects of surgery influencing complication rates and predictors for complications after robot-assisted radical prostatectomy Table 7 summarizes the studies assessing the effects of particular patient characteristics on complication rates. Specifically, one study evaluated the impact of patients BMI [32], one study evaluated prior abdominal surgery [35], two studies evaluated prostate volume [36,37], and one study evaluated clinical tumor stage [41]. All of the studies were of limited methodological quality, according to the Martin criteria. Only Link et al. demonstrated a statistically significant association between prostate volume and overall complication rates in univariable analysis, with patients with larger prostate being at higher risk of complications [36]. Conversely, Allaparthi et al. failed to demonstrate the same finding [37]. Table 8 summarizes the studies that evaluated the association of surgeon experience and surgical technique modifications with complication rates. Zorn et al. compared complication rates for the first 700 RARPs and demonstrated stable complication rates in the three consecutive groups (cases 1 300, cases , and cases ) [42]. Ou et al. adopted a similar approach in a smaller series of 200 cases stratified into four blocks (cases 1 50, cases , cases , cases ) and demonstrated rates for overall complications (18 vs 12 vs 18 vs 0, p = 0.017), minor complications (14 vs 10 vs 14 vs 0, p = 0.017), and major complications (4 vs 2 vs 4 vs 0, p = 0.017) that were significantly lower in the last 50 cases than in the prior 150 [63]. One other study compared the performance of surgeons who had fellowship training in RARP and surgeons without RARP training and demonstrated nonstatistically significant differences in overall, low-grade, and high-grade complications [43]. With regard to surgical technique modifications, data were available regarding comparisons of extraperitoneal and intraperitoneal approaches [45], anterior urethropexy versus standard [58], and posterior musculofascial reconstruction versus no reconstruction [55], and anterior and posterior reconstruction versus no reconstruction [16]. All of the studies failed to comply with many Martin criteria. Only the extraperitoneal approach for RARP was shown to be associated with a lower risk of complications compared with the transperitoneal approach (7 vs 19) [45], whereas anterior, posterior, and anterior plus posterior reconstruction of the vesicourethral anastomosis did not affect complication rates [16,55,58]. None of these studies reported formal multivariable models for assessment of predictors for complications. Deeper insights were provided by two further studies using multivariable models to evaluate predictors of complications [11,13]. Specifically, Novara et al. found that prostate volume and number of cases performed were independent predictors of the occurrence of complications of any grade, whereas only the number of cases performed was an independent predictor of high-grade complications [11]. Agarwal et al. analyzed a very large series of >3000 patients including >320 complications. They demonstrated that preoperative prostate-specific antigen (PSA) and presence of cardiac comorbidity were independent predictors of medical complications of any grade, whereas age, biopsy Gleason score, presence of hyperlipidemia, and gastroesophageal reflux disease were associated with surgical complications of any grade [13] Cumulative analysis of studies comparing robot-assisted radical prostatectomy with retropubic radical prostatectomy or laparoscopic radical prostatectomy Table 9 summarizes the comparative studies evaluating RRP and RARP that report perioperative parameters and

10 440 Table 5 Overall complication rates and grade of complications in robot-assisted radical prostatectomy series (all level 4 evidence) First author Institution Cases Study design Martin criteria Overall complication Complication Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Fischer, 2008 [61] Patel, 2008 [17] Carlucci, 2009 [19] Martin, 2009 [22] Klinich Hirslanden, Zurich, Switzerland Global Robotic Institute, Celebration, FL, USA Mount Sinai Medical Center, NY, USA Mayo Clinic, Phoenix, AZ, USA 210 Case series (unclear if prospective) 1500 Prospective 700 Prospective 509 Retrospective Murphy, 2009 [23] Melbourne, Australia 400 Prospective Coelho, 2010 [12] Jeong, 2010 [25] Lasser, 2010 [26] Novara, 2010 [11] Global Robotic Institute, Celebration, FL, USA Robert Wood Johnson Medical School, NJ, USA Warren Alpert Medical School at Brown University, Providence, RI, USA University of Padua, Padua, Italy 2500 Prospective 200 Retrospective 239 Prospective 415 Prospective Ploussard, 2010 [28] Creteil, Paris, France 206 Prospective Agarwal, 2011 [13] Bolenz, 2011 [29] Heldt, 2011 [30] Jayram, 2011 [31] Lebeau, 2011 [62] Vattikuti Urology Institute, Detroit, MI, USA University of Texas Southwestern Medical Center, Dallas, TX, USA Loma Linda University, Loma Linda, CA, USA University of Chicago, Chicago, IL, USA Pitié-Salpetriere Hospital, Paris, France 3317 Prospective 264 Retrospective 418 Retrospective 148 (D Amico high risk) Prospective 240 Prospective 4 fulfilled fulfilled fulfilled 3 3 fulfilled fulfilled fulfilled fulfilled fulfilled fulfilled fulfilled fulfilled case 3 fulfilled 3 3 fulfilled 16 7 fulfilled fulfilled Mean (range) 9 (3 26) 4 (2 11.5) 3 (2 9) 2 (0.5 7) 0.4 (0 1.5) 0.02 (0 0.5) EUROPEAN UROLOGY 62 (2012)

11 Table 6 Specific surgical complications in robot-assisted radical prostatectomy series (all level 4 evidence) First author Institution Cases Rectal injury, Hematoma, Lymphocele/ lymphorrhea, Deep venous thrombosis/pulmonary embolism, Urine leak, Urinary retention, Wound complications, Neurapraxia, Reoperation, Mortality, Fischer, 2008 [61] Klinich Hirslanden, Zurich, Switzerland Patel, 2008 [17] Global Robotic Institute, Celebration, FL, USA Carlucci, 2009 [9] Mount Sinai Medical Center, New York, NY, USA Martin, 2009 [22] Mayo Clinic Arizona, Phoenix, AZ, USA Murphy, 2009 [23] Epworth Hospital, Richmond, and Royal Melbourne Hospital, Australia Coelho, 2010 [12] Global Robotic Institute, Celebration, FL, USA Jeong, 2010 [25] Robert Wood Johnson Medical School, NJ, USA Lasser, 2010 [26] Warren Alpert Medical (1 case) School at Brown University, Providence, RI, USA Novara, 2010 [11] University of Padua, Padua, Italy Ploussard, 2010 [28] Creteil, Paris, France Agarwal, 2011 [13] Vattikuti Urology (1 case) Institute, Detroit, MI, USA Lebeau, 2011 [62] Pitié-Salpetriere Hospital, Paris, France Mean (range) 0.2 (0 1.5) 0.3 ( ) 3.1 (1.2 29) 0.2 (0 0.7) 1.8 ( ) 0.7 (0.4 4) 0.5 (0.1 2) 0.2 (0 1.5) 1.6 (0.5 7) 0.02 (0 0.4) EUROPEAN UROLOGY 62 (2012)

12 442 EUROPEAN UROLOGY 62 (2012) Table 7 Overall complication rates in robot-assisted radical prostatectomy series stratified by patient characteristics Complication Overall complication Martin criteria First author Institution Cases Study design and level of evidence Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 BMI <25: 216 Prospective comparative 7 fulfilled BMI 25 30: 464 study, level Wiltz, 2009 [32] University of Chicago, Chicago, IL, USA BMI >30: BMI 30 39: BMI >39: 23 9 Prior abdominal surgery: 251 Prospective comparative 7 fulfilled No prior abdominal surgery: 588 study, level Ginzburg, 2010 [35] Connecticut Health Center, Farmington, CT, USA ct1 2: 200 Retrospective comparative 5 fulfilled ct3: 123 study, level Ham, 2009 [41] Yonsei University College of Medicine, Seoul, Korea Prostate volume <30: 69 Prospective comparative 5 fulfilled 4.4 * : 883 study, level * Link, 2008 [36] City of Hope, Duarte, CA, USA 50 69: * 70: * Prostate volume <30 cm 3 : 10 Prospective comparative 6 fulfilled Prostate volume cm 3 : 182 study, level Allaparthi, 2010 [37] Turfts University, Brighton, MS, USA Prostate volume cm 3 : Prostate volume 80 cm 3 : Statistically significant. * complication rates. Cumulative analyses showed statistically significant differences in terms of rates for blood loss (WMD: ; 95 CI, ; p < ) and transfusion (OR: 7.55; 95 CI, ; p < ) in favor of RARP, whereas rates for operative time (WMD: 15.8; 95 CI, to 37; p = 0.56) and overall complications (OR: 1.25; 95 CI, ; p = 0.61) were similar for RARP and RRP (Fig. 5). Meta-analysis of catheterization time and in-hospital stay was not possible. Table 10 summarizes the comparative studies evaluating LRP and RARP that report perioperative parameters and complication rates. Rates for operative time (WMD: 34.78; 95 CI, 1.36 to 70.93; p = 0.06), blood loss (WMD: 54.21; 95 CI, to ; p = 0.41), and overall complications (OR: 1.4; 95 CI, ; p = 0.31) were similar for LRP and RARP. Only the transfusion rate (OR: 2.56; 95 CI, ; p = 0.005) was significantly lower in RARP patients (Fig. 6). Meta-analysis of catheterization time and in-hospital stay was not possible. 4. Discussion The data of the present systematic review suggest that RARP can be performed routinely in a reasonably short operative time, with low risk of blood loss and low transfusion rates. Some patient characteristics such as high BMI, large prostate volume, prior abdominal surgery, prior BPH surgery, or presence of median lobe may make the surgical procedure more difficult, possibly increasing operative time, blood loss, or catheterization time. Currently, postoperative complications are relatively uncommon, with overall mean figures around 10, but high-grade complications following RARP are quite uncommon. As expected, surgical experience plays a role in improving perioperative outcomes and complications, along with some clinical patient characteristics (eg, presence of comorbidities) and cancer characteristics (eg, PSA, biopsy Gleason score). Finally, cumulative analyses demonstrated that blood loss and transfusion rates were significantly lower with RARP than with RRP, and transfusion rates were lower with RARP than with LRP, although all other features were similar regardless of the surgical approach. As for every surgical procedure, perioperative complications are a major surgical outcome for RP, especially when multiple surgical approaches (ie, RRP, LRP, and RARP) are available. Several population-based studies compared RRP with MIRP, reporting data from different data sets and from different years (Table 11). The largest studies reported rates for overall complications for MIRP between 8 and 20, for medical complications from 5 to 9, for surgical complications from 1.4 to 4.7, and for transfusions as low as 2 [4,5,81]. The data of the present systematic review of the published RARP series showed lower overall complication rates (mean value of about 9) and low prevalence of specific surgical complications, such as lymphocele/lymphorrea, urine leak, and reoperation. Such a difference in overall complications might be explained by considering that population-based studies might be limited by inaccuracies in data collection, by

13 Table 8 Overall complication rates in robot-assisted radical prostatectomy series stratified by surgical experience and surgical technique First author Institution Cases Study design and level of evidence Martin criteria Overall complication Complication Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Zorn, 2009 [42] Ou, 2011 [63] Kwon, 2010 [43] Chung, 2011 [45] Johnson, 2011 [58] Joshi, 2010 [55] University of Chicago, Chicago, IL, USA Taichung Veterans General Hospital, Taiwan Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, USA Yonsei University College of Medicine, Seoul, Korea University of Michigan Health System, Ann Arbor, MI, USA Netherlands Cancer Institute, Amsterdam, The Netherlands No. of cases performed Cases Prospective comparative 7 fulfilled 9 Cases study, level 3 9 Cases Case 1 50 Prospective comparative 7 fulfilled 18 * 2 * 12 * 4 * 0 * 0 Case study, level 3 12 * 6 * 4 * 2 * 0 * Case * 4 * 10 * 0 * 4 * Case * 0 * 0 * 0 * 0 * 121 RARP by 4 fellowshiptrained surgeons 165 RARP by 8 robotically naïve LRP surgeons Hurtes, 2012 [16] Multicenter Anterior and posterior reconstruction: 39 * Statistically significant. Type of training Prospective comparative study, level 3 5 fulfilled Extraperitoneal vs transperitoneal approach Extraperineal: 155 Retrospective comparative 4 fulfilled 7 * Transperineal: 105 study with historical control, level 4 19 * Anterior reconstruction Anterior reconstruction: 87 Prospective with 5 fulfilled 14 Standard: 142 historical control, level 4 20 Posterior reconstruction Posterior reconstruction: 53 Prospective comparative 6 fulfilled 28 Standard: 54 study, level 3 24 Anterior and posterior reconstruction Prospective randomized study, level 2 7 fulfilled Standard: EUROPEAN UROLOGY 62 (2012)

14 444 Table 9 Perioperative parameters and complication rates after retropubic radical prostatectomy and robot-assisted radical prostatectomy Level of evidence First author Cases Operative time, min, median/mean Blood loss, ml, median/mean Transfusion Catheterization duration, d (range) In-hospital stay, d (range) Overall complication 3 Ficarra, 2009 [64] 105 RRP RARP Carlsson, 2010 [65] 485 RRP RARP 10 Doumerc, 2010 [66] 502 RRP 148 (75 330) (6 20) 5.5 (3 10) RARP 192 ( ) (6 21) 2.8 (2 7) 2 Kordan, 2010 [67] 414 RRP 450 ( ) RARP 100 (50 200) 0.8 Di Pierro, 2011 [68] 75 RRP RARP Caballero-Romeu, 2008 [69] 62 RRP 210 ( ) 1500 ( ) (19 26) 8 (7 9) RARP 210 ( ) 400 ( ) (11 14) 5 (4 6) 42 Drouin, 2009 [70] 83 RRP RARP Ou, 2009 [71] 30 RRP RARP Rocco, 2009 [72] 240 RRP RARP Breyer, 2010 [73] 695 RRP RARP 1 Lo, 2010 [74] 20 RRP RARP Truesdale, 2010 [75] 217 RRP RARP EUROPEAN UROLOGY 62 (2012) RARP = robot-assisted radical prostatectomy; RRP = retropubic radical prostatectomy.

15 EUROPEAN UROLOGY 62 (2012) Fig. 5 Comparison of (A) operative time, (B) blood loss, (C) transfusion rates, and (D) complication rates following robot-assisted radical prostatectomy or retropubic radical prostatectomy. CI = confidence interval; RARP = robot-assisted radical prostatectomy; OR = odds ratio; RRP = retropubic radical prostatectomy; SD = standard deviation; WMD = weighted mean difference.

16 446 EUROPEAN UROLOGY 62 (2012) Table 10 Perioperative parameters and complication rates after laparoscopic radical prostatectomy and robot-assisted radical prostatectomy Overall complication In-hospital stay, d (range) Catheterization duration, d (range) Transfusion Blood loss, ml, median/mean (range) First author Cases Operative time, min, median/mean Level of evidence 2 Asimakopoulos, 2011 [76] 64 LRP RARP Caballero-Romeu, 2008 [69] 70 LRP 345 ( ) 1270 ( ) (17 28) 8 (5 10) RARP 210 ( ) 400 ( ) (11 14) 5 (4 6) 42 Cho, 2009 [77] 60 LRP RARP Drouin, 2009 [70] 85 LRP RARP Hakimi, 2009 [78] 75 LRP RARP Trabulsi, 2010 [79] 45 LRP RARP Park, 2011 [80] 62 LRP 308 ( ) 214 (50 600) RARP 371 ( ) 220 (50 700) LRP = laparoscopic radical prostatectomy; RARP = robot-assisted radical prostatectomy. heterogeneity in surgical techniques, and by surgical experience, whereas surgical series should theoretically provide higher accuracy and homogeneity. However, when applying the Martin criteria as a reference standard for reporting complications [8], most of the published reports failed to comply with many criteria, and only three reports complied with nine or more of the Martin criteria [11 13]. Such data indicate that additional literature adopting rigorous methodology for reporting of surgical complications following RARP is needed, and the recently released recommendations of the ad hoc European Association of Urology guidelines panel might be a useful tool [87]. With regard to predictors of complications, the limited literature available showed that some patient characteristics (presence of comorbidity, prostate volume), cancer characteristics (PSA, biopsy Gleason score), and surgical experience [11,13] might predict the risk of complications. ThosedataareinlinewiththoseofotherRRPandLRP series. Specifically, in a large study performed at Memorial Sloan-Kettering Cancer Center that included >3400 RRP and 1100 LRP and complied with all 10 Martin criteria, Rabbani et al. demonstrated that comorbidity (valvular heart disease, procoagulable disease, pulmonary comorbidity, diabetes) and cancer characteristics (prostate volume, biopsy Gleason score) are independent predictors of either medical or surgical complications [9]. Notably, with regard to surgical experience, Budaus et al. stratified the risk of complications according to the annual case load in a relatively small population-based cohort of patients included in the Florida Hospital Inpatient Datafile from 2002 to They demonstrated that high-volume surgeons (>63 MIRPs per year) had significantly lower risk of overall complications, transfusions, respiratory complications, and miscellaneous medical and surgical complications in comparison with those performing <15 or MIRPs per year [82]. With regard to the comparisons of perioperative complications among RRP, LRP, and RARP, virtually all of the studies demonstrated better performance for MIRP patients in comparison with RRP, but patient characteristics were often unbalanced in favor of the MIRP groups. Once adjusted for different covariates, MIRP was associated with lower overall complication rates [4,5,83,86]; lower transfusion rates [4,5,81,84,86]; lower risk of cardiac [5], respiratory [5,84], vascular [5], miscellaneous surgical complications [84]; and lower perioperative mortality [4,84] in comparison with RRP. Conversely, in the present systematic review of the comparative studies, we found that only blood loss and transfusion rates were significantly lower for RARP in comparison with RRP, and transfusion rates were significantly lower for RARP in comparison with LRP; all the other parameters were similar regardless of the approach. Conversely, very recently, Tewari et al. reposted a systematic review and meta-analysis of RRP, LRP, and RARP series where propensity-score matching was used to adjust for the differences in preoperative Gleason score, preoperative PSA, and pathologic stage among series. The authors finally found that overall intraoperative complications, perioperative complications, and some other specific complications were

17 EUROPEAN UROLOGY 62 (2012) Fig. 6 Comparison of (A) operative time, (B) blood loss, (C) transfusion rates, and (D) complication rates following robot-assisted radical prostatectomy or laparoscopic radical prostatectomy. CI = confidence interval; LRP = laparoscopic radical prostatectomy; RARP = robot-assisted radical prostatectomy; OR = odds ratio; SD = standard deviation; WMD = weighted mean difference. significantly lower for RARP in comparisons with RRP and LRP [88]. However, although correct to adjust for case selection, the adopted approach was not able to adjust for other surgical covariates (eg, surgical proficiency or case load), which are usually difficult to retrieve from the available publications and may play a major role in perioperative outcomes. Although not clearly shown, it is likely that surgeon experience and patient selection are at least as important

18 448 Table 11 Perioperative complications in minimally invasive radical prostatectomy in population-based studies First, author Database Cases In-hospital stay, d Overall complications, Transfusion Cardiac complications, Respiratory complications, Vascular complications, Wound complications, Genitourinary complications, Miscellaneous medical, Miscellaneous surgical, Mortality, Schmitges, 2011 [81] Budaus, 2011 [82] Hu, 2008 [83] Hu, 2009 [84] Schmitges, 2011 [85] Williams, 2011 [86] Kowalczyk, 2012 [4] Trinh, 2012 [5] MIRP only NIS MIRP > 2 d Florida Hospital Inpatient Datafile Low annual case load (<15 MIRP) Intermediate annual case load (16 63 MIRP) High annual case load (>63 MIRP) 14 * 3.5 * * * 4 * 7.5 * 1 * * * 1.5 * 5.5 * 0.5 * * * 1.5 * Comparing RRP and MIRP 5 Medicare RRP * 36 * 6.6 * 11.7 * *# 8 * 16.3 * 8 sample MIRP * 30 * 4.3 * 6.7 * *# 4.4 * 11 * 6.6 Medicare sample RRP (2 4) * * 3 * 6.8 * MIRP (1 2) * * 2 * 4.2 * NIS RRP * homologous, 6.2 * autologous MIRP * homologous, 0.4 * autologous MarketScan RRP * 8.9 * 1.6 * 4.4 * 2.1 * 1.5 *# 2.6 * 5.8 * 4.1 * Medstat database MIRP * 1.5 * 0.9 * 2.3 * 1.3 * 1 *# 3.4 * 4.4 * 3.3 * Medicare RRP * 29.8 * 17.3 * 4.7 * 9.4 * 4.3 * 3.9 * 6.9 * 12.6 * 6 * 0.6 * sample MIRP * 19.6 * 2.6 * 2.2 * 4.1 * 2.7 * 1.8 * 4.8 * 8.8 * 4.2 * 0.2 * NIS RRP > 2d * 11.1 * * 2.6 * 0.6 * 0.6 * * * MIRP > 2d * 8.2 * * 1.2 * 0.4 * 0.4 * * * EUROPEAN UROLOGY 62 (2012) MIRP = minimally invasive radical prostatectomy; RRP = retropubic radical prostatectomy. * Statistically significant in univariable analysis. # Wound or bleeding.

19 EUROPEAN UROLOGY 62 (2012) as surgical approach in predicting the risk of complications [89]. Although the conclusions of this systematic review represent the best evidence available in the literature, some potential drawbacks must be taken into consideration. It was almost impossible to evaluate the real impact of surgeon ability on the reported results. Specifically, some studies demonstrated that significant oncologic and functional heterogeneity exists among surgeons performing RRP in a single institution, even among high-volume surgeons [90,91]. Although similar data are lacking for perioperative complications, it is likely that a similar effect might exist for RRP as well as for LRP and RARP. The papers included in the present systematic review included only five RCTs [54,56,59,60,76], most of which assessed details of surgical techniques and were underpowered for accurate evaluation of complications. Moreover, most of the other low-quality evidence did not adopt accurate methodology for reporting complications. Finally, our comparative analyses were not adjusted for the baseline differences in patient characteristics and surgical experience. Considering that most of the studies included were not RCTs, it is likely that major differences were present between study arms, and this might account for some of the observed findings. 5. Conclusions The data of the present systematic review suggest that RARP can be performed routinely with a reasonably limited risk of complications, although some patients with unfavorable clinical or cancer characteristics might be at higher risk. Surgical experience may play a role in improving perioperative outcomes and complications, but its impact has not been sufficiently studied. Finally, cumulative analyses demonstrated that blood loss and transfusion rates were significantly lower with RARP than with RRP, and transfusion rates were lower with RARP than with LRP, although all other features were similar regardless of surgical approach. Author contributions: Giacomo Novara 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: Novara, Ficarra, Montorsi. Acquisition of data: Novara. Analysis and interpretation of data: Novara. Drafting of the manuscript: Novara. Critical revision of the manuscript for important intellectual content: Novara, Ficarra, Rosen, Artibani, Costello, Eastham, Graefen, Guazzoni, Shariat, Stolzenburg, Van Poppel, Zattoni, Montorsi, Mottrie, Wilson. Statistical analysis: Novara. Obtaining funding: Wilson. Administrative, technical, or material support: Wilson, Rosen. Supervision: Montorsi, Mottrie, Rosen, Wilson. Other (specify): None. Financial disclosures: GiacomoNovaracertifiesthat all conflicts ofinterest, 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: Giacomo Novara was lecturer/ advisory board member for Astellas, Eli Lilly, Pierre Fabre, Provenge, Recordati Int., Takeda. Vincenzo Ficarra was speaker for Intuitive Surgical, Sunnyvale, CA, USA. Walter Artibani was lecturer for Astellas, Ipsen, Zambon. Giorgio Guazzoni, Francesco Montorsi, and Alexandre Mottrie acknowledge receiving research grants from Intuitive Surgical, Sunnyvale, CA, USA. Funding/Support and role of the sponsor: None. References [1] Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. 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