Objective. Patients and Methods. Conclusion. Results. Keywords. Introduction

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1 Functional and oncological outcomes of patients aged <50 years treated with radical prostatectomy for localised prostate cancer in a European population Andreas Becker*, Pierre Tennstedt*, Jens Hansen*, Quoc-Dien Trinh, Luis Kluth, Nabil Atassi*, Thorsten Schlomm*, Georg Salomon*, Alexander Haese*, Lars Budaeus*, Uwe Michl*, Hans Heinzer*, Hartwig Huland*, Markus Graefen* and Thomas Steuber* *Martini-Clinic, Prostate Cancer Center Hamburg-Eppendorf, Hamburg, Germany, Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada, and Department of Urology, University-Hospital Hamburg-Eppendorf, Hamburg, Germany Objective To address the biochemical and functional outcomes after radical prostatectomy (RP) of men aged <50 yearsinalarge European population. Patients and Methods Among patients who underwent RP for clinically localised prostate cancer at our centre ( ), 443 (3.3%) men aged <50 were identified. Biochemical recurrence (BCR) and functional outcomes (International Index of Erectile Function [IIEF-5], use of pads), were prospectively evaluated and compared between men aged <50 years and older patients. Results Men aged <50 years were more likely to harbour D Amico low-risk (49.4 vs 34.9%, P < 0.001), organ-confined (82.6 vs 69.4%, P < 0.001) and low-grade tumours (Gleason score <7: 33.1 vs 28.7%, P < 0.001). Multivariate Cox regression analysis showed that age <50 years (hazard ratio 0.99; confidence interval ; P = 0.9) was not a predictor of BCR. Urinary continence was more favourable in younger patients, resulting in continence rates of 97.4% vs 91.6% in most recent years ( ) for patients aged <50 vs 50 years. After RP, a median IIEF-5 drop of 4 points in younger men vs 8 points in older patients was recorded (P < 0.001). Favourable recovery of urinary continence and erectile function in patients aged <50 years compared with their older counterparts was confirmed after multivariable adjustment. Conclusion Men aged <50 years diagnosed with localised prostate cancer should not be discouraged from RP, as the postoperative rates of urinary incontinence and erectile dysfunction are low and probability of BCR-free survival at 2and5yearsishigh. Keywords prostate cancer, prostatectomy, prognosis, continence, potency, functional outcomes Introduction The risk of being diagnosed with prostate cancer rises from 1 in 41 patients during the fifth decade of life to 1 in 8 for patients aged >70 years [1]. Accordingly, 80% of prostate cancer cases are diagnosed in men aged 65 years. However, with the widespread use of PSA testing for early diagnosis, a shift towards younger age at diagnosis has been observed concomitantly with the well-described stage migration [2 5]. Specifically, the proportion of patients with prostate cancer aged <50 years has increased during recent decades from 1% in the 1970s and 1980s to 5% in the PSA era [6]. Several earlier publications from the pre-psa era suggested that men aged <50 years present with a more aggressive phenotype and thus, treatment of these tumours might result in worse prognosis relative to their older counterparts [7 9]. However, more contemporary analyses, focussing on North BJU Int 2014; 114: wileyonlinelibrary.com BJU International 2013 BJU International doi: /bju Published by John Wiley & Sons Ltd.

2 Men aged <50 years treated with RP for localised prostate cancer American PSA-screened populations, showed that men aged <50 years who underwent radical prostatectomy (RP) had more favourable pathological features and better oncological outcomes compared to older men [10 12]. However, recent studies have shown geographical differences between the USA and European countries for onset and extent of stage migration in newly diagnosed tumours, potentially resulting from the less intensive PSA screening practice in Europe [13]. Moreover, based on these considerations, we examined the pathological and biochemical outcome in men aged <50 years in a European population of patients treated with RP for clinically localised prostate cancer. Furthermore, we evaluated functional outcomes (erectile function and urinary continence) after RP in younger men and hypothesised that continence and potency rates may be more favourable compared with older men. Patients and Methods Between 1992 and 2011, men were treated with RP for clinically localised prostate cancer at a tertiary care centre. We identified 443 men aged <50 years at RP (3.3%). PSA testing was performed in selected patients with a family history of prostate cancer, unspecific LUTS or as part of a routine check-up examination by referring urologists. However, no systemic PSA screening comparable to the USA or other European countries participating in the European Randomized Study of Screening for Prostate Cancer (ERSPC) study [14], was implemented in Germany. In patients with elevated PSA values or clinical suspicion for prostate cancer, prostate biopsies were taken. Patients with localised prostate cancer where referred for RP after extensive counselling about possible treatment alternatives including active surveillance and radiation therapy, taking into account comorbidity, tumour characteristics and patients preference. Clinical characteristics (PSA level, clinical stage, biopsy Gleason grade) were reported using the D Amico risk groups for disease progression [15]. Standardised self-administrated questionnaires were routinely sent to all patients at 1 year after catheter-removal by our data manager. Information on continence was available for 60.0% of all patients without adjuvant treatment. According to previous publications, urinary continence was defined as use of 0 1 protective pad [16]. Giving consideration to changes in operative technique improving urinary continence recovery, such as implementation of posterior reconstruction [17] and full functional-length urethral sphincter preservation [18], we divided the study cohort in three eras: , 2007/2008 and Erectile function was assessed in 4009 preoperatively potent men who did not receive adjuvant treatment 1 year after nerve-sparing surgery, using a standardised questionnaire, which included the International Index of Erectile Function (IIEF-5). According to previous publications, patients with an IIEF-5 score of >16 (no erectile dysfunction [ED] or mild ED) were considered potent [19]. Clinical, pathological and functional outcomes were compared between men aged <50 years at RP and older patients. Prospective collection of data was approved by our Institutional Review Board and all patients provided written informed consent. Biochemical recurrence (BCR) was defined as a PSA-value of >0.2 ng/ml. All patients underwent open retropubic or robot-assisted RP. Intrafascial nerve-sparing was performed as previously described (NeuroSAFE) [20]. Surgical margins were considered positive if at least one malignant gland had contact with the inked surgical margin. Negative surgical margins were assumed in cases of negative re-resection after positive frozen section margin. Definitive surgical margin status was determined on the whole gland, including the NeuroSAFE sections [20]. We stratified patients at high risk of lymph node invasion who were candidates for lymphadenectomy using previously validated prediction tools to identify patients at risk of lymph node involvement [21]. Pathological outcome was assessed using the American Joint Cancer Committee (AJCC) 2002 staging system and tumour grading was classified using the Gleason Grading system ( ) and revised 2005 Gleason grading system afterwards [22]. Histopathological assessment was performed as previously described [20]. The chi-square/likelihood ratio for nominal variables and the Wilcoxon rank test for continuous variables were used to compare baseline characteristics. A logistic regression analyses was used to estimate the annual change in the proportion of patients aged <50 years undergoing RP at our institution. A propensity-matched analysis was performed in a regression model using time to follow-up as covariate. The R packages non-random was used as previously described [23]. BCR-free survival rates for each group were estimated using Kaplan Meier analysis. The log-rank test was used to compare BCR-free survival of younger vs older men. The impact of age <50 years on BCR-free survival was determined by multivariate cox regression analyses adjusted for preoperative PSA level, pathological Gleason score, local stage (pt), nodal status (pn) and positive surgical margins (PSMs), treatment era ( vs vs ) and robotassisted vs open RP. As interactions between continuously coded variables are difficult to interpret, we categorised PSA levels as 4 vs vs vs >20.0 ng/ml. Multivariable logistic regression analyses predicting recovery of urinary continence at 1 year after surgery were adjusted for treatment era, robot-assisted vs open RP and extent of nerve-sparing (no vs unilateral vs bilateral). Multivariable logistic regression analyses predicting recovery of erectile BJU International 2013 BJU International 39

3 Becker et al. function were additionally adjusted for preoperative IIEF-5 score and the use of phosphodiesterase type 5 (PDE5) inhibitor or intracavernosal injection (ICI) therapy. Results The proportion of patients aged <50 years rose by 3.6% per year (95% CI: %, P = 0.005) from 1.5% in 1992 to 3.8% in Oncological Outcome Within our study cohort, men aged <50 years were more likely to present with D Amico low-risk disease (49.4% vs 34.9%, P < 0.001; Fig. 1), organ-confined (84.2% vs 68.4%, P < 0.001), low-grade (Gleason score <7) tumours (33.1% vs 28.7%, P < 0.001), as well as lower rates of PSMs (11.5% vs 16.8%, P < 0.002; Table 1). Within patients with pt2 tumours, PSMs were found in 7.5% and 9.8% of all patients aged <50 and 50 years, respectively (P = 0.1). More patients aged <50 years underwent bilateral nerve-sparing RP (77.4% vs 61.5%, P < 0.001). There was no statistical difference in nodal status. The mean follow-up was significantly shorter in younger patients (42 vs 54 months; P < 0.001). Salvage radiation therapy was administered in 5.6% and 6.3% (P = 0.05) and salvage hormonal therapy was administered in 3.8% and 4.5% (P = 0.9) of all men aged <50 and 50 years, respectively. After matching for length of follow-up, Kaplan Meier analysis showed more favourable oncological outcomes for men aged <50 years as opposed to their older counterparts (2-, 5- and 10-year BCR-free survival: 89.7%, 80.7% and 63.0% vs 81.7%, 70.0% and 58.3%, respectively; P = 0.006). After multivariable adjustment for patient and tumour characteristics, age <50 years failed to achieve independent predictor status (hazard ratio 0.9; CI ; P = 0.9, Table 2). Urinary Continence The rates of continent patients aged <50 and 50 years were respectively, 97.4% vs 91.6% during the most recent era, 92.8% vs 83.5% (2007/2008) and 90.0% vs 79.0% ( ) (Fig. 2). The number of patients available for evaluation of urinary continence and proportion of patients aged <50 years was similar in each era ( : 90/2908 (3.1%); 2007/2008: 69/2221 (3.1%); : 76/2281 (3.3%), P = 0.9). After multivariable adjustment for extent of nerve sparing and treatment era, patients aged <50 years (odds ratio [OR] 2.5, 95% CI , P < 0.001), represented an independent predictor of urinary continence recovery at 1 year after RP (Table 3). Erectile Function Erectile function was assessed for all patients who underwent nerve-sparing RP (uni- or bilateral) and were potent before RP (IIEF-5 score >16). This resulted in 4009 (35.1%) assessable patients. The median IIEF-5 scores before and after RP were 25and21inpatientsaged<50 years vs 23 and 15 in patients aged 50 years. This represents a median IIEF-5 drop of 4 points in younger men vs 8 points in older men after RP (P < 0.001; Table 4). For the prediction of erectile function recovery at 1 year after RP,patient age <50 represented an independent predictor status after multivariable adjustment for extent of nerve sparing, treatment era, use of PDE5 inhibitor or intracavernous injection therapy (Table 3). Discussion Recent data suggest that tumour formation in young men involves a characteristic pathomechanism, associated with the specific emergence of androgen-driven structural genomic variations, potentially altering the clinical behaviour of these tumours [24]. Traditionally, prostate cancer in younger men was considered to be more aggressive [7 9]. However, contemporary studies on North American patients showed that men aged <50 years who underwent RP had more Fig. 2 Urinary continence at 1 year after RP, stratified by treatment era. Fig. 1 Patients aged <50 years and 50 years stratified according to the D Amico risk classification. Proportion 60% 49.4% 46.9% 50% P < % 34.9% 36.4% 30% 20% 14.2% 18.2% 10% Continent patients, % % Low risk Intermediate risk High risk Age < 50 Age > 50 Age < 50 Age BJU International 2013 BJU International

4 Men aged <50 years treated with RP for localised prostate cancer Table 1 Characteristics of patients who underwent RP for clinically localised prostate cancer between 1992 and Variable Patients aged <50 years Patients aged 50 years P No. of patients, (%) 443 (3.3) (96.7) Median (range) follow-up, months 25 ( ) 37( ) <0.001 N (%): PSA level, ng/ml: <0.001 <4 91 (20.8) 1 688(13.4) (61.6) 7 705(61.0) (10.5) 2 419(19.1) >20 31 (7.1) 827(6.5) Biopsy Gleason score: (61.6) 6 923(54.0) (26.3) 3 429(26.7) (6.5) 1 389(10.8) (5.6) 1 084(8.5) Clinical stage (ct): 0.3 ct1c 349 (82.1) 9 607(78.3) ct2a 43 (10.1) 1 576(12.8) ct2b 20 (4.7) 734(5.8) ct2c 7 (1.6) 176(1.4) ct3 6 (1.4) 204(1.7) D Amico risk group: <0.001 low risk 180 (49.3) 3 693(34.9) intermediate risk 133 (36.4) 4 966(46.9) high risk 52 (14.2) 1 925(18.2) Pathological stage (pt): <0.001 pt2 372 (84.2) 8 718(68.4) pt3a 42 (9.5) 2 594(20.3) pt3b 28 (6.3) 1 442(11.3) Gleason score: < (33.1) 3 636(28.7) (55.9) 6 745(53.3) (8.7) 1 733(13.7) (2.3) 549(4.3) Pathological nodal status (pn): 0.8 pn0 236 (53.6) 6 909(54.4) pn1 20 (4.5) 644(5.1) pnx 184 (41.8) 5 152(40.6) Nerve sparing: <0.001 bilateral 339 (77.4) 7 827(61.5) unilateral 75 (17.1) 3 179(25) none 24 (5.5) 1 716(13.5) NeuroSAFE*: <0.001 performed 266 (59.8) 5 923(46.2) not performed 175 (40.2) 6 902(53.8) Surgical margins: positive 51 (11.5) 2 161(16.8) negative 392 (88.5) (83.2) Approach: 0.08 open retropubic 425 (96.0) (93.9) robot-assisted 18 (4.0) 779(6.1) *NeuroSAFE, Neurovascular Structure-Adjacent Frozen-section Examination. favourable pathological features and better biochemical outcomes compared to older men [10 12,25]. Nonetheless, these studies did not address these outcomes in a European cohort of patients, which have been shown to differ significantly from North American cohorts, regarding disease characteristics and perioperative outcomes [13,26]. Moreover, in contrast to the present study, previous North American studies were limited by either single surgeons experience [10,27], small sample size of <100 patients aged <50 years [12,27] or reported on multiple treatment methods [11,25]. Based on these considerations, we examined the oncological and functional outcomes (erectile function and urinary continence) of men aged <50 years in a large European cohort of patients treated with RP. First, the present results showed that patients aged <50 years are significantly more likely to present with low-risk prostate BJU International 2013 BJU International 41

5 Becker et al. cancer according to the D Amico classification. This trend towards favourable disease characteristics probably resulted in better histopathological outcomes after RP: we found significantly more organ-confined tumours, less PSMs and more low-grade tumours (Gleason score <7) in patients aged <50 years. These findings corroborate previous publications [10,11,25]. For example, the largest multi-institutional North American study by Parker et al. [25] reported significantly more organ-confined tumours (72% vs 63% vs 63% vs 57%) in patients aged <50 years compared with patients in their sixth, seventh or eighth decade, respectively. As follow-up in the present cohort was significantly shorter for patients aged <50 years, we performed a 1:1 match for Table 2 Multivariate Cox regression analysis for the prediction of BCR. Variable Hazard ratio CI 95% P Era of treatment: vs vs Approach: robot-assisted vs open retropubic PSA level, ng/ml: 4 10 vs < vs < <0.001 >20 vs < <0.001 Pathological stage (pt): pt3a vs pt <0.001 pt3b vs pt <0.001 Gleason score: 3+4 vs < vs < vs <0.001 Pathological nodal status (pn): N+ vs N <0.001 Surgical margins: Positive vs negative <0.001 Age, years: <50 vs length of follow-up. After matching, Kaplan Meier analysis showed a significantly better BCR-free survival at 2, 5 and 10 years (89.7%, 80.7% and 63.0% vs 81.7%, 70.0% and 58.3%, respectively; P = 0.006) for younger patients. However, after multivariable adjustment for disease characteristics, age failed to reach independent predictor status for prediction of BCR. In this sense the favourable BCR-free survival in univariable analyses can most probably be attributed to a selection bias; patients aged <50 years seem to benefit from early diagnosis, being more likely to be diagnosed at a curable stage of disease. Removal of this selection bias by multivariable adjustment reveals a similar potential for systemic progression of tumours in patients aged <50 years. Interestingly, despite favourable local tumour characteristics in younger patients, we observed similar rates of nodal metastases. In contrast to the present results, Smith et al. [11] found that patients aged <50 years not only showed significantly lower initial PSA levels and more organ-confined tumours (65% vs 48%) but also more favourable BCR-free survival than patients aged 50 years. However, only six events were recorded in their analysis of 79 patients aged <50 years, and generalizability of their results seems questionable. Moreover, their study did not examine functional outcomes. As overall complications and morbidity after RP are low [28], ED and urinary incontinence remain the main concern for young men being diagnosed with prostate cancer. Second, we confirmed that patients aged <50 years had favourable functional results compared with their older counterparts. As patients aged <50 years have been diagnosed at more favourable stages, bilateral preservation of the neurovascular bundle was more frequently feasible (77.4% vs 61.5%, P < 0.001). Erectile function and urinary continence after RP have been shown to be associated with extent of nerve-sparing during RP [16]. By extension, functional results were better in patients aged <50 years. As there were Table 3 Multivariate logistic regression analysis for the prediction of recovery of urinary continence (7410 patients) and erectile function (4009 patients). Variable Urinary continence recovery Erectile function recovery OR CI 95% P OR CI 95% P Era of treatment: vs < < vs < Approach: robot-assisted vs open retropubic Nerve-sparing: none vs bilateral <0.001 unilateral vs bilateral <0.001 Use of PDE5 inhibitor or ICI therapy <0.001 Preoperative IIEF-5 score <0.001 Age, years <50 vs < <0.001 OR, odds ratio. 42 BJU International 2013 BJU International

6 Men aged <50 years treated with RP for localised prostate cancer Table 4 Erectile function before and 12 months after nerve-sparing RP. Variable Overall Patients aged <50 years Patients aged 50 years P No. of patients (%) 4009 (100.0) 175 (4.4) 3834 (95.6) IIEF-5 before RP: mean (median) 22.7 (24) 24.1 (25) 22.6 (23) <0.001 range IIEF-5 after RP: mean (median) 14.0 (15) 19.0 (21) 13.7 (15) <0.001 range IIEF-5 after RP (cat.), n (%) 1 7 (severe ED) 1253 (31.3) 17 (9.7) 1236 (32.2) < (moderate ED) 380 (9.5) 10 (5.7) 370 (9.7) (mild-moderate ED) 516 (12.9) 22 (12.6) 494 (12.9) (mild ED) 896 (22.3) 40 (22.9) 856 (22.3) (no ED) 964 (24.0) 86 (49.1) 878 (22.9) Use of PDE5 inhibitor or ICI therapy, n (%) yes 1026 (25.6) 39 (22.4) 985 (25.7) no 2983 (74.4) 136 (77.6) 2849 (74.3) cat., category. important modifications in our operative technique, strongly affecting urinary continence, e.g. implementation of posterior reconstruction [17] and full functional-length urethral sphincter preservation [18], which were introduced in 2006 and 2009, respectively, we divided the study cohort in to three eras. Accordingly, in every era, more men aged <50 years were completely continent at 1 year after RP, with continence rates of up to 97% in the most recent years. As patients aged <50 years reported better preoperative erectile function than their older counterparts (median IIEF-5: 25 vs 23points, P < 0.001) we chose to compare the drop in the IIEF-5 score after RP. In patients who were potent before nerve-sparing RP, the median IIEF-5 drop after RP was 4 points in younger men vs 8 points in their older counterparts (P < 0.001). We confirmed the effect of age <50 years on postoperative recovery of erectile function in preoperatively potent men who underwent nerve-sparing RP and did not receive hormonal treatment, adjusting for all available confounding factors (Table 4). However, erectile function after RP may be related to other factors, e.g. comorbidities or androgen levels [29,30] and, we cannot exclude that other confounders, may have contributed to the drop of IIEF-5 score. However, as the prevalence of the use of ICI or PDE5 inhibitor therapy for ED was similar in both groups (22.4% vs 25.7%, P = 0.4), and bilateral intraoperative nerve-sparing represented the most powerful predictor of postoperative erectile function recovery, we suggest that anatomical preservation of neurovascular structures contributed present difference in IIEF-5 drop between patients aged <50 years and their older counterparts. The present findings that functional outcomes are more favourable in younger patients are corroborated by the Labanaris et al. study [31]. In their cohort, bilateral nerve sparing was performed in 92.6% vs 65.7% of all patients aged <50 years vs 50 years, respectively. At 12 months after RP, they report about 95.5% vs 92.8% and 97.3% vs 66.2% of all patients in this subgroup being continent and potent, respectively. However, generalizability of their results is limited because they report on only 68 patients aged <50 years after robot-assisted RP (n = 2000). Moreover, patients with adjuvant treatment at follow-up and patients in whom bilateral nerve-sparing was not possible were excluded from their analysis of functional outcomes. To summarise, the present results confirm that patients aged <50 years show more favourable histopathological results and functional outcomes compared to patients aged 50 years, after RP for localised prostate cancer in a large contemporary cohort of patients. However, age <50 years was not protective of BCR after multivariable adjustment for disease characteristics. Nonetheless, the present study is not devoid of limitations. Whilst the present study provides the largest single-centre series of men aged <50 years undergoing RP for localised prostate cancer, generalizability needs to be confirmed in future multi-institutional studies. Second, erectile function and urinary continence may be affected by other factors, e.g. comorbidities, additional therapies (e.g. radiation therapy, androgen-deprivation therapy) and postoperative penile- or pelvic floor rehabilitation training. Although we reduced the responder bias by sending a standardised questionnaire rather than relying on direct patient interviews, an information bias applies due to patients lost to follow-up and functional results might differ for responders and non-responders. However, the rate of responders was similar for patients aged <50 years at RP (52%) and patients aged 50 years (56%). Third, as the proportion of patients aged <50 years undergoing RP increased during recent years, the mean follow-up for younger men was only 41.5 months. We tried to account for this source of confounding by performing a BJU International 2013 BJU International 43

7 Becker et al. matching for length of follow-up. However, a longer follow-up, to examine endpoints, such as quality of life and oncological parameters, is warranted to confirm the encouraging oncological and functional results from the present study. The present analyses of the largest contemporary European cohort of patients after RP indicates that patients aged <50 years have more favourable histopathology and better functional outcomes after RP for localised prostate cancer than patients aged 50 years. Therefore, patients aged <50 years diagnosed with localised prostate cancer should not be discouraged from RP as the postoperative rates of urinary incontinence and ED are low and probability of BCR-free survival at 2 and 5 years is high. Conflict of Interest None declared. References 1 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, CA Cancer J Clin 2010; 60: Hankey BF, Feuer EJ, Clegg LX et al. 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8 Men aged <50 years treated with RP for localised prostate cancer Correspondence: Andreas Becker, Martini-Clinic Prostate Cancer Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, Germany. Abbreviations: BCR, biochemical recurrence; ED, erectile dysfunction; ICI, intracavernosal injection; IIEF-5, International Index of Erectile Function; PDE5, phosphodiesterase type 5; PSM, positive surgical margin; RP, radical prostatectomy. BJU International 2013 BJU International 45