Preserved Postoperative Penile Size Correlates Well with Maintained Erectile Function after Bilateral Nerve-Sparing Radical Retropubic Prostatectomy

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1 european urology 52 (2007) available at journal homepage: Prostate Cancer Preserved Postoperative Penile Size Correlates Well with Maintained Erectile Function after Bilateral Nerve-Sparing Radical Retropubic Prostatectomy Alberto Briganti a, Fabio Fabbri a, Andrea Salonia a, Andrea Gallina a, Felix K.-H. Chun b, Federico Dehò a, Giuseppe Zanni a, Nazareno Suardi a, Pierre I. Karakiewicz c, Patrizio Rigatti a, Francesco Montorsi a, * a Department of Urology, Vita-Salute University, Milan, Italy b Department of Urology, University of Hamburg, Hamburg, Germany c Cancer Prognostics and Health Outcomes Unit, University of Montreal, Montreal, QC, Canada Article info Article history: Accepted March 16, 2007 Published online ahead of print on March 26, 2007 Keywords: Erectile dysfunction Penile size Radical prostatectomy Abstract Objectives: Controversial data on penile length after radical retropubic prostatectomy are available. We hypothesised that postoperative penile size correlates to erectile function following bilateral nerve-sparing radical retropubic prostatectomy (BNSRRP). Methods: Thirty-three consecutive patients with a preoperative erectile function domain of the International Index of Erectile Function (IIEF-EF) score indicating full potency (26) were prospectively enrolled. All patients underwent BNSRRP performed by one high-volume surgeon. All patients were preoperatively evaluated by IIEF-EF, analysis of comorbidities, physical examination, and penile power colour Doppler ultrasound using intracavernosal injection of prostaglandin E 1 (PGE 1 )20mg plus audiovisual and manual genital stimulation. Penile length and circumference were measured in flaccidity and at maximum erection. Six months postoperative, patients were assessed with the same protocol plus general assessment questions investigating penile structure and function. Statistical analysis was performed with an independent sample t test. Results: Mean patient age was 56.5 yr. We found no difference between the preoperative and the 6-mo postoperative mean IIEF-EF domain score (27.2 vs, 26.7, respectively; p = 0.35). difference was found in penile colour Doppler evaluation between the preoperative and postoperative periods (all p values 0.3). We found no differences in penile length and circumference between the preoperative and postoperative evaluation either in the flaccid or in the erect state. Mean flaccid penile length (cm; preop vs. postop): 13.2 vs. 13 ( p = 0.6). Mean flaccid penile circumference (cm; preop vs. postop): 11.1 vs. 11 ( p = 0.7). Mean erect penile length (cm; preop vs. postop): 16.8 vs ( p = 0.08). Mean erect penile circumference (cm; preop vs. postop): 15.6 vs ( p = 0.2). Conclusions: This is the first report on penile changes in flaccidity and at maximum erection after BNSRRP in patients treated by one high-volume surgeon. The postoperative preservation of erectile function positively correlated with the maintenance of penile length following surgery. We found no change in penile size after surgery. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Vita-Salute University, San Raffaele Hospital, Via Olgettina, 60, 20132, Milan, Italy. Tel ; Fax: address: montorsi.francesco@hsr.it (F. Montorsi) /$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 52 (2007) Introduction Radical prostatectomy (RP) represents an increasingly used therapeutic option for patients with clinically localised prostate cancer [1]. Despite continuous improvements in surgical technique, erectile dysfunction (ED) represents a common quality-of-life issue after RP, affecting 14 84% of the men after surgery [2 4]. Ofnote,mensuffering from postoperative ED may also complain of loss of penile length and girth [5]. Interestingly, this complaint has received marginal attention in clinical research; several reports have assessed erectile and urinary outcomes after RP, but only a few have focused on penile shortening after surgery [5 8]. In these trials, some penile shortening was observed in 9 71% of the patients enrolled. This is an important finding because loss of penile volume might have a significant negative impact on quality of life, even for patients who regain normal erectile function after surgery [8]. Therefore, it would be reasonable to suggest the need of an adequate preoperative counselling about this surgical outcome. However, this clinical condition has not been evaluated in methodologically sound studies. We prospectively tested the hypothesis that men who are fully potent preoperatively and maintain normal erectile function following surgery do not show significant reduction of penile length and girth. 2. Patients and methods Thirty-three patients treated with bilateral nerve-sparing radical prostatectomy (BNSRRP) by one high-volume surgeon (F.M.) at our institution were enrolled in this prospective trial. Inclusion criteria were as follows: age 65 yr, preoperative full potency (erectile function domain score of the International Index of Erectile Function [IIEF-EF] 26), no history of Peyronie s disease or previous penile surgery, absence of penile abnormalities at physical examination, clinical stage T1c, prostate-specific antigen (PSA) <10 ng/ml, and a biopsy Gleason score <7. All patients were preoperatively evaluated by means of IIEF-EF, assessment of comorbidities, physical examination, penile power colour Doppler ultrasound using intracavernosal injection of prostaglandin E 1 (PGE 1 )20mg plus audiovisual and manual genital stimulation. Cavernosal peak systolic velocity (PSV) and resistive index (RI) were bilaterally evaluated 20 min after intracavernosal PGE 1 injection [9]. Penile length and circumference were measured both in flaccidity and at maximum erection with a paper ruler to the nearest 0.5 cm, as reported by Munding et al [6]. Penile length was measured from the tip of the glans to the pubopenile skin junction; penile circumference was measured at the middle third of the shaft. Measurements were repeated twice to optimise the reliability of the results obtained. Table 1 General assessment questions (GAQs) assessing postoperative subjective erectile function Postoperative GAQs: Have you experienced penile shortening after surgery? Have you experienced penile curvature after surgery? Have you experienced postoperative painful erections? Are you satisfied with the quality of your erections? All patients underwent BNSRRP performed by one highvolume surgeon who applied a previously described surgical technique [10]. This technique basically implies incising the levator and prostatic fasciae high anteriorly (1 and 11 o clock positions) over the prostate, developing the plane between the prostatic capsule and the prostatic fascia, and displacing the neurovascular network localised between the two fasciae laterally. This allows for an efficient dissection of the neurovascular bundles at the level of the membranous urethra and prostatic apex, which significantly reduces the risk of cavernous nerve injury. Patients were encouraged to attempt sexual intercourse as soon as one possible following catheter removal and were stimulated to use a full dose of a phosphodiesterase type 5 (PDE5) inhibitor on demand. Six months after surgery patients were assessed with the same protocol used preoperatively, plus a series of nonvalidated general assessment questions (GAQs) (Table 1). Penile Doppler ultrasound and penile size measurements were performed by the same physician (F.F.) preoperatively and postoperatively. ne of the patients received any adjuvant or neoadjuvant treatment for prostate cancer. Statistical tests were performed with SPSS software version 13 (Chicago, IL, USA). Two-sided tests with significance at 0.05 were used. An independent sample t test was used to evaluate differences in penile length and erectile function between the preoperative and postoperative periods. The study was approved by the ethical board committee of our institution and patients signed an informed consent. 3. Results Patient age ranged from 50 to 65 yr, with a mean age of 56.5 yr. Mean preoperative PSA was 5.6 ng/ml (range: ng/ml). Biopsy Gleason score was 2 5 in 16 patients (48.5%) and 6 in 17 patients (51.5%). Table 2 shows the main results of the study. Mean preoperative IIEF-EF was 27.2 (range: 26 29). significant difference was found between the preoperative and postoperative mean IIEF-EF domain scores (27.2 vs, 26.7, respectively; p = 0.35). Only three patients (9%) complained of mild ED, according to IIEF-EF after surgery (mean value: 23). Mean PSV and RI of both cavernosal arteries did not show any significant difference before and after surgery (all p values 0.3; Table 2). Moreover, we found no significant differences in penile length and

3 704 european urology 52 (2007) Table 2 Comparison between preoperative and postoperative evaluation Variables Preoperative 6 mo after surgery p IIEF-EF Mean penile length, cm Flaccid Maximum erection Mean penile circumference, cm Flaccid Maximum erection Right cavernosal artery Mean PSV, cm/s Mean RI Left cavernosal artery Mean PSV, cm/s Mean RI Patients reporting postoperative subjective penile shortening (%) NA 9 (13.6) NA Patients reporting postoperative subjective penile curvature (%) NA 3 (4.5) NA Patients reporting postoperative painful erections (%) NA 0 (0) NA Patients satisfied with postoperative erections (%) NA 30 (90.1) NA IIEF-EF = Erectile function domain score of the International Index of Erectile Function; PSV = peak systolic velocity; RI = resistive index; NA = not available. circumference between the preoperative and postoperative evaluations in either the flaccid or in the erect state (all p values 0.08; Table 2). However, when patients were subjectively investigated with non-validated GAQs, nine (13.6%) reported some degree of penile shortening. Three patients (4.5%) reported a mild penile curvature, which was not confirmed at maximum erection office assessment obtained during colour Doppler sonography. ne of the patients had palpable or ultrasound-detected penile plaque after surgery and none complained of postoperative painful erections. Of 33 men, 30 (90.1%) reported full satisfaction with their penile erections (Table 2). 4. Discussion Several studies have recently elucidated the potential pathophysiology of ED after RP [11 13]. However, only few focused on the pathophysiology of penile length changes after RP [5 8]. Mulhall [11] recently proposed a novel classification for penile length modifications after RP. He divided penile length changes into two categories: early and delayed. The first is mainly due to a sympathetic overdrive that causes a contraction of penile smooth muscle in response to the neural injury during RP. Conversely, the delayed penile length changes are due to structural changes that result from irreversible structural modifications in the corporeal smooth muscle. These might be due to a combination of factors, including neural injury-associated denervation apoptosis and cavernosal hypoxia-induced collagenisation in men with a slow and delayed return of erectile function. Therefore, maintaining adequate penile oxygenation by preserving neurovascular bundles and thus erectile function, might play a key role in preserving penile anatomy and preventing irreversible penile fibrotic changes. Several human and animal studies seem to support this hypothesis [12 14]. In animal models, penile chronic hypoxia and denervation have been shown to stimulate apoptosis, which leads to increased deposition of connective tissue and decrease in penile distensibility [15 17]. User et al [12] randomised postpubertal rats to bilateral or unilateral cavernous nerve transection versus a sham operation. They found that wet weight of the denervated penises was significantly decreased after bilateral cavernous neurotomy, whereas unilateral cavernous neurotomy allowed much greater preservation of penile weight. DNA content was also significantly reduced in bilaterally denervated penises and no difference was found between unilaterally denervated penises and controls. Bilateral cavernous neurotomy also induced significant apoptosis, which peaked on postoperative day 2. Finally, the authors found that apoptotic cells were smooth muscle cells and not endothelial cells. The subsequent hypothesis suggested by the authors was that the bilateral injury to the cavernous nerves may induce significant apoptosis of smooth muscle cells, particularly in the subtunical

4 european urology 52 (2007) area, which causes penile fibrosis and abnormality of the veno-occlusive mechanism of the corpus cavernosum. Moreover, Leungwattanakij et al [13] showed that cavernosal neurotomy was associated with an up-regulation of fibrogenic cytokines and collagenisation of the corporal smooth muscle in animal models. Similar results have been confirmed in human models. Indeed, a recent clinical trial performed by Iacono et al [14] has clearly demonstrated how a progressive increase in penile organised collagen content and a decrease in interstitial elastic fibres and smooth muscle cell were evident after surgery in a selected preoperatively potent population of 19 nondiabetic patients who underwent RP and penile biopsies before surgery and 2 and 12 mo after surgery. Therefore, maintaining adequate penile innervation is key to preserving penile structure. Researchers have also postulated that a chronic absence of postoperative erections might lead to cavernosal hypoxia. This causes significant tissue damage, that is, increased corporeal fibrosis, which is at the root of the known penile haemodynamic abnormality and may cause postoperative decrease of penile length [5 8]. Conversely, when penile tissue is oxygenated, secretion of endogenous PGE 1 is stimulated and production of fibrogenic cytokine is inhibited [18]. In this context, Sattar et al [19] showed a correlation between corporal smooth muscle and content of intracavernosal po 2 levels. This has been indirectly confirmed by another clinical trial in which early use of high doses of sildenafil after RP was associated with preservation of smooth muscle content within human corporal cavernosa [20]. Our study represents the first attempt to prospectively evaluate changes of penile length after BNSRRP in a selected population of young and preoperatively fully potent patients treated by one high-volume surgeon. We found no change in postoperative mean penile length and circumference. Moreover, no significant difference was found in mean IIEF-EF score and in penile colour Doppler results between the preoperative and postoperative periods. Our results might have several causes. First, our cohort is represented by selected patients who were considered to be excellent candidates for a nervesparing approach: age <65 yr, fully potent (IIEF- EF 26), and with favourable tumour characteristics. This is important because correct patient selection is a key factor for performing a correct surgical technique, thus maintaining erectile function and preventing penile fibrosis [2 4]. Second, we believe that the surgical technique is key to explaining our results. In fact, all patients enrolled underwent a modified BNSRRP technique, in which the levator and prostatic fasciae are incised high anteriorly (at the 1 and 11 o clock positions) over the prostate, developing the plane between the prostatic capsule and prostatic fascia, and displacing the neurovascular network localised between the two fasciae laterally. By performing an incision of the levator fascia at the 1 and 11 o clock positions to start the dissection of the neurovascular bundle, one may preserve the largest possible fraction of the pelvic plexus branches, including cavernous nerve fibres. We speculate that a surgical approach that maintains postoperative erectile function adequate for sexual intercourse is a key factor in preserving penile structure and preventing fibrotic penile degeneration. Apart from surgical technique, it is important to note that 13 of 33 patients (39%) used sildenafil either 50 or 100 mg on demand postoperatively. This is relevant because use of sildenafil has been associated with preserved postoperative penile structure in patients undergoing radical prostatectomy [20]. However, we did not find any difference in penile size between sildenafil users and sildenafil naïve patients. Therefore, we believe that our results are unlikely to be influenced by sildenafil consumption. Third, surgical expertise may have played a key role in our results. Indeed, although the number of cases performed per unit of time (surgeon s volume) is a recognised predictive factor for success or failure to maintain erectile function after nerve-sparing surgery, Bianco et al [21] has suggested that the surgeon himself probably plays the most fundamental role in determining the patient s postoperative outcome; in other words, a high-volume surgeon may continue to do things wrong if the surgical technique is not adequate. We avoided this potential bias by including only patients who were treated by one high-volume surgeon using a standardised surgical technique [10]. Finally, our results derive from objective preoperative and postoperative penile measurements both in flaccidity and at maximum erection. It is noteworthy that despite the absence of any objective postoperative change in mean penile length, 13% of patients complained of a subjective decreased postoperative penile length. This discrepancy underlines the need for objective evaluation of sexual function in patients subjected to RP, as previously reported for preoperative erectile function [22]. Others have studied penile length changes after RP (Table 3). Fraiman et al [5] studied 100 men evaluated at <28 mo after RP. The authors measured the penis both in the flaccid state and at maximum

5 706 european urology 52 (2007) Table 3 Previous studies assessing penile length changes after radical prostatectomy Authors. of patients enrolled Preoperative EF objectively assessed Type of surgery Penile measurements Time after surgery, mo Fraiman et al [5] 100 BNSRRP Flaccid and erect <28 Munding et al [6] 31 NA Stretched 3 Savoie et al [7] 63 BNSRRP (n = 47) and Flaccid and stretched 3 UNSRRP (n = 26) Galzerano et al [8] 126 BNSRRP and UNSRRP Flaccid and stretched 3, 6, 12 Present series 33 BNSRRP Flaccid and erect (20 mg PGE 1 ) 6 EF = erectile function; BNSRRP = bilateral nerve-sparing radical retropubic prostatectomy; UNSRRP = unilateral nerve-sparing radical retropubic prostatectomy; NA = not available; PGE 1 = prostaglandin E 1. erection. These measurements showed an overall mean reduction in penile length of 9% and a mean reduction in penile volume of 22%. However, this study has important limitations. First, patients were not screened for preoperative ED. Second, all patients enrolled had ED after surgery even if they were previously treated with a nerve-sparing procedure. Thus, structural penile alterations might have already occurred in these patients who were referred for sexual evaluation because of ED. Munding et al [6] studied 31 men and measured penile length in the stretched flaccid state 3 mo after RP. They found that 22 patients (71%) had a postoperative decrease in stretched penile length (range: cm); 48% lost >1 cm. However, no information was provided about preoperative erectile function or about the surgical approach used (number of neurovascular bundles preserved), which represent key factors in postoperative erectile function. Similar results have been reported by Savoie et al [7], who evaluated 63 patients and measured flaccid and stretched penile length and circumference preoperatively and at 3-mo follow-up. In this report, 68% of patients had some degree of postoperative penile shortening; there was no difference between patients with or without postoperative ED. However, no objective measurements were used to assess preoperative and postoperative ED, which limits the validity of these results. Moreover, only 47 patients (74.6%) had a BNSRRP. Finally, Galzerano et al [8] recently reported data on 126 patients who underwent penile measurements (flaccid and stretched length) preoperatively and at 1-, 3-, and 12-mo follow-up after either unilateral or bilateral NSRRP. They showed that after a peak in penile shortening, which occurred when the catheter was removed, all penile parameters showed a lesser but significant decrease at all subsequent time intervals. Interestingly, at multivariate analysis, only nerve-sparing surgery was an independent predictor of penile length change after surgery. This suggests the role of neurovascular bundle preservation in maintaining penile anatomy. Our study has some limitations. First, the number of patients enrolled is limited, even though it is comparable to a previous published trial [6]. Second, these results might not be the same as those seen in the everyday clinical practice, where a correct patient selection and a standardised surgical technique might not always be applicable. Moreover, even when a correct approach is used, not all men are motivated to attempt sexual intercourse right after surgery. Despite these limitations, we consider our study as a proof of principle suggesting that in selected patients treated with BNSRRP with rapid return to normal erectile function after surgery, postoperative penile shortening is not an issue if it is objectively investigated. 5. Conclusions Our study represents the first prospective study reporting on penile length changes and erectile function in a select category of young and preoperatively fully potent patients who underwent BNSRRP performed by one high-volume surgeon. We reported no significant change in postoperative penile length and girth among these select patients, although roughly 15% reported subjective postoperative penile shortening. We suggest that, when a correct surgical technique is performed and patients are properly investigated, penile shortening does not represent an issue in men undergoing BNSRRP. Conflicts of interest The authors have no conflicts of interest to disclose. References [1] Aus G, Abbou CC, Bolla M, et al., European Association of Urology. EAU guidelines on prostate cancer. Eur Urol 2005;48:

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