Indication,Technique and Outcome of Retropubic Nerve-Sparing Radical Prostatectomy

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1 EAU Update Series EAU Update Series 3 (2005) Indication,Technique and Outcome of Retropubic Nerve-Sparing Radical Prostatectomy Markus Graefen a,b, *, Uwe H.G. Michl a, Hans Heinzer a, Martin G. Friedrich a, Christian Eichelberg a, Alexander Haese a, Hartwig Huland a,b a Department of Urology, University Hospital Hamburg-Eppendorf, Martnistr. 52, Hamburg, Germany b Martini-Clinic, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Germany Abstract Retropubic radical prostatectomy is the most commonly used therapeutic option for the treatment of clinically localized prostate cancer. An ongoing stage migration towards organ-confined cancers allows to perform a nervesparing procedure in a growing number of patients. Key elements for achieving convincing functional results are a sphincter preserving ligation of the distal part of Santorini s plexus and the subtle preparation of the neurovascular bundle. This article gives a detailed description of our operative technique. Furthermore, a strategy for patient selection and tumor selection for the indication of nerve-sparing radical prostatectomy (NSRP) is suggested. In addition, functional results addressing postoperative urinary continence and potency are reported. # 2005 Elsevier B.V. All rights reserved. Keywords: Prostate cancer; Radical prostatectomy; Nerve-sparing 1.Introduction Open retropubic radical prostatectomy is the most commonly used therapeutic option for the treatment of clinically localized prostate cancer. Numerous articles have been published demonstrating excellent tumor control and functional results in addition to a low morbidity of the procedure [1 3]. A nerve-sparing modification of the procedure has become standard practice since an ongoing stage migration towards early detected organ-confined cancers allow this technique in growing number of patients without compromising cancer control [4 7]. Furthermore, as more cancers are detected at a younger age patients demand a high level of post-therapeutic functional outcome. We report on tumor selection, operative technique and long-term cancer control rates and functional outcome of contemporary nerve-sparing radical prostatectomy (nsrp). * Corresponding author. Tel ; Fax: address: graefen@uke.uni-hamburg.de (M. Graefen). 2.Indication of a nerve-sparing procedure Tumor selection is a crucial step for indicating a nsrp. In organ-confined cancers a nsrp can be performed without compromising tumor control by producing artificial positive margins [6,7]. However, capsular penetration of the cancer harbors a high likelihood of neoplastic cells at the surgical margin when nerve preservation is performed. To decide whether or not and to what extend a nervesparing procedure should be performed (unilateral or bilateral) a tree-structures model (CART analysis) was developed calculating the likelihood of side-specific organ-confinement of the diagnosed cancer [8]. This algorithm represents a flexible tool that contributes to the individual tumor extent and tumor localization of each prostate lobe. In low risk patients characterized by not more than one positive biopsy with high-grade cancer and a PSA level below 10 ng/ml the likelihood of organ-confinement is almost 90%. Reliability of this predictive tool was confirmed in an internal prospective validation study, yet an external validation is missing [8]. Ohori et al. have recently reported an alternative approach, where predictions are generated /$ see front matter # 2005 Elsevier B.V. All rights reserved. doi: /j.euus

2 78 M. Graefen et al. / EAU Update Series 3 (2005) with a logistic regression based nomogram, with predictive accuracy of [9]. In a recent study we compared predictive accuracy of both models on a patient cohort consisting of 1117 men with clinically localized prostate cancer. Predictive accuracy of the side-specific nomogram by Ohori et al. was 0.84 vs for the tree-regression model of Graefen et al. [10]. This demonstrates the general superiority of continuously predicting model compared to a risk-group stratification scheme. However, both statistical tools have demonstrated a high reliability and we recommend their use for a reproducible indication of nsrp. Furthermore, pre-therapeutic patient counseling is more precise when the likelihood of unilateral or bilateral nsrp and the corresponding potency and continence rates are known prior to surgery. 3.Operative technique 3.1. General recommendations Open retropubic radical prostatectomy is the most commonly used operative technique. Numerous refinements were recently implemented making this procedure to a minimal invasive operation when commonly used definitions for minimal invasiveness are used [11]. In a recent study by Zacharias and Fornara, invasiveness of the open and laparoscopic RP were compared by pre-, intra-, and postsurgical measurement of the acute-phase C-reactive protein, serum amyloid A (SAA), interleukin-6 (IL-6) and interleukin-10 (IL-10). As to these indicators of any systemic reaction, no significant difference could be found during the entire clinical course between both surgical methods. In comparison with patients who underwent conventional open prostatectomy, patients with laparoscopic radical prostatectomy had identical to slightly higher serum levels of the acute-phase parameters, as evidence of an equal or a discretely manifested systemic response to the surgical trauma. Explanation for these results is the small median incision that should not exceed 10 cm. With the use of a retractor system an optimal and standardized exposure of the prostate and lymphatics can be achieved. Furthermore, cost-effectiveness of open RP is given as no disposable material is used and the procedure can be performed by 2 surgeons (see Picture 1). We strongly recommend the use of loops and a xenon-head-light to combine the potential advantages of laparoscopic RP (which are magnification and optimal light) with the advantages of open surgery (which are tactile sensation and 3-dimensional view). Furthermore, we recommend to perform nsrp in spinal anesthesia which allows a quick recovery of the patient. In addition, restriction of intraoperative infusion until the prostate is removed substantially reduces blood loss. In our series of 678 radical prostatectomies performed in 2004 mean blood loss was 540 cc. Picture 1. Open retropubic prostatectomy can be performed by 2 surgeons. We recommend the use of a self retaining retractor, loops, and head-light to guaranty optimal exposure of the prostate.

3 M. Graefen et al. / EAU Update Series 3 (2005) Surgical technique of open nerve sparing radical prostatectomy Following a 8 to 10 cm median incision the cavum retzii can bluntly be exposed with a sponge stick. Adjacent fat tissue is removed to expose the endopelvic fascia. The fascia is then incised and muscle fibers of the levator ani are removed from the prostate using either a small sponge stick or blunt scissors. The puboprostatic ligaments are bluntly exposed and incised close to the symphysis. The apex can precisely be identified when all muscle fibers are removed from the prostate. Usually coagulation is not necessary during this step.if bleeding occurs from the pelvic wall a bipolar forceps can be used. However, no coagulation should be used close to the neurovascular bundle or the prostate surface. The dorsal vein complex is oversewn close to the bladder to prevent backbleeding. The dorsal vein plexus is divided without any ligation starting with a knife followed by sharp scissors until the muscle fibers of the external sphincter are visible. If bleeding occurs, it can usually be reduced by giving less traction to the prostate. The divided dorsal vein plexus is then selectively oversewn from 10 to 2 O clock without touching the fibers of the striated external sphincter. This is possible, because these veins runs between 2 membranes. The upper membrane is the continuation of the endopelvic fascia, whereas the lower membrane is the fascia of the striated external sphincter (see Picture 2). It is important to identify and include the 2 whitish layers that cover the dorsal vein complex on its ventral and dorsal aspect. This guaranties a good control of bleeding and prevents that muscle fibers are accidentally incorporated in the suture. 5.The nerve-sparing procedure The parapelvic fascia is incised on the dorsal aspect of the prostate at 10 O clock and 2 O clock which is about 2 cm away from the neurovascular bundles. It is important to start the incision high up on the dorsal aspect of the prostate in order to preserve a maximum number of nerve fibers. A substantial number of fibers are located at the dorsal area (see Pictures 3 and 4) and it has been shown, that potency rates strongly correlates with the number of preserved nerve fibers (i.e. bilateral vs. unilateral). After a small incision of the parapelvic fascia covering the prostate it will be undermined using a small overholt. Underneath the fascia an areolar space containing fat, connective tissue, and small tethering vessels can be identified. These vessels need to be undermined and finally aid to identify the right plane for dissection. The fascia will then be clipped and divided (we prefer 5-mm titanium clips) throughout the whole lateral aspect of the prostate (see Picture 2). The neurovascular bundle is then gently pushed downwards and laterally using a peanut dissector or blunt forceps. It is crucial, not to use any coagulation or ultrasound dissector during this step as this will lead to nerve damage. If bleeding occurs, it should be controlled with clips or directed stitches. Close to the apex the dissection of the parapelvic fascia is performed at the upper third of the urethra. The direction of incision is antegrade down to the 10 Picture 2. The dorsal vein complex runs between 2 membranes. The upper membrane is the continuation of the endopelvic fascia, whereas the lower membrane is the fascia of the striated external sphincter.

4 80 M. Graefen et al. / EAU Update Series 3 (2005) Picture 3. Distribution of nerve fibers at the dorso-lateral aspect of the prostate. This anatomical study underlines the importance of the incision of the parapelvic fascia high up on the dorsal area in order to preserve a maximum of nerve fibers. O clock and 2 O clock position of the urethra. The neuro-vascular bundle is separated from Müller s ligament which runs laterally from the striated external sphincter. The neuro-vascular bundle will gently be pushed away from the apex. Now the membranous urethra and the external sphincter muscle are dissected at their upper circumference with clear identification of the apex. The neurovascular bundles are in safe distance to the urethra. Prior to dissection muscle fibers covering the apex can bluntly pushed towards the urethra in order to preserve as much functional tissue as possible. The striated external sphincter runs circular and it s fibers are attached at the outside of the apex. Once they are pushed away the longitudinal smooth muscle is visible that runs into the prostate. After this maneuver the apex is clearly visible. The urethra is cut from10 to 2 O clock. Four anastomotic sutures are placed(we use 3 0 PDSand an UR-6 needle) at 9, 11, 1 and 3 O clock. It is important to include only the ligated dorsal vein complex or Müller s ligament in addition to a small aspect of smooth muscle and urethral mucosa in that suture. This guaranties a reliable anastomosis with a minimum offunctional tissue incorporated. After retraction of the catheter further anastomotic sutures are placed at 5, 6, and 7 O clock. Care has to be taken that the terminal aspect of Denonvillier s fascia and the neurovascular bundle are not included in these sutures. The smooth muscle at the ventral circumference of the urethra is then dissected. Fibers from the striated sphincter muscle are bluntly removed from the terminal aspect of Denonvillier s fascia. The prostate is gently lifted up and Denonvillier s fascia is incised. The fascia remains on the prostate after a bilateral medial incision in safe distance to the preserved neuro-vascular bundles is performed. At the seminal vesicles the ventral layer of Denonvillier s fascia is incised and left in situ in order to protect the neuro-vascular bundle at it s medial aspect. The tips of the seminal vesicles are identified inbetween the 2 layers of Denonvillier s fascia, clipped and dissected. The vas deference is clipped and dissected. Again, no coagulation should be used in order to preserve the integrity of the nerve bundles that run in close relationship to the tips of the seminal vesicles. There are several reasons for difficulties during nerve preservation: - acute or chronic prostatitis - abandoned or crossing vessels - or tumor infiltrating the neuro vascular bundle. If there is any suspicion of cancer infiltration, a f- rozen section should be performed. 6.After removal of the prostate The bladder is opened cranial the prostate and the gland is dissected close to the trigonum. The mucosa is everted using a 4 0 Vicryl suture and the bladder

5 M. Graefen et al. / EAU Update Series 3 (2005) Picture 4. (a c) A small incision of the parapelvic fascia covering the prostate (a) it will be undermined using a small overholt (b). The fascia will then be clipped and divided (c) throughout the whole lateral aspect of the prostate.

6 82 M. Graefen et al. / EAU Update Series 3 (2005) outlet is narrowed using a tennis racket technique. The anastomotic sutures are placed and the anastomosis is tied after the transurethral catheter is inserted. We recommend to fill the bladder with saline to recognize eventual leakage. We routinely place one drainage, a suprapubic catheter is not necessary. An intracutaneous suture of the incision gives a good cosmetic result. 7.Intraoperative frozen section Intraoperative frozen section is another instrument to avoid positive surgical margins beside the preoperative use of statistical tools for tumor selection. If a nsrp is performed and intraoperative suspicion of extracapsular tumor growth arises, intraoperative frozen section is recommended. After the prostate is removed a slice from the lateral surface of the prostate should be taken and the area of the prostate capsule that was adjacent to the neuro-vascular bundle should be inked. In addition, the area from which the slice was taken should be inked in a different color for later differentiation of true surgical margin and margin of intraoperative frozen section (see Picture 5a and b). The slice should be taken from the apex to the base of the prostate. The frozen section is performed Picture 5. (a and b) If extra-capsular extension is suspected a slice from the lateral surface of the prostate should be taken after the prostate is removed (a) and the area of the prostate capsule that was adjacent to the neuro-vascular bundle should be inked. In addition, the area from which the slice was taken should be inked in a different color for later differentiation of true surgical margin and margin of intraoperative frozen section (b).

7 perpendicular and we recommend to remove the neurovascular bundle when cancer reaches the inked surface. Even thorough preoperative and intraoperative tumor selection are no guaranty for negative surgical margins. However, the prognostic impact of small positive margins undetected during frozen section but recognized in the final pathology work-up remains unclear and may be negligible [6]. M. Graefen et al. / EAU Update Series 3 (2005) Outcome of radical prostatectomy Excellent tumor control of radical prostatectomy has been documented by numerous centers worldwide. In organ-confined disease long-term recurrence-free survival is about 90%, when capsular penetration or seminal vesicle infiltration is present these rates drop to 50 60% and 20 35%, respectively [1,12]. Due to these well documented results, RP must still be considered the gold standard for the treatment of clinically localized prostate cancer. The role of positive surgical margins for prognosis remains controversial since the few studies that incorporated high-grade cancer volume as a prognostic parameter could not demonstrate an independent association of surgical margins on recurrence-free survival. However, the majority of studies investigating this issue found an independent impact of surgical margin on cancer control rates [1,13 15]. 9.Cancer control after nerve-sparing radical prostatectomy Complete cancer removal remains the most important goal of nsrp. In a recent study we investigated whether a nerve-sparing procedure itself is a risk factor for biochemical recurrence in patients selected according the above mentioned preoperative CART analyses [6]. We compared patients of our historical series who in retrospect were candidates for nerve-sparing procedure with a contemporary cohort of patients. With respect to stage migration and selection bias between these two groups we performed a multivariate analysis adjusting for all explanatory variables in the model. nsrp was performed in n = 723 patients (bilateral n = 359, unilateral n = 364) in comparison to n = 620 patients undergoing non-ns RP, comprising n = 756 patients within the favorable pt2 category. We examined the association of clinical and histopathological parameters in relation to PSA recurrence in uni- and multivariate analyses including the nerve-sparing procedure Fig. 1. Kaplan-Meier analyses of recurrence-free survival stratified to operative technique (nsrp vs. non-nsrp) and pathologic stage (n = 1755). as a potential risk factor for recurrence. Furthermore, for each prostate lobe separately we determined whether surgical procedure (nerve-sparing vs. nonnerve-sparing RP) resulted in a positive margin. In univariate analysis there was no difference in pt2 (log rank p = 0.091), pt3a (log rank p = 0.171) and pt3b (log rank p = 0.110) cancers between patients treated with nsrp compared to non-nsrp. The 3- and 5-year recurrence free survival rate for patients with pt2, pt3a and pt3b cancers treated by nsrp vs. non-nsrp were 96.3/94.9 vs. 94.9/90.8, 75.0/61.8 vs. 73.4/55.0 and 46/30 vs. 38/23 (see Figs. 1 and 2). Multivariate regression analysis showed no association with PSA failure (p = 0.798) for patients who Fig. 2. Number of radical prostatectomies (RRP), number of organ-confined cancers (pt2), and number of nerve-sparing procedures (NE) performed at the University Hospital Hamburg Eppendorf between 1/1992 and 12/2004.

8 84 M. Graefen et al. / EAU Update Series 3 (2005) underwent nsrp. The positive margin rate per each prostate lobe in pt2 cancers was 6.5% vs. 5.1% in nsrp and non-nsrp cases, 10.3% vs. 17.3% in patients with extracapsular extension and 15.0% vs. 25.1% in cases with seminal vesicle invasion respectively. These data are identical to the findings recently reported by Ward et al. [7]. It can be stated that a nerve-sparing procedure in carefully selected patients is not an independent adverse risk factor for positive surgical margins or progression-free survival. 10.Functional outcome of nerve-sparing radical prostatectomy Good functional results of nsrp are published for various operative techniques, however, the majority of data are based on open retropubic nsrp [2]. For the interpretation of these data it is of utmost importance to consider how the results were obtained. The most reliable data are probably those that were generated using anonymous and validated questionnaires. Furthermore, the time interval after the operation and the use of PDE-5 inhibitors have a strong impact on functional outcome when potency results are considered. Finally, the preoperative potency and continence status and the age of the patients additionally impact functional outcome. In our own series we could demonstrate of positive effect of nerve preservation on postoperative continence [16]. In a multivariate analyses considering age and cancer characteristics of the patients a nerve sparing procedure was independently associated with a better postoperative continence status. Ninety-two percent of patients reported on no urinary leakage at all after nsrp compared to 80% of men undergoing conventional RP. These findings are in line with other studies that investigated the impact of a nerve-sparing procedure for postoperative urinary continence [17]. We therefore recommend a nerve-sparing procedure in patients diagnosed with early stage disease even when erectile dysfunction is prevalent. Due to an ongoing stage migration the percentage of nsrp is about 90% of the patients in our institution (see Fig. 2). Reliable data on postoperative erectile function are important for patient counseling. In the light of effective therapeutic alternatives like brachytherapy and external beam radiation long-term morbidity of a therapeutic option has a growing impact in the treatment-decision-making process. It is crucial to document a baseline erectile status preferably by an anonymous, validated questionnaire. We routinely obtain these data utilizing the short form of the International Index of Erectile Function (IIEF-5) preoperatively and on a yearly base following RP [18]. In our institution data are collected and handled by a data manager independently from the surgeons in order to get reliable and objective data. Our latest investigation regarding postoperative potency following bilateral nsrp revealed that patients with good preoperative erectile function (IIEF score 19 out of 25) had the ability to perform unassisted (no medication at all) sexual intercourse in 62.6% (in men under the age of 60: 65.7% and in men over 60 years: 60.8%) (data not yet published). Following unilateral nsrp the corresponding rate is 40% (60 yrs.: 50% and >60 yrs.: 32.6%). The mean drop in the IIEF-5 was 7 points throughout the whole patient cohort. These data show an improvement of postoperative erectile function compared to our series published in 2002 which is due to ongoing refinements and experience using the above mentioned operative technique. In preoperatively potent men who used PDE-5 inhibitors following surgery 90% after bilateral nsrp and 71% after unilateral nsrp reported on erections sufficient for intercourse [2]. These data demonstrate the role of PDE-5 inhibitors and we encourage our patients to use such medication postoperatively until recovery of natural erectile function. 11.Summary Contemporary nerve-sparing retropubic radical prostatectomy is still the most commonly performed treatment for localized prostate cancer. Refinements of its technique especially in behalf of a nerve-sparing procedure allow excellent cancer control in combination with good and reproducible functional results. References [1] Hull GW, Rabbani F, Abbas F, Wheeler TM, Kattan MW, Scardino PT. Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol 2002 Feb;167(2 Pt 1): [2] Michl U, Graefen M, Noldus J, Eggert T, Huland H. Functional results of various surgical techniques for radical prostatectomy. Urol A 2003 Sep;42(9):

9 M. Graefen et al. / EAU Update Series 3 (2005) [3] Augustin H, Hammerer P, Graefen M, Palisaar J, Noldus J, Fernandez S, et al. Intraoperative and perioperative morbidity of contemporary radical retropubic prostatectomy in a consecutive series of 1243 patients: results of a single center between 1999 and Eur Urol 2003 Feb;43(2): [4] Derweesh IH, Kupelian PA, Zippe C, Levin HS, Brainard J, Magi- Galluzzi C, et al. Continuing trends in pathological stage migration in radical prostatectomy specimens. Urol Oncol 2004 Jul Aug;22(4): [5] Noldus J, Graefen M, Haese A, Henke RP, Hammerer P, Huland H. Stage migration in clinically localized prostate cancer. Eur Urol 2000 Jul;38(1):74 8. [6] Palisaar RJ, Noldus J, Graefen M, Erbersdobler A, Haese A, Huland H. Influence of nerve-sparing (NS) procedure during radical prostatectomy (RP) on margin status and biochemical failure. Eur Urol 2005 Feb;47(2): [7] Ward JF, Zincke H, Bergstralh EJ, et al. The impact of surgical approach (nerve bundle preservation versus wide local excision) on surgical margins and biochemical recurrence following radical prostatectomy. J Urol 2004 Oct;172(4 Pt 1): [8] Graefen M, Haese A, Pichlmeier U, Hammerer PG, Noldus J, Butz K, et al. A validated strategy for side specific prediction of organ confined prostate cancer: a tool to select for nerve sparing radical prostatectomy. J Urol 2001 Mar;165(3): [9] Ohori M, Kattan MW, Koh H, Maru N, Slawin KM, Shariat S, et al. Predicting the presence and side of extracapsular extension: a nomogram for staging prostate cancer. J Urol 2004 May;171(5): [10] Steuber T, Graefen M, Perotte P, Haese A, Chun FKH, Huland H, Karakiewicz P. Prediction of side specific extracasular extension at radical prostatectomy in European patients: accuracy of a novel, internally validated logistic regression based nomogram vs. tree structured regression analysis. Eur Urol Suppl, in press. [11] Fornara P, Zacharias M. Minimal invasiveness of laparoscopic radical prostatectomy: reality or dream? Aktuelle Urol 2004 Sep;35(5): [12] Graefen M, Hammerer PG, Haese A, Huland H. Indications for and results of radical prostatectomy. Urol A 2003 Sep;42(9): [13] Palisaar RJ, Graefen M, Karakiewicz PI, Hammerer PG, Huland E, Haese A, et al. Assessment of clinical and pathologic characteristics predisposing to disease recurrence following radical prostatectomy in men with pathologically organ-confined prostate cancer. Eur Urol 2002 Feb;41(2): [14] Graefen M, Noldus J, Pichlmeier U, Haese A, Hammerer P, Fernandez S, et al. Early prostate-specific antigen relapse after radical retropubic prostatectomy: prediction on the basis of preoperative and postoperative tumor characteristics. Eur Urol 1999;36(1): [15] Stamey TA, McNeal JE, Yemoto CM, Sigal BM, Johnstone IM. Biological determinants of cancer progression in men with prostate cancer. JAMA 1999 Apr 21;281(15): [16] Michl UHG, Graefen M, Haese A, Palisaar J, Hammerer P, Huland H. Prospective analysis of continence and micturition following nerve sparing (NRRP) and non nerve sparing radical retropubic prostatectomy (RRP). Significant impact of the nerve sparing procedure on continence. J Urol 2001;165:A1453. [17] Eastham JA, Kattan MW, Rogers E, Goad JR, Ohori M, Boone TB, et al. Risk factors for urinary incontinence after radical prostatectomy. J Urol 1996 Nov;156(5): [18] Rosen RC, Cappelleri JC, Gendrano III N. The International Index of Erectile Function (IIEF): a state-of-the-science review. Int J Impot Res 2002 Aug;14(4): CME questions Please visit to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. Preoperative estimation of organ-confined cancer growth can most reliably be estimate using A. serum PSA level and Gleason score at biopsy. B. Gleason score at biopsy alone. C. a combination of clinical stage and Gleason score at biopsy. D. a combination of clinical stage, biopsy results, and PSA level in a nomogram. 2. In order to achieve a maximum of nerves to be preserved during nerve sparing radical prostatectomy, the incision of the parapelvic fascia should start at A. the ventral aspect of the prostate. B. high up at the dorso-lateral aspect of the prostate. C. at the mid-lateral aspect. D. any of the abovementioned area, as this does not influence the number of preserved nerve fibers. 3. Data regarding the comparison of invasiveness of open retropubic and laparoscopic radical prostatectomy (RP) have shown that A. open retropubic is less invasive. B. invasiness is equal in both techniques. C. laparoscopic RP is less invasive. D. no data yet exist regarding that issue. 4. Performing a nerve-sparing radical prostatectomy compared to a non-nerve-sparing radical prostatectomy in carefully selected patients has demonstrated A. to compromise cancer control rates in nonorgan-confined disease. B. to compromise cancer control rates regardless of pathologic stage. C. to be equally effective regardless of pathologic stage. D. to be equally effective in organ-confined cancers only.