Radical cystectomy is the mainstay of treatment for

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1 Potency Preserving Cystectomy With Intrafascial Prostatectomy for High Risk Superficial Bladder Cancer Paolo Puppo, Carlo Introini, Franco Bertolotto and Angelo Naselli* From the Urology Unit, Department of Surgical Oncology, National Institute for Cancer Research, Genoa, Italy Purpose: We report the oncological and functional results of potency sparing cystectomy with intrafascial prostatectomy for high risk, superficial bladder cancer. Materials and Methods: A total of 37 patients underwent potency sparing cystectomy and orthotopic urinary substitution from 2001 to Inclusion criteria were age younger than 70 years, Charlson comorbidity index less than 2, high risk superficial bladder cancer, prostate specific antigen less than 4 ng/ml, free-to-total PSA ratio greater than 20% and normal digital rectal examination. Results: Median patient age was 58 years (range 52 to 66). Median followup was 35 months (range 24 to 71). One patient died of disease progression and 1 died of an unrelated cause. Of the 37 patients 35 (95%) were free of tumor. Daily continence was achieved in 36 patients (97.2%) and nighttime continence was achieved in 35 (95%). Two patients (5%) needed clean intermittent catheterization. A total of 35 patients (95%) stated that they maintained erectile function, including 28 (76%) without oral drugs. A significant decrease in the median International Index of Erectile Function score from baseline was noted 2 years after surgery (25 vs 21). A total of 32 patients (86%) had an International Index of Erectile Function score of greater than 17 at 2 years after cystectomy. Median scores on the International Continence Society male short form questionnaires did not show any significant difference before and after surgery. Prostate specific antigen was lower than 0.2 ng/ml in all cases. Conclusions: The main criticism about so-called sexuality sparing cystectomy has been the presence of consistent prostatic remnants. Performing intrafascial prostatectomy together with supra-ampullar cystectomy seems to warrant good functional results with while better preserving oncological safety. Key Words: bladder, bladder neoplasms, cystectomy, urinary diversion, penile erection Submitted for publication September 18, * Correspondence: Largo Rosanna Benzi 10, Genoa, Italy (telephone: ; FAX: ; angelo.naselli@libero.it). For another article on a related topic see pages 2014 and Radical cystectomy is the mainstay of treatment for recurrent, high grade superficial and muscle invasive bladder cancer. 1 It is highly morbid since it results in many changes in quality of life, including sexual and social function. In the last decades many steps have been made in the direction of improving quality of life in patients undergoing cystectomy. The orthotopic reservoir is a safe option in patients without posterior urethral involvement. It guarantees recovery of continence in a great proportion of cases. 2 On the other hand, the recovery of sexual activity, also after meticulous nerve sparing dissection, can be achieved in a percent of patients that is only 50% in experienced hands. 3,4 Preservation of the whole or part of the prostate and/or seminal vesicles has been proposed to attain a higher potency rate of 75% to 100% Potency sparing cystectomy is obviously reserved for select young potent patients after having reasonably excluded prostate cancer or bladder cancer prostatic involvement. However, an increased recurrence rate and chronic urinary retention rate, probably related to prostatic remnants, seem to be associated with such procedures. Moreover, the risk of prostate cancer remains unchanged. 14 We describe the results of modified potency sparing cystectomy, in which the seminal vesicles and deferential ampullae are spared and the prostate is completely removed with intrafascial dissection of the vascular pedicles. An orthotopic reservoir is then created and anastomosed to the urethral stump. Therefore, the continence and chronic retention rates are the same as for the standard orthotopic procedure. On the other hand, the pelvic plexus and erigentes nerves are spared and potency is preserved in most patients. MATERIALS AND METHODS Patient Selection From September 2001 to April 2005 of 289 cystectomies performed in male patients 37 (13%) underwent potency sparing cystectomy with orthotopic urinary substitution and complete prostate removal due to bladder cancer. Inclusion criteria were age younger than 70 years, Charlson comorbidity index 2 or less, high risk superficial bladder cancer, PSA 4 ng/ml or less, free-to-total PSA ratio 20% or less and normal digital rectal examination. Tumors growing into the bladder neck or prostatic urethra were excluded. Negative intraoperative frozen section of the proximal margin of the urethral stump was considered enough to safely proceed with an orthotopic reservoir after cystectomy /08/ / Vol. 179, , May 2008 THE JOURNAL OF UROLOGY Printed in U.S.A. Copyright 2008 by AMERICAN UROLOGICAL ASSOCIATION DOI: /j.juro

2 1728 POTENCY PRESERVING CYSTECTOMY FOR HIGH RISK BLADDER CANCER FIG. 1. Dissection in standard radical (STD, red line), nerve sparing radical (NS, blue line) and potency sparing (PS, green line) cystectomy. In standard version surgical plane is developed over rectum and vascular pedicles are sectioned in proximity to anterior rectal wall. In nerve sparing procedure same surgical plane is developed but vascular pedicles are sectioned in proximity to bladder wall, seminal vesicles and prostate to save damage to neurovascular bundles. In potency sparing technique surgical plane anterior to seminal vesicles is developed, which ends at ejaculatory ducts. Pelvic plexus is left completely untouched behind seminal vesicles. Voiding and sexual function were evaluated respectively by interviews on continence, pad use and erection using the ICS male SF and IIEF erectile function domain score questionnaire (questions 1 to 5 and 15). Patients were completely continent (pad free), stated that they were potent and had an IIEF score of 17 or greater before cystectomy. Surgical Technique All procedures were performed by the same surgeon (PP). The laterovesical peritoneum is divided bilaterally up to the internal inguinal ring. The vas deferens is identified and left in situ. The umbilical arteries are divided 1 cm from their origin and the ureters are divided in proximity to the bladder. The peritoneum is incised in transverse fashion about 3 cm anterior to the cul-de-sac. Care is taken to search for cleavage between the posterior bladder wall, and the seminal vesicles and deferential ampullae. Sharp dissection of the bladder from the seminal vesicles and deferential ampullae is performed until the ejaculatory ducts are exposed (figs. 1 and 2). Because there is no need to dissect posterior to these structures, the neurovascular plexus remains untouched. Cystectomy is completed with intrafascial prostatectomy, which is performed in a retrograde manner (figs. 3 and 4). The main difference respect to standard nerve sparing retropubic prostatectomy is that the rectourethralis ligament is not transected. A surgical plane is developed over the rectourethralis ligament and the anterior layer of Denonvilliers fascia (figs. 3 and 4). It is joined with the plane previously developed over the seminal vesicles and ampullae of the vas deferens at the level of the ejaculatory ducts. In this fashion the largest part of the pelvic plexus is spared, including the erigentes nerves. The pathological specimen includes the bladder and whole prostate with the apex. Frozen sections of the distal ureters and the distal urethral stump are sent for pathological evaluation. Bilateral iliac and obturator lymphadenectomy is performed. Dissection over the sacral promontory is performed with care taken to preserve the sympathetic fibers of the pelvic plexus. Finally, a Hautmann ileal neoblad- FIG. 2. Posterior dissection route over seminal vesicles until ejaculatory ducts are identified.

3 POTENCY PRESERVING CYSTECTOMY FOR HIGH RISK BLADDER CANCER 1729 FIG. 3. Prostatectomy nerve sparing (NS, blue line) and standard radical (ST, red line) cystectomy require section of rectourethralis ligament and whole Denonvilliers fascia is included in specimen. In potency sparing cystectomy (PS, green line) rectourethralis ligament is left untouched and dissection is carried over anterior leaflet of Denonvilliers fascia, thus, minimizing risk of damaging neurovascular bundles close to urethra. der is configured and anastomosed to the urethral stump in standard fashion. Followup Patients were prospectively followed with physical examination, post-void residual urine evaluation, serum PSA, urinary cytology, chest x-ray and abdominal ultrasonography at 3 months with abdominal computerized tomography or magnetic resonance imaging at 6 months and about every 6 months thereafter. Before surgery and every year thereafter voiding function was evaluated by interviews on continence and pad use, and by the ICS male SF. Sexual function was evaluated by interviews on erection and the IIEF erectile function domain score questionnaire (questions 1 to 5 and 15). Indications for CIC were a residual urine volume of at least 100 cc if accompanied by infection, frequency or incontinence. Otherwise a residual urine volume of up to 200 cc was acceptable. Continence was defined as no urinary loss (pad-free status). All patients who noticed adequate nightly erections and/or erections adequate for intercourse after cystectomy were considered to have maintained erectile function. Statistical Analysis Baseline (before surgery) and 2-year IIEF and ICS male SF questionnaires outcomes were compared using the Wilcoxon test. RESULTS FIG. 4. Anterior dissection plane over rectourethral ligament and anterior layer of Denonvilliers fascia. Table 1 lists patient characteristics, and oncological and functional outcomes. Median age was 58 years (range 52 to 66). The median hospital stay was 16 days (range 14 to 26). Medical complications were recorded in 2 patients (5%), including septicemia and deep venous thrombosis in 1 each. Surgical complications were recorded in 5 patients (13.5%), of which 3 were related to the orthotopic substitution. The surgical complications included ureteroileal stenosis in 2 patients, enteropouch fistula in 1 and pelvic lymphocele in 2. Ureteroileal stenosis in 1 case was managed conservatively and in 1 it was treated with reimplantation. The fistula was

4 1730 POTENCY PRESERVING CYSTECTOMY FOR HIGH RISK BLADDER CANCER TABLE 1. Clinical and pathological characteristics, and results corrected surgically. The median number of nodes removed was 21 (range 13 to 35). Of all patients pathological examination revealed under staging only in 2 (5%), who had pt2 disease at the final examination. One case (3%) was pn. Median preoperative PSA was 1.52 ng/ml (range 0.31 to 3.6). Three incidental prostate cancers (8%) were found, including 2 that were smaller than 5 mm, and Gleason score 3 3 and 3 2, respectively. Only 1 patient had significant prostate cancer (Gleason score 3 4) that extended to the 2 lobes and involved about 30% of the gland. Surgical margins were always negative, which was also true for prostate cancer. Median followup was 35 months (range 24 to 71). Remarkably about a third of the patients had more than 4 years of followup. Postoperative PSA was always less than 0.2 ng/ml during followup. The patient with pt1g3pn1 bladder cancer showed distant metastasis after 15 months of followup. Systemic chemotherapy was provided with partial regression of the lesions. After 26 months the patient died of uncontrolled metastatic disease. One patient died of an unrelated cause after 52 months of followup. All the other patients (95%) were free of tumor. The daily continence rate was 95% (35 of 37 patients) and the nighttime continence rate was 92% (34 of 37). Two patients (5%) needed CIC. Of the 37 patients 35 (95%) stated that they had maintained erectile function, including 28 (76%) without oral drugs. Table 2 shows the statistical analysis of IIEF and ICS male SF questionnaire outcomes before surgery vs at 2-year followup. Only median IIEF decreased significantly from 25 to 21 (p 6.521e-06). Of the 37 men 32 (86%) had an IIEF of 17 or greater 2 years after cystectomy. Voiding symptoms, incontinence, frequency, nocturia and quality of life scores on the ICS male SF questionnaire did not change significantly (table 2). DISCUSSION Preop Characteristics Median age (range) 58 (52 66) Median ng/ml PSA (range) 1.52 ( ) ng/ml No. pathological stage (%) pt0 1 (3) ptis 4 (8) pta T1 29 (78) pt2 2 (5) pn0 36 (97) pn1 1 (3) Associated Cis 3 (8) No. incidental prostate Ca (%)* 3 (8) Median No. nodes removed (range) 21 (13 35) Median mos followup (range) 35 (24 71) months No. daytime continence (%) 35 (95) No. nighttime continence (%) 34 (92) No. CIC (%) 2 (5) No. erectile function (%) 35 (95) No. erectile function without oral drugs (%) 28 (76) No. local or distant progression (%) 1 (3) after 16-mo followup No. death (%): 2 (5) Cause specific 1 Unrelated 1 Significant Gleason score 3 4 in 1 and 2 smaller than 5 mm. In 1986 Zinman and Libertino first described prostate sparing cystectomy. 15 An ileo-ascending colonic segment was anastomosed to the prostatic capsule after cystectomy combined with prostatic adenomectomy. Ureters were implanted in the ileum with the Wallace technique and the right colon was anastomosed to the prostatic capsule. In 1992 Koraitim and Khalil, 16 in 1998 Muto and Moroni, 17 and in 1999 Spitz et al 10 described potency sparing or sexuality preserving cystectomy. The prostate, seminal vesicles, ampullae of the vas deferens and ejaculatory ducts were spared with the intent to preserve erectile function and ejaculation. Koraitim and Khalil preserved the distal third of the prostatic capsule and inframontanal urethra, 16 Muto and Moroni preserved the prostatic capsule 17 and Spitz et al preserved the posterior prostate. 10 In this fashion no damage was done to the external urinary sphincter, the anastomosis with the reservoir was easier and the neurovascular bundles were left untouched. Furthermore, the dissection plane over the seminal vesicle allowed more complete preservation of the pelvic plexus. The resulting potency rate was dramatically increased in respect to that of nerve sparing radical cystectomy and ejaculation was sometimes maintained. Table 3 lists oncological and functional outcomes in the literature for potency sparing cystectomy Globally 75% to 100% of patients were postoperatively potent. The daytime continence rate was 95% to 100% and the nighttime continence rate was 31% to 100%. The rate of neobladder outlet obstruction was 0% to 16%. Continence was identical to that of standard cystectomy, while the CIC rate seemed to be higher. 18 Antegrade ejaculation and fertility data were anecdotal. Briefly, the consistent advantage of potency sparing cystectomy is the recovery of sexual activity. The results are undoubtedly better than those reported for nerve sparing radical cystectomy. 3,4 However, functional improvement is possibly achieved at the cost of higher relapse and chronic retention rates. Actually a recent review evidenced an unusual rate of oncological failure. 14 Probably prostatic remnants could explain the increased oncological failure rate and the increased chronic retention rate. Outlet obstruction caused by remaining prostate tissue is immediately comprehensible. The orthotopic reservoir is a low pressure system that empties passively, so that any adjunctive mechanical or functional resistance may lead to chronic urinary retention. The reason for the increased recurrence rate is more difficult to understand. The prostatic urethra is completely removed by transurethral prostatectomy or adenomectomy but there is some evidence that the healing process terminates with a prostatic fossa lined by urothelial epithelium from the urethral stump and not by intestinal mucosa, 19,20 also because the neobladder is anastomosed to the prostatic capsule and not to the urethral stump. The prostatic remnants covered by urothelium might TABLE 2. Statistical analysis of IIEF and ICS male SF outcomes Median Baseline (range)/2 Yrs p Value IIEF 25 (17 30)/21(7 29) 0.05 Score: Voiding symptom 1(0 3)/1(0 4) 0.22 Incontinence 0(0 3)/1(0 8) 0.21 Frequency 0(0 2)/1(0 3) 0.05 Nocturia score (range) 0(0 2)/1(1 4) 0.05 Quality of life 0(0 3)/1(1 3) 0.08

5 POTENCY PRESERVING CYSTECTOMY FOR HIGH RISK BLADDER CANCER 1731 TABLE 3. Oncological and functional results of sexuality preserving cystectomy in peer reviewed literature References No. Pts Median or Mean Followup (range) (mos) Daytime % Continence Nighttime % Sexual Active % Chronic Retention % Local Progression Only % Distant /or Local Progression % Alive Muto et al (6 152) Vallencien et al (2 111) Nieuwenhuijzen et al Terrone et al (10 228) Botto et al (12 50) 81 (27 pts) 81 (27 pts) 100 (29 pts) 4 (27 pts) Spitz et al (4 60) Martis et al (6 60) 98 at 24 mos 83 at 24 mos 80 at 24 mos Colombo et al Arroyo et al (3 27) host local recurrence because cancer cells could grow as the healthy epithelium grows. Botto et al explained the increased recurrence rate by metastatic diffusion originated during prostatic resection or during posterior dissection that spares the prostatic capsule and seminal vesicles. 9 To our knowledge we introduce a new technique of potency sparing cystectomy with complete prostate removal to overcome the negative aspects of the prostate sparing approach. Our technique differs from previously described potency sparing cystectomy in 2 main aspects. 1) The reservoir is anastomosed to the urethral stump, thus, avoiding the increased risk of chronic retention that is the main longterm functional complication of orthotopic urinary diversion. 18 2) There is no prostatic tissue left, thus, considerably decreasing the risk of local recurrence from residual or regenerated urothelium of the prostatic fossa and eliminating the risk of prostate cancer. The pelvic plexus and erigentes nerves remain equally intact. Continence and potency rates are fully comparable to those of the cited series of potency sparing cystectomy with partial prostate preservation. Complete prostate removal carries the disadvantage of a permanent loss of ejaculation but this does not seem to be a serious problem because it commonly occurs after surgery for benign prostatic hyperplasia. Functional results are stable with time and they were confirmed using standardized questionnaires. Median IIEF decreased slightly 2 years after the operation with respect to baseline (25 vs 21). Of the patients 86% had an IIEF of 17 or greater vs 100% before the operation. The ICS male SF questionnaire outcome was substantially unchanged. Only the frequency and nocturia domains were altered, mainly due to reservoir management. Cystectomy performed at an early clinical stage may explain the favorable oncological results in our series. As a matter of fact, at the median followup of 3 years no local recurrence had developed. The only oncological failure occurred in a node positive case. A third of the patients had a followup of longer than 4 years and they were disease-free. CONCLUSIONS Long-term followup is needed to evaluate the oncological safety of potency sparing radical cystectomy with intrafascial prostatectomy. However, mid-term functional and oncological results are encouraging. They show that the technique is feasible and may avoid all major objections to the previously described techniques, mainly incomplete prostate removal. In our opinion this technique should be reserved for recurrent or large volume high risk superficial bladder cancer. Abbreviations and Acronyms CIC clean intermittent catheterization ICS male SF International Continence Society male short form questionnaire IIEF International Index of Erectile Function PSA prostate specific antigen REFERENCES 1. Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S et al: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001; 19: Abol-Enein H and Ghoneim MA: Functional results of orthotopic ileal neobladder with serous-lined extramural ureteral reimplantation: experience with 450 patients. J Urol 2001; 165: Schoenberg MP, Walsh PC, Breazeale DR, Marshall FF, Mostwin JL and Brendler CB: Local recurrence and survival following nerve sparing radical cystoprostatectomy for bladder cancer: 10-year followup. J Urol 1996; 155: Kessler TM, Burkhard FC, Perimenis P, Danuser H, Thalmann GN, Hochreiter WW et al: Attempted nerve sparing surgery and age have a significant effect on urinary continence and erectile function after radical cystoprostatectomy and ileal orthotopic bladder substitution. J Urol 2004; 172: Muto G, Bardari F, D Urso L and Giona C: Seminal sparing cystectomy and ileocapsuloplasty: long-term followup. results. J Urol 2004; 172: Vallancien G, Abou El Fettouh H, Cathelineau X, Baumert H, Fromont G et al: Cystectomy with prostate sparing for bladder cancer in 100 patients: 10-year experience. J Urol 2002; 168: Nieuwenhuijzen JA, Meinhardt W and Horenblas S: Clinical outcomes after sexuality preserving cystectomy and neobladder (prostate sparing cystectomy) in 44 patients. J Urol 2005; 173: Terrone C, Porpiglia F, Cracco C, Tarabuzzi R, Cossu M, Renard J et al: Supra-ampullar cystectomy and ileal neobladder. Eur Urol 2006; 50: Botto H, Sebe P, Molinie V, Herve JM, Yonneau L and Lebret T: Prostatic capsule- and seminal-sparing cystectomy for bladder carcinoma: initial results for selected patients. BJU Int 2004; 4: Spitz A, Stein JP, Lieskovsky G and Skinner DG: Orthotopic urinary diversion with preservation of erectile and ejaculatory function in men requiring radical cystectomy for nonurothelial malignancy: a new technique. J Urol 1999; 161: 1761.

6 1732 POTENCY PRESERVING CYSTECTOMY FOR HIGH RISK BLADDER CANCER 11. Martis G, D Elia G, Diana M, Ombres M and Mastrangeli B: Prostatic capsule- and nerve-sparing cystectomy in organconfined bladder cancer: preliminary results. World J Surg 2005; 29: Colombo R, Bertini R, Salonia A, Naspro R, Ghezzi M, Mazzoccoli B et al: Overall clinical outcomes after nerve and seminal sparing radical cystectomy for the treatment of organ confined bladder cancer. J Urol 2004; 171: Arroyo C, Andrews H, Rozet F, Cathelineau X and Vallancien G: Laparoscopic prostate-sparing radical cystectomy: the Montsouris technique and preliminary results. J Endourol 2005; 19: Hautmann RE and Stein JP: Neobladder with prostatic capsule and seminal-sparing cystectomy for bladder cancer: a step in the wrong direction. Urol Clin North Am 2005; 32: Zinman L and Libertino JA: Right colocystoplasty for bladder replacement. Urol Clin North Am 1986; 13: Koraitim M and Khalil R: Preservation of urosexual functions after radical cystectomy. Urology 1992; 39: Muto G and Moroni M: Seminal-sparing cystectomy and ileocapsuloplasty. Acta Urol Ital 1998; 12: Hautmann RE, Volkmer BG, Schumacher MC, Gschwend JE and Studer UE: Long-term results of standard procedures in urology: the ileal neobladder. World J Urol 2006; 24: Theodorescu D, Binnington AG and Connolly JG: The intestinoprostatic capsule anastomosis: functional and anatomic results in a canine model. Can J Surg 1992; 35: Orihuela E, Pow-Sang M, Motamedi M, Cowan DF and Warren MM: Mechanism of healing of the human prostatic urethra following thermal injury. Urology 1996; 48: 600. EDITORIAL COMMENT These authors present the functional and oncological results of 37 potency preserving cystectomies in patients with high risk, nonmuscle invasive bladder cancer. Although the results are excellent, one must entertain certain caveats and questions. The most important caveat is that this is a highly select group of patients, that is 37 of 289 (13%) who underwent cystectomy. Only 2 cases were pathologically upstaged to pt2. In most cystectomy series 40% to 60% of cases are pathologically upstaged. Until there are improvements in radiological imaging of the bladder this will continue to be problematic. Also, the continence results are impressive, especially the nighttime continence rate of 92%. However, 5% of the patients performed CIC. It is unclear as to how the surgical modifications during cystectomy account for the improvement in nocturnal continence. I suspect that these results are a reflection of the relatively young age of this cohort of patients (median 58 years, range 52 to 66). Furthermore, the potency results are impressive, although in this age group the results of nerve sparing cystectomy may be comparable. The figures and description of the surgical technique in this article are concise and clear. However, it is my impression that, if this technique becomes widely adopted, a significant number of cases (inappropriately selected clinical T2) would show positive surgical margins and tumor cut across or into, especially posteriorly and laterally. I do not believe that this procedure should be widely accepted until a randomized multicenter trial is performed. The goals of this randomized trial would be to define appropriately selected patients and the potential sexual function benefits over those of nerve sparing cystectomy. Gary D. Steinberg Section of Urology University of Chicago Medical Center Chicago, Illinois