Cancer and Prostatic Diseases (2003) 6, 56–60 ß 2003 Nature Publishing Group All rights reserved 1365–7852/03 $25.00 www.nature.com/pcan Cavernous graft reconstruction during radical prostatectomy or radical cystectomy: safe and technically feasible

AG Anastasiadis1, MC Benson1, MP Rosenwasser2, L Salomon1, H El-Rashidy1, MA Ghafar1, JM McKiernan1, M Burchardt3 & R Shabsigh1* 1The Department of Urology, College of Physicians and Surgeons of Columbia University, New York, USA; 2The Department of Orthopedic , College of Physicians and Surgeons of Columbia University, New York, USA; and 3The Department of Urology, Heinrich-Heine-University, Du¨sseldorf, Germany

High local stage prostate and bladder cancers frequently require wide local resection and sacrifice of one or both cavernous to achieve a negative surgical margin, thus resulting in . This is a report on preliminary experience with cavernous nerve graft reconstruction using sural nerve grafts with radical prostatectomy or radical cystectomy. Pre-operative evaluation was performed and consent was obtained in 14 potent men with prostate (11) or bladder (three) cancer. Sural nerve grafts of resected cavernous nerves were performed using a microsurgical technique. Post-opera- tive treatment (Sildenafil or Alprostadil) was pursued until return of spontaneous function, documented by interview and adequate scores ( > 20) in the erectile function (EF) domain of the International Index of Erectile Function (IIEF). Twelve unilateral nerve grafts were performed, 10 during radical prostatectomy and two during radical . Two procedures were technically not possible because of locally advanced disease. Mean age was 57.5 y (36 – 68 y). Mean follow up was 16.1 months (7 – 28 months). Pathological stage of was pT2 in 2, pT3 in 7 and pT4 in one. Surgical margins were positive in five out of 10 (50%), and two (20%) had positive lymph nodes. Four patients (three post prostatectomy and one post cystectomy) were fully potent. Additionally, one patient post prostatectomy had improving partial erections. Six patients post prostatectomy and one patient post cystectomy had no erections. The only was one superficial wound infection in the sural nerve donor site. Preliminary experience shows that sural nerve grafts are feasible and safe after radical prostatectomy and cystectomy. However, candidates usually present with high stage disease, high risk for recurrence and frequent requirement for adjuvant therapy that further compromises erectile function. Randomized studies with more patients and long follow-up periods are necessary in order to define the ideal candidate for nerve graft procedures. Prostate Cancer and Prostatic Diseases (2003) 6, 56–60. doi:10.1038/sj.pcan.4500613

Keywords: sural nerve grafts; radical prostatectomy; radical cystectomy; erectile dysfunction

Introduction *Correspondence: R Shabsigh, Department of Urology, Columbia University, College of Physicians and Surgeons, 161 Fort Washington Although radical prostatectomy can be performed with Avenue, Herbert Irving Pavilion, 11th Floor, New York, NY 10032, USA. diminished morbidity due to improvement of surgical E-mail: [email protected] techniques, many patients will suffer from post-operative Received 18 April 2002; revised 5 June 2002; accepted 12 June 2002 erectile dysfunction (ED). Even with preservation of both Nerve graft reconstruction in radical urologic surgery AG Anastasiadis et al 57 neurovascular bundles (NVB), the potency rates range had not received neoadjuvant hormonal or radiation between 30% and 71%.1 – 3 After resection of both neuro- therapy. Patient characteristics are shown in Table 1. vascular bundles, spontaneous erections adequate for The patients were counseled that the nerve grafting intercourse are extremely rare.4 would be performed at the time of the radical prostatect- Rat model studies performed in 1991 were able to omy and that return of function might not be apparent for demonstrate clearly that erectile function returns after many months. After informing the subjects about the denervation and placement of nerve grafts. Using a risks of nerve grafting (infection and blood loss related genitofemoral nerve graft after bilateral resection of to the increased duration of the procedure, hematoma, 5 mm segments, Quinlan et al were the first to report the infection at the nerve donor site, pain, sensory deficit in return of potency 4 months post-operatively.5 In the same the lateral aspect of the foot, neuroma formation), written year, the authors investigated the ability of nerve growth consent was obtained. factor (NGF) as well as the use of fetal amniotic mem- brane as an alternative growth matrix to enhance regen- eration of ablated cavernous nerves. Their results Surgical technique suggested that the use of these materials could facilitate autonomic nerve regrowth.6 Kim et al4,8 have described the surgical technique exten- Encouraged by these experimental studies, Walsh car- sively. The main steps are (a) preparation and resection of ried out a randomized blind study of nerve grafts in the neurovascular bundle(s), (b) harvesting the sural patients who underwent wide excision of the neurovas- nerve, (c) placement of the graft, and (d) completion of cular bundle: in 12 men, six received a genitofemoral the vesicourethral anastomosis. The microsurgical team nerve graft and the other six served as controls. In a 5 y performs the harvesting of the sural nerve during follow-up, he could not observe any difference in the removal of the prostate by the Urologic Surgeon. Suffi- recovery of sexual function in these two groups.7 After cient nerve even for bilateral grafting is obtained from one this observation, he abandoned this technique. Years later, leg. A midline incision from the mid calf to the ankle is in March 1997, Kim et al 8 successfully performed the performed. The sural nerve is located at the lateral ankle. initial bilateral interposition grafts from the sural nerve After identification of the sural nerve between the median to both cavernous nerves in a 57-y-old, sexually active and the lateral heads of the M. gastrocnemius, the dissec- man. Since then, more than 300 procedures have been tion is performed in a retrograde fashion for the required performed at more then six centers and some patients length, which for a unilateral case is approximately 8 cm. have recovered after bilateral resection and grafts.9 A microsuction mat is helpful to keep the oozing bed of Recovery after unilateral grafts appears comparable to the resected prostate from obscuring vision. Additional recovery with bilateral nerve preservation.9–11 In this laxity is placed in the graft so that the following expan- preliminary study, we report our nerve grafting results sion of the bladder will not cause excessive tension on the from 12 pre-operatively potent patients undergoing radi- anastomosis. cal prostatectomy and cystectomy with a mean follow-up Gentle handling of the nerve using microsurgical of 16 months. instruments is important. Loupes are preferred for the anastomosis because of the difficulty in getting a micro- scope into the pelvis at the proper angle to see the distal anastomosis juncture. Initially, harvesting the nerve was Materials and methods performed by an orthopaedic surgeon trained in micro- Patient selection surgery (MPR), but now the senior author routinely harvests the nerve and performs the anastomosis himself. All selected individuals were patients with prostate or In order to identify and prepare the NVB accurately, a bladder cancer (mean age 57.5 y) and normal pre-opera- 4Â loupe magnification was used. Since the NVB is a tive erectile function, documented in a patient interview plexus of nerve fibers and vessels, a relatively bloodless and a score of 25 or above in the EF domain of the field is essential for proper preparation. Before (cysto)- International Index of Erectile Function (IIEF).12 They prostatectomy, proximal and distal marking sutures with

Table 1 Patient profiles and clinical status after unilateral sural nerve grafting procedure

Patient no. (patient age, y) Organ PSA (ng/ml) Stage Gleason score Surgical margins Follow-up (months) Clinical status

1 (48) Prostate 8.8 pT3c 7 negative 28 Spontaneous erections 2 (51) Prostate 10.0 pT2c 6 negative 17 Spontaneous erections 3 (48) Prostate 57.6 pT4 8 positive 23 No erections 4 (64) Prostate 3.8 pT3a 6 positive 24 Spontaneous erections 5 (55) Prostate 3.7 pT3a 9 positive 16 No erectionsa 6 (66) Prostate 6.4 pT3c 8 negative 15 No erectionsb 7 (66) Prostate 4.9 pT3c 9 negative 16 No erectionsc 8 (58) Prostate 5.8 pT2c 8 negative 14 Partial erections (25%) 9 (65) Prostate 5.6 pT3a 7 positive 9 No erectionsa 10 (65) Prostate 6.8 pT3a 7 positive 8 No erectionsc 11 (68) Bladder 2.1 pT3a NA negative 16 No erections 12 (36) Bladder 0.2 pT2 NA negative 7 Spontaneous erections aExternal beam radiation; bhormonal therapy; cintercavernous alprostadil injections.

Prostate Cancer and Prostatic Diseases Nerve graft reconstruction in radical urologic surgery AG Anastasiadis et al 58 therapy in an adjuvant setting. Postoperatively, the patients presented for a follow-up visit every 3 months, which included an interview and the IIEF questionnaire.

Results The procedure could not be performed in two patients (one with prostate cancer and one with bladder cancer). Due to extensive local disease, the distal stump was too short after resection; therefore, a tension free anastomosis was technically not possible in these patients. The out- come of the nerve grafting procedures is shown in Table 1. The mean follow-up for the 12 men was 16.1 months (range 7 – 28). Overall, four of the 12 patients were able to achieve spontaneous erections sufficient for intercourse with vaginal penetration, documented with a score of > 20 in the EF domain of the IIEF. The youngest (bladder cancer) patient (no. 12) reported erections 3 months post- operatively. The patient after bilateral NVB resection (no. 4) reported erections 20 months after the procedure. Patients nos. 1 and 2 returned to erectile function after 24 and 12 months, respectively. In addition, Patient no. 8 reported improving partial erections. Surgical margins were reported positive in five out of 10 patients with prostate cancer. The patients receiving adjuvant external beam radiation (nos 5 and 9), or hormonal therapy (no. 6) reported having no erections. The only postoperative complication was one superficial wound infection at the Figure 1 Sural nerve graft after tension-free anastomosis (arrow). donor site, which could be managed conservatively.

8-0 Prolene were placed. In order to identify the nerve Discussion stumps precisely, intraoperative nerve stimulation was performed using the CaverMap surgical aid (UroMed Although nerve grafting has found application in urology Corp., Norwood, MA, USA).13 A reading of þ 2or only during recent years, it is an otherwise well estab- more was used to determine bundle stump location. lished medical procedure: sural nerve grafts have been These parameters were used consistently. The graft was used extensively with brachial plexus, facial nerve and then inserted in an inverted fashion and the alignment of peripheral nerve injuries.17,18 Although it is myelinated, fascicles was carried out using 8-0 Prolene sutures after the sural nerve becomes functionally demyelinated placing the vesicourethal anastomotic sutures (Figure 1). during grafting.17 Whenever a tension free end-to-end After tying the vesicoanastomotic sutures very carefully, a nerve repair, as after resection of the NVB during prosta- suction drain with minimal suction was placed away tectomy, is not possible, a segment of a peripheral nerve from the area of the graft. All patients received unilateral can be used for implantation. The graft serves as a nerve grafts on the side where NVB involvement was channel or conduit for the regenerating axons on the palpable and was therefore resected. One patient, how- proximal side to reach the distal stump. It also serves as ever, received a unilateral nerve graft after resection of a source of Schwann cells and growth factors to help both NVBs (patient no. 4, Table 1). The average additional facilitate regeneration.19 Important aspects of nerve graft- operative time was 45 min. Histopathological examina- ing include the creation of a tension free repair, with a tion of the prostatectomy specimens was performed graft 10 – 20% longer than the defect to compensate for according to the 1997 TNM classification.14 the shrinkage, a graft slightly larger than the transected nerve ends to capture and channel regenerating axons, Post-operative care meticulous tissue handling and loupe magnification to avoid damage to the graft, and sparing use of nylon The time to discharge to home was unaffected by the microsuture.17 Since nerve grafts can be limited because additional grafting procedure. Patients were encouraged of limited length and sensory deficits at the site of to start therapy with sildenafil citrate or, in case of failure, removal, vein grafts, muscle-vein grafts, synthetic tubes intracavernous Alprostadil within the first postoperative as well as porous conduits have been examined for their month, since it could be demonstrated that immediate suitability to fill post-traumatic defects.20 The main dis- administration of these erectogenic agents is able to advantage of these grafts is that they can be used only for increase the recovery rate of spontaneous erections after short distance defects. Furthermore, synthetic materials radical prostatectomy.15,16 Patients with advanced patho- are not biodegradable and can lead to reactions of the logic parameters routinely received radiation or hormonal surrounding tissue.

Prostate Cancer and Prostatic Diseases Nerve graft reconstruction in radical urologic surgery AG Anastasiadis et al 59 Previous animal studies by Quinlan et al and Ball et al radical prostatectomy and radical cystectomy. In this pre- using the genitofemoral nerve demonstrated the ability of liminary study with a mean follow-up of 16.1 months, interposition nerve grafts to recover erectile function in four out of 12 patients after radical prostatectomy or the majority of denervated rats, as measured by mating radical cystectomy recovered spontaneous erections studies and electric pelvic nerve stimulation.3,21 Improve- sufficient for intercourse. Recovery in three of the four ment of erectile function was noted at 3 – 4 months post- men occurred after a time interval between 12 and 24 operatively. In humans, however, the procedure is tech- months. To the knowledge of the authors, this is the first nically more challenging, since the cavernous nerve is not report of a successful sural nerve graft in a radical a well-defined structure, but consists of multiple nerves, cystectomy patient. which are dispersed in a plexus surrounded by vessels.15 The choice of the ideal candidate for nerve graft In their recently published study, Kim et al 22 presented procedures remains problematic, since properly per- the return of varying degrees of erectile function in nine of formed, randomized studies are missing. Patient selection 12 men undergoing radical retropubic prostatectomy with criteria for these procedures have to be optimized, results wide bilateral cavernous nerve resection and interposition can be evaluated only after long follow-up periods, and of sural nerve grafts.22 In their 1 y follow-up study, three the small number of presented series does not justify men had rigid erections sufficient for intercourse. Tumes- a general enthusiasm about this innovative surgical cence was not reported until 5 months post-operatively, technique. and the best erections were observed at 18 months. According to the authors, the realization of the full benefit of these grafts may not be appreciated until at least 24 – 36 months postoperatively. In our study, similar results could be observed: three of the four men with return of References erectile function improved 12 – 24 months after the pro- 1 Davidson PJ, van den Ouden D, Schroeder FH. Radical prosta- cedure. It is interesting to observe, however, that one man tectomy: prospective assessment of mortality and morbidity. Eur returned to erectile function 3 months post-operatively. Urol 1996; 29: 168 – 173. One possible explanation for that could be his young age 2 Lowentritt BH et al. Sildenafil citrate after radical retropubic (36 y). It could be demonstrated that age is one of the prostatectomy. 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Nerve growth factor, nerve grafts and amniotic membrane grafts restore erectile (some patients recover erectile function when a single function in rats. J Urol 1991; 146: 463 – 468. nerve is preserved), the clear decrease in erectile function 7 Walsh PC. Nerve grafts are rarely necessary and are unlikely to after unilateral NVB resection has been extensively improve sexual function in men undergoing anatomic radical described recently by Scardino and Kim.9 In their series, prostatectomy. Urology 2001; 57: 1020 – 1024 men after unilateral nerve grafting had similar erectile 8 Kim ED et al. Interposition of sural nerve restores function of function according to the International Index of Erectile cavernous nerves resected during radical prostatectomy. JUrol 1999; 161: 188 – 192. function compared with those with both nerves preserved 9 Scardino PT, Kim ED. Rationale for and results of nerve grafting (78 vs 79%, respectively). during radical prostatectomym. Urology 2001; 57: 1016 – 1019. It should be pointed out that the use of sural nerve 10 Kadmon D et al. Unilateral interposition sural nerve grafting grafts has been controversial. In a recent review, Walsh following ipsilateral neurovascular bundle resection at radical expressed his scepticism about the value of nerve grafts in prostatectomy (RP) decreases the time to potency recovery. JUrol restoring sexual function in men who undergo wide 2001; 165(no. 5, Suppl): 149. excision of the NVB.7 Some important issues addressed 11 McKiernan JM et al. Cavernous nerve graft reconstruction follow- ing radical prostatectomy in 77 patients: feasibility, safety and in this review are the concept of excision of the NVB on early results. J Urol 2001; 165(no. 5, Suppl): 149. the side of the positive biopsy; the problem of invasion of 12 Rosen RC et al. 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