Potency after unilateral nerve sparing surgery: a report on functional and oncological results of unilateral nerve sparing surgery

Potency after unilateral nerve sparing surgery: a report on functional and oncological results of unilateral nerve sparing surgery F Van der Aa 1, S Joniau 1, D De Ridder 1 & H Van Poppel 1 * 1 Department of Urology, University Hospitals Leuven, Leuven, Belgium (2003) 6, 61 65 ß 2003 Nature Publishing Group All rights reserved 1365 7852/03 $25.00 www.nature.com/pcan The objective of the study was to evaluate unilateral nerve sparing prostate surgery. Patient files of men who underwent unilateral nerve sparing radical prostatectomy were analyzed retrospectively after a minimum follow-up period of 18 months. Of 46 patients who received unilateral nerve sparing surgery, 14 (30.4%) regained full potency after surgery. In 92.9% of these patients, recovery occurred within a period of 18 months. Age is the single most important factor in the recuperation of potency after unilateral nerve sparing surgery. Most of the patients (84.8%) reported the ability to achieve orgasm. Of eight patients with positive section margins, two had positive section margins at the spared side only. Unilateral nerve sparing surgery remains a feasible treatment option for prostate cancer. (2003) 6, 61 65. doi:10.1038/sj.pcan.4500626 Keywords: prostate cancer; nerve sparing surgery; potency Introduction Radical prostatectomy still stands as the gold standard for curative treatment of localized prostate carcinoma. Until the early 1980s, postoperative erectile dysfunction (ED) used to be an almost inevitable complication of radical prostatectomy, discouraging both patient and urologist from choosing this form of treatment. In 1982, Walsh introduced the anatomical radical retropubic prostatectomy. 1 A better understanding of the role of the pelvic plexus in the physiology of erection and the anatomical recognition of the neurovascular bundles resulted in a more anatomical approach. By limiting damage to neurovascular bundles, irreversible ED could be avoided in a great number of patients. Localized tumors are an increasing part of newly diagnosed prostate cancers, thus making nerve-sparing surgery more feasible. 2 To this date, several series have been published. 3 9 The role and outcome of a bilateral nerve sparing procedure is well established, although reported results of postoperative recovery of potency are *Correspondence: Professor H Van Poppel, Department of Urology, University Hospitals Catholic University Leuven, 49 Herestraat, 3000 Leuven, Belgium. E-mail: hendrik.vanpoppel@uz.kuleuven.ac.be Received 24 April 2002; revised 1 July 2002; accepted 24 July 2002 variable. The role of a unilateral nerve sparing procedure is less clear. Some authors report unsatisfying results and even doubt the benefit of this procedure. 8 In a retrospective study, we analyze our own experience in 72 patients who underwent unilateral nerve sparing surgery between 1988 and 1999. Materials and methods Between July 1988 and April 1999, 72 sexually active and mostly normally potent men with clinical T1a T3 prostate cancer underwent unilateral nerve sparing radical prostatectomy. Patient age ranged from 47 to 76 y (mean 60.5 y). Thirteen patients were excluded because they were lost for follow-up or refused participation. Clinical staging was performed by digital rectal examination, prostate specific antigen (PSA) and transrectal ultrasonography (TRUS) with prostate biopsies. All prostate core biopsies were graded according to the Gleason grading system. A bone scan and a contrast-enhanced computerized tomography (CT) of the pelvis with 4 mm slices were performed when a PSA > 10 ng/ml or a Gleason score 7 was noted. Patients underwent a bilateral staging pelvic lymphadenectomy without frozen section, followed by a radical retropubic prostatectomy under general anesthesia. Surgery was performed by one of two senior surgeons according to the technique as previously

62 described by Walsh. 1 All prostatectomy specimens were graded according to the Gleason grading system. Microscopic extension of malignant cells to the inked surface of the resected specimen was interpreted as a positive surgical margin. Patients had a transurethral catheter for 2 weeks. Pelvic floor re-education was started at the time of catheter withdrawal. Eleven patients received adjuvant radiotherapy. In this last group, three patients additionally received hormonal therapy. The patient files were analyzed retrospectively for pre- and postoperative potency. Whenever insufficient information was present, patients were contacted by telephone. Erectile function was categorized in three groups: absence of erection (no recovery); partial erection (partial recovery); and erection sufficient for intromission (complete recovery). Presence or absence of orgasm was also documented. A minimum follow-up period of 18 months was required. Results Fifty-five patients aged between 47 y and 76 y (mean 59.9 y) had preoperative erections sufficient for intercourse. In this group, postoperative adjuvant radiotherapy was administered to nine patients. Thus, 46 patients with preoperative normal erectile function underwent unilateral nerve sparing surgery as monotherapy. Patient characteristics are shown in Table 1. Mean age was 59.9 y (range 47 76 y). Mean preoperative PSA was 8.2 (range 0.5 23.8 ng/ml). Of all preoperative potent patients, 11 (23.9%) had a complete loss of erectile function postoperatively. Partial Table 1 Variables Patient characteristics Number of patients, n ¼ 46 (%) Age 40 49 y 2 (4.3) 50 59 y 17 (37) 60 69 y 24 (52.2) 70 79 y 3 (6.5) Procedure Nerve sparing left side 23 (50) Nerve sparing right side 23 (50) Preoperative PSA value < 4 8 (26.1) 4 10 27 (58.7) >10 11 (24) Clinical staging ct1 12 (26.1) ct2 30 (65.2) ct3 4 (8.7) Tumor grade Well-differentiated 6 (13) Moderately differentiated 38 (82.6) Poorly differentiated 2 (4.3) Pathological staging pt2 35 (76.1) pt3 11 (23.9) Adjuvant therapy (n ¼ 55) Yes 9 No 46 Table 2 Recovery of potency sufficient for intromission after unilateral nerve sparing surgery Variables Number of patients, (percentage of that category) Age 40 49 (n ¼ 2) 1 (50) 50 59 (n ¼ 17) 7 (33.3) 60 69 (n ¼ 24) 6 (24.1) 70 79 (n ¼ 3) 0 (0) Preoperative PSA value < 4(n¼8) 3 (37.5) 4 10 (n ¼ 27) 8 (29.6) > 10 (n ¼ 11) 3 (27.3) Clinical staging ct1 (n ¼ 12) 2 (16.7) ct2 (n ¼ 30) 10 (33.3) ct3 (n ¼ 4) 2 (50) Tumor grade Well-differentiated (n ¼ 6) 4 (66.7) Moderately differentiated (n ¼ 38) 9 (23.7) Poorly differentiated (n ¼ 2) 1 (50) Pathological staging pt2 (n ¼ 35) 11 (31.4) pt3 (n ¼ 11) 3 (27.3) recovery occurred in 21 patients (45.7%) and complete recovery occurred in 14 patients (30.4%). We analyzed the influence of different variables on postoperative recovery of erection. These data are summarized in Table 2. The single most important variable was patient age (Figure 1). In the category from 40 y to 49 y 50% had complete recovery, in the category from 50 y to 59 y a 33.3% recovery was seen and in the patients between 60 y and 69 y 24.1%. In the age category of men older then 69 y complete recovery was not noted. Timing of recovery varied from 6 to more than 18 months. When present, complete recovery occurred in 50% of patients after 12 months and in 92.9% after 18 months. 84.8% of all patients still experienced orgasms. In patients with complete and partial recovery of erectile function percentages were even higher (100 and 90.5%, respectively). Postoperative adjuvant radiotherapy was administered to nine out of 55 patients with a preoperative normal erectile function. Their characteristics are shown in Table 3. Seven patients received adjuvant radiotherapy only. This was administered immediately after surgery because of positive section margins in three cases or after several months because of local recurrence in four cases (mean time of recurrence was 47.25 months, ranging from 21 to 84 months). Two patients received additional hormonal therapy. In one case total androgen blockade was started because of PSA progression after 7 months and in the other LHRH-agonists because of PSA progression after 38 months with clinical evidence of local tumor recurrence. In the group with adjuvant treatment 77.8% had complete absence of erections after therapy, as compared to 23.9% in the group without adjuvant treatment. Both patients who received hormonal therapy had no postoperative erections and were not sexually active. Of 55 patients, one patient had a positive section margin at the side of wide excision, two patients had a positive section margin at the nerve spared side and another two

63 Figure 1 Difference in recovery of erectile function between different are groups. ( ) Full potency; ( ) intermediate potency; ( ) persistent impotence. also had a positive section margin at the nerve spared side, together with other positive section margins. Furthermore, three patients had positive apical section margins. Thus in total, eight patients had positive section margins. All of them received immediate or later postoperative adjuvant therapy and are included in Table 3. When this study was performed, 44 patients (80%) were alive without evidence of disease (median diseasefree survival of 49.98 months with a range from 18 to 104 months), 10 patients (18.2%) were alive with metastatic disease (median survival of 97.8 months with a range from 56 to 139) and one patient (1.8%) had died from another cause after 29 months (non-related cancer). Several patients used Sildenafil or intracavernous injections postoperatively. In the group of patients with postoperative partial recovery 14 patients (66.7%) used one of these methods, in the group of patients without recovery five (36.7%) and in the group of patients with full recovery three patients (28.6%). This is shown in Table 4. Discussion One of the major advantages of the anatomical approach of the retropubical radical prostatectomy is control of blood loss. 1 This results in a better peroperative identification of different structures. In this way, the surgeon can decide to spare one or both neurovascular bundles. During recent years a migration of pathological tumor stages of newly diagnosed prostate cancers towards more localized stages has occurred. 2 This has resulted in an increasing number of nerve sparing procedures performed at our institution. The benefit of unilateral nerve sparing procedures is not universally accepted. Earlier series report recovery rates varies from 13.3 to 69%. 4 6 We report a series of 46 patients treated with unilateral nerve sparing surgery only. The total recovery rate was 30.4%. After bilateral nerve sparing procedures recovery rates were higher, ranging from 31.2 to 76%. 3,4,6,7 Patientreported results tended to be lower. 8 Prospective documentation of the patient status, the use of quality of life surveys and treatment in high-volume centers result in better recovery rates. 9 An important fact is that most patients (84.8%) will still have the ability to achieve orgasm postoperatively. A number of factors may influence the recovery of erections after unilateral nerve sparing surgery (Table 2). Besides the type of surgery (unilateral vs bilateral nerve sparing), age is the most important factor. 3 8 In our series, an important agedependent response was also found, as displayed in Figure 1. Younger patients clearly have better recovery rates. They probably have greater erectile capacity and neural regenerative ability then older patients. Also, a Table 3 Patients who received adjuvant therapy after unilateral nerve sparing surgery Patient Spared side Section margin Adjuvant therapy Reason Timing (months) 1 Right 7 Radiotherapy Local recurrence 38 2 Right þ (left and right side) Radiotherapy a Local recurrence 21 3 Left þ (right side) Radiotherapy a Local recurrence 39 4 Right þ (apical) Radiotherapy 5 Right þ (apical) Radiotherapy 6 Left þ (left side and Radiotherapy both seminal vesicles) 7 Right (right side) Radiotherapy a Local recurrence 84 8 Right þ (apical) Radiotherapy 7 Hormone therapy 9 Right þ (right side) Radiotherapy Hormone therapy PSA progression PSA progression a These patients with positive section margins were randomized in a study to compare early (postoperative) radiotherapy to late (at time of PSA progression) radiotherapy. 38

64 Table 4 Alternatives used to improve erectile function after unilateral nerve sparing surgery Alternative method Postoperative erectile function a Number of patients/ patients in that category Total number of patients Sildenafil 0 3/11 1 9/21 2 1/14 13 Intracavernous injection 0 2/11 1 5/21 2 2/14 9 None 0 6/11 1 7/21 2 11/14 24 a Postoperative erectile function without therapy: 0, absence of erection; 1, partial erection; 2, erection sufficient for intercourse. younger population will have vascular problems to a lesser extent. Other variables seem to be less important In some series a correlation between postoperative erectile function and pathological stage is described. 7 We were not able to confirm this. In clinical staging, we even found an inverse relationship. Preoperative PSA value and tumor differentiation seem to have no influence. Higher preoperative frequency of intercourse is reported to correlate with higher recovery rates. 5 It is obviously difficult to analyze this variable in a retrospective way. Non-neurogenic causes also play a substantial role in the recovery of potency after nerve sparing surgery. Even after technically well-performed nerve sparing surgery, vascular injury can cause erectile dysfunction. 10,11 Damage to accessory pudendal arteries may be a contributing factor, although their clinical significance is questioned. 12,13 Different treatment strategies for postoperative erectile dysfunction exist. In our series intracavernous injections and Sildenafil were frequently used (Table 4). Mostly patients with postoperative intermediate erections were interested in medical treatment. However, three patients in the full recovery group also used Sildenafil. They mentioned that their erections, although sufficient for intercourse, did not have the same quality as before surgery. Since a number of patients still had the ability to achieve orgasm, intracavernous injections were an acceptable treatment. Early administration could increase the recovery rate of spontaneous erections after nerve sparing surgery. 14 Sildenafil was not available during a substantial period of our series, so the real use at present will be underestimated. The role of Sildenafil in the treatment of postoperative erectile dysfunction is still under investigation. By selectively inhibiting type V-phosphodiesterase, Sildenafil prolongs the presence of cyclic guanosine monophosphate, allowing for continued relaxation of smooth muscle and enhancement of erection. This mechanism of action requires functional neurovascular bundles. Thus, the postoperative response to Sildenafil is related to the amount of nerve tissue spared. 15,16 Baseline postoperative erectile function and the type of surgery performed (non-nerve sparing, unilateral or bilateral nerve sparing) will determine the effect of Sildenafil. Response is higher after bilateral nerve sparing surgery, although a response rate of 57% has been reported after unilateral nerve sparing surgery. 16 Different authors have already proposed techniques and assisting devices to localize the neurovascular bundles intraoperatively and to test their integrity during the intervention. These techniques should make a more accurate prediction of postoperative recovery of erections possible. 17,18 Unfortunately, the specificity of current techniques does not permit precise localization, which still makes prediction of postoperative potency difficult. 19 In our series we used none of these devices. In our experience the oncological results of unilateral nerve sparing surgery are satisfying. Of eight patients with positive section margins, only two had positive section margins at the spared side only. At the time of our study, the majority of patients were alive with no evidence of tumor activity. Conclusions The benefits of unilateral nerve sparing surgery are questioned in literature. Because of an increased detection of clinical and pathological low-stage prostate cancers, the demand for nerve sparing surgery is rising. Whenever tumor stage makes the sacrifice of one neurovascular bundle necessary, we believe it is beneficial to perform unilateral nerve sparing surgery since a substantial part of patients will eventually have complete recovery of erectile function and oncological results are satisfying. In our series one-third of patients had complete recovery. Objective prediction of postoperative recovery in individual patients remains difficult. Young patients in particular have better recovery rates. Complete recovery can take up to 18 months. Nevertheless, postoperative erectile dysfunction remains an unavoidable complication, even after technically well-performed nerve sparing surgery. Nonneurogenic causes such as vascular damage can contribute to these findings. Most patients will still have the ability to achieve orgasm. References 1 Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982; 128: 492 497. 2 Noldus J, Graefen M, Hammerer P et al. Entwicklung der Tumorselektion anhand des pathologischen Stadiums beim klinisch lokalisierten Prostatakarzinom. Urologe A 1998; 37(2): 195 198.

3 Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. JUrol1994; 152: 1831 1836. 4 Catalona WJ, Basler JW. Potency, continence and complication rates en 1870 consecutive radical retropubic prostatectomies. J Urol 1999; 162: 433 438. 5 Geary ES, Dendinger ET, Freiha SF et al. Nerve sparing radical prostatectomy: a different view. JUrol1995; 154: 145 149. 6 Walsh PC, Epstein JI, Lowe FC. Potency following radical prostatectomy with wide unilateral excision of the neurovascular bundle. JUrol1987; 138: 823 827. 7 Quinlan DM, Epstein JI, Carter BS et al. Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles. J Urol 1991; 145: 998 1002. 8 Talcott JA, Rieker P, Propert KJ et al. Patient-reported impotence and incontinence after nerve-sparing radical prostatectomy. J Natl Cancer Inst 1997; 89: 1117 1123. 9 Walsh PC, Marschke P, Picker D et al. Patient-reported urinary continence and sexual function after anatomic radical prostatectomy. Urology 2000; 55: 58 61. 10 Aboseif S, Shinohara K, Breza J et al. Role of penile vascular injury in erectile dysfunction after radical prostatectomy. Br J Urol 1994; 73: 75 82. 11 Bahnson RR, Catalona WJ. Papaverine testing of impotent patients following nerve-sparing radical prostatectomy. J Urol 1988; 139: 773 774. 12 Droupy S, Hessel A, Benoit G et al. Assessement of the functional role of accessory pudendal arteries in erection by transrectal color doppler ultrasound. JUrol1999; 162: 1987 1991. 13 Polascik TJ, Walsh PC. Radical retropubic prostatectomy: the influence of accessory pudendal arteries on the recovery of sexual function. J Urol 1995; 153: 150 152. 14 Montorsi F, Guazzoni G, Strambi LF et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injection of alprostadil: results of a prospective, randomized trial. J Urol 1997; 158: 1408 1410. 15 Zippe CD, Kedia AW, Kedia K et al. treatment of erectile dysfunction after radical prostatectomy with sildenafil citrate (Viagra). Urology 1998; 52: 953 966. 16 Lowentritt BH, Scardino PT, Miles BJ et al. Sildenafil citrate after radical retropubic prostatectomy. JUrol1999; 162: 1614 1617. 17 Drew JB, Begun FP, Jacobs SC. Doppler-assisted nerve-sparing radical prostatectomy. Urology 1999; 33(3): 228 229. 18 Rehman J, Christ GJ, Kaynan A et al. Intraoperative electrical stimulation of cavernosal nerves with monitoring of intracorporeal pressure in patients undergoing nerve sparing radical prostatectomy. Br J Urol Int 1999; 84: 305 310. 19 Walsh PC, Marschke P, Catalona WJ et al. Efficacy of first generation cavermap to verify location and function of cavernous nerves during radical prostatectomy: a multi-institutional evaluation by experienced surgeons. Urology 2000; 57(3): 491 494. 65