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1 International Journal of Urology (27) 14, doi:.1111/j x Impact of unilateral interposition sural nerve graft on the recovery of sexual function after radical prostatectomy in Japanese men: A preliminary study Seiichi Saito, 1 Shunichi Namiki, 1 Kenji Numahata, 1 Makoto Satoh, 1 Shigeto Ishidoya, 1 Akihiro Ito, 1 Haruo Nakagawa, 1 Yasuhiro Kaiho, 1 Takehiko Sanada, 2 Atsushi Yamada 2 and Yoichi Arai 1 Departments of 1 Urology and 2 Plastic Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan Purpose: To determine the effect of an interposition nerve graft on sexual function after radical prostatectomy. Methods: This study includes 64 patients, without hormonal therapy, who underwent a radical prostatectomy and intraoperative electrophysiological confirmation of cavernous nerve preservation. Twelve patients underwent a unilateral interposition sural nerve graft () for the resected neurovascular bundle. Twenty-one and 31 patients underwent bilateral nerve-sparing () and unilateral nerve-sparing () surgery without a nerve graft, respectively. As the age of patients was significantly younger in the group than in the other groups, age-matched analysis also was conducted. Sexual function, evaluated by a self-administered questionnaire using the University of California Los Angeles- Prostate Cancer Index, was compared statistically among the three groups. Results: In the age-matched analysis, the postoperative sexual function (SXF) score of the group showed an intermediate level of recovery between those of the and groups at 12 months and reached the same level as the score at 12 months of the group at 18 months postoperatively. The difference in the SXF score between the and groups began to appear after 6 months postoperatively and increased steadily with time. However, the background factors, such as the SXF score, the usage rate of phosphodiesterase 5 inhibitors, and the rate of comorbidities were different between the and groups. Conclusions: The difference of the SXF score between the and groups increased with time after 6 months postoperatively. However, it might be difficult at present to attribute a better recovery of the SXF score to the nerve graft because of the difference in the background factors between the groups. Key words: cavernous nerve-sparing, quality of life, radical prostatectomy, sexual function, sural nerve graft. Introduction Radical prostatectomy has gained popularity in Japan for the last decade as one of the definitive therapeutic options for patients with clinically localized prostate cancer. 1 As early prostate cancers are found with the advent of prostate-specific antigen (PSA), the survival of patients with prostate cancer is not so different between those undergoing a radical prostatectomy or radiotherapy. Although the primary goal of treatment for localized prostate cancer is cancer control, patients decisions regarding the treatment modality are greatly influenced by the potential morbidity of treatment, including the risk of erectile dysfunction, 2 one of the most important concerns for those who undergo definitive therapy. Cavernous nerve-sparing has been performed for the purpose of recovering erectile function after radical prostatectomy. The recovery rate of erectile function is 21 76% for bilateral nerve-sparing, while it decreases to 3% for unilateral nerve-sparing. 3 Therefore, the interposition sural nerve graft has been attempted to confer a greater chance of recovering erectile function for the patients undergoing unilateral or bilateral nerve resection. Scardino reported that, with a nerve graft for the side of the nerve resected, the erectile function of the patients undergoing unilateral nerve-sparing has recovered to a level approximating bilateral nerve-sparing. 3 Correspondence: Yoichi Arai MD, Department of Urology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-mach, Aoba-ku, Sendai , Japan. yarai@uro.med.tohoku.ac.jp Received 2 July 26; accepted 3 October 26. We also have attempted the interposition sural nerve graft for the purpose of improving erectile function for the patients undergoing cavernous nerve resection. In the current study, we examined the sexual function among the patients who underwent unilateral cavernous nervesparing with or without an interposition sural nerve graft and those who underwent bilateral cavernous nerve-sparing by a self-administered questionnaire using the internationally validated University of California Los Angeles-Prostate Cancer Index (UCLA-PCI). 4 Materials and methods Patients From January 22 to December 24, 117 patients underwent a radical retropubic prostatectomy with the intention of cavernous nervesparing at Tohoku University Hospital, Japan. The inclusion criterion for the analysis of sexual function was intraoperative electrophysiological confirmation on nerve preservation. Out of 117 patients, 28 were classified as bilateral nerve-sparing (), 16 as unilateral nervesparing with a unilateral sural nerve graft (), 39 as unilateral nerve-sparing without a nerve graft (), and 13 as nonnerve-sparing based on electrophysiological assessments. However, the electrophysiological assessments could not be performed for 19 patients without a nerve graft. The exclusion criteria were preoperative hormone therapy, only short-term health-related quality of life (HRQOL) data available, and non-nerve-sparing surgery. Two patients underwent a bilateral interposition nerve graft but were not included in the current study because the number was too small. Thus, 21 with, 12 with, and 31 with met the criteria and were 27 The Japanese Urological Association 133

2 S SAITO ET AL. included in this study. Phosphodiesterase 5 inhibitors (PDE5-I), which were recommended for all patients except if there were contraindications, were prescribed for the patients who wanted to use them. The data of those who had PSA failure were excluded at the time of PSA failure. Tumor clinical staging was assigned preoperatively according to the Tumor-Node-Metastasis system, published in The preservation of the neurovascular bundle (NVB) was assigned based on the results of intraoperative electrostimulation of a macroanatomically preserved NVB. 6 Statistics Statistical analysis was conducted between the and or groups using the t-test, Mann Whitney U-test or c 2 test. Age is the factor predicting postoperative recovery of erectile function and is significantly associated with the scores of preoperative and postoperative sexual function. 2,3 As the group was significantly younger than the other groups, age-matched analysis also was conducted (Table 1). For the age-matched analysis, the patients <66-years-old were selected from the and groups based on our previous study.,11 With age-matched analysis, the significant difference of age disappeared between the and other groups. Surgical procedure A radical prostatectomy and interposition sural nerve graft were performed according to modifications of the techniques described by Eastham 7 and Kim. 8 Briefly, after the dorsal vein complex was treated, preservation of the NVB was conducted with the incision of the lateral pelvic fascia just above the NVB and careful separation between the NVB and prostatic capsule by hemostasis of the communicating vessels with clips. Resection of the NVB was conducted as follows: the NVB was divided distally at the lateral side of the urethra and then the lateral pelvic fascia was incised on the rectum, widely apart from the prostate toward the lateral vascular pedicle. After the removal of the prostate, preservation of the cavernous nerve was confirmed by a monopolar needle electrode (Nippon Kohden, Tokyo, Japan), placed on a proximal point of the macroanatomically preserved NVB. The detailed procedure for electrostimulation has been reported elsewhere. 6 The sural nerve of a necessary length, which was usually 5 cm on each side, was harvested from the left leg. The sural nerve was interpositioned between the transected ends of the cavernous nerve, with the proximal end of the sural nerve to the distal transected end of the cavernous nerve and vice versa. Two interrupted 7 nylon sutures (Kono Seisakusho Company, Ichikawa, Japan) were placed to connect the cut ends of the nerves. The procedures for preservation of the NVB and interposition nerve graft did not change during the study period. Indication of cavernous nerve preservation Cavernous nerve preservation was determined based on the results of the biopsy data. The NVB on each side was preserved unless a highgrade cancer (Gleason score 4 + 4) was detected, the cancer was situated near the prostatic capsule, the number of positive biopsy cores was 3, and the percentage of the occupying cancer in the biopsy core was 5%. Self-administered questionnare All patients were informed of their cancer diagnosis before being asked to fill out the HRQOL questionnaires. We measured sexual function and sexual bother scores using the sexual domain of the UCLA-PCI, 4 which has been translated into Japanese, and its validity and reliability has been tested by Kakehi et al. 9 Every patient who agreed to participate in this study received a questionnaire from his urologist with an informed consent form and prepaid return envelope. The interview was conducted after the diagnosis. The follow-up interviews were conducted in person at scheduled visits 3, 6, 12, and 18 months after the radical prostatectomy. This study was approved by the Ethics Committee, Tohoku University School of Medicine. Results Background factors Except for age, no parameters were significantly different between the group and the or the groups in the overall analysis (Table 1). The difference between the macroanatomical and electrophysiological assessments for nerve-sparing is shown in Table 2. Eleven of the 128 sides (8.6%) by macroanatomical assessment were electrophysiologically incorrect. Among the comorbidities, hypertension was observed more frequently in the group than in the group (Table 3). The difference was nearly significant in the agematched analysis (P =.62). The number of patients who used PDE5-I is shown in Table 4. The total usage rate of PDE5-I was 75% (9/12) in the group, whereas it was 38.7% (12/31) overall (P =.33) and 46.6% (7/15) in the age-matched analyses (P =.136) in the group. The continuous usage rate of PDE5-I until 18 months postoperatively was 77.8% (7/9) in the group, whereas it was 3.4% (7/23) overall (P =.15) and 2% (2/) in the age-matched analyses (P =.11) in the group. Two patients in the group stopped using PDE5-I: one because of experiencing erections sufficient for intercourse without PDE5-I and one because of lowered sexual interest. Five patients in the group stopped using PDE5-I because of little or no effectiveness in four of them and because of an unknown reason in one patient. Sexual function At, the sexual function (SXF) score of the group was significantly higher than those of the other two groups in the overall analysis (Fig. 1a and Table 5) and still higher than that of the group in the age-matched analysis (Fig. 1b and Table 5). At 3 months postoperatively, the SXF score decreased to its nadir in all groups. The decline of the SXF score in the group was less prominent compared to those in the and groups, both of which deteriorated steeply to the bottom level. The postoperative score of SXF in the group continued to increase steadily after its nadir and reached an intermediate level between those of the and groups at 12 months in the age-matched analysis. At 18 months, the SXF score in the group reached the same level as the score at 12 months of the group. However, the postoperative recovery of the SXF score after its nadir was retarded in the group in both the overall and agematched analyses. Thus, the difference in the SXF score between the and groups began to appear after 6 months postoperatively and increased steadily with time in the age-matched analysis, although the difference was not significant at 18 months The Japanese Urological Association

3 Sural nerve graft and sexual function Table 1 Demographics of the study population Characteristic (n = 12) (n = 21) (13) (n = 31) (15) P-value vs vs Age ( ) ( ) <.5 (.) <.5 (.12) PSA (7. 2.7) ( ).23 (.21).34 (.23) ct.97 (.91).8 (.85) 1 17 (11) 26 (13) (2) 5 (2) 3 1 () 2 () b-gs.82 (.81).1 (.16) (4) 4 (2) (9) 19 (9) 8 1 () 4 (3) 9 () 4 (1) pt.12 (.22).66 (.56) () 17 (9) (3) 14 (6) 4 1 () () RP-GS.97 (.95).37 (.95) 7 17 () 21 (13) (1) 6 () 9 1 (1) 4 (2) ND 1 (1) () The values in parentheses are the age-matched values. b-gs, biopsy Gleason score;, bilateral nerve-sparing; ct, clinical T stage; ND, not determined; PSA, prostate-specific antigen; RP-GS, radical prostatectomy Gleason score;, unilateral nerve graft;, unilateral nerve-sparing. Table 2 Difference between macroanatomical and electrophysiological assessments for nerve-sparing Procedure Macroanatomical assessment N Electrophysiological assessment N None 2 Unilateral 12 Unilateral Unilateral 4 (1) Bilateral 21 Bilateral 17 (13) Bilateral 5 (2) Unilateral 31 Unilateral 26 (13) The values in parentheses are the age-matched values., bilateral nerve-sparing;, unilateral nerve graft;, unilateral nerve-sparing. Sexual bother In both the overall and age-matched analyses, the sexual bother (SXB) scores at the were almost the same among the three groups (Fig. 2a,b and Table 6). However, a change in the postoperative SXB score over time was characteristic of each group. The SXB score of the group fluctuated widely until 12 months and then showed a gradual change to the score at 18 months. The SXB score of the group showed a gradual increase from its nadir at 3 months to 18 months postoperatively in both analyses. The SXB score of the group showed a gradual decrease until 3 months postoperatively as compared to those of the other two groups and maintained comparatively the same level throughout the postoperative period after 3 months in the overall analysis, whereas it showed a narrow fluctuation in the age-matched analysis. It is of note that each SXB score converged to the same level at 18 months despite the characteristic change in the SXB score over time. Ability to have an erection and the frequency of intercourse From the questionnaires, the time courses regarding the ability to have an erection and the frequency of intercourse during 1 month before a scheduled interview are shown in Figure 3a and b. The ability to have an erection showed a recovery consistent with the SXF score, but the frequency of intercourse did not necessarily correlate with the ability to have an erection. 27 The Japanese Urological Association 135

4 S SAITO ET AL. Table 3 Comorbidities and history of other cancer Selected condition a) 7 6 SXF-overall Hypertension 1 4 (2) 11 (6 ) Diabetes mellitus 2 1 () 3 (1) Cardiovascular disease 1 3 () 3 (2) Cerebrovascular disease 1 (1) 4 (1) Bronchial asthma () 2 (2) Gastrointestinal disease 1 2 () 3 (2) Spinal disease 2 (2) 2 () Hyperlipidemia 2 1 (1) 2 (1) Other cancer 1 3 (2) () None 6 (7) 8 (4) b) SXF age-matched vs in age-matched analysis: P =.62. The values in parentheses are the age-matched values., bilateral nerve-sparing;, unilateral nerve graft;, unilateral nerve-sparing. Table 4 N Discussion Use of phosphodiesterase 5 inhibitors (n = 12) (n = 21) (13) (n = 31) (15) Total number of uses 9 13 (9) 12 (7) Continuous use 7 11 (7) 7 (2) The values in parentheses are the age-matched values., bilateral nerve-sparing;, unilateral nerve graft;, unilateral nerve-sparing. Scardino et al. for the first time performed autologous sural nerve grafts for the repair of resected cavernous nerves during radical retropubic prostatectomy. 3,8,12 They reported that the rate of recovering functional erections in unilateral and bilateral nerve grafts was 78% and 58%, respectively. 3 However, the rate of recovery in unilateral and bilateral nerve resections without a nerve graft was 3% and 2%, respectively. Their study indicated that the recovery rate with a unilateral nerve graft was higher than that without a nerve graft for the patients undergoing unilateral nerve resection, although a prospective, randomized, controlled trial is necessary to prove the efficacy of the unilateral nerve graft. We also attempted the sural nerve graft for the purpose of improving the sexual function of the patients who underwent cavernous nerve resection. Although the number of patients was small, the present study reported for the first time the outcome of the unilateral nerve graft based on both electrophysiological assessment and the use of the internationally validated questionnaire, UCLA-PCI. 4 Furthermore, by agematching our study and comparing the group with the and groups, we achieved positive and negative controls for the group, respectively. The SXF score of the group showed a tendency of recovery intermediate between those of the and groups. The difference in the SXF scores between the and groups increased steadily with time after 6 months postoperatively, whereas recovery of the SXF score in the group was retarded. However, it should be noted that the current study was not a prospective, randomized, controlled trial. Furthermore, the SXF score at the Fig. 1 (a) Longitudinal changes of the mean sexual function score over time: overall analysis. (b) Longitudinal changes of the mean sexual function score over time: age-matched analysis., bilateral nerve-sparing; SXF, sexual function;, unilateral nerve graft;, unilateral nerve-sparing. a) b) SXB-overall SXB-age matched Fig. 2 (a) Longitudinal changes of the mean sexual bother score over time: overall analysis. (b) Longitudinal changes of the mean sexual bother score over time: age-matched analysis., bilateral nerve-sparing; SXB, sexual bother;, unilateral nerve graft;, unilateral nerve-sparing. in the group was still higher than that in the group, even after age-matching. The total and continuous usage rates of PDE5-I were higher in the group than in the group. The group had more hypertension than the group in the The Japanese Urological Association

5 Sural nerve graft and sexual function Table 5 Statistical analysis of the sexual function score Variable Baseline 3 months 6 months 12 months 18 months (n = 12) (n = 12) (n = 12) (n = ) (n = 9) Overall (n = 21) (n = 19) (n = 2) (n = 19) (n = 12) Age-matched (n = 13) (n = 12) (n = 12) (n = 11) (n = 8) Overall (n = 31) (n = 31) (n = 29) (n = 26) (n = 23) Age-matched (n = 15) (n = 15) (n = 13) (n = 11) (n = ) P-value vs (overall) P-value vs (age-matched) , bilateral nerve-sparing;, unilateral nerve graft;, unilateral nerve-sparing. Table 6 Statistical analysis of the sexual bother score Variable Baseline 3 months 6 months 12 months 18 months (n = 12) (n = 12) (n = 12) (n = ) (n = 9) Overall (n = 21) (n = 19) (n = 2) (n = 19) (n = 12) Age-matched (n = 13) (n = 12) (n = 12) (n = 11) (n = 8) Overall (n = 31) (n = 31) (n = 29) (n = 26) (n = 23) Age-matched (n = 15) (n = 15) (n = 13) (n = 11) (n = ) P-value vs (overall) P-value vs (age-matched) , bilateral nerve-sparing;, unilateral nerve graft;, unilateral nerve-sparing. age-matched analysis. Therefore, the possibility cannot be ruled out that the difference of these background factors might have affected the postoperative recovery of sexual function. Thus, it might be difficult at present to attribute the better recovery of the SXF score in the group, as compared to the group, to the nerve graft. In the current study, the SXF score at 18 months for the group decreased compared to the score at 12 months. It might be because the number of patients analysed became smaller at 18 months. The rate of peripheral nerve regeneration averages 1 mm/day, which varies depending on age, hormonal factors, and gap distance. 8,12 A 5 6 cm graft will generally need 2 3 months to traverse initially and a further 6 15 months is required for full reinnervation of the end organ. Thus, it takes 8 18 months to regenerate from the proximal cut end of the cavernous nerve through the interposition nerve graft to the corpus cavernosum. In the current study, we found that the postoperative score of SXF in the group continued to improve steadily after its nadir at 3 months, through to the intermediate level at 12 months, between the scores of those in the and the groups, and reached the same level as the score at 12 months in the group, 6 months behind. From the time course of the SXF score in the group, it was suggested that the interposition nerve graft began to function after a certain period, which might be required for the nerve to regenerate, although it is difficult to prove nerve regeneration in the clinical setting. Probably because of nerve regeneration, the difference in the SXF score might have begun to appear after 6 months postoperatively between the and groups. From the questionnaires, the ability to have an erection showed a recovery consistent with the SXF score, but the frequency of intercourse did not necessarily correlate with the ability to have an erection. As intercourse depends on both a patient s personality and his partner, and these parameters are variable among patients, it might be difficult to measure the frequency of intercourse utilising the same conditions. The change in the SXB score over time was characteristic of each group. The SXB score of the group fluctuated widely with time until 12 months postoperatively and then changed gradually to the score at 18 months. For the group, changes in the SXB score 27 The Japanese Urological Association 137

6 S SAITO ET AL. a) % Ability to have erection % 9% 8% 7% 6% 5% 4% 3% 2% % very weak weak good strong % b) % Frequency of intercourse % 9% 8% 7% 6% 5% 4% none 3% once 2% % more than once % Fig. 3 (a) Longitudinal changes in the ability to have an erection. (b) Longitudinal changes in the frequency of intercourse. might reflect the expectation of the recovery of sexual function because of the interposition nerve graft. Therefore, it was assumed that the postoperative SXB score deteriorated to the bottom level at 3 months, reflecting the nadir of the SXF score, and steeply increased at 6 months as the SXF score showed an improvement. However, the SXB score decreased again at 12 months postoperatively, probably because the recovery of sexual function might not have been as expected. However, although the SXB score of the group deteriorated at 3 months, it increased steadily after its nadir, probably reflecting the improvement of the SXF score. The SXB score of the group was relatively stable after 3 months postoperatively. This is probably because this group was not so concerned about sexual function. It is of note that despite the variation of the postoperative SXB scores, the scores converged to the same level in the long-term. Further studies are necessary on whether this feature is characteristic of Japanese patients. Recently, Takenaka et al. have revealed the cavernous nerves run in a spray-like fashion from the pelvic splanchnic nerves to the prostate. 13 The cavernous nerves are distributed in the entire lateral surface of the prostate in 5% of cases 14 and pass through the rectourethral muscle. 15 Accordingly, the interposition nerve graft can cover only a part of the entire circumferential distribution of cavernous nerves around the prostate. Therefore, it is questionable to what extent the contemporary method of nerve graft works to recover sexual function. In future, there might be two ways to solve the problem. One is to use a wide, synthetic neural conduit, which could cover most of the distribution of cavernous nerves, as the biodegradable conduit graft contributed to the recovery of sexual function in rats. 16 The other is to detect prostate cancer within pathologically, organ-confined disease and preserve the entire circumferential distribution of the cavernous nerves, which achieved the recovery of erectile function sufficient for intercourse in 97% of cases. 17 We acknowledge several limitations in the current study. First, the number of patients was small and might not be adequate for statistical analysis. Second, the current study is not a prospective, randomized, controlled trial as the patient and his urologist selected the treatment. Third, the background factors, such as the scores, the usage rate of PDE5-I, and the rate of comorbidities, were quite different between the and groups. Therefore, it seems difficult to discuss whether the difference in the SXF score was due to the nerve graft. Fourth, because of the recent anatomical findings on cavernous nerves, the present method of nerve graft might not be enough to substitute for the resected nerve. Nevertheless, the current study could The Japanese Urological Association

7 Sural nerve graft and sexual function provide reference data for patients who are concerned about the recovery of sexual function. Conclusions The difference in the postoperative SXF scores between the and groups increased steadily with time after 6 months. However, it seems difficult at present to attribute the better recovery of the SXF score to the nerve graft because of the difference in the background factors between the two groups. References 1 Arai Y, Egawa S, Tobisu K et al. Radical retropubic prostatectomy: time trends, morbidity and mortality in Japan. BJU Int. 2; 85: Rabbani F, Stapleton AMF, Kattan MW et al. Factors predicting recovery of erections after radical prostatectomy. J. Urol. 2; 164: Scardino PT, Kim ED. Rationale for and results of nerve grafting during radical prostatectomy. Urology 21; 57: Litwin MS, Hays RD, Fink A et al. The UCLA Prostate Cancer Index: development, reliability, and validity of a health-related quality of life measure. Med. Care 1998; 36: Flemming ID, Cooper JS, Hemson DE et al (eds). American Joint Committee on Cancer Staging Manual, 5th edn. JP Lippincott, Philadelphia, Terada N, Arai Y, Kurokawa K et al. Intraoperative electrical stimulation of cavernous nerves with monitoring of intracorporeal pressure to confirm nerve sparing during radical prostatectomy: early clinical results. Int. J. Urol. 23; : Eastham JA, Kattan MW, Rogers E et al. Risk factors for urinary incontinence after radical prostatectomy. J. Urol. 1996; 156: Kim ED, Scardino PT, Hampel O et al. Interposition of sural nerve graft restores function of cavernous nerves resected during radical prostatectomy. J. Urol. 1999; 161: Kakehi Y, Kamoto T, Ogawa O et al. Development of Japanese version of the UCLA Prostate Cancer Index: a pilot validation study. Int. J. Clin. Oncol. 22; 7: Namiki S, Tochigi T, Kuwahara M et al. Recovery of health related quality of life after radical prostatectomy in Japanese men; A longitudinal study. Int. J. Urol. 24; 11: Namiki S, Saito S, Satoh M et al. Quality of life after radical prostatectomy in Japanese men: 2 year longitudinal study. Jpn J. Clin. Oncol. 25; 35: Canto EI, Nath RK, Slawin KM. Cavermap-assisted sural nerve interposition graft during radical prostatectomy. Urol. Clin. North Am. 21; 28: Takenaka A, Murakami G, Soga H et al. Anatomical analysis of the neurovascular bundle supplying penile cavernous tissue to ensure a reliable nerve graft after radical prostatectomy. J. Urol. 24; 172: Kiyoshima K, Yokomizo A, Yoshida T et al. Anatomical features of periprostatic tissue and its surroundings: a histological analysis of 79 radical retropubic prostatectomy specimens. Jpn J. Clin. Oncol. 24; 34: Takenaka A, Murakami G, Matsubara A et al. Variation in course of cavernous nerve with special reference to details of topographic relationships near prostatic apex: histologic study using male cadavers. Urology 25; 65: Hisasue S, Kato R, Sato Y et al. Cavernous nerve reconstruction with a biodegradable conduit graft and collagen sponge in the rat. J. Urol. 25; 173: Menon M, Kaul S, Bhandari A et al. Potency following robotic radical prostatectomy: a questionnaire based analysis of outcomes after conventional nerve sparing and prostatic fascia sparing techniques. J. Urol. 25; 174: The Japanese Urological Association 139