- Email: [email protected]
Early Versus Late Rehabilitation of Erectile Function after Nerve‐Sparing Radical Cystoprostatectomy: A Prospective Randomized Study
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ORIGINAL RESEARCH—ONCOLOGY Early Versus Late Rehabilitation of Erectile Function after Nerve-Sparing Radical Cystoprostatectomy: A Prospective Randomized Study jsm_2046
2106..2111
Ahmed Mosbah, MD, Magdy El Bahnasawy, MD, Yasser Osman, MD, Ihab A. Hekal, MD, FEBU, Essam Abou-Beih, MD, and Atallah Shaaban, MD Department of Urology and Radiology, Urology & Nephrology Center, Mansoura University, Mansoura, Egypt
[Correction added after online publication 4-Oct-2010: Dr. Hekal’s name has been corrected.] DOI: 10.1111/j.1743-6109.2010.02046.x
ABSTRACT
Introduction. Pharmacological rehabilitation of erectile function (EF) after nerve-sparing radical prostatectomy was repeatedly advocated. Aim. To compare early vs. late penile rehabilitation in patients with nerve-sparing (NS) radical cystoprostatectomy based on a prospective randomized trial. Methods. Eighteen patients without spontaneous erection 8 weeks after NS radical cystoprostatectomy were randomly divided into two groups; group I and II who started the erectogenic therapy at the 2nd and 6th month postoperatively, respectively. The pharmacological therapy constitutes of sildenafil citrate twice weekly to be shifted to intracavernosal injection (ICI) of prostaglandin E1 (PGE1) if not responding. The treatment continued for 6 months in both groups. Main Outcome Measures. The EF status was evaluated before and at the end of the treatment by International Index of Erectile Function questionnaire and penile Doppler ultrasonography (PDU). Results. Six out of nine patients recovered unassisted erection after treatment in group I compared to three out of nine patients in group II. Two patients in group I and three patients in group II were maintained on sildenafil therapy on demand basis. The remaining four patients were dependent on ICI of PGE1. At final evaluation, a significant improvement was found in the EF, the intercourse satisfaction and overall satisfaction domains (P = 0.02, 0.03, and 0.02, respectively) in group I compared with group II. Regarding PDU findings, significant improvement in end-diastolic velocity was elicited in the early rehabilitation group compared with the pretreatment value (P = 0.03) with no significant difference between both groups. Conclusion. Early compared with delayed erectile rehabilitation brings forward the natural healing time of potency and maintains nerve-assisted erection. Mosbah A, El Bahnasawy M, Osman Y, Hekal IA, Abou-Beih E, and Shaaban A. Early versus late rehabilitation of erectile function after nerve-sparing radical cystoprostatectomy: A prospective randomized study. J Sex Med 2011;8:2106–2111. Key Words. Erectile Dysfunction; Penile Rehabilitation; Radical Cystoprostatectomy; Radical Prostatectomy
Introduction
R
adical cystoprostatectomy is the current standard procedure for locally confined bladder cancer. However, a major drawback of this approach remains the frequently ensuing
J Sex Med 2011;8:2106–2111
postoperative erectile dysfunction (ED). The pioneering work of Walsh and Donker in delineating the cavernous nerves anatomy had led to the development of nerve-sparing (NS) radical prostatectomy [1] and later NS radical cystoprostatectomy [2]. © 2010 International Society for Sexual Medicine
Erectogenic Rehabilitation Post-Radical Cystectomy The value of early use of pharmacological prophylaxis for erectile function (EF) after nerve-sparing radical prostatectomy was initially suggested by Montorsi et al. in 1997, based on the fact that deleterious effect of prolonged lack of erection on cavernous tissue; as the tissue hypoxia will reduce the percentage of functional smooth muscle cells with a concomitant increase of cavernous fibrosis and deterioration of EF [3]. Since that landmark study, many investigators recommended the use of early therapy, either with intracavernosal injection (ICI) of prostaglandin E1 (PGE1) or substitution therapy with phosphodiesterase type 5 (PDE5) inhibitors or a combination of both and they demonstrated good results [4–6]. However, according to our knowledge, this issue had not been addressed in the setting of NS cystoprostatectomy. The aim of this study is to assess the value of early compared with late sexual rehabilitation of the EF in patients who underwent NS radical cystoprostatectomy in a prospective randomized manner. Material and Methods
This prospective study was conducted between March 2003 and March 2005 including 45 potent males (mean; 47 ⫾ 7.6 range; 31–58) with organconfined bladder cancer. Bilateral NS procedure was successful in 21 cases based on visual intraoperative preservation of intact neurovascular bundles on both sides. In the remaining 24, bilateral NS attempt could not be achieved because of technical or oncological factors and were excluded from our final analysis. All patients fulfilled the following criteria: preoperative sexual activity, evaluation by International Index of Erectile Function (IIEF) questionnaire [7] and penile Doppler ultrasonography (PDU), married, tumor confined to the bladder (clinically T3 or less) and the urethra and prostate are free of carcinoma. All patients were free from neurological and penile diseases and all signed an informed consent following approval from the local ethics committee. PDU was performed using Toshiba color duplex ultrasound equipment, model SSA-270 A. We used a linear transducer with 7.5 MHz frequency. PDU results were obtained after ICI of PGE1 at 5, 10, and 15 minutes. The peak systolic velocity (PSV) was assessed as follows: more than 30 cm/second was considered as normal, between 25 and 30 cm /second as mild, between 12, and 25 cm/second as moderate, and less than 12 cm/
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second as severe arteriogenic impotence [8]. The end-diastolic velocity (EDV) of 5 cm/second or less was considered normal value, and more than 5 cm/second was considered as veno-occlusive disorder.
Study Design All evaluable patients were encouraged to resume their sexual activity as early as the first 2 postoperative months. At the end of the second month, patients were asked to mention any spontaneous erectile event and asked to complete the IIEF questionnaire and were subjected to PDU. Patients who failed to regain spontaneous erection sufficient for sexual intercourse were divided in a prospective randomized way into two groups. The randomization process was carried out using a blind envelope technique where opaque sealed envelopes containing the undetermined study assignments were kept in the outpatient clinic to be opened at the end of second month. Group I included patients who started erectogenic therapy at the second month postoperatively (early rehabilitation group) while group II included those who received the therapy at the 6th month (late rehabilitation group). Patients of both groups received sildenafil citrate, 50 mg twice weekly. If there was no adequate response (tumescence sufficient to allow vaginal penetration) after 2 weeks, the dose was increased up to 100 mg twice weekly. A total of eight doses were tried before considering its failure and to shift to ICI of PGE1 (20 mcg). Follow-Up The rehabilitation program continued for 6 months and the patients were counseled every 2 weeks during the phase of pharmacological intervention. The EF was evaluated at the end of the treatment by IIEF questionnaire and PDU. The EF state was assessed according to IIEF as: no ED (EF domain >25), mild to moderate ED (EF domain 11–25), and severe ED (EF domain <11). Regarding the oncological outcome, all patients were followed every 2 months by clinical examination and abdominal US. Computed tomography scan was performed at 6 months intervals for the first 2 years then annually thereafter. All the patients were followed for a mean of 41 ⫾ 21 months (range, 9–72). Statistical Analysis The data were processed using SPSS 11.0 for Windows (SPSS, Chicago, IL, USA). Statistical analysis of the means of continuous variables was J Sex Med 2011;8:2106–2111
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performed through use of Student’s t-test (paired and unpaired), when appropriate. Analysis of categorical variables was performed using chi-square test. A P value of <0.05 was considered statistically significant. Results
Of the evaluable patients (no = 21), three (14.3%) regained their spontaneous erection (mean of EF domain was <25) within the first 2 months postoperatively and they were excluded from the rehabilitation program. The remaining 18 patients had unsuccessful attempts during these 2 months with mean sexual encounters of 3.7 ⫾ 1.2 (range 2–6) and were randomly distributed in both rehabilitation groups. Both rehabilitation groups were comparable regarding age, preoperative EF, and tumor stage. All the patients received orthotopic substitution but four who received continent cutaneous diversion (equally distributed between both groups) and all were free of early postoperative complications but one patient in group I who developed ileus and was managed conservatively and another in group II who developed wound dehiscence necessitating secondary sutures. In group I with mean age of 47 ⫾ 7.6 (range 31–58), eight patients responded to sildenafil therapy (50 mg). The remaining patient was not Table 1 groups
responding even after doubling the dose and he was maintained on ICI of PGE1. At the end of the 6 months, six patients reported the recovery of unassisted satisfactory erection for sexual intercourse (mean of EF domain was 25.7 ⫾ 1.2), two reported a need for sildenafil (50 mg) on demand basis (mean of EF domain was 16.5 ⫾ 0.7). The patient with initial failure to sildenafil therapy needed ICI of PGE1 in all attempts of sexual activity (EF domain was 8). In group II with mean age of 46 ⫾ 7 (range 41–52), three patients responded to sildenafil therapy (50 mg), three patients responded to sildenafil therapy (100 mg), and the last three patients did not respond to oral therapy and were maintained on ICI of PGE1. At the end of the 6 months, only three patients had satisfactory unassisted erection without aid (mean EF domain of 22), three maintained on sildenafil (100 mg) on demand basis (mean EF domain of 12.7 ⫾ 3.2), and the remaining three needed ICI of PGE1 in all attempts of sexual activity (mean EF domain of 4.7 ⫾ 0.6). Table 1 summarizes the difference between both rehabilitation groups regarding the IIEF questionnaire domains at different time points. Patients of both groups of rehabilitation showed a deterioration of all IIEF domains compared with the preoperative values with no significant difference elicited between both groups. Table 2 sum-
Comparison between pre-, postoperative (2nd month), and post-treatment IIEF questionnaire domains in both Early rehabilitation group
Late rehabilitation group
P
24.9 ⫾ 1.3 (23–27) 11.7 ⫾ 6.6 (1–20)† 21.7 ⫾ 6.5 (8–28)‡
25.7 ⫾ 1.3 (24–28) 8 ⫾ 5.3 (0–17)† 13.1 ⫾ 7.7 (4–22)§
0.2 0.2 0.02
Desire 0 2nd month post-treatment
8.4 ⫾ 0.8 (7–9) 4.4 ⫾ 0.8 (3–6)† 6 ⫾ 1.2 (3–7)‡
8.3 ⫾ 0.0 (7–9) 3.6 ⫾ 1.6 (2–6)† 5.2 ⫾ 1.4 (3–7)§
0.7 0.2 0.2
Orgasm 0 2nd month post-treatment
8.5 ⫾ 0.7 (8–10) 3.8 ⫾ 1.2 (2–6)† 4.6 ⫾ 1.6 (3–6)‡
8.7 ⫾ 0.9 (8–11) 2.1 ⫾ 1.3 (0–3)† 3 ⫾ 1.09 (2–5)§
0.5 0.7 0.1
10.9 ⫾ 2.1 (8–14) 2.6 ⫾ 2.5 (0–7)† 11 ⫾ 2.8 (4–13)‡
10.8 ⫾ 1.8 (8–13) 3.2 ⫾ 2.7 (0–6)† 7.9 ⫾ 2.5 (4–10)§
0.6 0.5 0.03
8.7 ⫾ 1 (8–10) 3.3 ⫾ 1.5 (2–6)† 5.4 ⫾ 2.4 (2–8)§
0.8 0.7 0.02
Erectile function 0 2nd month post-treatment
Intercourse satisfaction 0 2nd month post-treatment Overall satisfaction 0 2nd month post-treatment
8.7 ⫾ 1.05 (7–10) 3.1 ⫾ 1.3 (2–6)† 8.1 ⫾ 2.8 (3–10)‡
between pre- and postoperative (2nd month) IIEF questionnaire domains in both groups (P < 0.05). Comparison between pre and post-treatment IIEF questionnaire domains in early rehabilitation group (P < 0.001). § Comparison between pre and post-treatment IIEF questionnaire domains in late rehabilitation group (P < 0.05). †Comparison ‡
J Sex Med 2011;8:2106–2111
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Erectogenic Rehabilitation Post-Radical Cystectomy Table 2
Comparison between pre-, postoperative (2nd month), and post-treatment PDU parameters in both groups
PSV (cm/second) 0 2nd month post-treatment EDV(cm/second) 0 2nd month post-treatment
Early rehabilitation group
Late rehabilitation group
P
50 ⫾ 15.5 (30–75) 42.1 ⫾ 14.04 (30–77)† 40.5 ⫾ 8.7 (30–54.30)§
47.2 ⫾ 12.8 (30–75) 45 ⫾ 5.3 (33–50)† 48.9 ⫾ 9.5 (39–68.9)§
0.5 0.5 0.06
3.1 ⫾ 1.6 (0.3–5) 8.9 ⫾ 4 (4–17)‡ 6.6 ⫾ 1.9 (2–13)††
0.6 0.1 0.1
2.9 ⫾ 0.8 (2–4.5) 6.4 ⫾ 1.9 (2.7–9)‡ 4.5 ⫾ 1.3(3.9)¶
†
Comparison between pre- and postoperative (2nd month) PSV in both groups prior to rehabilitation (P = NS). between pre- and postoperative (2nd month) EDV in both groups prior to rehabilitation (P < 0.001). between pre- and post- treatment PSV in both groups (P = NS). ¶Comparison between pre- and post- treatment EDV in early rehabilitation group (P = 0.03). ††Comparison between pre- and post- treatment EDV in late rehabilitation (P = NS). ‡Comparison §Comparison
marizes the difference between both rehabilitation groups regarding the postoperative PDU parameters at different time points. Patients in both groups showed significant increase in EDV compared with the preoperative values, while no difference was observed regarding the PSV. Similarly, no significant difference was elicited between both groups. At time of final evaluation, both groups showed significant improvement in all IIEF domains compared with the pretreatment values with overall success rate of 77.8% (either spontaneously [50%] or with sildenafil aid [27.8%]). Nevertheless, there was a statistically significant difference favoring the early rehabilitation group regarding EF, the intercourse satisfaction, and overall satisfaction domains (Table 1). Regarding PDU findings, significant improvement in EDV was elicited in the early rehabilitation group compared with the pretreatment value; however, this was not translated into a significant difference between both groups (Table 2). Mild headache and nasal congestion in sildenafil users as well as tolerable injection site pain upon ICI were reported. Nevertheless, none of these side effects were severe enough to induce drug discontinuation. Discussion
ED is a common complication in all patients treated by radical cystectomy. In 1984, Walsh was the first to show that a modified surgical technique resulted in the increased postoperative potency of individuals who have undergone radical cystoprostatectomy [2]. Since that study, others have reported accepted rates of potency after NS radical cystectomy, ranging from 42% to 71% [9–12]. The variable results in the literature regarding the preservation of EF could be explained by difference in skills, surgical tech-
nique, and patient selection criteria. It may be also influenced by the methods evaluating the EF. Authors who evaluated the EF using questionnaire before surgery reported a relatively high potency rate [13,14], while those who used objective tests did not [15]. We evaluated our patients both objectively and subjectively providing a success rate of 77.8%. Montorsi et al. (1997) demonstrated that 8 of 15 radical prostatectomy patients who did not self-inject with alprostadil in the first 4 months after surgery had a color Doppler diagnosis of venous leakage, compared with only 2 of 12 of the treatment group [3]. Since that landmark study, many investigators recommended the early use of postoperative ED therapy; PDE5 inhibitors, intracavernosal injection of vasoactive agents, or a combination of both reported satisfactory outcome [4]. The question of which of these therapy strategies is the most effective and the time to start therapy can not be answered satisfactory yet. Preservation of neurovascular bundles is vital for the success of sildenafil citrate as it does not work when nitric oxide is not released from the neurovascular bundles [16–18]. Therefore, some investigators suggested that sildenafil may have a limited effect on ED in the first 6 months after NS radical prostatectomy because of prolonged neuropraxia. Zagaja et al. (2000) reported that, while in the first 6 months postoperatively only 26% of patients underwent NS radical prostatectomy benefited from sildenafil therapy, in up to 60% erection improved and normalized within the first 18 months [17]. Gontero and Kirby (2004) demonstrated that 3-monthly ICI of PGE1 starting in the first month after radical prostatectomy significantly enhanced the subsequent response to sildenafil compared to sildenafil alone started after 4 months (80% vs. 52%, respectively) [6]. On the other hand, others demonstrated good response J Sex Med 2011;8:2106–2111
2110 rate to sildenafil therapy when used within the first 3 months after NS surgery [5,19]. In a recent report, McCullough et al. demonstrated that nightly sildenafil for 9 months after bilateral NS radical prostatectomy will provide unassisted EF in 24% of 50-mg sildenafil recipients compared with 33% of 100-mg recipients 8 weeks after treatment termination [5]. In contrast to the previously cited data, our results were concluded from a prospective randomized trial. Our results showed that eight out of nine patients (88.9%) had a good response to sildenafil therapy when received at the 2nd month postoperatively. At time of final evaluation, six of them regained a satisfactory erection sufficient for sexual intercourse without pharmacological aids and the remaining two needed sildenafil on demand basis. On the contrary, only three patients achieved spontaneous erection at the end of therapy among the late rehabilitation group. Although significant improvement in all IIEF questionnaire domains was observed in both early and late penile rehabilitation groups at time of final evaluation, EF, intercourse satisfaction, and overall satisfaction domain scores were significantly better in the early rehabilitation group compared with that in the late rehabilitation group. The IIEF questionnaire is an applicable, previously tested, and amenable subjective tool for patients. Moreover, it assesses five domains that are of great value. The study could be criticized by the fact that both groups were evaluated at different time intervals from cystectomy time (though at the same time point from the start of the rehabilitation program with matched basal criteria). We do believe that future reporting of both groups at a more remote time point with same interval from surgery would strengthen our results. PDU data do not give reference to erectile response but only to vascular parameters. We selected the PDU for objective assessment because it gives more data about the etiology of post-radical cystoprostatectomy ED. PDU did not show significant deterioration in the PSV postoperatively in both early and late groups of rehabilitation. This may indicate that radical cystoprostatectomy did not compromise the penile arterial inflow. EDV had deteriorated significantly in both rehabilitation groups at the 2nd month postoperatively. Interestingly, significant improvement after erectogenic treatment was observed in the early rehabilitation group only that was reflected upon better improvement in the sexual satisfaction as evidenced by IIEF questionnaire in these patients compared with late J Sex Med 2011;8:2106–2111
Mosbah et al. rehabilitation group. The significant improvement of EDV in the early rehabilitation group could not be attributed to time factor gradual spontaneous resolution as the late rehabilitation group was assessed at a more remote time point. Generally, data derived from PDU could be always criticized by wide variability of its parameter results particularly in these small numbers. This study could be criticized also, by analyzing a small number of patients, but we aimed from the start to do NS cystoprostatectomy in all patients (no = 45) who were carefully selected to be comparable even in pathological aspects. The intraoperative surgical findings played an important role in the choice of standard cystoprostatectomy instead of NS technique in nearly 50% of patients. We believe that our excellent overall success rate of 77.8% could be attributed to younger patients’ age as well as high select patient population with bilateral NS in all. Nevertheless, we do believe that a study with a large patient population and longer follow-up is strongly advised. Our results encouraged us to start a new randomized trial protocol comparing the start of erectogenic therapy at 4 weeks compared with 8 weeks postoperatively. Conclusion
This prospective study with a relatively small sample size indicates that an early compared with a late erectile rehabilitation program brings forward the natural healing time of potency and maintains non-drug-aided erection in men who have undergone a radical cystoprostatectomy. Furthermore, it indicates that veno-occlusive dysfunction plays an important role in post-cystoprostatectomy ED. Corresponding Author: Yasser Osman, MD, Associated professor in Urology, Urology & Nephrology Center, Mansoura University, Mansoura, Egypt. Tel: 002050-2262222; Fax: 002050-2263717; E-mail: [email protected] Conflicts of Interest: None.
Statement of Authorship
Category 1 (a) Conception and Design Ahmed Mosbah; Magdy El Bahnasawy (b) Acquisition of Data Ihab A. Hekal; Ahmed Mosbah; Essam Abou-Beih (c) Analysis and Interpretation of Data Ahmed Mosbah; Yasser Osman; Ihab A. Hekal
Erectogenic Rehabilitation Post-Radical Cystectomy
Category 2 (a) Drafting the Article Ahmed Mosbah; Yasser Osman (b) Revising It for Intellectual Content Yasser Osman
Category 3 (a) Final Approval of the Completed Article Atallah Shaaban References 1 Walsh P, Donker P. Impotence following radical prostatectomy: Insight into etiology and prevention. J Urol 1982;128:492–7. 2 Walsh P, Mostwin J. Radical prostatectomy and cystoprostatectomy with preservation of potency. Results using a new nerve sparing technique. BJU 1984;56:694–7. 3 Montorsi F, Guazzoni G, Strambi L, Da Pozzo L, Naval L, Barbieri L, Rigatti P, Pizzini G, Miani A. Recovery of spontaneous erectile function after nerve-sparing radical reteropubic prostatectomy with and without early intracavernous injections of alprostadil: Results of a prospective randomized trial. J Urol 1997;158:1408–10. 4 Padma-Nathan H, McCullough A, Levine L, Lipshultz L, Siegel R, Montorsi F, Giuliano F, Brock G, Andrianne R, Bell D, Broderick G, Carrier S, Cuzin B, Deeths H, Hellstrom W, Herschorn S, Lewis R, Rosen R, Shabsigh R, Stricker P. Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy. Int J Impot Res 2008;20:479–86. 5 McCullough AR, Levine LA, Padma-Nathan H. Return of nocturnal erections and erectile function after bilateral nervesparing radical prostatectomy in men treated nightly with sildenafil citrate: Subanalysis of a longitudinal randomized double-blind placebo-controlled trial. J Sex Med 2008;5:476– 84. 6 Gontero P, Kirby R. Early rehabilitation of erectile function after nerve-sparing radical prostatectomy: What is the evidence? BJU Int 2004;93:916–8.
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7 Rosen R, Riley A, Wagner G, Osterloh I, Kirkpatrick J, Mishra A. The International Index of Erectile Function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822–30. 8 Schwartz A, Wang K, Mack L, Lowe M, Berger R, Cyr D, Feldman M. Evaluation of normal erectile function with color flow Doppler sonography. AJR 1989;153:1155– 60. 9 Brendler C, Steinberg G, Marshall F, Mostwin J, Walsh P. Local recurrence and survival following nerve-sparing radical cystoprostatectomy. J Urol 1990;144:1137–41. 10 Schoenberg M, Walsh P, Breazeale D, Marshall F, Mostwin J, Brendler F. Local recurrence and survival following nerve sparing radical cystoprostatectomy for bladder cancer: 10-year follow-up. J Urol 1996;155:490–4. 11 Marshall F, Mostwin J, Radebaugh L, Walsh P, Brendler C. Ileocolic neobladder post-cystectomy: Continence and potency. J Urol 1991;145:502–4. 12 Miyao N, Adachi H, Sato Y, Horita H, Takahashi A, Masumori N, Kitamura H, Tsukamoto T. Recovery of sexual function after nerve-sparing radical prostatectomy or cystectomy. Int J Urol 2001;8:158–64. 13 Beckendrof V, Hay M, Rozan R, Lagrange J, N’Guyen T, Giraud B. changes in sexual function after radiotherapy treatment of prostate cancer. Br J Urol 1996;77:118–23. 14 Catalona W, Carvalhal G, Mager D, Smith D. Potency, continence and complications rates in 1,870 consecutive radical retropubic prostatectomies. J Urol 1999;162:433–8. 15 Mulcahy J. Erectile function after radical prostatectomy. Semin Urol Oncol 2000;18:71–5. 16 Hart S, Skinner E, Meyerowitz B, Boyd S, Lieskovsky G, Skinner D. Quality of life after radical cystectomy for bladder cancer in patients with an ileal conduit or cutaneous or urethral kock pouch. J Urol 1999;162:77–81. 17 Zagaja G, Mhoon D, Aikens J, Brendler C. Sildenafil in the treatment of erectile dysfunction after radical prostatectomy. Urology 2000;56:631–4. 18 Müller A, Parker M, Waters B, Flanigan R, Mulhall J. Penile rehabilitation following radical prostatectomy: Predicting success. J Sex Med 2009;6:2806–12. 19 Walsh P. Radical prostatectomy for localized prostate cancer provides durable cancer control with excellent quality of life: A structured debate. J Urol 2000;163:1802–7.
J Sex Med 2011;8:2106–2111
ORIGINAL RESEARCH—ONCOLOGY Early Versus Late Rehabilitation of Erectile Function after Nerve-Sparing Radical Cystoprostatectomy: A Prospective Randomized Study jsm_2046
2106..2111
Ahmed Mosbah, MD, Magdy El Bahnasawy, MD, Yasser Osman, MD, Ihab A. Hekal, MD, FEBU, Essam Abou-Beih, MD, and Atallah Shaaban, MD Department of Urology and Radiology, Urology & Nephrology Center, Mansoura University, Mansoura, Egypt
[Correction added after online publication 4-Oct-2010: Dr. Hekal’s name has been corrected.] DOI: 10.1111/j.1743-6109.2010.02046.x
ABSTRACT
Introduction. Pharmacological rehabilitation of erectile function (EF) after nerve-sparing radical prostatectomy was repeatedly advocated. Aim. To compare early vs. late penile rehabilitation in patients with nerve-sparing (NS) radical cystoprostatectomy based on a prospective randomized trial. Methods. Eighteen patients without spontaneous erection 8 weeks after NS radical cystoprostatectomy were randomly divided into two groups; group I and II who started the erectogenic therapy at the 2nd and 6th month postoperatively, respectively. The pharmacological therapy constitutes of sildenafil citrate twice weekly to be shifted to intracavernosal injection (ICI) of prostaglandin E1 (PGE1) if not responding. The treatment continued for 6 months in both groups. Main Outcome Measures. The EF status was evaluated before and at the end of the treatment by International Index of Erectile Function questionnaire and penile Doppler ultrasonography (PDU). Results. Six out of nine patients recovered unassisted erection after treatment in group I compared to three out of nine patients in group II. Two patients in group I and three patients in group II were maintained on sildenafil therapy on demand basis. The remaining four patients were dependent on ICI of PGE1. At final evaluation, a significant improvement was found in the EF, the intercourse satisfaction and overall satisfaction domains (P = 0.02, 0.03, and 0.02, respectively) in group I compared with group II. Regarding PDU findings, significant improvement in end-diastolic velocity was elicited in the early rehabilitation group compared with the pretreatment value (P = 0.03) with no significant difference between both groups. Conclusion. Early compared with delayed erectile rehabilitation brings forward the natural healing time of potency and maintains nerve-assisted erection. Mosbah A, El Bahnasawy M, Osman Y, Hekal IA, Abou-Beih E, and Shaaban A. Early versus late rehabilitation of erectile function after nerve-sparing radical cystoprostatectomy: A prospective randomized study. J Sex Med 2011;8:2106–2111. Key Words. Erectile Dysfunction; Penile Rehabilitation; Radical Cystoprostatectomy; Radical Prostatectomy
Introduction
R
adical cystoprostatectomy is the current standard procedure for locally confined bladder cancer. However, a major drawback of this approach remains the frequently ensuing
J Sex Med 2011;8:2106–2111
postoperative erectile dysfunction (ED). The pioneering work of Walsh and Donker in delineating the cavernous nerves anatomy had led to the development of nerve-sparing (NS) radical prostatectomy [1] and later NS radical cystoprostatectomy [2]. © 2010 International Society for Sexual Medicine
Erectogenic Rehabilitation Post-Radical Cystectomy The value of early use of pharmacological prophylaxis for erectile function (EF) after nerve-sparing radical prostatectomy was initially suggested by Montorsi et al. in 1997, based on the fact that deleterious effect of prolonged lack of erection on cavernous tissue; as the tissue hypoxia will reduce the percentage of functional smooth muscle cells with a concomitant increase of cavernous fibrosis and deterioration of EF [3]. Since that landmark study, many investigators recommended the use of early therapy, either with intracavernosal injection (ICI) of prostaglandin E1 (PGE1) or substitution therapy with phosphodiesterase type 5 (PDE5) inhibitors or a combination of both and they demonstrated good results [4–6]. However, according to our knowledge, this issue had not been addressed in the setting of NS cystoprostatectomy. The aim of this study is to assess the value of early compared with late sexual rehabilitation of the EF in patients who underwent NS radical cystoprostatectomy in a prospective randomized manner. Material and Methods
This prospective study was conducted between March 2003 and March 2005 including 45 potent males (mean; 47 ⫾ 7.6 range; 31–58) with organconfined bladder cancer. Bilateral NS procedure was successful in 21 cases based on visual intraoperative preservation of intact neurovascular bundles on both sides. In the remaining 24, bilateral NS attempt could not be achieved because of technical or oncological factors and were excluded from our final analysis. All patients fulfilled the following criteria: preoperative sexual activity, evaluation by International Index of Erectile Function (IIEF) questionnaire [7] and penile Doppler ultrasonography (PDU), married, tumor confined to the bladder (clinically T3 or less) and the urethra and prostate are free of carcinoma. All patients were free from neurological and penile diseases and all signed an informed consent following approval from the local ethics committee. PDU was performed using Toshiba color duplex ultrasound equipment, model SSA-270 A. We used a linear transducer with 7.5 MHz frequency. PDU results were obtained after ICI of PGE1 at 5, 10, and 15 minutes. The peak systolic velocity (PSV) was assessed as follows: more than 30 cm/second was considered as normal, between 25 and 30 cm /second as mild, between 12, and 25 cm/second as moderate, and less than 12 cm/
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second as severe arteriogenic impotence [8]. The end-diastolic velocity (EDV) of 5 cm/second or less was considered normal value, and more than 5 cm/second was considered as veno-occlusive disorder.
Study Design All evaluable patients were encouraged to resume their sexual activity as early as the first 2 postoperative months. At the end of the second month, patients were asked to mention any spontaneous erectile event and asked to complete the IIEF questionnaire and were subjected to PDU. Patients who failed to regain spontaneous erection sufficient for sexual intercourse were divided in a prospective randomized way into two groups. The randomization process was carried out using a blind envelope technique where opaque sealed envelopes containing the undetermined study assignments were kept in the outpatient clinic to be opened at the end of second month. Group I included patients who started erectogenic therapy at the second month postoperatively (early rehabilitation group) while group II included those who received the therapy at the 6th month (late rehabilitation group). Patients of both groups received sildenafil citrate, 50 mg twice weekly. If there was no adequate response (tumescence sufficient to allow vaginal penetration) after 2 weeks, the dose was increased up to 100 mg twice weekly. A total of eight doses were tried before considering its failure and to shift to ICI of PGE1 (20 mcg). Follow-Up The rehabilitation program continued for 6 months and the patients were counseled every 2 weeks during the phase of pharmacological intervention. The EF was evaluated at the end of the treatment by IIEF questionnaire and PDU. The EF state was assessed according to IIEF as: no ED (EF domain >25), mild to moderate ED (EF domain 11–25), and severe ED (EF domain <11). Regarding the oncological outcome, all patients were followed every 2 months by clinical examination and abdominal US. Computed tomography scan was performed at 6 months intervals for the first 2 years then annually thereafter. All the patients were followed for a mean of 41 ⫾ 21 months (range, 9–72). Statistical Analysis The data were processed using SPSS 11.0 for Windows (SPSS, Chicago, IL, USA). Statistical analysis of the means of continuous variables was J Sex Med 2011;8:2106–2111
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Mosbah et al.
performed through use of Student’s t-test (paired and unpaired), when appropriate. Analysis of categorical variables was performed using chi-square test. A P value of <0.05 was considered statistically significant. Results
Of the evaluable patients (no = 21), three (14.3%) regained their spontaneous erection (mean of EF domain was <25) within the first 2 months postoperatively and they were excluded from the rehabilitation program. The remaining 18 patients had unsuccessful attempts during these 2 months with mean sexual encounters of 3.7 ⫾ 1.2 (range 2–6) and were randomly distributed in both rehabilitation groups. Both rehabilitation groups were comparable regarding age, preoperative EF, and tumor stage. All the patients received orthotopic substitution but four who received continent cutaneous diversion (equally distributed between both groups) and all were free of early postoperative complications but one patient in group I who developed ileus and was managed conservatively and another in group II who developed wound dehiscence necessitating secondary sutures. In group I with mean age of 47 ⫾ 7.6 (range 31–58), eight patients responded to sildenafil therapy (50 mg). The remaining patient was not Table 1 groups
responding even after doubling the dose and he was maintained on ICI of PGE1. At the end of the 6 months, six patients reported the recovery of unassisted satisfactory erection for sexual intercourse (mean of EF domain was 25.7 ⫾ 1.2), two reported a need for sildenafil (50 mg) on demand basis (mean of EF domain was 16.5 ⫾ 0.7). The patient with initial failure to sildenafil therapy needed ICI of PGE1 in all attempts of sexual activity (EF domain was 8). In group II with mean age of 46 ⫾ 7 (range 41–52), three patients responded to sildenafil therapy (50 mg), three patients responded to sildenafil therapy (100 mg), and the last three patients did not respond to oral therapy and were maintained on ICI of PGE1. At the end of the 6 months, only three patients had satisfactory unassisted erection without aid (mean EF domain of 22), three maintained on sildenafil (100 mg) on demand basis (mean EF domain of 12.7 ⫾ 3.2), and the remaining three needed ICI of PGE1 in all attempts of sexual activity (mean EF domain of 4.7 ⫾ 0.6). Table 1 summarizes the difference between both rehabilitation groups regarding the IIEF questionnaire domains at different time points. Patients of both groups of rehabilitation showed a deterioration of all IIEF domains compared with the preoperative values with no significant difference elicited between both groups. Table 2 sum-
Comparison between pre-, postoperative (2nd month), and post-treatment IIEF questionnaire domains in both Early rehabilitation group
Late rehabilitation group
P
24.9 ⫾ 1.3 (23–27) 11.7 ⫾ 6.6 (1–20)† 21.7 ⫾ 6.5 (8–28)‡
25.7 ⫾ 1.3 (24–28) 8 ⫾ 5.3 (0–17)† 13.1 ⫾ 7.7 (4–22)§
0.2 0.2 0.02
Desire 0 2nd month post-treatment
8.4 ⫾ 0.8 (7–9) 4.4 ⫾ 0.8 (3–6)† 6 ⫾ 1.2 (3–7)‡
8.3 ⫾ 0.0 (7–9) 3.6 ⫾ 1.6 (2–6)† 5.2 ⫾ 1.4 (3–7)§
0.7 0.2 0.2
Orgasm 0 2nd month post-treatment
8.5 ⫾ 0.7 (8–10) 3.8 ⫾ 1.2 (2–6)† 4.6 ⫾ 1.6 (3–6)‡
8.7 ⫾ 0.9 (8–11) 2.1 ⫾ 1.3 (0–3)† 3 ⫾ 1.09 (2–5)§
0.5 0.7 0.1
10.9 ⫾ 2.1 (8–14) 2.6 ⫾ 2.5 (0–7)† 11 ⫾ 2.8 (4–13)‡
10.8 ⫾ 1.8 (8–13) 3.2 ⫾ 2.7 (0–6)† 7.9 ⫾ 2.5 (4–10)§
0.6 0.5 0.03
8.7 ⫾ 1 (8–10) 3.3 ⫾ 1.5 (2–6)† 5.4 ⫾ 2.4 (2–8)§
0.8 0.7 0.02
Erectile function 0 2nd month post-treatment
Intercourse satisfaction 0 2nd month post-treatment Overall satisfaction 0 2nd month post-treatment
8.7 ⫾ 1.05 (7–10) 3.1 ⫾ 1.3 (2–6)† 8.1 ⫾ 2.8 (3–10)‡
between pre- and postoperative (2nd month) IIEF questionnaire domains in both groups (P < 0.05). Comparison between pre and post-treatment IIEF questionnaire domains in early rehabilitation group (P < 0.001). § Comparison between pre and post-treatment IIEF questionnaire domains in late rehabilitation group (P < 0.05). †Comparison ‡
J Sex Med 2011;8:2106–2111
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Erectogenic Rehabilitation Post-Radical Cystectomy Table 2
Comparison between pre-, postoperative (2nd month), and post-treatment PDU parameters in both groups
PSV (cm/second) 0 2nd month post-treatment EDV(cm/second) 0 2nd month post-treatment
Early rehabilitation group
Late rehabilitation group
P
50 ⫾ 15.5 (30–75) 42.1 ⫾ 14.04 (30–77)† 40.5 ⫾ 8.7 (30–54.30)§
47.2 ⫾ 12.8 (30–75) 45 ⫾ 5.3 (33–50)† 48.9 ⫾ 9.5 (39–68.9)§
0.5 0.5 0.06
3.1 ⫾ 1.6 (0.3–5) 8.9 ⫾ 4 (4–17)‡ 6.6 ⫾ 1.9 (2–13)††
0.6 0.1 0.1
2.9 ⫾ 0.8 (2–4.5) 6.4 ⫾ 1.9 (2.7–9)‡ 4.5 ⫾ 1.3(3.9)¶
†
Comparison between pre- and postoperative (2nd month) PSV in both groups prior to rehabilitation (P = NS). between pre- and postoperative (2nd month) EDV in both groups prior to rehabilitation (P < 0.001). between pre- and post- treatment PSV in both groups (P = NS). ¶Comparison between pre- and post- treatment EDV in early rehabilitation group (P = 0.03). ††Comparison between pre- and post- treatment EDV in late rehabilitation (P = NS). ‡Comparison §Comparison
marizes the difference between both rehabilitation groups regarding the postoperative PDU parameters at different time points. Patients in both groups showed significant increase in EDV compared with the preoperative values, while no difference was observed regarding the PSV. Similarly, no significant difference was elicited between both groups. At time of final evaluation, both groups showed significant improvement in all IIEF domains compared with the pretreatment values with overall success rate of 77.8% (either spontaneously [50%] or with sildenafil aid [27.8%]). Nevertheless, there was a statistically significant difference favoring the early rehabilitation group regarding EF, the intercourse satisfaction, and overall satisfaction domains (Table 1). Regarding PDU findings, significant improvement in EDV was elicited in the early rehabilitation group compared with the pretreatment value; however, this was not translated into a significant difference between both groups (Table 2). Mild headache and nasal congestion in sildenafil users as well as tolerable injection site pain upon ICI were reported. Nevertheless, none of these side effects were severe enough to induce drug discontinuation. Discussion
ED is a common complication in all patients treated by radical cystectomy. In 1984, Walsh was the first to show that a modified surgical technique resulted in the increased postoperative potency of individuals who have undergone radical cystoprostatectomy [2]. Since that study, others have reported accepted rates of potency after NS radical cystectomy, ranging from 42% to 71% [9–12]. The variable results in the literature regarding the preservation of EF could be explained by difference in skills, surgical tech-
nique, and patient selection criteria. It may be also influenced by the methods evaluating the EF. Authors who evaluated the EF using questionnaire before surgery reported a relatively high potency rate [13,14], while those who used objective tests did not [15]. We evaluated our patients both objectively and subjectively providing a success rate of 77.8%. Montorsi et al. (1997) demonstrated that 8 of 15 radical prostatectomy patients who did not self-inject with alprostadil in the first 4 months after surgery had a color Doppler diagnosis of venous leakage, compared with only 2 of 12 of the treatment group [3]. Since that landmark study, many investigators recommended the early use of postoperative ED therapy; PDE5 inhibitors, intracavernosal injection of vasoactive agents, or a combination of both reported satisfactory outcome [4]. The question of which of these therapy strategies is the most effective and the time to start therapy can not be answered satisfactory yet. Preservation of neurovascular bundles is vital for the success of sildenafil citrate as it does not work when nitric oxide is not released from the neurovascular bundles [16–18]. Therefore, some investigators suggested that sildenafil may have a limited effect on ED in the first 6 months after NS radical prostatectomy because of prolonged neuropraxia. Zagaja et al. (2000) reported that, while in the first 6 months postoperatively only 26% of patients underwent NS radical prostatectomy benefited from sildenafil therapy, in up to 60% erection improved and normalized within the first 18 months [17]. Gontero and Kirby (2004) demonstrated that 3-monthly ICI of PGE1 starting in the first month after radical prostatectomy significantly enhanced the subsequent response to sildenafil compared to sildenafil alone started after 4 months (80% vs. 52%, respectively) [6]. On the other hand, others demonstrated good response J Sex Med 2011;8:2106–2111
2110 rate to sildenafil therapy when used within the first 3 months after NS surgery [5,19]. In a recent report, McCullough et al. demonstrated that nightly sildenafil for 9 months after bilateral NS radical prostatectomy will provide unassisted EF in 24% of 50-mg sildenafil recipients compared with 33% of 100-mg recipients 8 weeks after treatment termination [5]. In contrast to the previously cited data, our results were concluded from a prospective randomized trial. Our results showed that eight out of nine patients (88.9%) had a good response to sildenafil therapy when received at the 2nd month postoperatively. At time of final evaluation, six of them regained a satisfactory erection sufficient for sexual intercourse without pharmacological aids and the remaining two needed sildenafil on demand basis. On the contrary, only three patients achieved spontaneous erection at the end of therapy among the late rehabilitation group. Although significant improvement in all IIEF questionnaire domains was observed in both early and late penile rehabilitation groups at time of final evaluation, EF, intercourse satisfaction, and overall satisfaction domain scores were significantly better in the early rehabilitation group compared with that in the late rehabilitation group. The IIEF questionnaire is an applicable, previously tested, and amenable subjective tool for patients. Moreover, it assesses five domains that are of great value. The study could be criticized by the fact that both groups were evaluated at different time intervals from cystectomy time (though at the same time point from the start of the rehabilitation program with matched basal criteria). We do believe that future reporting of both groups at a more remote time point with same interval from surgery would strengthen our results. PDU data do not give reference to erectile response but only to vascular parameters. We selected the PDU for objective assessment because it gives more data about the etiology of post-radical cystoprostatectomy ED. PDU did not show significant deterioration in the PSV postoperatively in both early and late groups of rehabilitation. This may indicate that radical cystoprostatectomy did not compromise the penile arterial inflow. EDV had deteriorated significantly in both rehabilitation groups at the 2nd month postoperatively. Interestingly, significant improvement after erectogenic treatment was observed in the early rehabilitation group only that was reflected upon better improvement in the sexual satisfaction as evidenced by IIEF questionnaire in these patients compared with late J Sex Med 2011;8:2106–2111
Mosbah et al. rehabilitation group. The significant improvement of EDV in the early rehabilitation group could not be attributed to time factor gradual spontaneous resolution as the late rehabilitation group was assessed at a more remote time point. Generally, data derived from PDU could be always criticized by wide variability of its parameter results particularly in these small numbers. This study could be criticized also, by analyzing a small number of patients, but we aimed from the start to do NS cystoprostatectomy in all patients (no = 45) who were carefully selected to be comparable even in pathological aspects. The intraoperative surgical findings played an important role in the choice of standard cystoprostatectomy instead of NS technique in nearly 50% of patients. We believe that our excellent overall success rate of 77.8% could be attributed to younger patients’ age as well as high select patient population with bilateral NS in all. Nevertheless, we do believe that a study with a large patient population and longer follow-up is strongly advised. Our results encouraged us to start a new randomized trial protocol comparing the start of erectogenic therapy at 4 weeks compared with 8 weeks postoperatively. Conclusion
This prospective study with a relatively small sample size indicates that an early compared with a late erectile rehabilitation program brings forward the natural healing time of potency and maintains non-drug-aided erection in men who have undergone a radical cystoprostatectomy. Furthermore, it indicates that veno-occlusive dysfunction plays an important role in post-cystoprostatectomy ED. Corresponding Author: Yasser Osman, MD, Associated professor in Urology, Urology & Nephrology Center, Mansoura University, Mansoura, Egypt. Tel: 002050-2262222; Fax: 002050-2263717; E-mail: [email protected] Conflicts of Interest: None.
Statement of Authorship
Category 1 (a) Conception and Design Ahmed Mosbah; Magdy El Bahnasawy (b) Acquisition of Data Ihab A. Hekal; Ahmed Mosbah; Essam Abou-Beih (c) Analysis and Interpretation of Data Ahmed Mosbah; Yasser Osman; Ihab A. Hekal
Erectogenic Rehabilitation Post-Radical Cystectomy
Category 2 (a) Drafting the Article Ahmed Mosbah; Yasser Osman (b) Revising It for Intellectual Content Yasser Osman
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