Erectile Function Rehabilitation in the Radical Prostatectomy Patient

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John P. Mulhall, MD,* Anthony J. Bella, MD,† Alberto Briganti, MD,‡ Andrew McCullough, MD,§ and Gerald Brock, MD, FRCSC¶ *Memorial Sloan-Kettering Cancer Center, Sexual and Reproductive Medicine, New York, NY, USA; †University of Ottawa, Urology, Ottawa, ON, Canada; ‡Department of Urology, Vita-Salute University, San Raffaele Hospital, Milan, Italy; § Male Sexual Health, Fertility and Microsurgery, NYU Langone Medical Center, New York, NY, USA; ¶University of Western Ontario, Urology, London, ON, Canada DOI: 10.1111/j.1743-6109.2010.01804.x

ABSTRACT

Introduction. Prostate cancer is common and is being diagnosed in younger men now compared with two decades ago. Long-term functional outcomes are of significant importance to patient and impact upon the patient decisionmaking process regarding choice of therapy. Erectile function preservation (rehabilitation) has gained significant traction worldwide despite the absence of definitive evidence in its favor. Aim. To define the role of rehabilitation in the prostate cancer patient who has undergone radical prostatectomy (RP). Methods. A committee of five experts in the field from three countries was convened, and using a thorough analysis of the literature and the Delphi approach to expert opinion, recommendations were arrived at for clinicians treating men with prostate cancer before and after definitive surgical management. Results. Recommendations arrived at included: that clinicians should discuss prevalence rates, the pathophysiology of erectile dysfunction after RP and the predictors of erectile function recovery, that validated instruments should be used using the published cut-offs for normalcy, that rehabilitation be discussed with patients, and that they be informed that significant potential benefits may be associated with rehabilitation. Conclusions. The International Consensus of Sexual Medicine (ICSM) 2001 committee on rehabilitation after radical prostatectomy recommended that a discussion occur regarding rehabilitation in all patients undergoing or who have undergone RP. However, the committee recognized the absence of definitive data to date and could not comment on the optimal approach to rehabilitation at this time. Mulhall JP, Bella AJ, Briganti A, McCullough A, and Brock G. Erectile function rehabilitation in the radical prostatectomy patient. J Sex Med 2010;7: 1687–1698. Key Words. Prostate Cancer; Prostatectomy; Radiation; Rehabilitation; PDE5 Inhibitor; Intracavernosal Injections; Smooth Muscle; Collagen; Oxygenation

Introduction

O

ur understanding of the pathophysiology of postradical prostatectomy (RP) erectile dysfunction (ED) has evolved over the past decade, with recognition of the anatomical location of the cavernous nerves, their essential role in erection, and the impact nerve injury has on cavernous smooth muscle content and function, as well as potentially the tunica albuginea[1–3]. Enhanced knowledge of the consequences of cavernous nerve injury from percussion, traction, cautery, and

© 2010 International Society for Sexual Medicine

transection, accessory pudendal arteries and ultimately their impact downstream on cavernous smooth muscle, has sparked important basic and clinical research evaluating various strategies aimed at minimizing the likelihood of postprostatectomy ED [4–12]. Excellent reviews of the prevalence[13] and pathophysiology[14] of ED after RP already exist and are not the focus of this article, but both are important to the understanding of penile rehabilitation after RP. It is the recommendation of the committee that clinicians should discuss ED prevalence rates and J Sex Med 2010;7:1687–1698

1688 the limitations and implications of the currently available literature at as early a point in the decision-making process as is feasible with the patient and partner. Furthermore, patients should be given individualized outcomes based on surgical technique, patient, and surgeon factors. On discussion, it was accepted that many urologists do not have accurate data on erectile function recovery from their own patient population. Our recommendation was to discourage the frequent occurrence of surgeons citing the best erectile function recovery figures in the literature, thus giving patients unrealistic expectations. It is another recommendation of the committee that clinicians should use a validated instrument with recognized cut-offs for normalcy and severity in their preoperative and postoperative evaluation of their patients. We recommend using either the International Index of Erectile Function-erectile function domain (IIEF-EFD) or Sexual Health Inventory for Men (SHIM), with score cut-offs of 26 and 21, respectively, to define normal erectile function. It is appreciated that many men with IIEF EFD scores of <26 and SHIM scores <21 are satisfied with their erectile function, and there was significant discussion as to whether an EFD score of 21–24 was adequate. In the final analysis, the committee believed that there were published validated cut-offs for the scores recommended. The concept of post-surgical patients regaining erectile function “back to baseline” was also discussed by the committee. We suggest that future research focus on capturing these data so that large data sets can be used to aid patients in defining the probability of returning to their baseline level of erectile function. The committee also appreciates that baseline erectile function assessment is problematic, and that the ideal timing of this assessment is poorly defined. The committee understands that the diagnosis of prostate cancer for many men has a significant negative effect on erectile function, and that assessment of EF immediately prior to RP may not be fully representative of the patient’s true function. The committee also recommends that clinicians should discuss the recognized predictors of erectile function recovery. These factors include patient age, baseline erectile function, and nerve sparing status. It should be pointed out to patients also that other factors such as comorbidity status and surgeon experience have been shown to be significant contributors to recovery. The committee further suggests that surgeons should discuss with patients the meaning of nerve sparing and its impliJ Sex Med 2010;7:1687–1698

Mulhall et al. cations. It is the clinical experience of the expert panel that patients do not have an adequate understanding of the concept of nerve sparing, thinking that nerve sparing always leads to complete preservation and that complete preservation means there will be absence of any transient postoperative ED. The committee also recommends that clinicians provide patients with a realistic time frame for EF recovery. Patients should be informed that the period of potential recovery is 6–36 months, but that the majority of patients have functional recovery within 12–24 months after RP. It is the clinical experience of the expert panel that many patients are given recovery time frames that are too short and unrealistic. The committee recommends that in an effort to facilitate the discussion on erectile function rehabilitation, clinicians should discuss the pathophysiology of erectile dysfunction after radical prostatectomy. Factors that clinicians should discuss include including the concepts of accessory pudendal artery injury, cavernosal oxygenation, erectile tissue structural alterations, and venous leak. Basic Science Evidence Regarding Rehabilitation

PDE5 Inhibitors (PDE5i) Recently, emerging experimental data have demonstrated a benefit to PDE5i use after cavernous nerve injury in animal models. Recent studies focusing on the molecular mechanisms of apoptosis and fibrosis have elucidated the potential mechanisms involved in the beneficial effect of chronic use of PDE5i in this animal model. Several studies have demonstrated a reduced amount of fibrosis in erectile tissue of animals chronically treated with PDE5i [15–20]. Ferrini et al. [15] found that chronic vardenafil was effective in preventing both the fibrosis and loss of smooth muscle seen following bilateral cavernous nerve resection. Compared with the sham group, rats exposed to nerve injury demonstrated a threefold increase in corporal smooth muscle apoptosis, a 60% reduction in the smooth muscle : collagen ratio and development of venocclusive dysfunction (CVOD). When vardenafil was given daily for 45 days to the animals that underwent bilateral nerve resection, the corporal smooth muscle : collagen ratio was normalized, and the subsequent CVOD was prevented [21]. Similar results have been reported in other animal models of post-RP ED using continuous long-term administration of sildenafil, as well as

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Erectile Function Rehabilitation in the Radical Prostatectomy Patient tadalafil [14–16,22–24]. Mulhall et al. [19] demonstrated that chronic administration of sildenafil given subcutaneously daily resulted in preservation of the smooth muscle-collagen ratio. In this series of experiments, the investigators also showed increased expression of the endothelial factor CD31 and increased phosphorylation of Akt and eNOS, which may account for the endothelial protection mediated by these agents. Similarly, Vignozzi et al. [20] found that chronic tadalafil administration (120 days) to rats reversed the decline in the cavernosal smooth muscle : collagen ratio that occurred after bilateral cavernous neurotomy. Behr Russel et al. [25] showed that a daily, 8-week treatment with sildenafil (60 mg/kg) administered subcutaneously to neurally intact rats was associated with enhanced endotheliumdependent relaxations of cavernosal strips to acetylcholine after chronic treatment with sildenafil. Conversely, relaxations in response to sodium nitroprusside were unchanged after sildenafil treatment. Moreover, the erectile responses to acute sildenafil were greater in chronically sildenafil treated rats. The findings suggested that the endothelium-dependent response is promoted by long-term PDE5i treatment and that the therapy does not confer an adverse effect on cavernosal tissue responsiveness involved in physiological erection. The investigators concluded that longterm sildenafil treatment may have long-lasting, physiologically significant erectile tissue benefits. The effect of chronic treatment with PDE5i seems to be mediated by increased Akt-dependent endothelial NOS (eNOS) activation [26]. Recent studies have suggested generation of endothelial progenitor cells (EPCs) to normal levels in patients with ED treated chronically with PDE5i (either sildenafil, tadalafil or vardenafil) [22–24,27]. The role of NO in EPC mobilization as well as activation has been recently demonstrated. The effect of chronic PDE5i in increasing the number of circulating EPCs might be the effect of the inhibition of PDE5 in the bone marrow. Finally, chronic administration of PDE5i has also been shown to reduce the cavernosal apoptotic process after cavernous nerve injury [19,28]. The effect of PDE5i in decreasing the number of penile apoptotic cells in cavernous injured models appears to be mediated by the phosphorylation of the survival associated kinases Akt and extracellular signal-regulated kinase (ERK) 1/2 [28]. The effect of chronic PDE5i in reducing apoptosis has

also been studied in clinical scenarios other than post-RP models. Salloum et al. demonstrated that both sildenafil and vardenafil reduced the area of cardiac necrosis in a rabbit model of cardiac ischaemia-reperfusion [29,30]. Das et al., using mouse cardiac myocyte cells exposed to hypoxia and reoxygenation, showed that sildenafil-treated cells demonstrated less necrosis and apoptosis than control cells [31,32]. Clinical Evidence Regarding Rehabilitation

Regardless of the technique, the removal of the prostate appears to result in an obligate period of neuropraxia with secondary end-organ damage and resulting ED of varying degrees [5]. In a longitudinal penile biopsy study after RP, profound histologic changes were observed in human erectile tissue microstructure in men not enrolled in any penile rehabilitation program [5]. These changes were observed as early as 2 months after surgery. The erectile tissue became progressively disorganized, with a decrease in the number of elastic and smooth muscle fibers, and an increased accumulation of collagen. This was accompanied by a complete lack of response to three challenges of 100 mgs of sildenafil at 2 months. Rehabilitation strategies have grown over the past decade and include (i) neuromodulatory agents; (ii) intracavernosal injections; (iii) PDE5i; (iv) intra-urethral alprostadil; and (v) vacuum therapy. In a survey conducted by Teloken et al. among 301 physicians from 41 countries, 84% performed some form of penile rehabilitation, including postoperative PDE5i (95%), ICI (75%), vacuum erection device (30%), and intraurethral alprostadil (10 [33].

Intracavernosal Injections The first prospective randomized post-RP rehabilitation study involved penile injection therapy. In the late 90s most urologists believed that longterm ED after nerve sparing radical retropubic prostatectomy (NSRRP) was due to poor surgical technique, and men were generally counseled to wait 1 year before addressing their post operative ED. Montorsi demonstrated a benefit to using intracavernosal injections using alprostadil (PGE1) monotherapy on the return of “spontaneous erections satisfactory for sexual intercourse” [34]. All men “reported normal preoperative erections allowing for satisfactory sexual intercourse at all times”. This study predated validated erectile function questionnaires, hence no baseline or postoperative questionnaires were used. Subjects J Sex Med 2010;7:1687–1698

1690 were randomized to intracavernosal injections of alprostadil three times per week vs. no therapy. Injections were started 1 month after surgery and continued for 3 months, after which the patients were evaluated. The outcomes were patient reported successful intercourse, nocturnal penile tumescence (NPT), and penile duplex Doppler studies. No preoperative NPT studies or Doppler studies were performed. Eight out of twelve (67%) completers in the treatment group recovered erections vs. 3/15 (20%) in the observation group. Interpretation of the objective results is difficult, as authors only provided summary data and did not indicate what NPT or Doppler parameters they considered “normal.” This study provided the first signal that intervening pharmacologically in the early postoperative period might beneficially impact recovery of erectile function after nerve sparing surgery, but the study suffered from low numbers and has never been duplicated or carried out on a larger scale. In 2005, Mulhall et al. in a nonrandomized study of 132 patients, compared men who opted for penile rehabilitation after RP vs. those who did not pursue rehabilitation [35]. All patients had partner-corroborated functional erections preoperatively. Patients studied were seen by a sexual medicine physician only after surgery but within the first 6 months. At that time, they opted for either the rehabilitation program or no intervention. The protocol consisted of an initial challenge with sildenafil (on four occasions at 100 mg). If an erection of “ⱖ60% rigidity” (penetration hardness) was obtained, patients were encouraged to use this medication to obtain three erections per week. If sildenafil failed to induce such an erection, patients were encouraged to consider penile injection therapy, depending on tolerability. Three erections per week were encouraged. All patients were followed every 4 months until they were 18 months postoperatively. Sildenafil failures were instructed to rechallenge themselves every 4 months after surgery to determine if they had become responders. Once this occurred, they were permitted to cease injections if they wished and to use sildenafil three times a week to achieve erections. All patients were followed every 4 months until they were 18 months postoperatively. Patients who decided not to pursue the program of treatment but who presented for follow-up for periodic evaluation of their erectile function constituted the no rehabilitation group” (74 men). Those in the rehabilitation group averaged 1.9 erections/week. The patients opting for rehabiliJ Sex Med 2010;7:1687–1698

Mulhall et al. tation had significant improvement in natural response (52% vs. 19%), sildenafil response (64% vs. 24%), and intracavernosal injection response (95% vs. 76%). Though the results are supportive of penile rehabilitation the strength of the conclusions are weakened by its non-randomized nature, introducing significant potential for investigator bias and patient motivation issues.

PDE5 Inhibitors There exist two large prospective, randomized, multicentered controlled studies after bilateral nerve sparing radical retropubic prostatectomy (BNSRRP), one assessing sildenafil and the other vardenafil. The sildenafil trial was designed shortly after the drug’s approval [9]. It was designed when the existing radical prostatectomy literature quoted “potency preservation” rates of greater than 80% after BNSRRP at centers of excellence, and penile rehabilitation was not widely available or promoted to the degree it is currently. The study designers set out to “evaluate the efficacy of prophylactic, nightly use of sildenafil in preventing long-term ED”. The second objective was to investigate the effects of sildenafil on nocturnal penile erections after BNSRRP. The a priori determined primary outcome in this trial was preservation of natural erectile function, defined as a combined score of at least 8 on questions 3 and 4 of the IIEF and a “yes” answer to the question, “Over the past 4 weeks, have your erections been good enough for sexual activity?” The secondary end points were mean IIEF-EF scores and NPT. The trial design was a three arm parallel design (placebo, sildenafil 50 mg, sildenafil 100 mg), with treatment starting 1 month after surgery and lasting for 9 months. At 48 weeks after surgery, men were then queried with the IIEF and the efficacy question. Though a longer period of observation to allow more complete return of function would have been preferable, it was felt that a longer placebo period might be detrimental to eventual return of function. Active recruitment ceased after 125 men, when a blinded review revealed a 25% response rate, far lower than that reported in contemporary surgical series from centers of excellence. At 48 weeks, 27% (14/51) of men on sildenafil vs. 4% (1/25) in the placebo arm were considered responders (P < 0.01). Overall mean IIEF-EFD score by treatment was 13.7 (sildenafil 100 mg), 12.4 (sildenafil 50 mg), and 8.8 (placebo) (Figure 1). In 54 men, NPT testing was done preoperatively and at five postoperative time points (4, 12, 24, 36, 48 weeks). In order to enter the study, men

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End Points in Sildenafil Post-RP Rehabilitation Trial (2008) 30

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IIEF Score

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15 Adapted from Padma Nathan el al. IJIR 2008 10

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Figure 1 End points in the nightly sildenafil postradical prostatectomy study. RP = radical prostatectomy; IIEF = International Index of Erectile Function.

0 IIEF Responder IIEF Nonresponder

had to demonstrate basal penile rigidity of greater than 55% rigidity for 10 minutes on at least 1 of two nights and have normal preoperative function. The primary penile NPT outcome was the duration at which penile rigidity (base and tip) was ⱖ55% of maximum rigidity (R ⱖ 55%). The clinical outcome measures were the same as those stated for the larger study. Forty-eight weeks after surgery, 6/18 (33%) men who received sildenafil 100 mg, 4/17 (24%) men who received sildenafil 50 mg, and 1/19 (5%) men who received placebo were categorized as study responders. These response rates in the NPTR subset are similar to those in the overall study (29, 26, and 4%, respectively). Though this abbreviated study met its end points and had highly statistically significant P values, it suffered from low numbers. Its strength lies in the congruence between the NPT data and the clinical outcome, and provides clinical data to support animal data. Mechanistically, it was suggested originally that men were obtaining nocturnal erections and oxygenating their corporal bodies. However, the NPT data demonstrate what little nocturnal erectile activity was occurring early after RP. Another less rigorous and smaller observational sildenafil rehabilitation study was conducted by Bannowsky et al. (unpublished) Forty three men after nerve sparing surgery by a single surgeon had NPT testing. The NPT testing was not done preoperatively and only once postoperatively, the night after catheter removal. Patients were

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assigned to sildenafil 25 mg nightly vs. no treatment. Sildenafil was started the day after NPT testing and continued for the 52 week observation period. Patients were “randomized” roughly equally between treatment group based on preoperative SHIM, NPT findings, and nerve sparing status. Men were seen at weeks 6, 12, 24, 36, and 52. The outcomes reported were SHIM score and “the ability to achieve and maintain an erection satisfactory for intercourse,” on and off sildenafil. At 36 and 52 weeks, a statistically significant difference in SHIM score was seen between the two groups, and at 52 weeks, a qualitative difference between intercourse success rates was observed. While statistically significant, the 3.2 and 4.8 point difference in SHIM scores between treatment and control patients at 36 and 52 weeks is likely only minimally clinically significant. However, this study lends support to the larger prospective study, and also demonstrates the profound early loss of clinical erectile function after NSRP. These analyses have forced us to analyze how a PDE5i may facilitate erectile function preservation. Given what we now know from animal studies, attention has been focused on endothelial protection, smooth muscle protection, and neuromodulation. Schwartz et al. conducted a randomized (nonplacebo) controlled trial evaluating the impact of sildenafil on corporal smooth muscle integrity in men after radical prostatectomy [36]. Twenty-one patients used sildenafil every other day at 50 or 100 mg. They had corporal biopsy performed prior to radical prostatectomy and 6 months postoperaJ Sex Med 2010;7:1687–1698

1692 tively. Histopathological analysis showed significant preservation of smooth muscle content with sildenafil use at both the 50 and 100 mg level. In this study, each patient served as his own control, as they all had preoperative corporal biopsies. Though supportive of the concept of penile rehabilitation, the interpretation of the biopsy material is extremely subjective and subject to observer bias and sampling error. No attempt was made to “blind” the person evaluating the tissue. More recently, the vardenafil (Recovery of Erections: INtervention with Vardenafil Early Nightly Therapy [REINVENT]) trial was published [7]. This study was designed to investigate the effect of early postoperative dosing with vardenafil in three different fashions: nightly (N), vardenafil on-demand (OD), or placebo (P) on the recovery of erectile function in men with ED following BNSRRP. As in the sildenafil study, its planning and design predated much of the strong supportive animal data for penile rehabilitation after cavernous nerve injury. The design of the study was complex. The P arm consisted of placebo nightly, with placebo on demand for sexual relations. The N arm consisted of 10 mg of vardenafil nightly with the ability to titrate the nightly dose downward but not upward, and then this group used placebo for on-demand sexual relations. The on-demand placebo was not titrated. The OD arm received nightly placebo with no titration, and for on-demand sexual relations, a titratable vardenafil dose (5, 10, or 20 mg). Thus, the different dosing permutations with 87 sites raises concerns regarding dose accountability. Intervention was for 9 months commencing 14 days after RP. Data was analyzed at three timepoints: at the end of the intervention phase (9 months); at the end of the 2 month single-blind placebo phase (11 months); at the end of a 2 month open label vardenafil on-demand phase (13 months). In this study, the primary outcome was the percentage of subjects with an IIEF-EF domain score ⱖ22 (mild-no ED) at the end of the single blind placebo washout period (11 months) as observed as last observation carried forward (LOCF). The end point of IIEF-EF domain score ⱖ22 has never been used before in a post-RP study, yet the rationale for using a score ⱖ22 was not made clear by the authors. A score of 22 translates into a mean score of 3.7, which means the answers lie somewhere between “about half the time” and “most of the time.” Concerns can be raised about using this score as a definition for erectile function recovery, although the true J Sex Med 2010;7:1687–1698

Mulhall et al. normal score of 26 the panel agrees may be overly rigorous as an end point. The use of LOCF in this study, though standard in pharmaceutical trials, could introduce a bias if the dropouts in one arm occur earlier than in another arm. As erectile function is known to improve with time, independent of treatment, if more men drop out early from one arm, their low IIEF-EFD score will be carried to the end of observation and hence lower the end-of-treatment IIEF score, even though they are likely to have improved. The dropout rates were similar between treatment arms: P (31%), N (35%), OD (32%), and were largely driven by adverse events. The primary efficacy variable was not met in the study. There was no difference between the P group and the vardenafil (N or OD) groups at the end of the single blind placebo washout phase. The proportions of patients with IIEF scores ⱖ22 were 29, 24, and 29% for the P, N, and OD, respectively (Fig. 2). Almost 30% of the P group had an IIEF-EF domain score ⱖ22, and it is unclear why this is so. Secondary outcomes included percentage of subjects with an IIEF EF domain score ⱖ22 at the end of the double blind treatment period (9 months) and at the end of the open label period (13 months). The secondary end points demonstrated superiority of OD over P at all data points during the double blind period. The OD arm was superior to the N arm at “several visits and at double blind LOCF (9 months),” though no data was presented to accompany the P-value of 0.0065. The superiority of on-demand therapy in the placebocontrolled trial is not surprising. Simply put, the OD arm used vardenafil for sexual relations, while the N arm used a placebo for sexual relations. It would be expected that the OD group would record higher IIEF EF domain scores, and SEP 2 and 3 rates at the end of the intervention phase. All superiority of the vardenafil arms was lost during the 2-month open-label period. This is a remarkable study, yet the results are in stark contrast to robust data from preclinical animal trials and the sildenafil trial. There was no benefit to rehabilitation with vardenafil at 11 and 13 months. The authors, in their conclusions, state that these data support a shift in the paradigm towards on-demand dosing of PDE5i post-RP, yet other than at the end of the intervention phase, the OD use was no more effective than the nightly dosing not the placebo. Possible explanations for the lack of difference in response between the placebo and vardenafil arms

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REINVENT Post-RP Rehabilitation Trial IIEF ≥22 at 11 months IIEF score ≥ 22 35 30

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Figure 2 Primary end point in the REINVENT study. RP = radical prostatectomy; IIEF = International Index of Erectile Function; REINVENT = Recovery of Erections: INtervention with Vardenafil Early Nightly Therapy.

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IIEF score > 22 at 46 weeks

after drug washout and at the end the open label period (13 months) include: (i) PDE5i plays no role in penile rehabilitation and the animal model is not relevant to humans. The number of potential confounding factors in the NSRP patient are: patient age at time of surgery, surgeon experience, surgeon expertise, preoperative sexual function, nerve sparing status, partner/relationship issues and status, confounding medications, medical comorbidities, hormonal status, and endothelial function among others. Future studies should be designed and powered to control these confounding variables to obtain clearer answers; (ii) There are differences in the molecular action of sildenafil compared with vardenafil. In the absence of a headto-head trial between different PDE5i in this population, this will be impossible to answer. However, all three PDE5i have been shown in animal studies at least to have a positive effect on erectile tissue and function preservation. On the other hand, there exists a randomized, controlled trial comparing all three PDE5i in the pulmonary hypertension literature demonstrating superiority of sildenafil over vardenafil in a number of end points (primarily pulmonary artery oxygenation) [37]; (iii) The vardenafil was not dosed correctly for rehabilitation. Of note, doses of vardenafil used in pulmonary hypertension are 10–15 mgs 2–3 times per day [38,39]; (iv) Confounders existed unrelated to lack of efficacy of vardenafil, including surgeon and nerve sparing quality variability related to the large number of centers and surgeons included in the trial; (v) It is also possible that the complexity of the trial design obscured any therapeutic effect.

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Alternative Strategies

More recently, two other strategies have been explored for the purposes of penile rehabilitation postprostatectomy. Vacuum device therapy has been around for more than a century and has continued to assume a role in the management of men with erectile dysfunction. A number of centers have studied the role of vacuum device therapy for the preservation of penile length postprostatectomy as well as for rehabilitation. It has been well documented that the pO2 and pCO2 levels in the cavernosal sinusoids following the application of a vacuum device remain in the venous range [40]. Indeed, the oxygen saturation is approximately 80%. If one believes that cavernosal oxygenation is critical to erectile tissue health and penile rehabilitation outcomes, this finding would undermine the role of vacuum device therapy as a rehabilitation strategy. Raina et al. study 109 patients who were randomized to vacuum device use daily for nine months vs. observation [41]. Thirty-two percent of patients in the vacuum device rehabilitation group vs. 37% in the observation group had recovery of natural erections at 9 months after surgery. Seventy percent of the vacuum device patients and 29% of those not using vacuum device were able to have sexual intercourse at that time. Dalkin et al. studied 39 men with good preoperative erectile function who underwent nerve sparing radical prostatectomy [42]. Stretched flaccid penile length was evaluated preoperatively and at 3-month postoperatively by a single examiner. The vacuum device was used daily starting the day after catheter J Sex Med 2010;7:1687–1698

1694 removal and was continued for 90 days. In men using the vacuum device on more than 50% of the possible days, only 3% had a decrease in stretched flaccid penile length of greater than 1 cm. Of the three men with poor vacuum device compliance, 67% had a penile length reduction of more than 1 cm. Kohler et al. analyzed 28 men who were randomized to early vacuum device or a control group [43]. The vacuum device group had therapy commenced 1 month after radical prostatectomy, while the control group had vacuum therapy instituted 6 months after radical prostatectomy. Postoperative SHIM scores were higher in the treatment group at 6 months 12.4 vs. 3.0 Furthermore, in the treatment group, no significant changes in stretched flaccid penile length were measured at 3 or 6 months postoperatively. In the control group, the mean penile length loss at 3 and 6 months was approximately 2 cm. Based on these small studies, there is a solid rationale for the conduct of a large multicenter analysis of vacuum device in a randomized controlled trial as a rehabilitation strategy. The current evidence in my opinion does not support the role of vacuum devices as monotherapy in penile rehabilitation. Recently, there has been resurgence in interest in transurethral prostaglandin (MUSE) as a treatment strategy in ED, as well as a penile rehabilitation strategy. Costabile et al., in a retrospective analysis of all MUSE clinical trial data, analyzed 384 patients who were postprostatectomy [44]. In this population, 40% had sexual intercourse on at least one occasion at home, and 18% of patients had urethral pain and burning. The limiting factor in the use of MUSE in the treatment of men postprostatectomy, particularly in the first year after surgery, is penile pain due to PGE1 hypersensitivity. Raina et al. studied 54 patients using MUSE post-radical prostatectomy [45]. Fifty-five percent of patients were capable of having sexual intercourse using MUSE, and 48% continued long-term therapy. The compliance with MUSE was 63% at a mean follow-up of 2.3 years. Mean SHIM scores went from 19 preoperatively to 5 immediately postoperatively, and this increased to 16 with the use of MUSE. While a score of 16 on the SHIM questionnaire is not normal, there appears to be a signal that there may be some benefit to MUSE as a rehabilitation strategy. The same authors studied 91 men who had undergone nerve sparing radical prostatectomy with a mean follow-up of 6 months. Fiftysix men were treated with MUSE at 125 or 250 mcg three times per week for 6 months. J Sex Med 2010;7:1687–1698

Mulhall et al. MUSE was started at 3 weeks after surgery. The control group were allowed to use erectogenic agents on-demand for sexual intercourse. Fifty percent of the MUSE rehabilitation patients had sexual intercourse without the use of any aides vs. 37% of the untreated patients. One hundred percent had penile pain, and 32% discontinued treatment. Once again, given the small number of studies and the small population sizes studied, while there is a signal that there may be of value to transurethral PGE1 administration as a rehabilitation strategy, there is a distinct need for the conduct of a large multicenter, randomized, controlled trial to define its role. Recently, McCullough has reported on a randomized trial comparing intra-urethral alprostadil (IUA) and sildenafil in the post-RP population. This study was conducted in the United States at three high volume prostatectomy centers. Approximately half of the patients had robotically assisted laparoscopic surgery, and the other half standard open radical prostatectomy. All surgeries were bilateral nerve sparing. The study consisted of two-arms comparing nightly IUA administration to nightly sildenafil 50 mg. Subjects had an IIEF EFD score of at least 26 at baseline. Patients were seen at the time of catheter removal (V2), and postoperative months 1 (V3), 3 (V4), 6 (V5), 9 (V6), 10 (V7), and 11 (V8). At V2, within 1 month after surgery, at the catheter removal visit, all men were randomized to either IUA (125 mcg) or Viagra (50 mg), in a 2:1 ratio and had measurement of stretched flaccid penile length (SPL). Subjects had to complete the sexual encounter profile (SEP) with each attempt at sexual intercourse throughout the trial. At V3 (1 month), IUA subjects were up-titrated to 250 mcg. All subjects were provided with a 2-month supply of IUA or sildenafil for nightly administration and remained on that dose for the remaining 8 months. The IIEF, SPL, adverse events (AE), SEP, and medication compliance data was collected at V3–V6 and V8. At V6 (month 9), all nightly medication was discontinued, and subjects were given no medication for 1 month. They attempted sexual activity during this time without using any erectogenic aids. At V7 (10 months), subjects were provided with six Viagra (100 mg) tablets and instructed to use each tablet on an empty stomach 1 hour before initiation of sexual activity over the ensuing month. At V8, 11 months after surgery, all subjects completed the Erectile Dysfunction Inventory of Treatment Satisfaction, in addition to the IIEF, Global Assessment Question (GAQ) and

Erectile Function Rehabilitation in the Radical Prostatectomy Patient Sexual Encounter Profile (SEP), and had stretched pelvic length (SPL) measured. One hundred and fifty-six subjects (97 IUA, 59 Viagra) completed the trial. Dropout rates were 19% for Viagra and 30% for IUA. Overall drug compliance as determined by ratio of dispensed to returned medication was 98% for Viagra and 79% for IUA. As in the REINVENT trial, the primary outcome was not met. Though IUA trended toward favoring an earlier return of function by all the metrics used, by 11 months, differences in outcomes were not statistically significant. The IIEF scores increased in both groups (sildenafil/IUA), respectively, from a mean of 9.9/10.4 at the 1-month visit to 15.3/17.7 at the end of the study. At the month 3 and 6 visits, there was a slight difference in IIEF EF domain scores in favor of IUA; these differences were not significant (P = 0.58 and P = 0.27 for months 3 and 6). The mean IIEF EF domain score differences were not clinically significant for the two groups at the end of treatment period or at the end of the study. Stretched penile length generally decreased in length for both treatment arms. The end-of-trial IIEF EF domain scores were similar to those in the sildenafil rehabilitation study and the percent of intercourse success were not dramatically different than the REINVENT trial. Despite aggressive rehabilitation, a loss of penile length was seen in both arms, occurring almost immediately. This is the first prospective longitudinal penile length study after RP in men undergoing penile rehabilitation and including only bilateral nerve sparing surgery. Absent of course was a control (no treatment) arm. The etiology of the loss of length remains uncertain, but rates of length loss were not affected by the rehabilitation strategies. In summary, the committee believes that the term “penile rehabilitation” is easy to understand by patients and should be retained, although some clinicians may prefer to use the term “erectile tissue preservation.” The committee defines rehabilitation as the use of a medication, combination of medications, devices (alone or in combination with medication) in the early stages after RP. The goal of rehabilitation is to maximize preservation of all components of the local erectile mechanism and optimize recovery of erectile function. The committee recommends that based on the strong animal and basic science evidence, understanding the strengths and weaknesses of the existing human studies and the negative consequences of long-term ED after RP, clinicians should discuss with the patient and partner that penile rehabili-

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tation has significant potential benefits for the patient/partner, and should be considered after RP. This was a unanimous recommendation of the committee, and is based on expert opinion, thus receiving a grade C because of supportive animal data, combined with conflicting and generally weak human data. The committee appreciates that the animal model may not be fully representative of the human model, or may be representative of only certain forms of nerve sparing surgery. The committee believes taking all of the human data into account, including the two RCTs, two nonrandomized studies, and also the data evaluating the positive impact of PDE5i on endothelial function and possibly corporal smooth muscle integrity health, that despite the data from the REINVENT study that there remained a signal that PDE5i use after RP had some potential benefit. While the data supporting ICI after RP is weak, the committee believes that the erection induced by ICI may be of benefit possibly mediated through cavernosal oxygenation and likely other hitherto unknown factors and pathways. The committee further recommends that key patient factors be taken into consideration when deciding on penile rehabilitation for an individual patient. These factors include, but are not limited to: cost to the patient and the health care system, time commitment for patient and clinician, exposure to medications and their adverse effects, the potential benefits of sequential follow-up, early return to sexual intercourse, and potentially maintenance of penile length. The committee appreciates that many patients have no health insurance coverage for medication utilization after RP. However, ICSM feel strongly that this decision should be made by the patient/couple, and that the cost be placed in perspective of the long-term sequelae of permanent ED. The ICSM also appreciates that rehabilitation is labor and time consuming for both the patient and clinical staff, and that patients be given realistic expectations regarding this prior to commencing rehabilitation. The committee suggests that a comprehensive discussion be held with patients regarding the adverse effects of all therapies employed in the rehabilitation program. It is also appreciated that consistent and regular follow-up with patients has potentially significant psychological benefits, including dissemination of realistic expectations, offering perspective and psychosocial support. Furthermore, the early institution of erectogenic therapy permits the early resumption of sexual intercourse with a J Sex Med 2010;7:1687–1698

1696 decrease in confidence erosion so often seen in patients who have delayed recovery of EF after RP. The ICSM understands the concept of penile length loss prevention through rehabilitation is highly controversial and based solely on anecdotal information; however, the majority of the committee felt it was reasonable leaving this statement within the recommendation. The committee could give no specific recommendations regarding the structure of the optimal rehabilitation regimen. Numerous confounding variables that at present remain undefined of the ideal rehabilitative approach were discussed, including: defining the best time to start rehabilitation after RP, frequency of medication utilization, specifically, daily vs. on-demand exposure, the best dosing schedule (low-dose vs. maximum dose), duration of rehabilitation after its commencement, and strategies used (PDE5i, ICI, transurethral prostaglandin suppository, vacuum therapy), but no definitive evidence exists favoring one rehabilitation strategy over another. This is a unanimous committee recommendation. It was clear that this was disappointing to many clinicians in the audience based on feedback during the presentation of the recommendations by the committee. Unfortunately, no trial has been conducted and likely will never be that will address all of the significant potential confounders. Corresponding Author: Gerald Brock, MD, FRCSC, Professor of Surgery, Division of Urology, Urology Program Director, University of Western Ontario, 268 Grosvenor Street, London, ON N6A 4V2, Canada.Tel: 519-646-6042; Fax: 519-646-6042; E-mail: gebrock@ sympatico.ca Conflict of Interest: Dr. Mulhall has grants from Pfizer and Timm Medical; is an investigator for Pfizer and Ethicon; serves on the advisory boards of Pfizer, Auxilium, Timm Medical, Slate, Fast-Size, Palatin Technologies and Vivus. Dr. Bella is a consultant and speaker for Bayer, Lilly, Pfizer and American Medical Systems. Dr. Briganti: No conflicts. Dr. McCullough is a research trial participant for Vivus, Warner Chicott: Research and Timm/Plethora. He is a compensated lecturer for Auxillium, sits on the Advisory Board for Slate and is a member of the Data Safety Advisory Board for Pfizer. Dr. Brock is a speaker, advisory board member and research trial participant for Bayer Lilly Pfizer J&J Coloplast, AMS, GSK. References 1 Briganti A, Salonia A, Gallina A, et al. Management of erectile dysfunction after radical prostatectomy in 2007. World J Urol 2007;25:143–8.

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Mulhall et al. 2 Burnett AL. Rationale for cavernous nerve restorative therapy to preserve erectile function after radical prostatectomy. Urology 2003;61:491–87. 3 Chuang MS, O’Connor RC, Laven BA, Orvieto MA, Brendler CB. Early release of the neurovascular bundles and optical loupe magnification lead to improved and earlier return of potency following radical retropubic prostatectomy. J Urol 2005;173:537–9. 4 Carrier S, Zvara P, Nunes L, Kour NW, Rehman J, Lue TF. Regeneration of nitric oxide synthase-containing nerves after cavernous nerve neurotomy in the rat. J Urol 1995;153: 1722–7. 5 Iacono F, Giannella R, Somma P, Manno G, Fusco F, Mirone V. Histological alterations in cavernous tissue after radical prostatectomy. J Urol 2005;173:1673–6. 6 Leungwattanakij S, Bivalacqua TJ, Usta MF, et al. Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J Androl 2003;24:239–45. 7 Montorsi F, Brock G, Lee J, et al. Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 2008;54:924–31. 8 Mulhall JP. Exploring the potential role of neuromodulatory drugs in the radical prostatectomy patient. J Androl 2009. 9 Padma-Nathan H, McCullough AR, Levine LA, et al. 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. 10 Parsons JK, Marschke P, Maples P, Walsh PC. Effect of methylprednisolone on return of sexual function after nervesparing radical retropubic prostatectomy. Urology 2004;64: 987–90. 11 Bannowsky A, Schulze H, van der Horst C, Hautmann S, Junemann KP. Recovery of erectile function after nervesparing radical prostatectomy: Improvement with nightly lowdose sildenafil. BJU Int 2008;101:1279–83. 12 Zippe CD, Pahlajani G. Penile rehabilitation following radical prostatectomy: Role of early intervention and chronic therapy. Urol Clin North Am 2007;34:601–18. 13 Mulhall JP. Defining and reporting erectile function outcomes after radical prostatectomy: Challenges and misconceptions. J Urol 2009;181:462–71. 14 Mulhall JP. Penile rehabilitation following radical prostatectomy. Curr Opin Urol 2008;18:613–20. 15 Ferrini MG, Davila HH, Kovanecz I, Sanchez SP, GonzalezCadavid NF, Rajfer J. Vardenafil prevents fibrosis and loss of corporal smooth muscle that occurs after bilateral cavernosal nerve resection in the rat. Urology 2006;68:429–35. 16 Ferrini MG, Kovanecz I, Sanchez S, Umeh C, Rajfer J, Gonzalez-Cadavid NF. Fibrosis and loss of smooth muscle in the corpora cavernosa precede corporal veno-occlusive dysfunction (CVOD) induced by experimental cavernosal nerve damage in the rat. J Sex Med 2009;6:415–28. 17 Kovanecz I, Rambhatla A, Ferrini M, et al. Long-term continuous sildenafil treatment ameliorates corporal venoocclusive dysfunction (CVOD) induced by cavernosal nerve resection in rats. Int J Impot Res 2008;20:202–12. 18 Kovanecz I, Rambhatla A, Ferrini MG, et al. Chronic daily tadalafil prevents the corporal fibrosis and veno-occlusive dysfunction that occurs after cavernosal nerve resection. BJU Int 2008;101:203–10. 19 Mulhall JP, Muller A, Donohue JF, et al. The functional and structural consequences of cavernous nerve injury are ameliorated by sildenafil citrate. J Sex Med 2008. 20 Vignozzi L, Filippi S, Morelli A, et al. Effect of chronic tadalafil administration on penile hypoxia induced by cavernous neurotomy in the rat. J Sex Med 2006;3:419–31.

Erectile Function Rehabilitation in the Radical Prostatectomy Patient 21 Gonzalez-Cadavid NF, Rajfer J. The pleiotropic effects of inducible nitric oxide synthase (iNOS) on the physiology and pathology of penile erection. Curr Pharm Des 2005;11: 4041–6. 22 Foresta C, Di Mambro A, Caretta N, De Toni L, Zuccarello D, Ferlin A. Effect of vardenafil on endothelial progenitor cells in hypogonadotropic hypogonadal patients: Role of testosterone treatment. Clin Endocrinol (Oxf) 2009;71:412–6. 23 Foresta C, Ferlin A, De Toni L, et al. Circulating endothelial progenitor cells and endothelial function after chronic Tadalafil treatment in subjects with erectile dysfunction. Int J Impot Res 2006;18:484–8. 24 Foresta C, Lana A, Cabrelle A, et al. PDE-5 inhibitor, vardenafil, increases circulating progenitor cells in humans. Int J Impot Res 2005;17:377–80. 25 Behr-Roussel D, Gorny D, Mevel K, et al. Chronic sildenafil improves erectile function and endothelium-dependent cavernosal relaxations in rats: Lack of tachyphylaxis. Eur Urol 2005;47:87–91. 26 Musicki B, Champion HC, Becker RE, Liu T, Kramer MF, Burnett AL. Erection capability is potentiated by long-term sildenafil treatment: Role of blood flow-induced endothelial nitric-oxide synthase phosphorylation. Mol Pharmacol 2005;68:226–32. 27 Foresta C, De Toni L, Di Mambro A, Garolla A, Ferlin A, Zuccarello D. The PDE5 inhibitor sildenafil increases circulating endothelial progenitor cells and CXCR4 expression. J Sex Med 2009;6:369–72. 28 Lysiak JJ, Yang SK, Klausner AP, Son H, Tuttle JB, Steers WD. Tadalafil increases Akt and extracellular signal-regulated kinase 1/2 activation, and prevents apoptotic cell death in the penis following denervation. J Urol 2008;179:779–85. 29 Salloum FN, Ockaili RA, Wittkamp M, Marwaha VR, Kukreja RC. Vardenafil: A novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits. J Mol Cell Cardiol 2006;40:405–11. 30 Salloum FN, Takenoshita Y, Ockaili RA, et al. Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial K(ATP) channels when administered at reperfusion following ischemia in rabbits. J Mol Cell Cardiol 2007;42:453–8. 31 Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling. J Biol Chem 2005;280:12944–55. 32 Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation 2005;111:1601–10. 33 Teloken P, Mesquita G, Montorsi F, Mulhall J. Post-radical prostatectomy pharmacological penile rehabilitation: Practice patterns among the international society for sexual medicine practitioners. J Sex Med 2009;6:2032–8. 34 Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: Results of a prospective, randomized trial. J Urol 1997;158:1408–10. 35 Mulhall J, Land S, Parker M, Waters WB, Flanigan RC. The use of an erectogenic pharmacotherapy regimen following radical prostatectomy improves recovery of spontaneous erectile function. J Sex Med 2005;2:532–40; discussion 40– 2. 36 Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves intracorporeal smooth muscle after radical retropubic prostatectomy. J Urol 2004;171:771–4.

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37 Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: A randomized prospective study. J Am Coll Cardiol 2004;44:1488–96. 38 Aizawa K, Hanaoka T, Kasai H, et al. Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension. Hypertens Res 2006;29:123–8. 39 Giacomini M, Borotto E, Bosotti L, et al. Vardenafil and weaning from inhaled nitric oxide: Effect on pulmonary hypertension in ARDS. Anaesth Intensive Care 2007;35:91–3. 40 Bosshardt RJ, Farwerk R, Sikora R, Sohn M, Jakse G. Objective measurement of the effectiveness, therapeutic succes and dynamic mechanisms of the vacuum device. BJU 1995;75:786– 91. 41 Raina R, Agarwal A, Ausmundson S, et al. Early use of vacuum constriction device following radical prostatectomy facilitates early sexual activity and potentially earlier return of erectile function. Int J Impot Res 2006;18:77–81. 42 Dalkin BL, Christopher BA. Preservation of penile length after radical prostatectomy: Early intervention with a vacuum erection device. Int J Impot Res 2007;19:501–4. 43 Kohler TS, Pedro R, Hendlin K, et al. A pilot study on the early use of the vacuum erection device after radical retropubic prostatectomy. BJU Int 2007;100:858–62. 44 Costabile RA, Spevak M, Fishman IJ, et al. Efficacy and safety of transurethral alprostadil in patients with erectile dysfunction following radical prostatectomy. J Urol 1998;160:1325–8. 45 Raina R, Agarwal A, Zaramo CE, Ausmundson S, Mansour D, Zippe CD. Long-term efficacy and compliance of MUSE for erectile dysfunction following radical prostatectomy: SHIM (IIEF-5) analysis. Int J Impot Res 2005;17:86–90.

Appendix

Recommendation

Grade B Clinicians should discuss ED prevalence rates and the limitations and implications of the currently available literature. Patients should be given individualized outcomes based on patient and surgeon factors. Recommendation

Grade A Clinicians should use a validated instrument with recognized cut-offs for normalcy and severity. It is recommended to use either the IIEF erectile function domain or SHIM with score cut-offs of 26 and 21, respectively, to define normal erectile function. Recommendation

Grade B Clinicians should discuss recognized predictors of erectile function recovery. J Sex Med 2010;7:1687–1698

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Mulhall et al.

Recommendation

Recommendation

Grade B Clinicians should provide patients with a realistic time frame for EF recovery.

Grade C It is recommended that key patient factors be taken into consideration when deciding on penile rehabilitation for an individual patient.

Recommendation

Grade C To facilitate the discussion on erectile function rehabilitation, clinicians should discuss the essential elements of the pathophysiology of erectile dysfunction after radical prostatectomy. Recommendation

Grade C It is recommended that clinicians discuss with the patient that penile rehabilitation has significant potential benefits for the patient/partner and should be considered after RP.

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Recommendation

Grade D No specific recommendation can given regarding the structure of the optimal rehabilitation regimen.