Advances in the Management of Post-Radical Prostatectomy Erectile Dysfunction: Treatment Strategies When PDE-5 Inhibitors Don’t Work

Abstract

Phosphodiesterase type-5 (PDE-5) inhibitors have revolutionized the treatment of post-radical prostatectomy erectile dysfunction. For those patients who undergo a non-nerve-sparing radical prostatectomy or whose condition fails to respond to PDE-5 inhibitors, alternative treatment with intracavernous injection therapy, transurethral alprostadil, vacuum erection devices, and recently described combination therapy is available. The goals of therapy are to provide the patient with a means of obtaining an erection so that the patient and his partner may resume sexual relations as soon as possible following radical prostatectomy. There is evidence that early institution of treatment may promote improvement in the return of spontaneous erections in patients who have undergone nerve preservation. In patients who undergo non-nerve-sparing procedures, therapy may improve penile rigidity. Intracavernous injection therapy, transurethral alprostadil, and vacuum devices are highly effective in the management of post-prostatectomy erectile dysfunction. High dropout rates, which are not related to adverse effects, have been described with all 3 modalities. Pre- and postoperative counseling may improve patient and partner satisfaction.

Phosphodiesterase type-5 (PDE-5) inhibitors are the first line of therapy in the management of erectile dysfunction in men who have undergone nerve-sparing radical prostatectomy. Improvements in frequency of penetration, the ability to maintain an erection, and both patient and spousal satisfaction are seen in up to 70% of cases.^1–4 However, there is some variability in success rates with PDE-5 inhibitors, which depend on patient age, dosage, and the extent of damage to the cavernous nerves.^5,6 A recent study implicates the quantity of time following surgery as an additional variable in determining the success of the PDE-5 inhibitors following radical prostatectomy.⁷ In this study, sildenafil was ineffective when taken within the first 9 months following bilateral nerve-sparing radical prostatectomy.

Recent work by Hong and associates⁸ has confirmed that patient satisfaction with sildenafil is a time-dependent process, implying that there is a postoperative period of neurapraxia in which erectile dysfunction is refractory to PDE-5 inhibitors. Finally, there are some patients who cannot tolerate PDE-5 inhibitors because of adverse effects or specific contraindications.

The result is that some men do not use PDE-5 inhibitors following radical prostatectomy because of lack of either efficacy or tolerability. For these PDE-5 nonresponders, a goal-oriented treatment strategy must be devised.

Goals in the Management of PDE-5 Nonresponse

The goals in treating post-radical prostatectomy patients whose condition fails to respond to PDE-5 inhibitors are 2-fold. The immediate goal is to develop a safe and effective therapeutic strategy in order to restore erectile function so that the patient and his partner may resume sexual relations in a timely fashion. Therapy must be acceptable from a physical and social standpoint, and it must fit in with the sexual behavior patterns and attitudes of the patient and his partner. Soloway and associates⁹ recently evaluated these specific functions of prostate cancer patients and their partners using a battery of validated and widely used self-administered instruments. There were considerable differences noted between the patient’s self-perceived level of sexual functioning and his partner’s perceptions. Specifically, partners reported that patients had lower levels of preoperative sexual performance and poorer quality erections than did the patients themselves. Nevertheless, partners expressed a higher level of sexual satisfaction. This data indicates that patients and their partners think differently about the sexual experience. It also underscores the importance of counseling the PDE-5 nonresponder with his partner as a couple.

For those patients who have reasonable preoperative sexual function and who undergo a nerve-sparing radical prostatectomy, the expectation is undoubtedly that therapy will be temporary. In many cases, it is not, and it is the physician’s responsibility to provide the patient and his partner with a balanced view and appropriate expectations before surgery. Up to 75% of men will not seek rehabilitative sexual treatment following radical prostatectomy,^10,11 a percentage that can be reduced by preoperative counseling.¹¹ Older patients have reported worse urinary and sexual function following radical prostatectomy,¹² but it is the younger patient who has more bother from the immediate loss of potency.¹³ The treating physician needs to be sensitive to these issues.

For patients who have erectile dysfunction preoperatively, or who undergo non-nerve-sparing surgery, development of a strategy that will demonstrate long-term efficacy and mutual acceptance between the patient and his partner requires careful preoperative planning. It is important to include the patient’s partner in these discussions. Studies have shown that the partner experiences greater psychological distress from a diagnosis of prostate cancer and is less concerned about sexual side effects of cancer surgery.¹⁴ In addition, a partner may be reluctant to actively participate in discussing sexual side effects of surgery in order to protect the patient’s dignity.¹⁵ Incorporating partners in preoperative counseling is vital in preventing alienation of the patient, who may not feel comfortable discussing his frustration with erectile dysfunction, particularly if he does not have success with PDE-5 inhibitors. Choices should be discussed preoperatively, as some men will opt to have a penile prosthesis placed—a procedure that adds no additional morbidity when performed simultaneously with a radical prostatectomy.¹⁶

The second goal in developing a regimen to treat PDE-5 inhibitor nonresponse is early institution of a successful treatment regimen that offers physiologic benefits in order to maintain cavernosal tissue integrity. Only recently has evidence emerged emphasizing the physiologic role of erections in maintaining normal erectogenic potential of the corpora cavernosa. In previously potent men who undergo radical prostatectomy, there is abrupt cessation of spontaneous erectile function in the early postoperative period, and nocturnal erections cease.¹⁷

Mulhall and coworkers¹⁸ evaluated 96 previously potent patients by penile Doppler ultrasonography and dynamic infusion cavernosometry and cavernosography following bilateral nerve-sparing prostatectomy. Although there were no significant time-dependent differences in arterial measures over the first year, there was a significant increase over time in the prevalence of corporeal veno-occlusive dysfunction (CVOD) in patients studied before 4 months (14%), 4 to 8 months (21%), 8 to 12 months (35%), and beyond 1 year (50%).

Other studies have confirmed a high prevalence of CVOD in patients following nerve-sparing radical prostatectomy.^19–22 The etiology for the development of CVOD in postprostatectomy patients has not been fully elucidated, but it is thought to result from a combination of denervation-induced cavernosal smooth muscle dysfunction as well as collagen deposition resulting from relative ischemia of the corporeal tissues. Collagen deposition, which may occur in as many as 40% of patients after radical prostatectomy,²³ may result in an inability to initiate a rise in cavernosal pressure despite adequate systolic arterial inflow, as well as an inability to maintain rigidity because of lack of passive compression of the emissary veins. In addition, it may account for the diminished penile length noted in a number of patients following radical prostatectomy^24,25 as well as penile curvature.²³ If not addressed in the early postoperative period, these changes may result in irreversible erectile dysfunction. In the study by Mulhall and associates¹⁸ only 8% of patients with CVOD had a return of spontaneous erections, compared with 47% of those men with normal Doppler studies results and 31% of those with isolated arteriogenic factors.

For patients undergoing non-nerve-sparing surgery, there also appears to be an advantage to early postoperative initiation of therapy. In a recent study by Gontero and coworkers,²⁶ patients who received intracavernous injection (ICI) therapy within the first 3 postoperative months had significantly more rigidity associated with erections compared with patients beginning therapy at a later time. Contrary to findings in patients who have undergone nerve-sparing procedures, Doppler studies in these patients suggested that arteriogenic factors may have contributed. Additional prospective trials are needed to confirm and explain these findings.

Beyond Oral Therapy: The Quest for an Effective, Well-Tolerated, and Mutually Acceptable Regimen for Patients and Their Partners

Currently there are several therapeutic modalities available to the patient who fails to have response to PDE-5 inhibitors. These include ICI therapy, transurethral prostaglandin E1 (alprostadil), and vacuum erection devices. In choosing one of these treatments or a combination of treatments, the patient and his partner must be informed regarding the potential benefits and adverse effects of each modality. The available literature provides us with a background for educating the patient and his partner about the efficacy, tolerability, and acceptance of the individual treatment modalities.

Intracavernous Injection Therapy

Intracavernous agents can be used either individually or as a combination regimen. The most widely studied regimens are currently prostaglandin E1 (PGE1) and a combination of phentolamine, papaverine, and PGE1 (Trimix). Quadrimix (Trimix + atropine), Forskolin, and a combination of phentolamine and papaverine (Bimix) are also available but are not as widely used in the United States.

ICI therapy is effective in 64% to 98% of patients with erectile dysfunction.^27–31 For patients who are motivated to continue therapy, ICI is associated with an increase in sexual activity,³² improvement in the quality of erections,^28,32–34 and improvements in sexual satisfaction for both the patient^32–34 and his partner.³³ In a small study in which 15 patients were examined before and following 6 months of ICI with the Duke University Health profile, Gheorghiu and colleagues³⁵ found that these effects translated into quality-of-life improvements in the domains of overall mental health, social health, and selfesteem for the patient. A larger open-label study of patients using ICI suggested improvement in sexual satisfaction, anxiety, depression, and overall mental health.³⁶

ICI therapy fulfills the criterion of offering immediate participation in sexual activity for the post-radical prostatectomy patient and his partner. The ensuing smooth muscle relaxation as a result of ICI is independent of endogenous vasoactive substance such as nitric oxide, which is impaired by nerve damage.³⁰ For those patients who begin therapy after fibrosis has already ensued, ICI may also result in adequate rigidity for penetration. This is because the degree of smooth muscle relaxation may be more complete with pharmacologically induced erections, so that a patient with a mild venous leak still may have veno-occlusion to the point of functional erection.³⁷

Complications specific to the use of ICI therapy are: subcutaneous hemorrhage, penile nodules and fibrosis, prolonged erections, and penile pain. The relative incidence of these complications in several contemporary series of patients treated with ICI is summarized in Table 1. Other than penile pain, which may occur in as many as 50% of patients receiving PGE1 monotherapy,³¹ the incidence of adverse effects from these agents is relatively low.

Table 1.

Complications of Intracavernous Injection Therapy in Several Contemporary Series

	Casabe et al (1998)27	Kunelius and Lukkarinen (1999)28	Baniel et al (2000)29	Linet et al (1996)31
Patients studied, N	189	69	625	683
Agent	Trimix	PGE1	Progressive*	PGE1
Penile ecchymoses, n (%)	40 (20.9)	7 (10.1)	31 (4.9)	57(8)
Corporeal fibrosis, n (%)	10 (5.3)	4 (5.8)	19 (3)	15 (2)
Prolonged erection, n (%)	7 (3.7)	3 (4.3)	19 (3)	40 (6)
Urethral bleeding, n (%)	2 (1.1)	0	0	0
Penile pain, n (%)	0	5 (7.2)	106 (16.9)	343 (50)

^*Several combinations including: 1) papaverine/phentolamine, 2) PGE1, 3) Trimix, and 4) Quadramix were used in a progressive manner. PGE1, prostaglandin El; Trimix, phentolamine, papaverine, and PGE1; Quadram Trimix plus atropine.

Adverse effects are a minor cause of patient dropout, which occurs in 30% to 50% of patients in ICI programs. The major factors interfering with longterm compliance with ICI regimens are lack of efficacy and dissatisfaction with the technique itself. Attrition and the reasons given for patient dropout from several contemporary ICI series are summarized in Table 2.

Table 2.

Attrition Rate and Reasons for Discontinuing Therapy in Contemporary Series Evaluating Intracavernous Injection Therapy

	Casabe et al (1998)27	Kunelius and Lukkarinen (1999)28	Raina et al (2003)30	Linet et al (1996)31
Patients studied, N	189	69	102	683
Follow-up	10.3 mo	36 mo	48 mo	6 mo
Agent	Trimix	PGE1	PGE1 or Trimix	PGE1
Discontinued therapy	98 (52)	32 (46.4)	53 (52)	212 (31)
Reasons given for discontinuation* :
Dissatisfaction, n (%)	15 (15)	9 (28)	18 (34)	56 (26)
Rejection of method, n (%)	10 (10)	2 (6.3)	12 (23)	23 (11)
Recovery of erections, n (%)	15 (15)	8 (25)	1 (1)	5 (2)
Loss of partner, n (%)	5 (5)	2 (6.3)	4 (8)	8 (4)
Other medical/sexual/relationship, n (%)	5 (5)	2 (6.3)	0	5 (3)
Pain, n (%)	0	4 (12.5)	0	43 (20)
Fibrosis, n (%)	0	3 (9.4)	0	0
Priapism, n (%)	0	0	1 (2)	3 (1)
Oral Therapy, n (%)	0	0	17 (32)	Not available
Other/unknown, n (%)	48 (49)	2 (6.3)	0	69 (33)†

^*Percentages calculated from population of patients who discontinued therapy only.

^†Includes 18 patients (9%) who had nonserious adverse events and 14 patients (7%) who discontinued therapy due to protocol violations.

PGE1, prostaglandin E1; Trimix, phentolamine, papaverine, and PGE1.

In a retrospective study evaluating 86 of 105 patients who remained on an ICI program for at least 3 months, the incidence of development of spontaneous erections, nonresponse to the treatment dose, corporeal fibrosis, and the development of prolonged erections was not significantly different in patients who discontinued therapy and those who continued it.³³ Patients discontinuing long-term intracavernous therapy were less motivated, were less satisfied with the quality of pharmacologically induced sexuality, considered the effort to perform injection therapy substantial, and did not have improved self-esteem as a result of ICI therapy. Lottman and associates³⁸ suggest that short-term counseling to educate the patient and his partner and to promote communication between them may significantly improve long-term acceptance of ICI therapy.

Intracavernous Injection Therapy in the Post-Radical Prostatectomy Patient

Remarkably few studies have specifically evaluated the long-term use of ICI therapy in patients following radical prostatectomy. Dennis and McDougal³⁹ reported that a combination of papaverine and phentolamine was 85% effective in producing erections in a small series of 14 patients who had undergone radical prostatectomy. Using structured interviews with patients and their partners, Baniel and associates⁴⁰ found that ICI was effective in 51 (85%) of 60 patients following radical prostatectomy.

With 4-year follow-up of 102 patients enrolled in an ICI program following radical prostatectomy, Raina and coworkers³⁰ found that 68% of patients achieved erections sufficient for sexual intercourse. Total Sexual Health Inventory for Men (SHIM) scores for the patients continuing with ICI were not significantly different from their pre-prostatectomy SHIM scores, and there was no significant difference in response between patients undergoing nerve-sparing or non-nerve-sparing procedures. A total of 49 patients (48%) continued long-term therapy, with a mean use of 3.7 ± 1.9 years. When discounting attrition secondary to loss of partner, initiation of oral therapy, and return of spontaneous erections, the overall compliance with ICI therapy was 70.6%. Patients with a SHIM score of less than 10 while on ICI therapy were more likely to discontinue therapy than those with post-therapy SHIM scores above 19.

Does Early ICI Promote Improvement of Erectile Function in Post-Radical Prostatectomy Patients?

There are currently 2 clinical studies that have specifically evaluated improvement in erectile function in post-prostatectomy patients who are treated with early ICI. The first was a randomized trial comparing patients who received 3-times-weekly injections of PGE1 for 3 months following radical prostatectomy with patients who were not treated.⁴¹ Treated patients began therapy at the 1-month postoperative visit and were reassessed at 6 months. The study reported that 8 (67%) of 12 patients who completed the active treatment arm compared with 3 (20%) of 15 patients in an observation group had a return of spontaneous erections sufficient for sexual intercourse at 6 months.

Although this study has provided the impetus to treat patients with ICI as soon as possible following nerve-sparing radical prostatectomy, there are several problems with the study that limit the ability to draw any global conclusions. First, the authors chose to use physician assessment of response. The physicians were not blinded, nor were any validated response instruments used. Second, the data were analyzed using the Student t test for unpaired data, which is a test that is used for measuring mean differences for internal data. The presence of recovery of spontaneous erections is a dichotomous variable, and a t test is inappropriate. Third, there were 3 patients in the treatment arm who discontinued therapy, and were not included in the final analysis. In a small study such as this, this diminishes the impact of the therapy.

When the data are analyzed by an intent-to-treat analysis, 53% of treated patients (n = 15) had spontaneous erections, compared with 20% of untreated patients (n = 15). Finally, the lack of an objective measure of the specifics of the erectile response in both arms, such as frequency of intercourse, rigidity, and ability to maintain erections, as well as overall patient and partner satisfaction, also limits its conclusions. Nevertheless, the study has considerable merit, and should promote more work in this area.

A second study by Raina and colleagues⁴² indirectly suggests that long-term ICI in the patient who has had nerve-sparing prostatectomy may lead to a favorable response to PDE-5 inhibitors at a later time. Thirty-six of 49 patients who had used ICI at a mean of 3.7 ± 1.9 years following radical prostatectomy participated in this open-label, dose-escalation trial of sildenafil citrate. It is implied that many of these patients had not initially had response to sildenafil during the early months following radical prostatectomy. Following a minimum of 5 attempts or 1 month of oral therapy, 15 patients (41%) successfully switched to PDE-5 inhibitors, with an additional 7 patients (19%) continuing use of sildenafil in order to enhance the efficacy of ICI. Future prospective randomized trials comparing aggressive institution of an ICI program in initial PDE-5 nonresponders versus observation are needed to see whether the effect is a function of the time-dependent resolution of neurapraxia or whether there are additional benefits as a result of ICI.

Transurethral Alprostadil

The Medicated Urethral System for Erection (MUSE) provides a needleless delivery system for PGE1. Using physician assessment of response, the initial MUSE clinical trial⁴³ and others^44–46 confirmed that 60% to 70% of patients can have successful titration in the office to a dose that provides sufficient rigidity for intercourse. Home success rates, which were defined as those patients reporting sexual intercourse occurring at least once during the 3-month study period, were slightly lower at 53% to 65%.

For responders, the use of transurethral alprostadil is associated with improvements in several quality-of-life domains. In a study conducted in Europe utilizing self-administered validated questionnaires, 159 patients were randomized to receive alprostadil or placebo for home use.⁴⁷ Three months after starting the home phase of the study, treated patients and their partners confirmed significant improvement in erection quality compared with the placebo group. In addition, patients reported improved self-esteem and sense of happiness as well as overall personal wellness. Patients receiving alprostadil as well as their partners believed that it positively influenced their relationship.

Penile pain during administration is the most common adverse effect of transurethral alprostadil. In the MUSE clinical trial, it occurred in 32.7% of men during home administrations and was reported after 11% of all administrations.⁴³ It was usually mild, and only 2.4% of men discontinued use of MUSE as a result. In the patients who had undergone radical prostatectomy, the incidence of penile pain is comparable to that in the other patients with erectile dysfunction, but the incidence of urethral pain and burning was higher (18.3% of post-prostatectomy patients vs 10.4% of all others, P = .027).⁴⁶

Hypotension is one of the most serious adverse effects of MUSE, occurring in up to 4% of patients.^43–46 True syncope occurs in less than 1%.^43–46 These are dose-dependent effects,⁴³ and as a result, the initial instillation of MUSE should be performed in the office, where the patient may be monitored.

Additional adverse effects include urethral bleeding, usually as a result of local penile trauma. Priapism occurs rarely.

Transurethral Alprostadil in the Post-Radical Prostatectomy Patient

A retrospective review of the initial MUSE clinical trial provides insight into its efficacy in the post-radical prostatectomy patient.⁴⁶ Three hundred and eighty-four (25%) of the initial 1511 patients enrolled in the trial had undergone radical prostatectomy. Data regarding pathologic stage and whether nerve preservation had been performed were not available. The patients in the post-prostatectomy group were older, had fewer early-morning erections, and had a shorter duration of erectile dysfunction than the remainder of the patients.

During the office dose-titration phase of the study, 70.3% of post-prostatectomy patients had an erection believed sufficient for intercourse, compared with 64.4% of the remaining patients (P = .035). Dose selection for post-radical prostatectomy patients was significantly lower than in the others, with 66.3% of all patients requiring 500 mcg or 1000 mcg of MUSE, compared with 73% of the remaining patients. Nevertheless, in the at-home treatment phase, intraurethral alprostadil was not as effective in the post-prostatectomy patients. Seventy-two (57.1%) of 126 post-prostatectomy patients compared with 227 (67.8%) of 335 other patients were able to have intercourse at least once (P = .033). Of those post-prostatectomy patients having intercourse at least once, approximately 70% of administrations were successful.

Comparisons of Transurethral Alprostadil With Intracavernous Injection Therapy

Several studies comparing ICI therapy with transurethral alprostadil have tempered the initial enthusiasm associated with MUSE.^48–50 Table 3 summarizes 3 of these series in which efficacy is compared. All 3 series utilized a flexible dose titration in the office phase, and success was graded upon the physician and patient-perceived assessments of rigidity. In 2 of the studies,^49,50 patients were sent home using the minimal effective dose for 3 months. Home efficacy was measured in terms of the percentage of patients achieving at least 1 erection with either agent, as well as overall efficacy of the number of administrations resulting in erections suitable for intercourse. All 3 studies showed that ICI is more efficacious than transurethral alprostadil.

Table 3.

Clinical Trials Comparing Intracavernous Injection (ICI) Therapy With PGE1 and Transurethral Alprostadil (MUSE)

	Porst (1997)48	Shokeir et al (1999)49	Shabsigh et al (2000)50
Type of study	Crossover, open-label	Prospective, randomized	Crossover, open-label, randomized
Office phase	N = 103	N = 30 ICI/30 MUSE	N = 95
Rigid for penetration	4/10*	90/60*	61.2/20*
Home phase	Not performed	N = 60	N = 68
At least 1 erection sufficient for intercourse	-	87/53*	92.6/61.8*
Overall successful administrations	-	85/55*	82.5/53*

^*ICI%/MUSE%.

MUSE, Medicated Urethral System for Erection.

In the study by Shabsigh and coworkers,⁵⁰ assessment of subjective criteria, as well as IIEF scores during the at-home treatment phase, was performed in 68 patients. Partners were assessed as well. IIEF scores in all 5 domains were significantly higher for intracavernous PGE1 than MUSE. Overall, patient and partner satisfaction were higher and the number of patients choosing to continue therapy with ICI was higher than with MUSE. In the study by Shokeir and associates,⁴⁹ ICI demonstrated improved efficacy; however, patients believed that administration of MUSE was easier than ICI in the home phase of the trial. Long-term follow-up will determine whether this benefit outweighs its inferior efficacy when the patient decides which therapy to continue.

Vacuum Erection Devices

Vacuum erection devices (VEDs) are an important part of the urologist’s armamentarium for patients with erectile dysfunction. They offer an additional option for post-radical prostatectomy patients who fail to have response to PDE-5 inhibitors. They promote engorgement of the penis through negative pressure effects on the corporeal chambers. When used with a venous constriction ring to maintain tumescence, they have proved to be highly effective in providing patients with a minimally invasive, reasonably inexpensive means to obtain an erection.

There are several distinct differences in the physiology of a spontaneous erection and that of an erection following use of a VED. Nadig and associates⁵¹ used plethysmography, which showed a decrease in blood flow to the penis with the constriction band in place. There was a progressive decrease in skin temperature distal to the band. Color-flow Doppler studies have demonstrated that following initiation of negative pressure to the penis, there is a transient increase in penile arterial inflow, which ceases distal to the site where a venous constriction band is applied.⁵² Finally, cavernosal blood gas analysis has confirmed that the engorgement of the penis following application of a VED and constriction ring is composed of predominantly venous blood.⁵³ The degree of ischemia and acidosis increases as a function of time during which the constriction ring is in place. The post-prostatectomy patient already has some degree of ischemia in the immediate postoperative period, and the effects of repetitive use of a VED warrants further study.

VEDs are widely used and are effective in treating erectile dysfunction, even in the era of PDE-5 inhibitors.⁵⁴ Efficacy rates of 67% to 90% have been reported in achieving satisfactory erections.^55–57 Subgroups involving post-prostatectomy patients share these high rates of response.^55,58 Patient satisfaction rates with the device are considerably lower, ranging from 34% to 68%.^55,56,59

In a randomized crossover trial comparing ICI with VEDs,⁵⁹ patients were evaluated by a self-administered questionnaire after using each modality at least 15 times. There were no significant differences in terms of perceived erection quality and penile sensation following use of intracavernous Trimix and VEDs. Despite this, patient and partner satisfaction rates were significantly higher in the ICI group. Subgroup analysis demonstrated that these differences in satisfaction were more pronounced in those patients who were younger than 60 years, had undergone radical prostatectomy, and who had had a relatively short duration of erectile dysfunction. The improved satisfaction with ICI translated into more than twice the number of patients opting for ICI than VEDs as a long-term therapeutic option.

Other studies have evaluated the impact of VEDs on quality of life and relationships. In a study by Turner and coworkers⁵⁷ a battery of self-administered questionnaires before and following initiation of VED therapy was given to patients and their partners. Six months following initiation of therapy, there were significant improvements in the quality of erections during foreplay and intercourse, frequency of intercourse attempts, frequency with which men and their partners were able to reach orgasm, and overall sexual satisfaction experienced by patients and their partners. Moreover, men using the VED felt more self-confidence in their own sexual attractiveness and had decreased feelings of depressed mood and pessimistic thinking, and there was a trend in improvement in marital satisfaction. There were no overall changes in the partners in terms of depression, marital relations, self-esteem, or anxiety.

Adverse effects are usually seen at the initiation of treatment and primarily involve penile pain, which occurs in 20% to 35% of patients.^55,57,60 With time and additional use of the device, there is a reduction in the perceived pain.^55,57,60 Other adverse effects are pain during ejaculation, inability to ejaculate, numbness of the penis distal to the constriction band, and pivoting due to the lack of rigidity proximal to the constriction band.^55,57,60 Finally, 21% to 39% of patients will experience skin bruising or ecchymosis.^{55,57,61–63}

Similar to that seen with the other therapeutic modalities, there is a significant dropout incidence of 19% to 65% among patients using VEDs.^55,57,60 This usually occurs within the first several months of therapy and is due to either the device being ineffective in providing successful erections^55,57,60 or the fact that the device is cumbersome.⁶⁰ Several investigators have reported difficulties that patients and their partners have with these devices.^{55,57,63–65} In one study, 63% of patients discontinuing therapy with a VED chose not to receive any other treatments.⁶⁰ This suggests that patients who choose vacuum therapy may not be as motivated as other patients.

Choices Between Ease of Administration, Patient and Partner Acceptance, and Efficacy

A trial by Baniel and colleagues⁴⁰ highlights the interaction between efficacy, ease of administration, and patient and partner acceptance in decisions regarding long-term usage of erectogenic agents following radical prostatectomy. In this study, 85 patients who had undergone primarily non-nerve-sparing radical prostatectomies were offered treatment in 4 progressive phases. They all began therapy with a VED. If this therapy failed, or if they were dissatisfied with the VED, they then began therapy with sildenafil. Sildenafil nonresponders then proceeded to ICI and then finally to combination therapy with ICI and a VED.

More than 50% of the patients did not have erectile dysfunction preoperatively, and the majority underwent non-nerve-sparing prostatectomies. One-year follow-up was provided.

Despite a 92% efficacy of the VEDs, only 11 patients (14%) continued with this method. Only 14 (20%) of the 69 remaining patients had response to sildenafil, likely a result of the fact that the majority of patients had non-nerve-sparing prostatectomies. Eleven sildenafil responders continued therapy at 1 year, with the remaining 3 patients switching to ICI. Overall, the highest acceptance rate was with ICI. At 1 year, 54 patients (71%) were using ICI alone, and an additional 4 patients (5%) were using ICI with a VED.

Whereas similar studies in men who have had nerve-sparing radical prostatectomies are likely to show an advantage to PDE-5 inhibitors, for those men in whom PDE-5 inhibitors fail, this study demonstrates that patients and their partners prefer ICI over VEDs. Future trials such as this are warranted, and they should incorporate a transurethral therapy arm as well.

Combination Therapy

A variety of combination therapy regimens have been studied recently in those patients who fail to have response to individual therapies. The use of combination therapy takes advantage of potential additive or synergistic effects that may be achieved by targeting 2 or more different areas within the erectile apparatus. The use of combination ICI, such as Trimix or Quadrimix, is an example of this principle. Others have used vacuum devices to augment the erectile rigidity achieved by ICI therapy. In a study by Marmar and colleagues,⁶⁶ penile buckling pressure during erection was significantly improved in 21 of 22 patients using a combination of a VED and ICI.

Several recent studies have evaluated the effects of oral pharmaceuticals in enhancing the efficacy of ICI or transurethral therapy. The results of these studies are summarized in Table 4.^67–69 In the study by Kaplan and associates,⁶⁷ synergy was demonstrated between doxazosin and intracavernous alprostadil. The mean dose of alprostadil used by patients in combination with doxazosin declined significantly from 34.7 mcg to 23.5 mcg after 12 weeks, demonstrating synergy. In the study by Nehra and colleagues,⁶⁹ the mean dose of sildenafil was reduced in 8 of 28 patients using combination therapy, also confirming a synergistic response. In this study, the combination of sildenafil and MUSE was a highly successful regimen, and at a mean follow-up of 30 months, all patients continued to use the combination.

Table 4.

Combination Therapy for Erectile Dysfunction: Comparison of Contemporary Series in the Literature

	Kaplan et al (1998)67	McMahon et al (1999)68	Nehra et al (2002)69
Combination studied	ICI + doxazosin	ICI + sildenafil	MUSE + sildenafil
Number of patients	38	61	28
Study parameters	IIEF,	IIEF questions 3 and 4,	Patient reported
	Global efficacy	Home diary
Efficacy parameters	61.5% increased frequency of penetration	47.5% able to have SI	100% able to have SI
	71.9% increased ability to maintain erection	Increased frequency of penetration
	Increased intercourse satisfaction	Increased ability to maintain erection
	Increased mean EF domain score
	Increased orgasmic function
	> 2x increase in global efficacy
Adverse effects	3 (7.9%)	20 (33%)	0

ICI, intracavernous injection; MUSE, Medicated Urethral System for Erection; IIEF, International Index of Erectile Function; EF, erectile function; SI, sexual intercourse.

In a recent review of potential targets for combination therapy, Steers⁷⁰ cautions that there are serious safety concerns about combination regimens. The fact that most of the erectogenic agents have smooth muscle relaxing properties may promote synergistic effects on the cardiovascular and gastrointestinal tract as well. Prospective, randomized trials are needed to confirm the safety and efficacy of these regimens.

Conclusions

Whereas PDE-5 inhibitors have revolutionized the treatment of erectile dysfunction for the post-radical prostatectomy patient, there are many patients in whom these agents are ineffective or have prohibitive adverse effects. Preoperative counseling of the patient and partner is important in educating the couple in order that they formulate reasonable expectations regarding sexual recovery. The approach in patients with preoperative erectile dysfunction that may already be refractory to PDE-5 inhibitors varies slightly, as they may choose to undergo a simultaneous penile prosthesis implantation. For patients with moderate and severe erectile dysfunction who do not wish to have this performed, and in patients who are expecting to have unilateral or bilateral nerve preservation in order to preserve erectile function, the early initiation of PDE-5 inhibitors is recommended. For those patients with early failure of PDE-5 inhibitors, treatment with a VED, ICI, or transurethral therapy is offered. This accomplishes 2 goals: it allows for immediate participation in sexual activity for the patient and his partner, and it may provide a protective role against the development of CVOD in patients who may have return of spontaneous erections in the future.

The choice of secondary treatment for post-prostatectomy erectile dysfunction is largely dependent on the wishes of the patient and his partner. The physician plays a very important role in attempting to educate the couple, remain objective, and promote communication between the couple, particularly when there is reluctance expressed in discussing these issues. All 3 second-line options are highly effective in post-radical prostatectomy patients. For the patient who is expecting a full return of erectile function following nerve-sparing prostatectomy, early data indicate an advantage of ICI in terms of patient acceptance, efficacy, tolerability, and possibly its therapeutic role in promoting the return of spontaneous erections or in downgrading therapy later to oral agents. Despite using second-line therapy when there is early PDE-5 nonresponse, PDE-5 inhibitors should be tried again at various intervals, particularly after 9 months of therapy.

For patients who have non-nerve-sparing procedures, or in those patients with significant erectile dysfunction preoperatively, there is little expectation of return of spontaneous erections. Data support that the early use of ICI improves penile rigidity, irrespective of whether never preservation was performed during surgery. Therefore, it should be encouraged. Follow-up in these patients and counseling with their partners may detect dissatisfaction with treatment early, which may prevent attrition. This would allow for a reassessment of the goals and potential therapeutic options, which may include penile prosthesis placement at any time, particularly in those patients with severe preoperative erectile dysfunction. For those patients who did not have erectile dysfunction and who undergo non-nerve-sparing radical prostatectomy, a small percentage may be responsive to PDE-5 inhibitors.¹ Waiting 18 to 24 months before recommending penile prosthesis may be justified in these patients.

For the long term, ICI, VEDs, and transurethral therapy are all highly effective regardless of whether patients undergo a nerve sparing or non-nerve-sparing procedure. Randomized trials, however, have demonstrated that patients prefer ICI because of its superior efficacy over VED and transurethral therapy. Ease of administration, concerns about injections, and partner preference may dictate otherwise, however.

Combination therapy may be highly effective in treating patients who do not respond to the individual agents. While judicious use of combination therapy may be effective, the reader is cautioned that off-label usage of combination therapy is not recommended by the manufacturers and may be accompanied by significant adverse effects.

For those patients who have severe preoperative erectile dysfunction, and for those patients who continue to use second-line treatment options for longer than 18 to 24 months, a penile prosthesis is an option. In an analysis of goal-directed therapy in the pre-PDE-5 era, patient satisfaction rates were higher with penile prosthesis placement than with all other medical treatments available. Still, 90% of patients preferred to continue with medical therapy despite its inferior efficacy.⁷¹ Patients who have undergone radical prostatectomy, however, may represent a more motivated group, and therefore future studies are warranted in this population of patients.

Main Points.

• Nonresponse to, or intolerance of, phosphodiesterase type-5 (PDE-5) inhibitors after radical prostatectomy creates a need for second-line treatments to restore erectile function; options include intracavernous injection (ICI) therapy, transurethral prostaglandin E1, and vacuum erection devices (VEDs).

• An effective treatment strategy requires careful preoperative planning, as early initiation of treatment may have advantages: in patients who have had nerve-sparing prostatectomies, corporal veno-occlusive dysfunction and collagen deposition may lead to irreversible erectile dysfunction over time, whereas early therapy after non-nerve-sparing procedures may elicit better results.

• ICI therapy has been shown to be effective in increasing sexual activity, quality of erections, and quality-of-life and mental health factors. More studies are needed to evaluate the long-term use of ICI therapy in patients following radical prostatectomy and whether it can affect the response to sildenafil added at a later date.

• Retropective review of the Medicated Urethral System for Erection (MUSE) trial, which evaluated transurethral alprostadil, shows that while the treatment was as effective in post-prostatectomy patients as in others during in-office titration, during at-home use, the prostatectomy patients had a lower success rate than other men.

• Several studies have shown that ICI is more efficacious than transurethral alprostadil, but long-term follow-up will show whether patient preference and compliance with both techniques will have an effect.

• VEDs are widely used and are effective in treating erectile dysfunction, including in post-prostatectomy patients; however, patient and partner satisfaction rates with the devices are considerably lower, and ICI is preferred as a long-term option by the majority.

• For the long term, ICI, VEDs, and transurethral therapy are all highly effective regardless of whether patients undergo a nerve-sparing or non-nerve-sparing procedure. Judicious use of combination therapy may be effective, however it is not currently recommended by the manufacturers and extreme caution should be exercised if it is undertaken. Patients who undergo nerve-sparing surgery and who are initial PDE-5 inhibitor nonresponders should be encouraged to try PDE-5 inhibitors at various intervals after initiating second-line therapy.