# Penile Rehabilitation Therapy with PDE-V Inhibitors Following Radical Prostatectomy: Proceed with Caution

Authors: M. Eric Brewer; Edward D. Kim
Journal: Advances in Urology
 (2009)

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## Abstract

Penile rehabilitation therapy following radical prostatectomy is a much debated topic. Erectile dysfunction is still a significant contributor to postoperative morbidity following radical prostatectomy, despite meticulous nerve-sparing technique.  Secondary smooth muscle changes in the penis have been identified as the underlying causes of penile atrophy, veno-occlusive dysfunction, and fibrosis. Initial observations that intracavernous injection therapies used on a regular basis postoperatively resulted in improvements in the return of spontaneous erectile function led to the development of penile rehabilitation protocols. Chronic dosing of PDE-V inhibitors is now commonly used by urologists after radical prostatectomy. Despite the current enthusiasm of penile rehabilitation therapy, current scientific evidence with clinical trials is still limited.


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## Body

## 1. Introduction

Erectile
dysfunction (ED) continues to be a significant complaint among men undergoing
radical prostatectomy (RP), despite meticulous nerve-sparing technique. The
discrepancy between preservation of the nerves and recovery of erectile function
leads us to believe that the etiology is likely multifactorial. Smooth muscle
alterations and fibrotic changes in the penis following surgery were identified
as underlying causes of penile atrophy, veno-occlusive dysfunction, and
Peyronie's-like changes. Other mechanisms, such as penile hypoxia, are likely
to contribute to post-RP erectile dysfunction as well.The topic
of penile rehabilitation therapy (PRT) has become an area of intense interest
over the last decade. Initial observations that intracavernous injection
therapies used on a regular basis postoperatively resulted in improvements in
the return of spontaneous erectile function led to the development of penile
rehabilitation protocols [1]. A central question is whether vasoactive
therapies, such as oral type V phosphodiesterase (PDE-V) inhibitors and
intracavernous or intraurethral alprostadil, can lessen or reverse the effects
of causative factors for ED. As several recent articles in Advances in Urology
have thoroughly reviewed the benefits of PRT, the purpose of this article is to
provide caution to the present enthusiasm for penile rehabilitation.


## 2. Penile Injury Following RP: Basic Science

The basic
science behind the mechanism of erection has been discussed previously and is
beyond the scope of this review [2]. With that said, it is important that we
understand the underlying hypothesis of penile rehabilitation therapy. In the 1990s, it was recognized that
denervation injury to the penis affects the cavernous smooth muscle. This is similar to the skeletal muscle
atrophy that is seen following spinal cord injury. Using a rat model, Klein et al. were the first to demonstrate
that denervation of the penis leads to apoptosis [3]. Then in 2003, User and
McVary were able to show penile apoptosis as early as 1 day after cavernous
nerve ablation in a rat model [4]. This apoptotic process is directly related
to atrophy and fibrosis. The hypothesis is that PDE-V inhibitors promote penile
rehabilitation by stimulating smooth muscle cell replacement via a cGMP
mechanism and reducing collagen synthesis via phosphokinase G activation [5].
By performing percutaneous penile biopsies at the time of RP and 6 months
later, Schwartz et al. were the first to demonstrate that early use of 100 mg
of sildenafil after RP may preserve intracorporeal smooth muscle content [6].
Interestingly, those taking 50 mg of sildenafil under the same dosing regimen
showed no statistically significant change in smooth muscle content. There was no control group in this study and
only 21 of the enrolled 40 men were available for follow-up. The effects on the
long-term return of erectile function were not determined. Rajfer et al. from UCLA demonstrated in
several studies that rats treated with PDE-V inhibitors had no significant
increase in the penile shaft collagen content [5, 7, 8]. These studies have
provided important animal model documentation of the benefit of PDE-V inhibitor
therapy for the prevention of functional and histologic changes in the penis
that can occur after nerve damage.


## 3. Limitations of Present Clinical Studies

While there have been many studies in the rat model
showing the benefits of local vasoactive therapies, the crossover to clinical
significance in the human has been more difficult to prove (see Table1).
Montorsi et al. showed in 1997 that men who performed penile injections had a
superior rate of return of adequate erections following RP than men who did not
do injections [1]. However, the study did not include preoperative parameters
of erectile function or the use of a validated questionnaire. Also, the small
number of patients included in the study decreases its power. Additionally, the short duration of follow-up of 12 weeks limits any
conclusions regarding long-term impact of therapy. Nevertheless, this study was
the first clinical report to suggest a benefit of a penile rehabilitation
strategy using a pharmacologic therapy.Table 1
Review of clinical studies.
Authorsn (number of patients)Conclusions andlimitationsMontorsi et al. (1997)30Alprostadil injections led to superior rate of return of adequate erections;no preoperative EF parameters, no questionnaire, small number of patients, short follow-upMulhall et al. (2005)132Pharmacologic penile rehabilitation protocol results in higher rates of
spontaneous erections and erectogenic drug response;no placebo arm, strong patient selection bias, dropouts were not includedMontorsi et al. (2006)80No significant difference is IIEF scores of patients using on demand versus
daily PDE5 inhibitors post-NSRRP;compliance not reportedBannowsky et al. (2008)43Daily low-dose sildenafil leads to improved recovery of EF post-NSRRP
(86% versus 66% placebo);small number of patients, not placebo-controlled,
single center, only included patients who showed preserved EF post-operative with
Rigiscan testingPadma-Nathan et al. (2008)76First placebo-controlled trial suggesting benefit of daily PDE5 inhibitor use:
nightly sildenafil increased return of spontaneous erections;low percentage
(4%) considered responders in placebo arm, but strict definition of respondersMcCullough et al. (2008)54Nightly sildenafil improved nocturnal erections versus placebo;nocturnal tumescence data do not necessarily correlate with clinically
usable erectionsMontorsi et al. (2008)628Nightly vardenafil did not have any effect beyond that of on demand useThe evidence for the use of oral agents for penile
rehabilitation is even weaker. In 2005, Mulhall et al. reported in a nonrandomized
study that men who underwent pharmacologic penile rehabilitation following RP
resulted in higher rates of spontaneous functional erections [9]. Men who had
fully functional erections by self-report preoperatively were encouraged to
participate in a penile rehabilitation program for at least 12 months following
surgery. Patients who decided to participate constituted the rehabilitation
group, while those who decided not to participate but presented for follow-up
for periodic evaluation of their erectile function constituted the
nonrehabilitation group. There were 58 men in the rehabilitation group and 74
in the nonrehabilitation group, but no placebo arm. This study had a strong
patient selection bias, as patients were allowed to select treatment or
observation. In addition, only men who completed 18 months of therapy were
included, meaning that men who dropped out due to lack of efficacy were not
part of the analysis.The benefit induced by a PDE-V inhibitor
rehabilitation approach compared to an on demand PDE-V administration has not
been confirmed. In a follow-up to their first study [1], Montorsi et al.
prospectively studied a cohort of 80 patients submitted to bilateral NSRRP with
adequate erectile function data 12 months after surgery, as presented in their
abstract at the 2006 annual meeting of the American Urological Association
[10]. Patients were assigned to four
different groups: no erectile therapy,
intracavernosal injection of prostaglandin E-1 on demand, PDE-V inhibitor on
demand, and PDE-V inhibitor therapy either daily or every other day for 3
months. No significant difference was found in the mean IIEF score between
patients treated with daily therapy versus on demand therapy.Bannowsky et al. from Germany reported in 2008 their
findings of low-dose sildenafil for rehabilitating erectile function after
nerve-sparing RP [11]. Twenty-three men with preserved erectile function based
on Rigiscan testing 1-2 weeks
postoperatively received sildenafil 25 mg nightly versus 18 men who received
placebo for 52 weeks. There was a significant difference in IIEF-5 score and
time of recovery of erectile function between the groups (P<.001),
with potency rates of 86% versus 66%. The authors concluded that in cases of
early penile erection, daily low-dose sildenafil leads to a significant
improvement in the recovery of erectile function. However, the limitations to
this study are that it was performed at a single center and 95% of patients had
nocturnal erections following catheter removal, which is not typical.Padma-Nathan et al. performed the first randomized,
placebo-controlled trial of chronic PDE-V inhibitor therapy for the purposes of
penile rehabilitation and presented their findings at the 2003 American
Urological Association annual meeting [12]. They concluded that nightly
administration of sildenafil for 9 months following nerve-sparing radical
retropubic prostatectomy (NSRRP) increased the return of spontaneous erections
compared with placebo. However, this study has been criticized for the
seemingly low percentage (4%) of men considered responders in the placebo arm.
Additionally, the criteria for being considered a responder were stringent, as
responders were defined as those having a combined score of >8 for IIEF Q3
and 4 and positive response to the question “Over the past 4 weeks, have your
erections been good enough for satisfactory sexual activity?” [13] The findings
of this study were recently published in the International Journal of Impotence
Research [14].A subset of these men had
nocturnal penile tumescence and rigidity (NPTR) testing performed
preoperatively and at various time points postoperatively [15]. The authors
concluded that nightly sildenafil objectively improved nocturnal erections
versus placebo.The limitation of this study is that while being suggestive, nocturnal tumescence data interpretation does not
necessarily correlate with return of clinically usable erections.In contrast, in the largest randomized, double-blind, double-dummy, multicenter, parallel study done to date, Montorsi et al. recently reported on a vardenafil trial after bilateral nerve-sparing RP [16]. A total of 628 men were randomized to placebo, nightly vardenafil, or on demand vardenafil for 9 months, followed by a 2-month washout period, and an optional 2-month open-label period. The results clearly show that nightly dosing with vardenafil did not have any effect beyond that of on demand use. Following washout, IIEF-EF scores ≥22 were achieved in 28.9%, 24.1%, and 29.1% of patients for placebo, vardenafil nightly, and vardenafil on demand groups, respectively, showing no statistically significant difference among the groups. Mean per-patient success rates for intercourse completion were not significantly different among treatment groups either. While on demand dosing was efficacious, nightly vardenafil for the purpose of penile rehabilitation was not efficacious. This well-designed study provides a cautionary note for the present enthusiasm of oral PDE-V inhibitors for penile rehabilitation therapy. The authors concluded that: “the finding that on demand dosing is more effective in improving both erectile function and sexual intercourse completion rates within this patient population prompts reconsideration of the current practice of prescribing nightly PDE5 inhibitor therapy, as on demand use of vardenafil if equally effective in men with ED following NSRP.”Point-counterpoint debates have become common
regarding the efficacy of penile rehabilitation following RP. In one such example, Abraham Morgentaler
from Harvard University listed several intriguing arguments [17]. First, he
questioned the theory that penile rehabilitation helps to reverse the chronic
hypoxia and ischemia of the flaccid penis following RP. “But why is there reason
to suspect that the flaccid penis is hypoxic, despite having venous oxygen
tension? After all, the endothelium of all venous structures suffers no ill
effects despite a lifetime of exposure to oxygen levels that are well below
those seen in arterial blood. Second,
there is no reason to believe that the penis is ischemic following RP. If it were ischemic, would it not eventually
become necrotic? Furthermore, PDE-V
inhibitors do not increase blood flow to the flaccid penis, so how can benefit
occur?”Similarly, in a more recent point-counterpoint
debate at the 2008 AUA Annual Meeting in Orlando, Fla, Craig Donatucci
from Duke University was charged with providing the contrary argument as whether penile
rehabilitation was effective after RP. He presented many of the same points listed above, describing the
pitfalls of the clinical trials that have been presented thus far. He stated: “There is not yet enough evidence
to declare penile rehabilitation effective; but I am not sufficiently convinced
of the ineffectiveness of penile rehabilitation to recommend against it. My
opinion is that the benefits of penile rehabilitation are “not proven”; yet it
is currently the standard of care” [18].


## 4. Conclusions

The study of penile rehabilitation is in active
evolution. There are intriguing data supporting the use of penile
rehabilitation in the animal model, but these studies may not translate into
human effect. While many published reports of clinical trials point toward
improved outcomes with active treatment, these studies have significant
limitations. Most recently, the only
large, randomized, placebo-controlled trial to date showed no clear benefit of
rehabilitation with vardenafil versus on demand dosing. In fact, quite the
opposite was shown. Clearly, more randomized, placebo-controlled trials are
needed. Unfortunately, these present
many challenges. First, these trials prove costly with poor long-term
compliance and significant early dropout rates. Second, it cannot be overlooked
that differences in nerve-sparing technique and outcomes between surgeons can
confound interpretation of results. Even
though the benefits of penile rehabilitation are still questionable, the
practice of frequent and chronic administration of PDE-V inhibitors has become
standard of care for many urologists. We suggest proceeding with caution when
encouraging our patients to adhere to a rehabilitation regimen, until more
definitive results are available.



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*Source: 852437-2009-02-25.xml*