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Scandinavian Journal of Urology
ISSN: 2168-1805 (Print) 2168-1813 (Online) Journal homepage: http://www.tandfonline.com/loi/isju20
Treatment effects of phosphodiesterase-5
inhibitors may improve with time following nervesparing radical prostatectomy
Mikkel Fode, Peter Busch Østergren, Christian Fuglesang S. Jensen, Henrik
Jakobsen & Jens Sønksen
To cite this article: Mikkel Fode, Peter Busch Østergren, Christian Fuglesang S. Jensen, Henrik
Jakobsen & Jens Sønksen (2017): Treatment effects of phosphodiesterase-5 inhibitors may
improve with time following nerve-sparing radical prostatectomy, Scandinavian Journal of Urology,
DOI: 10.1080/21681805.2017.1387603
To link to this article: http://dx.doi.org/10.1080/21681805.2017.1387603
Published online: 23 Oct 2017.
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Download by: [UAE University]
Date: 25 October 2017, At: 12:37
SCANDINAVIAN JOURNAL OF UROLOGY, 2017
https://doi.org/10.1080/21681805.2017.1387603
ORIGINAL ARTICLE
Treatment effects of phosphodiesterase-5 inhibitors may improve with time
following nerve-sparing radical prostatectomy
Mikkel Fode, Peter Busch Østergren, Christian Fuglesang S. Jensen, Henrik Jakobsen and Jens Sønksen
Downloaded by [UAE University] at 12:37 25 October 2017
Department of Urology, Herlev and Gentofte Hospital, Herlev, Denmark
ABSTRACT
ARTICLE HISTORY
Objective: Erectile dysfunction (ED) is common following radical prostatectomies, and phosphodiesterase type 5 inhibitors (PDE5 inhibitors) are generally considered the first choice of treatment. The purpose of this study was to analyze the long-term efficacy of PDE5 inhibitors in a group of men who did
not achieve sufficient erectile function from the medication in the short term following surgery.
Materials and methods: Prospectively collected data from patients with postprostatectomy ED, initial
failure of PDE5-inhibitor treatment at 3 and/or 6 months and at least 12 months’ follow-up were
included. All patients had completed the International Index of Erectile Function short-form questionnaires (IIEF-5) before surgery and at follow-up visits. Response to PDE5 inhibitors was defined as an
IIEF-5 score of at least 17.
Results: The inclusion criteria were fulfilled by 349 patients. At 12 months, 228 patients were still using
PDE5 inhibitors. Of these patients, 92 had undergone bilateral and 120 had undergone unilateral
nerve-sparing radical prostatectomies. Overall, 42 PDE5-inhibitor users (18%) were responders
at 12 months. Bilateral nerve sparing was the only independent predictor of a late response (odds
ratio ¼ 2.9). Thus, 28% of bilaterally nerve-spared patients were responders, while corresponding numbers for unilaterally nerve-spared patients and non-nerve-spared patients were 13% and 6%,
respectively.
Conclusions: Patients who have undergone bilateral nerve-sparing radical prostatectomy should be
rechallenged periodically with PDE5 inhibitors even if the treatment is unsuccessful initially. Unilaterally
nerve-spared patients and especially non-nerve-spared patients are likely to need more aggressive
treatment.
Received 1 June 2017
Revised 21 August 2017
Accepted 23 September 2017
Introduction
Surgical treatment of prostate cancer by radical prostatectomy has been shown to reduce disease-specific mortality
but the treatment often causes erectile dysfunction (ED) [1,2].
It is well accepted that the predominant mechanism is damage to the cavernous nerves, either in the form of nerve
resection with the traditional surgical approach, or as temporary neuropraxia with nerve-sparing techniques [3].
However, even with surgical developments and multiple
attempts at penile rehabilitation, ED remains an important
side-effect and warrants active treatment in many patients
[4,5]. Phosphodiesterase type 5 inhibitors (PDE5 inhibitors)
are generally considered the first choice in ED treatment [6].
If this treatment fails, more invasive and inconvenient
options including injection therapy, vacuum erection devices
and intraurethral alprostadil may be necessary. However,
postprostatectomy ED is most pronounced shortly following
surgery and may subsequently improve with time [7,8]. This
is especially the case following nerve-sparing procedures.
Logically, this would result in an improved response to PDE5
inhibitors with time following radical prostatectomy.
However, specific research is lacking in this area. The purpose
CONTACT Mikkel Fode
Denmark
mikkelfode@gmail.com
ß 2017 Acta Chirurgica Scandinavica Society
KEYWORDS
Erectile dysfunction; PDE5
inhibitors; prostate cancer;
radical prostatectomy;
sexual dysfunction
of this study was to analyze the long-term efficacy of PDE5
inhibitors in a group of men who did not achieve sufficient
erectile function from the medication in the short term
following surgery.
Materials and methods
The study used a prospectively collected database of all men
who had undergone radical prostatectomy at Herlev and
Gentofte Hospital between October 1999 and April 2010,
either by open prostatectomy or by a robot-assisted laparoscopic approach. Data were extracted on patient, tumor and
treatment characteristics, and on the abbreviated version of
the International Index of Erectile Function short form questionnaires (IIEF-5) [9] completed both before surgery and at
follow-up visits scheduled 3, 6 and 12 months after surgery.
Likewise, the use of any ED treatments was recorded.
Men without preoperative ED were included if they suffered from moderate to severe postprostatectomy ED with
initial failure of PDE5-inhibitor treatment at 3 and/or
6 months and had at least 12 months of complete follow-up.
Herlev and Gentofte Hospital, Department of Urology, HA54F1, Herlev Ringvej 75, DK-2730, Herlev,
2
M. FODE ET AL.
Table 1. Patient, tumor and treatment characteristics by nerve-sparing status
(percentages rounded to the nearest whole number).
Downloaded by [UAE University] at 12:37 25 October 2017
Unilateral
Bilateral
Non-nerve-sparing nerve-sparing nerve-sparing
n ¼ 39 (11%)
n ¼ 179 (51%) n ¼ 131 (38%)
Age (years)
63 (52–74)
Pathological tumor stage
T2
T3
T4
64 (47–73)
62 (45–74)
21 (54)
17 (43)
1 (3)
122 (68)
56 (31)
1 (1)
111 (85)
15 (11)
5 (4)
Gleason on pathology
6
7
8
9
Missing
7 (18)
24 (62)
5 (13)
3 (8)
0
50 (28)
104 (58)
12 (7)
9 (5)
4
72 (55)
53 (40)
2 (2)
1 (1)
3
D’Amico risk classification
1
2
3
2 (5)
16 (41)
21 (54)
24 (13)
110 (62)
45 (25)
62 (47)
57 (44)
12 (9)
Radical prostatectomy
Open
Robot-assisted
Missing
Preoperative IIEF-5 score
33 (85)
6 (15)
0
19 (17–25)
155 (88)
22 (12)
2
20 (17–25)
102 (78)
29 (22)
0
19 (17–25)
Data are shown as median (range) or n (%).
Response to PDE5 inhibitors was defined as an IIEF-5 score of
at least 17, corresponding to no or only mild ED.
Descriptive statistics were performed to describe the
cohort and to evaluate the number of late PDE5-inhibitor responders. A backward stepwise multivariate logistic regression
analysis was used to identify independent predictors of such
a response. Patient age, type of surgery (robot-assisted versus
open prostatectomy), surgeon, nerve-sparing status and
tumor characteristics were included in the multivariate analysis. Statistical analyses were conducted using SAS version
9.2 (SAS Institute, Cary, NC, USA). The study was approved by
the Danish Data Protection Agency in accordance with
Danish law.
Results
The inclusion criteria were fulfilled by 349 patients, with a
mean age of 65 years (range 45–74 years). Further details
on tumor and treatment characteristics according to nervesparing status are listed in Table 1. At 12 month follow-up,
228 out of 349 patients (65%) were still using PDE5 inhibitors. Of these patients, 92 had undergone bilateral nerve
sparing and 120 had undergone unilateral nerve-sparing. The
remaining 16 had undergone non-nerve-sparing procedures.
Overall, 42 PDE5-inhibitor users (18%) were considered responders at 12 months according to the study definition. The
logistic regression analysis revealed that only bilateral nerve
sparing was an independent predictor of a late response
(odds ratio ¼2.9, 95% confidence interval 1.4–5.8; p ¼ 0.003).
Thus, 26 out of 92 bilaterally nerve-spared patients (28%)
were late responders, while corresponding numbers for unilaterally nerve-spared patients and non-nerve-spared patients
were 16 out of 120 (13%) and one out of 16 (6%), respectively. The results of the multivariate analysis are summarized
in Table 2. Of the 121 patients who had abandoned PDE5
Table 2. Predictors of late phosphodiesterase type 5 inhibitor response by multivariate logistic regression analysis.
Predictive factor
Patient age
Gleason on pathology
Pathological tumor stage
D’Amico risk classification
Surgeon
Radical prostatectomy (robot-assisted vs open)
Nerve-sparing (bilateral vs non-bilateral)
p
0.52
0.94
0.72
0.41
0.82
0.14
0.003
inhibitors at 12 months, 30 patients had switched to other
erectogenic aids, comprising injection therapy (n ¼ 28), a vacuum erection device (n ¼ 1) and intraurethral alprostadil
(n ¼ 1). Twelve patients were potent on injection therapy and
one was potent using the vacuum device. The intraurethral
alprostadil treatment was unsuccessful. Finally, 91 patients
were not using any erectogenic aids at 12 months. Only one
of these patients had an IIEF-5 score >17.
Discussion
This study shows that a substantial number of men who
have undergone a radical prostatectomy and initially experience PDE5-inhibitor failure may benefit from the medication
1 year after surgery. Not surprisingly, the nerve-sparing status was decisive for late response to PDE5 inhibitors. This
can be related to the mechanism of action for the medication, as it only works to improve erections after initial
induction via nitric oxide produced by the cavernous nerves
[10]. Accordingly, a late effect in men who had undergone
less extensive nerve sparing was rare. Although the finding
may seem logical considering the natural history of postprostatectomy erectile function recovery, to the authors’
knowledge, this is the first study to directly document a
late effect of PDE5 inhibitors. The clinical significance of the
finding is that men should be encouraged to try PDE5
inhibitors periodically following nerve-sparing radical prostatectomy even if they have already moved on to other treatments. This is important because the alternatives to PDE5
inhibitors are all more invasive and allow for less spontaneity in sexual activity.
It is noteworthy that the study data were collected in an
era when the use of long-term PDE5 inhibitors, despite lack
of efficacy, was still offered as a part of the department’s
penile rehabilitation program. Since then, accumulating highlevel evidence has discredited this indication [11–13]. This
change in clinical practice is remarkable because it means
that men who initially fail PDE5-inhibitor treatment may have
become less likely to retry the medication later on. Although
long-term spontaneous erectile function is not improved by
long-term continuous treatment, two of these studies indirectly support the present findings. In the first study, 423 men
with no preoperative ED who underwent bilateral nervesparing radical prostatectomy were randomized to nightly
vardenafil, on-demand vardenafil or placebo medication for
9 months [11]. Patients were then evaluated after a 2 month
washout period and no difference in erectile function was
Downloaded by [UAE University] at 12:37 25 October 2017
SCANDINAVIAN JOURNAL OF UROLOGY
found between the three groups. Another assessment
was performed after a subsequent 2 month period with
open-label on-demand vardenafil treatment. While there
were still no significant differences between the groups, the
proportion of PDE5-inhibitor responders rose between 9 and
13 months following surgery for men who had received
active medication throughout the study. The second study
also included 423 men and had a similar design except that
tadalafil was used instead of vardenafil [12]. Here, an increase
in PDE5-inhibitor responders was also seen between 9 and
13 months. Unfortunately, neither of the studies reported the
proportion of short-term PDE5-inhibitor responders.
The main limitation of the present study is the lack of specific data on the type and dosing of PDE5 inhibitors. Thus, it
can be speculated that more men could have been turned
into PDE5-inhibitor responders if everyone had systematically
attempted the maximum dosing. Another limitation is the
relatively low number of patients and events in the groups
of unilaterally nerve-spared patients and non-nerve-spared
patients. However, the nerve-dependent mechanism of action
of the PDE5 inhibitor makes it unlikely that a larger cohort
would have yielded better long-term results. On the contrary,
there is a possibility that the group of PDE5-inhibitor users at
12 months may have contained a high proportion of men
with a relatively good response to the medication. This
means that the data could overestimate the proportion of
late responders. Meanwhile, 82% of users still suffered from
moderate to severe ED and only 30 patients had moved on
to more invasive treatments, which indicates that the results
are likely to be representative for the whole group. This is
supported further by the similarities between the present
results and those of previous studies [11,12]. Finally, this
study lacked data on comorbidities, which could influence
erectile function. The inclusion of such data in future studies
could help to better predict late responders to PDE5
inhibitors.
In conclusion, the effects of PDE5 inhibitors may
improve with time following nerve-sparing radical prostatectomies, probably as a result of improved nerve function.
Patients who have undergone bilateral nerve-sparing radical
prostatectomy should therefore be rechallenged periodically
with PDE5-inhibitor treatment even if the treatment is
unsuccessful initially. With this approach, almost one-third
of these patients may see a satisfactory effect within
1 year. Unilaterally nerve-spared patients and especially
non-nerve-spared patients are likely to need more invasive
treatment.
3
Disclosure statement
The authors report no conflicts of interest.
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