Stesura Seveso


Archivio Italiano di Urologia e Andrologia 2016; 88, 14

ORIGINAL PAPER

Results of tadalafil treatment in patients following 
an open nerve-sparing radical prostatectomy 

Erkan Hirik 1, Aliseydi Bozkurt 1, Mehmet Karabakan 1, Özkan Onuk 2, Mustafa Bahadır Can Balcı 2,
Memduh Aydın 2, Murat Çakan 1, Barış Nuhoğlu 1

1 Erzincan University Mengücek Gazi Education and Research Hospital, Urology Clinic, Turkey;
2 Gaziosmanpaşa Taksim Education and Research Hospital, Urology Clinic, Turkey.

Purpose: To evaluate the effect of post-
operatively administering a low daily dose

of tadalafil on the erectile function of patients who underwent
a nerve-sparing radical prostatectomy(NSRP) due to local-
ized prostate cancer (PCa).
Materials and Methods: Of 138 patients, who underwent
NSRP due to PCa between 2012 and 2014, 55 patients who
had not had pre-operative erectile dysfunction (ED) were
included in the study. The mean age of the patients was 64
(54-72). On the 15th day after surgery, after ultrasound
evaluation, all 55 patients started on a daily dose of 5 mg
tadalafil that was continued for 2.5 months. The erectile
function of patients was evaluated pre-operatively, post-oper-
atively, and at the 3rd and 6th month after surgery using the
International Index of Erectile Function (IIEF-5) test. None of
the patients was treated with hormonal therapy or radiother-
apy before or after surgery. 
Results: Three patients were excluded from the study due to
the adverse effects of tadalafil and two patients elected to dis-
continue the treatment. Of the remaining 50 patients whose
pre-operative erectile function had been found normal, at 3
months after surgery, 36 (72%) had normal erectile function;
of the remaining patients in the study six (12%) presented
with mild, two (4%) with moderate, and six (12%) with
severe ED. Six months after surgery, 35 patients (70%) had
normal erectile function while seven (14%) had mild, three
(6%) moderate and five (10%) severe ED. There was no sta-
tistically significant difference between the results obtained at
the 3rd and 6thmonth follow-up (p > 0.05). Three patients
reported adverse effects with tadalafil including flushes in 2
(3.6%) and a headache in 1 (1.8%).
Conclusions: The administration of a 5 mg post-operative
dose of tadalafil to patients that had undergone a bilateral
NSRP was found to have a positive effect on the recovery and
maintenance of erectile function. However, there is still a
need to investigate a larger series of cases.

KEY WORDS: Radical prostatectomy; Tadalafil; Erectile function.

Submitted 28 July 2015; Accepted 13 October 2015

Summary

No conflict of interest declared.

prostatectomy (RP) is a gold standard treatment for
organ-confined PCa (2). Erectile dysfunction (ED) devel-
oping after an RP (ED) is one of the most significant
problems that affect the quality of life (3). The definition
of anatomic RP and the development of a better under-
standing of the neuroanatomy of prostate in the last 20
years have resulted in a significant improvement in
retaining sexual functions after RP, however, the preva-
lence of post-operative ED is still above 50% (4, 5). To
eliminate the negative outcomes of the treatment for
PCa, ‘ED treatment and penile rehabilitation after RP’ has
become a widely investigated topic in preclinical and
clinical studies (6). Even though the first-line therapy for
ED is phosphodiesterase type 5 (PDE5) inhibitors, there
is still not a standard treatment program. In this study,
we evaluated the safety and effects of a low-dose of post-
operative tadalafil on the erectile functions of patients
who had undergone an NSRP due to localized PCa.

MATERIAL AND METHODS
Of 138 cases that were treated with NSRP due to PCa
between 2012 and 2014, 55 patients, who had not had
pre-operative erectile dysfunction (ED) and had under-
gone a bilateral NSRP, were included in the study. The
erectile function of the patients was evaluated pre-opera-
tively and post-operatively by the International Index of
Erectile Function (IIEF-5) test. An open RP was performed
using the classical technique and nerve-sparing approach.
Following an ultrasound examination on the post-opera-
tive 15th day, all patients were prescribed a daily dose of 5
mg tadalafil to be continued for 10 weeks. The erectile
functions of patients were evaluated at the 3rd and 6th post-
operative month. Potency was defined as the ability to
achieve unassisted sexual intercourse through vaginal pen-
etration. None of the patients received hormone therapy
or radiotherapy before or after surgery. In addition, to
exclude the possibility of androgen insensitivity syn-
drome, the pre-operative serum total testosterone and
body mass index (BMI) of the patients were measured.

RESULTS
The mean age of patients was 64 years (54-72) and the
mean BMI was calculated as 24.3 (18.1-33.4). Table 1

DOI: 10.4081/aiua.2016.1.4

INTRODUCTION
Prostate cancer (PCa) is the most frequent type of cancer
in men aged over 50 and the second most common rea-
son for cancer-related deaths (1). For cases in which
there is a life expectancy of more than 10 years, radical

Hirik_Stesura Seveso  08/04/16  11:22  Pagina 4



5Archivio Italiano di Urologia e Andrologia 2016; 88, 1

Results of tadalafil treatment in patients following an open nerve-sparing radical prostatectomy 

presents the demographic information on patients. Of
the 55 patients who had not had ED prior to the opera-
tion and had undergone a bilateral NSRP, three patients
were excluded from the study due to the adverse effect of
tadalafil and two patients discontinued the treatment. Of
the remaining 50 patients whose pre-operative erectile
function was found to be normal, at 3-month post-oper-
ative follow up, 36 (72%) had normal erectile function
while six (12%) presented with mild, two (4%) with
moderate, and six (12%) with severe ED. At 6 month fol-
low up after surgery, 35 patients (70%) had normal erec-
tile function while seven (14%) had mild, three (6%)
moderate and five (10%) severe ED. There was no statis-
tically significant difference between the results obtained
at 3- and 6- month follow-up (p > 0.05). Three patients
reported adverse effects with tadalafil; including flushes
in two (3.6%) and headache in one (1.8%). 

DISCUSSION
Our results show that most patients (72%) who were
treated with 5 mg tadalafil daily following a bilateral
NSRP had normal erectile function at 3-month post-
operative follow up while severe ED was observed in
12% of the patients. Similar results were obtained from
the evaluation at 6-month post-operative follow up.
Considering the 50% prevalence of ED reported in the
literature in patients who received no post-operative
treatment, the results of the current study indicate that
tadalafil treatment after RP contributes to the early recov-
ery of erection and the retention of this function even
after 6 months (24, 25).
The development of ED after RP has been reported to be
the result of an injury to cavernous nerves and pudendal

arteries (11-13). Factors that are known to have an effect
on the post-operative erectile function of patients are
age, pre-operative potency, and surgery with nerve spar-
ing intent. When surgical modalities are compared, no
significant difference has been observed in the preva-
lence of ED between the results of laparoscopic and open
NSRP whereas robotic surgery has been found to pro-
duce much better post-operative results compared to the
other two methods (13).
Most patients who are diagnosed with localized PCa are in
the advanced age group. Diseases that have already devel-
oped or will possibly develop due to old age increase the
process of ED (14). Since after RP it takes a long time to
recover normal erection function there is a need to seek for
a treatment option that will shorten this period. In the lit-
erature, the first study that monitored the results of
patients after NSRP for more than 5 years was conducted
by Zippe et al. This study showed the importance of ED
treatment but it has been commented that the process is
like a marathon race. According to the last report of Zippe
et al. after a follow-up of 6.4 ±1.8 years, only 50% of the
patients were sexually active, and of these patients, only
23% had a natural normal erection function with the
remaining 77% needing oral or other treatments (7).
Many papers have reported on various post RP treat-
ments; for example, PDE5 inhibitors induce cGMP accu-
mulation in corporal smooth muscles resulting in the
relaxation of these muscles. Goldstein et al. (15) reported
a success rate of 43% after the use of PDE5 inhibitors in
patients who had undergone RP. Raina et al. (16) showed
that bilateral NSRP produced better results than unilat-
eral NSRP and other treatments that do not involve the
use of nerve-sparing technique. In experimental studies,
PDE5 inhibitors have been reported to be effective in
preventing ED due to cavernous nerve trauma (17).
Kovanecz et al. investigated the effect of sildenafil on rats
who underwent a cavernosal nerve resection and found
that the treatment group had significantly better intra-
cavernosal pressure/mean arterial pressure (ICP/MAP);
the cell content of smooth muscles and endothelial fac-
tors were retained and apoptosis was reduced; there was
also an improvement in venous leak in the long term
(17). Similarly, studies conducted with vardenafil and
tadalafil reported that the use of these drugs prevent cor-
poral fibrosis, reduce collagen production and retain the
content of smooth muscles (18-20). PDE5 inhibitors
have been found to be effective in recovering and retain-
ing the erectile function in patients after NSRP (21-23).
The use of PDE-5 inhibitors for erection rehabilitation
after RP has recently become a widely discussed topic.
The reason for using these drugs is to make it easy for the
patient in the recovery period to have sexual intercourse,
also, as much as possible, reduce cavernosal hypoxia and
protect the penis from apoptosis and cavernosal fibrosis.
Since these drugs also increase corporal oxygenation,
they will ease night-time erections and protect the basal
functions of corpus cavernosum (8). Raina et al. report-
ed that starting the treatment of PDE5 inhibitors earlier
than 6 months after surgery significantly improves the
response to PDE5, and therefore, the authors suggested
the use of sildenafil post-operatively for a period of 3 to
6 months (9). As the RP-related neuropraxia heals over

Age 64 (54-72)
Body Mass Index (BMI) 24.3 (18.1-33.4)
Comorbidity
DM 8 (16%)
HT 32 (64%)
Hepatitis 3 (6%)
PSA 7.2 (2.5-18)
Biopsy Gleason Score
4-6 31 (62%)
7 17(34%)
8 2 (4%)

Erectile function 3-month post-operative 6-month post-operative 
(n = 50) (n = 50)

Normal 36 (72%) 35 (70%)
Mild ED 6 (12%) 7 (14%)
Moderate ED 2 (4%) 3 (6%)
Severe ED 6 (12%) 5 (10%)

Table 1. 
Demographic information on patients.

Table 2. 
Erectile function after prescribing 5 mg tadalafil daily to
patients without pre-operative ED who underwent
bilateral NSRP.

Hirik_Stesura Seveso  08/04/16  11:22  Pagina 5



Archivio Italiano di Urologia e Andrologia 2016; 88, 1

E. Hirik, A. Bozkurt, M. Karabakan, Ö. Onuk, M. Bahadır Can Balcı, M. Aydın, M. Çakan, B. Nuhoğlu

6

time, cavernosal smooth muscles respond better to PDE5
inhibitors. 
This is due to the increase in the nitric oxide (NO)
released by the nerve that starts to heal. Since recovery is
dependent on time, even when the response to sildenafil
is lower within the first 6 months after surgery, over time
it starts improving (10). Similarly, in the current study,
treatment with a daily 5 mg dose of tadalafil for 10 weeks
was found to be efficient. However, there is a need for
further studies that will comparatively evaluate larger
series of cases over a longer period of time. 

CONCLUSIONS
A 5 mg post-operative dose of tadalafil was found to have
a positive effect on patients that had undergone a bilat-
eral NSRP in terms of the recovery and maintenance of
erectile function. However, there is still a need to con-
duct studies on larger series of cases and including a con-
trol group for comparative purposes.

REFERENCES
1. Landis SH, Murray T, Bolden S, Wingo PA. Canser statistics,
1999, CA Cancer J Clin. 1999; 49:8-31.

2. Partin AW, Mangold LA, Lamm DM, et al. Contemporary update
of prostate cancer staging nomograms (PartinTables) for the new
millennium. Urology. 2001; 58:843-8.

3. Burnett AL, Aus G, Canby-Hagino ED, et al. Erectile function
outcome reporting after clinically localized prostate cancer treat-
ment. J Urol. 2007; 178:597-601.

4. Walsh PC, Donker PJ.Impotence following radical prostatecto-
my:insight into etiology and prevention. J Urol. 1982; 128:492-7.

5. Talcott JA, Rieker P, Propert KJ, Clark JA, et al. Patient-reported
impotence and incontinence after nerve-sparingradical prostatecto-
my. J Natl Cancer Inst. 1997; 89:1117-23.

6. Montorsi F, Briganti A, Salonia A, et al: Current and future strate-
gies for preventing and managing erectile dysfunction following rad-
ical prostatectomy. Eur Urol. , 2004; 45:123-33.

7. Zippe C, Nandipati K, Agarwal A, et al. Sexual dysfunction after
pelvic surgery. Int J Impot Res. 2006; 18:1-18.

8. Montorsi F, Briganti A, Salonia A, et al. Current and future strate-
gies for preventing and managing erectile dysfunction following rad-
ical prostatectomy review. Eur Urol. 2004; 45:123-33.

9. Raina R, Lakin MM, Agarwal A, et al: Efficacy and factors asso-
ciated with successful outcome of sildenafil citrate use for erectile
dysfunction after radical prostatectomy Urology. 2004; 63:960-966.

10. Padma-Nathan H. PDE-5 Inhibitor Therapy for Erectile
Dysfunction Secondary to Nerve-Sparing Radical Retropubic
Prostatectomy. Rev Urol. 2005; 7 (Suppl 2): 33-8.

11. Carrier S, Zvara P, Nunes L, et al. Regeneration of nitric oxide
synthase containing nerves after cavernous nerveneurotomy in the
rat. J Urol. 1995; 153:1722-7.

12. Zippe CD, Pahlajani G. Penile rehabilitation following radical
prostatectomy: role of early intervention and chronic therapy. Urol
ClinNorth Am 2007; 34: 601-18.

13. Akbal C, Simsek F. Radikal prostatektomi sonrası erektil dis-
fonksiyonönlenebilir mi? Cerrahi ve medikal alternatifler var mı?
Üroonkoloji Bülteni 112-6.

14. Martin-Morales A, Sanchez-Cruz JJ, Saenz de Tejada I, et al.
Prevalence and independent risk factors for erectile dysfunction in
Spain: results of theEpidemiologia de la Disfuncion Erectil
Masculina Study. J Urol. 2001; 166:569-75.

15. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in
the treatment of erectile dysfunction. SildenafilStudy Group. N Engl
J Med .1998; 338:1397-404.

16. Raina R, Lakin MM, Agarwal A, et al. Long-term effect of silde-
nafil citrate on erectile dysfunction after radical prostatectomy: 3-
year follow-up. Urology. 2003; 62:110-5.

17. Kovanecz I, Rambhatla A, Ferrini M, et al. Long-term continu-
ous sildenafil treatment ameliorates corporalveno-occlusive dysfunc-
tion (CVOD) induced by cavernosal nerve resection in rats. Int J
Impot Res. 2008; 20:202-12.

18. Ferrini MG, Davila HH, Kovanecz I, et al. Vardenafil prevents
fibrosis and loss of corporal smoothmuscle that occurs after bilater-
al cavernosal nerve resection in therat. Urology. 2006; 68:429-35.

19. Kovanecz I, Rambhatla A, Ferrini MG, et al. Chronic daily tadalafil
prevents the corporal fibrosis and venoocclusive dysfunction that occurs
after cavernosal nerve resection.BJU Int. 2008; 101:203-10.

20. Lysiak JJ, Yang SK, Klausner AP, et al. Tadalafil increases Akt
and extracellular signal-regulated kinase 1/2activation, and pre-
vents apoptotic cell death in the penis followingdenervation. J Urol.
2008; 179:779-85.

21. Nakano Y, Miyake H, Chiba K, Fujisawa M. Impact of penile
rehabilitation with low-dose vardenafil on recovery of erectile func-
tion in Japanese men following nerve-sparing radical prostatectomy.
Asian J Androl. 2014; 16:892-6.

22. Gandaglia G, Gallina A, Suardi N, et al. Preoperative erectile
function is the only predictor of the use of a high number of phos-
phodiesterase type-5 inhibitors after bilateral nerve-sparing radical
prostatectomy.nt J Impot Res. 2014; 26:2014.

23. Cathala N1, Mombet A, Sanchez-Salas R, et al. Evaluation of
erectile function after laparoscopic radical prostatectomy in a single
center. Can J Urol. 2012; 19:6328-35.

24. Stolzenburg JU, Graefen M, Kriegel C, et al. Effect of surgical
approach on erectile function recovery following bilateral nerve-
sparing radical prostatectomy: an evaluation utilising data from a
randomised, double-blind, double-dummy multicentre trial of
tadalafil vs placebo. BJU Int. 2015; 116:241-51.

25. Moncada I1, de Bethencourt FR, Lledó-García E, et al. Effects of
tadalafil once daily or on demand versus placebo on time to recov-
ery of erectile function in patients after bilateral nerve-sparing rad-
ical prostatectomy. World J Urol. 2015; 33:1031-8.

Correspondence
Erkan Hirik
ehirik@gmail.com
Aliseydi Bozkurt                                                         
Mehmet Karabakan
Murat Çakan
Barış Nuhoǧlu 
Erzincan University Mengücek Gazi Education and Research Hospital, 
Urology Clinic, Turkey

Özkan Onuk, 
Mustafa Bahadır Can Balcı, 
Memduh Aydın, 
Gaziosmanpaşa Taksim Education and Research Hospital, Urology Clinic, 
Turkey

Hirik_Stesura Seveso  08/04/16  11:22  Pagina 6