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. Submit your article to this journal Article views: 2 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=isju20 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 . 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 . 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 firstname.lastname@example.org 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)  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 . 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 . 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 . 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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