Nicolò Schifano
Università Vita-Salute San Raffaele,
Milan, Italy

Paolo Capogrosso
Università Vita-Salute San Raffaele,
Milan, Italy
Unit of Urology; URI; IRCCS Ospedale
San Raffaele, Milan, Italy

Radical prostatectomy (RP) is still considered the treatment of choice in most cases of clinically localized prostate cancer (PCa), allowing for excellent oncological outcomes¹. Although many advances have been made in both understanding prostate anatomy and in minimally invasive surgery, the occurrence of erectile dysfunction (ED) after RP remains a common adverse event negatively impacting on patients’ quality of life. Current series report postoperative ED rates ranging between 19 and 78 %². This wide variations in the erectile function (EF) outcomes largely depends on different applied definitions of postoperative ED and on differences in the baseline characteristics of included patients.

If we look at data from the Prostate Testing for Cancer and Treatment (ProtecT) trial³⁠ randomizing PCa patients to either RP, active monitoring or radiation therapy, the EF outcomes after surgery are even less encouraging: at baseline, prior to RP, 67 % of men reported levels of erections which were firm enough for intercourse, but in the prostatectomy group at the 6-month follow up this rate fell to 12 %. Erectile function remained worse in the prostatectomy group at all time points. Over the last decades, PCa has been more and more often diagnosed at an earlier stage⁴; as a consequence patients has been diagnosed at younger ages, hence the increased importance of focusing on post-operative sexual function. Erectile dysfunction after RP is mainly attributed to neurovascular bundle trauma, which cannot be completely avoided even with the best nerve-sparing techniques⁵.

Indeed, ED becomes clinically evident immediately after surgery, owing to a temporary damage of the cavernous nerves called neuropraxia. This results in a reduction of both daily and nightly erections and is associated with persistent levels of cavernous tissue hypoxia⁶. In vitro and in vivo data support the idea that penile hypoxia could prompt collagen accumulation, smooth-muscle apoptosis and fibrosis. All of these could lead to irreversible ED. Conversely, EF may return gradually after surgery, although it can take approximately 2 years or longer⁷and with only a fraction of patients able to recover their baseline EF.

Penile rehabilitation after surgery

Penile rehabilitation has been proposed as a strategy to stimulate the recovery of EF after surgery for PCa. The concept of penile rehabilitation, first suggested by Montorsi et al.8 in the late 1990s, is based on the use of any treatment/management approach aiming at preserving the EF through the improvement of cavernosal oxygenation to both maintain proper endothelial function and prevent smooth-muscle fibrosis. Several treatment protocols have been proposed over time to enhance EF recovery after surgery: the most common approaches of penile rehabilitation include the use of oral phosphodiesterase type 5 inhibitors (PDE5is); vacuum erection device (VED); intra-cavernous injection (ICI) therapy; or a combination of them6. Tal et al.9 analyzed penile rehabilitation practice patterns among American Urological Association (AUA) members and found that penile rehabilitation strategies were adopted in 89 % of cases after RP, with PDE5is being the preferred option, followed by VED and ICI.

Does penile rehabilitation actually work?

Several randomized control studies (RCTs) tried to answer this question by testing the efficacy of different oral PDE5is in promoting the recovery of unassisted erections in men treated with RP. Padma-Nathan et al.10 randomized 76 patients to receive either nightly sildenafil or placebo for 36 weeks after RP. After an 8-week drug-free period they observed better level of unassisted EF among patients treated with sildenafil. However, the encouraging findings of this first trial have not been further replicated: Pavlovich et al.11 comparing nightly vs on-demand sildenafil did not find any significant improvement in terms of unassisted EF recovery after surgery. Similarly, in a double-blind RCT, Montorsi et al.12 reported data assessing the effect of on-demand vs nightly vardenafil 10 mg: after a 2-month drug washout period, EF recovery rates did not significantly improve in either vardenafil group. Likewise in a large RCT13 comparing tadalafil 5 mg once daily vs. on demand vs. placebo, the authors found no EF differences between the two active treatments groups as compared to the the placebo arm, after a 6-week drug-free period. Overall, the investigators concluded that although tadalafil could not “rehabilitate” (i.e. promoting the onset of drug-unassisted EF recovery after RP), on demand dosing could still be considered to maintain the cavernosal tissue integrity levels. Those findings were further confirmed by Mulhall et al.14 showing that early treatment with daily tadalafil had no effect on unassisted EF recovery at 9 months after treatment cessation. Summarizing, although PDE5is can improve post-operative sexual function, the available level 1 data fail to clearly demonstrate an improvement in the chance of recovering spontaneous unassisted erections with PDE5Is treatment after RP. To date, consistent with most influential uro-andrological (AU, AUA, ESSM) guidelines, the advantage of any specific molecule or any penile rehabilitation protocol over the others has not been demonstrated.

Do we have to look backwards?

Intracavernous injection with alprostadil was the first proposed protocol to enhance EF recovery after RP. This treatment has been associated with high and immediate levels of effectiveness, especially in terms of penile hardness. Montorsi et al.8 reported data of 27 post-RP patients who were submitted to intracavernous injections (ICIs) of PGE1, 2-3 times per week. At 6-month follow up, 67 % of treated men showed levels of recovered EF, compared to only 20 % in the control group. Similarly, Mulhall et al.15 showed that performing ICIs 3 times per week after RP could lead to a 52 % return of functional erection at 18 months follow-up as compared to only 19 % in the control group. However, ICIs have been historically associated with low patients compliance: in their series Polito et al.16 observed that out of 430 patients who were offered a protocol of postoperative ICIs for sexual rehabilitation, 157 (36.5 %) refused to enter the protocol, and 18.6 % dropped out of treatment over the first 6 months.

Do we have to look forward?

In light of this data physicians may be more prone to look for novel rehabilitating strategies. Currently, few innovative treatments aimed to improve EF recovery after RP are under investigation in both preclinical and clinical studies.

Low-intensity extracorporeal shock wave therapy (LI-SWT) is a novel treatment modality which facilitates the occurrence of cellular microtrauma, which in turn stimulates the release of angiogenic factors and the eventual neo-vascularization of the treated tissue. Li et al.17 tested the effect and mechanisms of LI-SWT in a rat ED model induced by pelvic neurovascular injury. The authors showed that LI-SWT was able to promote a significant improvement in terms of nerve bundles compared to sham treatment, as assessed with immunofluorence staining of neurofilaments. Moreover an enhanced dedifferentiation and proliferation of Schwann cells in the dorsal nerve of the penis was also observed. In a similar animal model, Wang et al.18 showed that LI-SWT was able to ameliorate the negative functional and histologic effects of severe pelvic neurovascular injury. To date, two clinical studies have investigated the effect of LI-SWT in the post-operative setting. Zewin et al.19 reported data of 128 post nerve-sparing radical cystoprostatectomy subjects. All patients were allocated to one of three groups: LI-SWT; PDE5i; and control. During the follow-up, 16 % more patients in the LI-SWT group showed satisfactory EF recovery levels as compared to the control group. Although the difference was not statistically significant (p=0.14), the finding was still considered of clinical relevance. In a second study, Frey et al.20 reported data of 16 patients with mild to severe ED after 12 months since RP. All patients were treated with a 6-week course of LI-SWT and then re-assessed at 1- and 12-month after treatment with no other erectogenic aids allowed during the study period. Results showed a significant improvement in terms of EF recovery, as assessed with the IIEF-EF. As the authors correctly pointed out, it is possible that even better results could be achieved if the treatment is given at an earlier stage after surgery, thus preventing penile fibrosis.

One of the most promising strategies in post-RP penile rehabilitation setting is represented by the intracavernous injection of bone marrow-mononuclear cells (BM-MNCs). Following a range of preclinical encouraging results, a few phase 1 and 2 clinical trials are currently ongoing21. The BM-MNCs are a heterogeneous population of cells, which include mesenchymal stem cells, endothelial progenitor cells, and haematopoietic stem cells. These progenitor cells may exert anti-apoptotic, neurotrophic, and angiogenic effects. Yiou et al.22 selected 12 post-RP patients with localized PCa and whose ED had proved to be unresponsive to medical treatments. Patients were divided into four groups and were treated with escalating BM-MNC dosages. Compared to baseline levels, a significant improvement in terms of intercourse satisfaction and EF were observed at the 6-month follow up. Interestingly, clinical benefits were also associated with improvement of peak systolic velocity at the level of the cavernous arteries and with increased penile nitric oxide release.

A last and less-investigated novel treatment for restoring EF after RP is the intracavernous treatment with Platelet-rich plasma (PRP). The PRP is autologous blood plasma that contains platelet concentrations exceeding physiological standards by 3-7 times. This is obtained through multiple blood centrifugations. The PRP has been used in many branches of medicine for several decades, including cosmetology, ophthalmology, sports medicine, cardiology, trauma surgery, plastic surgery, tissue engineering, restoration of nerves, and treatment of type 2 diabetes mellitus complications23. Hence, it has been argued that the angiogenic, vasculogenic and regenerative effects of PRP could be useful to treat ED. Matz et al.24 reported data of 17 patients treated with PRP who were assessed with the International Index of Erectile Function (IIEF-5) questionnaire. The IIEF-5 scores improved by an average of 4.14 points after PRP therapy, with minor adverse effects. Despite PRP potential, Epifanova et. al23 recently suggested that the effectiveness of PRP treatment should be interpreted with caution, because of the lack of placebo-controlled studies and of the small sample size of published trials.

Conclusions

Despite the improvements in surgical techniques and post-operative management strategies, ED is still commonly observed after RP. Promising results with novel treatment modalities has been recently reported in both preclinical and small clinical studies. The preliminary findings of LI-SWT, PRP, and BM-MNCs appear exciting. However, available data are currently insufficient to draw definitive conclusions. Further large, placebo-controlled, multicenter trials should be encouraged to overcome the current existing gap in the setting of ED treatment after RP.

References

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