ESSM Newsletter # 40

16 ESSM Today Penile rehabilitation following radical prostatectomy: What do we know so far? by Run Wang and Jonathan Clavell-Hernandez Run Wang, MD, FACS Director of Sexual Medicine University of Texas McGovern Medical School at Houston and MD Anderson Cancer Center Houston, TX 77030, USA run.wang@uth.tmc.edu Jonathan Clavell-Hernandez, MD Medical School at Houston and University of Texas MD Anderson Cancer Center Houston, TX, USA Radical prostatectomy (RP) techniques have improved in the last few decades. 5-year sur- vival rates after treatment for localized prostate cancer are approximately 98% [1]. Despite its efficacy in treating localized prostate cancer, RP has been shown to have a detrimental effect on patient’s erectile function (EF), urinary con- tinence, and hence, the patient’s quality of life and general well-being [2,3]. Many urologists believe that we have maximized our techniques for nerve sparing with current technology. Un- fortunately, overall, the incidence of erectile dysfunction (ED) after RP is still very high and varies between 14% and 90% [3,4 – 6]. We need to look for other modalities to improve recovery of EF after prostatectomy. The concept of penile rehabilitation after RP was proposed in late 1990s. It is based on the understanding of the mechanisms that lead to ED and utilizing different treatment modalities to promote recovery of the male sexual function before and after any insult to the penile erectile physiologic axis [3,7]. It is believed that neu- ropraxia, ischemic and hypoxic insults, fibrotic remodeling and apoptosis of erectile cells con- tribute to ED even after meticulous dissection in an attempt to preserve the neurovascular bundle during prostatectomy [3]. Mechanical stretching of cavernous nerves during prostate retraction, thermal injury from electrocautery use, inflam- mation from surgical trauma and nerve ischemia secondary to blood supply damage, all lead to neuropraxia. Studies have shown that even in the most cautious dissection during nerve-sparing RP, neuropraxia can occur, and it may take up to 3 years for these nerves to recover [8 – 10]. Lack of erections associated with neuropraxia following RP can itself set up a cascade of harm- ful processes that negatively affect EF. In 2007, we described the mechanism of how chronic erectile dysfunction promotes hypoxia of the corporeal bodies [8]. Neuropraxia and ligation of the accessory internal pudendal arteries lead to hypoxia and lack of nocturnal erections. This later induces cavernosal fibrosis and transfor- mation of trabecular smooth muscle through collagen, which itself leads to the loss of the veno-occlusive mechanism required to maintain erections. The combination of nerve damage with decreased arterial inflow may exacerbate hypoxia and ultimately result in apoptosis [10]. After understanding these mechanisms, mul- tiple studies have been focused on evaluating ways to increase oxygenation of the cavernosal bodies, decrease tissue fibrosis and apoptosis, and consequently improve EF. Theoretically, the role of penile rehabilitation is to maintain tissue oxygenation and prevent tissue fibrosis until the cavernosal nerves recover from neuropraxia with the return of spontaneous un-assisted tumes- cence. This is done with daily programmed use of any means to stimulate erectile response. The daily phosphodiesterase 5 inhibitors (PDE5i) logi- cally became the first option due to its ease of use and accessibility. Unfortunately, most ran- domized controlled trials (RCTs) in last decade and a recent meta-analysis have established the consensus that daily phosphodiesterase 5 inhibitors (PDE5i) does not improve the recov- ery of spontaneous erections [11 – 13]. Two of these RCTs were the REINVENT and REACTT trials, both conducted by Montorsi’s group. These were multicenter prospective, double-blind, placebo-controlled in which patients with pre- operative good erections were randomized into taking PDE5i after surgery. The REINVENT trial evaluated the use of vardenafil, while REACTT assessed the use of tadalafil. Results of the REINVENT trial did not support nightly vardenafil over on-demand dosing and after a wash-out period, no improvement in IIEF score was noted for either protocol when compared to the placebo group [11]. REACTT found that after 9 months of treatment there was a significant difference in reaching the target IIEF-EF ≥ 22 in the tadalafil once daily group compared to placebo. However, after the drug-free washout period, there was no significant difference in EF between groups with 20.9%, 16.9% and 19.1% of patients reach- ing target IIEF-EF in the tadalafil once daily, on demand and placebo groups, respectively [12]. These previous trials evaluated the use of PDE5i by relying on self-reported outcomes to determine efficacy of therapy. To exclude the subjectivity of response bias, Kim et al [13] con- ducted a study in 2016 to evaluate the effects of PDE5i using a more objective approach with a Rigiscan, in addition to the IIEF-EF score. After randomizing 97 patients into taking daily silde- nafil with on-demand sildenafil or daily placebo with on-demand sildenafil, the group noted no significant difference in EF between treatment groups based on both IIEF-EF domain scores or RigiScan, therefore suggesting that nightly silde- nafil has no benefit over on-demand sildenafil. Other means of rehabilitation are to use non- oral modalities such as intracavernosal injection therapy, intraurethral alprostadil and vacuum- erection devices (VED). As with oral PDE5i, the use of these modalities has also being disap- pointing. A meta-analysis confirmed that ad- ministration of these modalities can increase EF while the treatment is being used, but once the treatment is discontinued, there was no improve- ment in recovery of spontaneous EF [14]. Un- fortunately, it is difficult to obtain good objective judgement from the available evidence due to limitations in the clinical trials. Most trials evalu- ated outcomes at one point (less than 12 – 13 months) which is sub-optimal given that EF has been suggested to take up to 4 years to recover [15]. With these mixed results in clinical studies,