This prospective randomized controlled trial (RCT) is designed to provide high level evidence on the efficacy of Low-intensity Extracorporeal Shock Wave Therapy (Li-ESWT) in the treatment of post-Robot-Assisted (RA) Radical Prostatectomy (RP) erectile dysfunction (ED) in addition to PDE5 inhibitors (PDE5i) versus PDE5i alone. Our hypothesis is that early andrological rehabilitation that combines Li-ESWT and PDE5i could lead to faster and better recovery of valid erections for intercourse, with a greater rate of postoperative International Index of Erectile Function-5 (IIEF-5) compared to patients receiving PDE5i alone.

Background / State of Art ED is a common complication after radical prostatectomy, with a prevalence ranging from 40% to 80% of patients 1,2.

This considerable variability depends on the degree (intrafascial vs interfascial) and laterality (unilateral vs bilateral) of nerve sparing performed, as well as the surgical approach.

There is still paucity of high-level evidences in terms of impact of surgical approach on postoperative outcomes after RP. Considering the same surgical approach, technique, surgeon experience, patient age and preoperative erectile function remain the main predictors of postoperative sexual function.

In this context rehabilitation is still debatable and there is a lack of clear recommendations regarding the use of PDE5i and other forms of therapy. However, a multi-centre double blind RCT (n = 423) in men aged < 68 years, with normal pre-treatment erectile function undergoing either open, conventional or robot-assisted laparoscopic nerve-sparing RP, tadalafil (5 mg) once per day improved participants EPIC (Expanded Prostate Cancer Index Composite) sexual domain-scores (least squares mean difference +9.6, 95% CI: 3.1-16.0) when compared to 20 mg 'on demand' or placebo at 9 months of follow-up 3. As a result, there has been a trend toward early use of PDE5i after RP as demonstrated in some studies 4.

Hypothesis and specific aims Hypothesis and Significance The use of nerve-sparing techniques during robotic surgery has been shown to improve recovery of erectile function. However, some patients still experience ED after undergoing bilateral nerve-sparing RARP. Possible causes can be the mechanical stretching or thermal damage to cavernous nerves, ischemic injuries or local inflammation caused by surgery itself 5. Moreover, after surgery this condition could be exacerbated by an increased fibrosis and decreased elasticity of the erectile tissue in the corpora cavernosa.

Current sexual rehabilitation is essentially based on PDE5i which have been shown to increase levels of cyclic GMP in penile smooth muscle cells, preserving smooth muscle content and reducing corpora cavernosa fibrosis 6,7. At the same time, the use of vacuum erection devices, intraurethral suppositories and intracavernous injections do not guarantee an optimal penile rehabilitation after RP 8.

In this scenario, LiESWT has been recently introduced, showing promising results 9,10. It differs from other ED treatments, due to its action on the underlying pathophysiology of ED 11, offering a local remodelling of the erectile tissue 12.

Different types of energies can be used for LiESWT. The electro-hydraulic or electromagnetic generator deliver sound waves directed to the corpora cavernosa and crura, at an energy density of around 0.09 mJ/mm². Another source of energy used for LiESWT is the piezo shockwave therapy. Piezo-ceramic elements are geometrically arranged on a concave surface so that when they are excited simultaneously by a brief, high-voltage pulse, they expand by a few micrometers to generate a pressure pulse. The piezo elements are precisely aligned so that each pressure pulse generated focuses in a specific area. This precise focusing of the pulse creates a shockwave at the point of focus. The piezo shockwave's "direct focusing" technology eliminates the need for additional reflectors, resulting in a compact therapy source design and a precise and well-defined focal zone. The virtually painless therapy is quiet and energy levels can be freely adjusted with almost no adverse effect on the size of the focal zone. Extracorporeal shockwaves are mechanical stressors capable of inducing biochemical changes in living tissue; at a molecular level these changes can influence gene expression in cells and, if used selectively, can produce specific reactions in tissue. This process is referred to as mechanotransduction. The therapy was first tested for vasculogenic ED in 2010 by Vardi et al. due to its potential to promote neovascularization in the myocardium 13,14. LiESWT has also been recognized to increase nitric oxide synthesis in penile tissue and supports stem cell proliferation 15. Multiple meta-analyses suggested that LiESWT is an effective treatment for ED, resulting in an improvement in the erectile function domain scores of IIEF-5, playing a significant role not only in vasculogenic ED (neoangiogenesis) but also in neurogenesis 16,17.

However, despite the promising results, there is still a lack of high-level evidences on the use of LiESWT for ED, especially in the specific setting of postoperative rehabilitation after RP.

Our hypothesis is that LiESWT in addition to PDE5i administration could improve sexual rehabilitation with faster recovery of valid erection and higher IIEF-5 scores in the short and medium-term follow-up.

OBJECTIVES:

Primary Objective

• To investigate the impact of LiESWT in combination with early PDE5i administration versus early PDE5i alone on the penile rehabilitation of erectile dysfunction (ED) after RARP.

ED remains a significant issue after radical prostatectomy, with some of the most reliable data on patient-reported outcome measures (PROMs), including erectile function, coming from the Prostate Testing for Cancer and Treatment (ProtecT) trial. The worst trend over time was observed in the RP group, with only 21% of patients reporting erections firm enough for intercourse after 3 years, and 17% after 6 years 18. However, data regarding optimal postoperative rehabilitation of ED are still limited. The International Index of Erectile Function short form (IIEF-5) questionnaire is the recognized tool for evaluating erectile function both preoperatively and during follow-up.

The primary endpoint of this study is to determine if the difference in the final mean IIEF-5 score at last follow-up, favours the use of LiESWT in combination with PDE5i compared to early PDE5i alone for penile rehabilitation after RARP, with a minimum clinically important difference (MCID) of at least 4 points 19.

Secondary Objectives

• To compare the rate of patients who achieve orgasm and their erectile hardness score (EHS) at the final follow-up.
• To evaluate the impact of LiESWT on continence status.
• To report any adverse effects and classify them according to the Clavien Dindo classification 20.
• To compare health-related quality of life (HRQoL) outcomes at 3-, 6- and 12-months (mo) follow-up post-surgery.

Subgroup analysis An exploratory subgroup analysis will be conducted to evaluate the efficacy of LiESWT for the treatment of ED also in patients at intermediate risk PCa and in patients undergoing radical cystectomy.

STUDY DESIGN Prospective randomized controlled trial (RCT) designed to provide high level evidences describing the role of LiESWT plus early introduction of PDE5i vs early PDE5i alone on penile rehabilitation of ED after RARP.

STUDY POPULATION

Inclusion criteria:

• Patients aged ≤75 yrs;
• PSA <10 ng/mL
• Prostate Cancer ISUP grade ≤2 and cT≤2 at prostate biopsy
• undergoing nerve sparing RARP;
• preoperative IIEF-5 score ≥ 17;
• First PSA (45d after surgery) <0.1
• Prostate Cancer ISUP grade ≤2 pT<3b and at final pathology
• ≥ 18 yrs old;
• compliants patients able to follow the study protocol and fill in IIEF-5 scores and EORTC quality of life questionnaires;
• patients able to provide a written informed consent for the trial.

Exclusion criteria:

• anaesthesiologic contraindications to robotic surgery
• patients submitted to pelvic radiotherapy or androgen deprivation
• patients reporting major postoperative complications (CD≥3)
• cardiovascular contraindications to PDE5i medical treatment

Methodologies All patients for whom eligibility criteria have been verified will be enrolled and randomized by the Promoter.

Then, patients will be randomized into:

• GROUP 1 (LiESWT + PDE5i): LiESWT plus early introduction of PDE5i
• GROUP 2 (PDE5i alone): control group, PDE5i alone with on a covariate adaptive randomization process based on the following variables: Age (≥ 65 vs < 65), BMI (≥ 30 vs <30), ASA score (1-2 vs 3-4) and preoperative IIEF-5 (17-21 vs 22-25).

Patients were allocated 1:1 in each group. RARP will be performed according to EAU guidelines 21.

ASSESSMENTS Both arms will start tadalafil at a dose of 5mg/day right after the removal of the transurethral catheter, which occurs between the 7th and 10th postoperative days. All patients will receive 5 mg tadalafil tablets (7 per week), which will be dispensed weekly at each follow-up visit. Patients will be monitored for continence status (measured by pads/days), sexual function (IIEF-5 and EHS scores), and possible adverse events.

Forty-five days (45d) after surgery, the first measure of PSA will be performed.

If PSA results <0.2 ng/ml patients will be randomized. The LiESWT (6-week period) will begin one week after PSA evaluation (52d after surgery). LiESWT will be performed with PiezoWave2 from Richard Wolf and ELvation® Medical. In a single session 12,000 shocks with an energy flux density of 0.16 mJ/mm2 will be applied (4,000 over the crura of the penis and 8,000 to the penil shaft). The penis is placed in a dedicated penile holder, stretched, and shockwaves are administered with a linear therapy source (applicator) using the linear shockwave tissue coverage (LSTC-ED®) technique which makes it possible to administer shockwaves homogenously to all of the erectile tissue. Specific adverse effects that could be related to LiESWT, such as hematomas, local pain, and neuropraxia, will be assessed, classified, and recorded. Therefore, at the last follow-up, 94 days after surgery (3mo after surgery) the final IIEF-5 and EHS scores will be assessed. Afterwards, IIEF-5 and EHS scores will be collected 6 and 12 mo after surgery.

After 1 yr from surgery both groups will be asked to stop PDE5i for 2 weeks (washout period) and then IIEF-5 and EHS score will be collected without PDE5i treatment.

Each treatment will be performed in accordance with the most recent scientific evidence and European guidelines, according to oncologic departments; adverse events will be managed according to normal clinical practice.

Erectile function and HRQoL assessment Erectile function will be assessed using IIEF-5 and EHS scores, pre- and postoperatively. HRQoL will be tested before surgery and at 3-, 6- and 12-months (mo) follow-up evaluation through a self-administered validated questionnaire (EORTC-QLQ-C30 and QLQ-BLM30).

CLINICAL DATA

The following data will be collected and analysed for each patient:

• demographic data (gender, age, etc.)
• clinical and pathologic data [BMI, ASA score, haemoglobin, clinical and pathologic TNM stage, renal function (eGFR)]
• HRQoL and erectile function data

SAMPLE SIZE AND STATISTICAL CONSIDERATION According to previous studies, 4-points of difference between the final IIEF-5 means is the minimal clinically important difference (MCID) in the EF domain of the IIEF-5 scale 19. Therefore, considering a standard deviation of 9 (calculated on a previous pilot study), a power of 0.80 and α (2-sided) of 0.05, a sample size of 158 patients (79 for each cohort) is needed to test our hypothesis.

The continuous data as mean and standard deviation or median and range will be reported. Binary data will be reported as frequency and percentage values. ANOVA with repeated measures will be used for estimate primary endpoint. Student's paired t-test will be used to compare mean values, when appropriate. A p-value ≤ 0.05 will be considered statistically significant. The statistical analysis program SPSS V21 (SPSS Inc., Chicago, IL) will be used.

RANDOMIZATION Participants will be randomly assigned to group 1 or 2, based on a computer-generated randomization schedule prepared before the study by the Promoter.

Randomization is centralized and will be generated by an independent group of the promoter.

Inclusion Criteria:

• Patients aged ≤75 yrs;
• PSA <10 ng/mL
• Prostate Cancer ISUP grade ≤2 and cT≤2 at prostate biopsy
• undergoing nerve sparing RARP;
• preoperative IIEF-5 score ≥ 17;
• First PSA (45d after surgery) <0.1
• Prostate Cancer ISUP grade ≤2 pT<3b and at final pathology
• ≥ 18 yrs old;
• compliants patients able to follow the study protocol and fill in IIEF-5 scores and EORTC quality of life questionnaires;
• patients able to provide a written informed consent for the trial.

Exclusion Criteria:

• anaesthesiologic contraindications to robotic surgery
• patients submitted to pelvic radiotherapy or androgen deprivation
• patients reporting major postoperative complications (CD≥3)
• cardiovascular contraindications to PDE5i medical treatment