Penile rehabilitation after prostate cancer treatment: Unresolved issue

Non medical therapies: optional for rehabilitation?

Ilan Gruenwald, Israel

The neuro-urology unit, Rambam Medical Center

Mechanisms involved in Post Radical ED

Apoptosis Corporal smooth muscle fibrosis

Vasculogenic

transection of the accessory pudendal arteries

- Poor smooth muscle relaxation. - Dysfunction of the venocclusive mechanism - Decrease in stretched penile length

Lack of tissue oxygenation-hypoxia

Long term ED

Neurogenic

cavernous nerve interruption, traction and/or dissection

What are the non-pharmacological options that could potentially delay or minimize these mechanisms?

Seems to be critical to the recovery and maintenance of

spontaneous penile erections after nerve-sparing radical prostatectomy.

Early intervention-

Vacum Erection Device (VED)

• According to an AUA survey, in 2011 it has been the second most commonly used method for penile rehabilitation after RP

• Recent studies with the use of a unique animal model and a newly designed VED for rats clarified that VED therapy preserves erectile function through antihypoxic, antiapoptotic and antifibrotic mechanisms by improving the arterial blood flow into the penis

• Welliver et al. confirmed that VED improves penile overall oxygen saturation, by showing increased oximetry measurement in the glans and the corporae.

• Thus, VED could potentially inhibit apoptosis and prevent cavernous tissue fibrosis.

Lin et al. 2013; Yuan et al. 2009, 2010a, 2010b

VED gained popularity in recent years

- Low complication rates

- Few side-effects

- Cost-effective

- Ensures multiple erections on a daily basis

- Can be used early in the penile rehabilitation period

- Has the potential to prevent early penile hypoxia

- It's mechanism that leads to erections works independently to the neural pathway and thus overcomes problems generated by neuropraxia.

VED can be used safely with other treatment modalities to achieve better erectile function results.

Studies on VED for post RP penile rehabilitation

• 28 men with IIEF scores of >11: Early daily VED use- (1m post RP).

Late on-demand VED prior to intercourse- (6m post RP).

• They found that men who had completed early VED use had significantly greater IIEF scores and a longer stretched penile length (2 cm) compared to the late on-demand group.

• However, at last follow-up (mean 9.5m) there was no significant difference in outcome, and none of the patients reported unassisted erections sufficient for intercourse.

Another prospective clinical trial of 109 men randomized into using daily VED vs no treatment.

After 9 months, 80% of those using VED had erections sufficient for intercourse and were less likely to report penile shrinkage (85% vs 23%, respectively).

Köhler et al. Raina et al. ]

long-term effects in erectile function after RP using VED+ PDE5i

Long-term prospective study :

Early use of VED alone or in combination with another ED treatment modality.

141 post RP initiated early penile rehabilitation. At 1 and 5-year follow-up, 80% and 62% of men, respectively, were sexually active.

After 5 years, 71% of sexually active men had natural erections sufficient for penetration without assistance.

These studies recognize VED as a valuable treatment in penile rehabilitation.

VED has an important role at least as an adjunct to oral therapy.

[37, Raina et al. [38

The neural pathway regeneration is crucial for successful penile rehabilitation.

There is a need to deeper investigate the effect of VED, and for longer rehabilitation periods

Penile Vibratory Stimulation (PVS)

• 68 patients were randomized into using PVS+PDE5is vs PDE5is only .

• They were instructed to stimulate the frenulum once daily for at least 1-week before

surgery and after catheter removal for a period of 6 weeks.

• IIEF scores were evaluated at 3, 6, and 12m after surgery.

• Results showed that IIEF scores were higher in the PVS group at all times.

• At 12m, 53% reached a score of at least 18, vs to 32% in PDE5I only group (P = 0.07).

[Sonksen J

• PVS stimulates branches of the pudendal nerves along the penile shaft.

• The stimulation of nerve terminal endings activates a reflex parasympathetic erection -

release of NO -activation of the cGMP /cAMP cycles -cavernosal smooth muscle dilation

and penile engorgement.

Penile Vibratory Stimulation (PVS)

[Sonksen J

• This study showed that PVS is both acceptable and tolerable for patients.

• Most importantly, it also pioneers the use of PVS as an agent in ED after nerve-sparing RP.

Low-Intensity Shockwave Treatment (LI-ESWT):

low-intensity extracorporeal shockwave

Human clinical studies have seen:

• High tolerability

• High safety

• Good clinical effect

• The overall satisfaction, ability to penetrate, and mean IIEF-EF scores of patients in the treatment group were significantly higher than those in the control group.

• Penile hemodynamics also revealed a significantly improved resting and maximal postischemic penile blood flow in LI-ESWT participants.

• These studies demonstrate that LI-ESWT may potentially serve as an adjunct to penile rehabilitation.

Human data have preceded the generation of basic science data.

low-intensity extracorporeal shockwave

• Shockwaves applied to the targeted tissue cause mechanical stress and micro-trauma that catalyze a set of biological reactions resulting in neovascularization of the tissue.

• In www.clinicaltrials.gov , 21 studies are listed on LI-ESWT but only 4 are active (NCT02412345, CT02152683, NCT02422277-mansoura, NCT02304679)

ED 1000

Does LI-ESWT have an effect after Radical Prostatectomy ?

• Patients with mild to severe postoperative ED who had undergone robot-assisted BNSRP more than a year ago

• No preoperative ED (median IIEF-5 score was 25)

• 15 patients, mean age 62y, 24m median time since surgery (range 12 to 54m).

• 6 treatments-2 sessions every other week- duration 6w, Duolith SD1 T-Top device (Storz), higher energy densities (20, 15 and 12 mj/mm2)

• IIEF-EF 5 item evaluation was done 1m and 1y post treatment on 15 patients

LI-ESWT in the treatment of post RP ED:a pilot. Frey A, Sønksen J, Fode M.

• The median preoperative IIEF-5 score was 25 • The median baseline IIEF-5 score was 9.5 • The median change in IIEF-5 scores was +3.5 at t1 (p = 0.0049) and +1 at t2 (p = 0.046) No severe side-effects were reported

Results

Our pooled data from 31 post RP patients

• 15 Patients as Pilot, 16 Patients in RCT.

•At least one year from RP surgery.

• Median age: 63.2 (27-78)

• Diabetes mellitus: 6 pts. (20%)

• Cardiovascular disease: 6 pts. (20%)

• Mean IIEF-EF = 8.83 (±2.53) : Severe ED

Method:

• All were under PDE5i therapy at V1 and FU1

• All underwent 12 shockwave sessions (Full treatment)

• Success was defined according to MCID criteria(1) for Δ IIEF-EF domain score

-Mild ED - Δ 2 points

-Mod. ED - Δ 5 points

-Severe ED - Δ 7 points

• Erectile Hardness Score (EHS)

• Flow Mediated Dilatation Test (FMD)

(1) RC Rosen, KR Allen, X Ni, AB Araujo. Minimal Clinically Important Differences in the Erectile Function Domain of the International Index of Erectile Function Scale. Euro Urol 2011, 60 (5): 1010-6

Results at one month follow-up

• IIEF-EF increased from mean 8.83±2.53 to 9.83±4.04 (p=0.06)

• EHS increased from 1.06±0.96 to 1.41±0.96 (NS)

• FMD (AUC) increased from 308.1±185.1 to 489.1±408.76 (p=0.0031)

• No side effects were registered

Four patients who received a total of 24-sessions:

3/4 succeeded in achieving an increase in IIEF-EF≥5 and EHS≥3

A rehabilitation protocol is needed: Early intervention Longer treatment course of LI-ESWT

What lies in the future for non-medical RP penile rehabilitation?

All are investigative :

• Impulse magnetic field therapy (PMT)

• affecting the cells’ water content, oxygen uptake (shafik, 40 men, full erections)

• Tissue engineering: Engineering a biological substitute to replace injured, diseased or malfunctioning organs (in rabbits)

• Nanoparticles

• Implanted drug delivery device

• Platelet-Rich Plasma (PRP) (three studies in China and Taiwan-rats)

An exciting future of technological options are just around the corner

Good communication with the patient and expectation management are crucial for future compliance and satisfaction with any rehabilitation program.