Rehab of the Penis Post-Prostatectomy -The Hopkins Experience

Arthur L. (Bud) Burnett, M.D., M.B.A., F.A.C.S.Patrick C. Walsh Distinguished Professor of Urology

The James Buchanan Brady Urological InstituteJohns Hopkins Medicine

Baltimore, Maryland

Disclosure Statement: In accordance with ACGME policy on relevant financial disclosure, I disclose financial relationships with the following entities: Boston Scientific, Coloplast, National Institutes of Health, Novartis Pharmaceuticals

Objectives

To present the rationale for invoking therapeutic strategies for enhancing erectile function recovery after radical prostatectomyTo assess possible therapeutic strategies for this purpose (targeting cavernous nerve function)To identify requirements and future possibilities for penile rehabilitation success

Radical Prostatectomy and ED

Surgery offers excellent long-term rates of cancer control1

ED is a historically known significant complication of the surgeryCavernous nerve-sparing techniques have reduced ED to 15-40%2

Other morbidities largely controlled today

1. Bill-Axelson A et al. N Engl J Med 352:1977, 2005.

2. Burnett AL. JAMA 293:2648, 2005.

“If it were possible to cure prostate cancer with surgery with few or no side effects there would be less debate on how patients

should be treated.”

Neuropathy despite Nerve-Sparing:Putative Mechanisms

Nerve tissue severanceNerve stretchingThermal damage to nervesIschemic effects involving nerve tissueNerve inflammation

Burnett AL, Urology 61: 491-7, 2003.

Possible Mechanisms for Erection Loss after Radical Prostatectomy

Surgical TraumaNeural injury Vascular injury

Psychosocial FactorsDepression, anxiety Relationship circumstances

Health Co-morbidities Cardiovascular disease states Age

Basic Concepts for Preserving Sexual Function

Minimize dysfunctionTreat EDPromote EF recovery Rehabilitation, e.g., ED interventions by

protocol Protection, e.g., neuro/vasculoprotective

therapies Reconstitution, e.g., nerve regeneration, tissue

reconstruction

PDE5 Inhibitor Therapy for Erection Recoveryafter Radical Prostatectomy

Postoperative nightly administration of sildenafil citrate trial (Padma-Nathan H et al. IJIR 2008; 20:479-86)

– Increased recovery of erections (IIEF, Q3/4≥8, ≥10 min of 55% base rigidity) at 12 months in 14 of 51 (27%) patients on sildenafil vs. 1 of 25 (4%) patients on placebo (p<0.05)

– Potential benefitREINVENT: nightly versus on demand vardenafil trial (Montorsi F et al. Eur Urol 2008; 54:924-31)

– No difference in IIEF-EF Domain Score ≥22 (~40%) or SEP 3 success rates (~50%) after washout or open-label periods between vardenafil groups and placebo group

– Sustained and sufficient benefit unclearREACTT: daily (5mg) versus on demand (20mg) versus placebo tadalafil trial (Montorsi F et al. Eur Urol 2014; 65: 5887-96)

– No difference in IIEF-EF Domain Score ≥22 (~20%) after washout between groups, but penile length loss was reduced in the tadalafil once daily group after double-blind treatment (p<0.05)

– Potential benefitNightly versus on demand sildenafil trial (Pavlovich CP et al. BJU Int 2013; 112: 844-51)

– No difference in IIEF-EF Scores after washout between groups– Chronic nightly sildenafil not supported

Sexual Rehabilitation after Treatment for Prostate Cancer:Fourth International Consultationfor Sexual Medicine (ICSM 2015)1

Recommendation 7: Data are conflicting as to whether penile rehabilitation with phosphodiesterase type 5 inhibitors improves recovery of spontaneous erections (LE=1, GR=A)

Recommendation 8: Data are inadequate to support any specific regimen as optimal for penile rehabilitation (LE=3, GR=C)

1. Salonia, A., et al. J. Sex Med 14: 285-96, 20172. Philippou YA et al. Cochrane Database Syst Rev 10: CD012414, 2018

Clinical Dilemma:How To Proceed

What can be offered (that works)?

How can we meet patient expectations?

Although we understand (some aspects of) the pathophysiology and clinical/psychosocial ramifications of the problem, we are currently faced with unproven strategies (lack of level 1 evidence-based medicine).

Post-Radical ProstatectomySexual Function Management:

What I DoEducation/Set Realistic Expectations– Natural history of sexual function recovery– Patient-specific sexual dysfunction risk factors– Patient goals and motivations

Somatic Intervention – “individualized”– Patient health fitness– On-demand treatments vs. definitive management– Rehabilitation options (PDE5i, statins, ARBs, erythropoietin)

Coaching/Counseling– Monitoring and follow-up visits (3,6,12, 18, 24 months)

– Psychosexual therapy ?

Clinical trials (erythropoietin, Viberect)

Clinical Trial Investigation

Immunophilin ligandsNo benefit in erectile function recovery

CorticosteroidsNo benefit in erectile function recovery

Stem cells Clinical trials in progress

Nerve Injury and Recovery

Chemical effect: elevation of intracellular calcium levels and overexcitation/generation of free radicals.Schwann cell activation: production of extracellular matrix components, axon remyelination, neurotrophin release.Neurotrophin actions: interaction with cellular receptors, causing trophic (neurite outgrowth) and tropic (neurite directionality).

Burnett AL. J Urol 170: S31-S34, 2003.

Genome Microarray of the Major Pelvic Ganglion after Cavernous Nerve Injury

Rat model of cavernous nerve injuryGlobal gene expression in the MPG 48h and 14d laterFindings: Early mobilization of genes involved in repair and

neuroprotection mechanisms (SERPINF1, IGF1, PLAU(PLAUR, ARG1) Changes in genes related to nervous system

development (ATF3, GJA1, PLAU, SERPINE1), nerve regeneration (SERPINE2, IGF1, ATF3, ARG1), and synaptic transmission (GJC1, GAL)

Calenda G et al. BJU Int 2012; 109: 1552-64

Strategies for Mechanism-Based Neuroprotection

Anti-inflammatory agentsSteroids (glucocorticoids, 21-aminosteroids)Sex steroids (estrogen, testosterone)Cyclo-oxygenase-2 inhibitorsMinocyclinePoly (adenosine diphosphate-ribose) polymerase inhibitor

Anti-oxidantsMelatoninNicotineAcetylcholineα-TocopherolFlavonoids (quercetin)Thioredoxin

Immune modulatorsImmunophilin ligandsMonoclonal antibodies

Ischemia counteractive agentsNimodipineDopamineAtropineAngiotensin receptor antagonists

Anti-excitotoxicity agentsGangliosidesOpiate blockersThyrotropin-releasing hormoneGlutamate receptor-selective drugs

Ionic/membrane stabilizersCalcium channel blockersSodium channel blockersBeta-blockersMitochondrial ATP-sensitive potassium channel activators

Anti-apoptotic agentsCalpain antagonistsCaspase inactivatorsErythropoietin

Burnett AL. Neuromodulatory Drugs for the Radical Prostatectomy Patient,In: Mulhall JP (Ed) Sexual Function in the Prostate Cancer Patient, 2009.

Strategies for Mechanism-Based Nerve Regeneration

Neurotrophic factorsClassic neurotrophins

Nerve growth factorBrain-derived neurotrophic factorNeurotrophin-3, neurotrophin-4Acidic fibroblast growth factor

Neuropeptide growth factorsBombesinNeurotensin

Atypical neurotrophic factorsGrowth hormoneNeurturinSonic hedgehog proteinErythropoietinVascular endothelial growth factor

Axonal outgrowth inhibitory neutralizersInhibitory myelin protein antagonistsMyelin-reactive T-lymphocyte vaccinesActivated autologous macrophagesRho-kinase pathway antagonistsPhosphodiesterase inhibitorsNitric oxide donorsChondroitinase

Axonal reconstructive substancesFusogens (polyethylene glycol)Nerve guides

Tissue engineering/stem cell therapyNon-glial cells (neurons, fibroblasts)Glial cells (Schwann cells, macrophages)Stem/progenitor cellsGenetically modified cellsTissues (peripheral nerves, omentum)

Nerve stimulationElectricalOpticalMechanical (low-intensity shockwave)

Burnett AL. Neuromodulatory Drugs for the Radical Prostatectomy Patient,In: Mulhall JP (Ed) Sexual Function in the Prostate Cancer Patient, 2009.

S. Bartesaghi et al. / Neuro Toxicology 26 (2005) 923-928.

Intracellular Signaling After Erythropoietin Receptor Activation

Erythropoietin to Enhance Erection Recoveryin Men following Radical Prostatectomy:

The ERECT Clinical TrialDouble-blind, prospective, phase II randomized, controlled trial (NCT 00737893)

Enrolled 56 potent patients receiving BNS-RP (robotic and open), treated with EPO (20,000 IU sc) or placebo day prior, day of, and day after surgery (1:1 group assignments)

Mean IIEF-EF scores at 6 mo (primary endpoint) as well as 3, 9 and 12 mo intervals were comparable between groups

H. Patel et al (unpublished), 2019.

Objective: To develop and evaluate a neurostimulation system for cavernous nerve electrical stimulation for future use as a chronic implantation device that neurotrophically promotes erectile function recovery after radical prostatectomyMethod: Temporary placement of electrode array and stimulation (20 Hz, 260 μ sec, 5-60 mA), and measurement of penile circumference in 12 menResults: Penile circumference increases demonstrated in 6 of 12 men; array placed with ease and no evidence of neurovascular bundle injury

J Sex Med 5: 1949-54, 2008

Objective: To develop a 2-dimensional flexible electrode array that can cover the entire cavernous nerve/pelvic plexus areaMethod: Temporary placement of electrode array (12 Hz, 1 ms, 7-10v, 6 mA), and measurement of penile circumference in 24 men at open radical prostatectomyResults: Penile circumference increases demonstrated in 18 of 24 men

J Sex Med 2018; 15:1558-69

Local Electrostimulation of Injured Cavernous Nerve Improves Erectile Function Recovery

in a Rat Model of Neurogenic Erectile DysfunctionBipolar implantable electrode placed at cavernous nerve injured site (hemostatic clamp crush)Treatment: Low intensity electrical stimulation (3V intensity, 0.1 ms pulse duration, 12Hz frequency) for 1hr per day for 7 days

M. Sturny, S. Karakus, R. Fraga-Silva, N. Stergiopulos, A. Burnett, 2018

Future DirectionsPharmacotherapy- Testosterone - Erythropoietin Nerve guides- Biological scaffoldsElectrical nerve stimulation- Implantable neurostimulatorTissue engineering/stem cell therapyGene therapy

ConclusionsSexual dysfunction side effects after radical prostatectomy remain a “final frontier” in need of intervention to achieve optimal sexual function quality of life outcomes.Autonomic nerve functional reconstitution for promoting recovery of erectile function post-operatively must continue to be elucidated and evaluated.Despite surgical modifications, potential therapies of the future promise ways to achieve optimal functional outcomes following radical prostatectomy.