Casa di Cura Villa Montallegro - Genova Antonio Casarico Polo Urologico Ist. Cl. Pavia e Vigevano – Ist. Cl. Beato Matteo -Vigevano Casa di Cura Villa Montallegro - Genova

Prostatectomia radicale PSA > DIAGNOSI PRECOCE Schroder, Prostate 2000 / Partin J Urol 1994 BASSO STADIO (pT1-2 / pN0 95%) Orozco, Urology 1998 / Soh, J Urol 1997 / Bishoff, Urology 1995 Partin, Urology 1997 / Petros J Urol 1992 GIOVANI – ASINTOMATICI – BUONO STATO DI SALUTE – SESSUALITA’ SODDISFACENTE LUNGA ASPETTATIVA DI VITA (20-30 ANNI) QUALITA’ DELLA VITA FUNZIONE ERETTILE

Alterazioni della sessualità correlate alla prostatectomia radicale peggiore QoL decisive per la scelta tra diverse terapie radicali o trattamento conservativo pazienti coinvolti nel processo decisionale accetteranno meglio le conseguenze della loro scelta

Prostatectomia Radicale Nerve sparing = potenza Non nerve sparing = DE ???

Eur Urol. 2015 Oct;68(4):550-1 Are We Targeting the Right Outcome for Sexual Health After Prostate Cancer Treatment? Wittmann D1, Skolarus TA2, Montie JE Satisfaction with sex life achievement combines the necessary components of erectile dysfunction prevention and treatment and reliance on patients' and partners' psychosocial strengths, regardless of either partner's sexual function. What is the “right” outcome with respect to sexual health in patients after Prostate Cancer Treatment? Sexual health goes beyond the ability to have an erection and involves many important bio-psychological factors. It affects not only their quality of life but also that of their partners. Emphasis on helping cancer patients to restore sexual health in the context of potential functional loss, rather than solely assisting with the recovery of erectile function

STUDI di SINGOLO CHIRURGO 1999 -2006 – Disfunzione Erettile dopo Prostatectomia Radicale Studio Anno paz Età media F-U (mesi) Tipo di Questionari Validati NSbil NSmon NonNS Terapia per DE Ripresa erez.(mesi) Note Walsh 2000 64 57 18 Prospettico Si 18% n.a. DE 14% con terapia >12 mesi GralneK 129 31 retrospettivo si 60,9% Chirurgo Dalkin Rabbani 314 60,5 25,4 no 24% <60 aa 44% 60-65 aa 75% n.a Chirurgo Scardino Cohn 2002 303 No 34% 48% DE 29% (NSbil) / 36% (NSmon) Noh 2003 188 >12 27% 61% Risultati con terapia (non disaggregati) Foley 440 61/65 Nessuna differenza significativa per volumi prostata ><75gr Kundu 2004 1834 61 65 24% 47% Chirurgo Catalona +/- PDE5-I Haffner 2005 342 56/61 >24 prospetttico Nessuna differenza significativa Non indagata >6-12 Dalkin 2006 105 62,9 24 prospettico 50-67-75% (<60/<69/>70) 100% 78%

STUDI ISTITUZIONALI 1999 -2006 – Disfunzione Erettile dopo Prostatectomia Radicale Studio Anno paz Età media F-U (mesi) Tipo di Questionari Validati NSbil NSmon NonNS Terapia per DE Ripresa erez.(mesi) Note Gaylis 1998 116 n.a. n.a prospettico no 82%. NON STRATIFICATA LA TECNICA Kao 2000 1069 > 6 retrospettivo si 88,4% Formenti 294 >36 66% 100% INTERVISTA TELEFONICA 57%<58anni>74% Siegel 2001 419 33% >70 anni 90% (nessuna differenza tra le tecniche o tra le età) INTERVISTA DEL CHIRURGO Fulmer 127 64 18 82% Augustin 2002 473 63.3 38 83,7% DE 68% con terapia Noldus 366 62.5 >12 75-39% 87-71% Meglio se <60 anni Schover 569 51 87% 95% DE 68-81-89% con terpia Cleveland Clinic Van der Aa 2003 46 >18 69,6% Campione inadeguato Hollembeck 671 4-52 Prospettico, trasversale(112 controlli) 40-60-69% 68-73-80% 69-95-90% Usati dal 47% Max 2-3 anni Meglio prostate <59 gr. (<58/58-69/>69 anni) Tsujimura 2004 67 51,9% 85,8% Varkarakis 26 <45 <12 37,5% DE 19% con terapia Tutti paz. giovanissimi Saranchuk 2005 647 58 15 75,8% DE 38% con terapia 24 Memorial Sloan Kettering Michl 2006 411 63/61 21 45,5% 70,2% Hamburg University

STUDI di POPOLAZIONE 1999 -2006 – Disfunzione Erettile dopo Prostatectomia Radicale Studio Anno paz Età media F-U Tipo di Questi onari Validat NSbil NSmon NonNS Terapia per DE Ripresa erez. (mesi) Note Litwin 1999 342 62 prospett si Sia la tecnica NS sia le terapie migliorano la FS n.a. >12 Capsure Schwartz 2002 130 24 no 76,6% Detroit Hu 2003 12079 retrospett Nessuna variazione tra gli anni esaminati Medicare Karakiewicz 2004 2227 17,5- 96 55% (<60) / 85% (>75) n..a Quebec Stanford 2000 1291 56% 58,6% 65,6% >18 Prostate Cancer Outcome Study Penson Johnson 2005 1288 60 Prospett 60% 77% 43% Sildena fil (13% Molto aiutati) Korfage 127 52 88% Rotterdam

PROSTATECTOMIA RADICALE PERINEALE 1999 -2006 – Disfunzione Erettile dopo Prostatectomia Radicale Studio Anno paz Età media F-U (mesi) Tipo di Questionari Validati NSbil NSmon NonNS Terapia per DE Ripresa erez. Note Lance 2001 316 62,2 47,1 retrospett no 91,8% n.a. n.a Nessuna differenza con PRR Harris 2003 508 65,8 2-24 65% >24 Brehmer 2005 88 prospett si 52% 24 Borchers 2006 128 12 91,9%

PROSTATECTOMIA RADICALE LAPAROSCOPICA 1999 -2006 – Disfunzione Erettile dopo Prostatectomia Radicale Studio Anno paz Età media F-U (mes) Tipo di Questionari Validati NSbil NSmon NonNS Terapia per DE Ripresa erez. (mesi) Note Anastasiadis 2003 230 64 12 prospett si 47% 19% (<60) 54% n.a. n.a Migliore rispetto a PRR Su 2004 177 24% Risultati +/- sildenafil 52% Rozet 100 6 36% 57% Chien 2005 56 58,9 50% 44% ROBOTIC 231 62 Risultati + tadalafil Kaul 2006 102 57,4 DE 29% + PDE5-I

685 in control arms (observed or placebo) Have rates of erectile dysfunction improved within the past 17 years after radical prostatectomy? A systematic analysis of the control arms of prospective randomized trials on penile rehabilitation Authors I. Schauer, E. Keller, A. Müller, S. Madersbacher Volume 3, Issue 4 July 2015 Pages 661–665 First published: 21 July 2015 systematic analysis of the control arms of all RCT (n = 11) on penile rehabilitation after RPE 2009 patients 685 in control arms (observed or placebo) Assessment of erectile function by (SEP) or (IIEF) Eight trials used SEP3 as study endpoint

SEP 3 (=erectile function sufficient for successful intercourse) Have rates of erectile dysfunction improved within the past 17 years after radical prostatectomy? A systematic analysis of the control arms of prospective randomized trials on penile rehabilitation Authors I. Schauer, E. Keller, A. Müller, S. Madersbacher Volume 3, Issue 4 July 2015 Pages 661–665 First published: 21 July 2015 SEP 3 (=erectile function sufficient for successful intercourse) 1997 20% 2003 10% 2004 19% 2008 25% 2010 21% 2011 67% 2013 2014 22% IIEF 2003 9,2 2004 13,3 2008 8,8 25% >22 2010 17,4 2011 58% >26 2013 9,3 2014 11,6

Have rates of erectile dysfunction improved within the past 17 years after radical prostatectomy? A systematic analysis of the control arms of prospective randomized trials on penile rehabilitation Authors I. Schauer, E. Keller, A. Müller, S. Madersbacher Volume 3, Issue 4 July 2015 Pages 661–665 First published: 21 July 2015 the rate of undisturbed erectile function is in the range 20–25% in most studies these rates have not substantially improved or changed over the past 17 years

Problemi non evidenziati da IIEF Erectile function after prostatectomy – do patients return to baseline? Fode M et al.EAU 30° Annual Congr; march 2015; Madrid IIEF similar to before surgery 24% «How are your erections compared with prior to the surgery?» 14/210=6% Problemi non evidenziati da IIEF Disfunzione orgasmica Disestesia peniena Accorciamento penieno

IIEF non progettato per RP IIEF sottostima gli esiti avversi di RP Erectile function after prostatectomy – do patients return to baseline? Fode M et al - EAU 30° Annual Congr; march 2015; Madrid Studio retrospettivo Non chiarita la tecnica (Nerve Sparing/mono/bil/NNS) Non chiarita l’esperienza del chirurgo IIEF non progettato per RP IIEF sottostima gli esiti avversi di RP NON sono fornite ai pz. informazioni sufficienti e corrette per una decisione valida

Survivorship Care -Key components ED Psychosexual Care in Prostate Cancer Survivorship - A Systematic Review Goonewardene SS, Persad R. Transl Androl Urol. 2015;4(4):413-420. Survivorship Care -Key components ED Acute and chronic medical comorbidity Side effects of therapy Unmet Needs Psycosexual Care (majority of studies) Great number of men with unmet needs

majority of U.S. hospital Web sites promote RARP USA (2004 -2010) total RP volume almost doubled Robotic surgery rate increased from 8% to 67% Lowrance WT et al. J Urol 2012;187:2087–92. majority of U.S. hospital Web sites promote RARP without mentioning the risks of postoperative ED and urinary incontinence provide a comparison that favors RARP over ORP, without supporting documentation Mulhall JP. BJU Int 2010 - Paolone D, AUA Ann Meet, 2012 - Mirkin JN, Health Aff (Millwood) 2012;31:760–9 patients should be realistically informed about the functional outcomes of cancer treatment options [60].

Results. published series shown EF recovery rates after robot-assisted RP (RARP) between 40% and 90% at 12 months. Some claim that RARP can also significantly shorten recovery time in return of EF when compared with open RP. On the other hand, some authors reported that patients undergoing minimally invasive RP have experienced even more ED on comparison. Conclusions. Although widely promoted by the industry and hospitals, at the moment there are not enough evidence-based data to answer the question, “Does RARP surgery provide better EF outcomes?.

Different surgical approaches and nonstandardized definition of EF hamper the validity of the studies assessing post-RP EF. currently available literature demonstrates recovery of EF after RP is significantly influenced by factors other than surgical method or the surgeon’s experience, such as age, baseline EF, nerve-sparing extension, techniques, and penile rehabilitation after surgery.

? UROLOGO = PINOCCHIO

erezioni notturne correlate al sonno REM scompaiono DE dopo PR NPT postop erezioni notturne correlate al sonno REM scompaiono Fraiman MC, J Urol, 1999 Fraiman MC, J Urol, 2000 EZIOLOGIA ORGANICA

DE dopo PR: Fisiopatologia MULTIFATTORIALE PSICOGENA NEUROGENA VASCOLARE ARTERIOGENICA VENOGENICA VASCOLARE MISTA (arterio-venogenica) DANNO DA NEUROPRASSIA

Etiologia della DE dopo PRR FATTORI PSICOLOGICI Stress preoperatorio: impotenza vs malattia / perdita di autostima / rabbia / paura / DEPRESSIONE Periodo di DE postoperatoria / aneiaculazione / < sensazione orgasmica / periodo d’incontinenza DINAMICA DISFUNZIONALE nella SESSUALITA’ di COPPIA

(disfunzione venocclusiva) DE dopo PR VASCOLARE Venogenica (disfunzione venocclusiva) 52% dopo PR Mulhall, Int J Imp Res, 1996 De Luca, Eur Urol, 1996 Rodriguez, Actas Urol Esp, 1997 Zelefsky, Int J Radiat Oncol Biol Phys, 1998

DE dopo PR VENOGENICA Disfunzione Venocclusiva 96 pz (54 anni) – eccellente FE – NSPRBIL - (cavernosomet+doppler) NO TERAPIA F-U 12 mesi 35% normale vascolare (47% potenti) 59% Arteriosa (31% potenti) Disfunzione Venocclusiva 14% a 4 mesi 35% a 9-12 mesi 50% > 12 mesi SOLO 9% POTENTI Mulhall, J Urol 2002

Mulhall, J Urol 2002

DE dopo PR VENOGENICA Take-home message “the longer after RP with poor erectile function, the greater the chance of venous leakage” “Prognosis is worst when venous leakage is present” “Appropriate to institute penile rehabilitation early after RP” Mulhall, J Urol 2002

DANNO DA PERDITA DELLE EREZIONI Neuroprassia Conseguente al trauma nervoso Erezioni impossibili (diurnal/nocturnal) Atrofia muscolatura liscia Incremento della apoptosi Klein, J Urol 1997

Cambiamenti strutturali penieni dopo PR Human corpus cavernosum Cambiamenti strutturali penieni dopo PR Iacono F and Mirone V, J Urol, 2005 Cavernous fibrosis 24 months postop cavernous ialinosis

Cambiamenti strutturali penieni dopo PR 19 pz - normale funzione erettile biopsia corpi cavernosi : prima, 2 e 12 mesi dopo RP F-U 2 mesi: Disorganizzazione strutturale in tutti i casi F-U 12 mesi: < fibre elastiche (p <0.0003) < muscolo liscio > collagene (p <0.0003) Iacono F and Mirone V, J Urol, 2005

Preserved postoperative penile size correlates well with maintained erectile function after BNSRRP 33 pts full potent (IIEF>/= 26) F-U 6 months no difference IIEF-EF domain score penile colour Doppler evaluation penile length and circumference preservation of erectile function positively correlated with maintenance of penile length no change found in penile size after surgery Briganti and Montorsi F, Eur Urol. 2007

(erezioni spontanee e non assistite) RIABILITAZIONE dopo PR Recupero di funzione (erezioni spontanee e non assistite) ? Evidence Based ?

PREVENZIONE e TERAPIA della DE dopo PRR Selezione e preparazione dei pazienti Prevenzione intraoperatoria Riabilitazione e terapia postop.

SELEZIONE e PREPARAZIONE dei PAZIENTI (1) Età <65 anni Walsh, Urology, 2000 (>60 aa più del 50% ha DE) Feldman, Massachussetts Male Aging Study, J Urol 1994 Basso stadio e grado della neoplasia: elementi necessari per PRRNS Aus, EAU guidelines, 2003 Valutazione della funzionalità erettiva (questionario validato, fattori di rischio per DE). Se dubbio > NPT +/- Doppler dinamico Paz. con qualsiasi grado di DE o che usino PDE5-I svilupperanno più probabilmente una DE grave dopo PR

SELEZIONE e PREPARAZIONE dei PAZIENTI (2) Valutazione psicosex di coppia Counseling preoperatorio (valutare e rinforzare le motivazioni alla terapia riabilitativa precoce) 1° iniezione intracavernosa con PGE (60% continua la FIC dopo 1 anno vs 33% in chi inizia dopo la PRR) Lebret, Prog Urol 1999

PREVENZIONE INTRAOPERATORIA Tecnica nerve sparing (Bilaterale >> Unilaterale) Risparmio arterie pudende accessorie No uso fonti energia/calore Stimolazione ed identificazione dei nervi (Cavermap) ??

PATHOPHYSIOLOGY OF ED AFTER RP. Mulhall JP et al PATHOPHYSIOLOGY OF ED AFTER RP. Mulhall JP et al. Standard operating procedure for the preservation of erectile function outcomes after radical prostatectomy. J Sex Med 2013;10:195–203. *Apoptosis occurs in nerves, smooth muscle, and endothelium as a result of neural trauma. APA = accessory pudendal artery; CCSM = corpora cavernosa smooth muscle; NVB = neurovascular bundle; pO2 = partial pressure of oxygen

EARLY REHABILITATION AFTER RADICAL PROSTATECTOMY “ERECTION IS GOOD FOR ERECTIONS” Moreland, Int J Imp Res 1998 Nehra e Goldstein, Urology 1999 EARLY REHABILITATION AFTER RADICAL PROSTATECTOMY

TERAPIA POSTOPERATORIA PDE5i Vacuum device PGE1 (Intrauretrale / Iniezioni intracavernose) Protesi

Terapie disponibili RIABILITAZIONE PDE5-I agiscono indirettamente per aumentare i livelli di cGMP indotti dal N0 endogeno (La cui produzione può essere alterata dal danno nervoso) PGE1 agisce direttamente sulla muscolatura liscia per aumentare cAMP

Taken bedtime increases nocturnal erections’ lenght and rigidity Sildenafil Taken bedtime increases nocturnal erections’ lenght and rigidity Montorsi, J Urol, 2000

preservation of smooth muscle preservation of endothelial function The Functional and Structural Consequences of Cavernous Nerve Injury are Ameliorated by Sildenafil Citrate Mulhall JP, J Sex Med, 2008 animal model - cavernous nerve (CN) crush injury model groups: no CN injury (sham), bilateral CN injury exposed to either no sildenafil (control) or sildenafil at two doses (10 and 20 mg/kg) subcutaneously daily for three different durations (3, 10, 28 days) Sildenafil use in the CN crush injury model preserves erectile function predominantly through preservation of smooth muscle preservation of endothelial function reduction in apoptosis

sildenafil “bed time” 50/100 mg every other day for 6 months 21 pts – after NSRRP sildenafil “bed time” 50/100 mg every other day for 6 months corpus cavernosum perc biopsy at RRP and 6 months later Smooth muscle and connective tissue examined

Mean smooth muscle content Sildenafil 50 mg (n=11) Sildenafil 100 mg (n=10) 51.5% 52.7% 42.8% 56.8% P=n.s. P<0.05 Mean smooth muscle content 50mg (11 pts) = no statistically significative change 100mg (10 pts) = statistically significative increase

Mc Cullough AR, Levine LA, Padma-Nathan H. J Sex Med; 5:476-84 2008 Return of nocturnal erections and erectile function after bilateral nerve-sparing radical prostatectomy in men treated nightly with sildenafil citrate: subanalysis of a longitudinal randomized double-blind placebo-controlled trial Mc Cullough AR, Levine LA, Padma-Nathan H. J Sex Med; 5:476-84 2008 Normal erectile function 8 weeks after treatment termination (48 weeks postop) 24% (4/17) of 50-mg sildenafil recipients 33% (6/18) of 100-mg sildenafil recipients 5% (1/19) of placebo recipients nightly sildenafil for 9 months post-BNSRRP objectively improved nocturnal erections and Pharmaceutically unassisted EF

The use of an erectogenic pharmacotherapy regimen following radical prostatectomy improves recovery of spontaneous erectile function Mulhall J, Land S, Parker M, Waters WB, Flanigan RC. J Sex Med. 2:532-40 2005 Prospective nonrandomized study 58 pts rehabilitation group (early postop oral sildenafil. Nonresponders: ICI 3 times a week) 74 no rehabilitation group penile rehabilitation results in higher rates of spontaneous functional erections and erectogenic drug response after RP

The use of an erectogenic pharmacotherapy regimen following radical prostatectomy improves recovery of spontaneous erectile function Mulhall J, Land S, Parker M, Waters WB, Flanigan RC. J Sex Med. 2:532-40 2005

Chronology of return of spontaneous erectile function (% rigidity) The use of an erectogenic pharmacotherapy regimen following radical prostatectomy improves recovery of spontaneous erectile function Mulhall J, Land S, Parker M, Waters WB, Flanigan RC. J Sex Med. 2:532-40 2005 Chronology of return of spontaneous erectile function (% rigidity) Time post RP Rehabil (n=58) No rehabil (n=74) P value ≤4 months (n=96) 12±16 12±19 NS ≤8 months (n=126) 16±23 11±17 ≤12 months (n=122) 31±26 19±27 0.03 ≤18 months (n=132) 53±21 26±43 <0.01

randomized, double-blind, placebo controlled, parallel group study enrolled patients at 53 sites in the United States to assess the safety and efficacy of avanafil in the treatment of mild to severe ED in men following bilateral nerve sparing radical prostatectomy. age up to 70 years ED of 6 months or more after bilateral nerve sparing retropubic radical prostatectomy pT2 or less and Gleason score 7 (4+3) or less Excluded diabetes or neurological disease, spinal cord injury or severe ED before prostate surgery.

highly experienced surgeons, met the criteria 5 or more of years experience after residency, 2) 250 or more radical prostatectomies using 1 technique 3) performance of 50 or more radical prostatectomies in the last calendar year 4) dedicated researcher coordinator and 5) ED specialist in the practice.

Change in co-primary end points (SEP2, SEP3 and IIEF-EF) from baseline to end of treatment (ITT population). a indicates difference compared with placebo (p 0.01). Siete riuscito ad inserire il pene nella vagina? L’erezione è durata abbastanza a lungo per avere un rapporto soddisfacente?

a indicates change from baseline not significant (p >0.05). Co-primary end points (SEP2, SEP3 and IIEF-EF) at end of treatment by baseline (BL) severity of ED a indicates change from baseline not significant (p >0.05). b indicates change from baseline (p <0.01). Siete riuscito ad inserire il pene nella vagina? L’erezione è durata abbastanza a lungo per avere un rapporto soddisfacente? L’erezione è durata abbastanza a lungo per avere un rapporto soddisfacente? Siete riuscito ad inserire il pene nella vagina?

ADVERSE EVENTS L’erezione è durata abbastanza a lungo per avere un rapporto soddisfacente?

L’erezione è durata abbastanza a lungo per avere un rapporto soddisfacente?

Mulhall JP, et al. A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy. J Urol 2013 189(6): p. 2229-36. double-blind, placebo-controlled, parallel-group, study in 298 patients with ED after bilateral NSRP randomised to 100 or 200 mg avanafil or placebo for 12 weeks significantly greater increases in SEP2 and SEP3 and change in mean IIEF-EF domain score with 100 and 200 mg avanafil vs. placebo (p < 0.01) Following Avanafil 36.4% (28 of 77) of sexual attempts (SEP3) at 15 minutes or less were successful vs. 4.5% (2 of 44) for placebo (p < 0.01)

TERAPIA POSTOPERATORIA PDE5i Vacuum device PGE1 (intrauretrale / Iniezioni intracavernose) Protesi

possible mechanisms of VED therapy for erectile dysfunction after radical prostatectomy Lin H, Wang R. Transl Androl Urol 2013;2(1):61-66

FDA – 2006 extended labeling for the VED to create and maintain erections by providing arterial blood to the penis during recovery from prostatectomy first device or drug to be cleared by the FDA for this specific indication.

Tissue oxygenation after 2 minutes/10-cycle application of VED. J Sex Med, 2014 Tissue oxygenation after 2 minutes/10-cycle application of VED.

TERAPIA POSTOPERATORIA PDE5i Vacuum device PGE1 (Intrauretrale / Iniezioni intracavernose) Protesi

30 pz potenti – PRNS - RANDOMIZZAZIONE RIABILITAZIONE – PGE1 30 pz potenti – PRNS - RANDOMIZZAZIONE PGE1 3/sett Nessun trattamento RECUPERO FE 67% terapia PGE1 20% non trattati (P<0,01) (i paz. che non recuperarono in entrambe i bracci avevano DISFUNZIONE VENOOCLLUSIVA) Montorsi F, J Urol, 1997

MUSE

TERAPIA POSTOPERATORIA Protesi peniene NON RESPONDERS ALLE TERAPIE, DA SOLE O IN ASSOCIAZIONE DE prima dell’intervento e non responders alle terapie > impianto nel corso della PRR Protesi gonfiabili (bi o tricomponenti) offrono il miglior risultato cosmetico e funzionale

POSSIBILITA’ FUTURE ESWT Immunophiline ligands Sonic Hedgehog protein Nerve growth factor Growth differentiation factor-5 Acidic fibroblast growth factor Polyadenosine diphosphate-ribose polymerase inhibitor Growth hormone Insuline-like growth factor Triiodothyronine Stem cell therapy Vascular endothelial growth factor ESWT Brain-derived neurotrophic factor PDE5i before RP Vibratory stimulation

La Rivoluzione delle Onde d’Urto 2015

Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 1 Knuppe Molec Urol Lab, Dept of Urol, Sch of Medic, Univ of California, San Francisco, CA,USA; 2 Dept of Urol, Peking Univers First Hospit and the Instit of Urol, Peking Univers, Beijing, P.R. China; 3 Diabetes Center, Univers of California, San Francisco, CA, USA; 4 Dept of Urol, Kaohsiung Med Univers Hospit, Dept of Uro, Faculty of Medic, Kaohsiung Med Univers, Kaohsiung, Taiwan J Sex Med 2016;13:22e32 Methods: 32 male Sprague-Dawley rats.…into 4 groups: sham surgery (Sham), pelvic neurovascular injury (PVNI) :bilateral cavernous nerve injury and internal pudendal bundle injury PVNI treated with LESW at Low energy: 0.06 mJ/mm2, 300 pulses 3 Hz PVNI treated with LESW at High energy: 0.09 mJ/mm2, 1000 pulses at 3Hz Main Outcome: The intracavernous pressure (ICP), histological examination, and Western blot (WB), Cell cycle, Schwann cell activation.

INTRACAVERNOUS PRESSURE (ICP) Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 INTRACAVERNOUS PRESSURE (ICP)

RECRUITING OF ENDOGENOUS PROGENITOR CELLS IN VIVO Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 RECRUITING OF ENDOGENOUS PROGENITOR CELLS IN VIVO

NEUROVASCULAR CHANGES IN PENILE TISSUE Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 NEUROVASCULAR CHANGES IN PENILE TISSUE

REGENERATION OF nNOS POSITIVE CAVERNOUS NERVES Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 REGENERATION OF nNOS POSITIVE CAVERNOUS NERVES

ACTIVATION OF SCHWANN CELLS IN VIVO Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 ACTIVATION OF SCHWANN CELLS IN VIVO

ACTIVATION OF SCHWANN CELLS IN VIVO Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 - J Sex Med 2016;13:22e32 ACTIVATION OF SCHWANN CELLS IN VIVO

nerve generation with more progenitor cells Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model Huixi Li,1,2 et al. and Tom F. Lue1 J Sex Med 2016;13:22e32 LESW treatment improves erectile function in a rat model of pelvic neurovascular injury by angiogenesis, tissue restoration nerve generation with more progenitor cells activation of Schwann cells (in vitro direct effect on Schwann cell proliferation). more complete re-innervation of penile tissue with regeneration of neuronal nitric oxide synthase (nNOS)-positive nerves.

Light Intensity Shock Wave Therapy DE CON COMPONENTE VASCOLARE LISWT Light Intensity Shock Wave Therapy INDICAZIONI DE CON COMPONENTE VASCOLARE (età, sovrappeso, sedentarietà, fumo, dislipidemia, ipertensione, diabete, malattie cardiovascolari, ictus, ipogonadismo, ipertrofia della prostata) PREVENZIONE: segni iniziali di DE (difficoltà/lentezza ad ottenere e/o mantenere l’erezione, erezione meno rigida): per evitare il peggioramento o la necessità di assumere farmaci TERAPIA: DE responsiva ai farmaci orali (Viagra, Cialis, Levitra, Spedra): per migliorare la funzione erettile e non dover utilizzare più i farmaci TERAPIA: non si possono assumere farmaci orali a causa degli effetti collaterali o per controindicazioni TERAPIA: DE non responsiva ai farmaci orali e/o ai farmaci per iniezione intracavernosa: per migliorare la funzione erettile e rispondere ai farmaci RIABILITAZIONE: dopo interventi di chirurgia pelvica (prostatectomia radicale, cistectomia radicale, interventi demolitivi al sigma-retto) per evitare i danni vascolari possibili nella fase postoperatoria

Linee Guida Auro.it sul Ca Prostatico Consensus Conference

Il rischio relativo di disfunzione erettile dopo PR vs WW è del 1,8 con un Incremento di Rischio del 35% LE II I fattori rilevanti per la ripresa di una valida funzione erettiva a breve termine dopo PR con o senza PDE5-I sono: età del paziente, valida funzione erettile preoperatoria, tecnica chirurgica e F-U di almeno 18-24 mesi LE III A lungo termine la disfunzione venoocclusiva è fattore fondamentale per il mancato recupero della funzione erettile.LE III L’utilizzo di qualsiasi fonte di energia per il controllo dell’emostasi nel corso dell’intervento di PR è elemento sfavorevole ai fini della conservazione della funzione erettiva. LE III La stimolazione intraoperatoria dei nervi cavernosi presenta risultati contraddittori LE III L’innesto nervoso intraoperatorio presenta risultati contraddittori LE IV

La terapia intracavernosa della DE dopo PR Nerve Sparing ha un’alta efficacia e compliance ed una quota di pazienti può recuperare la completa attività erettile. LE IV I pazienti che non rispondono al sildenafil o alla terapia con PGE intrauretrale possono rispondere ad una terapia combinata con i 2 farmaci. LE III La terapia della DE dopo PR con Vacuum device ha elevata efficacia ma compliance estremamente bassa LE III Un programma terapeutico multifasico può consentire ad una quota rilevante di soggetti con DE conseguente a PR di ottenere un risultato terapeutico valido e persistente nel tempo LE III L’inizio precoce di terapia “riabilitativa” con PGE1 intracavernosa, praticata 2 volte la settimana, può consentire il recupero della funzione erettile più rapidamente e più frequentemente LE II La terapia riabilitativa precoce combinata o sequenziale con PDE5-I e/o FIC fornisce risultati migliori per quanto riguarda il recupero della funzione erettile LE III

Prevention is better than cure: European Urology 62 (2012) 261-272 Prevention is better than cure: claim for intelligible discussion with the patient about the true prevalence of postoperative ED defining what is meant by (adequate) postoperative erectile function passes through the objective assessment of the baseline condition defining time to recovery and postoperative quality of erection is a compulsory task for the clinician Hardness of erection. Consistency of functional erections. choosing the right patient at the right time for the right surgery choosing the right cancer for the right surgery

tissue damage leads to structural alterations European Urology 62 (2012) 261-272 European Urology 62 (2012) 673-286 tissue damage leads to structural alterations rehabilit/treatm undoubtedly better than leaving the erectile tissue to its unassisted fate timing of rehabil/treatm major clinical importance

European Urology 62 (2012) 261-272 European Urology 62 (2012) 673-286 Penile rehabilitation (any form) should start as early as possible and certainly prior to penile fibrosis development. Treating patients early on postoperatively may lead to better long-term results in terms of both EF recovery and ED treatment possibilities.

European Urology 62 (2012) 261-272 European Urology 62 (2012) 673-286 PDE5i taken when needed may be used successfully in patients who underwent RP with a clear bilateral NS intent. There are no definitive conclusions on the superiority of daily use of PDE5-Is with rehabilitative intent compared with as-needed use of PDE5-Is. Young patients with good preoperative EF who underwent RP with a clear BNS intent may experience good EF recovery rates even without any treatment; however, using PDE5-Is after a clear BNSRP may further improve postoperative EF outcomes. Ideally, PDE5-Is could be initiated as early as the removal of the catheter or during the very first month after surgery.

European Urology 62 (2012) 261-272 European Urology 62 (2012) 673-286 When ICI is the treatment of choice, mainly because of the relative ineffectiveness of PDE5I, even in a number of post-NSRP patients, timing for starting ICI should be accurately defined because of a relatively high probability of alprostadil-associated painful erection. Penile pain may diminish with time. Despite being off-label, injectable erectogenic preparations other than alprostadil may ultimately lead to less frequent pain, both after injection and during erection. It is not possible to make a clear final suggestion for the best timing to begin postoperative early ICI in men who received either interfascial or intrafascial RP.

European Urology 62 (2012) 261-272 European Urology 62 (2012) 673-286 Psychological and sexual counseling is of major importance to improve any rehabilitation and treatment of postoperative EF impairment. A combined approach of psychological and sexual counseling with ‘‘organic’’ therapies for patients who underwent either BNSRP or NNSRP is certainly suggested. Postoperative EF rehabilitation could mean interventions designed to achieve faster and better natural EF recovery, but the term could also mean interventions that preserve sexual continuity without necessitating natural EF.

European Urology 62 (2012) 261-272 European Urology 62 (2012) 673-286 In eugonadal patients with PCa, serum testosterone ispositively correlated with sexual activity (ie, EF). Although the role of T replacement in postoperative ED recovery could be of great significance, hypogonadal men are not usually treated with T after RP because of the fear of stimulating dormant PCa cells. Over the last decade, exploratory data from some relatively small series of patients who have been treated with T replacement after RP showed positive results in terms of EF recovery and without significant increases in PSA values.

European Urology 62 (2012) 261-272 European Urology 62 (2012) 673-286 Patients with ED after BNSRP or NNSRP may benefit from penile prosthesis implantation after failure of less invasive treatments.

Management of ED post surgery 2013 Management of ED post surgery The restoration of EF usually involves proactive and early management strategies to: Minimise severity/duration of ED Improve cavernosal oxygenation Promote endothelial protection Prevent/minimise cavernosal structure changes

Postoperative recommendations 2013 Postoperative recommendations Re-assess sexual function at catheter removal or up to 10 days post surgery Treatment algorithm Consider first-line treatment with combination therapy Combination therapy is usually the most cost-effective therapy (generally, PDE5-I + VED) Consider daily PDE5-I therapy in patients with nerve-sparing surgery, especially during initial (early) management (although level 1 evidence is lacking for superiority of on-demand vs. daily treatment)

2013 In patients with low or high risk of ED, daily therapy showed significantly higher efficacy for the EF recovery rate compared with the on-demand PDE5-I administration schedule in patients with intermediate risk of ED Early high-dose PDE5-I may preserve the smooth muscle content within the corpora cavernosa Add intraurethral alprostadil/ICI followed by discussion of penile implants if these initial treatment strategies fail

2013 For non-nerve-sparing procedures, VED is generally the treatment of choice +/ ICI intraurethral alprostadil VED is a useful adjunct to medication and facilitates early sexual activity where drugs alone are not effective treatment

ED is common after RP, irrespective of the surgical technique used ED is common after RP, irrespective of the surgical technique used. LE 2b Several trials have shown higher rates of EF recovery after RP in patients receiving any drug (therapeutic or prophylactic) for ED. Early compared with delayed EF treatment seems to impact on the natural healing time of potency Salonia A, et al. Eur Urol 2012 62(2): p. 273-86. 3A.4.8 Recommendations for the treatment Pro-erectile treatments have to be given at the earliest opportunity after RP. LE 1b GR A

SCHEMA RIABILITATIVO INTEGRATO (18 – 24 MESI) FIC (PGE) PREOPERATORIA (1 volta) 2. FIC (PGE) POSTOPERATORIA PRECOCE (1-2/settimana) 3. PDE5i (max dose) + STIMOLAZIONE SEX (tentare almeno 3 volte/mese) PDE5i CRONICO / PRIMA DI DORMIRE VACUUM TERAPIA (non ischemizzante sec. Austoni) precocemente: 1-2/settimana

SCHEMA RIABILITATIVO INTEGRATO PDE5-I PDE5-I Immunofiline endotelio neuroprassia EPO Muscolo liscio PDE5-I PGE1