Gerald Brock Professor of Surgery University of Western Ontario

Treatment Induced Erectile Dysfunction Gerald Brock Professor of Surgery University of Western Ontario 1 1

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Should you believe in Rehab? 3 3

Should you believe in Rehab? Avoidance Education related to effects Understand the treatment approaches 4 4

Penile Innervation Pudendal nerve (somatic) Cavernous nerve (autonomic) 5

Adapted from Lue TF. N Engl J Med. 2000;342:1802-1813. Click here to advance to next slide 2002, PPS EIEF, 2002 6

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Should you believe in Rehab? Understand pathology Know risks / benefits of Tx Be able to transfer knowledge 8 8

Should you be offering Sexual Rehabilitation to your RRP patients? 9 9

My View ED common after RP ED - decreased QOL Penile rehabilitation associated with financial expenditure Penile rehabilitation is being used by clinicians In discussion with Patients the option should be advanced 10 10

A Good Idea 11

A Good Idea. IVF Let s Do a Real Life Study One that t looks at a natural setting with men like we all see. 12

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JAMA September 21, 2011 Vol 306, No.11 14 14

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What is Rehab Rehabilitation involves the use of a medication, combination of medications, devices (alone or in combination i with medication) i in the early stages after RP. The goal of rehabilitation is to maximize preservation of all components of the local erectile ec e mechanism and optimize recovery of erectile function. 21 21

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Rehabilitation Strategies Used ISSM Survey 25 25

Postprostatectomy ED: Proposed Mechanism Arterial injury Reduced/absent erection Neural injury Prolonged venous po 2 TGF- overexpression Excess collagen production Anxiety/stress Structural alterations Incomplete corporal musc expansion Erectile tissue apoptosis Subtunical venule decompression Venous leak 26 26

PG Production in Varied Oxygen States Moreland RB et al. Am J Physiol Heart Circ Physiol, 281:H552, 2001, 27 27

Histological Alterations in Erectile Tissue Pre-op 2 Months After RP Iacono F et al. J Urol, 163:1673-76, 76, 2005 28 28

Reduced O 2 Tension Inhibits Erectogenic Mechanisms Oxygen tension directly impacts physiological function and corpus cavernosum structure O 2 is required for NO production and normal endothelial function EFS, electrical field stimulation 29 Kim JJ et al. Int J Impot Res. 1998;10:145-150. 29

PDE5i & Systemic Hypoxia-Induced ED ICP (mmhg) Flow (ml/min) 100 80 60 40 20 0 100 21% FiO 2 20% FiO 2 19% FiO 2 18% FiO 2 Nerve stim PDE5i 60s Intracavernosal pressure (ICP) Pudendal flow ICP (mmhg g) Flow (ml/m in) 80 60 40 20 60s 0 Nerve stim 30 Wayman C et al. ESSM. 4-7 Dec 2005. Poster P-01-153. 30

Vardenafil Prevents Penile Fibrosis and Smooth- Muscle Cell Loss After Denervation in the Rat Smooth Muscle/ Collagen Ratio SHAM BCNX BCNX+ SHAM BCNX BCNX+ VARD 35 a VARD 0.25 30 c a 25 0.2 c 20 b 15 10 0.15 5 b 0 0.1 25 a c 0.05 20 15 b 0 10 5 BCNX - + + 0 VARD - - + % IOD % ASMA Positive Area Smooth muscle/collagen ratio was normalized (Masson trichrome staining) Smooth-muscle cell content was normalized (smooth-muscle cell marker staining) Erection response was maintained (papaverine injection, dynamic infusion cavernosometry) a 30 mg/l in drinking water x 45 days. Ferrini et al. Urology. 2006;68:429-435. BCNX - + + VARD - - + 31 31

Corporal Smooth Muscle Apoptosis Impact of Sildenafil 32 32

% Patient ts 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% CAI CVOD < 4 < 8 < 12 > 12 Time interval since radical prostatectomy (Months) 33 33

% patients with recovery of natural ere ections 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% * N A V Hemodynamic Pattern 34 34

Postprostatectomy ED: Proposed Mechanism Arterial injury Reduced/absent erection Neural injury Prolonged venous po 2 TGF- overexpression Excess collagen production Anxiety/stress Structural alterations Incomplete corporal musc expansion Erectile tissue apoptosis Subtunical venule decompression Venous leak 35 35

Animal Data Muller A et al. The functional and structural consequences of cavernous nerve injury are ameliorated by sildenafil citrate. J Sex Med, 2008 Kovanecz I et al. Long-term continuous sildenafil treatment ameliorates CVOD induced by cavernosal nerve resection in the rats. IJIR, 2008; 20:202 Ferrini M et al. Vardenafil prevents fibrosis and loiss of smooth muscle after bilateral l cavernosal nerve resection in the rat. Urology, 2006; 68:429 Vignozzi L et al. Effect of chronic tadalafil administration on penile hypoxia induced by cavernous neurotomy in the rat. J Sex Med; 2006; 3:419 Kovanecz I et al. Chronic daily tadalafil prevents the corporal fibrosis and venocclusive dysfunction that occurs after cavernosal nerve resection. BJUI; 2008; 101:203 Lysiak JJ et al. Tadalafil increases AKT and extracellular signal-related kinase 1/2 activation and prevents apoptotic cell death in the penis following denervation. J Urol, 2008; 179:779 36 36

Post-RP Nightly Sildenafil Study Study Design Preoperative assessment (1-4 weeks) Recovery period (4 weeks) Postoperative drug treatment (36 weeks) Drug-free postoperative assessment (8 weeks) Surgery Start drug End drug Padma-Nathan H, et al. IJIR, 20(5):479-486, 2008 37 37

% Re esponders 30 25 20 15 10 5 0 27 Results p=0.0156 Sildenafil Placebo 4 *Responders were defined as those having a combined score of 8 for IIEF Q3+4 and a positive response to GEQ (Over the past 4 wks, have your erections been good enough for satisfactory sexual activity) Padma-Nathan H, et al. IJIR, 20(5):479-486, 2008 38 38

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ED Rates post RRP 40 40

ED post RRP with Rehab 41 41

Moderate Risk Group 42 42

Effects of Tadalafil (TAD) Treatment on Erectile Function Recovery post Bilateral Nerve- Sparing Radical Prostatectomy t t (nsrp) Gerald Brock 1, Francesco Montorsi 2, Jens-Uwe Stolzenburg 3, John Mulhall 4, Ignacio Moncada 5, Hiten Patel 6, Daniel Chevallier 7, Kazimierz Krajka 8, Carsten Henneges 9, Ruth Dickson 10, Hartwig Büttner 9 1 University of Western Ontario, London, Canada; 2 Instituto Scientifico Universitario San Raffaele, Milan, Italy; 3 Universitätsklinikum Leipzig, Leipzig, Germany; 4 Memorial Sloan-Kettering Cancer Center, New York, USA; 5 Hospital La Zarzuela, Madrid, Spain; 6 University Hospital North Norway, Tromso, Norway; 7 Hôpital Universitaire Archet 2, Nice, France; 8 Uniwersyteckie Centrum Kliniczne, Gdansk, Poland; 9 Lilly Deutschland GmbH, Bad Homburg, Germany; 10 Lilly Canada Inc, Toronto, Canada 43

Study Design Drug-free Open-label Screening Double-blind bli treatment t t Washout tadalafil 5 mg OaD Tadalafil 5 mg OaD + Placebo PRN Placebo OaD + Tadalafil 20 mg PRN 6 wks 3-20 d 3 wks 2 m Placebo OaD + Placebo PRN 3 m 4 m 6 wks 3 m V1 V2 V3 V4 V5 V6 V7 V8 V9 Month 0 Baseline Month 9 Month10.5 Month 13.5 nsrp Randomization Primary endpoint Abbreviations: d = days; m = months; nsrp = bilateral nerve-sparing prostatectomy; OaD = once a day; PRN = pro re nata or on demand; V = visit; wks = weeks 44

Patient Disposition ITT and Safety Population (N = 422) Tadalafil OaD N = 139 Tadalafil PRN N =142 Placebo N = 141 Most frequent reasons for discontinuation: Entry criteria not met 23.1% Subject decision 22.2% Adverse event 19.4% Lack of efficacy 15.7% Lost to follow-up 13.0% Abbreviations: ITT = intention-to-treat; N = total number of subjects; OaD = once a day; PRN = on-demand. 45

Results: Baseline Characteristics Tadalafil OaD Tadalafil PRN Placebo (N = 139) (N = 143) (N = 141) Age (years), mean (SD) 58.6 (5.07) 57.5 (5.91) 57.6 (5.69) <61, n (%) 82 (59.0) 85 (59.4) 91 (64.5) 61-68, n (%) 57 (41.0) 58 (40.6) 50 (35.5) nsrp approach, n (%) Open surgery 68 (48.9) 65 (45.5) 56 (39.7) Conventional laparoscopy 29 (20.9) 31 (21.7) 28 (19.9) Robot-assisted laparoscopy 31 (22.3) 41 (28.7) 44 (31.2) Other 11 ( 7.9) 6 ( 4.2) 13 ( 9.2) Total nerve sparing score (range 1-4) 1, n(%) Perfect (2) 117 (84.2) 116 (81.1) 113 (80.1) Not perfect (>2) 22 (15.8) 27 (18.9) 28 (19.9) Abbreviations: nsrp = bilateral nerve-sparing prostatectomy; N = total number of subjects; n = number of available subjects; OaD = once a day; PRN = on-demand; SD = standard deviation. 1 Moscovic et al, J Sex Med 2011;8:255-260. 46

IIEF-EF: Mean Change from Baseline Abbreviations: CI = confidence interval; IIEF-EF =international index of erectile function-erectile function domain; LS = least square; MMRM = Mmixed-model for repeated measures; OaD = once a day; PLC = placebo; PRN = = pro re nata or on-demand; TAD = tadalafil. 47

IIEF-EF: Mean Change from Baseline Abbreviations: CI = confidence interval; IIEF-EF =international index of erectile function-erectile function domain; LS = least square; MMRM = Mmixed-model for repeated measures; OaD = once a day; PLC = placebo; PRN = = pro re nata or on-demand; TAD = tadalafil. 48

SEP-3: Yes Responses % Yes per subject (LS Mean) 70.0 60.0 50.00 40.0 30.0 20.0 10.00 0.0 Tadalafil OaD Tadalafil PRN Placebo 33.7 24.1 21.6 28.8 23.0 28.5 52.4 45.8 40.8 Month 9 Month 10.5 Month 13.5 Abbreviations: CI = confidence interval; IIEF-EF =international index of erectile function-erectile function domain; MMRM = mixed-model for repeated measures; n.s. = not significant; OaD = once a day; PLC = placebo; PRN = pro re nata or on demand. 49

Change in Penile Length (ANCOVA) Group difference, LS mean change, mm [95% CI]; p-value OaD vs. PRN 5.7 [1.93, 9.40]; 0.003 OaD vs. PLC 4.1 [0.35, 7.83]; 0.032 PRN vs. PLC -1.6 [-5.25, 2.10]; 0.399 Abbreviations: ANCOVA = analysis of covariance; CI = confidence interval; IIEF-EF =international index of erectile function-erectile function domain; LS = least square; n.s. = not significant; OaD = once a day; PLC = placebo; PRN = pro re nata or on demand; RT = randomized treatment. 50

Conclusions Strong animal and evolving human evidence of efficacy for sexual rehabilitation Widespread use and acceptance Only downside is cost 51 51

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Conclusions Strong animal and evolving human evidence of efficacy for sexual rehabilitation Widespread use and acceptance Only downside is cost Would you want Rehab if you had a RRP? 59 59

21 st Century Rigidometer 60