Gerald Brock Professor of Surgery University of Western Ontario

Transcription

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

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3 Should you believe in Rehab? 3 3

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

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

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

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

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

10 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

11 A Good Idea 11

12 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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14 JAMA September 21, 2011 Vol 306, No

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21 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

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25 Rehabilitation Strategies Used ISSM Survey 25 25

26 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

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

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

29 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:

30 PDE5i & Systemic Hypoxia-Induced ED ICP (mmhg) Flow (ml/min) % 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) s 0 Nerve stim 30 Wayman C et al. ESSM. 4-7 Dec Poster P

31 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 c a c 20 b b a c b BCNX 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: BCNX VARD

32 Corporal Smooth Muscle Apoptosis Impact of Sildenafil 32 32

33 % 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

34 % 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

35 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

36 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:

37 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): ,

38 % Re esponders Results p= 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): ,

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40 ED Rates post RRP 40 40

41 ED post RRP with Rehab 41 41

42 Moderate Risk Group 42 42

43 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

44 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

45 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

46 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:

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. 47

48 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

49 SEP-3: Yes Responses % Yes per subject (LS Mean) Tadalafil OaD Tadalafil PRN Placebo 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

50 Change in Penile Length (ANCOVA) Group difference, LS mean change, mm [95% CI]; p-value OaD vs. PRN 5.7 [1.93, 9.40]; OaD vs. PLC 4.1 [0.35, 7.83]; PRN vs. PLC -1.6 [-5.25, 2.10]; 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

51 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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59 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

60 21 st Century Rigidometer 60