Erectile dysfunction and Penile rehabilitation following radical prostatectomy 김 세 웅 여의도성모병원비뇨기과

Contents Introduction Potency rate of post RP-ED Pathophysiology of post RP-ED Penile rehabilitation Conclusion

Introduction Concept of penile rehabilitation and erectile dysfunction (ED) following radical prostatectomy (RP) started in 1990s Fact: RP is associated with ED Fact: ED is associated with reduced QoL Evolution of several dynamic themes regarding PCa PSA era, detection of lower volume cancers↑ → rate of biochemical cure rises 80~90% Newly diagnosed tumors: → most of all, GS 6/7 cancers and organ confined.

→ SEER study: 33% of all Pca in men under age 65 Subtantial drop in patients age at Dx. d/t earlier screening with PSA and improved U/S guided Bx. → SEER study: 33% of all Pca in men under age 65 higher in the subsequent 5-year report Jemal A, et al.; Cancer J Clinc 2006;56(2):106-30 Above all, reexamination of potency rates following various Tx. of ED after RP → younger PCa patients want information on potency rates and efficacy of the various Tx. options in ED

Potency rate of post RP-ED

Overall Potency Rate after RP Overall Potency Rate after RP? 40-86% by experienced surgeons (>1000 cases) 9-40% for most urologists

Potency rates following bilat nerve-sparing open radical prostatectomy Need to experineced skill !! Zippe, et al: UCNA 2007;34:601-618

Postoperative Potency: State of the Art Results in RP 3 months 6 months 12 months 18 months Continence (%) No pads 54 80 93 95 Bother (no/small) 96 98 Erections (%) Potent 38 73 86 49 64 76 84 Sildenfail 7 13 33 Walsh, et al: Urology 2000;55:58

Potency rates following bilat nerve-sparing laparoscopic radical prostatectomy Difficult to overcome learing curve !! Zippe, et al: UCNA 2007;34:601-618

Sexual Function following Laparoscopic RP 1 months 3 6 12 % of patients 33 41 29 87 Kartz, et al: J Urol 2002;168:2078-82

Domestic data – Catholic Medical Center (2008, 150 cases by laparoscopic RP) Variable Complete continence (%) immediate 111/144 (77.1) 3 months 134/114 (85.1) 6 months 119/129 (92.2) 12 months 104/111 (93.7) Potency rate (%) bilat. nerve sparing 8/15 (53.3) unilat. nerve sparing 10/19 (52.6)

Da Vinci robot system: Impressive results Potency rates following bilat nerve-sparing robotic-assisted radical prostatectomy Da Vinci robot system: Impressive results 3D visualization , 10 fold magnification and so on… Easy to learning curve !! Zippe, et al: UCNA 2007;34:601-618

Domestic data – Yonsei severance hospital (2008, 200 cases by da Vinci robot system) Rha, et al. KUA 2008;49:215-220

Pathophisiology of post RP-ED

Mechanical nerve stretching Thermal damage to nerve tissue Possible explantation about delay of postoperative of erection following RP Mechanical nerve stretching Thermal damage to nerve tissue Ischemic injury to nerve tissue Local inflmmatory effects

Pathophysiology of Post RP-ED : A New Look: penile hypoxia Injury to cavernous nerves Apoptosis (mainly in smooth muscle cells) Smooth muscle cells collagen fiber Veno-occlusive erectile dysfunction User, et al; J Urol 2003;169:11-75

ED secondary to RP Etiology Recovery Intraoperative neurapraxia with subsequent apoptosis Hypoxia due to arterial injury during operation, less likely (10%) Recovery Requiring up to 18-24 mo Consistent with slowly resolving neurapraxia

Recovery of erections

Nerve injury induced apoptosis Bilatera Neurotomy Unilateral Neurotomy Percent of Apoptotic Cells Localization of Apoptotic Cells (Rat CC) User et al, J Urol 2003;169:1175

Histologic change in human penis after RP

Predictive factors for recovery of erectile function Hu JC et al. J Urol 2004;171:703-707 Canada et al. Cancer 2005;104:2689-2700 Kendirci et al. Contemp Urol 2005;17:36-50

Penile Rehabilitation following RP

Postoperative rehabilitation Maximal erectile recovery is not witnessed until a mean period of 18 -24months after bilat. NSRP Walsh et al. Urology 2001;57:1020-1024 Clinical Strategy Early sexual stimulation Augmented blood flow to the penis

Recent Trend: Early Intervention Early intervention strategies can improve sexual activity and the return of natural spontaneous erections Potential early treatment option for ED following RP Pharmacologic agents 1) Oral (daily / 14-20 day/ month) : on demand or regular dose a. PDE5-inhibitors (sildenafil, tadalafil, vardenafil, mirodenafil, udenafil) 2) IC injection ( three times per week) a. PGE – I (alprostadil) b. low dose Trimix (alprostadil, papaverine, phentolamine) c. Bimix ( papaverine, phentolamine) 3) Intraurethral alprostadil (three times per week, 125 or 250 μg) 2. Non-pharmacologic agents VCD (daily for 5-10 minutes without ring) 3. Combination of above treatments

Treatment of ED after RP Oral PDE5 inhibitors are the first-line Tx Sildenafil (response rate 45%~80%) Zippe et al. Urology 2000;55:241-245 Zagaja et al. Urology 2000;56:631-634 Vardenafil (response rate 37%~71%) Brock et al. J Urol 2003;170:1278-1283 Nehra et al. J Urol 2005;173:2067-2071 Tadalafil (response rate 49%) Montorsi. Eur Urol 2004;45:339-344

Nightly Post-Operative Viagra Dramatically Improves the Return of Spontaneous Erections Following a Bilateral NS-RRP (Padma-Nathan et al, J Urol 2003;4:375) 76 men with normal preoperative erectile function, scheduled to undergo a bilateral NSRRP performed by an experienced surgeon Four weeks post-surgery, patients were randomized to either sildenafil (50 mg, n=23; 100 mg, n=28) or placebo (n=25) and entered a 36-week, double-blind treatment period with nightly drug administration Erectile function was assessed 8 weeks after discontinuation of drug treatment (week 48) by > asking the question “Over the past 4 weeks, have your erections been good enough for satisfactory sexual activity?” and by > IIEF and NPT assessments.

Results Forty-eight weeks after bilateral NSRRP, 14 of 51 (27%) patients receiving sildenafil were responders I.e.demonstrated return of spontaneous normal erectile function compared with 1 of 25 (4%) in the placebo group (P=0.0156) There were no serious adverse events reported, and 2 patients discontinued due to treatment related adverse events

Mean interval from RP to drug : 3 months 174(37%) impotent pts with RRP prescribed sildenafil (470 total, 227 seek) Mean interval from RP to drug : 3 months Assessed at baseline and I year after sildenafil use 100(57%) of 174 responded Urology 2004

Domestic Data 1-Young Dong Severance (2005 KUA, RRP 50 pts.) 3.52 2.63 1.93 1.78 1.38 11.25

Vardenafil Study following RP

Tadalafil Study following RP

Domestic Data 2-AMC (2005 KUA, 28 pts) Tadalafil 20mg Biw or tiw for 6mo. P-value Control No. Pts 16 12 Mean Age 61.2 0.09 64.2 IIEF-5 pre-op 18.5 0.56 17.9 IIEF-5 at no med 2.7 3.3 IIEF-5 at the end 10.3 0.05 3.5 No. Pts. recovered 4(25%)

Response to early use of VCD following RP: results at 9 months Riana R,et al. IJIR 2006;18:77-81

Intra-urethral alprostadil Placebo control study – postop 3 months 70% erection, 57% sexual life Costabile , et al. J Urol 1998;160:1325 Riana , et al. IJIR 2005; 17:86 Mechanism: alprostadil in urethra →direct relaxation of SM in cavernosum →bl. flow ↑ regeneration of CN → NO excretion↑ Side effect: penile pain, urethral burning, expensive

Intra-Cavernosal Injection (ICI) Improved potency rate like other methods. But, not popular due to low compliance of patients Starting point of ICI 1, 2, 4, 7 month 82%, 63%, 57%, 35% success rate At 1 month, increase failure rate due to severe pain Potency rate: Trimix > PGE 1(alprostadil) Montarsi, et al. J Urol 1997;158:1408

Combination Therapy: Cleveland clinic experience Cleveland clinic early intervention program: regimen of daliy VCD Tx. 5 minutes twice a day and maximum use of oral PDE5- Is

Cavernous Nerve graft Cavernous Nerve-interposition Grafting - Kim et al. J Urol 1999, 161:188-192 who enderwent non-nerve sparing prostatectomy 23 patients followed for at least 12 months 26% - spontaneous erections 26% - partial erections 48% - no response Kim et al. J Urol 2001;165:1950-1956

Neuroimmunophilin ligands Neuroprotection Erythropoietin promotes recovery of EF following cavernous nerve injury Denervated rats receive recombinant human erythropoietin(rhEPO) or saline rhEPO effectively recovered erection EPO receptor expression in penile nerves and endothelial cells within the penis rhEPO induced significant axonal regeneration as seen at EM Immunophillin ligands - FK506 cyclosporine A Allaf, et al. AUA 2005.abstract 869,

Conclusions ED is very common subsequent to surgery for prostate Ca. Factors that affect the development of ED are pre-surgery EF, age, stage of the cancer and nerve sparing nature Penile rehabilitation focus on preserve smooth muscle and endothelial function by preventing tissue hypoxia Early initiation of local treatment (PDE5-I, PGE-1, VCD) may return long term spontaneity, or at least to responsiveness to oral therapy We expect the new treatment approach including a genetic or growth factor through the development of the molecular biology More large scale placebo or active control studies are needed to elucidate the best post-op strategy