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

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

3. 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.

4. → 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

5. Potency rate of post RP-ED

6. Overall Potency Rate after RP
Overall Potency Rate after RP? % by experienced surgeons (>1000 cases) % for most urologists

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

9. 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

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

11. Sexual Function following Laparoscopic RP1
months 3 6 12
% of
patients 33 41 29 87
Kartz, et al: J Urol 2002;168:

12. 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)

13. 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:

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

15. Pathophisiology of post RP-ED

16. 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

17. 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

18. 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 mo
Consistent with slowly resolving neurapraxia

19. Recovery of erections

20. 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

21. Histologic change in human penis after RP

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

23. Penile Rehabilitation following RP

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

25. 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 / 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

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

27. 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.

28. 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

29. 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

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

31. Vardenafil Study following RP

32. Tadalafil Study following RP

33. 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%)

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

35. 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

36. Intra-Cavernosal Injection (ICI)
Improved potency rate like other methods.
But, not popular due to low compliance of patients
Starting point of ICI
1, , , 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

37. 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

38. Cavernous Nerve graft Cavernous Nerve-interposition Grafting
- Kim et al. J Urol 1999, 161:
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:

39. 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,

40. 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