The Science and the current use of Vacuum Therapy for ED after Radical Prostatectomy

1. The Science and the current use of Vacuum Therapy for ED after Radical Prostatectomy Run Wang, MD, FACS Cecil M. Crigler, MD Endowed Chair in Urology Director of Sexual Medicine University of Texas Medical School at Houston and MD Anderson Cancer Center Houston, TX 77030, USA

5. Introduction • Vacuum therapy (VT) uses negative pressure to distend the corporal sinusoids and to increase blood inflow to the penis. • VCD: a constricting ring is used at the base of the penis to prevent blood outflow from the corpora cavernosa, and an erection is maintained. • VED: without a constrictive ring to increase blood oxygenation (possibly other factors in the blood) in the corpora cavernosa and also to provide stretching effect.

6. History of Vacuum Therapy 1874 John King, MD (when there is impotency with a diminution of the size of the male organ, the glass exhauster should be applied to the part) 1917 Otto Lederer (first patent-surgical device to produce erection with vacuum in conjunction with a compression ring) 1960s Geddins Osbon (popularizing and perfecting the device with personal used the device for more than 20 years) 1982 Erecaid (first FDA approved VED) 1986-1989 (established efficacy and safety profiles) Nadig /Witherington, MDs 1996 AUA (recommendation in the guidelines as one of the treatment for organic ED)

7. Efficacy of VCDs: clinic data Authors Year Study design Enrollee (follow-up) Results Nadig et al. 1986 Prospective 35 (8–22 months) >90% achieved adequate erections. 80% use regularly Witherington 1989 Retrospective 1517 (8.6 months) 92% good erection Sidi et al. 1990 Prospective 100 (7.9 months) 68% satisfaction rate Cookson et al. 1993 Retrospective 216 (29 months) 70% use regularly. Quality of erection plus satisfaction 490% Segenreich et al. 1993 Prospective 150 (25 months) 75% achieved adequate erection. 490% satisfaction rate Blackard et al. 1993 Prospective 45 (?) 69% satisfaction rate Meinhart et al. 1993 Prospective 74 (3 weeks) 27% satisfaction rate Vrijhof et al. 1994 Prospective 67 (?) 50% achieved adequate erection Baltaci et al. 1995 Retrospective 61 (12.8 months) >80% satisfaction rate. 67% effectiveness rate Bosshardt et al. 1995 Prospective 30 (6 months) Quality of erection 80% Kolettis et al. 1995 Prospective 50 (?) 56% satisfaction rate. An acceptable treatment mode for CVOD Lewis et al. 1997 Retrospective 5847 (?) 65–83% success Dutta et al. 1999 Prospective 129 (37 months) High attrition rate (65%). 35% satisfaction rate Abbreviations: CVOD, corporeal veno-occlusive dysfunction; VCD, vacuum constriction device. Yuan J, Hoang An, Romero CA, Lin H, Dai Y, Wang R. IJIR 2010 , 22: 211-9

8. Attitudes and Practice Patterns of Penile Rehabilitation • 301 physicians from 41 countries • 83.7% performed rehab • Rehab strategies: - PDE5 inhibitors 95.4% - ICI 75.2% - VED 30.2% - MUSE 9.9% Reasons to not do rehab: - Cost 50% - No evidence 25% - not familiar 25%

9. Penile Rehabilitation - VED • VED is gaining popularity. • MD Anderson evaluated compliance and recovery of penile length and erectile function with programmed use of VED and ICI in patients who underwent unilateral nerve-sparing prostatectomy with or without unilateral sural nerve grafting.

10. Changes in penile length for patients using VED (Mean ± SD cm) 4 mo Compliance 8 mo Compliance 12 mo Compliance Good Poor Good Poor Good Poor N 35 5 15 9 10 7 Length 0.4 ± 0.8 -0.3 ± 0.5 0.8 ± 1.5 -0.2 ± 1.7 0.5 ± 06 -0.3 ± 1.5 P value 0.05 0.22 0.32 Compared with 6 week postoperative measurement

11. Penile Rehabilitation - VED • Raina et al (2006) found 17% vs 11% recovery of erectile function with daily use of VED; and only 23% vs 85% reporting penile shrinkage compared with control in a 9 month study with total of 109 patients. • Kohler et al (2007) conducted a multi-centered randomized study to compare early (1 month post nerve sparing RP) to traditional (6 months after surgery) use of the VED. The preliminary results showed that early use of VED for rehabilitation (10 min a day without the constriction ring) significantly improves the IIEF-EF scores and preserves penile length compared to control group.

12. Penile Rehabilitation - VED • Mean O2 saturation of corporeal blood immediately after VED induced erection was 79.2% compared to 94.5% from artery and 54.7% from vein. • 58% of blood with VED induced erection was arterial and 42% of blood was venous in origin. • The O2 saturation decreased significantly after 30 minutes with the ring in place. This finding established the rationale that we do not recommend using ring when VED is used for penile rehabilitation purpose. • Arterial blood may not only provide oxygen to the corporal tissues, it may also carry other nutrients such as certain growth factors to the tissues.

13. What is the Mechanism?

14. Design Rat VED Principle: Replicate human VED

15. Human VED

16. Rat VED Yuan JH, Westney OL, Wang R. JSM 6(12): 3247-53, 2009.

17. Pressure-Rat VED Pressure (mmHg) Time (5 Min) Yuan JH, Westney OL, Wang R. JSM 6(12): 3247-53, 2009.

18. Application-Rat VED Yuan JH, Westney OL, Wang R. JSM 6(12): 3247-53, 2009.

19. Method The rat bilateral cavernous nerve crush (BCNC) model was used to replicate the pathological change of post radical prostatectomy. • Sprague-Dawley rats, weighing 200–250g, were randomly and equally divided into three groups: • sham (CN expose surgery only, no nerve crushing, no VED therapy); • control (BCNC procedure, no VED therapy); • treatment group (BCNC procedure, VED therapy beginning at 2 weeks after BCNC surgery, 5 minutes twice daily with 1 minute duration, Monday to Friday, total VED treatment time four weeks).

20. Penile Sizes Length of the penes Diameter of the penes Length (mm) Diameter (mm) * * 0 4W 0 4W 0 4W 0 4W 0 4W 0 4W Sham BCNC+VED BCNC Sham BCNC BCNC+VED

21. ICP/MAP Ratios 1.25 2.5 5.0 7.5 Voltage ICP/MAP Ratios ** Control * BCNC BCNC + VED Eur Urol 58: 773-80, 2010

22. ED after Prostatectomy Radical prostatectomy Neuropraxia Reduction in arterial inflow Hypoxia Apoptosis The veno-occlusive mechanism defect ED

23. VED decreases hypoxia Cavernosal sinoids HIF-1α IHC Sham BCNC BCNC+VED Eur Urol 58: 773-80, 2010

24. VED decreases apoptosis TUNEL assay--cavernosal sinoids Sham BCNC BCNC+VED Eur Urol 58: 773-80, 2010

25. VED increases eNOS Cavernosal sinoids eNOS IHC Sham BCNC BCNC+VED Eur Urol 58: 773-80, 2010

26. Cavernosal sinoids α-SMA IHC Sham BCNC BCNC+VED VED increases α-SMA Eur Urol 58: 773-80, 2010

27. VED decreases TGF-β1 Cavernosal sinoids TGF-β1 IHC Sham BCNC BCNC+VED Eur Urol 58: 773-80, 2010

28. VED decreases collagen Cavernosal sinoids Masson’s trichrome stain Sham BCNC+VED BCNC Eur Urol 58: 773-80, 2010

29. Hypothesis VED Therapy Blood Neuropraxia Arterial inflow Hypoxia Apoptosis Veno-occlusive mechanism Erectile function

30. Conclusions • VED therapy improves erectile function and preserves penile size in rats with BCNC via anti-hypoxic, anti-apoptotic and anti-fibrotic mechanisms. • This study provides scientific evidence for VED therapy in penile rehabilitation after radical prostatectomy. This scientific evidence may motivate physicians’ recommendation and improve patients’ compliance. • Clinical studies with long-term results using VED for penile rehabilitation are not available at this time. • The multi-center, prospective study to compare the effectiveness of VED vs sildenafil in penile rehabilitation after RP should be conducted.