Post Radical Prostatectomy Penile Rehabilitation - AUA Update Series 2008

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AUA Update SeriesLesson 36 Volume 27 2008

Penile Rehabilitation After Radical Prostatectomy Learning Objective:At the conclusion of this medical education activity, the participantwill appreciate the pathophysiology of erectile dysfunction after radical prostatectomy aswell as the scientific evidence behind the concept of penile rehabilitation.

Rodrigo Blaya, M.D.Disclosures: Nothing to disclose

and John P. Mulhall, M.D.

Disclosures: Nothing to disclose

Division of UrologyMemorial Sloan-Kettering Cancer Center

New York, New York

This self-study continuing medical education activity is Credit Designation Statement: The American Urological of the audience with information on which they candesigned to provide urologists, Board candidates Association designates this educational activity for a make their own judgments. The program plannersand/or residents affordable and convenient access to maximum of 1.0 AMA PRA Category 1 Credit . Each must resolve any conflicts of interest prior to thethe most recent developments and techniques in physician should only claim credit commensurate with commencement of the educational activity. It remainsurology. The American Urological Association (AUA) is the extent of their participation in the activity. for the audience to determine if the facultysaccredited by the Accreditation Council for Continuing relationships may influence the educational contentAUA Disclosure Policy: As a provider accredited by theMedical Education (ACCME) to provide continuing with regard to exposition or conclusion. WhenACCME, the AUA must insure balance, independence,medical education for physicians. The AUA takes unlabeled or unapproved uses of drugs or devices areobjectivity and scientific rigor in all its activities. Allresponsibility for the content, quality and scientific discussed, these are also indicated.faculty participating in an educational activity providedintegrity of this CME activity. Unlabled/Unapproved Uses: It is the policy of the AUAby the AUA are required to disclose to the audience

to require the disclosure of all references toany relevant financial relationships with any unlabeled or unapproved uses of drugs or devicescommercial interest to the provider. The intent of thisprior to the presentation of educational content.disclosure is not to prevent faculty with relevantPlease consult the prescribing information for fullfinancial relationships from serving as faculty, butdisclosure of approved uses.rather to provide membersPublication date: November 2008

Expiration date: November 2011

2008 American Urological Association, Education and Research Inc., Linthicum,


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FIG. 1. Mechanisms of ED development after radical prostatectomy

FIG. 2. Diagram of veno-occlusive mechanism

muscle cells in culture. 26 Upon oxygenation, endogenous prostan-oids and cyclic adenosine monophosphate are produced. Endoge-nous PGE1 has among its actions the decrease in TGF- 1 produc-tion. The interaction between PGE and TGF- 1 pathways may bekey in determining connective tissue/smooth muscle balance in thecorpus cavernosum. 25

Recently, Mu ller et al demonstrated in a rat cavernous nerve

injury model that the early use of hyperbaric oxygen therapy im-proved erectile function recovery after cavernous nerve injury, en-dothelial nitric oxide synthase andnerve growth factorexpression. 27

In the sham group intracavernosal pressure-to-mean arterial pres-sure ratio was 70% compared to 30% in animals with cavernousnerve injury treated with room air and 55% in nerve injured animalstreated with 10 consecutive days of hyperbaric oxygen therapyat 3ATM (fig. 6). These data support the concept of cavernosaloxygenation concept as a protective mechanism for erectile func-tion, and suggest that these effects appear to be mediated via preser-vation of neurotrophic and endothelial factor expression. Animal evidence supporting pharmacological rehabilitation. Rats

exposed to bilateral cavernous injury treated with PDE5 inhibitors

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FIG. 3. Venous leak development with reducing corporal smoothmuscle content. As smooth muscle content is reduced (replacementwith collagen) venous leak severity increases.


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(vardenafil, sildenafil and tadalafil) had significant preservation(although not normalization) of erectile function using ICP/MAPas an end point. 28-33 In addition, smooth muscle loss and smoothmuscle apoptosis were reduced, and endothelial factor staining waspreserved in PDE5 inhibitor treated animals compared to controlanimals. Mulhall et al reported that sildenafil resulted in ICP/ MAP improvement, smooth muscle-to-collagen ratio protectionand preservation of expression of endothelial factors CD31 andendothelial nitric oxide synthase. 32 Ferrini 28 and Kovanecz 29et al studied sildenafil, vardenafil and tadalafil in rats aftercavernous nerve resection. Compared with the nerve resectiononly group, rats treated with PDE5 inhibitors had improvederectile hemodynamics and preserved smooth muscle-to-colla-gen ratio. Human evidence supporting pharmacological rehabilitation. In

1997 Montorsi et al postulated that the early postoperative use of pro-erectile therapy (alprostadil injections) would increase cavern-ous oxygenation and potentially avoid the damage related to theearly postoperative absence of spontaneous erections. 16 There wasa 3-fold increase in the ability of men to obtain spontaneouserections at 6 months after surgery (67% vs 20%). The mostfrequent vascular impairment noted was cavernous veno-occlu-sive dysfunction, which occurred more frequently in untreatedthan in alprostadil treated patients (53% vs 17%, p


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FIG. 6. Effect of hyperbaric oxygen on erectile function in cavern-ous nerve crush injury model. C/H , no nerve crush, no hyper-baric oxygen. C+/H , bilateral cavernous nerve crush, no hyper-baric oxygen. C+/H+, bilateral cavernous nerve crush, hyperbaricoxygen.

tion method is the unknown mechanism for improving spontaneouserection. In a randomized clinical trial Kohler et al showed thatinitiating the use of a VED protocol 1 month after RP improvesearly sexual function and helps preserve penile length. 36 However,no spontaneous erections adequate for intercourse were reportedat the last follow-up for any patient.

These data support the concept that the VED could be a tool forthe treatment of ED but it is not a rehabilitation tool. If one believes

FIG. 7. Penile rehabilitation algorithm at Memorial Sloan-Kettering Cancer Center. PDE5i , PDE5 inhibitor. V , sildenafil. L, vardenafil. C ,tadalafil. ICI , intracavernosal injections.

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in the concept of cavernosal oxygenation as a significant contributorto penile rehabilitation, then application of a vacuum device willlikely not contribute to rehabilitation. Application of a VED, evenwithout the use of a constriction band, fails to increase cavernosalPO 2 levels significantly. Bosshardt et al demonstrated that half of the blood within the corpora after vacuum device application wasvenous in nature. 37 However, there might be some intrinsic benefitfrom stretching the penis. After all, perhaps this is one of the meansby which erection may protect erectile tissue. In the final analysisthe role of the vacuum device in penile rehabilitation can only bedetermined by a large, multicenter controlled trial.

The transurethral PGE1 suppository was introduced in 1997 andthere has been a revival in interest in the use of this therapy forpost-RP rehabilitation. 38 Despite the absence of large, randomizedcontrolled trials, there is some scientific rationale to the use of PGE1 postoperatively in this patient population. Given the factthat endogenous PGE may have a controlling influence on TGF-

expression, alprostadil may have intrinsic beneficial effects forerectile tissue. Experimental studies are ongoing to analyze thisconcept.

STRUCTURE OF A PENILE REHABILITATION PROGRAM

In the final analysis it cannot be definitively stated which rehabili-tation regimen is optimal in the radical prostatectomy population.However, a multicenter, randomized controlled trial is about tocommence to assess the impact of oral PDE5 inhibitors with orwithout intracavernosal injections on erectile function recoveryafter RP. There are clear signals in the aforementioned animal andhuman data that regular PDE5 inhibitor use is of benefit to erectile


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tissue in this setting. There are also 2 human studies indicatingearly erection after RP using predominantly injection therapy. Thedata suggesting that venous leak increases as time passes after RPshould encourage clinicians to get patients on some rehabilitationstrategy soon after surgery.

At our institutions we urge all patients to commence rehabilitationno later than 3 months after surgery, as the data would suggest thatvenous leak rates increase steadily after 4 months. The algorithmpresented in figure 7 is one we currently use and is based on thecurrent best available evidence in favor of PDE5 inhibitor andintracavernosal injections. Currently we do not use alprostadil orvacuum devices in our rehabilitation program because of the ab-sence of robust data for these strategies at this time. Ongoingresearch is aimed at defining the value and impact of thisprogram, which is labor-intensive and benefits from the pres-ence of a full-time nurse practitioner to coordinate it.

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Cancer J Clin 2006; 56: 106.2. Han M, Partin AW, Pound CR et al: Long-term biochemical dis-

ease-free and cancer-specific survival following anatomic radicalretropubic prostatectomy. The 15-year Johns Hopkins experience.Urol Clin North Am 2001; 28: 555.

3. Stanford JL, Feng Z, Hamilton AS et al: Urinary and sexual func-tion after radical prostatectomy for clinically localized prostatecancer: the Prostate Cancer Outcomes Study. JAMA 2000; 283:354.

4. Marshall FF, Chan D, Partin AW et al: Minilaparotomy radicalretropubic prostatectomy: technique and results. J Urol 1998;160: 2440.

5. Catalona WJ, Carvalhal GF, Mager DE et al: Potency, continenceand complication rates in 1,870 consecutive radical retropubicprostatectomies. J Urol 1999; 162: 433.

6. Walsh PC and Donker PJ: Impotence following radical prostatec-tomy: insight into etiology and prevention. J Urol 1982; 128: 492.7. Burnett AL, Aus G, Canby-Hagino ED et al: Erectile function

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8. Litwin MS, Flanders SC, Pasta DJ et al: Sexual function andbother after radical prostatectomy or radiation for prostate cancer:multivariate quality-of-life analysis from CaPSURE. Cancer of theProstate Strategic Urologic Research Endeavor. Urology 1999;54: 503.

9. Greenlee RT, Murray T, Bolden S et al: Cancer statistics, 2000.CA Cancer J Clin 2000; 50: 7.

10. Litwin MS, Gore JL, Kwan L et al: Quality of life after surgery,external beam irradiation, or brachytherapy for early-stage prostatecancer. Cancer 2007; 109: 2239.

11. Rabbani F, Stapleton AM, Kattan MW et al: Factors predictingrecovery of erections after radical prostatectomy. J Urol 2000;164: 1929.

12. Walsh PC, Marschke P, Ricker D et al: Patient-reported urinarycontinence and sexual function after anatomic radical prostatec-tomy. Urology 2000; 55: 58.

13. Broderick GA and Arger P: Duplex Doppler ultrasonography: non-invasive assessment of penile anatomy and function. Semin Roent-genol 1993; 28: 43.

14. Droupy S, Hessel A, Benot G et al: Assessment of the functionalrole of accessory pudendal arteries in erection by transrectal colorDoppler ultrasound. J Urol 1999; 162: 1987.

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15. Mulhall JP and Graydon RJ: The hemodynamics of erectile dys-function following nerve-sparing radical retropubic prostatectomy.Int J Impot Res 1996; 8: 91.

16. Montorsi F, Guazzoni G, Strambi LF et al: Recovery of spontane-ous erectile function after nerve-sparing radical retropubic prosta-tectomy with and without early intracavernous injections of alpros-tadil: results of a prospective, randomized trial. J Urol 1997;158: 1408.

17. Mulhall JP, Slovick R, Hotaling J et al: Erectile dysfunction afterradical prostatectomy: hemodynamic profiles and their correlationwith the recovery of erectile function. J Urol 2002; 167: 1371.

18. Carrier S, Zvara P, Nunes L et al: Regeneration of nitric oxidesynthase-containing nerves after cavernous nerve neurotomy in therat. J Urol 1995; 153: 1722.

19. User HM, Hairston JH, Zelner DJ et al: Penile weight and cellsubtype specific changes in a post-radical prostatectomy model of erectile dysfunction. J Urol 2003; 169: 1175.

20. Hu JC, Elkin EP, Pasta DJ et al: Predicting quality of life afterradical prostatectomy: results from CaPSURE. J Urol 2004;171: 703.

21. Leungwattanakij S, Bivalacqua TJ, Usta MF et al: Cavernous neu-

rotomy causes hypoxia and fibrosis in rat corpus cavernosum. JAndrol 2003; 24: 239.

22. Nehra A, Azadzoi KM, Moreland RB et al: Cavernosal expandabil-ity is an erectile tissue mechanical property which predicts trabecu-lar histology in an animal model of vasculogenic erectile dysfunc-tion. J Urol 1998; 159: 2229.

23. Iacono F, Giannella R, Somma P et al: Histological alterations incavernous tissue after radical prostatectomy. J Urol 2005; 173:1673.

24. Schwartz EJ, Wong P and Graydon RJ: Sildenafil preserves intra-corporeal smooth muscle after radical retropubic prostatectomy. JUrol 2004; 171: 771.

25. Moreland RB: Is there a role of hypoxemia in penile fibrosis: a

viewpoint presented to the Society for the Study of Impotence. IntJ Impot Res 1998; 10: 113.

26. Moreland RB, Traish A, McMillin MA et al: PGE1 suppresses theinduction of collagen synthesis by transforming growth factor-beta 1 in human corpus cavernosum smooth muscle. J Urol 1995;153: 826.

27. Muller A, Tal R, Donohue JF et al: The effect of hyperbaric oxygentherapy on erectile function recovery in a rat cavernous nerveinjury model. J Sex Med 2008; 5: 562.

28. Ferrini MG, Davila HH, Kovanecz I et al: Vardenafil preventsfibrosis and loss of corporal smooth muscle that occurs after bilat-eral cavernosal nerve resection in the rat. Urology 2006; 68: 429.

29. Kovanecz I, Rambhatla A, Ferrini M et al: Long-term continuous

sildenafil treatment ameliorates corporal veno-occlusive dysfunc-tion (CVOD) induced by cavernosal nerve resection in rats. Int JImpot Res 2008; 20: 202.

30. Kovanecz I, Rambhatla A, Ferrini MG et al: Chronic daily tadalafilprevents the corporal fibrosis and veno-occlusive dysfunction thatoccurs after cavernosal nerve resection. BJU Int 2008; 101: 203.

31. Lysiak JJ, Yang SK, Klausner AP et al: Tadalafil increases Akt andextracellular signal-regulated kinase 1/2 activation, and preventsapoptotic cell death in the penis following denervation. J Urol2008; 179: 779.

32. Mulhall JP, Mu ller A, Donohue JF et al: The functional and struc-tural consequences of cavernous nerve injury are ameliorated bysildenafil citrate. J Sex Med 2008; 5: 1126.


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33. Vignozzi L, Filippi S, Morelli A et al: Effect of chronic tadalafiladministration on penile hypoxia induced by cavernous neurotomyin the rat. J Sex Med 2006; 3: 419.

34. Mulhall J, Land S, Parker M et al: The use of an erectogenicpharmacotherapy regimen following radical prostatectomy im-proves recovery of spontaneous erectile function. J Sex Med 2005;2: 532.

35. Padma-Nathan H, McCullough AR, Levine LA et al: Randomized,

double-blind, placebo-controlled study of postoperative nightlysildenafil citrate for the prevention of erectile dysfunction afterbilateral nerve-sparing radical prostatectomy. Int J Impot Res 2008;20: 479.

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36. Kohler TS, Pedro R, Hendlin K et al: A pilot study on the earlyuse of the vacuum erectiondeviceafter radical retropubic prostatec-tomy. BJU Int 2007; 100: 858.

37. Bosshardt RJ, Farwerk R, Sikora R et al: Objective measurementof the effectiveness, therapeutic succes and dynamic mechanismsof the vacuum device. Br J Urol 1995; 75: 786.

38. Costabile RA, Spevak M, Fishman IJ et al: Efficacy and safetyof transurethral alprostadil in patients with erectile dysfunction

following radical prostatectomy. J Urol 1998; 160: 1325.


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Study Questions Volume 27 Lesson 36

1. The incidence of venous leak 12 months after radical prosta-tectomy isa. 10%b. 20%c. 30%d. 40%e. 50%

2. Arteriogenic erectile dysfunction after radical prostatectomyis related to injury of the

a. Internal iliac arteryb. Common penile arteryc. Bulbourethral arteryd. Internal pudendal arterye. Accessory pudendal artery

3. A man complains of penile sensory loss 6 months after radicalprostatectomy. The cause of this is most likely

a. Psychogenicb. Cavernous nerve tractionc. Ilioinguinal nerve injuryd. Postoperative periprostatic fibrosise. Genitofemoral nerve injury

Take this test online at http://www.auanet.org/eforms/cme/

4. Venous leak after radical prostatectomy is due toa. Tunical fibrosisb. Smooth muscle collagenationc. Accessory pudendal artery injuryd. Excess circulating adrenalinee. Androgen deficiency

5. Structural changes to erectile tissue after radical prostatec-tomy have been documented as early as

a. 2 Monthsb. 4 Monthsc. 6 Monthsd. 12 Monthse. 18 Months

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