Penile Rehabilitation Following Pelvic Surgery

FICTIONAlexander W. Pastuszak, MD, PhD

Assistant ProfessorCenter for Reproductive Medicine

Division of Male Reproductive Medicine and SurgeryScott Department of UrologyBaylor College of Medicine

Houston, TX

Disclosures

I have no relevant financial relationships to disclose

I am going to discuss off-label management of a clinical condition

Objectives

To understand the paucity of high quality evidence supporting penile rehab

To understand the (low quality) studies that support benefits of penile rehab

To understand the (high quality) studies that do not support penile rehab

Fact vs. FictionFACT:

Penile hypoxia leads to penile atrophy, smooth muscle apoptosis, venocclusive dysfunction, and fibrosisPDE5’s improve erectile function in ratsUse of PDE5’s, ICI, MUSE improves erectile function while on therapyPenile traction / VED improves penile length

FICTION:Treatment of HUMAN males post pelvic oncologic treatment using PDE5i’s, MUSE, ICI

Improves erectile functionImproves responsiveness to erectogenic aidsRestores erectile function soonerPrevents loss of erectile function

Levels of Evidence – Oxford Criteria

1a – Systematic review of homogenous RCTs

1b – Individual RCT with narrow CI

2b – Individual cohort study (or low quality RCT)

3b – Case-control study

4 – Case-series

5 – Expert opinion, bench research, animal studies

CEBM; Oxford Levels of Evidence – March 2009.

Level 1 is BETTER than Level 5Improves penile hypoxia

smooth muscle contentendothelial cell apoptosis

Prevents venous leakresponse to penile injectionoverall erectile function

Affects smooth muscle genesoxidative stresssurvival kinases, cGMP, NOpro-fibrotic TGF-β1

Neuroprotective

Animal Studies – PDE5i’s in a Nerve Crush Model

There is NO question that there is STRONG Level 5 evidence

arguing for penile rehabilitation

Levels of Evidence – Oxford Criteria

1a – Systematic review of homogenous RCTs

1b – Individual RCT with narrow CI

2b – Individual cohort study (or low quality RCT)

3b – Case-control study

4 – Case-series

5 – Expert opinion, bench research, animal studies

CEBM; Oxford Levels of Evidence – March 2009.

Trials Supporting Penile Rehabilitation

Pace et al.N=40

Post-NS RP

*P<0.05

24 wks treatment

IIEF 25.2* IIEF 17.4Results

Sil 50/100mg QHS Placebo

2 wks

Penile Rehab Following Nerve Sparing Radical Prostatectomy

Disabil Rehabil. 2010; 32: 1204.

Medication unassisted intercourse 54% vs. 21%Normal EF in 34% vs. 18%

Padma-Nathan et al.N=76

Post-NS RP

Sil 50 mg qhs

Sil 100 mg qhs Placebo

*Response ≥ 8 on Q3-4 IIEF; p=0.02

36 wks treatment

8 wks washout

26%*IIEF-12.4

29%*IIEF-13.7

4%*IIEF-8.8

4 wks

PDE5i’s Following Nerve Sparing Radical Prostatectomy

Int J Impot Res. 2008; 20: 479.

Positive response in 27% (sildenafil) vs. 4% (placebo)

Padma-Nathan et al.N=76

Post-NS RP

Sil 50 mg qhs

Sil 100 mg qhs Placebo

26%*IIEF-12.4

29%*IIEF-13.7

4%*IIEF-8.8

PDE5i’s Following Nerve Sparing Radical Prostatectomy

Meta-analysis, expected placebo response 34% (CI 30-38%)2

Trial halted prematurely due to lack of response

Authors hypothesized that low placebo response due to strict criteria

Meta-analysis used similar criteria

*Response ≥ 8 on Q3-4 IIEF; p=0.02Int J Impot Res. 2008; 20: 479.

Int J Radat Oncol Biol Phys. 2002; 54: 1063.

Montorsi et al. N=27 Post-NS RP

Alprostadil3x/wk Observation

*P<0.01

12 wks treatment

67% spontaneous

erections*

20% spontaneous

erections*

Results(6 months)

4 wks

No washout!

PGE1 Following Nerve Sparing Radical Prostatectomy

J Urol. 1997; 158:1408.

No preop EF assessmentNo validated questionnaires

No long-term data

Trials Failing to Support Rehab

Montorsi et al.N=423

Post-NS RP

Var 10 QHS + Plc prn

Plc QHS + Var 5-20 prn Placebo

Primary outcome IIEF≥22 after washout

36 wks treatment

8 wks washout

Var prn

4 wks

8 wks open-label

Nightly vs. On-Demand Vardenafil After Nerve Sparing Radical Prostatectomy (REINVENT)

Eur Urol. 2008; 54:924.

Nightly vs. On-Demand Vardenafil After Nerve Sparing Radical Prostatectomy (REINVENT)

Eur Urol. 2008; 54:924.

Conclusions:Biggest RCT 400+ patientsNO difference in IIEF scores AFTER washoutNo additional benefit to daily dose group during subsequent prn dosing

Montorsi et al. N=315 Post-NS RP

Tad 5 mg Daily

Tad 20 mg prn Placebo

Primary outcome IIEF≥22 after washoutSpecifically targeted UNASSISTED erections

36 wks treatment

6 wks washout

Tad 5 mg Daily

Screening period

12 wks open-label

Eur Urol. 2014; 65:587.

Daily vs. On-Demand Tadalafil After Nerve Sparing Radical Prostatectomy (REACTT)

Eur Urol. 2014; 65:587.

Washout

Conclusions:NO difference in IIEF scores AFTER washoutNo additional benefit to daily dose group during subsequent prn dosing

Eur Urol. 2014; 65:587.

Pavlovich et al.N=74Sil 50 QHS + Plc prn vs. Plc QHS + Sil 50 prnOptimal cohort ≤65 yo, IIEF≥26 preop, NS RP

Kim et al.N=74Sildenafil 50 QHS vs. PlcPrn sildenafil use permitted

Both 12 mo treatment + 1 mo washoutNo true placebo arms – combined with treatment

BJU Int. 2013; 112:844.Andrology. 2016; 4:27.

Other Anti-Penile Rehab Randomized Controlled Trials

Daily vs. On-Demand Sildenafil After Nerve Sparing Radical Lap / RoboticProstatectomy

BJU Int. 2013; 112:844.Andrology. 2016; 4:27.

CONCLUSIONS:No difference in IIEF scores or potency Favorable recovery regardless of PDE5i dosing

No other RCTs

Yiou et al.Retrospective, N=75Post-NS lap RP, good erections pre-opICI with PGE1 beginning 1 mo, twice weeklyAssessments at 12, 24 months

What About ICI?

No difference in IIEF with or without ICITx satisfaction decreased 12 mo (67%) to 24 mo (47%)

Sex Med. 2015; 3:42.

No RCTs

Raina et al.Prospective, N=91Post-NS RP56 men on MUSE, 35 not treatedMUSE starting 3 weeks postop, thrice weeklyAssessments at median 6 monthsOnly 68% (38) of men completed the study

What About MUSE?

21/56 (38%) in MUSE group vs. 36% in untreated group with spontaneous erections at 6 months

BJU Int. 2007; 100:1317.

Very few studies

Köhler et al.RCT, N=28Post-NS RP, baseline IIEF >11 (mean IIEF = 22)VED starting 1 mo vs. 6 mo postop, 10 min/day for 5 months

What About VED?

IIEF higher in early intervention group (12.4) vs. late intervention (3.0) at 6 months

Preservation of stretched penile length in early intervention group

BJU Int. 2007; 100:858.

VED may facilitate maintenance of penile length in men post-RP and may result in

improved erectile function

Summary - Pro vs. Con RCT/PC TrialsPro (N=103):

Pace (2010) N=40Miraculous IIEF results (baseline) – not repeated in any other study

Padma-Nathan (2008) N=36Stopped own trial d/t lack of efficacyPlacebo several SD below expected

Montorsi (1997) N=27Assessed while still on tx!!

Con (N=912):Montorsi (2008), N=423Montorsi (2014), N=315Pavlovich/Kim (2013, 2016), N=174

Con

Pro

The Data Are Clear:

PDE5i’s do NOT work – if you offer them, you’re recommending an expensive placebo

Inadequate evidence to suggest ANY therapy improves spontaneous erectile function

Lack of proper washout limits study interpretation

VED may maintain / improve penile length

The ONLY Role for Penile Rehab:Clinical trial - experimental

Penile Rehab - FICTIONCombination therapies PDE5i ± VED ± ICIBetter understanding and targeting of the mechanisms of ED after pelvic surgery

Immune Modulation (Immunophilin)Animals better EF (Level 5)Humans no neuroprotective benefit (Level 1a)

Vascular/Nerve Growth Factors (VEGF, NGF, FGF)Animals better EF (Level 5) Humans no data

Stem CellsAnimals better EF (Level 5) Humans pending…

What’s Missing?

When Using Penile Rehab, Hope That Luck is on Your Side…

http://www.azquotes.com/quote/720198

Thank you!

pastusza@bcm.edupppppppppppppppppppppppaaaaaaaaaaaaaaaaaaaaaassssssssssssssssssssstttttttttttttttttttttttuuuuuuuuuuuuuuuuuuuuuusssssssssssssssssssssszzzzzzzzzzzzzzzzzzzzzzzaaaaaaaaaaaaaaaaaaaaaaa@@@@@@@@@@@@@@@@@@@@@@bbbbbbbbbbbbbbbbbbbbcccccccccccccccccccccmmmmmmmmmmmmmmmmmmmmmmm....................eeeeeeeeeeeeeeeeeeeeeeddddddddddddddddddddddduuuuuuuuuuuuuuuuuuuuuu

Testosterone Therapy for Penile Rehabilitation

Alexander W. Pastuszak, MD, PhDAssistant Professor

Center for Reproductive MedicineDivision of Male Reproductive Medicine and Surgery

Scott Department of UrologyBaylor College of Medicine

Houston, TX

Disclosures

I have no relevant financial relationships to disclose

ObjectivesTo understand the incidence and natural history of ED after pelvic surgery

To understand the role of testosterone in erections and sexual function

To examine the role of testosterone therapy after pelvic surgery

To explore the relationship between testosterone therapy and prostate cancer

Sexual Dysfunction After Pelvic SurgeryTypes of Sexual Dysfunction:

Erectile Dysfunction (ED) Changes in penile size / shape (i.e. PyD)Ejaculatory / orgasmic dysfunctionPsychosexual impairment

Incidence of ED:ED after CaP therapy (RP and XRT) 60-70%

Data lacking re: patient-reported outcomes, comparison of surgical techniques,

J Sex Med. 2013; 10 Suppl 1: 102.Eur Urol. 2012; 62: 273.

J Sex Med. 2007; 4: 538.

Erectile Dysfunction Following Radical Prostatectomy

In the U.S., 180,890 men with prostate cancer in 2016. ¹

~45% of men have RP for definitive local therapy.²

AUA panel of experts literature review from 1991-2004 ED in 10-100% of men. ³

72% of men are unable to achieve a natural erection sufficient for penetration 60 months after a RP.²

~75,000 new patients per year suffering from ED following RP

Results from neuropraxia, venous leak, and arterial insufficiency

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Role of Testosterone Following Radical Prostatectomy

http://www.prohormonesupplements.org/tag/testosterone-therapy/

Role of Testosterone in Maintaining Erectile Function

Androgen deficiency results in:Increased penile tissue atrophy and apoptosis Increased adipose tissue within the subtunical regionDecreased cavernosal blood flow Decreased nitric oxide synthase (NOS) levels

Venous leak can be reversed with TTh

Most hypogonadal men with ED can restore erectile function with TTh, but not with the administration of PDE5i alone

Intnt J J Impotot Reses. s. 2003; 15: 26.

Do testosterone levels predict corporal venous leakage in patients with organic erectile dysfunction?

Kumaran Sathyamoorthy, Mohit Khera, Jesse N. Mills, David M. Fenig, Larry I. LipshultzScott Department of Urology, Baylor College of Medicine, Houston, Texas, USA.

•

•

••

Methods:45 men with ED and penile duplex ultrasoundExclusion criteria: history of RP or Peyronie’s disease44 men with serum T levels grouped into

Hypogonadal (T<300 ng/dl) Eugonadal (T>300 ng/dl)

OR for or venous s leak in n hypogonadalal vs. s. eugonadalal men: 3.6

yp gyy666 (95% CI: I: I 0.686868, 19999)

(((p=0.1222222)

Testosterone and Sildenafil in Hypogonadal Men with ED

J J Urol.l. 2004; 172: 658.

IIEF-4.4 IIEF-2.1

12 wks treatment

Assessed at 4, 8, 12 weeks

4 week results

N=75 T<400, failed Sil

100mg prn

T 1% gel + Sil 100mg prn

Placebo + Sil 100mg prn

P=0.029

Testosterone and Sildenafil in Hypogonadal Men with ED

J J Urol.l. 2004; 172: 658.

Quality of Life

IIEF Total Score

Conclusion:Testosterone improves erectile function in hypogonadal men with ED who are unresponsive to sildenafil alone

Testosterone Therapy in HypogonadalMen Who Fail Sildenafil Treatment

Urologygy. 2006; 67:571.

AndroGel + Sil 100mg prn

4 wks treatment

Additional 12 weeks treatment

N=90Failed Sil 100mg prn x 3 months

AndroGel

N=24T <400 ng/dL

22/24 (92%) with improved potency

Testosterone and CavernosalNerves

Androgen receptors are present in ~40% of major pelvic ganglion neurons, which innervate the corpora cavernosa of the rat penis.¹

There is a significant reduction in nerve fibers in the corpora cavernosa and dorsal nerves in castrate rats.² ³

¹ ¹ J J Neuroendocrinolol. 1997; 7; 9: 9: 141.oend²

docrinoend² Urology

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Conclusion:Nerves innervating the penis are testosterone-dependent

Other Roles of Testosterone in Sexual Function

Regulates NOS expression

Facilitates synthesis of cGMP and PDE5

Modulates adrenergic responsiveness of corporal cavernosal smooth muscle

Modulation of other biochemical pathways: Smooth muscle ion channels Ca2+, K+

RhoA RhoA KinaseVcsa1, sialorphin, VEGF, Erk1/2, Bcl2, Bax, SHH

Can increase corporal cavernosal smooth muscle and decrease connective tissue

J Sex Meded. 2016; 13: 1183.

Testosterone Therapy (TTh) and Prostate

Cancer:Should We Be Concerned?

Historical Basis for Concern

In 1941 1 –– Huggins & In 19411 Huggins & HHodges reported:

•• Reducing T to castrate Reducing T to castrate Rlevels caused prostate levels caused prostcancer to regress

•• “Administration of Administration of exogenous T caused exogenous T caused prostate cancer to prostategrow”gggg

Based on a Single Patient!

Cancer Res. 1941; 1:293.

None!? Number of published articles showing testosterone therapy causes prostate

cancer progression in PSA era…

Effect of TThon Normal

Prostate Tissue?

Marks et al.R, DB, PC trial of 44 men (44-78 years)Inclusion criteria:

T < 300 ng/dlSymptoms of hypogonadism

Randomized to 150 mg TE or placebo q 2 weeks X 6 months12-core TRUS prostate biopsies at baseline and 6 monthsPrimary outcomes: 6-month change in prostate T & DHT

Effects of TTh on Prostate Tissue of Aging Men with Low Serum T

JAMAA. 2006; 6; 296:2351.

282

640

282 273

28 47 28 260

100

200

300

400

500

600

700

Baseline 6 Months Baseline 6 Months

NG

/G

Serum Levels

Testosterone DHT

TThh (n=21) Placebo (n=19)

Effects of TTh on Prostate Tissue of Aging Men with Low Serum T

640640*

*747

** *

* p < .001 p < .001** p < .002

Effects of TRT on Prostate Tissue of Aging Men with Low Serum T

0

1

2

3

4

5

6

7

8

9

Baseline 6 Months Baseline 6 Months

NG

/G

Prostatic Tissue

Testosterone DHT

TRT (n=21) Placebo (n=19)

Prostate Saturation Model

100100 200200 300300 400400 800800500500 600600 70070000

Serum testosterone level (Serum testosterone level (ng/dLng/dL))

Pros

tate

Grow

th (P

SA)

Pros

tate

Gro

wth

(PSA

)

Saturation EffectSaturation Effect

Unsaturate

d

Unsaturate

d

““Normal Physiologic Range”Normal Physiologic Range”Virtually Virtually CastrateCastrate

SaturationSaturation Model of Physiologic Testosterone ReplacementModel of Physiologic Testosterone Replacement

Eur Urol. 2008; 55:310.

120-150 ng/ml

= PSA= PSA

Changes in PSA After T Gel TherapyKhera et al.

451 hypogonadal men started on T gel for 12 monthsDivided into 2 groups

Group A: Testosterone < 250ng/dlGroup B: Testosterone > 250ng/dl

Only in group A (T < 250ng/dl)PSA increased 0.3 ng/mL with TThStabilized by 12 monthsA continuous PSA rise > 0.3 requires investigation

J Urol. 2011; 186:1005.

Does giving testosterone to men with a history of prostate

cancer increase the risk of recurrent prostate cancer?

Global Pooled Longitudinal Study of Hormones and CaP Risk

3,886 men with CaP6,448 age-matched controls

J Natl Cancer Inst. 2008;100:170.

Quintiles

No significant relationship

between serum androgens and

CaP

Incidence of Prostate Cancer in Men on TTh

CaP rate in 7 published TTh trials was similar to screening trials of general population1

Meta-analysis of 19 placebo-controlledtestosterone therapy studies in men with low or low-normal testosterone ²

Comparison of men treated with testosterone vs. placebo revealed no difference in:

CaP incidence Change in PSAUrinary symptom scores

1. Epidemiol Rev, 2001; 23: 42.2. J Gerontol A Bio Sci Med Sci. 2005; 60:1451.

TTh and Prostate Cancer

Kaplan et al.SEER data linked to Medicare data114,354 men with CaP between 1992-2007

1,181 (0.79%) received testosterone

Urologygy. 2013; 82:321.

No differences in overall or cancer-specific survival, or use of salvage ADT in men with or

without TTh after CaP diagnosis.

103 hypogonadal men with low, intermediate, and high risk CaP treated with RP and TTh

49 non-hypogonadal men with CaP treated with RP, no TTh

T and PSA monitored Q 3-6 months median 28 months

Statistically, but not clinically, significant PSA increasesNon-high risk: 0.004 0.007 ng/mL (p=0.005)High risk: 0.004 0.009 ng/mL (p=0.012)PSAV not supportive of recurrence

BCR: 4 (4%) men in treatment group 8 (16%) men in the reference group J Urol. 2013; 190:639.

98 hypogonadal men with low, intermediate, and high risk CaP treated with radiation therapy

Started on TTh

T and PSA monitored Q 3 months median 41 months

Low Risk CaP no significant PSA increase

High Risk CaP PSA increase from 0.10 0.36 ng/mL (p=0.018)

BCR 6.1%J Urol. 2015; 194:1271.

Kacker et al.

124 hypogonadal men with CaP on AS24 men treated with TTh96 men not treated with TTh

T and PSA monitored median ~40 months

Asian J Androl. 2016; 18:16.

TTh in Men on Active Surveillance

Progression rates not significantly different between groups

SummaryED and sexual dysfunction are common after treatment for pelvic malignancy

Testosterone is involved in numerous cellular processes tied to sexual function

TTh can improve the erectile response

Testosterone can result in a limited rise in PSA

Testosterone does not appear to increase the risk of CaP

TTh in men with non-high risk CaP does not appear to increase the risk of recurrence / progression; evidence in patients with high risk CaP is less clear

Thank you!

pastusza@bcm.edupppppppppppppppppppppppaaaaaaaaaaaaaaaaaaaaassssssssssssssssssssstttttttttttttttttttttttuuuuuuuuuuuuuuuuuuuuuuusssssssssssssssssssssszzzzzzzzzzzzzzzzzzzzzzzaaaaaaaaaaaaaaaaaaaaaa@@@@@@@@@@@@@@@@@@@@@@bbbbbbbbbbbbbbbbbbbbbbccccccccccccccccccccmmmmmmmmmmmmmmmmmmmmmm.................eeeeeeeeeeeeeeeeeeeeddddddddddddddddddddddduuuuuuuuuuuuuuuuuuuuuuu