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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
11httptp://////www.cancer.org/cancer/prostatecancer/detailedguide/prostatete-ee cancere -err keyey-yy statisticstthttppp://////// ww.cancer.org/cg/g ancer/pr/pp ostatecancer/det/ ailedguigg de/p/pprostaww atat²
ancecacancactteee-cttee c²²²² J Urol.
rrr- eekeyyy- atisticstastr eekeyyyyyy atisticstastnceeernceeerll 2003; 170:2279.
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d. d 2007; 4:98.
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
9971 7;nool. gyy. 2000; 56
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49: 16: 533
41.33.
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otot Res000; 000;yy 2020. 2. 2
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5:5: 26.
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