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Penile rehabilitation is beneficial
after pelvic oncology surgery: PRO
Trinity J. Bivalacqua MD PhD
Disclosures
• Grants: NIH K08, NIH R03, AUA Rising
Star Award, Prostate Cancer Spore Grant,
Johns Hopkins Greenberg Bladder Cancer
Institute.
• Clinical trials: Heat Biologics, Taris
Biomedical, Photocure, FKD, NCI.
• Consultant: Photocure
• Speaker: Pfizer
Realities of post-pelvic oncology surgery
ED
• Current treatments are “on-demand” and
temporary
• Current treatments are less than satisfying
• We still have not identified a corrective
intervention and/or preventive strategy that has
a true disease-specific molecular approach to
preservation of penile erection.
• Discussion with patient and partner about :
– Predictability of erection loss
– Time-course of erection recovery.
– Psychological stress on couple
Sexual Dysfunction after Radical
Prostatectomy
• May take up to 4 years to recover
• May have compromised full erections
(diminished erection quality)
• Requires erection aids in the interim (PDE5
inhibitors, intracavernous injections, MUSE,
VED)
• Other sexual dysfunctions also associated
with RP – climacturia, penile shortening,
peyronie’s disease, changes in orgasm.
Walsh PC, et al. Urology 2000
Mulhall JP, Bivalacqua TJ, Becher E J Sex Med 2013
Histological Alterations In Cavernous Tissue
After Radical Prostatectomy
A, C – Before RRP; B, D – 2 mths after RRP
Marked Increase in Collagen Fibers,
Decrease in Elastic and Smooth Muscle Cell Fibers
Erectile tissue microstructure in patients after RRP
becomes progressively disorganized
Iacono F et al., J Urol 2005
Penile Rehabilitation
• Definition: Penile rehabilitation (erectile tissue
preservation) is defined as the use of any drug
or device at or after radical prostatectomy to
maximize erectile function recovery
• Purpose: The prevention of corpus cavernosal
smooth muscle structural alterations to
maximize chances of a man returning to his
preoperative erectile function level
Current Medical Management for Erection
Preservation following Radical Prostatectomy
•
•
•
•
•
PDE5 inhibitor therapy.
Intracavernous injection therapy (ICI)
Vacuum Erection Device (VED)
MUSE (intraurethral alprostadil)
Experimental approaches – EPO, FK506,
ARBs, Statins, stem cells
Landon Trost MD
So does it work?
• My esteemed colleague will present you data to
suggest its ineffective…..
• Its not cost-effective….
• RCT don’t support its use….
• Ok so now lets really talk about evidence and why
we as a society should support “penile
rehabilitation” !!
Erectile Function Rehabilitation after RP:
Practice Patterns among AUA Members
Aim: To explore EF rehabilitation practice patterns of AUA
urologists.
Results: 43% rehabilitate all patients, 57% only selected
patients;
89% of RP surgeons performed rehabilitation vs. only 66%
who do not perform RP (P < 0.0001).
Tal R et al. J Sex Med 201
The timing of penile rehabilitation after NSRP affects the recovery of erectile function
* Retrospective analysis
Mulhall JP et al. BJU Int. 2010
REINVENT Trial
Montorsi F et al. Eur Urol 2008
* BILATERAL NERVE SPARING RADICAL PROSTATECTOMY
REINVENT Trial: Vardenafil.
Montorsi F et al. Eur Urol 2008
Percentage of Men with IIEF-6 > 21
for PRN vs. Nightly Viagra patients at 1 - 13 months post-surgery
Percentage with IIEF6 > 21
50
PRN
40
Nightly
30
20
10
0
1.
3.
6.
9.
12.
13.
30
34
38
36
Months
PRN n:
Nightly n:
48
46
39
42
38
44
38
36
Pavlovich CP et al. BJU Int. 201
REACTT Trial: Tadalafil
* BILATERAL NERVE SPARING RADICAL PROSTATECTOMY
Montorsi F et al. Eur Urol 2014
Mulhall JP et al. J Sex Med. 2016
Effect of PDE5 inhibitor therapy on
penile length
Montorsi F et al. Eur Urol 2014
PDE5 inhibitors are
myogenic
Sham
BCNR
I Kovanecz et al. IJIR 2008
BCNR + sildenafil
Sun XZ et al. Clin Exp Pharm Physiol. 2010
PDE5 localization within ECs
HAEC
BAEC - Immuno-EM for PDE5
BAEC
60X
Gebska MA et al. Cardiovasc. Res.
Limitations to current RCT
•
•
•
•
Performed in bilateral NS RP patients
One dose of PDE5 inhibitors.
Duration of use may be sub-optimal
Evaluated one time point (12-13mths) post
treatment
• More importantly, EF was only assessed not the
impact of treatment on patient and partner…
The impact of post-RP sexual dysfunction on
couples.
• Partners are distressed about the loss of sexual
relationships (Tanner, J Midwifery & Women’s Health, 2013, Harden,
Onc Nsg Forum, 2013, Ramsey, J Sex Med, 2013)
• Couples struggle, often unsuccessfully, to maintain sexual
intimacy (Sanders, Clin J Onc Nsg, 2006, Gilbert, Sem in Onc Nsg,
2011, Galbraith, 2012, Rivers, J Canc Ed, 2012)
• Men treated for prostate cancer are bewildered, sad, feel a
loss of masculinity, ability to meet partners’ sexual needs
and confidence in interactions with others (Bokhour, J Gen
Intern Med, 2001, Hedestig, Acta Oncol, 2005, Katz, Cancer Nsg,
2007, Galbraith, Clin J Onc Nsg, 2012, Crowley, J Cancer Ed, 2015)
Courtesy Daniels Wittmann PhD LMSW – U. Mich
Men's experience with penile rehabilitation
following radical prostatectomy
Six primary themes emerged:
(1)frustration with the lack of information about post surgery
ED;
(2)negative emotional impact of ED and avoidance of
sexual situations;
(3)negative emotional experience with penile injections and
barriers leading to avoidance;
(4)the benefit of focusing on the long-term advantage of ER
versus short-term anxiety;
(5)using humor to help cope; and
(6)the benefit of support from partners and peers.
Nelson CJ et al. Psychooncology 2015
What helps sexual recovery for couples
after radical prostatectomy?
• Fostering realistic expectations prior to treatment
• Engagement in penile rehabilitation as an aspect
of sexual self-care.
• Early use of erectile function treatments in regular,
ongoing sexual activity.
Walker, Nature Reviews Urology, 2015
Wittmann, J Sex Med, 2014
Management of prostate
cancer in the USA and
internationally
Surveillance for favorable risk prostate
cancer has been adopted around the world
Study
Years
Proportion of men on
active surveillance (%)
UNITED STATES
CAPSURE (Cooperberg 2015)
2010-2013
40
2012-1013
49
SWEDEN
National registry (Loeb 2013)
2007-2011
46
AUSTRALIA
Registry (Weerakoon 2015)
2010-2012
40
MUSIC (Womble 2014)
Johns Hopkins Radical Prostatectomy
Experience
• We examined the risk classification of men who underwent radical
prostatectomy (RP) at our institution since January 2001, with particular focus
on the contemporary era (2011-2015).
• The proportion of the RP population composed of high-risk (HR) and very highrisk (VHR) cancers increased from 5.1% in 2001-2005 to 7.6% in 2006-2010 and
13.5% from 2011 to present (p<0.001).
25
High-Risk Men in RP Popula on
20.2
Propor on (%)
20
18.2
15.6
15
11.5
10
6.9
5
0
2011
2012
2013
2014
2015
Jeffrey J. Tosoian, MD, MPH, Ashley E. Ross, MD, PhD –
AUA 2016
How should we be addressing post-RP
ED?
• Medical Therapy
– PDE5 inhibitors, ICI may allow for preservation in current
RP population.
• Patient Selection
– Penile rehab may be helpful in men who undergo nonNS/partial NS.
• Bottom line, we can do better with trials addressing
different patient populations, different agents, and
good translational science to address the
problem….
What does the future hold for
enhanced recovery and
preservation of erectile function
following pelvic oncologic surgery?
Pathophysiology of Post-RP
ED
Injury to Cavernous Nerves
NVB Apoptosis & Neuronal Cell Death
Decrease in Smooth Muscle and Endothelial Cell Conten
PENIS
FIBROSIS
Erectile Dysfunction
(Veno-Occlusive and/or Arterial)
Local applications: penile and MPG
Delivery methods :
• Intravenous
• Intracavernosal
• Local application on neurovascular bundle
BUT THE MOST IMPORTANT ASPECT IS
TIMING AND TREATING THE UNDERLYING
DISEASE PROCESS!!!
Bivalacqua TJ, Strong T. J Sex Med. 2008 5:268-75
Kim IG et al. Tissue Eng Part A. 2013;19:14-23
Next generation therapies
• Protein and gene therapies to augment natures own
repair pathways
• Stromal Derived Factor-1 is a small, highly
conserved, chemokine, which binds to CXCR4 and
CXCR7
• Upregulated in multiple tissues (neuronal, heart,
muscle) following injury
• Potent stem cell chemo-attractant
• Endogenous anti-apoptotic, angiogenic, and
neurogenic properties
SDF-1 Treatment
Ex-Vivo Organoid
In-Vivo
BCNI + Penile Saline Injection
140
120
BCNI + Penile SDF-1 Injection
140
140
130
110
130
130
120
120
120
100
110
110
110
90
100
100
100
Intracavernosal
Pressure
m Hg)
System ic Pressure
(m m(m
Hg)
Intracavernosal
Pressure
m Hg)
System ic Pressure
(m m(m
Hg)
80
90
70
80
70
60
60
50
90
90
80
80
70
70
60
60
50
50
50
40
40
40
40
30
30
30
30
20
20
20
20
10
10
49:00
49:00
50:00
55 50:00
51:00
66 51:00
52:00
52:00
2v
53:00
53:00
54:00
54:00
55:00
55:00
56:00
56:00
77
57:00
57:00
88
58:00
58:00
59:00
59:00
1:00:00
1:00:00
1:01:00
1:01:00
4v
1:02:00
1:02:00
1:03:00
1:03:00
1:04:00
1:04:00
1:05:00
1:05:00
1:06:00
1:07:00
9
1:08:00
10
1:09:00
1:10:00
1:11:00
6v
1:12:00
1:13:00
1:14:00
1:15:00 111:16:00 121:17:00
30:00
31:00
32:00
8v
33:00 3
34:00 4
35:00
36:00
37:00
38:005
2v
39:006
40:00
41:00
42:00
4v
43:00
44:00
7
8v
6v
4v
2v
8v
6v
4v
10
10
2v
48:00
48:00
45:00
8
46:00
46:00
6v
1.0
p=0.02
ICP/MAP
0.8
0.6
0.4
0.2
0.0
Sham
BCNI
SDF-1
Sopko N et al. AUA Moderated poster
2016
47:00
47:00
48:00
48:00
49:00
49:00
99
50:00
50:00
10
10
51:00
51:00
8v
52:00
52:00
Novel Delivery Methods – Hydrogel Conjugation
Sopko N, Torga G, Jia X, Pienta K, Bivalacqua TJ
2016
Conclusion
• The utilization of medical therapy to enhance
erection recovery post-RP goes beyond just simply
erections but assists in improvement in sexual
health, engagement in cancer treatment, and
relationship with partner.
• We clearly need to develop disease-specific
therapies focusing on preservation of autonomic
innervations of penis as well as corporal vasculature.