Sexual Issues following Prostate Cancer Treatments. Seacourses December 30, 2017 January 6, 2018 Dr. Stacy Elliott

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1 Sexual Issues following Prostate Cancer Treatments Seacourses December 30, 2017 January 6, 2018 Dr. Stacy Elliott

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 Prostate Cancer Treatments Active Surveillance (AS) Surgery ( radical prostatectomy) Radiation brachytherapy - external beam Alternates : Cryotherapy and HIFU Adjuvant therapy : Androgen deprivation therapy (ADT), salvage radiation, etc

4 How can prostate cancer treatments affect sexual function? Sexual Drive alterations Erectile function: concept of penile rehabilitation Ejaculatory function Orgasmic changes Pain with sexual activity Urinary incontinence and sexual avoidance

5 Sexual Rehabilitation Penile functioning Loss of ejaculate Orgasmic alterations Orgasmic pain Penile shortening Alterations in body image Incontinence and sexual incontinence Anxiety, depression and grief affecting sexuality Disturbances in partner relationships

6 How can prostate cancer treatments affect sexual function? Sexual Drive alterations Erectile function: concept of penile rehabilitation Ejaculatory function Orgasmic changes Pain with sexual activity Urinary incontinence and sexual avoidance

7 Sexual Drive Depression of PCa diagnosis Anxiety of unknown, waiting Grief and loss of sexual function Alterations to sexual self-esteem Hormonal deprivation ( ADT) Increase in weight, increased cardiovascular risks, pain, feeling aged Role changes in relationship Intimacy loss/expectations

8 How can prostate cancer treatments affect sexual function? Sexual Drive alterations Erectile function: concept of penile rehabilitation Ejaculatory function Orgasmic changes Pain with sexual activity Urinary incontinence and sexual avoidance

9 Erection Dysfunction Can be caused by all treatments, including AS Surgery causes loss immediately with some potential recovery, radiation causes loss of erection over time Rates of ED are 40 80% things are never the same, ED therapy includes focusing on lowered expectations and acceptance

10 What is the incidence of ED following radical prostatectomy? ED is caused after prostate surgery regardless of the operative techniques used Prostate Cancer Outcomes study ( 1) : - 60% self-reported ED 18 months post-op - 28% reported erections adequate for intercourse at 5 year follow-up CaPSURE ( 2) reported only 20% of patients were at preoperative erectile functioning one year post RP Robotic (RALP) only showed pronounced improved potency rates at high-volume clinics with experienced surgeons (3) 1. Stanford et al JAMA 2000;Penson et al J Urol Hu et al J Urol Whelan et al Ind J Urol 2014

11 Post- RP pathophysiology

12 Neurogenic injury causing ED Intraoperative Neuropraxia Thermal injury to cavernous nerves Secondary injury from traction Neural related injuries increase type I and III collagen and upregulate fibrogenic cytokines Postoperative Neuropraxia causes cavernosal tissue damage and atropy Cavernosal injury directly causes smooth muscle apotosis and secondary endothelial changes Reduced oxygenation from fewer nocturnal erections Nerve injury = loss of nocturnal erections and increased sympathetic tone

13 Vascular injury causing ED Damage to accessory pudendal arteries (which can be a major tributary to penile arterial flow) Venous leak as a vascular injury demonstrated on penile Doppler ultrasound post RP ( secondary to corporal fibrosis and smooth muscle apoptosis) In male Sprague- Dawley rats, use of tissue sealing sheet on the dissected cavernosal nerve attenuated postoperative inflammatory changes and oxidative stress and improved EF Yamashita et al J Sexual Medicine 2016;13:

14 Predictors Bilateral nerve sparing ( improved with surgical precision and reduced complication rates), younger age, good baseline EF, tumor size independently associated with erectile recovery Surgical options Men undergoing RALP more likely to regain sexual function at 1 year post-op than RRP Meta-analysis of RALP vs LRP have only shown only a trend in favor of RALP in potency recovery Whelan Ind J Urol 2014

15 Does intracavernosal injection (ICI) improve chances of spontanous erection recovery after RP? Most studies done on nerve sparing Montorsi et al RCT N= 27 ICI injection of PGE1 2-3 times per week started one month after surgery 67% of those with ICI had erections at 6 months as compared to 20% with no treatment Mulhall et al 132 men following RP, non-randomized ( comparative analysis) ICI 3 times/weekly x 18 months 52% return of functional erection vs 19% in control group Montorsi et al J Urol 1997 Mulhall et al J Sex Med 2005

16 Penile rehabilitation definition The use of any pharmacological agent or device after PCa treatments to maximize erectile function recovery and long term erectile function Prevent alterations of the smooth muscle Limit venous leak development Maximize the chances of returning to pre-surgical erectile function GOAL: improve blood flow to the penis to improve oxygenation and facilitate preservation ( preservation: to keep safe from harm or injury)

17 Proactive Goals for penile rehabilitation 1) Better/earlier spontaneous erectile recovery ((+ / PDE5i) 2) Decrease the level of intervention in ED tx -Shift level of treatment ( spontaneous vs PDE5i vs ICI) - Lower ICI dosing - Prevent venous leak 3) Preservation of penile smooth muscle and endothelial function 4) Preservation of penile length

18 Animal models PDE5i prevented corporal veno-occulsive dysfunction by preserving smooth muscle content ( activating genes) and inhibiting fibrosis (down regulated genes) in numerous studies NO has paradoxical activity in regulating cancer growth ( too much NO not good) and some signal of worry ( Michl et al J Urol 2015) However, no increase in biochemical occurrence is seen with PCa in recent meta-analysis ( Gallina et al Eur Urol 2015 ;68:750 and Loeb et al Eur Urol 2016)

19 PDE5i trials in humans 3 large randomized DB PC evaluation PDE5i as penile rehab following RP have been performed Padma- Nathan ( Int J Impot Res 2008) n=78 - positive response in 27% ( sildenafil) vs 4 % P Montorsi et al ( Eur Urol:54:924 31) n=423 - (REINVENT) no difference in IIEF scores after washout Bannowsky et al (BJU Int 2008:101: )

20 Summary PDE5i big trials IIEF EF scores may be higher but not impressive clinically One stopped prematurely since response rates less than expected from spontaneous recovery Initial higher IIEF EF was lost after drug-free washout ( although satisfaction often remained) Patient selection likely critical

21 CON penile rehab There is strong level 5 evidence arguing for penile rehab but no level 1 evidence Inadequate evidence to suggest ANY therapy improves spontaneous erectile function ( but improves erectile function while ON therapy) What s missing is combination therapies (i.e. PDE5i + VED+ICI)

22 PRO Penile Rehab Evidence for early intervention Evidence for lesser fibrosis and more intracorporeal muscle ( bx) with sildenafil Structured program for 18 months erections returned faster in those men who followed rehab protocol ( and realistic expectations) and include the partner! Studies with clinical benefit are small #s, show small but statistically significant improvement (PDE5, ICI) but studies limited by design and potential bias Schwartz J Urol : , Mulhall et al J Sex Med 2005 ; 2:

23 The Great Debate on PDE5i rehab use Two camps: not enough high level evidence in humans VS those who feel it is harmful NOT to do something and furthermore more smaller studies coming out every day showing positive result. Consensus is that there isn t a window of missed opportunity without PDE5i and that prevention by increasing oxygenation to avoid architectural changes is reasonable Is the benefit more that EF improves to the point where someone is a PDE5i responder vs nonresponder versus trying to improve spontaneous return of erections or return to baseline erectile function?

24 TAKE HOME MESSAGES ED Assess whether patient utilized medication appropriately Optimize the dose of the current PDE5 inhibitor Consider other PDE5 inhibitors Consider daily dosing of PDE5 inhibitors Treat underlying low testosterone levels Modify associated risk factors Psychosexual counselling Consider alternative therapies for ED

25 Penile vibrostimulation (PVS) Would enhancing the afferent/efferent reflex improve healing for neuropraxia? Looked at the effect of PVS in the preservation and restoration of erectile function and urinary continence in conjunction with nerve-sparing radical prostatectomy (RP)in men with preop IIEF- EF of at least 18 ( n= 30/38 c) PVS daily pre-op and for six weeks after catheter removal At 12 months, IIEF- ED > 18 for 53% PVS vs 32% controls, with same continence rates Non-significant (P=0.07) but trend, towards better erectile function probably too short a time ( 2 months) Method acceptable to most patients

26 Stem Cell therapy If stem cells can be retained in the corpora cavernosa, they may maintain the penile architecture after CNI by promoting CN regeneration and prevention of fibrosis Acellular scaffolds containing stem cells helped CN regeneration but not smooth muscle cell recovery (1) Stem cells injected into the corpora cavernosa tend to washout immediately Low intensity pulsed ultrasound (LIPUS) suppresses adipogenesis and promotes osteogenesis of mesenchymal stem cells (2) Low energy shock wave therapy ( LESWT) has been shown to recruit endogenous MSC within the corpora cavernosa as compared with sham controls ( AUA,T. Lue 2016) 1) Ying et al Cell Mol Neurobio ) Xin et al Trans Androl Urol 2016

27 Upstream thinking If nerve injuries ( tension, crush, resection) interrupts communication and transportation of molecules both retrograde and antegrade, demyelinates the cavernosal nerve and causes degradation of non-myelinated nerves that leads to downstream apoptosis ( which starts within 2 days) Return of potency is dependent on axonal regeneration and successful functional re-innervation of the penis with intact NO release Can cavernosal regeneration ( with novel factors to improve neural glial interaction ) or delivering strategies for the cavernosal repair ( nanotechnology?) PDE5i only affect corporal smooth muscle cell function and do not serve as neurotrophic agents

28 Issues with penile rehab protocols Labour intensive Lack of standardization High cost High drop out rate Unclear outcomes No definition of optimal regime Balance the worth to the patient for potential benefit

29 Penile prosthesis Changes after prostate or pelvic surgery are upsetting since men may be used to having erections on demand PDE5i, MUSE,ICI take the spontaneity out of it and may not be reliable Argument for reliability of penile implant and earlier if severe ED to reduce psychological sequela of ED May be placed with artificial sphincter if urinary continence severe

30 Pelvic floor therapies Randomized n=52 men for early post-op pelvic floor biofeedback weekly for 3 months vs control group verbal instruction to contract pelvic floor 12 month potency rates ( SHIM >20) were 47.1% and 12. 5% in the treatment groups vs controls (1) Persistent ED after 12 months post RP found PFMT x 3 months helped more than no intervention, was maintained x 15 months, and helped climacturia (2) 1.Prota et al Int J Impot Res Geraerts et al In J Impot Res 2016

31 Don t forget the psychological therapies

32 Other penile changes following RP Increased risk for Peyronie s disease ( 15.9%) Penile shortening ( fibrosis ) 2 3 cm after 12 months post RP ( McCullough 2008) Some evidence for penile traction and vacuum devices to assist with this but studies are short ADT increases risk for venous leak ( 60% vs 20% at 6 months)

33 How can prostate cancer treatments affect sexual function? Sexual Drive alterations Erectile function: concept of penile rehabilitation Ejaculatory function Orgasmic changes Pain with sexual activity Urinary incontinence and sexual avoidance

34 Ejaculation Changes Loss of ejaculate with surgery Loss or decrease with brachytherapy, external beam and ADT Brachytherapy may have temporarily discoloured ( blood) ejaculate Men need to be asked about fertility before treatments commence

35 Orgasmic changes after PCa treatments Anorgasmia Decreased intensity of orgasm Dysorgasmic ( painful orgasm)often self-limiting within 24 months Climacturia RP :1/3 ( 22 33%)same, 1/3 (37%)decreased orgasmic intensity, 4% increased intensity and 15% experiencing pain RALP n=1000: only 27% had reliable orgasm after 3 years Poor orgasmic ability associated with age, ED, and Lower QoL Brachytherpay : ½ notice alteration ( weak, difficult,absent) ADT will make it more difficult to attain Matsushita 2012;Barnas 2005;Ostby-deglum 2016;Delaunay 2011

36 Incontinence post PCa treatments Most noted after radical prostatectomy from mild ( gone by 3 months and/or 1 pad) to severe ( requiring artificial sphincter) but can get post radiation cystitis and UTI Interferes with sexual motivation, associated with anxiety, depression and decreased QoL 3 types of sexual incontinence ( penile tension rings, condoms) - spontaneous leak with sexual thought - incontinence with sexual arousal - climacturia Some benefit seen with pelvic floor therapy, improved erections, alleviation of stress and urge incontinence, post micturition dribble, fecal incontinence

37 Prostate Cancer and sexual dysfunction Primary : erection dysfunction (direct nerve, vascular damage and apoptosis), loss of ejaculatory fluid Secondary: incontinence (neurogenic bladder), use of androgen deprivation therapy ( ADT) Tertiary : depression, emotionality, role change

38 The % of side effects in men on ADT for Prostate Cancer Adverse Effects Prevalence Rate (%) Genital shrinkage: penile length los93% Cessation of sexual activity 80-93% Mild anemia 82% Erectile dysfunction/impotence 73-95% Weight gain 70% Hyperglycemia 65% Concern about body image 60% Loss of libido/sexual interest/drive58-91% Metabolic syndrome (risk as early 55% Hypertriglyceridemia 55% Osteoporosis 2 years on ADT 53% Perceived loss of masculinity 50% Hot flashes 44-80% Decline in executive functioning 38-48% HDL cholesterol < 40mg/dL 35% Fatigue or decreased energy 33-47% Decline in spatial ability 24-47% Breast swelling 25% Decline in verbal memory 19-48% Breast tenderness 19% Average increase in arterial stiffen 17% Osteoporosis 10 years on ADT 15-81% Depression 14% Bone fracture 14% Gynecomastia 13% Average HDL rise at 3 months 9-20% Diabetes type II risk 9% Night sweats 5% Mood swings 2% Walker et al. (2013) Clinical Genitourinary Cancer.

39 ADT : Sexual Adverse Events Adverse Event Prevalence Rate (%) Genital shrinkage: penile length loss > 1cm 93% Cessation of sexual activity 80-93% Loss of sexual drive/libido 58-91% Erectile dysfunction 73-95% Weight gain 70% Concern with body image 60% Hot flashes 44 80% Breast swelling/tenderness ( gynecomastia 13%) 19 25% Perceived loss of masculinity 50%

40 Potential Complications from ADT: Patient Perspective What physicians commonly tell you What you feel What you see What you don t see Loss of libido Fatigue or loss of energy, initiative Weight gain Loss of bone mineral density Erectile dysfunction Aches and pains Loss of muscle mass and strength Changes in lipids Hot flashes Low spirits, depression Increased subcutaneous tissue, especially hips and thighs Glucose intolerance, diabetes Emotional lability Gynecomastia Anemia Cognitive changes Decrease in testicular size and penile length Loss of body hair Increased cardiovascular risk? Modified from Higano C (2006) Hematol Oncol Clin North Am.

41 Effects of primary therapy and ADT on sexuality and intimacy Primary Therapy ADT Incontinence Climacturia Altered or painful orgasm Dry ejaculation Weight gain Erectile dysfunction Loss muscle mass Penile shortening Gynecomastia Low/no libido Testicular atrophy Depression Loss of body hair Altered couple relationship Hot flashes Fatigue Partner distress Lack of initiative Mood disturbances Higano J (2012) J Clin Oncol.

42 Castration : what happens to the genitals? Changes the critical balance of trabecular smooth muscle (apoptosis) and connective tissue (increase in intracellular matrix) Accumulation of fat containing cells just below the tunica, contributing to the impaired veno-occlusive mechanism. Penile fibrotic changes may be permanent: philosophy of penile rehabilitation. Translation : loss of erectile capacity The genitals shrink: penis length, girth and testicular volume Penile rehabilitation plays a role in preservation

43 Assisting with Sexual Side Effects Take the complete sexual history ( erection, no ejaculate, orgasmic delay, potential pain with orgasm, body image difficulties, sexual self-esteem) and not just focus on erection enhancement Men may not know erection not required for orgasm Can be a dissociation between lack of libido and the need to have an erection don t assume men on ADT don t wish to have an erection if libido is low Men wish to remain sexual for intimacy purposes, just like their partners (positive affirmation of life)

44 Sexual decline with ADT: How can you help? Exercise, lifestyle improvements are the substrates of sexual energy and motivation Medical therapies for erection improvement - most often ED in older men is comorbid with vascular issues - below a threshold of testosterone of 10.4 nmol/l, the efficacy of PDE5i is suboptimal - often require penile injection therapy (PGE1 may or may not be tolerated) or vacuum erection device - past quality of sexual life and partner involvement best + predictors Deal with orgasmic problems refer? Psychological and/or relationship counseling Access: specialized sexual health services in BC

45 Management of sexuality after PCa treatments is multidisciplinary Biomedical approaches for all treatments Psychosocial approaches - psychosocial assessment and education - reinforcement of resumption or maintenance of sexual activity - pro-erectile treatment decision making support - providing strategies for incorporation pro-erectile therapy into sexual activity Elliott and Matthew Sex Med Rev 2017 Sexual Recovery after PCa

46 Thank you for listening! Questions?