Sexual Dysfunction Caused by Cancer Treatments Issues in Men. Dr Christopher Love

Transcription

1 Sexual Dysfunction Caused by Cancer Treatments Issues in Men Dr Christopher Love Urological and Prosthetic Surgeon Bayside Urology 66 Balcombe Rd., Mentone Men s Health Melbourne Level M 233 Collins St., Melbourne 1800 DRLOVE

2 1) Incidence and types of sexual dysfunction 2) Factors causing sexual dysfunction 3) Prostate cancer associated dysfunctions, particularly erectile dysfunction 4) Penile Rehabilitation 5) Treating Established Erectile Dysfunction

3 Incidence of Sexual Dysfunction in Cancer Treatment Many types of cancer and cancer therapies are frequently associated with sexual dysfunction Estimates range from % of patients Derogatis LR, Kourlesis SM. CA Cancer J Clin 31 (1) ; 46 50, 1981

4 Incidence of Sexual Dysfunction in Cancer Treatment Most of the published information relates to women who have breast or gynaecological cancers, or men who have prostate cancer Less is known about how other types of cancer affect sexuality

5 The Most Common Problems The most common sexual problems for people with cancer are: Decreased libido (men and women) Erectile Dysfunction Dyspareunia Ejaculation changes and failure to reach orgasm (men) Changes in genital sensation and failure to reach orgasm (women) Schover LR, Montague DK, Lakin MM. Cancer: Principles and Practice of Oncology, 5 th Ed, pp Lippincott-Raven Publishers 1997

6 The Impact of Sexual Dysfunction Unlike many other physiological side-effects of cancer treatment, sexual dysfunction does not tend to resolve, and has influences on cancerfree quality of life (1) Erectile dysfunction is an important issue for patients who have undergone radical prostatectomy. Urologists tend to underestimate patient s distress and their desire for early treatment (2) 1. Litwin MS, Hayes RD et al. JAMA 273 (2); , Chartier-Kastler,E. J Sex Med 2008; 5:

7 Impact of Post-Operative Erectile Dysfunction Erectile function is precipitously, severely and extendedly lost following this and other pelvic surgeries causing significant emotional and psychological distress for many men and their partners (1) ED has a significant negative impact on the patient s quality of life and self esteem (2) 1. Burnett A. et al. J Sex Med 2008; 5 : Mulhall J.P. J Sex Med 2008: 5 (supp): 197

8 Factors Causing Sexual Dysfunction Sexual dysfunction, as it relates to cancer treatments, may be multifactorial, with both physiological and psychological factors contributing to its development. Doctors and patients tend to focus on the medication-intensive treatment of the cancer itself, and perhaps less on the quality of life side-effects. Cakar B, Karaca B, Uslu R. J BUON. 18 (4); Oct Dec 2013

9 Factors Causing Sexual Dysfunction Physiological factors: Functional damage, fatigue, pain and pain medications Testosterone levels affected by many chronic illnesses and some medications Cancer therapies such as surgery, chemotherapy, hormone therapy, radiation therapy and bonemarrow transplant may all have direct physiological impact on sexual function Watson M, Wheatley K et al. Cancer 86(7):

10 Factors Causing Sexual Dysfunction Psychological factors: Misbeliefs about origin of the cancer Guilt related to those misbeliefs Co-existing depression Changes in body image Stresses to relationships secondary to cancer diagnosis and treatment Schover LR, Montague DK, Lakin MM. Cancer: Principles and Practice of Oncology, 5 th Ed, pp Lippincott-Raven Publishers 1997

11 Therapy Related Factors - Surgery Many surgical treatments for cancer have a direct physiological effect on sexual function This applies particularly to surgery for breast cancer, gynaecological cancer, rectal cancer, prostate cancer, testicular cancer and penile cancer, with potential vascular, nerve and end organ damage Common predictors of post-operative sexual function include age, pre-treatment sexual function, tumour location, tumour size, and extent of surgical resection.

12 Therapy Related Factors Chemotherapy Loss of libido and decreased frequency of intercourse are noted in many patients undergoing chemotherapy, and are probably related to general side-effects of the treatment, like nausea, fatigue, diarrhoea, mucositis, altered sense of taste and smell, alopecia, all possibly leading to the patient feeling asexual. Chemotherapy agents rarely play a role in the development of erectile dysfunction or ejaculatory problems, but some can interfere with testosterone production Gradishai WJ and Schilsky Rl. Crit Rev Oncol Haematol 8(2): , 1988

13 Therapy Related Factors Radiotherapy As with chemotherapy, general side-effects like fatigue and changes in bladder and bowel function may play a role in loss of libido Pelvic nerves or vessels may be damaged ED Prostate scarred no semen Time course is different- The ED takes longer to happen with radiation than surgery, suggesting gradual arterial insufficiency But by 3yrs minimal difference in incidence of ED between radiation and surgery

14 Therapy Related Factors Hormone Therapy The hormone therapy used in prostate cancer, aiming to reduce circulating androgens as low as possible, will result in loss of libido, erectile dysfunction and possibly difficulty achieving orgasm in most men Strategies, including delayed commencement of therapy, intermittent hormone therapy, or alternatives like finasteride and androgen-receptor blocker combinations, have been tried to minimise side-effects. Potasky Al et al. J Natl Cancer Inst 94(6):

15 Prostate Cancer Surgery Associated Problems RADICAL PROSTATECTOMY (open / laparoscopic / robotic) (There is no difference in these side effects no matter which surgical technique is used) 1-5 % - severe incontinence and 5-15 % - mild stress incontinence during physical exertion Erectile dysfunction occurs in up to 85 % of men after a radical prostatectomy Penile shortening or curvature is reported Ejaculation is not possible after RP as the ejaculatory glands have been removed. Anorgasmia, or painful orgasm have both been reported Climacturia loss of urine with climax Bladder neck scarring 2-10% Bowel injury <1% Psychological distress anxiety, depression, loss of self-esteem, don t feel like a man anymore, quality of life reduced.

16 Post-prostatectomy Sexual Dysfunction other than ED Orgasm changes Orgasmic pain reported in 14% of men after radical prostatectomy Thought to be associated with bladder neck and pelvic floor spasm, as many cases are helped by selective alpha-blocker Tamsulosin (1) 37% prevalence of complete absence of orgasm, as well as of decreased orgasm intensity (2) But orgasmic function tends to improve linearly over 48 months after radical prostatectomy. Absence of seminal vesicle and prostatic contractions may account for less satisfying orgasms. There is no effective treatment to allow return to baseline function Urine Leak with Climax (climacturia) Up to 20 % of men Behavioural therapy decrease fluid intake, empty bladder before sex Mechanical therapy condom, constriction ring Surgery urethral slings, particularly urethral re-positioning or elongating slings 1. Barnas J, Parker M, Guhring P et al. Eur Urol 2005; 47 (3): Barnas JL, Pierpaoli S, et al. BJU Int 2004; 94:

17 Post prostatectomy Sexual Dysfunction other than ED Loss of Penile Length 71% of men report this after radical prostatectomy > 1.5 cm length loss in 48% of men at 3 months (1) Thought to be related to Fibrosis, following on from hypoxia and an increase in fibrogenic cytokines like TGF-beta 1, leading to increased collagen deposition Sympathetic hyperinnervation as neuropraxia improves, sympathetic nerves recover quicker, causing an increase in sympathetic tone and therefore decreased distensibility and relaxation of corpora Neuropraxia may also contribute to smooth muscle degeneration in the penis 1. Munding M D, Wessells HB, Dalkin BL. Urology 2001; 58 (4):

18 Erectile Dysfunction (ED) is just a part of Sexual Dysfunction (SD) SD ED

19 The scope of the ED problem Disparate rates of erectile dysfunction ranging from 20 90% in various studies 1 Prostate Cancer Outcome Study 2 Looks at the changes in erectile function for up to 5 years post-operatively Pre-Op 6 months 12 months 24 months 60 months 1213 patients. Based on self reported erections firm enough for intercourse 81% 9% 17% 22% 28% Back to Baseline at 24 months 3 - Same erections as before surgery (without medication) 16% who had normal function pre-op, and only 5% if over age Burnett A.L. et al J Urol 2007; 178: Penson et al. J Urol 2008; 5: Mulhall et al J Sex Med 2013; 10:

20 The Nature of Erectile Dysfunction After Radical Prostatectomy Very common early after surgery Generally improves with time Improved surgical techniques have helped ( nerve sparing ) - but not as much as expected Can keep improving for 36 months in some cases BUT If nothing happening at 6-12 months unlikely to recover

21 Prostate Cancer Surgery Improvements in surgical technique have lead to improved long-term cure (1) and significantly better continence rates (2) after surgery. This has increased the attention given to, and perhaps the significance of, erectile dysfunction after surgery. 1. Han M et al Urol Clin North Am 2001; 28: Catalona W.J. et al J Urol 1999; 162: 433

22 Neurovascular Bundles

23 Nerve-sparing technique

24 The question about ED after prostate surgery Why have we not seen, despite meticulous nerve-sparing techniques, the same improvement in post-operative potency rates that have now become normal for continence after radical prostatectomy?

25 The ongoing surgical problem Even in nerve sparing surgery, manipulation, traction and stretching of the cavernous nerves occurs, resulting in some degree of neuropraxia. Neuropraxia itself results in structural changes in the penis including vascular, neural and cavernous smooth muscle changes (1) 1.Blaya R. and Mulhall J.P. AUA Update 2008; 27: Lesson 36

26 The ongoing surgical problem 2 Even with good surgical technique there may be possible vascular damage to functional accessory pudendal arteries (1) Added to this, the chronic lack of erections secondary to the neuropraxia results in failure of cavernosal oxygenation with the potential for further structural damage (2) 1. Rogers C.G. et al Urology 2004; 64: Moreland R.B. Int J Imp Res 1998; 10:

27 The ongoing surgical problem 3 Clinical manifestations of these changes may be 1. corporal veno-occlusive dysfunction(cvod) (1) 2. shrinkage and atrophy of the penis (2) 3. the development of Peyronie s like plaques and curvatures (3) 1. Ferrini M. et al J Sex Med 2009; 6: Savoie M et al J Urol 2003; 169: Cianco S.J. et al BJU Int 2000; 85:

28 How the penis becomes erect: Cavernosal Artery Tunica albuginea Subtunical venules Corpora cavernosum - Smooth muscle and vascular spaces

29 How the penis becomes erect: FLACCID ERECT 1 Dilation of cavernosal artery and increased arterial inflow 2 Engorgement of corpora cavernosum with blood, and relaxation of smooth muscle 3 Passive occlusion of sub-tunical venules against tunica 4 Intra-cavernosal pressure rises and rigidity occurs

30 Nerve Damage Neuropraxia This may eventually recover in months No signal to penis to become engorged Poor Erections Minimal blood flow = hypoxia Venous leak Fibrosis and poor compliance of penis Permanent ED Penile shortening

31 Basic Science Injury Mechanisms Apoptosis Denervation of the rat penis leads to apoptosis of corporal bodies (1) Penile apoptosis as early as 1 day after cavernous nerve ablation. Most apoptosis directly under tunica albuginea (2) Cavernous nerve crush injury model causes apoptosis in both smooth muscle and endothelium (3) 1.Klein L.T. et al J Urol 1997;158: User H.M. et al J Urol 2003; 169: Mullerad M. et al J Sex Med 2006; 3: 77-83

32 Basic Science Injury Mechanisms Fibrosis Neuropraxia results in alterations in smooth muscle collagen ratios (1) Neuropraxia causes upregulation of fibrogenic cytokines such as TGF-beta1, which increases collagen types I and III synthesis (1) Cavernous nerve injury results in endothelial cell retraction (2) 1. Leungwattanakij S. et al J Androl 2003; 24: Klein L.T. et al J Urol 1997; 158:

33 Basic Science Injury Mechanisms Cavernosal Deoxygenation Low oxygen tensions upregulate fibrogenic cytokines, such as TGF-beta1, resulting in increased fibrosis (1) Oxygenation upregulates the production of endogenous prostanoids as well as camp (1) Prostanoids such as PGE1, inhibit TGF-beta1 activity and reduce collagen production (2) Prostanoids are protective for smooth muscle (1) 1. Moreland R.B. et al Am J Physiol Heart Circ 2001; 281: H552 H Moreland R.B. et al Int J Impot Res 1998; 10:

34 Basic Science Injury Mechanisms Venous Leak If corporeal smooth muscle fails to expand, some or all of the sub-tunical venules are left in a non-compressed state, leading to venous leakage Corporeal smooth muscle fails to expand most commonly due to adrenaline, and structural changes such as fibrosis

35 Signal transduction pathways Adapted from Lue T. N Engl J Med 2000; 342:

36 Basic Science Injury Mechanisms Venous Leak Venous leak occurs once smooth muscle content in the penis drops below 40% (1) Collagen deposition in erectile tissues increases markedly as early as 2 months after surgery (2) Haemodynamic studies show that more than half the men with ED after radical prostate surgery have venous leakage, and the incidence of venous leakage increases with time from surgery, particularly after four months (3) 1. Nehra A et al J Urol 1996; 156: Iacono F et al J Urol 2005; 173: Mulhall J.P. et al Int J Imp Res 1996; 8: 91-94

37

38

39 Penile Rehabilitation Use of any medication or device, after pelvic surgery, to maximise the recovery of erectile function Concept: Improve oxygen to penile tissues Protection of the cells lining the blood spaces Prevent cavernosal nerve injury-induced structure changes Penile rehabilitation is an assortment of strategies directed towards preventing the structural alterations in the penis, whilst the nerve damage resolves, and therefore restoring penile health after radical prostatectomy

40 Penile Rehabilitation We think most nerve damage, with good surgical technique, will eventually recover, but will the penis still work by the time the nerves have healed? We now understand that regular erections are important for the health of the penis stretching of elastic tissues, fresh blood and oxygen to keep the penis healthy. If you don t use it you lose it When there are no erections for a time, irreversible structural damage occurs in the penis.

41 Basic Science Possible Repair Mechanisms Prostaglandin PGE1 may promote the recovery of erectile function by the promotion of cavernosal oxygenation levels By stimulating the formation of adenyl cyclase, PGE1 increases the concentration of camp within smooth muscle cells. Ruis Rubio J.L. et al J Urol 2004; 171:

42 Basic Science Possible Repair Mechanisms PDE5 inhibitors stimulate smooth muscle cell replacement via a cgmp mechanism and reduce collagen synthesis via protein kinase G activation If PGE5 inhibitors can induce cavernosal oxygenation in the absence of erection, they may function as endothelial protectants and preserve smooth muscle Kovanecz I et al BJU Int 2007; 101:

43 Evidence Supporting Penile Rehabilitation Animal Data Sildenafil shows significant improvement in intra-cavernosal /mean arterial pressure ratio (ICP/MAP) in rats commencing on the day of cavernous nerve injury Sildenafil treatment in rats having cavernous nerve injuries resulted in preservation of corporeal smooth muscle content, better endothelial factors, reduced apoptosis and increased phosphorylation of AKT and enos, both critical to endothelial function for penile erection Mulhall J.P. et al J Sex Med 2008; 5:

44 Evidence Supporting Penile Rehabilitation Animal Data Vardenafil prevents fibrosis and loss of corporeal smooth muscle after bilateral cavernous nerve resection in rats. This may be by vasoactive effector stimulatory mechanisms (1) PDE5 inhibitors work by anti-oxidative mechanisms (2) Statin therapy may improve penile endothelial function (2) 1. Ferrini M.G et al Urology 2006; 68: DeYoung L.X. et al Int J Imp Res 2003; 15:

45 Evidence Supporting Penile Rehabilitation Human Data Intracavernous PGE1 three times a week for 12 weeks post RP. At 6 months 67% of treatment group had erections sufficient for intercourse compared to 20% of untreated group (1) Corporeal biopsies at time of RP and 6 months later shows that Sildenafil treated patients showed histopathological evidence of preservation of smooth muscle content compared to untreated patients (2) 1. Montorsi F et al J Urol 1997; 158: Schwartz E.J. et al J Urol 2004; 171:

46 Evidence Supporting Penile Rehabilitation Human Data Randomised, placebo controlled trial of Sildenafil nightly from 4 weeks to 36 weeks 27% of patients receiving Sildenafil demonstrated return of spontaneous erectile function compared to 4% in the placebo group at 48 weeks A subset of these patients had nocturnal penile tumescence and rigidity studies pre- and post operatively, showing a gradual dose-dependent improvement in the treatment group Padma Nathan H. et al Int J Imp Res 2008; 20:

47 Other Strategies for Penile Rehabilitation Vacuum Device Therapy daily use for men wishing to preserve penile length (1) Early use of VCD facilitated preservation of penile length and girth (2) Trans-urethral PGE1 (MUSE) 3 times a week for 9 months post-operatively. Only 68% completed the study. (3) 40% in treatment group had return of natural erections compared to 11% in observation group (3) 1. Dalkin B.L. and Christopher B.A. Int J Imp Res 2007; 19: Raina R et al J Sex Med 2008; 5(Supp 1): Raina R. et al BJU Int 2007; 100:

48 Nerve Damage

49 Penile Rehabilitation does it work? Penile Rehabilitation Treatment Options (alone or in combination) Oral Medications (PDE-5) Vacuum Erection Device (VEDs) Intraurethral Suppository Intracorporeal Injections Sildenafil 25 mg daily (Bannowsky 2008) Sildenafil 50 or 100 mg daily (McCullough 2008) VED (Raina 2006) Urethral Suppository (Raina 2007) Intracorporeal Injection (Montorsi 1997) Intracorporeal Injection or sildenafil 100 mg (Mulhall 2005) Rehabilitation Control 11/23 (47%) 5/18 (28%) 10/35 (28%) 1/19 (5%) 10/60 (17%) 4/35 (11%) 21/38 (55%) 4/35 (11%) 8/12 (67%) 3/15 (20%) 30/58 (52%) 14/74 (19%)

50 Current Role of Penile Rehabilitation Arguments For Mechanisms for protection of endothelial function and smooth muscle are known Animal models of chronic dosing with PDE5 i demonstrate improvements Human data point to improvement Argument against Present human studies have significant limitations and many lack Level 1 evidence Cost of rehabilitation at least $ 120+ per month (? for how long)

51 Cost - Effectiveness Penile rehabilitation was found to be not cost-effective when compared to other therapeutic options Simultaneous penile prosthesis implantation at the time of radical prostatectomy appears to be the most cost-effective treatment option Hellstrom W.J.G. et al J Sex Med 2008; 5 (supp 1): 4-41

52 Penile Rehabilitation Programme Mulhall - MSKCC 1. Low dose PDE5 nightly for two weeks pre-op. 2. Two weeks post op commence nightly low dose PDE5 6 nights/ week and weekly maximal dose PDE5 with sexual stimulation 3. If responding (erectile activity) at 6 weeks, continue maximum dose two nights a week and low dose other five nights 4. If not responding then PGE1 twice weekly and low dose PDE5 other nights until response 5. +/- use of vacuum-erection device

53 PREVENTION OF POST PROSTATECTOMY ED Be aged less than 60 Don t have any ED before prostate cancer treatment Don t have diabetes, cholesterol issues, high blood pressure Have a motivated partner Don t be overweight Don t be a smoker Pick your surgeon rather than the surgical technique Meticulous dissection nerve sparing Surgeon experience is important Start a Penile Rehabilitation programme

54

55 Potential options: 1 st Line: Oral Medications 2 nd Line: Vacuum Erection Devices Penile injections 3 rd Line: Penile prostheses (implant)

56 Safe (Viagra 1998, Cialis and Levitra 2003) Easily accessible Easily taken (oral) Efficacious but less likely in post-prostatectomy

57 Phosphodiesterase 5 inhibitors (PDE5s) in Penile Rehabilitation? Protect smooth muscle and endothelial cells? Minimise fibrosis? Help nocturnal blood flow and erections NANC

58 Dr Love s Medication Musts 1.Must know the potential benefit and limitations Need to be able to get some erections on your own Not a magic pill 2.Must take them as directed Dose Timing (V) >1 time and type 3.Must know side effects Headache, facial flushing, stuffy nose (<10%) Indigestion, blue tinge (V) Temporary 4.Must NOT take Nitrate medication 5.Must not buy off the internet

59

60

61 Vacuum Erection Device (VED) in Penile Rehabilitation Keep penis stretched? More blood into penis

62 Seems great No drugs Works One off cost

63 Blue Cold Painful Hinge effect Tedious Interrupts the flow of things

64

65 Intracavernosal injections in Penile Rehabilitation Cross-section of the shaft of the penis Midline Vasoactive drug injected directly into the corpus away from the midline Corpus cavernosum A way of getting an erection and keeping the penis stretched Fresh blood into penis If you use it you are less likely to lose it

66 Many men who try it continue in the long term* Simple Effective Cheap Minimal discomfort Very few serious side effects * When adhere to secrets of success

67 Education 2 x sessions Tiny needle Less sensitive area Small dose increments Support 24 hr Involve partner

68 Painful Prolonged erection (priapism) May not work leaky valve venous leak Problems with dexterity/limited eyesight (partner) Travel Just cant do it

69 What If Penile Rehabilitation Doesn t Work? Eventually, if erections are not recovering, or are insufficient for penetrative intercourse, decisions will need to be made. When is the right time? What is the right next step?

70 Penile Prostheses Paired inflatable inner tubes inserted surgically into the penis. Ideal for men who have tried other treatments without success On the market for 40 years 30,000 penile implants per year 1 Over 450,000 implants to date 2 High patient and partner satisfaction 3 1 Millenium Research Group. US Markets for Urological Devices May "Penile Prosthesis." The Sexual Medicine Web Site European Society for Sexual Medicine. 23 Jan 3 Levine LA, Estrada CR, Morgentaler A.. J Urol Sep;166(3):932-7

71 Penile Prosthesis The cylinders (placed within the penis) The reservoir (placed within the abdomen) The pump (placed within the scrotum)

72

73 Proven Benefits of Penile Implants Achieve an erection easily and maintain it as long as required Looks and feels like a normal penis Erection hard enough for penetration and allows you to complete sexual intercourse 1 Easy to use Sensation, orgasm same as before Dependable, works every time Restores spontaneity 30 minute operation Usually one night stay in hospital 1 "Benefits of Penile Implants." Erectile Dysfunction Institute Erectile Dysfunction Institute. 23 Jan

74 Penile Prosthesis Minimally Invasive Surgery

75 The Results of Penile Implant Surgery

76 Penile prosthesis - satisfaction Series of approx men and their partners ~90% said they were satisfied ~80% of partners were satisfied ~85% said they would have the operation again ~85% would recommend it to a friend 80 % 60% 40 % 20 % Carson C, Mulcahy J et al Penile Implant Oral Medication Penile Injections

77 Why such high patient and partner satisfaction rates? Works! Quick to inflate seconds Concealed Confidence Spontaneous Preserves sensation and orgasm(s) Individually tailored Age is no barrier

78 However, there are some aspects that concern patients about penile implants. Requires surgery Risk of surgical complications which may include infection(< 1%) Cost may be prohibitive without insurance Possible discomfort or pain from use Non-reversible There may be mechanical failures which may require revision surgery (< 5% at 10 years) Requires some manual dexterity

79 1. Sexual Dysfunction is common after prostate cancer, and other cancer treatments 2. SD is not just ED 3. Check testosterone 4. Penile rehabilitation 5. Numerous treatments available for established ED 6. Each have their own benefits, limitations and side effects 7. 1 st, 2 nd, 3 rd line treatments Increasingly effective Penile Prosthesis has the highest satisfaction rate

80 ED is important even in nature

81 Thank you DRLOVE ( )