Boback M. Berookhim, MD, MBA
BASICS
DESCRIPTION
• Erectile dysfunction (ED), defined as the inability to achieve or maintain an erection for sexual activity, is very common after major pelvic surgery or radiation.
• Curative therapy for prostate cancer, particularly radical prostatectomy (RP) and radiation therapy (RT), are well-defined causes of ED.
• ED after pelvic surgery is sudden in onset with gradual improvement within 24 mo postoperatively.
• ED after pelvic RT has an insidious onset, with a “honeymoon” period of 1 yr following treatment and significant worsening between 3–5 yr.
EPIDEMIOLOGY
Incidence
Not reported
Prevalence
• Rates of ED post-RP/RT vary widely due to definitions, patient populations, and time-point following treatment
• 30–90% after RP
• 6–90% after RT, including brachytherapy (BT)
• Prospective, multicenter, cohort study reported 2-yr ED rates: (1)[B]
– 65% post RP
– 63% post external beam RT
– 57% post BT
RISK FACTORS
• Age
• Pretreatment erectile function
• Quality of nerve sparing
• Surgeon experience and volume
• Concomitant androgen deprivation therapy (ADT) with RT
• RT dose and duration
• Cardiovascular disease and risk factors
Genetics
• Single nucleotide polymorphisms (SNPs) have been identified that are associated with ED following RT but require validation.
• Genetics of cavernous nerve regeneration following RP are under investigation.
PATHOPHYSIOLOGY
• Pelvic Surgery/RP:
– Injury to cavernosal nerves leading to neuropraxia and lethal axonal damage.
– Apoptosis of smooth muscle and endothelium within the penis.
– Potential end-organ failure with corporal smooth muscle fibrosis leading to cavernous venocclusive dysfunction over time.
– Role of arterial injury is not well defined.
Data suggests preservation of accessory pudendal arteries may help prevent post-op ED.
• RT:
– Endothelial cell and microvascular arterial injury leading to arterial insufficiency and ultimately ischemia.
– Small likely role of cavernous nerve injury following RT.
– RT-induced corporal tissue fibrosis leading to cavernosal vono-occlusive dysfunction (CVOD aka venous leak).
ASSOCIATED CONDITIONS
Treatment effects are generally dependent upon the modality used and are discussed elsewhere.
GENERAL PREVENTION
• Pelvic surgery/RP:
– Cavernous nerve sparing surgery
– Sparing of accessory pudendal arteries intraoperatively
• RT:
– Reducing volume of tissue irradiated is postulated to reduce likelihood of ED
– No definitive evidence supporting use of intensity-modulated radiation therapy (IMRT), BT, or proton beam RT to reduce ED
– Treatment plans limiting RT to the corpora cavernosa may have a beneficial effect
• Penile rehabilitation:
– Signals from studies suggesting early rehabilitation (phosphodiesterase Type 5 Inhibitors [PDE5i], intracavernosal injections) can impact posttreatment erectile status after RP and RT
– Goals: Cavernosal oxygenation, preservation of endothelial function, prevention of corporal smooth muscle fibrosis
– Optimal regimen for rehabilitation is not understood
DIAGNOSIS
HISTORY
• Medical history: Risk factors for general ED
– Cardiovascular disease
– Diabetes mellitus
– Smoking
– Peripheral neuropathy
– Depression
– Alcoholism
• Surgical history
– Type and date of surgery
– Nerve sparing status (if RP or radical cystectomy)
• Radiation history
– Dose, template, radiation modality, and date
– Use of ADT
• ED history
– Validated questionnaires, ie, International Index of Erectile Function (IIEF)
– Onset and severity of ED
– Consistency of erectile quality
– Presence of nocturnal erections
– Prior use of therapy and response
PHYSICAL EXAM
• General physical exam
• Penile exam focusing on presence of tunical plaques and penile compliance
• Testicular volume and consistency as screening for hypogonadism
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Generally noncontributory.
• If evidence of hypogonadism, check early morning serum testosterone.
Imaging
• Duplex Doppler ultrasound of the penis
– Can be used to evaluate for presence of vasculogenic ED
– Peak systolic velocity <30 cm/s indicative of arterial insufficiency
– End diastolic velocity >5 cm/s indicative of CVOD
Diagnostic Procedures/Surgery
N/A
Pathologic Findings
N/A
DIFFERENTIAL DIAGNOSIS
• Hyperprolactinemia
• Medication induced: Antihypertensives, psychotropics, antiandrogens
• Neurogenic ED
• Profound hypogonadism
• Psychogenic ED
• Vasculogenic ED
TREATMENT
GENERAL MEASURES
• Perform cardiovascular risk assessment to evaluate fitness for sexual activity prior to treatment.
• Patient and partner should be informed of relevant treatment options, risks, and benefits.
MEDICATION
First Line
• PDE5i (2)[A]
– Likely to be ineffective immediately after surgery given cavernosal nerve injury
– Daily dosing frequently used in rehabilitation regimens
– When used on-demand only, decreased response noted 2–3 yr after RT
– Medications:
Sildenafil 50–100 mg: Onset 15–60 min, duration of action 4 hr
Vardenafil 10–20 mg: Onset 15–60 min, duration of action 2–8 hr
Tadalafil 10–20 mg: Onset 15–120 min, duration of action 24–36 hr
Avanafil 100–200 mg
– Contraindications to PDE5i use:
Absolute contraindications: Use of nitrates
Sildenafil: Should be postponed for 4 hr after taking α-adrenergic antagonists
Vardenafil: Should not be taken with type 1A or type 3 antiarrhythmics or patient with long QT syndrome
– Side effects: All associated with headache, dyspepsia, facial flushing
Tadalafil: Backache, myalgia
Sildenafil: Blurred/blue vision—reacts with PDE6 in retina
Second Line
• Intracavernosal injection therapy
– Highly efficacious with up to an 89% response rate post-RP (3)[C]
– Risks include priapism, penile pain, ecchymosis
– Used in a variety of formulations
Single agent: Prostaglandin E1
Bimix: Papaverine and phentolamine
Trimix: Papaverine, phentolamine, and prostaglandin E1
• Intraurethral prostaglandin E1 suppository (MUSE)
– Variable efficacy
– Penile pain frequently reported, especially in the immediate postoperative period
SURGERY/OTHER PROCEDURES
• Vacuum constriction devices
– Low patient satisfaction given cumbersome application
– Cooler, cyanotic appearance of vacuum-assisted erection appears “unnatural” to some
• Penile prosthesis implantation
– Definitive therapy for patients failing or refusing 1st- and 2nd-line treatments
– Generally, postponed until 2-yr post-RP as regeneration of cavernous nerves during this time may preclude need for surgical therapy
– High patient satisfaction in appropriately selected population
– Implant infection and malfunction risk must be discussed with patient preoperatively
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• Limited data on combining modalities has been reported
– Level 3 evidence: PDE5i + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone
– Level 4 evidence: Enhanced efficacy with the combination of vacuum-erection therapy + either PDE5i or transurethral PGE1 or intracavernosal injection therapy
Complementary & Alternative Therapies
• Data does not support use of trazodone, yohimbine, and herbal therapies. These medications are not recommended for use in ED by the American Urological Association
• Testosterone therapy
– May be useful in aiding erectile function recovery only in patients with documented hypogonadism
– Controversial; must discuss risks/benefits of androgen supplementation before initiating therapy, particularly in patients with a history of prostate cancer
ONGOING CARE
PROGNOSIS
• Improvement in erectile function can be noted after pelvic surgery, with maximal improvement noted between 18 and 24 mo postoperatively.
• Low likelihood of improvement in erectile quality after 2 yr postoperatively.
• Nadir of erectile function 3 to 5 yr after RT.
• Penile rehabilitation likely improves the prognosis of postsurgical/post-RT ED. Definitive data are pending.
COMPLICATIONS
• Significant effect on patient quality of life
– Noted to be strongest predictor of patient satisfaction after prostate cancer therapy
• Depression
FOLLOW-UP
Patient Monitoring
• Variable dependent upon patient response to treatment.
• Close follow-up is recommended in patients on rehabilitation protocols to evaluate for erectile recovery.
Patient Resources
Mulhall JP. Saving Your Sex Life: A Guide for Men with Prostate Cancer. 1st ed. Chicago, IL: Hilton Publishing Company; 2008.
REFERENCES
1. Alemozaffar M, Regan MM, Cooperberg MR, et al. Prediction of erectile function following treatment for prostate cancer. JAMA. 2011;306(11):1205–1214.
2. Candy B, Jones L, Williams R, et al. Phosphodiesterase type 5 inhibitors in the management of erectile dysfunction secondary to treatments for prostate cancer: Findings from a Cochrane systematic review. BJU Int. 2008;102(4):426–431.
3. Coombs, PG, Heck M, Guhring P, et al. A review of outcomes of an intracavernosal injection therapy programme. BJU Int. 2012;110(11):1787–1791.
ADDITIONAL READING
• Mendenhall WM, Henderson RH, Indelicato DJ, et al. Erectile dysfunction after radiotherapy for prostate cancer. Am J Clin Oncol. 2009;32:443–447.
• Mulhall JP, Bivalacqua TJ, Becher EF. SOP for the preservation of erectile function outcomes after radical prostatectomy. J Sex Med. 2013;10:195–203.
See Also (Topic, Algorithm, Media)
• Erectile Dysfunction/Impotence, General Considerations
• Penile Doppler Ultrasound, Indications and Parameters
• Penile Rehabilitation
• Reference Tables: International IIEF (Sex Function Survey)
CODES
ICD9
607.84 Impotence of organic origin
ICD10
• N52.31 Erectile dysfunction following radical prostatectomy
• N52.32 Erectile dysfunction following radical cystectomy
• N52.39 Other post-surgical erectile dysfunction
CLINICAL/SURGICAL PEARLS
• ED after pelvic surgery and RT is highly prevalent and frequently underestimated in physician marketing materials.
• ED after pelvic surgery is immediate in onset with 18- to 24-mo time to maximal recovery.
• ED after RT has an insidious onset, with nadir of erectile function at 3- to 5-yr post-RT.
• Data on penile rehabilitation is conflicting but increasingly shows an improvement in posttreatment erectile recovery.
• The majority of postpelvic surgery/RT ED patients are effectively treated with PDE5i ± intracavernosal injection therapy.