Understanding and Managing Erectile Dysfunction in Patients Treated for Cancer

Abstract

Cancer can cause sexual adverse effects by direct and indirect pathways. It can involve sexual organs, indirectly affect body image, or cause fatigue or depression with subsequent effects on libido. Erectile dysfunction (ED), the inability to obtain or maintain an erection firm enough for sexual intercourse, can also result from adverse effects of cancer treatment, such as fatigue, pain, or anxiety about therapy. In addition, depressed feelings about having cancer can affect sexuality, causing a range of signs and symptoms that can lead to ED. Chemotherapy, hormone therapy, surgery, and radiation can all cause sexual adverse effects. Additional factors that play a role include patient age and degree of ED before starting cancer treatment. In this article, we discuss how chemotherapy, hormone therapy, surgery, and radiation affect erectile function as well as possible treatment options for ED.

INTRODUCTION

Cancer can cause sexual adverse effects by direct and indirect pathways. It can involve sexual organs, indirectly affect body image, or cause fatigue or depression with subsequent effects on libido. Erectile dysfunction (ED) can also result from adverse effects of cancer treatment, such as fatigue, pain, or anxiety about therapy. ED is the inability to obtain or maintain an erection firm enough for sexual intercourse; this differs from infertility, which is the inability to conceive a child. In addition, depressed feelings about having cancer can affect sexuality, causing a range of signs and symptoms that can lead to ED.

Chemotherapy, hormone therapy, surgery, and radiation can all cause sexual adverse effects (Table 1). Additional factors that play a role include patient age¹ and degree of ED before starting cancer treatment.² In this article, we discuss how chemotherapy, hormone therapy, surgery, and radiation affect erectile function as well as possible treatment options for ED.

Table 1.

Cancer Treatment Effects on Sexual Dysfunction in Men

Cancer Treatment	Physical Effects	Post-treatment Adverse Effects
Orchiectomy	Lowers testosterone	Loss of libido
Androgen-deprivation therapy for prostate cancer		Decreased arousal
		Erectile dysfunction
		Trouble achieving orgasm
Radical prostatectomy	Damage to pelvic blood supply and nerves	Difficulty achieving and maintaining erections
Radical cystectomy	Removal of prostate and seminal vesicles	Having a dry orgasm with a feeling of pleasure but no ejaculate
Abdominoperineal resection	Creation of an ostomy	May leak urine at the moment of orgasm
Chemotherapy	Toxicity to pelvic blood supply, nerves	Orgasms may not feel the same as they did before cancer treatment
Pelvic radiation therapy	Toxicity to pelvic blood supply, nerves	Difficulty achieving and maintaining erections
RPLND for testicular cancer	Damage to nerves controlling ejaculation	Having a dry orgasm
		Orgasms may not feel the same as they did before cancer treatment
Partial or total penectomy for cancer of the penis	Removal of part or all of the penis	Erection possible after partial penectomy
		Orgasms and ejaculation continue to be possible, but body image affected

Abbreviation: RPLND, retroperitoneal lymph node dissection.

NORMAL ANATOMY AND PHYSIOLOGY OF PENILE ERECTIONS

Penile erection is achieved through five phases: initial filling, partial erection, full erection, rigid erection, and return to flaccid state. Psychologic and physical stimulation lead to smooth muscle relaxation of the arteries, which increases blood flow to the penis during the filling phase. Full erection occurs when full rigidity is obtained. During return to flaccid state, muscle contractions result in increased venous outflow, decreasing penile length and girth.³

The primary innervation comes from the dorsal nerve of the penis, a branch of the pudendal nerve. The cavernosal nerves are a part of the autonomic nervous system and incorporate both sympathetic and parasympathetic fibers.³ The nerves travel along the prostate and enter the corpora cavernosa and corpus spongiosum to regulate blood flow during erection and detumescence. The dorsal somatic nerves are also branches of the pudendal nerves. They are primarily responsible for penile sensation.

The ability to achieve and maintain an erection depends on the penile innervation as well as the peripheral nerves, the integrity of the vascular supply, and biochemical signaling within the corpora.⁴ The autonomic nervous system is involved in erection, orgasm, and tumescence. The parasympathetic nervous system is primarily involved in sustaining and maintaining an erection (S2 to S4 nerve roots).

CHEMOTHERAPY, HORMONE THERAPY

Chemotherapy and hormone therapy can play a role in ED. Many chemotherapy and cancer treatment options include androgen- or testosterone-deprivation therapy.

Androgen-deprivation therapy (ADT) is commonly used in the treatment of prostate cancer. The majority of men receiving continuous ADT who are potent before therapy develop ED. Loss of libido usually develops within the first several months, and ED follows. Sexual dysfunction should be anticipated and couples counseled before ADT is started. Recovery of erectile function is possible after discontinuation of short-term ADT (eg, in men who receive neoadjuvant and adjuvant ADT with radiation therapy for high-risk localized or locally advanced prostate cancer). However, recovery may be delayed or incomplete.^5,6

Chemotherapy agents such as cisplatin or vincristine may interfere with the nerves and vasculature that control erection. Adverse effects of cisplatin in combination with vinblastine and bleomycin treatment include nephrotoxicity, myelosuppression, pulmonary toxicity, therapy-related secondary malignancies, vascular toxicity, neurotoxicity, and infertility.⁷ In relation to ED, chemotherapy-induced vascular toxicity and neurotoxicity are likely the most relevant; however, the answer is not clear.

Wiechno et al⁸ assessed 269 men treated with platinum-based chemotherapy with complete remission of testicular cancer for more than 2 years. They found that 40% of these men had ED on standardized questionnaires.

A cross-sectional study by Bumbasirevic et al⁹ followed 202 men after undergoing platinum-based chemotherapy for testicular cancer. The mean follow-up time since treatment was 47.3 ± 26.8 months, at which point 20.8% of patients reported ED.⁹

RADIATION THERAPY

ED is common after radiation therapy for prostate cancer, yet the etiology is poorly understood and the true incidence unknown. The reported incidence ranges from 10% to 60%.^10-12

Several animal model studies have examined stereotactic body radiation therapy to the prostate, neurovascular bundles, and penile bulb. Nolan et al¹³ showed that prostatic irradiation caused arterial damage (specifically, altered internal pudendal arterial tone) and decreased motor function in the pudendal nerve (from axonal degeneration and loss). Kimura et al¹⁴ found decreased cyclic guanosine monophosphate levels (important in mediating erections) in the radiated group (25 Gy) compared with controls.

Rivin del Campo et al¹⁵ conducted a review of the literature to examine whether there was a relationship between the radiation dose to the penile bulb and risk of ED in men treated for prostate cancer with external-beam radiation therapy (EBRT). Of 146 reviewed articles that were assigned reliability scores, half showed a relationship between dose of radiation and ED. Overall, this analysis supported a dose effect of external-beam radiation to ED and noted a mean dose of > 50 Gy to the penile bulb as significant.

Brachytherapy has a higher rate of preservation of erectile function than EBRT: 68% compared with 58% for EBRT.¹⁰ In addition, increased age (> 60 years) diminished pretreatment erectile function, and combination therapy with EBRT and/or ADT significantly increases ED after brachytherapy. Typically, little improvement is seen in ED percentages over time.¹¹ Occasionally, these numbers stabilize or return to baseline. This was demonstrated by Siglin et al,¹⁶ who followed several domains of sexual function in men who had undergone EBRT. They noted that sexual function maximally decreases within the first 24 months after radiation and stabilizes thereafter.¹⁶

In addition, radiation therapy is often part of the regimen used to prepare a patient for bone marrow transplant (eg, treatment of leukemias and lymphomas). Chatterjee et al¹⁷ proposed that microangiopathy and subsequent cavernosal vascular insufficiency is the key causative factor for ED in patients treated for multiple myeloma with high-dose chemotherapy and total-body irradiation.

PELVIC SURGERY

Men with cancer in the pelvis are more likely than are men with other cancers to have ED after treatment, given the location of the neurovascular pathways responsible for erections. A severed nerve can lead to weakened erections or the inability to achieve an erection, whereas interruption to normal blood supply can affect the ability to maintain an erection.

Colon and Rectal Surgery (eg, abdominoperineal resection)

Postoperative sexual dysfunction ranges from 10% to 50%, depending on the assessments used.^18,19 Duran et al²⁰ noted a 17.8% decrease in the sexual function of men compared with the preoperational period after abdominoperineal resection and low anterior resection. Both erection and ejaculation were impaired significantly. They proposed that this was secondary to nerve injury in the hypogastric plexus and autonomic nerves encountered during the dissection of Denonvilliers fascia. Celentano et al²¹ showed that avoiding macroscopic damage to nerves intraoperatively (nerve sparing) helps with preserving erectile function. Unfortunately, this technique is not applicable in every patient.

Bladder Surgery (eg, radical cystectomy)

Zippe et al²² followed 49 preoperatively potent subjects who had undergone radical cystectomy for 47 months. After surgery, 86% of patients were unable to achieve vaginal penetration, and only 37% of patients who had undergone a nerve-sparing procedure had erections sufficient for vaginal penetration.

Hekal et al²³ evaluated penile vascular changes in patients undergoing nerve-sparing and non–nerve-sparing radical cystectomy via penile duplex ultrasound. They noted a statistically significant increase in penile end-diastolic velocity (suggesting a veno-occlusive dysfunction), which was improved significantly after 12 months in the nerve-sparing group. Spontaneous erections in the nerve-sparing group variably returned over 12 months. The time delay was believed to be due to the so-called neurapraxia phenomenon, a temporary injury in the cavernosal nerves that prevents any form of erection.²⁴

In addition, certain urinary diversions may require creation of an ostomy that allows urine to collect in a bag that attaches to the body. This has been found to impair sexual function, especially in women.²⁵

Prostate Surgery (eg, radical prostatectomy)

In assessing postprostatectomy erectile function in a group of 210 patients, Fode et al²⁶ found that only 6.7% of patients reported that their erections were comparable to those before surgery. Bilateral nerve sparing was the only significant predictor of a return to baseline erectile function. Of patients who did use erectile aids, 32.9% maintained their preoperative erectile function score. The authors concluded that a return to subjective baseline erectile function after radical prostatectomy is rare.

Of note, pelvic lymph node dissection was not associated with an increased risk of postoperative ED.²⁷ Only patient age at surgery, preoperative erectile function, and pathologic tumor stage predicted erectile function recovery.

Penile Surgery (eg, total penectomy)

Squamous cell carcinoma of the penis can, in certain instances, be treated with partial penectomy. Scarberry et al²⁸ reported on sexual function after partial penectomy. Although their numbers were small (n = 6), they noted 50% reported normal erections but described intercourse as “not very enjoyable” and were dissatisfied with their sex life. The remaining 50% consistently reported no sexual activity and denied feeling sexual desire.

In a larger study, Gulino et al²⁹ looked at ED after glansectomy for locally confined carcinoma of the penis in 42 patients. Their results showed that 6 months after surgery, 73% of patients reported spontaneous rigid erections and 60% reported coital activity.

Testicular Cancer (eg, retroperitoneal lymph node dissection, orchiectomy)

In testicular cancer survivors, rates of ED are reported to be between 12% and 40%, regardless of the cancer treatment method.^8,30 In 2014, Tal et al³¹ studied men who developed ED after testicular cancer treatment. Of patients with seminoma, 66% were treated with radiation therapy; 79% with nonseminomatous germ cell tumor received chemotherapy, 18% underwent primary retroperitoneal lymph node dissection, and 20% underwent postchemotherapy retroperitoneal lymph node dissection. Penile duplex Doppler ultrasonography was used to assess blood flow and erectile hemodynamics to differentiate vasculogenic ED from psychogenic ED. It was noteworthy that 84% of patients complained of loss of erections and 24% had episodes of transient ED before their testicular cancer diagnosis.

All patients had a normal Doppler ultrasound 12 months after treatment of testicular cancer, and there were no differences in hemodynamics between those men with and without hypogonadism. This finding led the authors to postulate that ED in this group of men was not mediated by vascular factors.

ED TREATMENTS FOR PATIENTS WITH CANCER

Numerous treatment options for ED are available for patients with cancer. Here we review the most commonly used penile rehabilitation methods and their successes and limitations. Table 2 provides a summary.

Table 2.

Erectile Dysfunction Treatments for Patients With Cancer

Treatment	Advantages	Disadvantages and Adverse Effects
PDE5i (sildenafil, tadalafil, vardenafil)	Easy to use in pill form	Adverse effects of facial flushing, stuffy nose, upset stomach, priapism
	Fast onset of action	Contraindicated with use of nitrites for chest pain
		Contraindicated if not stable on α-blockers
		Cost if not covered by insurance
		May be less effective in men with diabetes or after some treatments for prostate cancer
Vacuum erection device	One-time expense	Adverse effects of penile bruising, discomfort, numbness, or coldness
	Can be combined with PDE5i	Insufficient erections
		Blocked ejaculation
		Mechanical difficulties
Intraurethral suppository (alprostadil)	Easy to use	Adverse effects of penile and/or urethral pain or burning, priapism
	Alternative in patients failing PDE5i and/or vacuum erection device	Cost if not covered by insurance
Injection therapy (alprostadil, papaverine, phentolamine, or combination)	Easy to use	Adverse effects of penile pain or fibrosis, priapism
	Can be used on demand	Cost if not covered by insurance
		Some patients uncomfortable with injection to penis
Inflatable penile prosthesis	Effective in majority of men	Adverse effects include destruction of natural erectile tissue, risk of infection
	Becomes part of a man’s body	Device repairs require surgery
	Inflatable types are not visible	Hand dexterity needed to operate
	Erection looks and feels natural	Not a reversible treatment
	Usually covered by insurance

Abbreviation: PDE5i, phosphodiesterase type 5 inhibitor.

Phosphodiesterase Type 5 Inhibitors

Currently, the most common treatment of ED after prostatectomy is a phosphodiesterase type 5 inhibitor (PDE5i).³² The most commonly used medications in this class of drugs are sildenafil, tadalafil, and vardenafil.

All PDE5i medications share the same mechanism of action, but vardenafil and sildenafil have a faster onset of action, approximately 30 minutes to 1 hour, as opposed to tadalafil, for which the onset of action is approximately 2 to 4 hours. Common adverse effects include headache, facial flushing, stuffy nose, and upset stomach. PDE5i use is contraindicated in patients taking nitrates for chest pain, and caution should be used when concurrently prescribed with α-blockers. Patients should be stable on their α-blocker therapy before using an oral PDE5i. These medications may also be less effective in patients with diabetes. There are currently no direct comparison studies available to determine which currently available PDE5i offers better results for ED or penile rehabilitation.³³

Vacuum Erection Devices

Vacuum erection devices have been in use since the 1980s; they consist of a hollow plastic tube, a hand- or battery-powered vacuum pump, and a tension ring. The tube is placed over the penis, which creates a vacuum that pulls blood into the penis. Once an erection is achieved, an elastic tension ring is placed at the base of the penis to help maintain the erection.

These devices are a good option for many patients because they are a one-time expense and can be used in conjunction with a PDE5i to help maintain and sustain an erection. However, they are often abandoned as a treatment option because of adverse effects, such as infection, cavernosal fibrosis, penile discomfort, bruising or numbness, or various mechanical failures of the device.³⁴

Intraurethral Suppositories

A medicated urethral suppository for erection was developed in the 1990s. An applicator is used to deliver a small, medicated pellet containing alprostadil into the urethra. Alprostadil is a prostaglandin E1 (PGE1) that creates a vasodilatory effect on the blood vessels of the penis. Once the pellet is dissolved, it leads to increased blood flow to the penis and creates an erection. At one time, this was believed to be the next best treatment option for patients with ED. However, adverse effects, such as penile and urethral pain or burning, are a deterrent for many patients, and overall efficacy is poor (approximately 30%).³⁵

Injection Therapy

Self-injection therapy, as the term implies, uses a needle to inject medication directly into the base or side of the penis. Much like the medicated urethral suppository for erection, this approach creates an erection by increasing blood flow into the penis via direct delivery of vasoactive substances into the corporal bodies. Alprostadil, papaverine plus phentolamine, and papaverine, phentolamine, and PGE1 are the formularies used for injection therapy.

Papaverine works by dilating smooth muscle, and phentolamine causes vasodilation as an α-adrenergic antagonist. This treatment option is successful and is used regularly for ED and penile rehabilitation. However, like many treatments for ED, this option presents adverse effects that deter its use, including pain, penile fibrosis, and priapism.

Inflatable Penile Prosthesis

Inflatable penile prosthesis is the mainstay of therapy for medically refractory ED. There are three models of implants currently on the market: three-piece inflatable implants (pump, cylinders, reservoir), two-piece inflatable implants (pump, cylinders), and one-piece malleable implants (cylinders).

The device is entirely contained within the body and is operated by squeezing and releasing a pump in the scrotum. The three-piece implant is seen as the gold standard for patients with ED who find medications, injections, and vacuum erection devices ineffective or unsatisfactory. It has high patient and partner satisfaction rates of > 90%.^35,36

In the longest follow-up study to date on 10- and 15-year revision-free survival from first-time inflatable implants, Wilson et al³⁷ found excellent satisfaction rates (98% at 10 and 15 years), low infection rates (7% by 10 years, 9% by 15 years), and good mechanical survival (79% by 10 years, 71% by 15 years). Complications include urethral and corporal perforation, crossover, infection, impending erosion, and/or glans appearance deformity.

PENILE REHABILITATION TREATMENT PLAN

When patients are diagnosed with cancer, erectile restoration may not be discussed until treatment or surgery has been completed. There is currently an increasing interest in developing penile rehabilitation programs, the goal of which is to ameliorate the destructive processes that occur after cancer treatment to preserve pretreatment erectile function. Currently, there is no consensus on when or which treatment should be started or for how long. Montorsi et al³⁸ performed a study to determine if nightly versus on-demand vardenafil would help in the recovery of erectile function in men after bilateral nerve-sparing radical prostatectomy. The study concluded that on-demand vardenafil had a greater success rate (34.5%) for restoration of erections when compared with nightly dosing (25%). Another study suggested that nightly sildenafil (50 to 100 mg) can markedly increase the return of spontaneous erections after bilateral nerve-sparing radical prostatectomy.³⁹ Both studies indicate that further long-term research is needed to determine the best approach to penile restoration. There is also growing interest in identifying patients before planned treatment who will likely benefit from penile rehabilitation as well as start of rehabilitation early in the postoperative period^39-41 or even during radiation therapy regimens.⁴²

It is the authors’ recommendation that patients undergoing treatment or surgery would ideally be started on a PDE5i approximately 2 to 4 weeks before treatment or surgery until 2 to 4 weeks after completion of treatment or surgery. A combination of full-dose sildenafil (100 mg), vardenafil (20 mg), or tadalafil (20 mg) and a low dose (25 mg, 5 mg, and 5 mg, respectively) would be used. If patients are able to attain an erection, PDE5i therapy is then reassessed every 4 months until 2 years after surgery. If patients do not respond to PDE5i therapy, penile injection therapy is instituted three times a week, with low-dose PDE5i between each injection day. Injection therapy will continue for 6 months, and the patient will be challenged with a full dose of sildenafil (100 mg), vardenafil (20 mg), or tadalafil (20 mg). If a response to PDE5i is demonstrated, patients can continue with PDE5i alone; if there is no response, injection therapy is continued. The overall goal is for the patient to achieve two to three erections per week.⁴³

SUMMARY

Although research is still needed to determine the best therapeutic regimen for male cancer survivors with ED, many effective therapies exist. These treatments can help patients achieve good quality of life after chemotherapy, radiation, or surgery. A referral to a urologist is the appropriate next step for patients seeking treatment options for ED.

It is important to manage patient expectations on return of erections. Erectile function may take up to 2 years to return or may never return, depending on the treatment and comorbidities of the patient. Clinicians, providers, and surgeons must be aware that many patients may not realize the dramatic effects that loss of erectile function may have on their quality of life. Providers should facilitate an open and honest discussion with patients before treatment initiation. This will help to prepare patients for subsequent adverse effects as they occur and provide knowledge of available treatment options. Knowledge and managing expectations will help deter the patient anxiety, depression, and stigma that often coincide in men with ED.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Collection and assembly of data: Maria Voznesensky, Kiran Annam

Data analysis and interpretation: Kiran Annam

Manuscript writing: All authors

Final approval of manuscript: All authors

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Understanding and Managing Erectile Dysfunction in Patients Treated for Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml.

Maria Voznesensky

No relationship to disclose

Kiran Annam

No relationship to disclose

Karl J. Kreder

Consulting or Advisory Role: Medtronic, Symptelligence Medical Informatics, Tengion