Clinical Review
Understanding and Managing Erectile Dysfunction in Patients Treated for Cancer Maria Voznesensky, MD, Kiran Annam, ARNP, and Karl J. Kreder, MD
University of Iowa, Iowa City, IA
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.
ASSOCIATED CONTENT See accompanying commentaries on pages 305 and 307 DOI: 10.1200/JOP.2016.010678
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,
Copyright © 2016 by American Society of Clinical Oncology
and radiation affect erectile function as well as possible treatment options for ED. 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
Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
297
Voznesensky, Annam, and Kreder
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.
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 298
Volume 12 / Issue 4 / April 2016
n
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 platinumbased 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
Journal of Oncology Practice
Copyright © 2016 by American Society of Clinical Oncology
ED in Oncology Patients
for testicular cancer. The mean follow-up time since treatment was 47.3 6 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. Copyright © 2016 by American Society of Clinical Oncology
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 Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
299
Voznesensky, Annam, and Kreder
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 5 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. 300
Volume 12 / Issue 4 / April 2016
n
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. 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 a-blockers. Patients should be stable on their a-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
Journal of Oncology Practice
Copyright © 2016 by American Society of Clinical Oncology
ED in Oncology Patients
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 a-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)
Injection therapy (alprostadil, papaverine, phentolamine, or combination)
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
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.
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 Copyright © 2016 by American Society of Clinical Oncology
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 Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
301
Voznesensky, Annam, and Kreder
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 a-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 302
Volume 12 / Issue 4 / April 2016
n
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 period39-41 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
Journal of Oncology Practice
Copyright © 2016 by American Society of Clinical Oncology
ED in Oncology Patients
deter the patient anxiety, depression, and stigma that often coincide in men with ED.
15. Rivin del Campo E, Thomas K, Weinberg V, et al: Erectile dysfunction after radiotherapy for prostate cancer: A model assessing the conflicting literature on dose-volume effects. Int J Impot Res 25:161-165, 2013
Acknowledgment M.V. and K.A. contributed equally to this work.
16. Siglin J, Kubicek GJ, Leiby B, et al: Time of decline in sexual function after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 76: 31-35, 2010
Authors’ Disclosures of Potential Conflicts of Interest Disclosures provided by the authors are available with this article at jop.ascopubs.org.
17. Chatterjee R, Andrews HO, McGarrigle HH, et al: Cavernosal arterial insufficiency is a major component of erectile dysfunction in some recipients of high-dose chemotherapy/chemo-radiotherapy for haematological malignancies. Bone Marrow Transplant 25:1185-1189, 2000
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 Corresponding author: Karl J. Kreder, MD, University of Iowa, Department of Urology, 200 Hawkins Dr, 3 RCP, Iowa City, IA 52242-1089; e-mail: [email protected].
18. Eveno C, Lamblin A, Mariette C, et al: Sexual and urinary dysfunction after proctectomy for rectal cancer. J Visc Surg 147:e21-e30, 2010 19. Lange MM, van de Velde CJ: Urinary and sexual dysfunction after rectal cancer treatment. Nat Rev Urol 8:51-57, 2011 20. Duran E, Tanriseven M, Ersoz N, et al: Urinary and sexual dysfunction rates and risk factors following rectal cancer surgery. Int J Colorectal Dis 30: 1547-1555, 2015 21. Celentano V, Fabbrocile G, Luglio G, et al: Prospective study of sexual dysfunction in men with rectal cancer: Feasibility and results of nerve sparing surgery. Int J Colorectal Dis 25:1441-1445, 2010 22. Zippe CD, Raina R, Massanyi EZ, et al: Sexual function after male radical cystectomy in a sexually active population. Urology 64:682-685, 2004; discussion 685-686
References 1. Gareri P, Castagna A, Francomano D, et al. Erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives. Int J Endocrinol 2014: 878670, 2014 2. Alemozaffar M, Regan MM, Cooperberg MR, et al: Prediction of erectile function following treatment for prostate cancer. JAMA 306:1205-1214, 2011 3. Lue TF: Physiology of penile erection and pathophysiology of erectile dysfunction, in: Wein AJ, Kavoussi LR, Partin AW, et al: (eds): Campbell-Walsh Urology (ed 11). Philadelphia, PA, Elsevier, 2016, pp 612-642 4. Andersson KE: Erectile physiological and pathophysiological pathways involved in erectile dysfunction. J Urol 170:S6-S13, 2003; discussion S13-S14 5. Wilke DR, Parker C, Andonowski A, et al: Testosterone and erectile function recovery after radiotherapy and long-term androgen deprivation with luteinizing hormone-releasing hormone agonists. BJU Int 97:963-968, 2006 6. Li R, Ruckle HC, Schlaifer AE, et al: The effect of androgen deprivation therapy before salvage whole-gland cryoablation after primary radiation failure in prostate cancer treatment. Urology 85:1137-1142, 2015 7. van Basten JP, Hoekstra HJ, van Driel MF, et al: Sexual dysfunction in nonseminoma testicular cancer patients is related to chemotherapy-induced angiopathy. J Clin Oncol 15:2442-2448, 1997 8. Wiechno P, Demkow T, Kubiak K, et al: The quality of life and hormonal disturbances in testicular cancer survivors in cisplatin era. Eur Urol 52:1448-1454, 2007
23. Hekal IA, Mosbah A, El-Bahnasawy MS, et al: Penile haemodynamic changes in post-radical cystectomy patients. Int J Androl 34:27-32, 2011 24. Leungwattanakij S, Bivalacqua TJ, Usta MF, et al: Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J Androl 24:239-245, 2003 25. Mahjoubi B, Mirzaei R, Azizi R, et al: A cross-sectional survey of quality of life in colostomates: A report from Iran. Health Qual Life Outcomes 10:136, 2012 26. Fode M, Frey A, Jakobsen H, et al: Erectile function after radical prostatectomy: Do patients return to baseline? Scand J Urol 10.3109/21681805.2015.1102964 [epub ahead of print on November 5, 2015] 27. Hatzichristodoulou G, Wagenpfeil S, Wagenpfeil G, et al: Extended versus limited pelvic lymph node dissection during bilateral nerve-sparing radical prostatectomy and its effect on continence and erectile function recovery: Long-term results and trifecta rates of a comparative analysis. World J Urol 10.1007/s00345-015-1699-9 [epub ahead of print on September 29, 2015] 28. Scarberry K, Angermeier KW, Montague D, et al: Outcomes for organ-preserving surgery for penile cancer. Sex Med 3:62-66, 2015 29. Gulino G, Sasso F, Palermo G, et al: Sexual outcomes after organ potency-sparing surgery and glans reconstruction in patients with penile carcinoma. Indian J Urol 29: 119-123, 2013 30. Rossen P, Pedersen AF, Zachariae R, et al: Sexuality and body image in long-term survivors of testicular cancer. Eur J Cancer 48:571-578, 2012
9. Bumbasirevic U, Bojanic N, Pekmezovic T, et al: Health-related quality of life, depression, and sexual function in testicular cancer survivors in a developing country: A Serbian experience. Support Care Cancer 21:757-763, 2013
31. Tal R, Stember DS, Logmanieh N, et al: Erectile dysfunction in men treated for testicular cancer. BJU Int 113:907-910, 2014
10. Snyder KM, Stock RG, Buckstein M, et al: Long-term potency preservation following brachytherapy for prostate cancer. BJU Int 110:221-225, 2012
32. Albaugh JA: Addressing and managing erectile dysfunction after prostatectomy for prostate cancer. Urol Nurs 30:167-177, 2010
11. Rana Z, Hong RL, Abugideiri M, et al: Sexual, irritative, and voiding outcomes, following stereotactic body radiation therapy for prostate cancer. Radiat Oncol 10: 182, 2015
33. Schwartz BG, Kloner RA: Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation 122:88-95, 2010
12. Girelli G, Franco P, Sciacero P, et al: Image-guided intensity-modulated radiotherapy for prostate cancer employing hypofractionation and simultaneous integrated boost: Results of a consecutive case series with focus on erectile function. Anticancer Res 35:4177-4182, 2015 13. Nolan MW, Marolf AJ, Ehrhart EJ, et al: Pudendal nerve and internal pudendal artery damage may contribute to radiation-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 91:796-806, 2015 14. Kimura M, Zodda AR, Mahmood J, et al. Pilot study evaluating a rat model of radiation-induced erectile dysfunction using an image-guided microirradiator. Urology 85:1214.e1-1214.e6, 2015
Copyright © 2016 by American Society of Clinical Oncology
34. Hellstrom WJ, Montague DK, Moncada I, et al: Implants, mechanical devices, and vascular surgery for erectile dysfunction. J Sex Med 7:501-523, 2010 35. Mulhall JP, Jahoda AE, Ahmed A, et al: Analysis of the consistency of intraurethral prostaglandin E(1) (MUSE) during at-home use. Urology 58:262-266, 2001 36. Deveci S, Martin D, Parker M, et al: Penile length alterations following penile prosthesis surgery. Eur Urol 51:1128-1131, 2007 37. Wilson SK, Delk JR, Salem EA, et al: Long-term survival of inflatable penile prostheses: Single surgical group experience with 2,384 first-time implants spanning two decades. J Sex Med 4:1074-1079, 2007
Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
303
Voznesensky, Annam, and Kreder
38. Montorsi F, Brock G, Lee J, et al: Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 54:924-931, 2008
41. Salonia A, Burnett AL, Graefen M, et al: Prevention and management of postprostatectomy sexual dysfunctions part 2: Recovery and preservation of erectile function, sexual desire, and orgasmic function. Eur Urol 62:273-286, 2012
39. Padma-Nathan H, McCullough AR, Levine LA, et al: Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy. Int J Impot Res 20:479-486, 2008
42. Zelefsky MJ, Shasha D, Branco RD, et al: Prophylactic sildenafil citrate improves select aspects of sexual function in men treated with radiotherapy for prostate cancer. J Urol 192:868-874, 2014
40. Mulhall JP: The role and structure of a postradical prostatectomy penile rehabilitation program. Curr Urol Rep 10:219-225, 2009
43. Mulhall JP. Saving Your Sex Life: A Guide for Men with Prostate Cancer. Bethesda, MD, Hilton Publishing Company, 2010
304
Volume 12 / Issue 4 / April 2016
n
Journal of Oncology Practice
Copyright © 2016 by American Society of Clinical Oncology
ED in Oncology Patients
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 5 Immediate Family Member, Inst 5 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
Copyright © 2016 by American Society of Clinical Oncology
Karl J. Kreder Consulting or Advisory Role: Medtronic, Symptelligence Medical Informatics, Tengion
Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
Understanding and Managing Erectile Dysfunction in Patients Treated for Cancer Maria Voznesensky, MD, Kiran Annam, ARNP, and Karl J. Kreder, MD
University of Iowa, Iowa City, IA
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.
ASSOCIATED CONTENT See accompanying commentaries on pages 305 and 307 DOI: 10.1200/JOP.2016.010678
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,
Copyright © 2016 by American Society of Clinical Oncology
and radiation affect erectile function as well as possible treatment options for ED. 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
Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
297
Voznesensky, Annam, and Kreder
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.
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 298
Volume 12 / Issue 4 / April 2016
n
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 platinumbased 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
Journal of Oncology Practice
Copyright © 2016 by American Society of Clinical Oncology
ED in Oncology Patients
for testicular cancer. The mean follow-up time since treatment was 47.3 6 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. Copyright © 2016 by American Society of Clinical Oncology
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 Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
299
Voznesensky, Annam, and Kreder
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 5 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. 300
Volume 12 / Issue 4 / April 2016
n
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. 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 a-blockers. Patients should be stable on their a-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
Journal of Oncology Practice
Copyright © 2016 by American Society of Clinical Oncology
ED in Oncology Patients
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 a-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)
Injection therapy (alprostadil, papaverine, phentolamine, or combination)
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
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.
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 Copyright © 2016 by American Society of Clinical Oncology
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 Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
301
Voznesensky, Annam, and Kreder
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 a-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 302
Volume 12 / Issue 4 / April 2016
n
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 period39-41 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
Journal of Oncology Practice
Copyright © 2016 by American Society of Clinical Oncology
ED in Oncology Patients
deter the patient anxiety, depression, and stigma that often coincide in men with ED.
15. Rivin del Campo E, Thomas K, Weinberg V, et al: Erectile dysfunction after radiotherapy for prostate cancer: A model assessing the conflicting literature on dose-volume effects. Int J Impot Res 25:161-165, 2013
Acknowledgment M.V. and K.A. contributed equally to this work.
16. Siglin J, Kubicek GJ, Leiby B, et al: Time of decline in sexual function after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 76: 31-35, 2010
Authors’ Disclosures of Potential Conflicts of Interest Disclosures provided by the authors are available with this article at jop.ascopubs.org.
17. Chatterjee R, Andrews HO, McGarrigle HH, et al: Cavernosal arterial insufficiency is a major component of erectile dysfunction in some recipients of high-dose chemotherapy/chemo-radiotherapy for haematological malignancies. Bone Marrow Transplant 25:1185-1189, 2000
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 Corresponding author: Karl J. Kreder, MD, University of Iowa, Department of Urology, 200 Hawkins Dr, 3 RCP, Iowa City, IA 52242-1089; e-mail: [email protected].
18. Eveno C, Lamblin A, Mariette C, et al: Sexual and urinary dysfunction after proctectomy for rectal cancer. J Visc Surg 147:e21-e30, 2010 19. Lange MM, van de Velde CJ: Urinary and sexual dysfunction after rectal cancer treatment. Nat Rev Urol 8:51-57, 2011 20. Duran E, Tanriseven M, Ersoz N, et al: Urinary and sexual dysfunction rates and risk factors following rectal cancer surgery. Int J Colorectal Dis 30: 1547-1555, 2015 21. Celentano V, Fabbrocile G, Luglio G, et al: Prospective study of sexual dysfunction in men with rectal cancer: Feasibility and results of nerve sparing surgery. Int J Colorectal Dis 25:1441-1445, 2010 22. Zippe CD, Raina R, Massanyi EZ, et al: Sexual function after male radical cystectomy in a sexually active population. Urology 64:682-685, 2004; discussion 685-686
References 1. Gareri P, Castagna A, Francomano D, et al. Erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives. Int J Endocrinol 2014: 878670, 2014 2. Alemozaffar M, Regan MM, Cooperberg MR, et al: Prediction of erectile function following treatment for prostate cancer. JAMA 306:1205-1214, 2011 3. Lue TF: Physiology of penile erection and pathophysiology of erectile dysfunction, in: Wein AJ, Kavoussi LR, Partin AW, et al: (eds): Campbell-Walsh Urology (ed 11). Philadelphia, PA, Elsevier, 2016, pp 612-642 4. Andersson KE: Erectile physiological and pathophysiological pathways involved in erectile dysfunction. J Urol 170:S6-S13, 2003; discussion S13-S14 5. Wilke DR, Parker C, Andonowski A, et al: Testosterone and erectile function recovery after radiotherapy and long-term androgen deprivation with luteinizing hormone-releasing hormone agonists. BJU Int 97:963-968, 2006 6. Li R, Ruckle HC, Schlaifer AE, et al: The effect of androgen deprivation therapy before salvage whole-gland cryoablation after primary radiation failure in prostate cancer treatment. Urology 85:1137-1142, 2015 7. van Basten JP, Hoekstra HJ, van Driel MF, et al: Sexual dysfunction in nonseminoma testicular cancer patients is related to chemotherapy-induced angiopathy. J Clin Oncol 15:2442-2448, 1997 8. Wiechno P, Demkow T, Kubiak K, et al: The quality of life and hormonal disturbances in testicular cancer survivors in cisplatin era. Eur Urol 52:1448-1454, 2007
23. Hekal IA, Mosbah A, El-Bahnasawy MS, et al: Penile haemodynamic changes in post-radical cystectomy patients. Int J Androl 34:27-32, 2011 24. Leungwattanakij S, Bivalacqua TJ, Usta MF, et al: Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J Androl 24:239-245, 2003 25. Mahjoubi B, Mirzaei R, Azizi R, et al: A cross-sectional survey of quality of life in colostomates: A report from Iran. Health Qual Life Outcomes 10:136, 2012 26. Fode M, Frey A, Jakobsen H, et al: Erectile function after radical prostatectomy: Do patients return to baseline? Scand J Urol 10.3109/21681805.2015.1102964 [epub ahead of print on November 5, 2015] 27. Hatzichristodoulou G, Wagenpfeil S, Wagenpfeil G, et al: Extended versus limited pelvic lymph node dissection during bilateral nerve-sparing radical prostatectomy and its effect on continence and erectile function recovery: Long-term results and trifecta rates of a comparative analysis. World J Urol 10.1007/s00345-015-1699-9 [epub ahead of print on September 29, 2015] 28. Scarberry K, Angermeier KW, Montague D, et al: Outcomes for organ-preserving surgery for penile cancer. Sex Med 3:62-66, 2015 29. Gulino G, Sasso F, Palermo G, et al: Sexual outcomes after organ potency-sparing surgery and glans reconstruction in patients with penile carcinoma. Indian J Urol 29: 119-123, 2013 30. Rossen P, Pedersen AF, Zachariae R, et al: Sexuality and body image in long-term survivors of testicular cancer. Eur J Cancer 48:571-578, 2012
9. Bumbasirevic U, Bojanic N, Pekmezovic T, et al: Health-related quality of life, depression, and sexual function in testicular cancer survivors in a developing country: A Serbian experience. Support Care Cancer 21:757-763, 2013
31. Tal R, Stember DS, Logmanieh N, et al: Erectile dysfunction in men treated for testicular cancer. BJU Int 113:907-910, 2014
10. Snyder KM, Stock RG, Buckstein M, et al: Long-term potency preservation following brachytherapy for prostate cancer. BJU Int 110:221-225, 2012
32. Albaugh JA: Addressing and managing erectile dysfunction after prostatectomy for prostate cancer. Urol Nurs 30:167-177, 2010
11. Rana Z, Hong RL, Abugideiri M, et al: Sexual, irritative, and voiding outcomes, following stereotactic body radiation therapy for prostate cancer. Radiat Oncol 10: 182, 2015
33. Schwartz BG, Kloner RA: Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation 122:88-95, 2010
12. Girelli G, Franco P, Sciacero P, et al: Image-guided intensity-modulated radiotherapy for prostate cancer employing hypofractionation and simultaneous integrated boost: Results of a consecutive case series with focus on erectile function. Anticancer Res 35:4177-4182, 2015 13. Nolan MW, Marolf AJ, Ehrhart EJ, et al: Pudendal nerve and internal pudendal artery damage may contribute to radiation-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 91:796-806, 2015 14. Kimura M, Zodda AR, Mahmood J, et al. Pilot study evaluating a rat model of radiation-induced erectile dysfunction using an image-guided microirradiator. Urology 85:1214.e1-1214.e6, 2015
Copyright © 2016 by American Society of Clinical Oncology
34. Hellstrom WJ, Montague DK, Moncada I, et al: Implants, mechanical devices, and vascular surgery for erectile dysfunction. J Sex Med 7:501-523, 2010 35. Mulhall JP, Jahoda AE, Ahmed A, et al: Analysis of the consistency of intraurethral prostaglandin E(1) (MUSE) during at-home use. Urology 58:262-266, 2001 36. Deveci S, Martin D, Parker M, et al: Penile length alterations following penile prosthesis surgery. Eur Urol 51:1128-1131, 2007 37. Wilson SK, Delk JR, Salem EA, et al: Long-term survival of inflatable penile prostheses: Single surgical group experience with 2,384 first-time implants spanning two decades. J Sex Med 4:1074-1079, 2007
Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
303
Voznesensky, Annam, and Kreder
38. Montorsi F, Brock G, Lee J, et al: Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy. Eur Urol 54:924-931, 2008
41. Salonia A, Burnett AL, Graefen M, et al: Prevention and management of postprostatectomy sexual dysfunctions part 2: Recovery and preservation of erectile function, sexual desire, and orgasmic function. Eur Urol 62:273-286, 2012
39. Padma-Nathan H, McCullough AR, Levine LA, et al: Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy. Int J Impot Res 20:479-486, 2008
42. Zelefsky MJ, Shasha D, Branco RD, et al: Prophylactic sildenafil citrate improves select aspects of sexual function in men treated with radiotherapy for prostate cancer. J Urol 192:868-874, 2014
40. Mulhall JP: The role and structure of a postradical prostatectomy penile rehabilitation program. Curr Urol Rep 10:219-225, 2009
43. Mulhall JP. Saving Your Sex Life: A Guide for Men with Prostate Cancer. Bethesda, MD, Hilton Publishing Company, 2010
304
Volume 12 / Issue 4 / April 2016
n
Journal of Oncology Practice
Copyright © 2016 by American Society of Clinical Oncology
ED in Oncology Patients
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 5 Immediate Family Member, Inst 5 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
Copyright © 2016 by American Society of Clinical Oncology
Karl J. Kreder Consulting or Advisory Role: Medtronic, Symptelligence Medical Informatics, Tengion
Volume 12 / Issue 4 / April 2016
n
jop.ascopubs.org
