Erectile Dysfunction in Cancer Patients
Erectile dysfunction (ED) occurs as a consequence of many cancer treatments, and can impact heavily on a patient's quality of life (Peltier, van Velthoven & Roumeguere, 2009). The psychological effects of ED may result in loss of self-esteem, disturbed romantic relationships, and emotional distress (Peltier, van Velthoven & Roumeguere). For these reasons, it is important that medical providers are able to identify, assess, and treat ED in cancer patients (Galbraith & Crighton, 2008). Various effective treatments for ED are available, and many new options are on the horizon.
Erectile Dysfunction (ED) is a significant problem for cancer patients—both cancer survivors and those being actively treated for cancer. Exact statistics for ED in cancer patients as a group are difficult to measure due to the effect of different diseases and treatments on ED and its multifactorial nature. ED has been studied most frequently in prostate cancer patients, but it can come about as a consequence of many cancer diagnoses and treatments (Bergman, Gore, Penson, Kwan & Litwin, 2009; Galbraith & Crighton, 2008). In addition to those with prostate cancer, patients with colorectal, bladder, rectal, penile, testicular, colon, and hematologic malignancies, among others, may experience ED (Galbraith & Crighton, 2008; Masterson, Wedmid, Sandhu & Eastham, 2009). It is estimated that 60-90% of men experience sexual dysfunction following prostatectomy and 67-85% following radiotherapy for prostate cancer (Miles et. al), and that 30-51% of men treated for localized prostate cancer use an erectile aid within five years of receiving cancer therapy (Bergman, gore, Penson, Kwan & Litwan, 2009). Despite a large amount of research and many recent advances in surgery for prostate cancer, such as nerve-sparing techniques, laparoscopic procedures, and robotic-assisted procedures, a significant number of men continue to experience ED after prostatectomy (Galbraith & Crighton).
No matter what the cancer diagnosis, factors such as surgeries, radiation treatments, chemotherapy treatments, hormone therapy, changes in testosterone levels, changes in physical functionality, and depression / anxiety all play a role in sexuality, and thus contribute to the problem of ED (Miles et. al, 2007). Erectile function is key to a man's sense of identity and his relationship with his significant other, and has a significant impact on quality of life for cancer patients due to its impact on many psychosocial areas, including affect, loneliness, psychological adjustment, marital happiness, and depression, among other things (Galbraith & Crighton, 2008; Schroeck et. al, 2008). Addressing the issue of ED as well as its sequelae may allow patients to focus on, and cope better, with other difficulties caused by their cancer treatments.
Pathophysiology of Erectile Dysfunction in Cancer Patients
Penile erection occurs as a result of a complex intracellular cascade of reactions (Kuan, 2008). The nervous system may be triggered as a response to stimulation of the senses, as a reflex to direct genital stimulation, or during REM sleep as a nocturnal erection (Kuan). Any of these types of stimulation will initiate a very complicated cascade of reactions (Kuan). Nitric oxide, guanylate cyclase, guanosine triphosphate (GTP), cyclic guanosine monophosphate (cGMP), intracellular calcium, and phosphodiesterase-5 all play a role in the cascade (Kuan). As a result of these chemical reactions, penile cavernosal smooth muscle is relaxed, sinusoidal blood flow to the penis is increased, and venous outflow from the penis is occluded, resulting in a penile erection (Kuan). Interference with any part of this intricate system will result in ED.
Surgeries to the pelvis done to remove tumors or organs may alter both vascular supply to and enervation of sexual organs, thereby contributing to ED (Galbraith & Crighton). ED after radical prostatectomy is thought to be due to injury to the nerve plexus that provides the autonomic enervation to the corpora cavernosa of the penis (Mendenhall et. al, 2009). Additionally, hormonal balances may change with the removal or alteration of organs (Galbraith & Crighton). Surgery for colorectal cancer can damage the pelvic nerve, and also may result in the use of an ostomy appliance, thus affecting ED in both a physiological and psychological manner (Galbraith & Crighton). Radical cystectomy for bladder cancer results in urinary diversion, which may affect ED due to mechanical reasons as well as affecting body image, self-confidence, as well as sexual desire (Galbraith & Crighton). After surgical resection, men with penile cancer are also faced with body image issues, as well as problems with physical functioning, although their pelvic nerves may still be intact (Galbraith & Crighton).
Many patients are treated with pelvic radiation for various types of cancer, and this can also be a significant contributor to ED. Prostate cancer patients can receive photon external-beam radiation, brachytherapy, transperineal implantation of radioactive ioidine-125 seeds, proton beam radiation, or conformal external beam radiation (Galbraith & Crighton, 2008). Other types of cancer are treated with pelvic or abdominal radiation as well, depending on type of cancer and size and spread of the malignancy. The exact mechanism by which radiation therapy (RT) leads to ED is unknown (Mendenhall et. al, 2009). It is known, however that RT usually does not damage the nerves of the pelvis; it creates scar tissue within the pelvis and hardens and constricts vasculature, which can lead to ED (Galbraith & Crighton; Mendenhall et. al, 2009). DNA damage caused by RT is also thought to play a role (Mendenhall et. al). The effects of ED caused by radiation treatment may not become apparent until months or years after treatment has finished (Galbraith & Crighton).
Chemotherapy treatments can affect erectile function in cancer patients for several reasons. Its effects on fast-growing gonadal tissue may alter hormone levels in the body, and fatigue, nausea, and altered body image all may contribute to altered sexual functioning if not directly to ED (Galbraith & Crighton, 2008).
Hormone therapies for prostate cancer are designed to work against androgens in order to prevent further cancer growth in the prostate, but because androgens play a large role in sexual desire and performance, patients receiving hormone therapies often have difficulties with ED (Galbraith & Crighton, 2008). Additionally, androgen deprivation may cause depression, mood swings, anxiety, hot flashes, loss of libido, and body composition changes such as gynecomastia, which affect body image (Galbraith & Crighton).
Clinical Presentation of Erectile Dysfunction
Assessment of sexual function in men undergoing cancer treatment is very important (Schroeck et. al). When a patient is identified to have or to be at risk for ED, his assessment should first include a detailed medical history, including cancer history, treatment history, as well as any history of hypertension, diabetes, cardiac disease, hyperlipidemia, renal insufficiency, hypogonadism, neurologic disorders, psychiatric disorders, chronic illnesses, recreational drug use, and alcohol use (Wespes et. al, 2006). Any of these factors can contribute to or exacerbate ED. [See Figure 1.] A relaxed atmosphere where communication can be more easily facilitated between the patient and the provider is ideal for this discussion, and at some point, the patient's partner should be involved in the conversation as well to facilitate conversation and problem solving in the couple (Wespes et. al).
ED Assessment Guide
Adapted from "Sexual History Topic Guide," by M. E. Galbraith & F. Crighton, 2008, Seminars in Oncology Nursing, 24, p. 107.
Important issues to address when assessing the problem of ED in a cancer patient are: timing of the onset of the problem, the quality of erections, and distinguishing between the ability to obtain versus maintain an erection (Kuan, 2008). Descriptions of rigidity and duration of morning, erotic, and masturbation-induced erections, as well as arousal, ejaculation, and orgasmic problems should be obtained (Wespes et. al). Other information that should be obtained includes quality of the man's libido, genital sensation, presence of pain or numbness in the genitals, and the presence of sexual dysfunctions such as rapid, delayed or dry ejaculation or orgasmic disorders (Kuan). Patients may verbally complain of generalized unresponsiveness, lack of sexual arousability, problems with sexual intimacy, sexual dysfunction such as rapid ejaculation, or performance anxiety, among other things (Kuan).
ED arising from organic etiology would have gradual onset, occurs in all sexual scenarios, is associated with poor non-coital erections, and leads to secondary psychosexual problems, leading to relationship distress and additional anxiety (Kuan, 2008). ED arising from psychogenic etiology is often acute, varies by situation, and may be caused by the stress of relationships, anxiety, or fear (Kuan). It is important to differentiate between the two etiologies because they may be treated differently (Montague et. al, 2005).
The focused physical exam for a cancer patient with ED should include the genitourinary, endocrine, vascular, and neurologic systems (Montague et. al, 2005; Wespes et. al, 2006). The goal of the physical exam is to identify any possible cardiac, vascular, neurological, and hormonal disturbances that may be contributing to the patient's ED (Kuan, 2008; Montague et. al). A focused genital exam should include palpation of the penis and testes for any physical irregularities (Kuan; Montague et. al). Degree of androgenization should be assessed by patterns of hair distribution and the presence of gynecomastia (Kuan). In men with a history of prostate cancer and men over fifty years old, a digital rectal exam should be done in order to detect any abnormalities (Kuan; Montague et. al).
For diagnostic laboratory tests, patients should have a fasting glucose level, lipid profile, total testosterone level, bioavailable / free testosterone if available, and prostate specific antigen (PSA) if indicated (Montague et. al, 2005; Wespes et. al, 2006). If testosterone levels are low, prolactin, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels should be obtained (Wespes et. al). If fasting blood glucose is greater than 125 (or hemoglobin A1C is greater than 6.5% in diabetics), fasting lipid profile is abnormal, PSA is much higher than expected, or TSH is elevated, the causes of those changes should be investigated and treated (Kuan, Montague et. al). [Figure 2]
Algorithm for Evaluation of ED
Adapted from "General diagnostic evaluation algorithm according to the European Association of Urology," by A. Peltier, R. van Velthoven, & T. Roumeguere, 2009, Current Opinion in Oncology, 21, p. 304.
There are many freely available self-assessment tools for ED in prostate cancer patients, including the Funtional Assessment of Cancer Therapy-Prostate (FACT-P), the University of California-Los Angeles Prostate Cancer Index (UCLA-PCI), the Expanded Prostate Cancer Index Composite (EPIC), and The International Index of Erectile Function (IIEF) (Schroeck et. al). The IIEF is a well-tested and freely available tool that can be used for patients of any cancer etiology, and exists in abbreviated forms as well as more extensive versions (Schroeck et. al). The extensive version consists of fifteen questions, and addresses all domains of male sexual dysfunction: erectile dysfunction, orgasmic function, sexual desire, ejaculation, intercourse, and overall satisfaction (Kuan, 2008). [see Appendix A.]
Management Strategies for Erectile Dysfunction in Cancer Patients
The first step in treating ED in a cancer patient is to determine the etiology of the dysfunction (Spark, 2010). It is important to point out that even in nerve sparing oncologic surgeries, there is initial nerve dysfunction, which can last 6 months to 3 years. In cancer patients who have recently undergone abdominal surgery, early erectile function rehabilitation is critical to the recovery and maintenance of spontaneous penile erections (Peltier, van Velthoven, & Roumeguere, 2009). In rat models, it has been demonstrated that penile changes can appear as soon as two days after nerve injury (Peltier, van Velthoven, & Roumeguere).
In addition to hormonal changes, radiation, and abdominal surgery, a patient's comorbidities may also play a role, and control of these factors may lead to improvement of ED (Kuan, 2008; Montague et. al, 2005). Treatment of ED in cancer patients is largely the same as treatment of ED in the general population, and this methodology has been verified by many studies (Miles et. al, 2007). Therapy for ED focuses on two main factors: the capacity to acquire and sustain penile erections and the restoration of libido (Sparkm, 2010). The first-line intervention for ED in cancer patients is the use of phosphodiesterase-5 (PDE-5) inhibitors (Montague et. al; Spark). Second-line treatments include penile self-injectable drugs, intraurethral alprostadil, and vacuum devices (Montague et. al; Spark). Third-line treatments include penile implants, penile prostheses, psycho-educational interventions such as counseling and psychotherapy, and complementary medicine interventions (Miles et. al; Spark). For men with sexual dysfunction and low serum testosterone levels, testosterone replacement therapy should be used either independently or in conjunction with these therapies (Spark, 2010).
PDE-5 inhibitors include sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) (Montague et. al, 2005; Spark, 2010). PDE-5 inhibitors improve erectile function by using anti-fibrotic activity to preserve intra-corporeal smooth erectile muscle (Miles et. al). The role of nitric oxide-induced vasodilation also plays a role in the mechanism of the drugs as well (Spark, 2010). Sildenafil, the first PDE-5 inhibitor, was introduced in 1998 (Miles et. al). The Cochrane Collaboration reported that PDE-5 inhibitors provided significant improvement in erectile function (EF) and vaginal penetration ability, as well as patient satisfaction in all trials in its 2007 review (Miles et. al). 61-71% of men in the general population who are prescribed these drugs are able to achieve successful intercourse (Kuan, 2008). Sildenafil and vardenafil are effective for a period of four hours, while tadalafil is effective for thirty-six hours after being taken (Spark). Choice of PDE-5 inhibitor should be based on patient preferences, cost, ease of use, and side effects (Spark). Notable side effects of PDE-5 inhibitors are headaches, flushing, myalgia, and dyspepsia (Miles et. al; Montague et. al). PDE-5 inhibitors are contraindicated for treatment of patients who take nitrates for cardiac disorders as well as alpha adrenergic agents, due to possible hypotention with this drug combination (Miles et. al; Montague et. al; Spark). PDE-5 inhibitors are also contraindicated for patients with severe cardiovascular disease, unstable angina, heart failure, uncontrolled arrhythmias, hypotension, uncontrolled hypertension, stroke within the past six months, myocardial infarction within the past ninety days, degenerative retinal disorders, or tendency to develop priapism (erection lasting longer than 4 hours) (Kuan, 2008; Montague et. al).
Intracavernous injection therapy is the most effective non-surgical treatment for ED, but it is also invasive and has the highest potential for priapism of the ED treatments (Montague et. al, 2005). Self-injectable drugs include alprostadil (prostaglandin E1, Caverjet), papaverine, papaverine and phentolamine (BiMix) or alprostadil with papaverine and phentolamine (Tri-Mix) (Spark, 2010). These drugs can be used once per day, and are injected directly into the lateral aspect of the penis, near the base (Kuan, 2008; Montague et. al). They work by encouraging relaxation of smooth muscle, and allowing blood to engorge the penis, as well as impeding venous outflow from the penis so that an erection may be maintained (Spark). 31-72% of men in the general population are able to achieve successful intercourse with these drugs (Kuan). The main side effect noted for these drugs is priapism, which is treatable if medical attention is sought quickly (Spark). The goal of this treatment is attain an erection that lasts up to one hour, and patients should be titrated to the minimum amount of drug to achieve this goal, with the aim of avoiding priapism (Kuan).
Studies indicate that transurethral alprostadil (MUSE) is successful as a less invasive alternative to penile injections, although it is slightly less effective overall than injections (Miles et. al, 2007; Spark, 2010). Alprostadil is a synthetic vasodilator (Montague et. al, 2005). In the general population, about 66% of men are able to achieve successful intercourse with this drug (Kuan, 2008). Side effects of transurethral alprostadil included urethral pain and burning and penile pain (Miles et. al). Priapism occurs as a side effect much less with transurethral alprostadil than with injections (Spark).
Vacuum constriction devices (VCD) are another very effective option, and are available over the counter (Kuan, 2008). The Cochrane Collaboration noted one study done in cancer patients in 2006 in which 81% of participants using a VCD were able to achieve sexual intercourse by using the devices (Miles et. al, 2007). VCDs utilize vacuum suction to pull blood into the spongy tissue of the penis, and a ring can then be applied at the base of the penis in order to prevent outflow of this blood (Spark, 2010). Manual dexterity is required to operate VCDs, and so some patients may be unable to use them, or may need practice (Spark). A patient using a VCD for intercourse is also unable to ejaculate due to compression of the urethra by the ring at the base of the penis (Spark). The American Urological Association (AUA) recommends that VCDs have a vacuum limiter in order to prevent injury to the penis from extremely high negative pressure (Montague et. al, 2005).
Prosthetic penile implants and inflatable devices are an option for men who have failed first- and second-line therapies (Montague et. al, 2005; Spark, 2010). Two highly effective methods of prosthetic devices are available: malleable rods and inflatable prostheses (Montague et. al; Spark). Side effects for prosthetic implants include a 1-2% risk of infection and a 6-16% risk mechanical failure in a five year time period, as well as permanent damage to penile tissue (Kuan, 2008; Spark). Patients should be made aware that this surgery is irreversible, and that after it is done, they will never be able to achieve an erection naturally (Kuan; Montague et. al).
Treatment Algorithm for ED
"Curable" causes of ED include hormonal causes, posttraumatic arteriogenic ED, and psychological problems
Adapted from "General treatment algorithm according to the European Association of Urology," by A. Peltier, R. van Velthoven, & T. Roumeguere, 2009, Current Opinion in Oncology, 21, p. 305.
Advantages and Disadvantages of Various ED Treatments
Adapted from "Erectile Dysfunction Treatments," by M. E. Galbraith & F. Crighton, 2008, Seminars in Oncology Nursing, 24, p. 110.
Sexual counseling with or without a partner is also another option for treatment. Studies indicate that in heterosexual couples, sexual counseling was successful both with and without a female partner present, and was associated with improvement in sexual function and satisfaction (Miles et. al, 2007). A randomized clinical trial of couples counseling sessions for patients with ED and their partners resulted in higher QOL, more self-efficacy, better communication, and less negative appraisal of care giving, uncertainty, hopelessness, and symptom distress (Peltier, van Velthoven & Roumeguere, 2009). Support groups may also aid patients in coping with the consequences of ED. One study showed that support groups for men with prostate cancer were very successful due to the male ability to use humor therapeutically, as a support mechanism (Oliffe et. al, 2009).
Testosterone replacement with testosterone gels, patches, or injections is an option for men with androgen deficiency (Spark, 2007). However, they are contraindicated for patients on androgen-deprivation therapy for prostate cancer. The AUA does not recommend the use of testosterone in men whose testosterone level is normal (Montague et. al, 2005).
Vascular repair therapy may also be an option for men whose ED stems from vascular damage during surgery (Spark, 2007). The AUA states that arterial reconstructive surgery is a treatment option only in healthy patients with recently acquired ED secondary to a focal arterial occlusion and in the absence of any evidence of generalized vascular disease (Montague et. al, 2005). Therefore, very few cancer patients undergoing treatment would be eligible for arterial vascular surgery to treat ED. The AUA does not recommend surgeries with the intent to limit the venous outflow of the penis, due to lack of evidence (Montague et. al). Results of these surgeries are not shown to be effective long-term (Spark).
There are also several herbal treatments for ED available. The AUA does not recommend the use of herbal supplements to treat ED due to the fact that their mechanisms of action, effectiveness, and safety of these agents have not been documented in repeated, randomized clinical trials with independent data monitoring (Montague et. al, 2005). There is also a lack of regulation for the manufacturing and distribution of herbal therapies, which may result in inexact product potency, contamination, and fraudulent representation of ingredients (Montague et. al). With that said, various studies on herbal supplements for ED do exist. L-arginine is a substance that produces excess nitric oxide, triggering vasodilatation in the penis (Stanislavov, Nikolova, & Rohdewald, 2008). In a 2008 study, L-arginine was shown to be able improve ED in 31% of patients (Stanislavov, Nikolova, & Rohdewald). Prelox is a pine bark extract which, when given with L-arginine, was shown to have an 80-92% success rate of treating ED in one study, although further studies of this drug combination must be done to confirm (Stanislavov, Nikolova, & Rohdewald). Korean red ginseng has been found to have greater effect than placebo in treating ED, however, a systematic review published by the British Journal of Clinical Pharmacology in 2008 found that most of the studies were too low-powered to provide suggestive evidence of the effectiveness of red ginseng in treating ED (Jang et. al, 2008).
There is a significant amount of research currently being done on new treatments for ED. Some of these include effectiveness of ED treatments in homosexual patients, stem cell therapy, neurotrophins, and immunophilin ligands to encourage nerve growth, the use of neuromodulatory and perineural neuroprotective agents, and continuing to develop surgical strategies to minimize nerve injury during surgery, and protect endothelium and cavernosal smooth muscle in the penis (Galbraith & Crighton, 2008; Kuan, 2008; Peltier, van Velthoven & Roumeguere, 2009).
The effects of ED on a cancer patient's quality of life are significant (Galbraith & Crighton, 2008). Due to the sensitive nature of the topic, as well as the huge impact it can play in patients' lives, providers must be vigilant in identifying, assessing, and treating ED in their patients (Galbraith & Crighton). Special concern should be given to cancer patients due to their possible psychosocial and emotional instability, given the potentially life-threatening consequences of a cancer diagnosis (Peltier, van Velthoven, & Roumeguere, 2009).
Bergman, J., Gore, J. L., Penson, D. F., Kwan, L., & Litwin, M. S. (2009). Erectile aid use by men treated for localized prostate cancer. Journal of Urology, 182(2), 649-654.
Galbraith, M. E., & Crighton, F. (2008). Alterations of sexual function in men with cancer. Seminars in Oncology Nursing, 24(2), 102-114.
Jang, D. J., Lee, M. S., Shin, B. C., Lee, Y. C., & Ernst, E. (2008). Red ginseng for treating erectile dysfunction: A systematic review. British Journal of Clinical Pharmacology, 66(4), 444-450.
Kuan, J. K. (2008). Erectile dysfunction. Epocrates Online. Retrieved from https://online.epocrates.com.
Masterson, T. A., Wedmid, A., Sandhu, J. S., & Eastham, J. A. (2009). Outcomes after radical prostatectomy in men receiving previous pelvic radiation for non-prostate malignancies. British Journal of Urology, International, 104(4), 482-485.
Mendenhall, W. M., Henderson, R. H., Indelicato, D. J., Keole, S. R., & Mendenhall, N. P. (2009). Erectile dysfunction after radiotherapy for prostate cancer. American Journal of Clinical Oncology, 32(4), 443-447.
Miles, C. L., Candy, B., Jones, L., Williams, R., Tookman, A., & King, M. (2007). Interventions for sexual dysfunction following treatments for cancer. Cochrane Database of Systematic Reviews, (4), 005540.
Montague, D. K., Jarow, J. P., Broderick, G. A., Dmochowski, R. R., Heaton, J. P., Lue, T. F., Milbank, A. J., Nehra, A., & Sharlip, I. D. (2005). The management of erectile dysfunction: An AUA update. Journal of Urology, 174(1), 230-239.
Oliffe, J. L., Ogrodniczuk, J., Bottorff, J. L., Hislop, T. G., & Halpin, M. (2009). Connecting humor, health, and masculinities at prostate cancer support groups. Psycho-Oncology, 18(9), 916-926.
Peltier, A., van Velthoven, R., & Roumeguere, T. (2009). Current management of erectile dysfunction after cancer treatment. Current Opinion in Oncology, 21(4), 303-309.
Rosen, R. C., Riley, A., Wagner, G., Osterloh, I. H., Kirkpatrick, J., & Mishra, A. (1997). The International Index of Erectile Function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urology, 49(6), 822-830.
Schroeck, F. R., Donatucci, C. F., Smathers, E. C., Sun, L., Albala, D. M., Polascik, T. J., Moul, J. W., & Krupski, T. L. (2008). Defining potency: A comparison of the International Index of Erectile Function Short Version and the Expanded Prostate Cancer Index Composite. Cancer, 113(10), 2687-2694.
Spark, R. F. (2010). Treatment of male sexual dysfunction. Up to Date. Retrieved from http://www.uptodate.com.
Stanislavov, R., Nikolova, V., & Rohdewald, P. (2008). Improvement of erectile function with prelox: A randomized, double-blind, placebo-controlled, crossover trial. International Journal of Impotence Research, 20(2), 173-180.
Wespes, E., Amar, E., Hatzichristou, D., Hatzimouratidis, K., Montorsi, F., Pryor, J., & Vardi, Y.. (2006). EAU guidelines on erectile dysfunction: An update. European Urology, 49(5), 806-815.
International Index of Erectile Function (IIEF) Questionnaire
Adapted from "Individual items of International Index of Erectile Function Questionnaire and response options (US version)," 1997, Urology, 49, p 829.