Genevieve Ann Hollis is a nurse practitioner in the Department of Radiation Oncology at the Hospital of the University of Pennsylvania and is an Advanced Senior Lecturer-B in the Biobehavioral and Health Sciences Division at the University of Pennsylvania School of Nursing in Philadelphia.

There are approximately 2.8 million prostate cancer (PC) survivors in the United States,

 and 233,000 will be diagnosed with this disease in 2014.

 Approximately 75% to 82% of men diagnosed at age 75 or younger will be treated with surgery, radiation, and/or androgen deprivation therapy (ADT).

 Most of these men will live for many years after completing treatment. Thus, addressing long—term treatment-related toxicities and their impact on health-related quality of life is critical.

At the population level, it is estimated that 52% of all adult men experience erectile dysfunction (ED). Risk factors for ED include coronary artery disease, hypertension, diabetes, depression, neurologic diseases, and associated medications, with advancing age conferring the highest risk.

 Since the incidence of PC also increases with advancing age, many men will have ED and/or its risk factors prior to PC diagnosis. Despite advances in surgical and radiation therapy techniques, a commonly dreaded toxicity of all PC treatments is a markedly increased risk for ED.

A cohort analysis from the multicenter Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment (PROSTQA) clearly demonstrated that the ED risk in this patient population is greatly influenced by disease state, treatment modalities, and various baseline patient characteristics.

 Immediately post-prostatectomy virtually all men experience ED that may improve over time, typically by 18-24 months.

 The ED risk increases from 17% pre-prostatectomy to 65% (range 30%-94%) at 2 years after prostatectomy.

In comparison, erectile function is essentially unchanged immediately after radiation therapy but can decline over the subsequent 6-30 months.

 The ED risk increases from 47% pre-external beam radiation therapy (EBRT), to 63% (range 8%-84%) at 2 years after EBRT. Furthermore, the ED risk increases from 33% pre-brachytherapy to 57% (range 8%-84%) at 2 years after brachytherapy.

Younger age, nerve-sparing prostatectomy, and pre-prostatectomy PSA ≤10 is protective in those who undergo prostatectomy. Absence of neoadjuvant ADT and pre-EBRT PSA ≤4 are protective in the EBRT cohort. Younger age, African American race/ethnicity, and lower body mass index were protective in the brachytherapy cohort.

 Men who receive ADT typically have a profound loss of libido and are rarely sexually active.

Our knowledge of how PC treatments contribute to ED continues to evolve, but it clearly is a multifactorial pathogenesis. These factors include damage to the cavernosal nerve bundles that arise from the pelvic plexus, lie lateral and posterior to the prostate, and innervate the highly vascularized corpora cavernosa in the dorsal aspect of the penis. It has been theorized that PC treatments also can cause vascular leakage that ultimately leads to deterioration and fibrosis of the corpora cavernosa structures.

Penile rehabilitation is the use of medical interventions to decrease corpora cavernosa hypoxia and fibrosis to potentially preserve spontaneous erectile function after PC treatment.

 While controversial, advances in understanding how PC treatments impact the physiology of erections have led to increased interest in penile rehabilitation interventions for these patients. The use of phosphodiesterase type 5 (PDE5) inhibitors has gained particular interest due to studies which suggest that these medications are potent protectors of endothelial and smooth muscle tissue in the corpora cavernosa and that they may have neuroprotective and regeneration properties.

Most of the PC penile rehabilitation research has been conducted with men post- prostatectomy. The recognition that cavernosal nerve severance during prostatectomies caused irreversible ED led to nerve-sparing surgical approaches which markedly improved post-prostatectomy ED rates.

 While this nerve dysfunction is likely, the major contributor to ED post prostatectomy, substantial venous leakage and corpora cavernous structure fibrosis also occur in the early post-prostatectomy time period and continues for many months.

Post-prostatectomy studies of therapies that aim to improve penile blood flow include those using vacuum constriction devices (VCD)

 and intracavernosal alprostadil injections,

 and the PDE5 inhibitors sildenafil and vardenafil.

 While most of the studies demonstrated at least short-term improvement in ED rates with these interventions, limitations include use of various interventions; the timing of interventions relative to prostatectomy; intervention schedules ranging from on-demand to daily for 6-12 months; generally small sample sizes; frequent lack of randomization and placebo, and short patient follow-up.

Venous leakage with corpora cavernosa fibrosis is theorized to be the major contributor to ED after radiation therapy and to a lesser degree neural injury.

 Two studies randomized men undergoing treatment with EBRT to sildenafil or placebo for 6 months. While men receiving sildenafil had lower ED rates while taking the medication, this benefit decreased over time and was not sustained when no longer taking the sildenafil.

 Unfortunately a recent randomized controlled study of daily tadalafil or placebo for 6 months in men receiving EBRT or brachytherapy did not demonstrate improved erectile function in the tadalafil arm.

Nurses play a critical role in assisting the PC survivor and his partner in adapting to potential and actual ED. This includes acknowledging that ED is a common concern, providing counseling regarding patient’s individualized risk using the PROSTQA model, and ongoing assessment for the presence of ED using validated self-report tools such as the Expanded Prostate Cancer Index Composite (EPIC-26) or International Index of Erectile Dysfunction (IIEF-5). It is also important to assess for psychological distress, problems with intimacy or relationships, and self-esteem in PC survivors experiencing ED.

Given the findings and limitations of the current evidence, widespread use of early penile rehabilitation to prevent ED is controversial. More studies are needed to more fully understand the underlying pathology as well as determine the most effective interventions and schedules. If ED symptoms are present, these same therapies can be used “on demand” prior to planned sexual activity. It is important to note that not all these interventions are covered by insurance, limiting their availability to many patients outside a clinical trial. Side effects or cardiovascular comorbidity will limit PDE5 inhibitor use by some patients and use of penile pumps or intracavernosal injections will not be acceptable to others. Surgical placement of a penile prosthesis can be considered for refractory ED.

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Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Men Aging Study.

Alemazaffar M, Regan MM, Cooperberg MR, et al. Prediction of erectile function following treatment for prostate cancer. 

Dall’Era JE, Mills JN, Koul HK, Meacham RB. Penile rehabilitatin after radical prostatectomy: important therapy or wishful thinking? 

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Jung, J., Jo, H.W., Kwon, H., Jeong, N. Y. (2014). Clinical neuroanatomy and neurotransmitter-mediated regulation of penile erection.

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Raina R, Agarwal A, Ausmundson S, et al. Early use of vacuum constriction device following radical prostatectomy facilitates early sexual activity and potentially earlier return of erectile function.

Montorsi F, Guazzoni G, Strambi LF, et al. Recovery of spontaneous erectile function after nerve sparing radical retropubic prostatectomy with and results of a prospective, randomized trial without early intracavernous injections of alprostadil. 

Bannowsky A, Schulze H, Van Der Horst C, et al. Recovery of erectile function after nerve-sparing radical prostatectomy: improvement with nightly low-dose sildenafil. 

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.

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. 

Ilic D, Hindson B, Duchesne G, Millar JL. A randomised, double-blind, placebo-controlled trial of nightly sildenafil citrate to preserve erectile function after radiation treatment for prostate cancer. 

Zelefsky MJ, Shasha D, Branco RD, et al. (2014). Prophylactic sildenafil citrate improves select aspects of sexual function in men treated with radiotherapy for prostate cancer. 

Pisansky TM, Pugh SL, Greenberg RE, et al. Tadalafil for Prevention of Erectile Dysfunction After Radiotherapy for Prostate Cancer The Radiation Therapy Oncology Group [0831] Randomized Clinical Trial. 

Articles

While controversial, advances in understanding how prostate cancer treatments impact the physiology of erections have led to increased interest in penile rehabilitation interventions for these patients. 

Genevieve Ann Hollis, MSN, CRNP, AOCN

Articles

Penile Rehabilitation in Prostate Cancer Patients