Erectile Dysfunction Following Radical Prostatectomy

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GRAND ROUNDS CLINICIAN’S CORNER AT THE JOHNS HOPKINS BAYVIEW MEDICAL CENTER

Arthur L. Burnett, MD Erectile dysfunction following radical prostatectomy for clinically localized pros- CASE PRESENTATION tate cancer is a known potential complication of the surgery. Because pros- DR BURNETT: Mr G is a previously tate cancer is diagnosed today more frequently than in the past and because healthy 51-year-old man who works as the diagnosis is made in increasingly younger men, there is an urgent need to a health program administrator. Dur- develop effective interventions that preserve erectile function after surgery. ing a prostate health screening, he was In this presentation, a 51-year-old man with adenocarcinoma of the prostate found to have a prostate-specific anti- underwent a bilateral nerve-sparing radical prostatectomy, after which he lost gen (PSA) level of 4.2 ng/mL (normal natural erectile function for approximately 9 months. The case highlights the range: 0.0-4.0 ng/mL). On digital rec- tal examination, the prostate was of av- fact that following surgery in which the nerve-sparing radical prostatectomy erage size and without nodules or technique is used, between 60% to 85% of men eventually recover erectile masses. A urological consultation was function. This constitutes a dramatic improvement over an earlier era, when recommended. postprostatectomy erectile dysfunction was the nearly universal rule. The case Mr G underwent a transrectal ultra- also emphasizes that despite expert application of the nerve-sparing prosta- sound-guided biopsy of the prostate tectomy technique, early recovery of natural erectile function is uncommon. gland. There were no sonographic ab- Many patients experience erectile dysfunction for as long as 2 years after the normalities, but the 12-core biopsy es- procedure, requiring the use of erectile aids for sexual activity during this pe- tablished the diagnosis of adenocarcinoma, with a Gleason score of 6 (see riod until natural erections recover. Corrective, cause-specific advances such TABLE 1 for explanation of Gleason as neuromodulatory therapy offer valuable adjuncts to this surgery. score).1,2 The cancer involved 80% of a JAMA. 2005;293:2648-2653 www.jama.com single core from the right base region of the prostate. Because Mr G was judged to have a low risk for metastatic dis- used cigarettes. He was taking nutri- agnosis and how you arrived at a deci- ease, further imaging studies were not tional supplements that included saw sion about your treatment? indicated. He was counseled regarding palmetto, fish oil, and various vita- MR G: I was stunned when first told management options for his diagnosis mins. To his knowledge, no one in his that I had cancer. I never, ever expected of clinically localized prostate cancer. family had ever been diagnosed with that diagnosis. I thought I was in great I saw Mr G for the first time about 5 prostate cancer. We reviewed his physical shape, doing all the right things weeks later for a second opinion. His clinical presentation and workup, to live a long, happy life. Before meet- vital signs were within normal limits. which was consistent with an early ing Dr Burnett, I had actually done a con- In fact, he appeared quite fit, with a stage prostate cancer of intermediate siderable amount of study about pros- body mass index of 24 (Յ25 consis- grade. We next discussed applicable tate cancer. I had explored the different tent with healthy weight). He stated that management options, including sur- Author Affiliations: Johns Hopkins University School he experienced no urinary complaints veillance (watchful waiting); radical of Medicine, Department of Urology, The James and his erectile function was fully in- prostatectomy; radiation therapy ad- Buchanan Brady Urological Institute, The Johns Hop- ministered by external beam and/or in- kins Medical Institutions, Baltimore, Md. tact, as evidenced by a score of 25 Corresponding Author: Arthur L. Burnett, MD, De- (range: 0-25) on the Sexual Health In- terstitial implants; and cryotherapy partment of Urology, The Johns Hopkins Hospital, 600 3 (freezing the prostate). We reviewed the N Wolfe St, Marburg 407, Baltimore, MD 21287- ventory for Men (SHIM). He had never 2411 ([email protected]). advantages and disadvantages of each Grand Rounds at The Johns Hopkins Bayview Medi- option. cal Center Section Editors: John H. Stone, MD, MPH, Charles Weiner, MD, Stephen D. Sisson, MD, The Johns CME available online at DR BURNETT: Mr G, could you please www.jama.com Hopkins Hospital, Baltimore, Md; David S. Cooper, MD, tell us about your reaction to your di- Contributing Editor, JAMA.

ERECTILE DYSFUNCTION FOLLOWING RADICAL PROSTATECTOMY treatment options and felt certain I on my own! It is a wonderful thing. (His Table 1. Explanation of the Gleason Score* should have my prostate removed. Sur- 12-month postoperative SHIM score Biopsy gery seemed to offer the best chance for was 18.) Aggressiveness Level Incidence, % a cure, and since I am a young man, I fa- Low 2 vored a treatment that would give me the DISCUSSION Gleason 2 (1 ϩ 1) Gleason 3 (1 ϩ 2) best chance for living a lot longer. But Mr G’s case illustrates several key con- Gleason 4 (2 ϩ 2) the notion that I might lose erectile func- cepts in the current management of pros- Intermediate 70 Gleason 5 (2 ϩ 3-3ϩ 2) tion was still devastating. Fortunately, my tate cancer. Among solid-organ malig- Gleason 6 (3 ϩ 3) wife was very supportive. I’m not sure nancies, prostate cancer is the most Intermediate-High 20 how I would have moved forward with- commonly diagnosed tumor and the sec- Gleason 7 (3 ϩ 4) Gleason 7 (4 ϩ 3) out her. I recall her saying: “I don’t have ond-leading cause of cancer-related High 8 a relationship with your penis. I have a deaths among men in the United States.4 Gleason 8 (4 ϩ 4) Gleason 9 (4 ϩ 5-5ϩ 4) relationship with you.” Mr G’s presentation typifies some of the Gleason 10 (5 ϩ 5) DR BURNETT: Mr G opted for radical common dilemmas facing many pa- *The pathological patterns of prostate cancer range from prostatectomy, which was performed tients diagnosed today with this dis- 1 (almost normal-looking) to 5 (very poorly differenti- ated). The Gleason system of evaluating prostate can- successfully 1 year ago. We used a bi- ease. Our improved diagnostic capabili- cer is based on this range with grades termed for these 5 specific patterns of cancer-cell architecture. The score lateral cavernous nerve-sparing tech- ties have led to the fact that many prostate refers to the addition of the numbers of the first and sec- nique at surgery to maximize his like- cancer patients receive their diagnoses at ond most common patterns. Note that the grouping for “intermediate-high” aggressiveness includes 2 biologi- lihood of erection preservation. The final relatively young ages. In considering the cally distinct tumors for Gleason 7, with score 4 ϩ 3=7 pathology confirmed the presence of or- impact of the various treatment ap- behaving more aggressively than score 3 ϩ 4=7.1,2 gan-confined prostate cancer with nega- proaches on their quality of life, many tive surgical margins, pelvic lymph patients place paramount importance on several weeks, return of urinary conti- nodes, and seminal vesicles, consistent the possibility of retaining natural erec- nence is achieved by more than 95% of with disease eradication. No adjuvant tile function.5 This matter is frequently patients within a few months, and erec- therapy was indicated. Serial PSA mea- important to young men who by age sta- tion recovery with ability to engage in surements every 3 months since sur- tus are more likely to have intact erec- sexual intercourse is regained by most gery confirmed undetectable levels. tile function than older men; however, patients with or without oral phospho- DR BURNETT: Mr G, how did you fare for all men having normal preoperative diesterase type 5 (PDE 5) inhibitors with your recovery? erectile function irrespective of age, pres- within 2 years.7 It is acknowledged that MR G: I did great with the surgery. I ervation of this function is understand- these expectations reflect results was back at work within a few weeks. ably important postoperatively. achieved at major academic centers, I was continent of urine in 1 month and Although radical prostatectomy has which may not be representative of the 27 days! (I am told that this is rather been referred to as the gold standard for patterns of care experienced by most quick for the recovery of continence.) definitive cure of early stage prostate men treated for localized prostate can- But I was concerned by my lack of erec- cancer, this option has been chal- cer in the United States. tions. I know Dr Burnett explained that lenged frequently in recent years, prin- Regardless of clinical practice set- erection recovery could take as much cipally over questions related to the ting, the reality of the recovery pro- as 2 years, but I felt the pressure. The degree of functional recovery in many cess after radical prostatectomy today, pressure was not from my wife; I had areas. Historically, radical prostatec- nonetheless, is that erectile function re- my own pressure as a man. I was the tomy has carried high risks of postop- covery lags behind other functional re- one who really wanted something to be erative complications, including covery in other areas. Patients are un- done and done quickly. Most men are decreased physical capacity for as much derstandably concerned about this issue that way. By 6 months after the sur- as a year after surgery, long-term uri- and, following months of erectile dys- gery, nothing much was going on. I nary incontinence in the majority of function, become skeptical of reassur- wanted to know what was happening. patients, and permanent erectile dys- ances that their potency will return. I talked to Dr Burnett about the vari- function in almost all men undergoing Current clinical surveys show that ous treatment options. I considered this procedure. Following a series of among patients eventually recovering Viagra, but it only helps reliably with anatomical discoveries of the prostate erectile function, the quality of erec- at least partial erections to build on, and its surrounding structures about 2 tions is frequently inferior to that of which was not the case for me yet. I decades ago, changes in the surgical those achieved preoperatively.8 Thus, decided to begin penile injection approach permitted the procedure to be in addition to whether erections will re- therapy. It worked for me, and I knew performed with significantly improved turn after radical prostatectomy, the it wouldn’t interfere with my own erec- outcomes.6 Now after the surgery, timing and extent of postoperative erections coming back. After 9 months and expectations are that physical capacity tile function are matters of profound im- 16 days, I finally could get an erection is fully recovered in most patients within portance to patients.

ERECTILE DYSFUNCTION FOLLOWING RADICAL PROSTATECTOMY

Definition and Pathogenesis This discovery led to modifications of nique is contraindicated.10 In the cur- A landmark article by Walsh and the surgical approach to radical pros- rent era of nerve-sparing radical Donker9 in 1982 revealed that the com- tatectomy whereby preservation of the prostatectomy, the rates of erectile func- mon basis for erectile dysfunction fol- cavernous nerves—the so-called nerve- tion recovery satisfactory for sexual in- lowing radical prostatectomy was the sparing technique—offered many men tercourse following the surgery re- severance of the cavernous nerves. These opportunities to regain erectile func- ported at major academic centers nerves, which mediate autonomic neu- tion that would have been all but cer- performed by highly experienced sur- roregulatory function, course along the tainly eliminated without such modi- geons range between 60% and 85%, a lateral aspects of the prostate and rec- fications. Under certain circumstances, dramatic improvement over the ear- tum, providing innervation to the proxi- eg, the finding at surgery of local can- lier era.7,8,11,12 It is acknowledged that mal penis in the deep pelvis (FIGURE).9 cer spread, the nerve-sparing tech- contemporary results outside of such centers may differ. For instance, a sub- Figure. Schematic of the Cavernous Nerves and Their Preservation During Radical set analysis from the cohort study of the Prostatectomy Cancer of the Prostate Strategic Uro- logic Research Endeavor (CaPSURE), A Basic Anatomy, Lateral View Ureter representing 29 academic and commu- Ductus Deferens nity-based sites across the United States,

B L A D D E R R indicated a 75% potency rate in men E C younger than 65 years after radical pros- T 13

U tatectomy. This same database af- Seminal Vesicle M firmed that other demographic vari- Symphysis ables including race/ethnicity, Pubis Left Pelvic (Inferior Hypogastric) education, and relationship status did Prostate Plexus not affect potency outcomes after the Left Cavernous P surgery, whereas household income E N Nerve I S greater than $30 000 and fewer comor- Prostatic bidities were associated with return to Corpus Cavernosum Nerves baseline sexual function.13 Corpus Spongiosum Urethral Sphincter Even when the nerve-sparing surgery is performed with immaculate tech- B Basic Anatomy, Oblique View C Postsurgical Anatomy, Oblique View nique, however, patients do not recover Ureter erectile function as quickly as they do uri- Right Pelvic nary continence. In fact, the cavernous R Plexus E C T U M nerves are typically functionally inac- Ductus B L Left Pelvic tive for as long as 2 years after surgery, Deferens A D D E R Plexus even when nerve-sparing technique is 7,8 Seminal Cavernous Nerves used. (In contrast, most men are again Vesicle Preserved in continent of urine within 6 months of the Nerve-Sparing 7 Right Cavernous Technique surgery.) In a recent series by Walsh and Nerve Left Cavernous colleagues among preoperatively potent Nerve men who underwent prostatectomy Corpora Cavernosa Prostatic using the bilateral nerve-sparing tech- Nerves nique, maximal erection recovery was not Prostate observed until a mean period of 18 months had elapsed following surgery.7 P E Urethra and N I A number of explanations have been pro- S Urethral Sphincter posed for this phenomenon of delayed recovery, including mechanically A, Lateral view of the male pelvis illustrating the course and distribution of the left cavernous nerve fiber, as induced nerve stretching that may occur part of the left neurovascular bundle within intrapelvic fascia coverings. The cavernous nerve travels from the pelvic plexus proximally to the penis distally, in close anatomical relationship to the seminal vesicle, prostate, during prostate retraction, thermal dam- striated urethral sphincter, bladder, and rectum. B, Anterosuperior oblique view of the same anatomical struc- age to nerve tissue caused by electroco- tures. C, Anterosuperior oblique view illustrating preservation of the cavernous nerves after bilateral nerve- agulative cautery during surgical dissec- sparing prostatectomy and bladder neck anastomosis to the urethral stump. The cavernous nerve fibers are preserved by division and clipping of small prostatic nerves alongside the prostate. When non–nerve-sparing tion, ischemic injury to nerve tissue amid surgery is required for cancer eradication either unilaterally or bilaterally, wide excision of periprostatic soft attempts to control surgical bleeding, and tissue includes the cavernous nerves en bloc with the removed surgical specimen. local inflammatory effects associated with

ERECTILE DYSFUNCTION FOLLOWING RADICAL PROSTATECTOMY surgical trauma.14 Consistent with cur- ferent approaches exist; detailed review agnosed and treated without random- rent neurobiological concepts of major of these controversies is beyond the ization to treatment options for prostate axonal injury,15 the injured cavernous scope of this discussion. Nevertheless, cancer in the mid-1990s, erectile dys- nerve fibers undergo a process of Wal- an objective shared by all approaches function rates in radical prostatectomy lerian degeneration, with loss of normal to the nerve-sparing prostatectomy and external beam radiation therapy nerve tissue connections to the corpora technique is to maximize the likeli- groups were similarly considerable (79% cavernosa and associated neuroregula- hood of erectile function recovery after and 63%, respectively) at 5 years postint- tory functions. In addition, the neuropa- the surgery. Meaningful determina- ervention.23 However, whether and how thy induces cavernosal tissue degenera- tions of success with different well nerve-sparing surgery was per- tion and atrophy.16 These complications approaches in the future will rely on rig- formed remain unclear in this study, and frequently lead to irretrievable loss of the orously designed clinical trials, serial the results may not be representative of veno-occlusive function necessary for assessments over sufficient periods of the technique’s highest level of perfor- penile rigidity.17,18 The fact that erec- time, the use of validated inventories mance. In another community-based tions are eventually recovered in many and questionnaires of sexual activity, study, which specified performance of men who undergo nerve-sparing sur- and the involvement of unbiased out- nerve-sparing technique at radical pros- gery further supports a neurogenic patho- come assessors.14 tatectomy, sexual function score was genesis for the disorder, consistent with Several surgical advances may also equivalent in men receiving this modi- the biology of peripheral nerve recov- improve functional outcomes. Optical fication of the surgery and men having ery and regeneration after initial injury. magnification and avoidance of tissue- undergone pelvic radiation by 2-year fol- An issue of major interest is why all destructive energy sources in the vi- low-up.24 men do not achieve recovery when cinity of the cavernous nerves during nerve sparing is performed. The most surgery are widely advocated.10 Intra- Management of Erectile obvious determinant of postoperative operative nerve stimulation has also Dysfunction Complications erectile dysfunction is preoperative po- been explored with the idea that this Men undergoing radical prostatec- tency status. Some men may experi- technique may assist the surgeon in pre- tomy assign major importance to their ence a decline in erectile function over serving the cavernous nerves and even resumption of sexual activity postop- time, as an age-dependent process.19 predicting a patient’s likelihood of erec- eratively and are prepared to use erec- Furthermore, postoperative erectile dys- tion recovery. The utility of nerve tile aids to be functional.25-27 The cur- function is compounded in some pa- stimulation techniques, however, re- rent options, which include both tients by preexisting risk factors that in- mains unproven.20 pharmacological and nonpharmaco- clude older age, comorbid disease states logical interventions, are summarized (eg, cardiovascular disease, diabetes Preservation of Erectile Function: in TABLE 2.28 Pharmacotherapies in- mellitus), lifestyle factors (eg, ciga- Surgery vs Radiation clude the oral PDE 5 inhibitors (silde- rette smoking, physical inactivity), and With regard to erection preservation fol- nafil, tadalafil, and vardenafil), intra- the use of medications such as antihy- lowing treatment, a pertinent question urethral suppositories (alprostadil), and pertensive agents that have erectolytic is how radical prostatectomy compares intracavernous injections (alprostadil effects.19 The impact of these risk fac- with other interventions for clinically lo- and vasoactive drug mixtures). Non- tors on patients’ eventual outcomes has calized prostate cancer. The growing in- pharmacological therapies, which do led to the acknowledgment that rating terest in pelvic radiation, including not rely on the biochemical reactivity erection recovery potential after sur- brachytherapy, as an alternative to sur- of the erectile tissue, include vacuum gery should involve stratification ac- gery can be attributed in part to the sup- constriction devices and penile im- cording to relevant risk factors.8 position that surgery carries a higher risk plants (prostheses). With the excep- of erectile dysfunction. Clearly, surgery tion of penile implants, these options Radical Prostatectomy: is associated with an immediate, precipi- are considered “on-demand” thera- Current Status tous loss of erectile function that does not pies requiring repeated administra- In recent years, physicians caring for occur when radiation therapy is per- tions when sexual activity is desired. men with prostate cancer have focused formed, although with surgery, recov- The treatment algorithm for man- on less-invasive prostate surgery. Con- ery is possible in many with appropri- agement of erectile dysfunction after sequently, in addition to open proce- ately extended follow-up. Radiation radical prostatectomy generally ad- dures via retropubic (abdominal) or therapy, by contrast, often results in a heres to stepwise process of care mod- perineal approaches, laparoscopic pro- steady decline in erectile function to a els.29 With the increased availability of cedures with freehand or robotic instru- hardly trivial degree over time.21-23 As options in the past 2 decades, prin- mentation have been developed. Much demonstrated recently by the Prostate ciples of minimal invasiveness, ease of debate but no consensus about the Cancer Outcomes Study, a retrospec- administration, and cost are impor- advantages and disadvantages of the dif- tive survey of community-based men di- tant considerations in addition to as-

ERECTILE DYSFUNCTION FOLLOWING RADICAL PROSTATECTOMY

lar use of PDE 5 inhibitors or other cur- Table 2. Pharmacological and Nonpharmacological Interventions for Erectile Dysfunction rently available, “on-demand” thera- Therapy Treatment Option Role Efficacy, %* Comment pies is widely touted after surgery for Oral PDE 5 inhibitors First line 70-80 (nerve sparing) Function of “nitric purposes of erection rehabilitation, such 0-15 (non–nerve-sparing) oxide-producing” penile therapy is mainly empirical. Evidence for nerves essential; sexual stimulation required its success remains limited. Intraurethral Second line 20-40 In-office instruction and titration medications (penile recommended Neurogenic Erectile suppository) Dysfunction Treatments Intracavernosal Second line 85-90 In-office instruction and titration injections recommended The next frontier in the clinical man- Vacuum constriction Second line 90-100 Basic instruction sufficient agement of erectile dysfunction after devices radical prostatectomy has centered on Penile implants Third line 95-100 Surgical expertise required strategies that restore nerve function. (malleable and inflatable) Recent strategies have included cav- Abbreviation: PDE 5, phosphodiesterase type 5. ernous nerve interposition grafting and *Efficacy refers to percentage range of men having successful sexual intercourse.28 neuromodulatory therapy. The former, as a surgical innovation meant to rees- tablish continuity of the nerve tissue to sessing levels of reliability, efficacy, and maximize cavernous nerve preserva- the penis, may be particularly appli- safety, and both patient and partner in- tion are associated with the best thera- cable when nerve tissue has been ex- terest in and preferences for manage- peutic responses to PDE 5 inhibitors.33-37 cised during prostate removal.42-44 In the ment. In addition, combination thera- In spite of the overall acceptance and modern era of commonly early diag- pies have also been described.30,31 general efficacy of intraurethral and in- nosed prostate cancer, nerve-sparing tracavernosal vasoactive drugs and me- technique remains indicated for the ma- Special Management chanical devices, these options have limi- jority of surgically treated patients.45 Considerations tations. Discontinuation rates ranging Neuromodulatory therapy, compris- A fundamental stipulation in the con- from 50% to 80% are reported with these ing both neuroprotective and neuro- text of radical prostatectomy-related erec- treatments, with reasons for dissatisfac- trophic treatments, represents an ex- tile dysfunction is that men who have un- tion including insufficient response to citing, rapidly developing approach to dergone nerve-sparing technique should therapy, unacceptable adverse effects, revitalize intact nerves and promote be offered therapies that are not ex- and a sense that the treatment is “un- nerve growth. These interventions are pected to interfere with the potential re- natural.”38-40 applicable with nerve-sparing surgery covery of spontaneous, natural erectile and would likely benefit even the re- function. In this light, penile prosthesis Erection Rehabilitation constitution of nerve function after surgery would not be considered an op- The ordeal of immediate and complete nerve grafting procedures. Therapeu- tion in this select group, at least in the sexual loss experienced by many men fol- tic prospects include neurotrophins, initial 2-year postoperative period, un- lowing prostatectomy has encouraged neuroimmunophilin ligands, neuro- til it becomes evident in some individu- the development of erection “rehabili- nal cell death inhibitors, nerve guides, als that such recovery is unlikely. For tation.” This relatively new strategy in tissue engineering/stem cell therapy, men receiving non–nerve-sparing sur- clinical management after radical pros- electrical stimulation, and even gene gery, all options may be explored and tatectomy arose from the idea that early therapy. Among these, nonimmuno- have been shown to be consistently ef- induced sexual stimulation and blood suppressant neuroimmunophilin li- fective with the exception of oral flow in the penis may facilitate the re- gands, drugs derived from the immu- pharmacotherapy. turn of natural erectile function and re- nosuppressive agent tacrolimus and In considering the role of PDE 5 in- sumption of medically unassisted sexual shown to possess nerve-sprouting ac- hibitors, which currently represent first- activity. In this respect, an early strat- tions, are emerging as promising clini- line intervention in erectile dysfunc- egy is intracavernous injection therapy,41 cal interventions, as evidenced by an tion management, the integrity of the although its application has not oc- under way multi-institutional phase 2 cavernous nerves has clear therapeutic curred widely, mostly because of pa- clinical trial of such therapy in men un- implications. These oral medications are tient reluctance to perform needle inser- dergoing bilateral nerve-sparing radi- well demonstrated to be efficacious in re- tions into the penis on a regular basis. cal prostatectomy.46,47 sponse to the sufficient release of the The interest in using oral PDE 5 inhibi- chemical mediator nitric oxide from cav- tors is not surprising, since this therapy CONCLUSION ernous nerve terminations within the is noninvasive, convenient, and highly In summary, Mr G’s presentation rep- erectile tissue.32 Surgical approaches that tolerable. However, while the early, regu- resents a common scenario for pa-

ERECTILE DYSFUNCTION FOLLOWING RADICAL PROSTATECTOMY tients undergoing management for cal prostatectomy: insight into etiology and prevention. the recommendations on sexual dysfunctions in men. J Urol. 1982;128:492-497. In: Lue TF, Basson R, Rosen R, Giuliano F, Khoury S, prostate cancer today. In a relatively 10. Walsh PC. Anatomic radical retropubic Montorsi F, eds. Sexual Medicine Sexual Dysfunc- young man diagnosed with early stage prostatectomy. In: Walsh PC, Retik AB, Vaughan ED tions in Men and Women. Paris, France: Health Pub- Jr, Wein AJ, eds. Campbell’s Urology, Eighth Edi- lications; 2004:605-627. prostate cancer, radical prostatectomy tion. Philadelphia, Pa: Saunders; 2002:3107-3129. 30. Mydlo JH, Volpe MA, Macchia RJ. Initial results using a nerve-sparing technique eradi- 11. Walsh PC, Partin AW, Epstein JI. Cancer control utilizing combination therapy for patients with a sub- cated his malignancy. 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