Mary K. Samplaski1 and Kirk C. Lo2
(1)
Department of Surgery, Institute of Urology, University of Southern California, Los Angeles, CA, USA
(2)
Division of Urology, Department of Surgery, Mount Sinai Hospital, Faculty of Medicine, Institute of Medical Science, University of Toronto, 60 Murray Street, 6th floor, Box# 19, Toronto, ON, Canada, M5T 3L9
Kirk C. Lo
Email: klo@mtsinai.on.ca
Keywords
Erectile dysfunctionProstate cancerMalesPenile rehabilitationRadiotherapy
9.1 Introduction
Prostate cancer (PCa) has a wide range of pathologies and treatment modalities, many of which can negatively affect erectile function. The incidence of erectile dysfunction (ED) after treatment for PCa ranges from 14 to 89 % after surgery [1] and 2–56 % after radiation therapy [2]. The National Institutes of Health (NIH) defines erectile dysfunction (ED) as “the consistent inability to obtain or maintain an erection satisfactory for sexual performance” [3]. However, the phrase “sexual performance ” is vague and does not mention the use of erectogenic aids. It is clear that there are individual patient-related, disease-related, treatment-related, and psychological factors that compromise erectile function in the setting of PCa. In addition, PCa continues to be diagnosed in younger men, in whom potency preservation is an important consideration [4, 5].
9.2 Baseline Erectile Function
Pretreatment erectile function is a predictor of posttreatment erectile function in men treated for PCa [6, 7]. However, there are many factors that play into pretreatment erectile function, including age and comorbidities. Age is a significant risk factor for both PCa and ED [8], and men with PCa may already be experiencing an age-related decline in erection quality [9]. In the 2008 Prostate Cancer Outcomes Study , a significant relationship was found between age and sexual function following nerve sparing radical prostatectomy (RP), ranging from 61 % of men <55 years of age to 18 % of men >65 years having functional erections [10]. Related to age are comorbidities and body mass index (BMI), type 2 diabetes, and depression—all confounders of baseline ED [7].
Further, the psychological distress associated with a cancer diagnosis and proximity to treatment may skew evaluation of a patient’s true baseline erectile function [11]. In this way, validated questionnaires may not accurately represent male sexual function. Indeed, there are men whose scores on validated questionnaires decline after PCa treatment who still consider themselves fully sexually functional [12–14]. Finally, there is wide variability on baseline erectogenic aid use in the literature, and clearly an unbiased assessment of a man’s pretreatment erectile function will allow for more realistic expectations for erectile outcomes after PCa treatment.
9.3 Setting Realistic Expectations
Clinicians are responsible for preemptively addressing sexual function prior to any PCa treatment and setting realistic posttreatment expectations. Ideally this topic should be addressed with both the patient and his partner [15] and should encompass evaluation of pretreatment sexual function, individualized treatment, and clinician factors such as medical and surgical experience [16]. There is also substantial variation in the definition of posttreatment ED [12]. A 2009 meta-analysis found that most of the published literature “does not meet strict criteria for reporting posttreatment erectile function,” although even in this article, “strict criteria” were not defined [17]. In addition, outcomes for erectile function are often reported only for a small proportion of men undergoing treatment [17]. In light of these factors, it may be challenging to provide patients with realistic expectations; however, every effort should be made to set expectations based on individual patient circumstances.
9.4 Surgical Issues
Predisposing factors for post-radical prostatectomy (RP) ED include age, preoperative erectile function, comorbidities [18], prostate-specific antigen (PSA), race, BMI, and intended treatment details [19]. Briganti et al. [18] developed a risk-stratification tool, grouping men into low, intermediate, and high risk for postoperative ED. The 3-year erectile function recovery rates were 85 %, 59 %, and 37 %, respectively. This scheme has been applied to men undergoing robot-assisted RP with similar predictive outcomes [6].
The etiology of ED after RP is likely due to mechanical injury to the corporal cavernosal nerve plexus [20]. Nerve sparing is recommended when men have normal preoperative erectile function and organ-confined disease [21]. However, functional outcomes are not always optimal, and a meta-analysis comparing potency rates after treatment for PCa demonstrated that the probability of maintaining erectile function after nerve sparing RP was 34 % at 1 year and 25 % at 2 years and for standard RP was 25 % at 1 year and 2 years [2].
The discrepancy between desired and actual outcomes appears to be related to other surgical factors, as even during nerve-sparing procedures, the cavernous nerves are affected by direct trauma, stretching, heating, ischemia, and local inflammation [22, 23]. This results in neuropraxia , a temporary blockage of nerve transmission, despite anatomically intact nerves. In addition, damage to the accessory pudendal arteries [24] and development of venous leak after RP appears to further impair recovery of erectile function [16, 25, 26]. Men with venous leak are more likely to experience ED, with 9 % of men with venous leak having erections sufficient for intercourse, as opposed to 47 % of those without [27]. In addition, men with venous leak have been shown to be less likely to respond to phosphodiesterase type 5 inhibitors (PDE5-Is) [28].
The loss of daily and nocturnal erections typical of the post-RP recovery period may result in chronically decreased cavernosal oxygenation and erectile tissue damage from the production of proapoptotic factors within the corpora [16, 25, 29]. The presence of TGF-β1 [30, 31] and hypoxia inducible factor-1α [30] and the overexpression of endothelin-1 type B receptor [32] strongly suggest that hypoxia plays a role in the physiology of ED. Histologically supporting this, an increase in corporal fibrosis and collagen deposition after RP has been demonstrated in humans, with a corresponding decrease in elastic and smooth muscle fibers [29].
9.5 Radiation Issues
While many men believe that radiation will have reduced effects on sexual function, ED rates seem to be similar between radiation and RP patients [33]. Across radiation treatment modalities, brachytherapy may result in a slightly higher preservation of erectile function versus external beam radiotherapy (EBRT) [34]. While possibly multifactorial, the predominant etiology of radiation-induced impotence is from vascular damage to the cavernosal nerves [35–37]. This effect is progressive, and there is oftentimes a lag between the administration of therapy and development of adverse effects, evidenced histologically by the development of cavernosal fibrosis for 3 years after radiotherapy [33].
After radiotherapy for PCa , decreased frequency and intensity of erections have been reported in 2–56 % of men [38–40]. Specifically, a meta-analysis [2] looking at maintaining erectile function found that for brachytherapy the probability was 76 % at 1 year, for brachytherapy plus EBRT 60 %, and for EBRT alone 55 %. Two recent prospective trials have observed a 30–40 % incidence of ED in EBRT-treated men [36, 41]. After brachytherapy, ED rates have ranged from 5 to 51 %, with the highest rates seen after combination EBRT and brachytherapy [42–44].
Factors that play a role in the development of post-radiotherapy ED include age, comorbidities, previous pelvic surgery, medications, pretreatment sexual function, hormonal treatment [44], and the presence of lower urinary tract symptoms [45]. Interestingly, while there is some conflicting evidence, most studies suggest that the radiation dose received by the corpora cavernosa and/or penile bulb is not related to the development of post-radiotherapy ED [36]. However, it is rational that reducing the volume of tissue irradiated may reduce the likelihood of developing ED, as with intensity-modulated radiation therapy or proton beam radiotherapy [46–48].
In addition, emerging evidence suggests that some men may be genetically predisposed to developing post-radiation ED. Certain TGF-β1 single-nucleotide polymorphism genotypes have been associated with the development of ED and rectal bleeding in patients treated with radiotherapy for PCa, possibly due to a propensity for developing fibrosis [49]. Gene therapy to target neurotropic factors to promote neuronal regeneration is promising, but still in development [50]. Similarly, studies using erythropoietin as a neuromodulatory agent have found increased recovery of erections [51].
9.6 Posttreatment Recovery of Erectile Function
Erectile function improves for up to 48 months after RP [12, 52–54]. The timeline is not uniform, and factors associated with quicker recovery include younger age, pre-RP sexual function, nerve sparing, and surgeon experience [15]. The ability to obtain an erection, either spontaneously or with PDE5-I support, within 3 months of a RP is an excellent prognostic indicator for long-term erectile function [52]. ED after radiotherapy seems to develop during the first 2 years, and plateaus from then on [36, 41].
The hypoxia theory has raised hope that erectile function can be improved by oxygenating the cavernosal tissue during neuropraxia, resulting in penile rehabilitation efforts. However, there is little consensus regarding the best approach [55, 56]. Strategies investigated, either alone or in combination, include PDE5-Is, intracavernosal injections (ICI), intraurethral prostaglandin, or vacuum erection devices (VED) [57]. PDE5-Is have gained popularity as they improve oxygenation to the corporal bodies by maintaining nitric oxide-mediated vasodilation, thereby inhibiting collagen synthesis, maintaining penile elasticity, and preserving endothelial and cavernosal functions [30, 58, 59]. Animal models have shown that the PDE5-I sildenafil promotes smooth muscle preservation and ameliorates fibrosis through the modulation of extracellular matrix and tissue growth factor gene expression after bilateral cavernosal nerve resection [60].
While the use of penile rehabilitation programs is common, much of the available data are extrapolated from either in vitro or animal studies [16, 25]. In spite of these limitations, the International Consensus of Sexual Medicine (ICSM) recommends that clinicians counsel men on the possibility of postoperative ED and options for rehabilitation, including PDE5-Is, ICI, intraurethral prostaglandin, VED, or neuromodulatory devices [16], although the optimal treatment protocol remains undefined [25, 61–63]. Men who are most likely to recover erectile function using a penile rehabilitation protocol after RP are those <55 years of age with a preoperative International Index of Erectile Function (IIEF) score of >22 [64]. In addition, even men undergoing nonnerve-sparing procedures should be considered candidates for penile rehabilitation, as these men may also benefit [65, 66].
In a series of post-RP men using postoperative PDE5-Is at a high-volume center, the 3-year erectile function recovery rates were higher in men using PDE5-Is compared with those who did not (73 vs. 37 %) [18]. Corroborating this, a randomized, double-blind, placebo-controlled study demonstrated that in men with normal preoperative erectile function undergoing RP, nightly sildenafil for 36 weeks resulted in the return of spontaneous erections in 27 % of men versus 4 % of controls, as well as improvement in IIEF scores [62]. While both of these studies support the use of PDE5-Is, the optimal dosing schedule remains unknown. While this study supports nightly PDE5-I use, other data suggest that on-demand use of a PDE5-Is as efficacious as daily use [25].
Management strategies for recovery of erectile function after radiation therapy (RT) are derived predominantly from the RP literature and are primarily based on PDE5-Is. Two randomized, double-blind trials of men developing ED after RT have demonstrated an increase in IIEF scores and also more men reporting successful intercourse (55 vs. 18 %) after treatment with sildenafil [67, 68]. Similar results have been found using tadalafil, with more men reporting successful intercourse with treatment (48 vs. 9 %) [39, 40]. Early treatment with PDE5-Is in the setting of RT seems to be optimal [69].
In men in whom PDE5-Is are ineffective, ICI may be attempted [16, 25, 70]. From a physiologic perspective, if we hypothesize that therapies that increase corporal oxygen will be the most efficacious, then erections induced by the VED or urethral prostaglandin may be less functional [71]. However, VED use in early penile rehabilitation has resulted in higher IIEF and SHIM scores and no loss in stretched penile length [72].
Finally, dietary supplements with endothelial nitric oxide synthase (eNOS) have shown promise in the treatment of ED not related to RP. L-arginine has been shown to increase eNOS [71], and pycnogenol stimulates the conversion of L-arginine to nitric oxide by eNOS [73]. Four trials consistently demonstrated increased patient-reported erectile function with these supplements [74–77]. In light of this, one protocol for post-RP penile rehabilitation includes dietary supplementation with L-arginine and pycnogenol [71].
9.7 Penile Prosthesis
Men failing medical therapy for ED after treatment for PCa may be candidates for penile prosthesis [78, 79]. These are rarely used, as a recent review found that for a group of 68,558 men treated with either surgery or radiation for PCa, the penile implant utilization rate was 0.78 % [79]. This is not due to a lack of technical feasibility, and implants can safely be placed in men who have had a RP [69] with minimal morbidity [71] and high patient satisfaction rates [79–81]. Conversely, patients who have already had a three-piece inflatable penile implant placed can safely undergo either open- or robot-assisted RP [82, 83]. Finally, the concurrent performance of a nonnerve-sparing RP and placement of a penile prosthesis has been reported [84], although this is not standard of care.
9.8 Testosterone Supplementation
There is evidence that testosterone (T) may regulate NO formation [85] and cavernosal PDE5 expression [85–87], helping to maintain penile innervation [85]. In addition, preoperative serum T levels have been shown to correlate with post-RP erectile function [88]. Because of this, there has been some interest in T replacement in men with ED and PCa. The role of T replacement in this population is hotly debated though, given concerns that dormant PCa cells will be stimulated by T. There are several retrospective studies supporting the relative safety of T replacement in men after RP and its benefits to sexual function without leading to a clinically significant increase in PSA [89–92]. Regardless, T replacement in these men should be accompanied by a thorough and frank discussion about the risks and benefits, and close monitoring during treatment.
It is clear that androgen deprivation therapy, either as primary therapy or adjunctive to surgical or radiation, negatively impacts erections. There is also emerging evidence that androgen deprivation therapy may be associated with a reduced response to PDE5-Is [93, 94]. In light of this, it has been speculated that a combination of PDE5-I and T therapy may be beneficial in penile rehabilitation, a concept that is being tested in a randomized trial (NCT00848497). The data from this and other trials will help to guide the role of T in the treatment of ED in men with PCa.
9.9 Psychosexual Counseling
The shock of receiving a PCa diagnosis and the ensuing uncertainties of cancer prognosis, treatment, and treatment-related physical changes has been associated with increased patient anxiety [95], cardiovascular events, and suicide [96, 97]. This anxiety may correlate with erectile function, as men with cancer after prostate biopsy have been shown to have a decrease in scores on all IIEF domains [98]. The impact on sexual function of carrying a diagnosis of PCa without undergoing treatment will likely become increasingly prominent with the increasing use of active surveillance protocols [99]. Because of this, sexual counseling is an important aspect of both therapy and prevention of ED. Patients should be informed of the possible sequelae of treatment on their sexual functioning.
Increasing evidence shows that any penile rehabilitation program should include sexual counseling. Without counseling, up to half of men will not even fill the PDE5-I prescription given to them, and a large percentage of those that do will stop taking the medication after not seeing a result [100]. Further studies have shown that in men using ICI for post-RP penile rehabilitation, those receiving sexual counseling reported higher scores on multiple IIEF domains, the lowest discontinuation rate, and the highest degree of couple satisfaction when compared with men not receiving sexual counseling [101]. Finally, men in couples undergoing sexual counseling after radiation therapy or surgery for PCa had increased use of erectogenic aids and showed improvements in overall distress, male global sexual function, and female global sexual function as assessed using the IIEF and Female Sexual Function Index (FSFI) [102].
The literature suggests that most oncologic professionals are reluctant to address sexuality and the majority of sexologic professionals do not feel that they have adequate expertise to discuss cancer and its treatment effects [103, 104]. It is likely that a more formalized collaborative effort would improve patient care fostering a more educated experience of what to expect after treatment, avoid misconceptions, obtain education about the available therapies, and an understanding about their options for sexual dysfunction after PCa treatment (Fig. 9.1) [66].
Fig. 9.1
Algorithm for preservation of erectile function in men with prostate cancer. Pre-diagnosis, treatment-related, and posttreatment erectile function rehabilitation factors should be considered to preserve erectile function in these patients and provide them with accurate expectations.
9.10 Conclusions
ED in the setting of PCa is a common problem. The etiology of ED in the setting of PCa appears to be multifactorial, with some sexual dysfunction being present at the time of diagnosis as a function of age and comorbid conditions, some arising from the diagnosis itself and some being treatment related. A more sophisticated understanding of the etiology of PCa-related ED would allow for more individualized therapy. The literature is inconsistent on its definition of “normal” erectile function both before and after PCa treatment, and validated sexual function questionnaires should be utilized consistently to track progress. Clinicians should frankly discuss the known risk factors for and predictors of recovery of erectile function in men being treated for PCa, and patients should be given individualized outcomes based on their baseline erectile function, factors related to each treatment modality, surgeon-specific factors, and timing. In this way, patients can have the most realistic expectations for their recovery.
After treatment, there are no optimal penile rehabilitation strategies, although the literature supports a proactive approach. The optimal regimen for post-PCa treatment-related ED is still evolving. Emerging evidence for the use of oral agents and genetic predispositions is compelling. Testosterone replacement in these men may eventually play a role but presently should be considered experimental. Finally, evidence supports a multidisciplinary approach including sexual and psychiatric counseling to optimally manage these men.
Commentary: Erectile Dysfunction in the Setting of Prostate Cancer
Christian J. Nelson3
(3)
Memorial Sloan Kettering Cancer Center, New York, NY, USA
As Samplaski and Lo highlight in the preceding chapter, a diagnosis of erectile dysfunction (ED) in the prostate cancer patient can be challenging to manage. Not only does the etiology of prostate cancer-related ED differ from that in most cases of ED, relating more directly to treatment for the cancer, it is often accompanied by psychological ramifications that can be further debilitating and are magnified as a result of the cancer diagnosis and treatment. However, the psychological impact of prostate cancer, its treatment, and the subsequent physical effects are often overlooked. As such, the treatment challenges of prostate cancer-related ED are further multiplied by the presence of a significant psychological burden in these men. Often, a treatment approach focused exclusively on medical or surgical therapies will have suboptimal results. Therefore, it is imperative that clinicians consider the psychological impact of ED in men with prostate cancer and appropriately treat or refer men they are unable to manage themselves.
In the following commentary, Nelson looks under the proverbial hood of the man with ED related to prostate cancer, pointing out the key psychological factors—depression and anxiety—that are often present concomitantly with ED in these patients and the resultant avoidance of sexual behaviors and negative impact on relationships. The stark reality of a contribution from psychological factors to sexual dysfunction broadly, and even more significantly in men with prostate cancer, should be considered and addressed in all patients towards the goal of optimized treatment using a multidisciplinary approach.
The Editors
Commentary
It is important to understand that men with erectile dysfunction (ED) often experience comorbid depression and anxiety [1–5]. In one study of 120 men presenting to a sexual medicine clinic, 33 % reported high levels of depression and anxiety with major depression being the most common [6]. Of note, only about one third of these men were identified by their urologist as having a psychological concern, highlighting the need for medical care givers to ask about psychological sequelae of ED [6]. In another study of 103 men with ED, 63 % had a detectable psychiatric diagnosis including depressive symptoms in 25.2 %, anxiety disorders in 11.7 %, depression anxiety in 6.8 %, and personality disorders in 5.8 % [7].
Depressive Symptoms Related to ED
The association between ED and depression has been demonstrated in a number of well-designed population-based studies of aging men in the USA, Finland, Brazil, Japan, and Malaysia [2, 3, 8]. Data from the Massachusetts Male Aging Study (MMAS) confirm that men 40–70 years old with clinically significant depressive symptoms are nearly two times more likely to report ED compared to their nondepressed peers, controlling for important sociodemographic and medical factors [9]. ED is associated with a higher incidence of depressive symptoms independent of age, marital status, and comorbid medical conditions [1]. The association between ED and depression is considered a bidirectional relationship in which the two conditions reinforce each other in a “downward spiral” [9]. When focusing on prostate cancer, some authors have argued that depression or distress related to ED is mitigated as patients focus on the lifesaving nature of treatment [10]. Nevertheless, data confirms the presence of depressive symptoms, ED bother, and loss of masculine identity in men with ED following prostate cancer treatments [11, 12].
Anxiety and Sexual Performance
Anxiety is also an important concern in men with ED and can play a role in the maintenance of ED. For many men, erectile problems will heighten sexual anxieties due to increased concerns about erectile response leading up to and during sexual encounters [5]. This heightened focus on performance and feeling self-conscious are cognitive distractions that exacerbate problems with arousal and performance [13, 14]. These pressures increase the likelihood of failure and reinforce the pressure to perform during successive encounters, resulting in a vicious cycle of failure and escalating performance anxiety [5]. Ultimately, the anticipation of failure may cause avoidance of sex altogether, which may also detrimentally impact other aspects of intimacy in his relationship.
Relationship Impact
Not surprisingly, both patients and partners are impacted by the changes that ED may have on their relationships and must adjust to those changes individually and as a couple. Regret and feelings of loss are reported by both men and their partners in the face of sexual dysfunction [15]. Partner and relationship factors are important considerations in assessing men’s reactions to ED, the impact of a cancer diagnosis, and the impact ED may have on their psychological well-being and quality of life.
Avoidance
Given the psychological consequences of ED, it is not surprising that many men have difficulty accepting they have ED and delay pursuing treatment [16]. Although the embarrassment related to ED may be mitigated in men whose ED is caused by a medical condition such as prostate cancer, many men delay seeking treatment, hoping their ED will improve spontaneously. Only 50 % of men who report an interest in ED treatment actually pursue it [17]. Additionally, a growing body of literature is showing that compliance with ED treatments is poor. Disappointment, shame, and relationship strain may impact men’s ability to commit to and sustain the use of ED medications, and current data indicate that 50–80 % of men discontinue use of medical interventions (i.e., pills, injections, vacuum devices) for ED within a year [18, 19]. Phosphodiesterase 5 inhibitors (PDE5-Is) are used as first-line therapy in about 90 % of men who seek ED treatment; however, despite being safe and effective, discontinuation rates are 30–50 % [20–23]. Although men may stop ED treatment for a number of reasons, those who develop a pattern of avoidance may be particularly prone to poor adherence. This type of avoidance can be especially damaging in the context of prostate cancer and penile rehabilitation. Avoidance may cause men to miss the post-prostatectomy treatment window that maximizes the impact of penile rehabilitation, which may then lead to chronic ED, further prolonging or exacerbating the negative effects of a man’s ED on emotional and relational well-being.
Case Example
James is a 64-year-old man who was diagnosed with early stage, intermediate risk prostate cancer. He had a difficult time deciding on a treatment option and wanted to avoid treatment altogether. He was concerned about how prostate cancer treatment would impact his sexual function, and his first priority was to maintain his erections. James’ doctors all agreed that treatment was needed and encouraged him repeatedly to be treated. Despite these persistent recommendations, James continued to decline treatment. Finally, through the urging of his wife and family, he decided to have a radical prostatectomy. With regard to cancer treatment, the surgery was a success. However, James experienced ED following prostatectomy and reported significant distress and depressive symptoms related to his ED. While initially motivated to participate in a penile rehabilitation program, he quickly began avoiding penile injections and withdrew physically and emotionally from his wife. This created marital conflict, leading to an increase in his personal distress as well as increased anxiety related to intimate situations.
The reaction that James had to his ED and the resulting impact on his relationship is relatively typical for men with ED following prostate cancer treatment. Even though they are thankful the cancer was successfully treated, men often experience ED, which leads to shame, embarrassment, and emotional distress. These psychosocial ramifications highlight the importance of working with mental health professionals to mitigate these issues in the context of sexual dysfunction following cancer treatment. James worked with a psychologist to help address his depression and avoidance using techniques from Acceptance and Commitment Therapy with the primary goal of reducing James’ avoidance of penile injections and engaging in sexual situations. Using this approach, James began to use the penile injections at the rate suggested for penile rehabilitation, and he was able to reconnect with his wife on an intimate level. These two successes then led to reduced distress and relationship tension. Eventually, James recovered erectile function several months after his prostatectomy and no longer needed treatment for ED.
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