How Can We Effectively Address the Medical and Psychological Concerns of Survivors of Pelvic Malignancies?

Sexual and urinary morbidities resulting from treatment of pelvic malignancies are common. These treatment sequelae are significantly bothersome to patients and challenging to address. Awareness of these complications is critical in order to properly counsel patients regarding potential side effects and to facilitate prompt diagnosis and management. Addressing these issues often necessitates a coordinated multidisciplinary approach; however, the effort required often translates into improvement in patient quality of life. Herein we review the sexual and urinary side effects that may arise during or after treatment of pelvic malignancies.

Introduction

In 2016, the estimated number of new cancer cases was projected to be 1.68 million, of which pelvic malignancies were expected to account for approximately 19%.[1] Based on current trends, the projected prevalence of cancer survivors in 2024 is predicted to exceed 18 million people; survivors of pelvic malignancies are expected to account for 31% to 40% of that number.[2] Over the last several decades, a tremendous focus on improving cancer therapies has led to improved cancer survival.

Genitourinary and sexual morbidity may result from these improved cancer treatments, especially in patients treated for pelvic malignancies. During treatment, focusing on cancer care is paramount; however, after treatment, many patients report difficulty with adjusting to the changes in their physical appearance, functioning, and social roles that often result from aggressive therapies. These issues have resonated in our society, leading to a growing interest in enhancing healthcare system support and programs for cancer survivors. In 2004, the President’s Cancer Panel published a report highlighting the need for improvement in education on and awareness of late side effects, establishment of follow-up care plans, and optimization of regulations to facilitate cancer survivorship support.[3] Foundational to all such efforts is that practitioners have a clear understanding of the urinary and sexual sequelae of treatments used for pelvic malignancies, which will enable them to help these patients manage the factors that affect their quality of life (QOL) in survival.

Herein we describe some of the most common sexual and genitourinary side effects encountered following treatment of pelvic malignancies.

Urinary and Sexual Effects of Surgical Treatment of Colorectal Malignancies

Urinary and sexual dysfunction are common sequelae of treatment for colon and rectal malignancies. The incidence of these in the existing literature is highly variable due to the difficulty in capturing functional outcomes. However, it is estimated that between 12% and 70% of patients have some degree of urinary dysfunction, with sexual dysfunction an even more common problem.[4-7]

Depending upon the size and location of a tumor, several operative approaches can be utilized for curative resection. Although an abdominoperineal resection carries a greater risk of sexual or urinary dysfunction than a low anterior resection, the autonomic nerves responsible for normal urinary and sexual function are at risk with both surgical approaches.[8]

High ligation of the inferior mesenteric artery requires dissection around the superior hypogastric plexus. Dissection along the lateral pelvic sidewall requires identification of pelvic autonomic nerves. Total mesorectal excision, a technique developed in the 1970s to improve oncologic outcomes, has had the added benefit of facilitating identification and preservation of these structures, which can result in preservation of urinary function.[9,10]

The use of minimally invasive surgical approaches has become increasingly widespread because of their association with improved perioperative outcomes and oncologic equivalence. However, despite anticipated benefits, including improved visualization of key structures during pelvic dissection, neither laparoscopic nor robotic approaches have been shown to reduce the incidence of genitourinary side effects.[5,11]

Neoadjuvant radiation therapy (RT) is a key component of the multimodal approach to rectal cancer because of its ability to downstage disease, turning unresectable tumors into resectable surgical targets. The use of pelvic RT for colorectal cancer does not appear to have any impact on the postoperative incidence of urinary dysfunction; however, it has been associated with significantly worsened sexual function in both men and women.[6,12-14]

Urinary and Sexual Effects of Surgical Treatment of Prostate Cancer

A well-recognized concern associated with surgical management of prostatic malignancy is the subsequent risk of urinary incontinence and erectile dysfunction. Urinary continence may depend on a combination of function of the external urinary sphincter, the patient’s age and body mass index, urethral length, whether a nerve-sparing technique was used, and the surgeon’s experience.[15-17] The spectrum of outcomes is wide and may range from complete urinary control to total incontinence.

Immediately after prostatectomy, the majority of patients experience urinary leakage that improves over the course of 3 to 12 months. A recent study evaluating health-related QOL outcomes in 708 men following prostatectomy demonstrated that at 3 months after surgery, the rate of continence was 39%. These rates improved over time.[18] Continence rates at 12 months after open or robotic prostatectomy performed by an experienced surgeon can be expected to be between 74% and 96% (Table 1).[18-30] The most common type of incontinence in the postprostatectomy setting is stress incontinence. However, a subset of men may also experience urge or mixed urinary incontinence. Men bothered by the degree of their incontinence should be considered for anti-incontinence procedures following a thorough urologic evaluation, although many practitioners will wait 6 to 12 months after the prostatectomy before considering an anti-incontinence procedure. We feel strongly that significant incontinence that has stopped improving early in the post-recovery period should be addressed with the patient at this time.

Erectile dysfunction is an even more common side effect of surgical management of prostate cancer. Walsh et al revolutionized the way prostatectomies are performed by describing the technique of a nerve-sparing prostatectomy, which allows erectile function to be preserved in a number of men.[31] Despite this advance, preserved erectile function rates still range between 50% and 80% in most studies. However, there is some discrepancy between provider-reported outcomes and patient-reported outcomes. The rate of adequate erectile function in this patient cohort may be lower than the rates reported in studies.[18] A recent prospective analysis of patient-reported outcomes in 1,643 men demonstrated that at 24 months, 81% of patients treated with prostatectomy had erections that were not firm enough for intercourse. This is compared with 53% of men on active surveillance and 66% of men who had undergone RT. Sexual dysfunction was reported as a moderate or severe problem in 57.5% of patients who had undergone prostatectomy, compared with 34.4% of patients on active surveillance, and 36.6% of patients treated with RT.[26]

A growing body of literature now recognizes additional sexual function effects, including climacturia (urinary leakage during orgasm) in 22% to 29% and orgasmic pain in 7% to 14%.[32-35] Few data exist regarding management of climacturia; however, one randomized controlled trial demonstrated improvement with implementation of pelvic floor muscle training (PFMT).[36] Rates of climacturia were similar between patients treated with open prostatectomy and those treated with robotic prostatectomy. However, orgasmic pain occurred with more frequency in the open prostatectomy patients.[33]

Urinary and Sexual Side Effects of RT for Prostate Cancer

Radiation toxicity has two components: the acute toxicity experienced during treatment, which typically resolves within 4 to 6 weeks of treatment ending, and late or chronic toxicity, which is less common but more persistent when it does occur.

A prospective longitudinal study of patient-reported QOL outcomes after prostatectomy, brachytherapy, or intensity-modulated radiation therapy (IMRT) reported that overall, RT modalities resulted in less urinary incontinence but more irritative symptoms compared with surgery.[37] This finding mirrors earlier data comparing the three modalities just mentioned, although the later study showed a decrease in acute urinary toxicity across all treatment types.[38,39]

Factors associated with late genitourinary toxicity include the presence of acute genitourinary toxicity during treatment, advanced patient age, previous transurethral resection of the prostate, large prostate volume, diabetes, pretreatment use of α-blockers, and certain bladder dose parameters (Table 2).[40-43] In a study using the Expanded Prostate Cancer Index Composite (EPIC)-26 health-related QOL questionnaire to compare IMRT, brachytherapy, and stereotactic body radiotherapy (SBRT), brachytherapy was associated with greater change in urinary symptoms than IMRT or SBRT.[44] A subanalysis of one arm of a randomized trial compared patient-reported QOL outcomes associated with three-dimensional conformal RT vs outcomes associated with IMRT and found no differences between these modalities.[45]

In some men, postprostatectomy radiotherapy (PORT) may be needed, with clinical indications including positive surgical margins. When this occurs, the toxicity of surgery and RT overlap, and some distinct trends can be noted. First, prospective data comparing patients who underwent PORT following prostatectomy vs prostatectomy patients who did not undergo PORT have shown that urinary incontinence continues to improve after PORT.[46] However, the degree of continence reached in this study was diminished in the nonrandomized PORT arm compared with the men who never required salvage RT. In a secondary analysis of randomized trial data by Mark et al, less acute urinary toxicity is associated with PORT compared with primary RT to an intact prostate.[47] No difference in late urinary toxicity was noted between men who received RT to intact prostates and men who received postoperative bed irradiation.

Sexual dysfunction presents quite differently in RT patients compared with those who are treated with surgery alone. While the exact mechanism is unclear, it is hypothesized that radiation injury to the neurovascular bundles and the penile bulb ultimately results in erectile dysfunction over time, with the mechanism possibly involving apoptosis of the periprostatic cavernous nerve cells.[48,49] Clinically, this damage may present as slowly progressive erectile dysfunction.

Prospective patient-reported QOL studies show that the change from baseline function varies between modalities, with sexual function less affected by RT than by surgery.[37] Older studies demonstrate an initial dip in patient-reported sexual function at the time of treatment with either RT or surgery, then recovery, and then slow decline. However, the initial decline in sexual function in these studies is greater for surgery than for RT.[38,39]

Anejaculation is a near-universal but under-addressed side effect of prostate RT. A prospective study of men undergoing external RT or brachytherapy found that 89% of men reported anejaculation 5 years after treatment.[50] This side effect was more common in older men treated with brachytherapy or androgen deprivation therapy (ADT) or those whose pretreatment prostate size was small.

Urinary and Sexual Side Effects of RT and Surgical Treatment for Gynecologic Malignancies

Treatment of gynecologic malignancies may adversely affect both sexual and urinary function. In a survey of more than 1,200 survivors of gynecologic malignancies, one-third of the women experienced sexual or urinary dysfunction during or after cancer treatment.[50] Among women with cervical cancer, over 40% reported difficulty in one or both of these areas.[51]

The mechanisms underlying patient-reported outcomes may differ based on treatment modality. The performance of a radical hysterectomy for early-stage cervical cancer results in vaginal shortening, with the possibility of decreased lubrication and/or fibrosis, which can result in dyspareunia.[52] Sexual arousal or orgasm may be affected by autonomic nerve damage.[53] RT for advanced or recurrent cervical cancer in premenopausal patients leads to premature ovarian failure if the ovaries have not been moved out of the radiation field, with resultant vasomotor symptoms and vaginal dryness.[52] Survey data suggest that women who receive RT for management of cervical cancer are more likely to experience sexual dysfunction compared with women who undergo other treatment modalities.[51]

Urinary dysfunction may worsen or persist for many years after cervical cancer treatment, as in the patient in Case 2.[51] The mechanism differs depending on treatment modality; for those treated with initial surgical management, urinary symptoms may be due to changes in nerve supply and pelvic floor anatomical relations. Irritative and obstructive symptoms have been reported as more frequent than stress-related symptoms in patients who undergo radical hysterectomy. Long-term urinary problems may occur in 30% of patients who undergo radical hysterectomy and debilitating problems may occur in up to 16%.[54] Outcomes of RT for cervical cancer have been urodynamically compared with those achieved with radical hysterectomy. Patients who underwent RT had decreased bladder compliance and increased bladder sensation.[55] Urinary dysfunction in patients treated with RT, specifically incontinence, may be secondary to fistula formation. In this setting, the possibility of recurrent disease should be assessed first.

Although they are in the minority, premenopausal women with endometrial cancer may enter surgical menopause as a result of a bilateral salpingo-oophorectomy performed as part of the staging procedure. Not surprisingly, survey data demonstrate that women under the age of 40 at diagnosis may be most at risk for sexual side effects of endometrial cancer treatment.[51] The use of RT in the management of endometrial cancer increases the likelihood of urinary complaints. Women undergoing multimodality treatment with surgery, chemotherapy, and RT are at highest risk.[51] Sexual dysfunction, rather than urinary tract complaints, is more common in women who are treated for ovarian cancer, perhaps because RT is seldom used in the management of this malignancy.[51]

Despite the prevalence of sexual dysfunction in survivors of gynecologic malignancies, only a small fraction of women seek care for these issues, suggesting a need for members of the healthcare team to actively inquire about these symptoms.[56]

Urinary and Sexual Complications Associated With Chemotherapy and Hormonal Therapy

Urinary complications associated with chemotherapy have been well documented, especially in pediatric populations in whom high doses of chemotherapeutic agents, particularly cyclophosphamide and ifosfamide, have been extensively studied. The most common and severe urinary complication is hemorrhagic cystitis, which can vary from relatively asymptomatic microscopic hematuria to life-threatening hemorrhage. In a large retrospective series from St. Jude Children’s Research Hospital, several risk factors for grade 3 or higher hemorrhagic cystitis were identified, including pelvic RT, bone marrow transplantation, BK virus positivity, acute lymphocytic leukemia, cyclophosphamide exposure, and male sex.[57] The cause of hemorrhagic cystitis resulting from treatment with cyclophosphamide or ifosfamide is believed to be the conversion of cyclophosphamide or ifosfamide to urotoxic metabolites, such as acrolein. Mesna is an organosulfur frequently administered with alkylating agents to assist in detoxifying their metabolites via reaction of its sulfhydryl group with α,β-unsaturated carbonyl-containing compounds such as acrolein.[58] Other anti-inflammatory agents have also demonstrated effectiveness in decreasing the severity of hemorrhagic cystitis in preclinical models, including ketamine and interleukin-1 receptor antagonists.[59,60] This is obviously an area where the value of prophylactic treatment is well established. However, early recognition of the signs of this toxicity (eg, microscopic hematuria) and discontinuation of treatment for progressive symptoms are critical to its successful management.

Sexual dysfunction associated with chemotherapy is common and likely underreported in the literature. Premature ovarian failure is a common consequence of chemotherapy in reproductive-age women, and, as a result, fertility issues and sexual dysfunction occur frequently in women who have undergone chemotherapy. Sexual dysfunction associated with estrogen withdrawal and psychological stress is also widespread in female cancer survivors. Women who suffer from sexual dysfunction may benefit from counseling and targeted interventions.[61] A recent Cochrane review of the literature evaluated several clinical trials looking at psychoeducational interventions, as well as pharmaceutical interventions and pelvic floor exercise, but failed to definitively identify a pattern of benefit associated with any of these interventions.[62]

Sexual dysfunction in men is related to chemotherapy primarily when the agents used cause hypogonadism. Chemotherapy-induced hypogonadism is well documented with several agents, especially alkylating agents, and is more common in patients with renal disease and in those undergoing treatment for Hodgkin lymphoma; it may be proportional to gonadal activity.[63] It remains unclear whether gonadal quiescence during chemotherapy is protective.

ADT, by definition, lowers testosterone and commonly results in loss of libido and erectile dysfunction.[64] While these side effects are expected during therapy, recovery once androgen suppression is discontinued can be variable. Recognizing the signs and symptoms associated with an ongoing hypogonadal state is the first step in identifying the problem. In many cases, the side effects are transient and men recover once the therapy is complete; however, chronic symptoms associated with low levels of testosterone persisting for 12 months or longer after completion of therapy may be an indication for testosterone supplementation. This complication is likely underappreciated by many cancer survivors, who end up suffering from a treatable condition.

Overview of Treatment of Urinary and Sexual Complications in Cancer Survivors

In general, cancer survivors experiencing urinary side effects are bothered by symptoms of urinary incontinence, urinary retention, bladder overactivity, hematuria, and/or bladder pain. These symptoms may be isolated or overlapping, making treatment challenging to physicians-and confusing and frustrating to patients.

In men with urinary incontinence, an assessment of the driving cause of their incontinence is critical if the practitioner is to provide adequate counseling regarding management options. Stress incontinence can be managed, after a detailed urologic evaluation, with PFMT, a transobturator urethral sling, or an artificial urinary sphincter.[65,66] These interventions have been shown to improve overall QOL in these patients, as in the patient in Case 1. Women with stress urinary incontinence after treatment of a gynecologic malignancy should be evaluated for fistulous disease or cancer recurrence. In the absence of an ominous finding, surgical treatment with a midurethral sling, retropubic colposuspension, or injection of bulking agents is feasible. The choice of approach is driven by the effect of the incontinence on the patient’s QOL, the severity of leakage, and the degree of lower urinary tract dysfunction.

Urinary frequency, urgency, and nocturia classically are considered irritative lower urinary tract symptoms secondary to bladder overactivity. These changes may occur after either an insult to bladder mucosa or bladder innervation. Surgery, chemotherapy, and RT can all lead to bothersome irritative urinary tract symptoms. Such symptoms may respond to dietary modifications (avoiding bladder irritants), antimuscarinic drugs, treatment with a β₃ agonist, onabotulinum toxin A intravesical injections, or neuromodulation. When these therapies are exhausted, urinary diversion may be indicated in very-well-selected patients-such as the woman in Case 2.

Urinary retention after pelvic surgery may present as overflow incontinence or frank retention. In this setting, appropriate bladder drainage is necessary. Urethral catheterization is reasonable in the acute setting; however, urethral catheterization or suprapubic catheterization is not an appropriate long-term form of bladder management and is discouraged. Clean intermittent catheterization carries a lower risk of urinary tract infection, allows more flexibility in daily activities, and is a safe mode of bladder management in patients who are able to reliably self-catheterize or who have an adequate support structure to assist with catheterization.

Erectile dysfunction is commonly seen in men treated for pelvic malignancies. Erectile dysfunction is normally managed initially with phosphodiesterase type 5 (PDE5) inhibitors. PDE5 inhibitors are excellent treatments for erectile dysfunction resulting from RT.[67-69] A recent survey of erectile function in prostate cancer patients treated with hormonal therapy and IMRT showed that PDE5 inhibitors provided satisfactory response in 66% of men using the medications.[70] Additional therapies include vacuum erection devices, intraurethral alprostadil suppositories, intracavernosal injections (papaverine, phentolamine, alprostadil), and penile prostheses. All of these modalities have been shown to improve QOL in patients with erectile dysfunction.

Sexual dysfunction may be present in both men and women with pelvic malignancies. The interplay between physical, psychological, and social factors influences sexual desire, libido, and satisfaction. Therapists specializing in psychosexual care can help address the psychological and social component of sexual dysfunction at the same time that medical and surgical therapies are being used to address the biological facets of the problem. This is an area where a great need for additional support has been identified. However, this need is not yet well addressed in the comprehensive care of cancer survivors.

Exercise and Physiotherapy in the Management of Urinary and Sexual Dysfunction Resulting From Treatment of Pelvic Malignancies

Exercise and physiotherapy are of interest for management of both urinary and sexual dysfunction after treatment of pelvic malignancies because many of the etiologies of these dysfunctions are physical in nature. Making maximal use of exercise and physiotherapy has numerous advantages, including improvement in other comorbid conditions, overall well-being, low cost, ease of implementation, and relatively few side effects.

Data supporting exercise or physiotherapy as interventions in sexual dysfunction are limited. A recent Cochrane review identified 11 contemporary randomized controlled trials that assessed the effectiveness of treatments for sexual dysfunction resulting from cancer treatment in women.[62] Only one of the trials evaluated the effect of exercise on sexual function.[71] Of 34 patients with gynecologic cancers and pelvic floor dysfunction following radical hysterectomy and pelvic lymph node dissection, 24 completed a 4-week pelvic floor rehabilitation program (PFRP) or usual care. Outcomes included pelvic floor dysfunction (as measured by the pelvic floor dysfunction questionnaire), pelvic floor muscle strength, motor-evoked potential of the sacral nerve, and patient-reported health-related QOL. At 4 weeks, there were improvements in the PFRP group in pelvic floor strength and sexual functioning, as well as QOL. However, the systematic review concluded that the evidence that pelvic floor exercise improves sexual function is weak.[62]

In men, the evidence for the impact of exercise or physiotherapy is most abundant by far in prostate cancer patients. One trial randomized men post radical prostatectomy to usual care or exercise for 6 months. While improvements in measures of physical fitness were found in the exercise group, exercise had no impact on recovery of erectile function.[72] Recently, higher levels of physical activity have been correlated with better erectile and sexual function in men treated for prostate cancer.[73]Overall, given the likely favorable risk-benefit ratio, PFRP for women and exercise for men with sexual dysfunction seem reasonable.

There is somewhat stronger evidence that physiotherapy may improve urinary incontinence in patients following treatment of pelvic malignancies. In the case of stress incontinence, the chief culprit appears to be pelvic floor weakness. Although an earlier systematic review concluded that PFMT for the treatment of urinary incontinence after radical prostatectomy hastens the return to continence, a more recent systematic review concluded that the benefit of conservative measures is uncertain.[74,75] The authors of the more recent review did, however, note moderate evidence of an overall benefit from PFMT vs no PFMT in reduction of urinary incontinence.

Physiotherapy in survivors of gynecologic cancers may increase recovery of urinary function. A small pilot randomized controlled trial (N = 40) in which the majority of patients had uterine cancer (60%) and were treated with multimodality therapy (RT, 18%; surgery, 95%; chemotherapy, 35%) randomly assigned patients to 12 weeks of PFMT plus behavioral therapy or to usual care. After 12 weeks, the PFMT group had significantly improved urinary continence. Of note, a Cochrane review found that there is evidence of widespread recommendation of PFMT for women without cancer who have stress or any other type of urinary incontinence.[76] Overall, given this evidence, PFMT seems reasonable as conservative treatment of urinary incontinence, particularly anatomic or stress incontinence, in patients with a history of treatment of a pelvic malignancy.

Conclusion

The management of pelvic malignancies with surgery, chemotherapy, and RT is complicated by the prevalent urinary and sexual side effects that affect long-term patient QOL. Recognition of possible problems with urinary function, such as urge or stress incontinence or hemorrhagic cystitis, is critical if practitioners are to adequately counsel patients and manage their posttreatment course. Similarly, sexual dysfunction-including dyspareunia, vaginal shortening/stenosis, sensory loss, erectile dysfunction, and ejaculatory dysfunction-affects patients psychologically and socially. Having a clear understanding of the sequelae of treatment of pelvic malignancies allows for clinical recognition and improvement in health-related QOL outcomes.

Financial Disclosure:Dr. Peterson is a consultant for American Medical Systems/Boston Scientific. Boston Scientific provides an educational grant for the reconstructive urology fellowship at Duke University Medical Center. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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