Reconstruction of Radiation-induced Injuries of the Lower Urinary Tract

This article presents an overview of reconstruction of lower urinary tract injury caused by radiation therapy for prostate cancer. Discussions include cause, patient evaluation, reconstructive techniques, and outcomes following repair.

Key points

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Radiation therapy for prostate cancer has been used with increased frequency in the past 2 decades. Higher radiation doses with modern techniques seem to be a significant risk factor for formation of urethral stricture, bladder neck contracture, and rectourethral fistula.
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Radiation delivered to the apex of the prostate during interstitial therapy is a significant risk factor for the formation of urethral stricture in the bulbar and membranous urethra. Dose modifications may limit formation of urethral stricture.
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Intensity-modulated radiation therapy has shown no increased risk of lower urinary tract injury compared with three-dimensional conformal external beam radiation therapy.
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Urethral stricture caused by radiation therapy is often located in the bulbar and membranous region. Most of these strictures are short, and most often can be repaired with excision and primary anastomosis. Longer strictures are amenable to substitution urethroplasty.
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Rectourethral fistula caused by radiation therapy is a serious complication. Urinary and bowel function can be successfully restored with reconstruction in many patients.

Introduction

Radiation therapy for the treatment of prostate cancer has been evolving since its introduction in the early twentieth century. The discovery of radioactivity, the weak form of uranium, by Henri Becquerel in 1896 and the discovery of radium by Marie and Pierre Curie in 1898 ushered in a new era in medical technologies. Early knowledge of the effects of radiation on human tissue was identified through incidental exposures by early researchers. The subsequent medical applications with this new technology attempted to maximize the dose of radiation and minimize the effects on normal tissue. The following 2 decades led to refined technologies and techniques of administration to prostate tissue through mainly intracavitary means that were used by prominent urologists of the era, including Hugh Hampton Young. Benjamin Barringer is credited with pioneering the interstitial implantation techniques currently used via a perineal and suprapubic approach using glass-encapsulated radon. The 1930s saw the first use of external beam radiation therapy (EBRT). More effective use of external and interstitial therapies now relies on modern imaging techniques of computed tomography (CT) scans and transrectal ultrasound to maximize treatment and limit side effects.

Prostate cancer is the most common non–skin-related malignancy of men in the United States. In 2012, an estimated 241,740 new cases will be diagnosed, which accounts for 29% of all new cancer diagnoses in men. According to the 2007 American Urological Association guidelines, use of either brachytherapy (BT) or EBRT may be used alone or in combination for first-line therapy for localized prostate cancer. Analysis of the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) database, a national disease registry of more than 10,000 men, found that radiation therapy was used in more than 20% of newly diagnosed low-risk prostate cancer from 1993 to 2001. This same study also showed an increase in the use of BT from 4% to 22% during the study time period. The SEER (Surveillance, Epidemiology, and End Results) database, which includes primarily men more than the 65 years of age, has shown a rapid adoption of use in recent years of intensity-modulated radiation therapy (IMRT), a modality of EBRT that can deliver high doses of radiation. The use of IMRT compared with three-dimensional conformal EBRT increased from 0.15% of total men treated with EBRT in 2000 to 95.6% in 2008. Despite little knowledge of the long-term genitourinary morbidity, rapid adoption of high-dose IMRT and BT have become more prevalent in the treatment of prostate cancer.

Lower urinary tract injury caused by radiation treatment of pelvic malignancy includes formation of urethral stricture, bladder neck contracture (BNC), and rectourethral fistula (RUF). Each of these conditions can be a serious complication to the patient both physically and mentally. This article focuses on the pathophysiology, risk, evaluation, surgical reconstruction, and long-term considerations for patients with lower urinary tract injury caused by radiation therapy.

Introduction

Radiation therapy for the treatment of prostate cancer has been evolving since its introduction in the early twentieth century. The discovery of radioactivity, the weak form of uranium, by Henri Becquerel in 1896 and the discovery of radium by Marie and Pierre Curie in 1898 ushered in a new era in medical technologies. Early knowledge of the effects of radiation on human tissue was identified through incidental exposures by early researchers. The subsequent medical applications with this new technology attempted to maximize the dose of radiation and minimize the effects on normal tissue. The following 2 decades led to refined technologies and techniques of administration to prostate tissue through mainly intracavitary means that were used by prominent urologists of the era, including Hugh Hampton Young. Benjamin Barringer is credited with pioneering the interstitial implantation techniques currently used via a perineal and suprapubic approach using glass-encapsulated radon. The 1930s saw the first use of external beam radiation therapy (EBRT). More effective use of external and interstitial therapies now relies on modern imaging techniques of computed tomography (CT) scans and transrectal ultrasound to maximize treatment and limit side effects.

Prostate cancer is the most common non–skin-related malignancy of men in the United States. In 2012, an estimated 241,740 new cases will be diagnosed, which accounts for 29% of all new cancer diagnoses in men. According to the 2007 American Urological Association guidelines, use of either brachytherapy (BT) or EBRT may be used alone or in combination for first-line therapy for localized prostate cancer. Analysis of the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) database, a national disease registry of more than 10,000 men, found that radiation therapy was used in more than 20% of newly diagnosed low-risk prostate cancer from 1993 to 2001. This same study also showed an increase in the use of BT from 4% to 22% during the study time period. The SEER (Surveillance, Epidemiology, and End Results) database, which includes primarily men more than the 65 years of age, has shown a rapid adoption of use in recent years of intensity-modulated radiation therapy (IMRT), a modality of EBRT that can deliver high doses of radiation. The use of IMRT compared with three-dimensional conformal EBRT increased from 0.15% of total men treated with EBRT in 2000 to 95.6% in 2008. Despite little knowledge of the long-term genitourinary morbidity, rapid adoption of high-dose IMRT and BT have become more prevalent in the treatment of prostate cancer.

Lower urinary tract injury caused by radiation treatment of pelvic malignancy includes formation of urethral stricture, bladder neck contracture (BNC), and rectourethral fistula (RUF). Each of these conditions can be a serious complication to the patient both physically and mentally. This article focuses on the pathophysiology, risk, evaluation, surgical reconstruction, and long-term considerations for patients with lower urinary tract injury caused by radiation therapy.

Pathophysiology and risk factors for lower urinary tract injury

Radiation interacts with living cells in several ways that make it an effective cancer treatment. The effects may be divided into direct or indirect interactions with ionizing radiation. The direct interaction occurs when the energy from the photon directly damages either the cellular DNA and/or tissue protein. This damage leads to immediate cell death or mutation of the DNA. The indirect interaction occurs when the ionizing radiation interacts with water in the cell and leads to the formation of free radicals that interact with enzymes leading to cell death or future mutation. Both of these interactions lead to cellular injury that can cause division delay, reproductive failure, or interphase death through the apoptosis mechanism, which is more common in rapidly dividing cells. These interactions and resultant cellular injury are dose dependent and occur in a linear threshold model. When normal tissue is damaged with exposure greater than the injury threshold, several changes occur that result in a cycle of scar and subsequent healing. Damage to basement membranes of vessels can lead to occlusion, thrombosis, and eventually reduced neovascularization. The subsequent fibrosis is caused by an increase of fibroblasts that no longer make mature collagen, which accounts for the atrophy and contraction of the tissue.

Urethral stricture results from replacement of the corpus spongiosum with fibrosis and resultant occlusion of the urethral lumen. With a more thorough understanding of radiation biology it is logical that increases in radiation doses would result in a higher rate of urethral stricture. High-dose-rate BT (HDRBT) and EBRT, either alone or in combination, have been used to achieve higher disease-free survival for the treatment of prostate cancer. This strategy has developed out of improved technology and imaging techniques that allow more focused concentration of radiation to the intended tissue. Data from the CaPSURE database showed the stricture rate for BT to be 1.8%, EBRT 1.7%, and combined therapy 5.2%. Another more recent study compared the rate of stricture formation in 1903 patients after EBRT, low-dose-rate BT, and HDRBT. The rates of urethral stricture formation were 2%, 4%, and 11% respectively, indicating that despite modern imaging techniques and modifications the amount of radiation damage delivered to normal tissue is significant.

The use of HDRBT has shown a high incidence of urethral stricture formation. Sullivan and colleagues showed that after HDRBT the actuarial rate of urethral stricture formation at 6 years was estimated to be 12% for all urethral locations and 10.8% for the bulbomembranous location. Overall, the investigators concluded that 90% of urethral strictures following HDRBT occur in the bulbomembranous region. When combined with EBRT, HDRBT has a similar rate of stricture formation as HDRBT alone at 11.8%.

As expected, the dose of radiation delivered to the urethra has been shown to be a significant risk factor in the development of urethral stricture as well as the location of the delivered radiation dosage. Merrick and colleagues has shown that, in patients with urethral stricture formation following BT, the dose delivered to the apex of the prostate was significantly higher than in case-controlled patients who did not form urethral strictures. By limiting the dosage to the apex of the prostate, the investigators showed a relative risk reduction of stricture formation of greater than 30% Earley and colleagues found that the radiation delivered by low-dose-rate BT within 5 mm of the urethra at the apex of the prostate was significant. Of the patients treated in this study, the 6.5% who formed urethral stricture had roughly 30% more dosage delivered to the apex of the prostate.

The amount of radiation delivered per treatment also affects the rate of urethral stricture following treatment. When 18 to 20 Gy of radiation were delivered by HDRBT over 2, 3, or 4 fractionated dosages, the stricture rate was different. The fractionated dosages were delivered during a single hospital admission with at least 6 hours between treatments. The urethral stricture rate increased to 31.6% when delivered over 2 treatments, compared with 3.4% for 3 treatments and 2.3% for 4 treatments. The investigators concluded that the amount delivered per treatment was the most significant factor in urethral stricture formation, which led to a change in their treatment algorithm.

EBRT may be delivered in a variety ways. The most common modern techniques are three-dimensional conformal therapy and IMRT, which have a similarly low rate of stricture formation, typically reported to be less than 3%. However men who have undergone previous transurethral resection of the prostate before conformal EBRT have an increased risk of urethral stricture formation ranging from 4% to 16%. Another high-risk group for urethral stricture formation includes men who undergo adjuvant EBRT therapy for high-risk prostate cancer following radical prostatectomy in whom the rate of urethral stricture formation is reported to be as high as 17%.

Proton beam therapy (PBT) uses high-velocity particles instead of photons to deliver energy to the prostate. In theory, PBT delivers less energy to normal tissue because the proton’s energy is dissipated at preset depths depending on the velocity of the proton. Genitourinary complications seem to be comparable with external beam therapies, although limited data make these rates difficult to compare. In one phase III clinical trial that compared high-dose EBRT alone or with an additional boost of conformal PBT, the rate of urethral stricture increased from 8% of 99 patients who received EBRT therapy alone to 19% of 103 patients who received a PBT boost to EBRT.

Data on the rate of formation of BNC after radiation are limited; however, it is estimated to be between 2% and 12%. The risk factors for the development of BNC following radiation have not been studied as extensively as urethral stricture formation, but it can be inferred that similar factors such as the dose and location of radiation delivery play a major role.

RUF formation following radiation therapy has been reported with greater frequency in the literature over the last decade. The process that results in RUF formation following radiation is speculated to be the result of fibrosis and microvascular injury leading to mucosal ulcers and eventual fistulization. Lane and colleagues concluded that, before 1997, radiation therapy accounted for only 12% of the total RUF. After 1997, RUF caused by radiation increased to 49.6% of the total RUF reported in the literature. The investigators concluded that reporting bias may have been partially responsible for this finding but likely the increase in use of radiation therapy for prostate cancer was also responsible. Nonetheless, the overall incidence of RUF is uncommon after EBRT (0%–0.6%) and after BT (0.3%–3%). As with radiation-induced urethral stricture, this process seems to be dose dependent, but this has not been confirmed.

The risk of RUF may increase after endoscopic or open manipulation of the urethra, prostate, or rectum following radiation therapy. In one study, RUF was linked to postradiation transurethral resection of the prostate in 38%, postradiation rectal biopsy in 38%, and argon beam therapy for postradiation proctitis in 13% of patients. This same study also showed a high rate of concomitant urethral and rectal strictures, which may cause high-pressure elimination, a contributing factor in the development of RUF.

Salvage therapy after primary radiotherapy for recurrent prostate cancer significantly increases genitourinary complications. Salvage radical prostatectomy can result in an anastomotic urethral stricture rate of up to 41% with an average rate of 20%. Salvage cryotherapy results in urethral sloughing and subsequent stricture formation in 15% of patients, BNC in up to 28% of patients, and RUF in 3.4% of patients. Salvage BT after primary radiotherapy results in grade 3 to 4 genitourinary toxicity in 14% to 47% of patients, but specific percentages of urethral stricture are difficult to determine. Following salvage BT, RUF has been reported to occur in up to 12% of patients. High-intensity focused ultrasound (HIFU), when used for biochemical recurrence following radiation therapy, results in BNC formation in 17% of patients and RUF formation in up to 16% of cases.

Patient evaluation

Multiple urinary symptoms may occur as a result of radiation injury to the lower urinary tract. Storage-related symptoms such as frequency, urgency, and urge-related incontinency occur mainly as a result of bladder damage and loss of capacity; postmicturition and obstructive symptoms such as hesitancy, postvoid dribbling, and weakened stream occur mostly secondary to occlusion of the lower urinary tract. Up to 70% of patients may report these symptoms in a progressive manner that may even manifests months or years after the initial radiation injury. A validated questionnaire specific to urethral strictures has not been fully established; however, Jackson and colleagues provided methodology and initial results for a urethral stricture–specific questionnaire with good content and criterion validity to assess urinary complaints. When fully developed, such a tool may aid in the noninvasive evaluation and follow-up for patients with urethral stricture disease. Urinary tract infection, hematuria, or acute urinary retention may also occur in these patients, but less commonly as the presenting complaint. Physical examination can be used to determine urethral meatus patency and may reveal suprapubic fullness if urinary obstruction is present. On rectal examination, a RUF may be palpated, especially if the defect is large.

Diagnostic studies useful for the evaluation of urethral strictures and BNC consist of urinary flow studies, urodynamics, endoscopic studies, and radiologic evaluation. Urinary flow studies are commonly performed and often show a flat curve with low urinary flow rate in men with obstruction from BNC or urethral stricture disease. Urodynamic studies may be helpful to determine whether a patient is a candidate for reconstructive repair of BNC following radiation therapy, although catheter placement may be challenging. For patients with bladder volumes less than 200 mL or severe detrusor instability, conservative measures to increase bladder volume may be attempted before reconstruction. However, other options such as bladder augmentation before reconstruction or urinary diversion can be discussed with the patient. Postvoid residual may also be performed but this study is nonspecific and may be subject to user variation. Retrograde urethrography offers the ability to determine the length and location of the obstruction ( Figs. 1 and 2 ). If necessary, voiding cystourethrogram allows for full evaluation of the posterior urethra as well as the urethra proximal to the stricture if retrograde urethrogram is inconclusive. If a suprapubic tube is present, simultaneous antegrade endoscopy and retrograde urethrography can be performed ( Fig. 3 ). MRI and CT scan rarely provide useful staging information before urethroplasty. Ultrasound of the urethral stricture may also provide useful staging information about the extent of the spongiofibrosis.

RUF is often more obvious than urethral stricture or BNC and presents with urine persistently leaking from the rectum. The fistula typically develops several months to years after treatment with radiation. In addition to the urinary leakage, patients may present with pneumaturia, dysuria, perineal pain, or pelvic pain. Fecaluria is less common with RUF than colovesical fistula because of the higher pressure of the urethra compared with the bowel. Digital rectal examination may assist with the diagnosis if the defect is large. Retrograde urethrogram and cystogram should be performed to confirm the suspected diagnosis and to determine whether there is a concomitant urethral stricture or BNC in addition to the RUF ( Fig. 4 ). Proctoscopy and cystoscopy should also be performed under anesthesia to fully delineate the location and extent of the fistula and guide planning. Examination should also focus on evaluation of a rectal stricture, because almost all patients who are treated with BT have some degree of rectal stenosis. Biopsy should be taken of all fistula tracts before surgery to assess for cancer recurrence at the fistula site. Abdominal and pelvic imaging with CT or magnetic resonance imaging also helps to delineate the location of the fistula and the degree of surrounding tissue viability.

Diversion with a colostomy or ileostomy has been reported before or at the time of definitive reconstructive management for tissue healing and symptomatic improvement. Although it has been stated that all patients who develop a complex RUF following radiation therapy should undergo fecal diversion, this has not been established. Mundy and Andrich reported a series of radiation-induced RUF repaired with and without fecal diversion. The investigators showed no impact of preoperative fecal diversion on the success of the repair. It was postulated by the investigators that, if fecal diversion was not performed after the initial diagnosis, then a colostomy was not necessary at the time of repair. In general, the decision to perform fecal diversion should be based on the viability of the tissue surrounding the RUF. Counseling is important with these patients because urinary and fecal diversion can be used as definitive long-term management in lieu of reconstruction for symptomatic relief. Permanent fecal diversion may be considered in patients with extensive damage to the rectum and anal sphincter with a low probability of fecal continence after surgery.

When considering reconstruction of the urinary tract for RUF, urodynamic studies should be considered. Urodynamics may be difficult to obtain in patients with RUF, because the bladder may not hold adequate volumes because of urinary leakage. Nonetheless an assessment of bladder capacity is necessary. As with patients diagnosed with radiation-induced urethral stricture or BNC, men with a radiation-induced RUF and a significantly limited bladder capacity are often best suited for urinary diversion with cystectomy and ileal conduit.

Sexual function should be evaluated and assessed before and following reconstruction of lower urinary tract injuries caused by radiation. Sexual function, as assessed by patient report, was preserved in the 50% of patients undergoing anterior urethroplasty for radiation-induced urethral stricture who reported normal sexual function before surgery. However, validated patient-reported outcome measures were not used in this study. The International Index of Erectile Function (IIEF) questionnaire has been helpful in the assessment of men with urethral stricture of various causes. Erickson and colleagues reported on a prospective analysis of 52 men who underwent urethroplasty for anterior urethral stricture disease. Thirty-eight percent (20/52) of patients experienced worsened erectile function after surgery. At 6 months following urethroplasty, 90% (18/20) of these men recovered their preoperative level of sexual function. Ejaculatory function also seems to be preserved following urethroplasty for anterior urethral stricture disease of various causes. Prospective use of the Male Sexual Health Questionnaire has shown that 89% (38/43) of men report stable or improved ejaculatory function after surgery. Ejaculatory function has not been evaluated in men with radiation-induced urethral stricture diseases. Doppler ultrasound may prove useful to assess penile blood flow before urethroplasty for stricture disease, but its usefulness to assess erectile function in patients with radiation injury to the lower urinary tract remains unknown. The impact of lower urinary tract reconstruction on sexual function in men with radiation-induced BNC or RUF remains to be studied.

Urethral stricture surgical reconstruction

Dilation and endoscopic incision of urethral stricture caused by radiation is often reported with high success in the radiation oncology literature, although there is a paucity of data on long-term follow-up and recurrence following these endoscopic options. A limited number of studies have specifically addressed outcomes following urethroplasty in men with urethral stricture formation after radiation therapy.

The first report on reconstructive outcomes in men with radiation-induced urethral stricture disease focused on a small single-center series that showed that excision and primary anastomosis (EPA) was effective for strictures less than 2 cm in 6 of 7 patients. One patient who underwent a genital skin fasciocutaneous flap for a stricture less than 2 cm recurred. Time to recurrence, incontinence, and sexual function outcomes were not reported in this study.

A retrospective, multiinstitutional study reported on the follow-up of 30 patients who underwent reconstructive repair of urethral strictures following radiation therapy for prostate cancer. The study population consisted of 15 men (50%) treated with EBRT alone, 7 men (24%) treated with BT alone, and 8 patients (26%) treated with combined EBRT and BT. All of the urethral strictures were in the bulbomembranous urethra, averaging 2.9 cm in length with a range of 1.5 cm to 7 cm. EPA was used in 24/30 (80%) patients with an average stricture length of 3 cm. The remaining repairs consisted of genital fasciocutaneous skin flap use in 4/30 (13%) and buccal graft onlay in 2/10 (7%) patients, with an average stricture length of 4.3 cm. A total of 27% (9/30) of the patients in this series recurred at a mean of 5.1 months and 2 required balloon dilation. No patients required eventual urinary diversion. The new onset of incontinence was seen in 50% (15/30) of men, and resolved in 3/30 (10%). An artificial urinary sphincter (AUS) was placed in 4/30 (13%) men. Erectile function was preserved in the men who reported normal preoperative function.

In the largest reported single series to date, Glass and colleagues retrospectively reported on a total of 29 men with urethral stricture formation following radiation treatment of prostate cancer. Eleven patients treated with EBRT alone (38%) were included; radical prostatectomy followed by adjuvant EBRT, 7 (24%); combined EBRT/BT in 7 (24%); and BT alone 4 (14%). The average stricture length was 2.6 cm in the series, with location identified in the bulbar urethra, 12/29 (41%); membranous urethra, 12/29 (41%); bladder neck, 3/29 (10%); and panurethral, 2/29 (7%). EPA was performed in 22/29 (76%) patients, whereas 5/29 (17%) underwent substitution urethroplasty with buccal graft, and 2/29 (7%) with fasciocutaneous flap onlay. One EPA, 1 buccal graft, and 1 fasciocutaneous flap onlay case each recurred for an overall series success rate of approximately 90%. The new onset of urinary incontinence was reported in only 2 patients (7%) with 1 patient opting for an AUS to manage urinary incontinence. Erectile function was not reported before or after surgery.

Although limited in patient number and design, these studies show acceptable success rate with EPA in patients undergoing urethroplasty for short, proximally located, radiation-induced urethral strictures. Substitution urethroplasty seems to be most effective for anatomically more distal strictures in the bulbar or penile urethral and those of greater length. Longer follow-up is needed to assess the durability of these outcomes.

The technical approach for radiation-induced urethral stricture disease is similar to that for other causes. For proximally located stricture disease, the patient may be placed in the exaggerated or dorsal lithotomy position for perineal exposure of the urethra to the level of the prostate. Mobilization of the urethra off the corpora cavernosa to the proximal penile urethra is often necessary to achieve a tension-free anastomosis. Other extensive maneuvers such as splitting the corpora cavernosa or removal of the pubic bone have been described but are rarely necessary.

Complete scar excision to the level of the prostatic apex is often necessary in patients with bulbomembranous stricture disease. At times, the ability to place sutures in the apex of the prostate for a primary anastomosis with the bulbar urethra may be limited with standard needle drivers. Use of the Capio device (Boston Scientific) can assist in placing these proximal sutures at the desired depth ( Fig. 5 ). The device was originally designed for placement of sutures in complex female urology procedures. The curve of the Capio device makes it ideal for passing suture at an oblique angle, and is superior to other suture-passing devices used in laparoscopy that only pass suture at a right angle. With these maneuvers it is possible to properly place sutures into the mucosa of the apical prostate to create a watertight anastomosis with the bulbar urethra.