REVIEW URRENT C OPINION
Urethral strictures and the cancer survivor Amanda C. Chi, Justin Han, and Chris M. Gonzalez
Purpose of review Urethral stricture disease is poorly understood in prostate cancer survivors who have undergone radiation or ablative treatments. We review the cause and incidence of urethral strictures (excluding bladder neck contracture) in this setting, as well as risk factors and treatment options. Recent findings Stricture rates differ for various modalities of radiation therapy, with the highest rate in high-dose-rate brachytherapy. Risk factors include higher dose of radiation delivered to prostate apex, radiation delivered per treatment, and prior transurethral resection of prostate. Cryoablation and high-intensity focused ultrasound of the prostate also carry high risk of urethral stricture formation, particularly in the salvage setting. Dilation or direct vision incision of the urethra can be utilized as a temporizing technique, with frequent recurrence. Urethral stenting is also an option; however, this is associated with a high rate of incontinence. Urethroplasty has durable outcomes for radiation-induced strictures, with a preference for excision and primary anastomosis because of the bulbomembranous location and relatively short length of these strictures. Salvage radical prostatectomy has been described in a small series as treatment for posterior urethral strictures and bladder neck contractures resulting from ablative therapies. Summary Prostate cancer survivors treated with radiation or ablative therapies are at risk for urethral stricture formation. Urethroplasty is a feasible and durable treatment option and should be considered in the appropriate patient. Keywords cryoablation, high-intensity focused ultrasound ablation, prostate cancer, radiation, urethral stricture
INTRODUCTION Iatrogenic causes account for a large proportion of urethral strictures in the developed world today, with rates as high as 38.6–45.5% of all cases [1,2]. Many of these patients are cancer survivors who have undergone treatment for genitourinary malignancies. Urethral stricture after cancer treatment has been inadequately studied, in part because of under-reporting and its relative infrequency. Although over the past few years a growing body of literature has emerged, most published reports are still single institutional series comprising small numbers and short follow-up. Furthermore, clinical understanding is hampered by the lack of a standardized definition or categorization of urethral strictures within the published literature. Many studies group strictures of the anterior urethra and stenoses of the posterior urethra together and refer to them generally as ‘urethral strictures’. We will primarily discuss here urethral stricture disease (excluding bladder neck contractures) in the setting of radiation and ablative treatments for prostate cancer.
INCIDENCE AND CAUSE OF URETHRAL STRICTURES IN PROSTATE CANCER SURVIVORS Prostate cancer is the most commonly diagnosed noncutaneous cancer in American men. In the USA, an estimated 238 590 men were newly diagnosed with prostate cancer in 2013, with an estimated 2617 682 men currently living with prostate cancer [3]. Conventional treatment options for localized prostate cancer include radical prostatectomy, various radiotherapy techniques, and increasingly minimally invasive ablative therapies. Radiation options range from external-beam radiotherapy (EBRT), low-dose-rate brachytherapy (LDR-BT), high-dose-rate brachytherapy (HDR-BT), proton Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Correspondence to Chris M. Gonzalez, 675 North St. Clair St., Galter 20-150, Chicago, IL 60611, USA. Tel: +1 312 695 8146; e-mail: [email protected] Curr Opin Urol 2014, 24:415–420 DOI:10.1097/MOU.0000000000000070
0963-0643 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-urology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Reconstructive urology and the cancer survivor
KEY POINTS Radiation therapy and ablative therapy for prostate cancer are associated with risk of urethral stricture formation, with high-dose-rate brachytherapy demonstrating the highest rate of urethral stricture formation among radiation therapy modalities. Higher dose of radiation delivered to apex of prostate and higher dose delivered per treatment increase risk for urethral stricture formation. Prior transurethral resection of prostate increases risk of urethral stricture formation in radiation therapy treatment patients. Urethral strictures secondary to radiation therapy are commonly located in the bulbomembranous urethral location. Most of these strictures are relatively short and can be repaired with EPA with durable outcome. FIGURE 1. Urethral stricture following brachytherapy.
beam therapy (PBT), and various combinations thereof. Analysis of the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database showed that from 1993 to 2001 more than 20% of newly diagnosed low-risk prostate cancer patients underwent radiation therapy [4]. Urethral strictures are a known complication of pelvic radiation therapy. When normal tissue is exposed to radiation that is greater than the tissue’s injury threshold, a cycle of scarring and healing is induced. It may reduce neovascularization and lead to eventual loss of vessels and replacement by fibrous tissue. Owing to permanent fibroblast injury and subsequent collagen defects and shortage, acute-phase wound healing becomes limited and can lead to the late effects of atrophy, contraction, and fibrosis [5]. When fibrosis develops in the corpus spongiosum, urethral stricture can occur [6]. Stricture rates differ depending on the modality of radiation therapy. The CaPSURE database showed a stricture rate of 1.8% for brachytherapy, 1.7% for EBRT, and 5.2% for combined radiotherapy [7]. In a more recent study of 1903 patients, the rate of stricture after EBRT was 2%, 4% after LDR-BT, and 11% after HDR-BT, reflecting a dose-dependent relationship in the brachytherapy groups [8]. In the same study, HDR-BT was shown to have an actuarial rate of stricture formation of 12% at 6 years for all urethral locations and 10.8% for the bulbomembranous urethra, which accounts for 90% of all strictures following HDR-BT (Fig. 1). EBRT can be delivered in many ways, including three-dimensional conformal therapy and intensity-modulated radiation therapy. To date, such modalities have generally low rates of stricture formation, quoted to be less than 3% [7–9]. Similar 416
www.co-urology.com
to strictures following brachytherapy, the vast majority of post-EBRT urethral strictures are located in the bulbomembranous urethra or more proximally within the prostate. Unlike conformal photon beam radiation, PBT has properties that theoretically lead to a substantial reduction in integral dose, or the dose delivered to normal tissue; however, there is a paucity of data on the rate of urethral stricture formation in patients who undergo PBT. This is most likely secondary to the fact that most studies use PBT to boost conventionally fractionated EBRT. Slater et al. showed a stricture rate of less than 1% in a group of 1225 patients who received either PBT alone or in combination with photon beam therapy/EBRT [10]. In another study, the urethral stricture rate of combined EBRT followed by PBT for higher risk prostate cancer was 13%, as compared with 5% in EBRT alone [11]. Higher radiation dosage appears to be an independent risk factor in the development of urethral stricture. Merrick et al. [12] showed that the total dose delivered to the prostatic apex in brachytherapy-related urethral strictures was higher than casecontrolled patients who did not form urethral strictures. Similarly, Earley et al. [13 ] noted amongst a group of brachytherapy patients an overall stricture rate of 6.5%. In this matched case–control study, patients who developed urethral stricture had a significantly higher mean radiation dose delivered to the apical prostatic urethra (200 vs. 174 Gy). The difference between radiation doses further distally on the urethra was not predictive of stricture formation. The urethral stricture group was also subject to higher radiation in the peri-apical urethral region as compared with control [13 ]. &
&
Volume 24 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Urethral strictures and the cancer survivor Chi et al.
FIGURE 2. Prostatic urethral stricture following high-intensity focused ultrasound.
Stricture formation is not only associated with a higher total dose of radiation delivered to the prostatic apex, but also the amount of radiation delivered per treatment. Hindson et al. [14] showed that with a similar total dose of radiation of 18–20 Gy delivered by HDR-BT, the stricture rate increased from 2.3% when radiation was separated into four treatments to 3.4% for three treatments and 31.6% for two treatments. Another potential risk factor for urethral stricture development following radiation includes prior surgical intervention on the prostate. Studies of transurethral resection prior to conformal EBRT demonstrate urethral stricture rates ranging from 4 to 16% [15,16], whereas radical prostatectomy prior to adjuvant EBRT has resulted in stricture rates of approximately 10% (including bladder neck contracture), ranging from 1.3 to 17% in the literature [17]. Beyond surgery and radiotherapy for prostate cancer, other forms of prostate cancer treatment can leave survivors with urethral stricture disease. Minimally invasive ablative therapies such as prostate cryoablation and high-intensity focused ultrasound (HIFU) of the prostate carry potential risks of urethral stricture-related complications following their administration (Fig. 2). Following primary HIFU, the median incidence of urethral stricture/ stenosis is approximately 10% with the incidence ranging anywhere from 1.8 to 36% [18,19]. There also appears to be a cumulative increase in the incidence of urethral stricture/stenosis following HIFU. Ripert et al. [20] examined a series of 74 HIFU procedures over a 5-year period and found an early
urethral stricture rate of 3.6% with a longer-term stricture rate of 9% at a follow-up of 3.5 years. For patients after salvage HIFU, the stricture/stenosis rate is approximately double that of primary treatment [21]. Despite these adverse outcomes, Komura et al. [22] conversely found that the development of urethral stricture was associated with a favorable disease-free survival rate. The study, which involved 144 HIFU patients, determined that urethral stricture development was an independent predictor of disease-free survival and perhaps a byproduct of an adequate extent of treatment. Primary prostate cryoablation has been associated with a urethral stricture rate of 13% at 4 years [7]. In a Cochrane review, pooling results from smaller single institutional series, the stricture rates ranged from 2.2 to 17% [23]. For salvage cryoablation, there does not appear to be an increased risk for urethral stricture as compared with primary treatment, with rates ranging from 5 to 20% at relatively short-term follow-up [24,25]. Although some experts have suggested that utilizing a urethral warming catheter can minimize the risks of urethral damage and sloughing and thereby decrease potential stricture rates, the Cochrane review illustrates no significant protective effect of urethral warming during cryoablation [26 ]. &&
PRESENTATION AND EVALUATION OF PROSTATE CANCER-RELATED URETHRAL STRICTURES Patients who undergo pelvic radiotherapy can experience a host of genitourinary complaints. In a retrospective study of 72 men who underwent urethroplasty for radiation-induced urethral stricture, 95.5% had lower urinary tract symptoms (LUTS), of whom 57.1% had obstructive symptoms, 14.2% had irritative symptoms, and 23.8% mixed [27 ]. Oftentimes, patients are not diagnosed with a radiation-induced urethral stricture for several years following treatment. In a study of prostate brachytherapy patients, the authors reported a median time to stricture development of 26.6 months following treatment [12]. In another study of pelvic radiation patients (brachytherapy and EBRT), Hofer et al. [27 ] demonstrated a median time from radiation to treatment for urethral stricture of 6.4 years. Patients with LUTS following pelvic radiotherapy should undergo a thorough history and physical examination with special attention to the patency of the urethral meatus, suprapubic exam, and rectal examination. When indicated, postvoid residual by ultrasound can assess bladder emptying. Cystourethroscopy and retrograde urethrogram provide further detail on the location and length of the urethral
0963-0643 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
&&
www.co-urology.com
417
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Reconstructive urology and the cancer survivor
FIGURE 3. Cystoscopic appearance of urethral stricture after external-beam radiotherapy.
stricture (Fig. 3), and in patients with suprapubic catheters, antegrade cystourethoscopy and urethrogram are useful. Bladder capacity evaluation is integral for treatment planning because of the potential deleterious effects of radiation therapy on the bladder. In those patients with a relatively small bladder capacity (
Urethral strictures and the cancer survivor Amanda C. Chi, Justin Han, and Chris M. Gonzalez
Purpose of review Urethral stricture disease is poorly understood in prostate cancer survivors who have undergone radiation or ablative treatments. We review the cause and incidence of urethral strictures (excluding bladder neck contracture) in this setting, as well as risk factors and treatment options. Recent findings Stricture rates differ for various modalities of radiation therapy, with the highest rate in high-dose-rate brachytherapy. Risk factors include higher dose of radiation delivered to prostate apex, radiation delivered per treatment, and prior transurethral resection of prostate. Cryoablation and high-intensity focused ultrasound of the prostate also carry high risk of urethral stricture formation, particularly in the salvage setting. Dilation or direct vision incision of the urethra can be utilized as a temporizing technique, with frequent recurrence. Urethral stenting is also an option; however, this is associated with a high rate of incontinence. Urethroplasty has durable outcomes for radiation-induced strictures, with a preference for excision and primary anastomosis because of the bulbomembranous location and relatively short length of these strictures. Salvage radical prostatectomy has been described in a small series as treatment for posterior urethral strictures and bladder neck contractures resulting from ablative therapies. Summary Prostate cancer survivors treated with radiation or ablative therapies are at risk for urethral stricture formation. Urethroplasty is a feasible and durable treatment option and should be considered in the appropriate patient. Keywords cryoablation, high-intensity focused ultrasound ablation, prostate cancer, radiation, urethral stricture
INTRODUCTION Iatrogenic causes account for a large proportion of urethral strictures in the developed world today, with rates as high as 38.6–45.5% of all cases [1,2]. Many of these patients are cancer survivors who have undergone treatment for genitourinary malignancies. Urethral stricture after cancer treatment has been inadequately studied, in part because of under-reporting and its relative infrequency. Although over the past few years a growing body of literature has emerged, most published reports are still single institutional series comprising small numbers and short follow-up. Furthermore, clinical understanding is hampered by the lack of a standardized definition or categorization of urethral strictures within the published literature. Many studies group strictures of the anterior urethra and stenoses of the posterior urethra together and refer to them generally as ‘urethral strictures’. We will primarily discuss here urethral stricture disease (excluding bladder neck contractures) in the setting of radiation and ablative treatments for prostate cancer.
INCIDENCE AND CAUSE OF URETHRAL STRICTURES IN PROSTATE CANCER SURVIVORS Prostate cancer is the most commonly diagnosed noncutaneous cancer in American men. In the USA, an estimated 238 590 men were newly diagnosed with prostate cancer in 2013, with an estimated 2617 682 men currently living with prostate cancer [3]. Conventional treatment options for localized prostate cancer include radical prostatectomy, various radiotherapy techniques, and increasingly minimally invasive ablative therapies. Radiation options range from external-beam radiotherapy (EBRT), low-dose-rate brachytherapy (LDR-BT), high-dose-rate brachytherapy (HDR-BT), proton Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Correspondence to Chris M. Gonzalez, 675 North St. Clair St., Galter 20-150, Chicago, IL 60611, USA. Tel: +1 312 695 8146; e-mail: [email protected] Curr Opin Urol 2014, 24:415–420 DOI:10.1097/MOU.0000000000000070
0963-0643 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-urology.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Reconstructive urology and the cancer survivor
KEY POINTS Radiation therapy and ablative therapy for prostate cancer are associated with risk of urethral stricture formation, with high-dose-rate brachytherapy demonstrating the highest rate of urethral stricture formation among radiation therapy modalities. Higher dose of radiation delivered to apex of prostate and higher dose delivered per treatment increase risk for urethral stricture formation. Prior transurethral resection of prostate increases risk of urethral stricture formation in radiation therapy treatment patients. Urethral strictures secondary to radiation therapy are commonly located in the bulbomembranous urethral location. Most of these strictures are relatively short and can be repaired with EPA with durable outcome. FIGURE 1. Urethral stricture following brachytherapy.
beam therapy (PBT), and various combinations thereof. Analysis of the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database showed that from 1993 to 2001 more than 20% of newly diagnosed low-risk prostate cancer patients underwent radiation therapy [4]. Urethral strictures are a known complication of pelvic radiation therapy. When normal tissue is exposed to radiation that is greater than the tissue’s injury threshold, a cycle of scarring and healing is induced. It may reduce neovascularization and lead to eventual loss of vessels and replacement by fibrous tissue. Owing to permanent fibroblast injury and subsequent collagen defects and shortage, acute-phase wound healing becomes limited and can lead to the late effects of atrophy, contraction, and fibrosis [5]. When fibrosis develops in the corpus spongiosum, urethral stricture can occur [6]. Stricture rates differ depending on the modality of radiation therapy. The CaPSURE database showed a stricture rate of 1.8% for brachytherapy, 1.7% for EBRT, and 5.2% for combined radiotherapy [7]. In a more recent study of 1903 patients, the rate of stricture after EBRT was 2%, 4% after LDR-BT, and 11% after HDR-BT, reflecting a dose-dependent relationship in the brachytherapy groups [8]. In the same study, HDR-BT was shown to have an actuarial rate of stricture formation of 12% at 6 years for all urethral locations and 10.8% for the bulbomembranous urethra, which accounts for 90% of all strictures following HDR-BT (Fig. 1). EBRT can be delivered in many ways, including three-dimensional conformal therapy and intensity-modulated radiation therapy. To date, such modalities have generally low rates of stricture formation, quoted to be less than 3% [7–9]. Similar 416
www.co-urology.com
to strictures following brachytherapy, the vast majority of post-EBRT urethral strictures are located in the bulbomembranous urethra or more proximally within the prostate. Unlike conformal photon beam radiation, PBT has properties that theoretically lead to a substantial reduction in integral dose, or the dose delivered to normal tissue; however, there is a paucity of data on the rate of urethral stricture formation in patients who undergo PBT. This is most likely secondary to the fact that most studies use PBT to boost conventionally fractionated EBRT. Slater et al. showed a stricture rate of less than 1% in a group of 1225 patients who received either PBT alone or in combination with photon beam therapy/EBRT [10]. In another study, the urethral stricture rate of combined EBRT followed by PBT for higher risk prostate cancer was 13%, as compared with 5% in EBRT alone [11]. Higher radiation dosage appears to be an independent risk factor in the development of urethral stricture. Merrick et al. [12] showed that the total dose delivered to the prostatic apex in brachytherapy-related urethral strictures was higher than casecontrolled patients who did not form urethral strictures. Similarly, Earley et al. [13 ] noted amongst a group of brachytherapy patients an overall stricture rate of 6.5%. In this matched case–control study, patients who developed urethral stricture had a significantly higher mean radiation dose delivered to the apical prostatic urethra (200 vs. 174 Gy). The difference between radiation doses further distally on the urethra was not predictive of stricture formation. The urethral stricture group was also subject to higher radiation in the peri-apical urethral region as compared with control [13 ]. &
&
Volume 24 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Urethral strictures and the cancer survivor Chi et al.
FIGURE 2. Prostatic urethral stricture following high-intensity focused ultrasound.
Stricture formation is not only associated with a higher total dose of radiation delivered to the prostatic apex, but also the amount of radiation delivered per treatment. Hindson et al. [14] showed that with a similar total dose of radiation of 18–20 Gy delivered by HDR-BT, the stricture rate increased from 2.3% when radiation was separated into four treatments to 3.4% for three treatments and 31.6% for two treatments. Another potential risk factor for urethral stricture development following radiation includes prior surgical intervention on the prostate. Studies of transurethral resection prior to conformal EBRT demonstrate urethral stricture rates ranging from 4 to 16% [15,16], whereas radical prostatectomy prior to adjuvant EBRT has resulted in stricture rates of approximately 10% (including bladder neck contracture), ranging from 1.3 to 17% in the literature [17]. Beyond surgery and radiotherapy for prostate cancer, other forms of prostate cancer treatment can leave survivors with urethral stricture disease. Minimally invasive ablative therapies such as prostate cryoablation and high-intensity focused ultrasound (HIFU) of the prostate carry potential risks of urethral stricture-related complications following their administration (Fig. 2). Following primary HIFU, the median incidence of urethral stricture/ stenosis is approximately 10% with the incidence ranging anywhere from 1.8 to 36% [18,19]. There also appears to be a cumulative increase in the incidence of urethral stricture/stenosis following HIFU. Ripert et al. [20] examined a series of 74 HIFU procedures over a 5-year period and found an early
urethral stricture rate of 3.6% with a longer-term stricture rate of 9% at a follow-up of 3.5 years. For patients after salvage HIFU, the stricture/stenosis rate is approximately double that of primary treatment [21]. Despite these adverse outcomes, Komura et al. [22] conversely found that the development of urethral stricture was associated with a favorable disease-free survival rate. The study, which involved 144 HIFU patients, determined that urethral stricture development was an independent predictor of disease-free survival and perhaps a byproduct of an adequate extent of treatment. Primary prostate cryoablation has been associated with a urethral stricture rate of 13% at 4 years [7]. In a Cochrane review, pooling results from smaller single institutional series, the stricture rates ranged from 2.2 to 17% [23]. For salvage cryoablation, there does not appear to be an increased risk for urethral stricture as compared with primary treatment, with rates ranging from 5 to 20% at relatively short-term follow-up [24,25]. Although some experts have suggested that utilizing a urethral warming catheter can minimize the risks of urethral damage and sloughing and thereby decrease potential stricture rates, the Cochrane review illustrates no significant protective effect of urethral warming during cryoablation [26 ]. &&
PRESENTATION AND EVALUATION OF PROSTATE CANCER-RELATED URETHRAL STRICTURES Patients who undergo pelvic radiotherapy can experience a host of genitourinary complaints. In a retrospective study of 72 men who underwent urethroplasty for radiation-induced urethral stricture, 95.5% had lower urinary tract symptoms (LUTS), of whom 57.1% had obstructive symptoms, 14.2% had irritative symptoms, and 23.8% mixed [27 ]. Oftentimes, patients are not diagnosed with a radiation-induced urethral stricture for several years following treatment. In a study of prostate brachytherapy patients, the authors reported a median time to stricture development of 26.6 months following treatment [12]. In another study of pelvic radiation patients (brachytherapy and EBRT), Hofer et al. [27 ] demonstrated a median time from radiation to treatment for urethral stricture of 6.4 years. Patients with LUTS following pelvic radiotherapy should undergo a thorough history and physical examination with special attention to the patency of the urethral meatus, suprapubic exam, and rectal examination. When indicated, postvoid residual by ultrasound can assess bladder emptying. Cystourethroscopy and retrograde urethrogram provide further detail on the location and length of the urethral
0963-0643 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&&
&&
www.co-urology.com
417
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Reconstructive urology and the cancer survivor
FIGURE 3. Cystoscopic appearance of urethral stricture after external-beam radiotherapy.
stricture (Fig. 3), and in patients with suprapubic catheters, antegrade cystourethoscopy and urethrogram are useful. Bladder capacity evaluation is integral for treatment planning because of the potential deleterious effects of radiation therapy on the bladder. In those patients with a relatively small bladder capacity (
