- Email: [email protected]
Visual Internal Urethrotomy With Intralesional Mitomycin C and Short-term Clean Intermittent Catheterization for the Management of Recurrent Urethral Strictures and Bladder Neck Contractures
Reconstructive Urology Visual Internal Urethrotomy With Intralesional Mitomycin C and Short-term Clean Intermittent Catheterization for the Management of Recurrent Urethral Strictures and Bladder Neck Contractures Michael R. Farrell, Benjamin A. Sherer, and Laurence A. Levine OBJECTIVE
MATERIALS AND METHODS
RESULTS
CONCLUSION
To evaluate our longitudinal experience using visual internal urethrotomy (VIU) with intralesional mitomycin C (MMC) and short-term clean intermittent catheterization (CIC) for urethral strictures and bladder neck contractures (BNC) after failure of endoscopic management. This case series involved review of our prospectively developed database of all men who underwent VIU with MMC and CIC in a standardized fashion for urethral stricture or BNC between 2010 and 2013 at our tertiary care medical center. Etiology was identified as radiationinduced stricture (RIS) or non-RIS and analyzed by stricture location. Cold knife incisions were made in a tri or quadrant fashion followed by intralesional injection of MMC and 1 month of once daily CIC. All 37 patients previously underwent at least 1 intervention for urethral stricture or BNC before VIU with MMC and CIC. Mean stricture length was 2.0 cm (range, 1-6 cm; standard deviation, 1.0 cm). Over the median follow-up period of 23 months (range, 12-39 months), 75.7% of patients required no additional surgical intervention (RIS, 54.5%; non-RIS, 84.6%; P ¼ .051). In those that did recur, median time to stricture recurrence was 8 months (range, 2-28 months). One patient with recurrence required urethroplasty. VIU with MMC followed by short-term CIC provides a minimally invasive and widely available tool to manage complex recurrent urethral strictures (<3 cm) and BNC without significant morbidity. This approach may be most attractive for patients who are poor candidates for open surgery. UROLOGY 85: 1494e1500, 2015. 2015 Elsevier Inc.
U
rethral strictures arise from a process of fibrosis within the urethral mucosa that can be initiated by a variety of insults. Although urethral strictures may be idiopathic, many are iatrogenic and result from a history of urethral catheterization, cystoscopy, transurethral resection of the prostate, prostatectomy, prostate radiation therapy, or hypospadias repair. Other notable causes of urethral strictures include pelvic trauma, urethritis, and lichen sclerosus.1
Financial Disclosure: Laurence A. Levine is a speaker in AbbVie, officer in Absorption Pharmaceuticals, consultant and speaker in American Medical Systems, Auxilium, and Coloplast, and also an investigator in Auxilium. The remaining authors declare that they have no relevant financial interests. From the Department of Urology, Rush University Medical Center, Chicago, IL Address correspondence to: Laurence A. Levine, M.D., Department of Urology, Rush University Medical Center, 1725 West Harrison Street, Suite 352, Chicago, IL 60612. E-mail: [email protected] Submitted: November 3, 2014, accepted (with revisions): February 13, 2015
1494
ª 2015 Elsevier Inc. All Rights Reserved
Radiation-induced urethral strictures (RIS) are uncommon, but when they do occur, they are often complex and traditionally have been difficult to manage. Previous investigation of stricture occurrence after radiation therapy for prostate cancer has been described with a reported incidence of 1.8% after brachytherapy, 1.7% after external beam radiotherapy (EBRT), and 5.2% after combination radiation therapy.2 Additional studies report urethral stricture development in 2.4%-8.2% of patients after prostate brachytherapy, which typically occur at the bulbomembranous urethra or the bladder neck.3,4 Multiple modalities are available for the treatment of urethral strictures including self-catheterization, urethral dilation, laser incision, urethral stent placement, visual internal urethrotomy (VIU), and open repair. Endoscopic internal urethrotomy has been promoted as the standard initial treatment for bulbar urethral strictures.5 However, after a http://dx.doi.org/10.1016/j.urology.2015.02.050 0090-4295/15
single VIU, the long-term cure rates for noneradiationassociated strictures are as low as 30%-40%.6 In an effort to decrease the rate of urethral stricture recurrence after VIU, supplemental injection of mitomycin C (MMC) has been proposed owing to its ability to mitigate scar formation via inhibition of fibroblast proliferation.7,8 In the present study, we aim to describe a safe and widely available endoscopic alternative to open surgical reconstruction that is more durable than VIU alone in patients with recalcitrant urethral strictures and bladder neck contractures (BNC) of various etiologies. We propose that VIU with MMC and short-term clean intermittent catheterization (CIC) may be a particularly attractive option for patients who are not candidates for definitive open urethroplasty. Although previous studies of VIU with MMC focused specifically on anterior urethral strictures or BNC with a small population undergoing radiation therapy, we include all stricture loci in one of the largest reported cohorts with the longest postoperative follow-up to date.7,8 Furthermore, given the unique and traditionally problematic nature of strictures owing to radiation, we compare our findings from RIS with nonradiation etiologies.
MATERIALS AND METHODS This study was designed as a case series involving review of a prospectively developed database of all men presenting for reconstructive urethral surgery between 2010 and 2013 to our tertiary care medical center. Men included in this study had symptoms of urinary obstruction, had urethral stricture or BNC confirmed via office cystoscopy, and were poor surgical candidates for open surgery or refused open repair. Selected patients subsequently underwent VIU with MMC followed by a short period of CIC. Retrospective analysis was conducted, and complete data were available for all included subjects. Informed consent was obtained from all subjects in this study at the time of initial patient visit. Patient demographic data included age, history of prior stricture interventions, and stricture etiology. Stricture length was determined by retrograde urethrogram and/or intraoperatively under direct vision based on the length of the cold knife incision of the stricture. Preoperative postvoid residual (PVR), uroflow, and any history of incontinence were recorded. We further analyzed this database to identify stricture etiology as radiation vs noneradiation induced. The RIS group included patients with a history of prostate EBRT and/or brachytherapy. Non-RIS were analyzed as all other stricture etiologies. Cystourethroscopy with a 22F rigid cystoscope was performed to allow for passage of a wire through the stricture site and into the urinary bladder. Direct VIU with cold knife incisions of the scar was made at the 12-, 3-, and 9-o’clock positions through the full thickness of the scar down to the level of healthy-appearing underlying tissue, if possible. Cold knife incisions at the 6-o’clock position were also performed when the bladder neck alone was involved. Using sharp cold knife incisions, we are able to directly visualize the change in tissue character from fibrosis to vascularized underlying tissue regardless of stricture location. Strictures with greater depth required a deeper incision down to the healthy-appearing tissue. This was followed by multiple UROLOGY 85 (6), 2015
injections of 0.4-mg/mL MMC in 0.2- to 0.4-mL aliquots at various points along the length of each incision for a total volume of 10 mL using a 23F Wolf (Vernon Hills, IL) injection or aspiration scope and a standard injection needle. Patients were routinely discharged the same day with a 16-18F silastic Foley catheter, which was subsequently removed in the office in 5-7 days. CIC was performed by the patient once daily with a 16F straight or coude catheter after removal of the Foley catheter that was placed at the time of surgery.9 Longitudinal follow-up data were collected to investigate the relationship between stricture etiology and the success rate of VIU with MMC. Postoperative evaluation at 1, 3, 6, and 12 months, followed by further evaluation at 6-month intervals, thereafter, included urethral patency via cystoscopy, PVR, uroflowometry, and stricture recurrence requiring reoperation. Stricture recurrence was defined as the inability to pass a 16F flexible cystoscope through the stricture site. Data analysis was conducted using PASW Statistics 18 software (SPSS, Inc., Chicago, IL). Continuous variables were reported as mean and standard deviation, with analyses conducted via a 2-sample t test. For continuous variables that did not follow a normal distribution, median and range were reported, with analysis conducted using a Mann-Whitney U test. Categorical data were shown as counts and percentages. Associations across categorical independent variables were evaluated using the Pearson chi-square univariate analysis. For all analyses, variables are considered significant predictors if the P value associated with the appropriate test statistic is <.05.
RESULTS Thirty-seven patients underwent VIU with MMC and CIC for refractory urethral strictures and BNC. Stricture location included 5 pendulous, 15 bulbar, 6 posterior urethral stricture, and 11 BNC. There were no statistical differences in patient age, stricture length, and number of procedures before VIU with MMC and CIC when analyzed by stricture location (P >.05; Table 1). Urethral stricture etiology was attributed to radiation in 11 patients, whereas 26 non-RIS patients were identified. Among RIS patients, 81.8% (n ¼ 9) previously underwent brachytherapy alone and 18.2% (n ¼ 2) had a history of both brachytherapy and EBRT. The most common stricture etiology among the non-RIS cohort was previous urethral instrumentation (34.6%) followed by radical prostatectomy (26.9%), infection (11.5%), hypospadias requiring pediatric repair (11.5%), idiopathic (11.5%), and external trauma to the urethra (7.7%). There were no differences in stricture length between RIS and non-RIS patients; however, RIS were subjectively noted to have deeper, full thickness spongiofibrosis (Table 1). The mean age of men undergoing VIU with MMC was 59 years (range, 22-80 years). All patients had at least 1 failed intervention for urethral stricture before VIU with MMC and CIC (range, 1-6). The 22-year-old patient had recurrent strictures after previous repair of a urethral distraction injury that was associated with a pelvic fracture. As such, he had previously undergone and failed urethroplasty and subsequently preferred VIU with MMC. Overall, 29.7% patients (n ¼ 11) failed previous 1495
Table 1. Baseline characteristics of patients undergoing VIU with MMC and CIC including analysis by stricture etiology Overall (N ¼ 37) Stricture location, n (%) Pendulous Bulbar Membranous Bladder neck Age, mean (SD), y Number of previous procedures, mean (SD) Stricture length, mean (SD; range), cm
5 15 6 11 59.0 2.7 2.0
(13.5) (40.5) (16.2) (29.7) (14.8) (1.6) (1.0; 1-6)
RIS (N ¼ 11) 0 4 6 1 65.9 1.5 2.1
(0) (36.6) (54.5) (9.1) (7.9) (1.4) (0.4; 2.0-3.0)
Non-RIS (N ¼ 26) 5 11 0 10 56.1 2.6 1.96
(19.2) (42.3) (0) (38.5) (16.1) (1.6) (1.1; 1.0-6.0)
P Value
.064 .079 .651
CIC, clean intermittent catheterization; MMC, mitomycin C; RIS, radiation-induced stricture; SD, standard deviation; VIU, visual internal urethrotomy.
Table 2. Postoperative outcomes for patients undergoing VIU with MMC and CIC independent of success including analysis by stricture etiology Overall (N ¼ 37) Operative time, mean (SD), min Postoperative complication, n (%) Preoperative, mean (SD) Uroflow (mL/s) PVR (mL) Postoperative, mean (SD) Uroflow (mL/s) PVR (mL)
36.7 (11.4) 5 (13.5)
RIS (N ¼ 11) 40 (13.9) 0
Non-RIS (N ¼ 26)
P Value
35.2 (10.1) 5 (19.2)
.252 .295
9.5 (4.9) 112.3 (103.0)
8.2 (8.2) 122.2 (113.7)
10.1 (3.1) 106.7 (99.6)
.492 .711
15.3 (8.2) 54.5 (91.6)
18.4 (12.2) 105.7 (169.4)
14.6 (7.1) 37.4 (38.7)
.359 .088
PVR, postvoid residual; other abbreviations as in Table 1.
urethroplasty. Patients with RIS and non-RIS underwent a similar number of previous procedures before MMC with VIU and CIC (Table 1). Overall, the median length of time from previous intervention to VIU with MMC was 7 months (range, 1-120 months). A surgical complication was noted in 13.5% of patients overall, with complications occurring solely in the nonRIS cohort (Table 2). Postoperative complications included one of each of the following: erectile dysfunction, acute renal failure, hematuria requiring transfusion in a patient with baseline anemia, laryngospasm as a complication of anesthesia (Clavien grade II), and persistent hematuria requiring admission for continuous bladder irrigation with subsequent resolution after endoscopic intervention (Clavien grade IIIb). Postoperative follow-up was obtained for a median of 23 months overall (range, 12-39 months). RIS patients were followed up for a median of 28 months (range, 15-39 months). Median follow-up was 21 months (range, 12-38 months) for non-RIS. Postoperative uroflow and PVR measurements were not different between RIS and non-RIS patients as measured at the longest point of follow-up and did not differ by stricture location (P >.05; Table 2). There was a significant increase in the maximum uroflow rate (Qmax) after VIU with MMC in the non-RIS cohort (P ¼ .049). Additionally, PVR decreased significantly after VIU with MMC in the non-RIS cohort (P ¼ .006). There was no significant improvement in the postoperative Qmax or significant decrease in the postoperative PVR for the RIS cohort (Qmax P ¼ .158; PVR P ¼ .813; Table 2). Overall, success of VIU with MMC and CIC without the need for additional therapy occurred in 75.7% of the study 1496
population as a whole over the follow-up period. Recurrence-free success of VIU with MMC and CIC was not statistically different between RIS and non-RIS patients (RIS 54.5% vs 84.6% non-RIS; P ¼ .051). In those that did recur (n ¼ 9, 24.3%), median time to recurrence was 8 months (range, 2-28 months). When analyzed by etiology, RIS recurred at a median of 13 months (range, 3-28 months), whereas non-RIS recurred at a median of 7 months (range, 2-12 months; P >.05). Recurrence-free success is shown by location of stricture or BNC in Table 3. Of the 9 patients who experienced recurrence, only 1 patient with a non-RIS of the bulbar urethra subsequently required urethroplasty with a ventral buccal mucosal graft. There was no change in stricture length for this patient at the time of MMC with VIU and on recurrence (2 cm). One patient with a bulbar stricture and 1 patient with a BNC underwent a second VIU with MMC and CIC with successful maintenance of urethral patency over the 31 and 6 months of subsequent follow-up, respectively. The remaining recurrences were managed by transurethral resection (TUR) with MMC (n ¼ 1), TUR without MMC (n ¼ 1), VIU without MMC (n ¼ 2), and transurethral resection of the bladder neck (TURBN) (n ¼ 1). There were 8 patients (21.6% overall, 9.1% RIS, and 16.9% non-RIS) with pre-existing incontinence that was successfully managed with artificial urinary sphincter placement after VIU with MMC and CIC at a mean of 6 months postoperatively (range, 3-14 months).
COMMENT We describe the presenting characteristics and outcome variables including stricture recurrence among patients UROLOGY 85 (6), 2015
Table 3. Recurrence free success after VIU with MMC and CIC over the study period by stricture location Recurrence-free Success, n (%) Location
RIS
Non-RIS
Overall
Pendulous 0/0 5/5 (100) 5/5 (100) Bulbar 3/4 (75.0) 9/11 (81.8) 12/15 (80.0) Membranous 3/6 (50.0) 0/0 3/6 (50.0) BNC 0/1 (0) 8/10 (80.0) 8/11 (72.7) Overall 6/11 (54.5) 22/26 (84.6) 28/37 (75.8) BNC, bladder neck contractures; other abbreviation as in Table 1.
undergoing VIU with MMC and short-term CIC for the management of recurrent urethral strictures and BNC of various etiologies. The mechanism of MMC involves inhibition of scar formation by impeding fibroblast proliferation. In vitro investigations demonstrate that MMC decreases 18S ribosomal ribonucleic acid transcript levels with correlated in vivo studies identifying inhibited protein translation.10 In relation to specific urologic applications of MMC, in vivo rat studies have shown that MMC injected into the injured urethra resulted in a decrease in hemosiderin-laden macrophages, mononuclear cell infiltration, and fibrosis in a dose-dependent manner.11 In humans, Mazdak et al7 identified stricture recurrence at 6 months in 2 patients (10%) undergoing VIU with MMC for non-RIS anterior urethral strictures vs 10 patients (50%) treated with VIU alone. Further study by Vanni et al8 involving 18 patients treated with VIU and MMC for BNC after radical prostatectomy established patency in 72% of patients after a single procedure and 89% after 2 procedures over a 12-month period. Other studies have evaluated the utility of deep transurethral incisions without MMC for the treatment of noneradiation-induced recurrent BNC, reporting that 72% of patients did not require additional surgeries over nearly a 13-month follow-up period.12 A recent multicenter study provided the largest cohort to date of 55 men with BNC undergoing VIU with MMC.13 They reported that 58% of patients achieved a stable bladder neck at a median follow-up of 9.2 months with no difference in stricture-free success when analyzed by radiation (n ¼ 14) vs noneradiation-induced etiologies (n ¼ 41). Maintenance of bladder neck patency using VIU with MMC was notably less than in our study as well as data previously reported by Vanni et al despite a shorter median follow-up period.8 Perhaps, the difference in success as compared with our study is in part attributable to the short course of postoperative CIC. Additionally, median time to recurrence was 3.7 vs 8 months in our cohort. Importantly, Redshaw et al noted serious adverse events in 7% of patients including 2 cases of osteitis pubis and 1 case of rectourethral fistula and bladder floor necrosis, all of which required cystectomy and urinary diversion.13 The total dose of MMC was 4 mg in 3 of these 4 patients; therefore, it was speculated that greater UROLOGY 85 (6), 2015
MMC doses may have contributed to such events. However, in our experience, we report no such serious adverse events with the use of 0.4 mg/mL of MMC and a total dose of 4 mg. In contrast to several previous studies, we used cold rather than hot knife incisions.12,13 Clearly the goal was to incise down to the level of healthy appearing vascularized tissue, which is more readily accomplished in non-RIS. We prefer using cold knife, as we feel it is easier to delineate this border, although the hot knife will usually cut through RIS more readily. In the present study, we report an overall success of 75.7% over a median follow-up period of 23 months after a single VIU with MMC and CIC; thus, our success is similar to those previously reported by Mazdak et al and Vanni et al.7,8 Similar to these reports, our experience is applicable to shorter length strictures with an overall mean stricture length of 2.0 cm (standard deviation ¼ 1.0 cm; range ¼ 1-6 cm). However, it is notable that our study included only patients who failed prior treatment, as well as patients with radiation-induced etiologies, thus adding to the difficulty in preventing stricture recurrence. These patients had a longer median postoperative followup of 23 months compared with that of previous studies by Mazdak et al, Vanni et al, and Redshaw et al, providing further support for longer term success.7,8,13 Our results are inclusive of all stricture locations and BNC, suggesting that VIU with MMC and CIC may be applied to anterior and posterior urethral strictures along with BNC to reduce stricture recurrence over a median follow-up period of nearly 2 years. It should be noted that patients with anterior strictures performed a trial of endoscopic intervention or had comorbidities that made them suboptimal candidates for open urethroplasty, as we believe that urethroplasty remains the gold standard for repair of anterior strictures in appropriate candidates. Short-term CIC was integrated into our protocol after VIU with MMC to allow the antifibrotic effect of MMC to stabilize the tissue in its patent state, thereby encouraging a prolonged effect. The authors acknowledge that adding short-term CIC adds a confounding variable; however, our goal was to optimize outcomes even with a multimodal approach. Subsequent larger trials could randomize patients to undergo VIU and MMC with or without short-term CIC. We further aimed to investigate outcomes according to stricture etiology. RIS are of particular interest, as radiation elicits a notably dense scar, not only due to damage of the urethral tissue but also secondary to compromised wound healing. Radiation induces vascular changes while also altering fibroblast function resulting in a particularly recalcitrant scar.14 Management of RIS, therefore, has traditionally been difficult. Eisenburg et al used urethral stents for RIS in an attempt to minimize the morbidity associated with urethral reconstruction in patients with RIS and noted stricture recurrence in 42% of patients.15 Additional studies have investigated the utility of open urethroplasty specifically for RIS, reporting stricture-free success in 1497
71%, 73%, and 90% at 10, 21, and 40 months follow-up, respectively.16-18 Our study identified stricture-free success in 54.5% of the RIS cohort over a mean follow-up period of 18 months. It is necessary to consider individual patient fitness when selecting the surgical approach to stricture repair, as VIU with MMC and CIC is far less invasive. The majority of our patients with advanced recurrent RIS were not good reconstruction candidates because of additional comorbidities. Mundy and Andrich have suggested that radiation-associated bladder dysfunction limits the utility of reconstructive surgery.19 Importantly, in this series, patients with RIS did not fare statistically different with respect to recurrence when compared with non-RIS patients, although it is likely that a larger study population would demonstrate higher stricture recurrence in the RIS group. Postoperative parameters including uroflow and PVR were not significantly different between RIS and nonRIS. However, significant postoperative improvement in uroflow and PVR was found in non-RIS patients alone. Although both RIS and non-RIS may be effectively managed with VIU plus MMC and CIC, the greater postoperative improvement seen with non-RIS is likely attributable to the more severe and increased depth of fibrosis in the RIS patients. Among the RIS patient population, fibrosis is typically full thickness and frequently extends well beyond the depth of the VIU. In addition, measurement of uroflow and PVR was less meaningful among RIS patients as many had preoperative urinary incontinence. Although our study represents 3 years of operative experience, our findings may be limited by our sample size of 37. Our analysis does not include a true control arm in which MMC or CIC was not used. However, all patients had undergone at least 1 previous failed attempt of stricture treatment without MMC before entering this study (with a median recurrence <7 months after previous intervention). Other potential limitations include the retrospective nature of the study and the representative experience of a single tertiary medical center that may reflect more severe and complex disease processes. Although the total number of patients with penile strictures was limited, we did have the highest success rates in this group as all 5 patients had success at 23 months median follow-up. A larger sample size of pendulous strictures would be useful to confirm reliable success in this population. Stricture location is a possible confounder as there may be differences in outcomes by location. Our statistical power to detect differences in recurrence by stricture location was limited by our sample size. We do not offer VIU with MMC for strictures caused by lichen sclerosus. Rather, we recommend definitive 1or 2-stage open repair, as this is most likely to be successful. For scenarios in which dilation, urethroplasty, and transurethral resection alone have been unsuccessful at establishing urethral patency, our study provides evidence for the utility of transurethral incision of the tissue focally 1498
followed by injection of MMC and a short course of postoperative CIC in patients with either RIS or non-RIS particularly of shorter length (<3 cm) at all urethral locations, as well as the bladder neck. Although we recognize that longer strictures are more likely to fail, there may be circumstances that should be elucidated by further experience in which this evolving procedure may be used. Additional experience with larger cohorts, longer follow-up, and randomization to VIU and MMC with or without CIC are needed to further validate our findings.
CONCLUSION VIU with MMC followed by a short period of CIC provides a minimally invasive and widely available tool to manage complex, recurrent, relatively short (<3 cm) urethral strictures and BNC by obviating or temporizing the need for open surgical reconstruction without significant morbidity. References 1. Lumen N, Hoebeke P, Willemsen P, et al. Etiology of urethral stricture disease in the 21st century. J Urol. 2009;182:983-987. 2. Elliott SP, Meng MV, Elkin EP, et al. Incidence of urethral stricture after primary treatment for prostate cancer: data from CaPSURE. J Urol. 2007;178:529-534; discussion 534. 3. Merrick GS, Butler WM, Wallner KE, et al. Risk factors for the development of prostate brachytherapy related urethral strictures. J Urol. 2006;175:1376-1380; discussion 1381. 4. Hindson BR, Millar JL, Matheson B. Urethral strictures following high-dose-rate brachytherapy for prostate cancer: analysis of risk factors. Brachytherapy. 2013;12:50-55. 5. Andrich DE, Mundy AR. Urethral strictures and their surgical treatment. BJU Int. 2000;86:571-580. 6. Latini JM. Minimally invasive treatment of urethral strictures in men. Curr Bladder Dysfunct Rep. 2008;3:111-116. 7. Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol. 2007;51:1089-1092; discussion 1092. 8. Vanni AJ, Zinman LN, Buckley JC. Radial urethrotomy and intralesional mitomycin C for the management of recurrent bladder neck contractures. J Urol. 2011;186:156-160. 9. Carr LK, Webster GD. Endoscopic management of the obliterated anastomosis following radical prostatectomy. J Urol. 1996;156: 70-72. 10. Snodgrass RG, Collier AC, Coon AE, Pritsos CA. Mitomycin C inhibits ribosomal RNA: a novel cytotoxic mechanism for bioreductive drugs. J Biol Chem. 2010;285:19068-19075. 11. Ayyildiz A, Nuhoglu B, Gulerkaya B, et al. Effect of intraurethral mitomycin-C on healing and fibrosis in rats with experimentally induced urethral stricture. Int J Urol. 2004;11:1122-1126. 12. Ramirez D, Zhao LC, Bagrodia A, et al. Deep lateral transurethral incisions for recurrent bladder neck contracture: promising 5-year experience using a standardized approach. Urology. 2013;82:14301435. 13. Redshaw JD, Broghammer JA, Smith TG, et al. Intralesional injection of mitomycin C at transurethral incision of bladder neck contracture may offer limited benefit: TURNS Study Group. J Urol. 2014. http://dx.doi.org/10.1016/j.juro.2014.08.104. 14. Tibbs MK. Wound healing following radiation therapy: a review. Radiother Oncol. 1997;42:99-106. 15. Eisenberg ML, Elliott SP, McAninch JW. Preservation of lower urinary tract function in posterior urethral stenosis: Selection of appropriate patients for urethral stents. J Urol. 2007;178:2456-2460; discussion 2460-2461.
UROLOGY 85 (6), 2015
how to effectively use MMC in the treatment of urethral strictures and bladder neck contractures. To better understand the best use of MMC, however, a larger number of patients across multiple institutions with a pre-defined concentration(s) of MMC are necessary.
16. Hofer MD, Zhao LC, Morey AF, et al. Outcomes after urethroplasty for radiotherapy induced bulbomembranous urethral stricture disease. J Urol. 2014;191:1307-1312. 17. Meeks JJ, Brandes SB, Morey AF, et al. Urethroplasty for radiotherapy induced bulbomembranous strictures: a multi-institutional experience. J Urol. 2011;185:1761-1765. 18. Glass AS, McAninch JW, Zaid UB, et al. Urethroplasty after radiation therapy for prostate cancer. Urology. 2012;79:1402-1405. 19. Mundy AR, Andrich DE. Posterior urethral complications of the treatment of prostate cancer. BJU Int. 2012;110:304-325.
Bryan B. Voelzke, M.D., M.S., Department of Urology, Harborview Medical Center at the University of Washington, Seattle, WA
EDITORIAL COMMENT
References
1
The authors present a case series of patients who underwent internal urethrotomy and injection of mitomycin C (MMC) followed by 1 month of once daily intermittent catheterization. The stricture location was heterogeneous, resulting in a range of 0-11 patients per stricture location. Patients were further stratified by radiation history. It is difficult to interpret the success rates because of limited numbers in each stricture location category. Furthermore, prior data have confirmed that success after internal urethrotomy differs based on anatomic location in the urethra.2 As such, I disagree with providing an overall success rate stratified only by radiation presence. Despite these limitations, the data are worthwhile owing to limited data on this topic. Three previous studies have examined the effect of internal urethrotomy with MMC alone.3-5 Contrary to the comments by Levine et al that their study is unique by including patients with previous endoscopic interventions and radiation, 2 previous studies included patients with prior interventions (80%,4 100%5) and radiation. The concentration of MMC instilled differed across all available studies (0.1,3 0.4-10,4 1.2-1.6,5 and 4 mg; Levine et al), preventing optimal outcome comparison. Despite limited numbers and varying concentrations of MMC, it is still interesting to compare the outcomes for any suggestive benefit that 1 month of postsurgical intermittent catheterization might provide. Mazdak et al performed a randomized trial of internal urethrotomy with and without MMC alone for bulbar strictures.3 Their follow-up was only 6 months. Although the follow-up Levine et al study is longer, their success for bulbar nonradiated patients with an additional caveat of 1 month of intermittent catheterization was similar (81.8%, n ¼ 11 vs 80%, n ¼ 203). Lahey clinic examined the effect of internal urethrotomy and MMC for patients with bladder neck contractures alone.5 The majority of patients in the Lahey series were not radiated (16 of 18). Both Levine et al and the Lahey series had limited radiated patients (0 in the study by Klein et al and 2 in the Lahey series) precluding any inferences. Among nonradiated patients, success after the first endoscopic attempt was higher with 1 month of additional intermittent catheterization (80%, 8 of 10 in the study by Levine et al and 69%, 11 of 16 in the Lahey series). Finally, a multi-institutional series of patients with bladder neck contractures undergoing internal urethrotomy and MMC alone noted a lower success rate of 58% after the first attempt of urethrotomy and MMC; however, the success rate increased to 75% after a second attempt.4 The success of radiated bladder neck contractures was better without adjuvant use of 1 month of intermittent catheterization (64%, 9 of 14) in this multi-institutional study; however, the number of urethrotomy or MMC treatments of this select radiated cohort was not disclosed. Overall, the study by Levine et al is important and delivers additional information to improve the existing understanding of UROLOGY 85 (6), 2015
1. Farrell MR, Sherer BA, Levine LA. Visual internal urethrotomy with intralesional mitomycin c and short-term clean intermittent catheterization for the management of recurrent urethral strictures and bladder neck contractures. Urology. 2015;85:1494-1500. 2. Pansadoro V, Emiliozzi P. Internal urethrotomy in the management of anterior urethral strictures: long-term followup. J Urol. 1996;156: 73-75. 3. Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol. 2007;51:1089-1092; discussion 1092. 4. Redshaw JD, Broghammer JA, Smith TG III, et al. Intralesional injection of mitomycin C at transurethral incision of bladder neck contracture may offer limited benefit: TURNS Study Group. J Urol. 2015;193:587-592. 5. Vanni AJ, Zinman LN, Buckley JC. Radial urethrotomy and intralesional mitomycin C for the management of recurrent bladder neck contractures. J Urol. 2011;186:156-160.
http://dx.doi.org/10.1016/j.urology.2015.02.051 UROLOGY 85: 1499, 2015. 2015 Elsevier Inc.
REPLY We appreciate the cautious and supportive remarks by the Editor1 about making conclusions with this difficult-to-treat problem. The goal of this study was to describe our broad experience with this modality in a complex patient population rather than compare outcomes strictly by stricture location or etiology. We acknowledge that the success of visual internal urethrotomy differs by anatomic location of the urethra.2 However, despite our 4-year experience at a large referral center, our power to stratify by stricture location was limited by our sample size. We did stratify by etiology, as our study adds additional information about radiation-induced strictures, which represents a particularly recalcitrant population. Additionally, we recognize that the use of short-term clean intermittent catheterization (CIC) is a confounding variable. However, CIC may provide benefit by maintaining urethral patency during which time mitomycin C (MMC) is given an opportunity to prevent early postoperative fibrosis. It is important to compare outcomes and complications across studies. We agree that this should be done with caution not only due to differences in MMC dosage but also given differing lengths of follow-up and operative techniques. Our investigation had the longest follow-up period, which may have influenced success relative to other reports, as a longer follow-up may capture additional cases of late recurrence (mean, 15 months3; median, 12,4 9.2,5 and 23 months; Levine et al). Additionally, a recent well-conducted multiinstitution study by Redshaw et al used transurethral incision of the bladder neck with MMC using hot or cold knife incisions depending on the institution.5 Three of the 4 complications (7% overall) occurred after hot knife incision 1499
including osteitis pubis, bladder floor necrosis, and rectourethral fistula necessitating cystectomy. In contrast, our study used only cold knife incisions and found no significant complications stemming from the use of MMC at a similar dose (4 mg in the study by Levine et al vs 2-4.5 mg among Redshaw et al complications). It is difficult to compare the effect of MMC concentration on complications and success as concentration ranged from 0.1 to 1.0 mg/mL in the study by Redshaw et al vs 0.4 mg/mL in our study. Whether the complications reported by Redshaw et al were in fact related to incision technique is unclear. Nonetheless, future investigations would be strengthened by a unified MMC dosage and operative technique. The utility of MMC will be best elucidated by larger cohorts with a clearly defined control group. Given the relatively low incidence of urethral stricture disease, single-center studies have been unable to accrue sufficient patients for prospective trials. Larger multi-institutional studies should be better able to stratify by radiation-induced etiology and location. Despite its limitations, our study adds important data to the developing literature regarding the safety and efficacy of visual internal urethrotomy with MMC for both urethral strictures and bladder neck contractures while introducing short-term postoperative CIC. The goal of this approach was to treat a difficult problem that is often times found in patients who are poor operative candidates for definitive open reconstruction.
1500
Michael R. Farrell, M.P.H., Benjamin A. Sherer, M.D., and Laurence A. Levine, M.D., Department of Urology, Rush University Medical Center, Chicago, IL
References 1. Voelzke BB. Visual internal urethrotomy with intralesional mitomycin C and short-term clean intermittent catheterization for the management of recurrent urethral strictures and bladder neck contractures [Editorial Comment]. Urology. 2015;85:1494-1500. 2. Pansadoro V, Emiliozzi P. Internal urethrotomy in the management of anterior urethral strictures: long-term followup. J Urol. 1996;156: 73-75. 3. Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol. 2007;51:1089-1092; discussion 1092. 4. Vanni AJ, Zinman LN, Buckley JC. Radial urethrotomy and intralesional mitomycin C for the management of recurrent bladder neck contractures. J Urol. 2011;186:156-160. 5. Redshaw JD, Broghammer JA, Smith TG, et al. Intralesional injection of mitomycin C at transurethral incision of bladder neck contracture may offer limited benefit: TURNS Study Group. J Urol. 2014. http://dx.doi.org/10.1016/j.juro.2014.08.104.
http://dx.doi.org/10.1016/j.urology.2015.02.052 UROLOGY 85: 1499e1500, 2015. 2015 Elsevier Inc.
UROLOGY 85 (6), 2015
MATERIALS AND METHODS
RESULTS
CONCLUSION
To evaluate our longitudinal experience using visual internal urethrotomy (VIU) with intralesional mitomycin C (MMC) and short-term clean intermittent catheterization (CIC) for urethral strictures and bladder neck contractures (BNC) after failure of endoscopic management. This case series involved review of our prospectively developed database of all men who underwent VIU with MMC and CIC in a standardized fashion for urethral stricture or BNC between 2010 and 2013 at our tertiary care medical center. Etiology was identified as radiationinduced stricture (RIS) or non-RIS and analyzed by stricture location. Cold knife incisions were made in a tri or quadrant fashion followed by intralesional injection of MMC and 1 month of once daily CIC. All 37 patients previously underwent at least 1 intervention for urethral stricture or BNC before VIU with MMC and CIC. Mean stricture length was 2.0 cm (range, 1-6 cm; standard deviation, 1.0 cm). Over the median follow-up period of 23 months (range, 12-39 months), 75.7% of patients required no additional surgical intervention (RIS, 54.5%; non-RIS, 84.6%; P ¼ .051). In those that did recur, median time to stricture recurrence was 8 months (range, 2-28 months). One patient with recurrence required urethroplasty. VIU with MMC followed by short-term CIC provides a minimally invasive and widely available tool to manage complex recurrent urethral strictures (<3 cm) and BNC without significant morbidity. This approach may be most attractive for patients who are poor candidates for open surgery. UROLOGY 85: 1494e1500, 2015. 2015 Elsevier Inc.
U
rethral strictures arise from a process of fibrosis within the urethral mucosa that can be initiated by a variety of insults. Although urethral strictures may be idiopathic, many are iatrogenic and result from a history of urethral catheterization, cystoscopy, transurethral resection of the prostate, prostatectomy, prostate radiation therapy, or hypospadias repair. Other notable causes of urethral strictures include pelvic trauma, urethritis, and lichen sclerosus.1
Financial Disclosure: Laurence A. Levine is a speaker in AbbVie, officer in Absorption Pharmaceuticals, consultant and speaker in American Medical Systems, Auxilium, and Coloplast, and also an investigator in Auxilium. The remaining authors declare that they have no relevant financial interests. From the Department of Urology, Rush University Medical Center, Chicago, IL Address correspondence to: Laurence A. Levine, M.D., Department of Urology, Rush University Medical Center, 1725 West Harrison Street, Suite 352, Chicago, IL 60612. E-mail: [email protected] Submitted: November 3, 2014, accepted (with revisions): February 13, 2015
1494
ª 2015 Elsevier Inc. All Rights Reserved
Radiation-induced urethral strictures (RIS) are uncommon, but when they do occur, they are often complex and traditionally have been difficult to manage. Previous investigation of stricture occurrence after radiation therapy for prostate cancer has been described with a reported incidence of 1.8% after brachytherapy, 1.7% after external beam radiotherapy (EBRT), and 5.2% after combination radiation therapy.2 Additional studies report urethral stricture development in 2.4%-8.2% of patients after prostate brachytherapy, which typically occur at the bulbomembranous urethra or the bladder neck.3,4 Multiple modalities are available for the treatment of urethral strictures including self-catheterization, urethral dilation, laser incision, urethral stent placement, visual internal urethrotomy (VIU), and open repair. Endoscopic internal urethrotomy has been promoted as the standard initial treatment for bulbar urethral strictures.5 However, after a http://dx.doi.org/10.1016/j.urology.2015.02.050 0090-4295/15
single VIU, the long-term cure rates for noneradiationassociated strictures are as low as 30%-40%.6 In an effort to decrease the rate of urethral stricture recurrence after VIU, supplemental injection of mitomycin C (MMC) has been proposed owing to its ability to mitigate scar formation via inhibition of fibroblast proliferation.7,8 In the present study, we aim to describe a safe and widely available endoscopic alternative to open surgical reconstruction that is more durable than VIU alone in patients with recalcitrant urethral strictures and bladder neck contractures (BNC) of various etiologies. We propose that VIU with MMC and short-term clean intermittent catheterization (CIC) may be a particularly attractive option for patients who are not candidates for definitive open urethroplasty. Although previous studies of VIU with MMC focused specifically on anterior urethral strictures or BNC with a small population undergoing radiation therapy, we include all stricture loci in one of the largest reported cohorts with the longest postoperative follow-up to date.7,8 Furthermore, given the unique and traditionally problematic nature of strictures owing to radiation, we compare our findings from RIS with nonradiation etiologies.
MATERIALS AND METHODS This study was designed as a case series involving review of a prospectively developed database of all men presenting for reconstructive urethral surgery between 2010 and 2013 to our tertiary care medical center. Men included in this study had symptoms of urinary obstruction, had urethral stricture or BNC confirmed via office cystoscopy, and were poor surgical candidates for open surgery or refused open repair. Selected patients subsequently underwent VIU with MMC followed by a short period of CIC. Retrospective analysis was conducted, and complete data were available for all included subjects. Informed consent was obtained from all subjects in this study at the time of initial patient visit. Patient demographic data included age, history of prior stricture interventions, and stricture etiology. Stricture length was determined by retrograde urethrogram and/or intraoperatively under direct vision based on the length of the cold knife incision of the stricture. Preoperative postvoid residual (PVR), uroflow, and any history of incontinence were recorded. We further analyzed this database to identify stricture etiology as radiation vs noneradiation induced. The RIS group included patients with a history of prostate EBRT and/or brachytherapy. Non-RIS were analyzed as all other stricture etiologies. Cystourethroscopy with a 22F rigid cystoscope was performed to allow for passage of a wire through the stricture site and into the urinary bladder. Direct VIU with cold knife incisions of the scar was made at the 12-, 3-, and 9-o’clock positions through the full thickness of the scar down to the level of healthy-appearing underlying tissue, if possible. Cold knife incisions at the 6-o’clock position were also performed when the bladder neck alone was involved. Using sharp cold knife incisions, we are able to directly visualize the change in tissue character from fibrosis to vascularized underlying tissue regardless of stricture location. Strictures with greater depth required a deeper incision down to the healthy-appearing tissue. This was followed by multiple UROLOGY 85 (6), 2015
injections of 0.4-mg/mL MMC in 0.2- to 0.4-mL aliquots at various points along the length of each incision for a total volume of 10 mL using a 23F Wolf (Vernon Hills, IL) injection or aspiration scope and a standard injection needle. Patients were routinely discharged the same day with a 16-18F silastic Foley catheter, which was subsequently removed in the office in 5-7 days. CIC was performed by the patient once daily with a 16F straight or coude catheter after removal of the Foley catheter that was placed at the time of surgery.9 Longitudinal follow-up data were collected to investigate the relationship between stricture etiology and the success rate of VIU with MMC. Postoperative evaluation at 1, 3, 6, and 12 months, followed by further evaluation at 6-month intervals, thereafter, included urethral patency via cystoscopy, PVR, uroflowometry, and stricture recurrence requiring reoperation. Stricture recurrence was defined as the inability to pass a 16F flexible cystoscope through the stricture site. Data analysis was conducted using PASW Statistics 18 software (SPSS, Inc., Chicago, IL). Continuous variables were reported as mean and standard deviation, with analyses conducted via a 2-sample t test. For continuous variables that did not follow a normal distribution, median and range were reported, with analysis conducted using a Mann-Whitney U test. Categorical data were shown as counts and percentages. Associations across categorical independent variables were evaluated using the Pearson chi-square univariate analysis. For all analyses, variables are considered significant predictors if the P value associated with the appropriate test statistic is <.05.
RESULTS Thirty-seven patients underwent VIU with MMC and CIC for refractory urethral strictures and BNC. Stricture location included 5 pendulous, 15 bulbar, 6 posterior urethral stricture, and 11 BNC. There were no statistical differences in patient age, stricture length, and number of procedures before VIU with MMC and CIC when analyzed by stricture location (P >.05; Table 1). Urethral stricture etiology was attributed to radiation in 11 patients, whereas 26 non-RIS patients were identified. Among RIS patients, 81.8% (n ¼ 9) previously underwent brachytherapy alone and 18.2% (n ¼ 2) had a history of both brachytherapy and EBRT. The most common stricture etiology among the non-RIS cohort was previous urethral instrumentation (34.6%) followed by radical prostatectomy (26.9%), infection (11.5%), hypospadias requiring pediatric repair (11.5%), idiopathic (11.5%), and external trauma to the urethra (7.7%). There were no differences in stricture length between RIS and non-RIS patients; however, RIS were subjectively noted to have deeper, full thickness spongiofibrosis (Table 1). The mean age of men undergoing VIU with MMC was 59 years (range, 22-80 years). All patients had at least 1 failed intervention for urethral stricture before VIU with MMC and CIC (range, 1-6). The 22-year-old patient had recurrent strictures after previous repair of a urethral distraction injury that was associated with a pelvic fracture. As such, he had previously undergone and failed urethroplasty and subsequently preferred VIU with MMC. Overall, 29.7% patients (n ¼ 11) failed previous 1495
Table 1. Baseline characteristics of patients undergoing VIU with MMC and CIC including analysis by stricture etiology Overall (N ¼ 37) Stricture location, n (%) Pendulous Bulbar Membranous Bladder neck Age, mean (SD), y Number of previous procedures, mean (SD) Stricture length, mean (SD; range), cm
5 15 6 11 59.0 2.7 2.0
(13.5) (40.5) (16.2) (29.7) (14.8) (1.6) (1.0; 1-6)
RIS (N ¼ 11) 0 4 6 1 65.9 1.5 2.1
(0) (36.6) (54.5) (9.1) (7.9) (1.4) (0.4; 2.0-3.0)
Non-RIS (N ¼ 26) 5 11 0 10 56.1 2.6 1.96
(19.2) (42.3) (0) (38.5) (16.1) (1.6) (1.1; 1.0-6.0)
P Value
.064 .079 .651
CIC, clean intermittent catheterization; MMC, mitomycin C; RIS, radiation-induced stricture; SD, standard deviation; VIU, visual internal urethrotomy.
Table 2. Postoperative outcomes for patients undergoing VIU with MMC and CIC independent of success including analysis by stricture etiology Overall (N ¼ 37) Operative time, mean (SD), min Postoperative complication, n (%) Preoperative, mean (SD) Uroflow (mL/s) PVR (mL) Postoperative, mean (SD) Uroflow (mL/s) PVR (mL)
36.7 (11.4) 5 (13.5)
RIS (N ¼ 11) 40 (13.9) 0
Non-RIS (N ¼ 26)
P Value
35.2 (10.1) 5 (19.2)
.252 .295
9.5 (4.9) 112.3 (103.0)
8.2 (8.2) 122.2 (113.7)
10.1 (3.1) 106.7 (99.6)
.492 .711
15.3 (8.2) 54.5 (91.6)
18.4 (12.2) 105.7 (169.4)
14.6 (7.1) 37.4 (38.7)
.359 .088
PVR, postvoid residual; other abbreviations as in Table 1.
urethroplasty. Patients with RIS and non-RIS underwent a similar number of previous procedures before MMC with VIU and CIC (Table 1). Overall, the median length of time from previous intervention to VIU with MMC was 7 months (range, 1-120 months). A surgical complication was noted in 13.5% of patients overall, with complications occurring solely in the nonRIS cohort (Table 2). Postoperative complications included one of each of the following: erectile dysfunction, acute renal failure, hematuria requiring transfusion in a patient with baseline anemia, laryngospasm as a complication of anesthesia (Clavien grade II), and persistent hematuria requiring admission for continuous bladder irrigation with subsequent resolution after endoscopic intervention (Clavien grade IIIb). Postoperative follow-up was obtained for a median of 23 months overall (range, 12-39 months). RIS patients were followed up for a median of 28 months (range, 15-39 months). Median follow-up was 21 months (range, 12-38 months) for non-RIS. Postoperative uroflow and PVR measurements were not different between RIS and non-RIS patients as measured at the longest point of follow-up and did not differ by stricture location (P >.05; Table 2). There was a significant increase in the maximum uroflow rate (Qmax) after VIU with MMC in the non-RIS cohort (P ¼ .049). Additionally, PVR decreased significantly after VIU with MMC in the non-RIS cohort (P ¼ .006). There was no significant improvement in the postoperative Qmax or significant decrease in the postoperative PVR for the RIS cohort (Qmax P ¼ .158; PVR P ¼ .813; Table 2). Overall, success of VIU with MMC and CIC without the need for additional therapy occurred in 75.7% of the study 1496
population as a whole over the follow-up period. Recurrence-free success of VIU with MMC and CIC was not statistically different between RIS and non-RIS patients (RIS 54.5% vs 84.6% non-RIS; P ¼ .051). In those that did recur (n ¼ 9, 24.3%), median time to recurrence was 8 months (range, 2-28 months). When analyzed by etiology, RIS recurred at a median of 13 months (range, 3-28 months), whereas non-RIS recurred at a median of 7 months (range, 2-12 months; P >.05). Recurrence-free success is shown by location of stricture or BNC in Table 3. Of the 9 patients who experienced recurrence, only 1 patient with a non-RIS of the bulbar urethra subsequently required urethroplasty with a ventral buccal mucosal graft. There was no change in stricture length for this patient at the time of MMC with VIU and on recurrence (2 cm). One patient with a bulbar stricture and 1 patient with a BNC underwent a second VIU with MMC and CIC with successful maintenance of urethral patency over the 31 and 6 months of subsequent follow-up, respectively. The remaining recurrences were managed by transurethral resection (TUR) with MMC (n ¼ 1), TUR without MMC (n ¼ 1), VIU without MMC (n ¼ 2), and transurethral resection of the bladder neck (TURBN) (n ¼ 1). There were 8 patients (21.6% overall, 9.1% RIS, and 16.9% non-RIS) with pre-existing incontinence that was successfully managed with artificial urinary sphincter placement after VIU with MMC and CIC at a mean of 6 months postoperatively (range, 3-14 months).
COMMENT We describe the presenting characteristics and outcome variables including stricture recurrence among patients UROLOGY 85 (6), 2015
Table 3. Recurrence free success after VIU with MMC and CIC over the study period by stricture location Recurrence-free Success, n (%) Location
RIS
Non-RIS
Overall
Pendulous 0/0 5/5 (100) 5/5 (100) Bulbar 3/4 (75.0) 9/11 (81.8) 12/15 (80.0) Membranous 3/6 (50.0) 0/0 3/6 (50.0) BNC 0/1 (0) 8/10 (80.0) 8/11 (72.7) Overall 6/11 (54.5) 22/26 (84.6) 28/37 (75.8) BNC, bladder neck contractures; other abbreviation as in Table 1.
undergoing VIU with MMC and short-term CIC for the management of recurrent urethral strictures and BNC of various etiologies. The mechanism of MMC involves inhibition of scar formation by impeding fibroblast proliferation. In vitro investigations demonstrate that MMC decreases 18S ribosomal ribonucleic acid transcript levels with correlated in vivo studies identifying inhibited protein translation.10 In relation to specific urologic applications of MMC, in vivo rat studies have shown that MMC injected into the injured urethra resulted in a decrease in hemosiderin-laden macrophages, mononuclear cell infiltration, and fibrosis in a dose-dependent manner.11 In humans, Mazdak et al7 identified stricture recurrence at 6 months in 2 patients (10%) undergoing VIU with MMC for non-RIS anterior urethral strictures vs 10 patients (50%) treated with VIU alone. Further study by Vanni et al8 involving 18 patients treated with VIU and MMC for BNC after radical prostatectomy established patency in 72% of patients after a single procedure and 89% after 2 procedures over a 12-month period. Other studies have evaluated the utility of deep transurethral incisions without MMC for the treatment of noneradiation-induced recurrent BNC, reporting that 72% of patients did not require additional surgeries over nearly a 13-month follow-up period.12 A recent multicenter study provided the largest cohort to date of 55 men with BNC undergoing VIU with MMC.13 They reported that 58% of patients achieved a stable bladder neck at a median follow-up of 9.2 months with no difference in stricture-free success when analyzed by radiation (n ¼ 14) vs noneradiation-induced etiologies (n ¼ 41). Maintenance of bladder neck patency using VIU with MMC was notably less than in our study as well as data previously reported by Vanni et al despite a shorter median follow-up period.8 Perhaps, the difference in success as compared with our study is in part attributable to the short course of postoperative CIC. Additionally, median time to recurrence was 3.7 vs 8 months in our cohort. Importantly, Redshaw et al noted serious adverse events in 7% of patients including 2 cases of osteitis pubis and 1 case of rectourethral fistula and bladder floor necrosis, all of which required cystectomy and urinary diversion.13 The total dose of MMC was 4 mg in 3 of these 4 patients; therefore, it was speculated that greater UROLOGY 85 (6), 2015
MMC doses may have contributed to such events. However, in our experience, we report no such serious adverse events with the use of 0.4 mg/mL of MMC and a total dose of 4 mg. In contrast to several previous studies, we used cold rather than hot knife incisions.12,13 Clearly the goal was to incise down to the level of healthy appearing vascularized tissue, which is more readily accomplished in non-RIS. We prefer using cold knife, as we feel it is easier to delineate this border, although the hot knife will usually cut through RIS more readily. In the present study, we report an overall success of 75.7% over a median follow-up period of 23 months after a single VIU with MMC and CIC; thus, our success is similar to those previously reported by Mazdak et al and Vanni et al.7,8 Similar to these reports, our experience is applicable to shorter length strictures with an overall mean stricture length of 2.0 cm (standard deviation ¼ 1.0 cm; range ¼ 1-6 cm). However, it is notable that our study included only patients who failed prior treatment, as well as patients with radiation-induced etiologies, thus adding to the difficulty in preventing stricture recurrence. These patients had a longer median postoperative followup of 23 months compared with that of previous studies by Mazdak et al, Vanni et al, and Redshaw et al, providing further support for longer term success.7,8,13 Our results are inclusive of all stricture locations and BNC, suggesting that VIU with MMC and CIC may be applied to anterior and posterior urethral strictures along with BNC to reduce stricture recurrence over a median follow-up period of nearly 2 years. It should be noted that patients with anterior strictures performed a trial of endoscopic intervention or had comorbidities that made them suboptimal candidates for open urethroplasty, as we believe that urethroplasty remains the gold standard for repair of anterior strictures in appropriate candidates. Short-term CIC was integrated into our protocol after VIU with MMC to allow the antifibrotic effect of MMC to stabilize the tissue in its patent state, thereby encouraging a prolonged effect. The authors acknowledge that adding short-term CIC adds a confounding variable; however, our goal was to optimize outcomes even with a multimodal approach. Subsequent larger trials could randomize patients to undergo VIU and MMC with or without short-term CIC. We further aimed to investigate outcomes according to stricture etiology. RIS are of particular interest, as radiation elicits a notably dense scar, not only due to damage of the urethral tissue but also secondary to compromised wound healing. Radiation induces vascular changes while also altering fibroblast function resulting in a particularly recalcitrant scar.14 Management of RIS, therefore, has traditionally been difficult. Eisenburg et al used urethral stents for RIS in an attempt to minimize the morbidity associated with urethral reconstruction in patients with RIS and noted stricture recurrence in 42% of patients.15 Additional studies have investigated the utility of open urethroplasty specifically for RIS, reporting stricture-free success in 1497
71%, 73%, and 90% at 10, 21, and 40 months follow-up, respectively.16-18 Our study identified stricture-free success in 54.5% of the RIS cohort over a mean follow-up period of 18 months. It is necessary to consider individual patient fitness when selecting the surgical approach to stricture repair, as VIU with MMC and CIC is far less invasive. The majority of our patients with advanced recurrent RIS were not good reconstruction candidates because of additional comorbidities. Mundy and Andrich have suggested that radiation-associated bladder dysfunction limits the utility of reconstructive surgery.19 Importantly, in this series, patients with RIS did not fare statistically different with respect to recurrence when compared with non-RIS patients, although it is likely that a larger study population would demonstrate higher stricture recurrence in the RIS group. Postoperative parameters including uroflow and PVR were not significantly different between RIS and nonRIS. However, significant postoperative improvement in uroflow and PVR was found in non-RIS patients alone. Although both RIS and non-RIS may be effectively managed with VIU plus MMC and CIC, the greater postoperative improvement seen with non-RIS is likely attributable to the more severe and increased depth of fibrosis in the RIS patients. Among the RIS patient population, fibrosis is typically full thickness and frequently extends well beyond the depth of the VIU. In addition, measurement of uroflow and PVR was less meaningful among RIS patients as many had preoperative urinary incontinence. Although our study represents 3 years of operative experience, our findings may be limited by our sample size of 37. Our analysis does not include a true control arm in which MMC or CIC was not used. However, all patients had undergone at least 1 previous failed attempt of stricture treatment without MMC before entering this study (with a median recurrence <7 months after previous intervention). Other potential limitations include the retrospective nature of the study and the representative experience of a single tertiary medical center that may reflect more severe and complex disease processes. Although the total number of patients with penile strictures was limited, we did have the highest success rates in this group as all 5 patients had success at 23 months median follow-up. A larger sample size of pendulous strictures would be useful to confirm reliable success in this population. Stricture location is a possible confounder as there may be differences in outcomes by location. Our statistical power to detect differences in recurrence by stricture location was limited by our sample size. We do not offer VIU with MMC for strictures caused by lichen sclerosus. Rather, we recommend definitive 1or 2-stage open repair, as this is most likely to be successful. For scenarios in which dilation, urethroplasty, and transurethral resection alone have been unsuccessful at establishing urethral patency, our study provides evidence for the utility of transurethral incision of the tissue focally 1498
followed by injection of MMC and a short course of postoperative CIC in patients with either RIS or non-RIS particularly of shorter length (<3 cm) at all urethral locations, as well as the bladder neck. Although we recognize that longer strictures are more likely to fail, there may be circumstances that should be elucidated by further experience in which this evolving procedure may be used. Additional experience with larger cohorts, longer follow-up, and randomization to VIU and MMC with or without CIC are needed to further validate our findings.
CONCLUSION VIU with MMC followed by a short period of CIC provides a minimally invasive and widely available tool to manage complex, recurrent, relatively short (<3 cm) urethral strictures and BNC by obviating or temporizing the need for open surgical reconstruction without significant morbidity. References 1. Lumen N, Hoebeke P, Willemsen P, et al. Etiology of urethral stricture disease in the 21st century. J Urol. 2009;182:983-987. 2. Elliott SP, Meng MV, Elkin EP, et al. Incidence of urethral stricture after primary treatment for prostate cancer: data from CaPSURE. J Urol. 2007;178:529-534; discussion 534. 3. Merrick GS, Butler WM, Wallner KE, et al. Risk factors for the development of prostate brachytherapy related urethral strictures. J Urol. 2006;175:1376-1380; discussion 1381. 4. Hindson BR, Millar JL, Matheson B. Urethral strictures following high-dose-rate brachytherapy for prostate cancer: analysis of risk factors. Brachytherapy. 2013;12:50-55. 5. Andrich DE, Mundy AR. Urethral strictures and their surgical treatment. BJU Int. 2000;86:571-580. 6. Latini JM. Minimally invasive treatment of urethral strictures in men. Curr Bladder Dysfunct Rep. 2008;3:111-116. 7. Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol. 2007;51:1089-1092; discussion 1092. 8. Vanni AJ, Zinman LN, Buckley JC. Radial urethrotomy and intralesional mitomycin C for the management of recurrent bladder neck contractures. J Urol. 2011;186:156-160. 9. Carr LK, Webster GD. Endoscopic management of the obliterated anastomosis following radical prostatectomy. J Urol. 1996;156: 70-72. 10. Snodgrass RG, Collier AC, Coon AE, Pritsos CA. Mitomycin C inhibits ribosomal RNA: a novel cytotoxic mechanism for bioreductive drugs. J Biol Chem. 2010;285:19068-19075. 11. Ayyildiz A, Nuhoglu B, Gulerkaya B, et al. Effect of intraurethral mitomycin-C on healing and fibrosis in rats with experimentally induced urethral stricture. Int J Urol. 2004;11:1122-1126. 12. Ramirez D, Zhao LC, Bagrodia A, et al. Deep lateral transurethral incisions for recurrent bladder neck contracture: promising 5-year experience using a standardized approach. Urology. 2013;82:14301435. 13. Redshaw JD, Broghammer JA, Smith TG, et al. Intralesional injection of mitomycin C at transurethral incision of bladder neck contracture may offer limited benefit: TURNS Study Group. J Urol. 2014. http://dx.doi.org/10.1016/j.juro.2014.08.104. 14. Tibbs MK. Wound healing following radiation therapy: a review. Radiother Oncol. 1997;42:99-106. 15. Eisenberg ML, Elliott SP, McAninch JW. Preservation of lower urinary tract function in posterior urethral stenosis: Selection of appropriate patients for urethral stents. J Urol. 2007;178:2456-2460; discussion 2460-2461.
UROLOGY 85 (6), 2015
how to effectively use MMC in the treatment of urethral strictures and bladder neck contractures. To better understand the best use of MMC, however, a larger number of patients across multiple institutions with a pre-defined concentration(s) of MMC are necessary.
16. Hofer MD, Zhao LC, Morey AF, et al. Outcomes after urethroplasty for radiotherapy induced bulbomembranous urethral stricture disease. J Urol. 2014;191:1307-1312. 17. Meeks JJ, Brandes SB, Morey AF, et al. Urethroplasty for radiotherapy induced bulbomembranous strictures: a multi-institutional experience. J Urol. 2011;185:1761-1765. 18. Glass AS, McAninch JW, Zaid UB, et al. Urethroplasty after radiation therapy for prostate cancer. Urology. 2012;79:1402-1405. 19. Mundy AR, Andrich DE. Posterior urethral complications of the treatment of prostate cancer. BJU Int. 2012;110:304-325.
Bryan B. Voelzke, M.D., M.S., Department of Urology, Harborview Medical Center at the University of Washington, Seattle, WA
EDITORIAL COMMENT
References
1
The authors present a case series of patients who underwent internal urethrotomy and injection of mitomycin C (MMC) followed by 1 month of once daily intermittent catheterization. The stricture location was heterogeneous, resulting in a range of 0-11 patients per stricture location. Patients were further stratified by radiation history. It is difficult to interpret the success rates because of limited numbers in each stricture location category. Furthermore, prior data have confirmed that success after internal urethrotomy differs based on anatomic location in the urethra.2 As such, I disagree with providing an overall success rate stratified only by radiation presence. Despite these limitations, the data are worthwhile owing to limited data on this topic. Three previous studies have examined the effect of internal urethrotomy with MMC alone.3-5 Contrary to the comments by Levine et al that their study is unique by including patients with previous endoscopic interventions and radiation, 2 previous studies included patients with prior interventions (80%,4 100%5) and radiation. The concentration of MMC instilled differed across all available studies (0.1,3 0.4-10,4 1.2-1.6,5 and 4 mg; Levine et al), preventing optimal outcome comparison. Despite limited numbers and varying concentrations of MMC, it is still interesting to compare the outcomes for any suggestive benefit that 1 month of postsurgical intermittent catheterization might provide. Mazdak et al performed a randomized trial of internal urethrotomy with and without MMC alone for bulbar strictures.3 Their follow-up was only 6 months. Although the follow-up Levine et al study is longer, their success for bulbar nonradiated patients with an additional caveat of 1 month of intermittent catheterization was similar (81.8%, n ¼ 11 vs 80%, n ¼ 203). Lahey clinic examined the effect of internal urethrotomy and MMC for patients with bladder neck contractures alone.5 The majority of patients in the Lahey series were not radiated (16 of 18). Both Levine et al and the Lahey series had limited radiated patients (0 in the study by Klein et al and 2 in the Lahey series) precluding any inferences. Among nonradiated patients, success after the first endoscopic attempt was higher with 1 month of additional intermittent catheterization (80%, 8 of 10 in the study by Levine et al and 69%, 11 of 16 in the Lahey series). Finally, a multi-institutional series of patients with bladder neck contractures undergoing internal urethrotomy and MMC alone noted a lower success rate of 58% after the first attempt of urethrotomy and MMC; however, the success rate increased to 75% after a second attempt.4 The success of radiated bladder neck contractures was better without adjuvant use of 1 month of intermittent catheterization (64%, 9 of 14) in this multi-institutional study; however, the number of urethrotomy or MMC treatments of this select radiated cohort was not disclosed. Overall, the study by Levine et al is important and delivers additional information to improve the existing understanding of UROLOGY 85 (6), 2015
1. Farrell MR, Sherer BA, Levine LA. Visual internal urethrotomy with intralesional mitomycin c and short-term clean intermittent catheterization for the management of recurrent urethral strictures and bladder neck contractures. Urology. 2015;85:1494-1500. 2. Pansadoro V, Emiliozzi P. Internal urethrotomy in the management of anterior urethral strictures: long-term followup. J Urol. 1996;156: 73-75. 3. Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol. 2007;51:1089-1092; discussion 1092. 4. Redshaw JD, Broghammer JA, Smith TG III, et al. Intralesional injection of mitomycin C at transurethral incision of bladder neck contracture may offer limited benefit: TURNS Study Group. J Urol. 2015;193:587-592. 5. Vanni AJ, Zinman LN, Buckley JC. Radial urethrotomy and intralesional mitomycin C for the management of recurrent bladder neck contractures. J Urol. 2011;186:156-160.
http://dx.doi.org/10.1016/j.urology.2015.02.051 UROLOGY 85: 1499, 2015. 2015 Elsevier Inc.
REPLY We appreciate the cautious and supportive remarks by the Editor1 about making conclusions with this difficult-to-treat problem. The goal of this study was to describe our broad experience with this modality in a complex patient population rather than compare outcomes strictly by stricture location or etiology. We acknowledge that the success of visual internal urethrotomy differs by anatomic location of the urethra.2 However, despite our 4-year experience at a large referral center, our power to stratify by stricture location was limited by our sample size. We did stratify by etiology, as our study adds additional information about radiation-induced strictures, which represents a particularly recalcitrant population. Additionally, we recognize that the use of short-term clean intermittent catheterization (CIC) is a confounding variable. However, CIC may provide benefit by maintaining urethral patency during which time mitomycin C (MMC) is given an opportunity to prevent early postoperative fibrosis. It is important to compare outcomes and complications across studies. We agree that this should be done with caution not only due to differences in MMC dosage but also given differing lengths of follow-up and operative techniques. Our investigation had the longest follow-up period, which may have influenced success relative to other reports, as a longer follow-up may capture additional cases of late recurrence (mean, 15 months3; median, 12,4 9.2,5 and 23 months; Levine et al). Additionally, a recent well-conducted multiinstitution study by Redshaw et al used transurethral incision of the bladder neck with MMC using hot or cold knife incisions depending on the institution.5 Three of the 4 complications (7% overall) occurred after hot knife incision 1499
including osteitis pubis, bladder floor necrosis, and rectourethral fistula necessitating cystectomy. In contrast, our study used only cold knife incisions and found no significant complications stemming from the use of MMC at a similar dose (4 mg in the study by Levine et al vs 2-4.5 mg among Redshaw et al complications). It is difficult to compare the effect of MMC concentration on complications and success as concentration ranged from 0.1 to 1.0 mg/mL in the study by Redshaw et al vs 0.4 mg/mL in our study. Whether the complications reported by Redshaw et al were in fact related to incision technique is unclear. Nonetheless, future investigations would be strengthened by a unified MMC dosage and operative technique. The utility of MMC will be best elucidated by larger cohorts with a clearly defined control group. Given the relatively low incidence of urethral stricture disease, single-center studies have been unable to accrue sufficient patients for prospective trials. Larger multi-institutional studies should be better able to stratify by radiation-induced etiology and location. Despite its limitations, our study adds important data to the developing literature regarding the safety and efficacy of visual internal urethrotomy with MMC for both urethral strictures and bladder neck contractures while introducing short-term postoperative CIC. The goal of this approach was to treat a difficult problem that is often times found in patients who are poor operative candidates for definitive open reconstruction.
1500
Michael R. Farrell, M.P.H., Benjamin A. Sherer, M.D., and Laurence A. Levine, M.D., Department of Urology, Rush University Medical Center, Chicago, IL
References 1. Voelzke BB. Visual internal urethrotomy with intralesional mitomycin C and short-term clean intermittent catheterization for the management of recurrent urethral strictures and bladder neck contractures [Editorial Comment]. Urology. 2015;85:1494-1500. 2. Pansadoro V, Emiliozzi P. Internal urethrotomy in the management of anterior urethral strictures: long-term followup. J Urol. 1996;156: 73-75. 3. Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol. 2007;51:1089-1092; discussion 1092. 4. Vanni AJ, Zinman LN, Buckley JC. Radial urethrotomy and intralesional mitomycin C for the management of recurrent bladder neck contractures. J Urol. 2011;186:156-160. 5. Redshaw JD, Broghammer JA, Smith TG, et al. Intralesional injection of mitomycin C at transurethral incision of bladder neck contracture may offer limited benefit: TURNS Study Group. J Urol. 2014. http://dx.doi.org/10.1016/j.juro.2014.08.104.
http://dx.doi.org/10.1016/j.urology.2015.02.052 UROLOGY 85: 1499e1500, 2015. 2015 Elsevier Inc.
UROLOGY 85 (6), 2015