- Email: [email protected]
Internal Urethrotomy With Intralesional Mitomycin C: An Effective Option for Endoscopic Management of Recurrent Bulbar and Bulbomembranous Urethral Strictures
Accepted Manuscript Title: Internal Urethrotomy with Intralesional Mitomycin C: an Effective Option for Endoscopic Management of Recurrent Bulbar and Bulbomembranous Urethral Strictures Author: M. Ryan Farrell, Cedric Lawrenz, Laurence A. Levine PII: DOI: Reference:
S0090-4295(17)30755-0 http://dx.doi.org/doi: 10.1016/j.urology.2017.07.017 URL 20563
To appear in:
Urology
Received date: Accepted date:
3-5-2017 13-7-2017
Please cite this article as: M. Ryan Farrell, Cedric Lawrenz, Laurence A. Levine, Internal Urethrotomy with Intralesional Mitomycin C: an Effective Option for Endoscopic Management of Recurrent Bulbar and Bulbomembranous Urethral Strictures, Urology (2017), http://dx.doi.org/doi: 10.1016/j.urology.2017.07.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Internal Urethrotomy with Intralesional Mitomycin C: An Effective Option for Endoscopic Management of Recurrent Bulbar and Bulbomembranous Urethral Strictures
M. Ryan Farrell MD, MPH; Cedric Lawrenz BS; Laurence A. Levine, MD Department of Urology, Rush University Medical Center, Chicago, IL, USA
Corresponding Author: M. Ryan Farrell, MD, MPH Rush University Medical Center, Department of Urology 1725 West Harrison Street, Suite 348 Chicago, Illinois, United States, 60612 Email: [email protected] Phone: 312-942-6447
Keywords: urethral stricture; mitomycin; endoscopy; radiation; minimally invasive surgical procedure
Financial disclosures: M. Ryan Farrell and Cedric Lawrenz have no financial disclosures. Laurence Levine is a paid consultant for Absorption Pharmaceuticals, Endo, Boston Scientific and Coloplast; Speaker for Abbvie; all listed disclosures are outside the submitted work.
Abstract: Objective: To describe our experience with direct visual internal urethrotomy (DVIU) and mitomycin C (MMC) for recurrent bulbar/bulbomembranous urethral strictures of radiation and non-radiation induced etiologies.
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Methods: We reviewed our database of consecutive patients presenting to our tertiary care institution with recurrent bulbar/bulbomembranous urethral strictures who underwent DVIU with MMC from 2011-2016. Patients were stratified by radiation-induced strictures (RIS) versus non-RIS. Cold-knife incisions were made at 12-,3-,and 9-o’clock positions followed by intralesional injection of 10 mL MMC (0.4mg/mL) in 0.2-0.4 mL aliquots and 1 month of postoperative daily clean intermittent catheterization (CIC).
Results: All 44 patients (RIS n=18, non-RIS n=26) failed prior endoscopic management or urethroplasty. Median stricture length was 2.0 cm (Interquartile range (IQR) 1.0-2.5). Over a median follow-up of 25.8 months (IQR 12.9- 47.2), 75.0% (33/44) of patients required no additional surgical intervention (RIS 12/18, 66.7%; non-RIS 21/26, 80.8%). Median time to stricture recurrence among those who recurred was 10.7 months (IQR 3.9-17.6; RIS 9.4 months, IQR 3.5-17.6; non-RIS 11.2 months, IQR 8.0-25.6). Four patients (RIS n=2, non-RIS n=2) elected to undergo urethroplasty for recurrence. A second DVIU with MMC was performed in the remaining recurrences (n=7) with no further surgical intervention required in 92.5% (37/40) of patients overall (RIS 14/16, 87.5%; non-RIS 23/24, 95.8%). No long-term complications were attributable to MMC.
Conclusions: DVIU with MMC and short-term CIC for recurrent, short, bulbar/bulbomembranous urethral strictures is a safe endoscopic modality with promising early results. This
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approach may be useful for patients who are suboptimal candidates for open reconstruction.
Introduction Urethral stricture disease is a common condition of urethral fibrosis, which in the United States accounts for thousands of hospital visits, tens of thousands of ambulatory surgeries, and a three-fold increase in annual health care expenditures relative to men without urethral strictures.1 For a subpopulation of patients with particularly recalcitrant disease, especially those with radiation induced strictures (RIS), urethral strictures can present a management challenge.
Direct visual internal urethrotomy (DVIU) has been recommended as the initial approach for bulbar urethral strictures.2 However, the long-term recurrence free rates are as low as 30-40%.3 As a result, the antifibrotic agent mitomycin C (MMC) has been studied as a supplement to DVIU.4
Several studies have evaluated the use of DVIU with MMC for bladder neck contractures noting mixed results regarding recurrence free success and complications.5,6,7 Additionally, there is a paucity of literature that specifically evaluates anterior urethral strictures.8,9,10
We report our efficacy and safety outcomes after DVIU with MMC followed by shortterm clean intermittent catheterization (CIC) for recurrent bulbar and bulbomembranous
3
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urethral strictures, with one of the largest cohorts of anterior urethral strictures and the longest follow up period to date in the literature.
Methods We conducted a retrospective review of consecutive patients presenting to our tertiary care medical center with recurrent bulbar and bulbomembranous urethral strictures over a 6-year period (2011-2016). All patients included in the study had clinical symptoms of urinary obstruction and had failed at least one prior intervention for bulbar or bulbomembranous urethral stricture disease. A diagnosis of bulbar or bulbomembranous stricture was confirmed by inability to pass a 16 Fr flexible cystoscope. Urine cultures were obtained preoperatively, positive cultures were treated, and all patients were administered preoperative antibiotics. All included patients underwent DVIU with MMC followed by a short period of CIC. Institutional review board approval was obtained for this study.
Patient demographic data was analyzed including prior failed interventions and stricture etiology. Data was stratified by stricture etiology being RIS versus non-RIS. Stricture length was determined via retrograde urethrogram and/or intraoperatively under direct vision based on the required length of the cold knife incision to open the stricture.
Operative technique was consistent across all patients in the study population. Cystourethrosopy was performed using a 22 Fr rigid cystoscope to allow for a wire to be passed through the stricture and into the urinary bladder. DVIU involved cold knife
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incisions at the 12-, 3-, and 9- o’clock positions through the full thickness of the fibrosis to healthier appearing tissue. A 23 Fr Wolf (Vernon Hills, IL) injection scope and a standard injection needle was used to inject 0.4 mg/mL of MMC in 0.2 mL to 0.4 mL aliquots along the length of each incision into healthier appearing tissue for a total of 10 mL (4 mg dose of MMC; Figure 1). Patients were discharged the same day with a short course of antibiotics and a 16-18 Fr silastic Foley catheter that was removed in 5 days. Once daily CIC was performed by the patient using a 16 Fr straight or coude catheter for one month postoperatively following removal of the Foley catheter.10,11
Postoperative follow up was conducted at 1, 3, 6, and 12 months followed by interval evaluation every 6 months thereafter. Patients were seen sooner if they experienced symptoms of recurrence. Evaluation included flexible cystoscopy, post void residual (PVR), and maximum urinary flow rate (Q max) via uroflowmetry. Stricture recurrence was defined as the inability to pass a 16 Fr flexible cystoscope through the stricture and/or need for additional procedures based on obstructive voiding symptoms. Patients with recurrence were first offered a repeat DVIU with MMC.
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 two-sample t-test. Continuous variables that did not follow a normal distribution were reported as median and range or interquartile range (IQR), with analysis conducted using a Mann-Whitney U test. Categorical data were reported as counts and
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percentages. Binomial variables were compared using the Pearson chi-square univariate analysis. Statistical significance was determined using a p value <0.05 for all analyses.
Results A total of 44 patients (RIS n=18, non-RIS n=26) underwent DVIU with MMC and CIC for recurrent bulbar and bulbomembranous urethral strictures. The mean age of subjects was 59 years (SD 14.5 years). Patients underwent a median of 1 previous procedure (range 1-6). Prior to presentation to our institution for DVIU with MMC, 17 (38.6%) patients underwent urethroplasty and experienced stricture recurrence either at the surgical site or independent from the surgical site along the bulbar or bulbomembranous urethra. Among the RIS cohort, 55.6% (n=10) had a history of brachytherapy alone, 22.2% (n=4) underwent external beam radiation therapy alone, and 22.2% (n=4) were exposed to both brachytherapy and external beam radiation therapy. Median stricture length was 2.0 cm (IQR 1.0-2.5) and there was no difference in stricture length between the RIS (2.0 cm, IQR 2.0-3.0) and non-RIS (2.0 cm, IQR 1.0-2.0) cohorts (p=0.30).
Overall, the median postoperative follow up was 25.8 months (IQR 12.9-47.2). RIS patients were followed for a median of 23.1 months (IQR 10.8-31.5) and non-RIS patients had a median of 32.3 months of follow up (IQR 14.7-47.8; p=0.37).
Following DVIU with MMC, uroflowmetry (Q max) increased significantly among the entire study population (p=0.02). An increase in mean postoperative Q max was also observed among the non-RIS cohort (p<0.01), however, there was no increase in mean Q
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max among RIS patients (p=0.59). There was no significant decrease in PVR volume overall or when analyzed by RIS versus non-RIS etiologies (Table 1).
No additional surgical interventions were required in 75.0% (33/44) of patients (RIS 12/18, 66.7%; non-RIS 21/26, 80.8%; p=0.31). The median time to stricture recurrence was 10.7 months among patients that recurred (IQR 3.9-17.6; RIS 9.4 months, IQR 3.517.6; non-RIS 11.2 months, IQR 8.0-25.6). For patients with prior urethroplasty, success after DVIU with MMC was seen in 70.6% (12/17) with a median time to stricture recurrence of 11.2 months (IQR 5.2-35.7 months). Following DVIU with MMC for patients with prior endoscopic management, success was observed in 77.8% (21/27) with a median time to stricture recurrence of 13.1 months (IQR 8.2-17.6 months).
In those who had stricture recurrence following the first DVIU with MMC, four patients (RIS n=2, non-RIS n=2) elected to undergo urethroplasty. The remaining seven patients experiencing stricture recurrence underwent a second DVIU with MMC. No further surgical intervention was required in 92.5% (37/40) of patients overall. Among the RIS and non-RIS cohorts, 87.5% (14/16) and 95.8% (23/24) respectively required no further surgical intervention (p=0.55; Figure 2). Throughout the follow up period, there were no complications attributable to MMC.
Discussion We describe our long-term outcomes following DVIU with MMC and short-term CIC for patients with recurrent bulbar and bulbomembranous urethral strictures. Urethroplasty
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has been established as the gold standard for urethral stricture disease. However, DVIU with MMC may be considered given its availability to a large population of urologists as well as for patients who are poor open reconstructive candidates. In our study, patients were stratified according to stricture etiology with particular attention to RIS, as this represents a subpopulation with especially recalcitrant stricture disease. RIS merit an independent analysis, as radiation causes a dense scar that results from direct damage to the urethral tissue, vascular changes, compromised wound healing, and altered fibroblast function.12
Mitomycin C mitigates scar formation by inhibiting fibroblast proliferation. In vitro studies have shown that MMC decreases 18S ribosomal ribonucleic acid transcript levels with in vivo rat studies demonstrating an inhibitory effect on protein translation.4 In a rat model with induced urethral injury, intraurethral irrigation with mitomycin C led to a dose-dependent decrease in mononuclear cell infiltrates, hemosiderin-laden macrophages, and fibrosis.13 During DVIU with MMC, the existing fibrotic stricture is incised down to healthier appearing tissue and attention is turned to preventing the development of fibrosis in the exposed healthier urethra. MMC is injected into this tissue to prevent fibroblast infiltration during the process of scar remodeling, with the goal of mitigating stricture recurrence.
Mazdak et al., evaluated DVIU with MMC (MMC injected into 4 quadrants pre-cold knife incision at 12-o’clock, 0.5 mg/mL, total dose 0.4mg) for bulbar urethral strictures by randomizing patients to DVIU with (n=20) or without (n=20) MMC. After 6 months
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of follow-up, there were significantly fewer stricture recurrences in the DVIU with MMC cohort (10% vs. 50%, p= 0.006).8 Further study by Ali et al., also used a randomized, controlled design but with a larger cohort of patients with both bulbar and penile urethral strictures who did not have recurrent strictures, prior DVIU or prior urethroplasty (DVIU with MMC, n=78; DVIU without MMC, n=73). It was found that significantly fewer patients in the DVIU with MMC cohort experienced stricture recurrence over an 18 month follow-up period (14.1% vs. 36.9%, p=0.002). MMC was injected after DVIU at a concentration of 0.1% at the 1-, 11-, and 12-o’clock positions, however, the total dose of MMC was not described. 9
We report recurrence free success after a single DVIU with MMC for recurrent bulbar and bulbomembranous urethral strictures of 75.0% (RIS 66.7%; non-RIS 80.8%). Including second DVIU with MMC if indicated, 92.5% had no requirement for further procedures over the 25.8 month follow up period (RIS 87.5%; non-RIS 95.8%). It is notable that our study included the longest median follow-up period of over 2 years, included only patients that had failed prior treatment, involved relatively longer stricture length (median 2.0 cm; Mazdak et al. 0.74 cm 8; Ali et al. 1.86 cm 9), and evaluated a cohort of patients with radiation-induced etiologies. This lends further support for longterm success in a patient population with particularly complex stricture disease.
Comparison of outcomes between studies is difficult, as definitions of bulbar stricture recurrence are inconsistent, ranging from unspecified to obstructive voiding symptoms prompting retrograde urethrography.8,9 We defined stricture recurrence as the inability to
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pass a 16 Fr flexible cystoscope in the office and/or requirement for an additional procedure, with the intention of capturing anatomic and symptomatic recurrences.
We found that Q max on uroflowetry was significantly increased after DVIU with MMC overall and among non-RIS patients suggesting functional improvement associated with the procedure. This difference was not observed among the RIS cohort, which is consistent with the notably dense scar associated with radiation damage to the urethral tissue. There was no significant decrease in PVR volume postoperatively, which may be a function of relatively low preoperative PVR volumes. Further, it is possible that there was little change in the postoperative PVR volumes as patients with urethral strictures often present with varying degrees of urinary incontinence.
The safety of intraurethral injection of MMC is an important consideration. Redshaw et al., reported significant adverse events following DVIU with MMC for bladder neck contractures in 7% (n=4) of their study population.7 Complications included osteitis pubis (n=2) and rectourethral fistula with bladder floor necrosis (n=1). Each of these patients required at least cystectomy and urinary diversion. Another patient experienced bladder neck necrosis and prolonged pain. Of note, operative technique for these complications involved doses of MMC between 2 mg and 4.5 mg, and both hot (n=3) and cold knife (n=1) incisions were used for DVIU. There were no such adverse outcomes reported in other DVIU with MMC studies for bladder neck contractures by Vanni et al., and Nagpal et al..5,6 In their study of DVIU with MMC for anterior urethral strictures, Ali et al., also reported no adverse outcomes.9 Furthermore, throughout our close longitudinal follow-up,
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there were no complications attributable to MMC. We avoid injection of MMC into areas of dense fibrosis, as the drug usually will not pass into this tissue. A more controlled injection into healthier urethra may reduce the risk of sudden over distension and flooding of local tissue with MMC, which may predispose to increased risk of necrosis or fistula.
Despite including 6 years of experience, our study is primarily limited by the small sample size and the retrospective design. While DVIU with MMC is an operative modality that is readily available, our experience is that of a tertiary care medical center, which may involve patients with more complex disease processes. Additionally, our study was observational and did not include a control arm. We utilized short-term CIC as part of our postoperative protocol with the purpose of allowing the antifibrotic effect of MMC to stabilize the urethra in its patent state. The use of short-term CIC may be a confounding variable; however, our goal was to establish a consistent, multimodal approach that optimizes endoscopic outcomes in a patient population prone to recurrent strictures. Further studies involving randomization of larger cohorts to DVIU with and without MMC and short-term CIC may further elucidate the isolated effect of MMC on stricture recurrence. We do not recommend DVIU with MMC for lichen sclerosis or long urethral strictures (>3cm).
While urethroplasty remains the gold standard for bulbar and bulbomembranous urethral strictures, it is also a more extensive open procedure requiring appropriate patient selection that can be limited by comorbidities and ability to safely tolerate general
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anesthesia. DVIU with MMC may be considered for patients with short bulbar and bulbomembranous urethral strictures who are suboptimal candidates for open reconstruction or in patients that wish to avoid open surgery and elect for an endoscopic approach.
In conclusion, DVIU with MMC followed by short-term CIC provides a safe, effective, and widely available endoscopic modality for the management of complex, recurrent, short (<3 cm) bulbar and bulbomembranous urethral strictures. This approach is particularly attractive for poor open surgery candidates and provides an alternative to multiple repeat procedures or urethroplasty, which remains the gold standard.
References: 1. Santucci RA, Joyce GF, Wise M. Male urethral stricture disease. J Urol. 2007;177(5):1667-1674. 2. Andrich DE, Mundy AR. Urethral strictures and their surgical treatment. BJU Int. 2000;86(5):571-580. 3. Latini JM. Minimally invasive treatment of urethral strictures in men. Current Bladder Dysfunction Reports. 2008;3:111-116. 4. 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(25):19068-19075. 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(1):156-160. 6. Nagpal K, Zinman LN, Leibis C, Vanni AJ, Buckley JC. Durable results of mitomycin C injection with internal urethrotomy for refractory bladder neck contractures: Multiinstitutional experience. Urology Practice. 2015;2(5):250-255. 7. Redshaw JD, Broghammer JA, Smith TG, et al. Intralesional injection of mitomycin C at the time of transurethral incision of bladder neck contracture may offer limited benefit: From the TURNS study group. J Urol. 2014; doi: 10.1016/j.juro.2014.08.104. 12
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8. Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol. 2007;51(4):1089-92; discussion 1092. 9. Ali L, Shahzad M, Orakzai N, Khan I, Ahmad M. Efficacy of mitomycin C in reducing recurrence of anterior urethral stricture after internal optical urethrotomy. Korean J Urol. 2015;56(9):650-655. 10. 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(6):14991500. 11. Carr LK, Webster GD. Endoscopic management of the obliterated anastomosis following radical prostatectomy. J Urol. 1996;156(1):70-72. 12. Tibbs MK. Wound healing following radiation therapy: A review. Radiother Oncol. 1997;42(2):99-106. 13. 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(12):1122-1126.
Figure 1. Endoscopic images from DVIU with MMC. A) Initial bulbar urethral stricture traversed with wire B) incision with cold knife at 12-o’clock position to healthier appearing tissue with subsequent incisions at 3- and 9-o’clock C) injection of mitomycin C along length of incision into healthier appearing tissue D) open bulbar urethra at conclusion of procedure. Figure 2. Outcomes following DVIU with MMC and short-term of CIC.
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Table 1. Baseline and post-DVIU with MMC maximum urinary flow rate (Q max) via uroflowmetry and post void residual values (PVR).
Q max (mL/s), mean (SD) PVR (mL), mean (SD)
Overall RIS Non-RIS Overall RIS Non-RIS
Pre-DVIU with MMC 9.2 (5.8) 8.9 (5.6) 9.4 (6.0) 92.9 (107.4) 94.3 (129.1) 96.5 (96.9)
Post-DVIU with MMC 15.4 (11.8) 7.8 (2.3) 19.6 (12.8) 61.9 (99.4) 49.1 (73.2) 70.8 (115.3)
P-value 0.02 0.59 <0.01 0.22 0.28 0.44
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S0090-4295(17)30755-0 http://dx.doi.org/doi: 10.1016/j.urology.2017.07.017 URL 20563
To appear in:
Urology
Received date: Accepted date:
3-5-2017 13-7-2017
Please cite this article as: M. Ryan Farrell, Cedric Lawrenz, Laurence A. Levine, Internal Urethrotomy with Intralesional Mitomycin C: an Effective Option for Endoscopic Management of Recurrent Bulbar and Bulbomembranous Urethral Strictures, Urology (2017), http://dx.doi.org/doi: 10.1016/j.urology.2017.07.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Internal Urethrotomy with Intralesional Mitomycin C: An Effective Option for Endoscopic Management of Recurrent Bulbar and Bulbomembranous Urethral Strictures
M. Ryan Farrell MD, MPH; Cedric Lawrenz BS; Laurence A. Levine, MD Department of Urology, Rush University Medical Center, Chicago, IL, USA
Corresponding Author: M. Ryan Farrell, MD, MPH Rush University Medical Center, Department of Urology 1725 West Harrison Street, Suite 348 Chicago, Illinois, United States, 60612 Email: [email protected] Phone: 312-942-6447
Keywords: urethral stricture; mitomycin; endoscopy; radiation; minimally invasive surgical procedure
Financial disclosures: M. Ryan Farrell and Cedric Lawrenz have no financial disclosures. Laurence Levine is a paid consultant for Absorption Pharmaceuticals, Endo, Boston Scientific and Coloplast; Speaker for Abbvie; all listed disclosures are outside the submitted work.
Abstract: Objective: To describe our experience with direct visual internal urethrotomy (DVIU) and mitomycin C (MMC) for recurrent bulbar/bulbomembranous urethral strictures of radiation and non-radiation induced etiologies.
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Methods: We reviewed our database of consecutive patients presenting to our tertiary care institution with recurrent bulbar/bulbomembranous urethral strictures who underwent DVIU with MMC from 2011-2016. Patients were stratified by radiation-induced strictures (RIS) versus non-RIS. Cold-knife incisions were made at 12-,3-,and 9-o’clock positions followed by intralesional injection of 10 mL MMC (0.4mg/mL) in 0.2-0.4 mL aliquots and 1 month of postoperative daily clean intermittent catheterization (CIC).
Results: All 44 patients (RIS n=18, non-RIS n=26) failed prior endoscopic management or urethroplasty. Median stricture length was 2.0 cm (Interquartile range (IQR) 1.0-2.5). Over a median follow-up of 25.8 months (IQR 12.9- 47.2), 75.0% (33/44) of patients required no additional surgical intervention (RIS 12/18, 66.7%; non-RIS 21/26, 80.8%). Median time to stricture recurrence among those who recurred was 10.7 months (IQR 3.9-17.6; RIS 9.4 months, IQR 3.5-17.6; non-RIS 11.2 months, IQR 8.0-25.6). Four patients (RIS n=2, non-RIS n=2) elected to undergo urethroplasty for recurrence. A second DVIU with MMC was performed in the remaining recurrences (n=7) with no further surgical intervention required in 92.5% (37/40) of patients overall (RIS 14/16, 87.5%; non-RIS 23/24, 95.8%). No long-term complications were attributable to MMC.
Conclusions: DVIU with MMC and short-term CIC for recurrent, short, bulbar/bulbomembranous urethral strictures is a safe endoscopic modality with promising early results. This
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approach may be useful for patients who are suboptimal candidates for open reconstruction.
Introduction Urethral stricture disease is a common condition of urethral fibrosis, which in the United States accounts for thousands of hospital visits, tens of thousands of ambulatory surgeries, and a three-fold increase in annual health care expenditures relative to men without urethral strictures.1 For a subpopulation of patients with particularly recalcitrant disease, especially those with radiation induced strictures (RIS), urethral strictures can present a management challenge.
Direct visual internal urethrotomy (DVIU) has been recommended as the initial approach for bulbar urethral strictures.2 However, the long-term recurrence free rates are as low as 30-40%.3 As a result, the antifibrotic agent mitomycin C (MMC) has been studied as a supplement to DVIU.4
Several studies have evaluated the use of DVIU with MMC for bladder neck contractures noting mixed results regarding recurrence free success and complications.5,6,7 Additionally, there is a paucity of literature that specifically evaluates anterior urethral strictures.8,9,10
We report our efficacy and safety outcomes after DVIU with MMC followed by shortterm clean intermittent catheterization (CIC) for recurrent bulbar and bulbomembranous
3
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urethral strictures, with one of the largest cohorts of anterior urethral strictures and the longest follow up period to date in the literature.
Methods We conducted a retrospective review of consecutive patients presenting to our tertiary care medical center with recurrent bulbar and bulbomembranous urethral strictures over a 6-year period (2011-2016). All patients included in the study had clinical symptoms of urinary obstruction and had failed at least one prior intervention for bulbar or bulbomembranous urethral stricture disease. A diagnosis of bulbar or bulbomembranous stricture was confirmed by inability to pass a 16 Fr flexible cystoscope. Urine cultures were obtained preoperatively, positive cultures were treated, and all patients were administered preoperative antibiotics. All included patients underwent DVIU with MMC followed by a short period of CIC. Institutional review board approval was obtained for this study.
Patient demographic data was analyzed including prior failed interventions and stricture etiology. Data was stratified by stricture etiology being RIS versus non-RIS. Stricture length was determined via retrograde urethrogram and/or intraoperatively under direct vision based on the required length of the cold knife incision to open the stricture.
Operative technique was consistent across all patients in the study population. Cystourethrosopy was performed using a 22 Fr rigid cystoscope to allow for a wire to be passed through the stricture and into the urinary bladder. DVIU involved cold knife
4
Page 4 of 14
incisions at the 12-, 3-, and 9- o’clock positions through the full thickness of the fibrosis to healthier appearing tissue. A 23 Fr Wolf (Vernon Hills, IL) injection scope and a standard injection needle was used to inject 0.4 mg/mL of MMC in 0.2 mL to 0.4 mL aliquots along the length of each incision into healthier appearing tissue for a total of 10 mL (4 mg dose of MMC; Figure 1). Patients were discharged the same day with a short course of antibiotics and a 16-18 Fr silastic Foley catheter that was removed in 5 days. Once daily CIC was performed by the patient using a 16 Fr straight or coude catheter for one month postoperatively following removal of the Foley catheter.10,11
Postoperative follow up was conducted at 1, 3, 6, and 12 months followed by interval evaluation every 6 months thereafter. Patients were seen sooner if they experienced symptoms of recurrence. Evaluation included flexible cystoscopy, post void residual (PVR), and maximum urinary flow rate (Q max) via uroflowmetry. Stricture recurrence was defined as the inability to pass a 16 Fr flexible cystoscope through the stricture and/or need for additional procedures based on obstructive voiding symptoms. Patients with recurrence were first offered a repeat DVIU with MMC.
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 two-sample t-test. Continuous variables that did not follow a normal distribution were reported as median and range or interquartile range (IQR), with analysis conducted using a Mann-Whitney U test. Categorical data were reported as counts and
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percentages. Binomial variables were compared using the Pearson chi-square univariate analysis. Statistical significance was determined using a p value <0.05 for all analyses.
Results A total of 44 patients (RIS n=18, non-RIS n=26) underwent DVIU with MMC and CIC for recurrent bulbar and bulbomembranous urethral strictures. The mean age of subjects was 59 years (SD 14.5 years). Patients underwent a median of 1 previous procedure (range 1-6). Prior to presentation to our institution for DVIU with MMC, 17 (38.6%) patients underwent urethroplasty and experienced stricture recurrence either at the surgical site or independent from the surgical site along the bulbar or bulbomembranous urethra. Among the RIS cohort, 55.6% (n=10) had a history of brachytherapy alone, 22.2% (n=4) underwent external beam radiation therapy alone, and 22.2% (n=4) were exposed to both brachytherapy and external beam radiation therapy. Median stricture length was 2.0 cm (IQR 1.0-2.5) and there was no difference in stricture length between the RIS (2.0 cm, IQR 2.0-3.0) and non-RIS (2.0 cm, IQR 1.0-2.0) cohorts (p=0.30).
Overall, the median postoperative follow up was 25.8 months (IQR 12.9-47.2). RIS patients were followed for a median of 23.1 months (IQR 10.8-31.5) and non-RIS patients had a median of 32.3 months of follow up (IQR 14.7-47.8; p=0.37).
Following DVIU with MMC, uroflowmetry (Q max) increased significantly among the entire study population (p=0.02). An increase in mean postoperative Q max was also observed among the non-RIS cohort (p<0.01), however, there was no increase in mean Q
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max among RIS patients (p=0.59). There was no significant decrease in PVR volume overall or when analyzed by RIS versus non-RIS etiologies (Table 1).
No additional surgical interventions were required in 75.0% (33/44) of patients (RIS 12/18, 66.7%; non-RIS 21/26, 80.8%; p=0.31). The median time to stricture recurrence was 10.7 months among patients that recurred (IQR 3.9-17.6; RIS 9.4 months, IQR 3.517.6; non-RIS 11.2 months, IQR 8.0-25.6). For patients with prior urethroplasty, success after DVIU with MMC was seen in 70.6% (12/17) with a median time to stricture recurrence of 11.2 months (IQR 5.2-35.7 months). Following DVIU with MMC for patients with prior endoscopic management, success was observed in 77.8% (21/27) with a median time to stricture recurrence of 13.1 months (IQR 8.2-17.6 months).
In those who had stricture recurrence following the first DVIU with MMC, four patients (RIS n=2, non-RIS n=2) elected to undergo urethroplasty. The remaining seven patients experiencing stricture recurrence underwent a second DVIU with MMC. No further surgical intervention was required in 92.5% (37/40) of patients overall. Among the RIS and non-RIS cohorts, 87.5% (14/16) and 95.8% (23/24) respectively required no further surgical intervention (p=0.55; Figure 2). Throughout the follow up period, there were no complications attributable to MMC.
Discussion We describe our long-term outcomes following DVIU with MMC and short-term CIC for patients with recurrent bulbar and bulbomembranous urethral strictures. Urethroplasty
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has been established as the gold standard for urethral stricture disease. However, DVIU with MMC may be considered given its availability to a large population of urologists as well as for patients who are poor open reconstructive candidates. In our study, patients were stratified according to stricture etiology with particular attention to RIS, as this represents a subpopulation with especially recalcitrant stricture disease. RIS merit an independent analysis, as radiation causes a dense scar that results from direct damage to the urethral tissue, vascular changes, compromised wound healing, and altered fibroblast function.12
Mitomycin C mitigates scar formation by inhibiting fibroblast proliferation. In vitro studies have shown that MMC decreases 18S ribosomal ribonucleic acid transcript levels with in vivo rat studies demonstrating an inhibitory effect on protein translation.4 In a rat model with induced urethral injury, intraurethral irrigation with mitomycin C led to a dose-dependent decrease in mononuclear cell infiltrates, hemosiderin-laden macrophages, and fibrosis.13 During DVIU with MMC, the existing fibrotic stricture is incised down to healthier appearing tissue and attention is turned to preventing the development of fibrosis in the exposed healthier urethra. MMC is injected into this tissue to prevent fibroblast infiltration during the process of scar remodeling, with the goal of mitigating stricture recurrence.
Mazdak et al., evaluated DVIU with MMC (MMC injected into 4 quadrants pre-cold knife incision at 12-o’clock, 0.5 mg/mL, total dose 0.4mg) for bulbar urethral strictures by randomizing patients to DVIU with (n=20) or without (n=20) MMC. After 6 months
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of follow-up, there were significantly fewer stricture recurrences in the DVIU with MMC cohort (10% vs. 50%, p= 0.006).8 Further study by Ali et al., also used a randomized, controlled design but with a larger cohort of patients with both bulbar and penile urethral strictures who did not have recurrent strictures, prior DVIU or prior urethroplasty (DVIU with MMC, n=78; DVIU without MMC, n=73). It was found that significantly fewer patients in the DVIU with MMC cohort experienced stricture recurrence over an 18 month follow-up period (14.1% vs. 36.9%, p=0.002). MMC was injected after DVIU at a concentration of 0.1% at the 1-, 11-, and 12-o’clock positions, however, the total dose of MMC was not described. 9
We report recurrence free success after a single DVIU with MMC for recurrent bulbar and bulbomembranous urethral strictures of 75.0% (RIS 66.7%; non-RIS 80.8%). Including second DVIU with MMC if indicated, 92.5% had no requirement for further procedures over the 25.8 month follow up period (RIS 87.5%; non-RIS 95.8%). It is notable that our study included the longest median follow-up period of over 2 years, included only patients that had failed prior treatment, involved relatively longer stricture length (median 2.0 cm; Mazdak et al. 0.74 cm 8; Ali et al. 1.86 cm 9), and evaluated a cohort of patients with radiation-induced etiologies. This lends further support for longterm success in a patient population with particularly complex stricture disease.
Comparison of outcomes between studies is difficult, as definitions of bulbar stricture recurrence are inconsistent, ranging from unspecified to obstructive voiding symptoms prompting retrograde urethrography.8,9 We defined stricture recurrence as the inability to
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pass a 16 Fr flexible cystoscope in the office and/or requirement for an additional procedure, with the intention of capturing anatomic and symptomatic recurrences.
We found that Q max on uroflowetry was significantly increased after DVIU with MMC overall and among non-RIS patients suggesting functional improvement associated with the procedure. This difference was not observed among the RIS cohort, which is consistent with the notably dense scar associated with radiation damage to the urethral tissue. There was no significant decrease in PVR volume postoperatively, which may be a function of relatively low preoperative PVR volumes. Further, it is possible that there was little change in the postoperative PVR volumes as patients with urethral strictures often present with varying degrees of urinary incontinence.
The safety of intraurethral injection of MMC is an important consideration. Redshaw et al., reported significant adverse events following DVIU with MMC for bladder neck contractures in 7% (n=4) of their study population.7 Complications included osteitis pubis (n=2) and rectourethral fistula with bladder floor necrosis (n=1). Each of these patients required at least cystectomy and urinary diversion. Another patient experienced bladder neck necrosis and prolonged pain. Of note, operative technique for these complications involved doses of MMC between 2 mg and 4.5 mg, and both hot (n=3) and cold knife (n=1) incisions were used for DVIU. There were no such adverse outcomes reported in other DVIU with MMC studies for bladder neck contractures by Vanni et al., and Nagpal et al..5,6 In their study of DVIU with MMC for anterior urethral strictures, Ali et al., also reported no adverse outcomes.9 Furthermore, throughout our close longitudinal follow-up,
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there were no complications attributable to MMC. We avoid injection of MMC into areas of dense fibrosis, as the drug usually will not pass into this tissue. A more controlled injection into healthier urethra may reduce the risk of sudden over distension and flooding of local tissue with MMC, which may predispose to increased risk of necrosis or fistula.
Despite including 6 years of experience, our study is primarily limited by the small sample size and the retrospective design. While DVIU with MMC is an operative modality that is readily available, our experience is that of a tertiary care medical center, which may involve patients with more complex disease processes. Additionally, our study was observational and did not include a control arm. We utilized short-term CIC as part of our postoperative protocol with the purpose of allowing the antifibrotic effect of MMC to stabilize the urethra in its patent state. The use of short-term CIC may be a confounding variable; however, our goal was to establish a consistent, multimodal approach that optimizes endoscopic outcomes in a patient population prone to recurrent strictures. Further studies involving randomization of larger cohorts to DVIU with and without MMC and short-term CIC may further elucidate the isolated effect of MMC on stricture recurrence. We do not recommend DVIU with MMC for lichen sclerosis or long urethral strictures (>3cm).
While urethroplasty remains the gold standard for bulbar and bulbomembranous urethral strictures, it is also a more extensive open procedure requiring appropriate patient selection that can be limited by comorbidities and ability to safely tolerate general
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anesthesia. DVIU with MMC may be considered for patients with short bulbar and bulbomembranous urethral strictures who are suboptimal candidates for open reconstruction or in patients that wish to avoid open surgery and elect for an endoscopic approach.
In conclusion, DVIU with MMC followed by short-term CIC provides a safe, effective, and widely available endoscopic modality for the management of complex, recurrent, short (<3 cm) bulbar and bulbomembranous urethral strictures. This approach is particularly attractive for poor open surgery candidates and provides an alternative to multiple repeat procedures or urethroplasty, which remains the gold standard.
References: 1. Santucci RA, Joyce GF, Wise M. Male urethral stricture disease. J Urol. 2007;177(5):1667-1674. 2. Andrich DE, Mundy AR. Urethral strictures and their surgical treatment. BJU Int. 2000;86(5):571-580. 3. Latini JM. Minimally invasive treatment of urethral strictures in men. Current Bladder Dysfunction Reports. 2008;3:111-116. 4. 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(25):19068-19075. 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(1):156-160. 6. Nagpal K, Zinman LN, Leibis C, Vanni AJ, Buckley JC. Durable results of mitomycin C injection with internal urethrotomy for refractory bladder neck contractures: Multiinstitutional experience. Urology Practice. 2015;2(5):250-255. 7. Redshaw JD, Broghammer JA, Smith TG, et al. Intralesional injection of mitomycin C at the time of transurethral incision of bladder neck contracture may offer limited benefit: From the TURNS study group. J Urol. 2014; doi: 10.1016/j.juro.2014.08.104. 12
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8. Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol. 2007;51(4):1089-92; discussion 1092. 9. Ali L, Shahzad M, Orakzai N, Khan I, Ahmad M. Efficacy of mitomycin C in reducing recurrence of anterior urethral stricture after internal optical urethrotomy. Korean J Urol. 2015;56(9):650-655. 10. 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(6):14991500. 11. Carr LK, Webster GD. Endoscopic management of the obliterated anastomosis following radical prostatectomy. J Urol. 1996;156(1):70-72. 12. Tibbs MK. Wound healing following radiation therapy: A review. Radiother Oncol. 1997;42(2):99-106. 13. 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(12):1122-1126.
Figure 1. Endoscopic images from DVIU with MMC. A) Initial bulbar urethral stricture traversed with wire B) incision with cold knife at 12-o’clock position to healthier appearing tissue with subsequent incisions at 3- and 9-o’clock C) injection of mitomycin C along length of incision into healthier appearing tissue D) open bulbar urethra at conclusion of procedure. Figure 2. Outcomes following DVIU with MMC and short-term of CIC.
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Table 1. Baseline and post-DVIU with MMC maximum urinary flow rate (Q max) via uroflowmetry and post void residual values (PVR).
Q max (mL/s), mean (SD) PVR (mL), mean (SD)
Overall RIS Non-RIS Overall RIS Non-RIS
Pre-DVIU with MMC 9.2 (5.8) 8.9 (5.6) 9.4 (6.0) 92.9 (107.4) 94.3 (129.1) 96.5 (96.9)
Post-DVIU with MMC 15.4 (11.8) 7.8 (2.3) 19.6 (12.8) 61.9 (99.4) 49.1 (73.2) 70.8 (115.3)
P-value 0.02 0.59 <0.01 0.22 0.28 0.44
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