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Mitomycin-C and urethral dilatation: A safe, effective, and minimally invasive procedure for recurrent vesicourethral anastomotic stenoses
Urologic Oncology: Seminars and Original Investigations 35 (2017) 672.e15–672.e19
Original article
Mitomycin-C and urethral dilatation: A safe, effective, and minimally invasive procedure for recurrent vesicourethral anastomotic stenoses Michael Wadih Sourial, M.D.a,*, Patrick O. Richard, M.D., M.Sc.a,b, Mathieu Bettez, M.D.c, Mazen Jundi, M.D.d, Le Mai Tu, M.D., M.Sc.a a
Departments of Surgery, Faculté de Médecine et Science de la Santé de l’Université de Sherbrooke, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada b Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Québec, Canada c Department of Surgery, Hôpital Cité-de-la-Santé de Laval, Laval, Québec, Canada d Department of Surgery, CSSS Trois-Rivière, Centre Hospitalier Affilié Universitaire Régional, Trois-Rivière, Québec, Canada Received 30 March 2017; received in revised form 30 June 2017; accepted 31 July 2017
Abstract Purpose: To report the safety and efficacy of mitomycin-C (MMC) injection followed by urethral dilatation for the treatment of recurrent vesicourethral anastomotic stenosis (VUAS) post-radical prostatectomy, and to report the outcome for patients treated for concomitant postprostatectomy incontinence. Materials and methods: A total of 29 patients with postprostatectomy incontinence and diagnosed with recurrent VUAS were recruited between March 2009 and January 2014 in this longitudinal case series. Under sedation, MMC was injected at the 3, 6, and 9 o’clock position, followed by urethral dilatation to 26 F. Cystoscopy was performed to evaluate for patency at set intervals. Patients had the possibility to receive a salvage MMC injection if recurrence was noted. Patients with resolved VUAS were offered an anti-incontinence surgery. Results: Median (interquartile range [IQR]) patient age was 67 years (63–72). Overall, 17 patients had ≥2 prior treatments for the VUAS (median ¼ 2, IQR: 1–3 treatments); 23 patients (79%) had a patent bladder neck at the 12 months follow-up cystoscopy after a single MMC injection and dilatation. Overall, 3 patients opted for a salvage MMC injection for recurrence, and 2 of those were salvaged, improving the success rate to 86%. No adverse events were reported. Overall, 20 patients (69%) opted for an anti-incontinence surgery, and all were either cured or improved of their incontinence after a median (IQR) follow-up of 58 months (48–77). Conclusions: MMC injection with urethral dilatation is a safe, effective, and minimally invasive treatment option for recurrent VUAS after radical prostatectomy. Favorable long-term results can be expected even after anti-incontinence procedures. r 2017 Elsevier Inc. All rights reserved.
Keywords: Dilatation; Male; Mitomycin; Urethral stricture; Urinary incontinence
1. Introduction The reported incidence of vesicourethral anastomotic stenosis (VUAS) after radical prostatectomy (RP) is 0.4% to 32% in contemporary series, and the incidence is decreasing with the rising use of laparoscopic and robotic-assisted techniques [1–4]. The Societe Internationale d’Urologie (SIU) has recently suggested replacing the commonly used, *
Corresponding author. E-mail address: [email protected] (M.W. Sourial). http://dx.doi.org/10.1016/j.urolonc.2017.07.031 1078-1439/r 2017 Elsevier Inc. All rights reserved.
but misleading term “bladder neck contracture” with “vesico-urethral anastomotic stenosis [5].” The exact underlying mechanism is unknown, but excessive fibrosis has been previously described [6]. Surgical technique and various patient-based factors such as age, obesity, and a propensity to hypertrophic scarring were also previously associated with a higher likelihood of VUAS [7,8]. Several authors have commented on VUAS and postprostatectomy incontinence (PPI), and VUAS has been shown to be an independent risk factor for PPI [9]. VUAS may impair the ability of a normally functioning external
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M.W. Sourial et al. / Urologic Oncology: Seminars and Original Investigations 35 (2017) 672.e15–672.e19
sphincter to close the bladder outlet. Concomitant VUAS and PPI is a rather challenging clinical scenario, and the VUAS must be aggressively treated and stabilized before any anti-incontinence surgery [8]. Various treatment options for VUAS are described in the literature, including scheduled dilatation or self-catheterization, endoscopic procedures, placement of a urethral stent, and open bladder neck reconstruction. There is no clear consensus on the management of recurrent VUAS. A graded approach is described in a recent SIU review article, beginning with endoscopic procedures, followed by more invasive procedures [10]. Although most VUAS will resolve after a single procedure, the management of patients with recurrent VUAS can be quite challenging. Mitomycin-C (MMC) is an antibiotic with antineoplastic and antiproliferative properties [11]. It has been shown to inhibit fibroblast proliferation, collagen deposit, and scar formation [12,13]. Its antiproliferative and antiscarring properties have been successfully used to treat glaucoma, laryngotracheal stenosis, and vaginal and anal strictures [11,14,15]. More recently, few series have looked at its use in the post-RP population with promising results [16–18]. The objectives of this study are to present our experience with intralesional MMC injection followed by urethral dilatation for recurrent VUAS post-RP, and to report on the outcome of patients treated for concomitant PPI. 2. Materials and methods 2.1. Patient selection After Institutional Review Board and Health Canada approval, we performed a prospective, longitudinal case series pilot study on patients with recurrent VUAS following RP. Between March 2009 and January 2014, 29 patients were recruited and followed until November 30, 2015. These patients were all evaluated in the context of PPI by a single urologic surgeon (L.M.T.). The diagnosis of VUAS was based on clinical voiding symptoms and confirmed by urethrocystoscopy as the inability to pass a 15 F flexible cystoscope through the anastomosis. Data collected included history and physical examination, RP technique, use of adjuvant therapy, number and type of prior treatment(s) for VUAS, and urethrocystoscopy findings using a 15 F flexible cystoscope. Baseline characteristics are outlined in Table 1. Inclusion criteria included men treated by RP and one or more prior treatment(s) for VUAS. Exclusion criteria included uncorrected coagulopathy, hypersensitivity to MMC, and active urinary tract infection. All patients had a sterile urine culture before MMC injection. 2.2. Operative technique Mild sedation and analgesia using intravenous midazolam and fentanyl were given to the patient along with
Table 1 Baseline characteristics of patients Characteristics
n (%)
Age (y), median (IQR) Radical retropubic prostatectomy, n (%) Open Laparoscopic Positive history of adjuvant external beam radiotherapy, n (%) Prior procedures for VUAS, n (%) Number of prior treatments, median (IQR) Type of proceduresa Urethral dilatation One time ≥ 2 times Cold-knife incision Laser incision Transurethral bladder neck resection Recurrence-free at 12 mo, n (%) After one salvage injection, n (%)
67 (63–72)
a
25 (86) 4 (14) 8 (28) 2 (1-3) 25 13 12 7 6 1 23 25
(86) (52) (48) (24) (21) (3) (79) (86)
Some patients had multiple procedures.
appropriate antibiotic prophylaxis before the procedure. The patient was placed in the dorsal lithotomy position, and a total of 0.1 mg of MMC in 2 ml of normal saline (i.e., a concentration of 0.05 mg/ml) was injected into the stricture with a 35 cm, 1.7-mm needle (Coloplast, Denmark) via a rigid cystoscope at the 3, 6, and 9 o’clock position. This concentration has been previously demonstrated to be safe and effective in a prospective, randomized clinical trial in patients with anterior urethral strictures [11]. A guidewire was then passed through the VUAS and serial dilatation up to 26 F was performed. A 16 F Council tip catheter was then introduced in the bladder and was kept in place for 3 days. 2.3. Postoperative evaluation Follow-up urethrocystoscopies were done at 2, 6, and 12 months, at the time of anti-incontinence surgery, and when dictated by clinical symptomatology. Success (patency) was defined as the ability to pass the 15 F flexible cystoscope or the passage of a 14 F Foley catheter thereafter on subsequent follow-up visits. If recurrence was noted during the first 12 months of follow-up, patients were given the opportunity to undergo either a salvage MMC injection followed by dilatation, or to undergo another treatment option for the VUAS. Once VUAS was stabilized for ≥12 months, patients were evaluated for their incontinence and offered anti-incontinence surgery. PPI was categorized as mild (0–2 ppd or 24-h pad weight o100 g), moderate (3–5 ppd or 24-h pad weight 100–400 g), or severe (45 ppd or 24-h pad weight 4400 g). Posttreatment incontinence status was defined as cured if the patients wore no pads, improved if he wore between 0 and 1 ppd or ≥50% daily pad reduction, and not improved if he had o50% daily pad reduction.
M.W. Sourial et al. / Urologic Oncology: Seminars and Original Investigations 35 (2017) 672.e15–672.e19
2.4. Endpoints The primary objective was to report the patency rate at 12 months following MMC injection by urethrocystoscopy. Secondary objectives were to report (1) the long-term patency of the vesicourethral anastomosis at the time of anti-incontinence surgery and thereafter on subsequent follow-up visits (2) its safety, and (3) the outcome for patients treated for concomitant PPI. 2.5. Statistical analysis Descriptive statistics were used to characterize the clinical characteristics and outcome of the study cohort. Continuous variables were reported as medians (interquartile range [IQR]), while categorical variables were described with proportions. All data were recorded and statistical analyses were conducted using SAS v.9.3 (SAS Institute Inc., Cary, NC).
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further treatments. There were no reported adverse events in our series. The overall median (IQR) follow-up was 58 (48–77) months. Patients with a patent bladder neck at the 12 months follow-up visit were offered an anti-incontinence procedure. Overall, 20 patients (69%) opted for an antiincontinence procedure. Depending on the clinical evaluation and patient preference, initial implantation included the artificial urinary sphincter in 7 patients (35%), or various male slings in 13 patients (65%). All patients with an artificial urinary sphincter were cured of their incontinence. Of the 13 patients with a sling, 10 were cured or improved of their incontinence, and 3 had persistent incontinence requiring the implantation of the artificial urinary sphincter (all of whom were cured at their last follow-up visit). One patient had his male sling removed after an infection and refractory perineal pain, and remarkably remained continent.
4. Discussion 3. Results A total of 29 patients were recruited in the study. All patients had RP for localized prostate cancer and were initially evaluated in the context of PPI. Median (IQR) patient age was 67 years (63–72). Seventeen patients (59%) had ≥2 treatments before the MMC injection, with a median (IQR) of 2 (1–3) treatments. A summary of the cohort’s baseline characteristics can be found in Table 1. All 29 patients underwent cystoscopy at 2 months, and 5 were noted to have recurrence at that time. Two of these 5 recurrences were reinjected and restarted the follow-up schedule (cystoscopy at 2, 6, and 12 months). The 24 patients who did not recur underwent cystoscopy at 6 and 12 months per protocol (with 1 recurrence noted at 12 months, and the patient opted for reinjection). Six (21%) patients had a recurrence of VUAS during the first 12 months of follow-up. Recurrence was noted at the 2 months follow-up cystoscopy in 5 patients (17%), and at the 12 months follow-up cystoscopy in 1 patient (3%). Of these recurrences, 3 opted for a salvage MMC injection, while the other 3 opted for different treatment modalities such as direct vision cold knife or laser urethrotomy if it hasn’t been tried yet. Of the ones who received a salvage MMC injection, 2 were patent at their 12 months follow-up visit, improving the success rate after a salvage injection to 86% (25 of 29 patients). The three patients who received other treatments all developed recurrent VUAS. Of the 6 patients who had a recurrence after their first MMC injection, 4 were patients who had ≥2 treatments before the MMC injection. The one patient who recurred after the salvage injection had 9 treatments for VUAS before MMC injection, in addition to a rectourethral fistula repair, and multiple false passages. The patient refused
MMC is an antibiotic derived from Streptomyces caespitosus [11,14]. As an antiproliferative agent, it has been shown to inhibit fibroblast proliferation and decrease scar formation in vivo and in vitro [13]. Kunitomo and Mori first reported its use in the treatment of pterygium in 1963, and it has since been used to treat various medical conditions [11,14,15]. Its exact mechanism of action is unknown. Studies have shown that in addition to its inhibitory effect on fibroblasts, MMC cross-links DNA preferentially where genes are being induced. Its antiproliferative effect in fibroblasts is apparent at concentrations as low as 0.04 mg/ml [13]. In our study, we used the dosage of 0.1 mg of MMC diluted in 2 ml of normal saline (concentration of 0.05 mg/ml). The success rate using this protocol was 79% at the 12 months follow-up visit, with 23 of the 29 patients requiring only one MMC injection. The success rate improved to 86% (25 of 29 patients) after 1 salvage injection. The rationale to choose dilatation was two-fold. One is that cold-knife incision or other treatment modalities may be a confounding factor to the MMC injection, since those more invasive treatment options may salvage recurrent VUAS alone [19,20]. Secondly, dilatation is a less traumatic option and perhaps causes less recurrence of scarring than other procedures. We also injected MMC before performing the dilatation, and hypothesized that this allows the MMC to infuse into key areas immediately after the dilatation occurs. MMC was well tolerated and no adverse events were reported. The procedure is technically easy to perform, noninvasive, and can safely be carried out in a cystoscopy suite under mild sedation and analgesia, avoiding the general or regional anesthesia typically required for more invasive treatment options. Recurrent VUAS post-RP can be a particularly challenging complication with significant effect on quality of life.
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There is currently no consensus regarding management of this pathology [10]. Simple dilatation is often the first line of treatment, with initial success rates varying between 60% and 70% [21]. Other second-line treatments include endoscopic procedures such as cold-knife incision, laser incision, or transurethral resection of the bladder neck, with success rates up to 87% in some series [20,22]. Urethral stents have also been described in the literature, but their use is limited due to high failure rates and stent complications [23]. Combination of endoscopic procedures with a pharmacological agent has previously been described in the literature. Vanni et al. [16] published the first known series using MMC for recurrent VUAS. The authors evaluated the use of MMC injection following cold-knife incision for recurrent VUAS after RP. In all, 18 patients were treated with 3 or 4 cold-knife incisions, followed by 0.3 to 0.4 mg/ml of MMC at each incision site and bladder neck dilatation up to 26 F. Reported success rate was 72% after 1 injection, and 89% after 2 injections at a mean 9.4 months follow-up, comparable to results of the current series. More recently, a multi-institution series from the Trauma and Urologic Reconstruction Network of Surgeons study group showed the efficacy of intralesional injection of MMC at transurethral incision of the bladder neck (with Collins or cold knife) to be lower than previously reported (58% after 1 procedure; 75% after 2 procedures) in 55 patients analyzed, with 4 patients (7%) experiencing a serious adverse events [osteitis pubis
(2), rectourethral fistula with necrosis of bladder floor (1), and extensive necrosis of bladder neck (1)] [18]. The high rate of adverse events in their series may have been due to the higher doses of MMC used, ranging between 2 and 4.5 mg in those 4 patients (range: 0.4–10 mg in the entire series). The optimal dosing regimen for MMC injection has yet to be defined, but the dosage used in our series (0.1 mg of a 0.05 mg/ml solution) seems to be both safe and effective. Other series evaluating the use of similar endoscopic procedures and their results are summarized in Table 2. Concomitant PPI with VUAS is a particularly challenging scenario, and VUAS must be aggressively treated and stabilized before any anti-incontinence surgery is undertaken [8]. Twenty patients (69%) in the current series eventually had an anti-incontinence procedure, and all of these patients were cured or improved of their incontinence at their last follow-up visit, suggesting that MMC can help render patients with recurrent VUAS eligible for antiincontinence surgery, and also provide favorable long-term results with a median overall follow-up of 58 months. Limitations of this study include its small sample size and lack of a control arm where MMC was not used. In addition, due to the large referral base at our tertiary center, it is difficult to know how aggressively the VUAS were treated before the MMC injections. This, to our knowledge, is the largest series looking at MMC injection followed by dilatation alone, which avoids the more invasive procedures
Table 2 Series on recurrent VUAS treatment options and results Series
Treatment method
Giannarini et al. [20] Dilatation, followed by CKI at 4, 8, and 12 o’clock Ramirez et al. [19] Balloon dilatation (4 cm × 24 F), followed by deep transurethral incision (Collins knife) at 3 and 9 o’clock Eltahawy et al. [2] Ho-YAG laser incision at 3 and 9 o’clock, followed by triamcinolone injection Vanni et al. [16] CKI followed by dilatation to 26 F, followed by MMC injection × 3-4 incision site Lyon et al. [17] Bipolar transurethral incision of bladder neck with PK button electrode or Plasma-CISE, followed by MMC injection at 1, 4, 8, and 11 o’clock Redshaw et al. [18] Transurethral resection or incision of bladder neck (CKI or Collins knife), followed by MMC injection Nagpal et al. [24] CKI followed by dilatation to 26 F, followed by MMC injection × 3–4 incision site Farrell et al. [25]
Current series
N
Total dosage of MMC (concentration)
Adverse events n (%)
Results
43
–
N/R
74% success
50
–
N/R
24
–
N/R
72% success 86% after second procedure 83% success
18
N/R (0.3–0.4 mg/ml)
3 (16.7)
72% success
13
2 mg (40% solution)
1 (7.7)
55
0.4–10 mg (0.1–1 mg/ml)
4 (7)
40
N/R (0.3–0.4 mg/mL)
0
4 mg (0.4 mg/ml × 10 ml)
5/37a (13.5)
62% success 77% after other procedures 58% success 75% after second procedure 75% success 87.5% after second procedure 72.7% success
0.1 mg (0.05 mg/ml)
0
CKI at 12, 3, 6, and 9 o’clock, followed by MMC 11a injection at the incision sites, then daily CIC using MMC injection at 3, 6, 9 o’clock followed by 29 dilatation to 26 F
79% success 86% after second procedure
CIC ¼ clean intermittent catheterization; CKI ¼ cold-knife incision; N/R ¼ not reported. Total cohort included 37 patients with strictures in various locations, 11 of which were at the bladder neck. In all, 5 patients in the overall cohort had a complication. a
M.W. Sourial et al. / Urologic Oncology: Seminars and Original Investigations 35 (2017) 672.e15–672.e19
and need for anesthesia. Future prospective studies comparing different MMC protocols, including different concentrations and number of injections, may help identify the best technique to maintain long-term bladder neck patency while avoiding adverse events.
5. Conclusion MMC injection combined with urethral dilatation is a safe, effective, and minimally invasive treatment option for recurrent VUAS after RP. Even if recurrence is noted after a first injection, a salvage MMC injection may potentially resolve the VUAS. MMC injection can safely be used to stabilize the VUAS before PPI surgery, and provides favorable long-term results even after anti-incontinence procedures. References [1] Bader MJ, Tilki D, Gratzke C, et al. Ho:YAG-laser: treatment of vesicourethral strictures after radical prostatectomy. World J Urol 2010;28:169. [2] Eltahawy E, Gur U, Virasoro R, et al. Management of recurrent anastomotic stenosis following radical prostatectomy using holmium laser and steroid injection. BJU Int 2008;102:796. [3] Surya BV, Provet J, Johanson KE, et al. Anastomotic strictures following radical prostatectomy: risk factors and management. J Urol 1990;143:755. [4] Buckley JC. Complications after radical prostatectomy: anastomotic stricture and rectourethral fistula. Curr Opin Urol 2011;21:461. [5] Latini JM, McAninch JW, Brandes SB, et al. SIU/ICUD consultation on urethral strictures: epidemiology, etiology, anatomy, and nomenclature of urethral stenoses, strictures, and pelvic fracture urethral disruption injuries. Urology 2014;83:S1. [6] 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. [7] 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. [8] King T, Almallah YZ. Post-radical-prostatectomy urinary incontinence: the management of concomitant bladder neck contracture. Adv Urol 2012;2012:295798. [9] Eastham JA, Kattan MW, Rogers E, et al. Risk factors for urinary incontinence after radical prostatectomy. J Urol 1996;156:1707.
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[10] Herschorn S, Elliott S, Coburn M, et al. SIU/ICUD consultation on urethral strictures: posterior urethral stenosis after treatment of prostate cancer. Urology 2014;83:S59. [11] Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol 2007;51:1089. [12] Simman R, Alani H, Williams F. Effect of mitomycin C on keloid fibroblasts: an in vitro study. Ann Plast Surg 2003;50:71. [13] Lee DA, Lee TC, Cortes AE, et al. Effects of mithramycin, mitomycin, daunorubicin, and bleomycin on human subconjunctival fibroblast attachment and proliferation. Invest Ophthalmol Vis Sci 1990;31:2136. [14] Rosseneu S, Afzal N, Yerushalmi B, et al. Topical application of mitomycin-C in oesophageal strictures. J Pediatr Gastroenterol Nutr 2007;44:336. [15] Mueller CM, Beaunoyer M, St-Vil D. Topical mitomycin-C for the treatment of anal stricture. J Pediatr Surg 2010;45:241. [16] 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. [17] Lyon TD, Ayyash OM, Ferroni MC, et al. Bipolar transurethral incision of bladder neck stenoses with mitomycin C injection. Adv Urol 2015;2015:758536. [18] 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 2015;193: 587. [19] 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;82:1430. [20] Giannarini G, Manassero F, Mogorovich A, et al. Cold-knife incision of anastomotic strictures after radical retropubic prostatectomy with bladder neck preservation: efficacy and impact on urinary continence status. Eur Urol 2008;54:647. [21] Popken G, Sommerkamp H, Schultze-Seemann W, et al. Anastomotic stricture after radical prostatectomy. Incidence, findings and treatment. Eur Urol 1998;33:382. [22] Yurkanin JP, Dalkin BL, Cui H. Evaluation of cold knife urethrotomy for the treatment of anastomotic stricture after radical retropubic prostatectomy. J Urol 2001;165:1545. [23] Magera JS Jr., Inman BA, Elliott DS. Outcome analysis of urethral wall stent insertion with artificial urinary sphincter placement for severe recurrent bladder neck contracture following radical prostatectomy. J Urol 2009;181:1236. [24] Nagpal K, Zinman LN, Lebeis C, et al. Durable results of mitomycin C injection with internal urethrotomy for refractory bladder neck contractures: multi-institutional experience. Urol Pract 2015;2:250–5. [25] 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.
Original article
Mitomycin-C and urethral dilatation: A safe, effective, and minimally invasive procedure for recurrent vesicourethral anastomotic stenoses Michael Wadih Sourial, M.D.a,*, Patrick O. Richard, M.D., M.Sc.a,b, Mathieu Bettez, M.D.c, Mazen Jundi, M.D.d, Le Mai Tu, M.D., M.Sc.a a
Departments of Surgery, Faculté de Médecine et Science de la Santé de l’Université de Sherbrooke, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada b Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Québec, Canada c Department of Surgery, Hôpital Cité-de-la-Santé de Laval, Laval, Québec, Canada d Department of Surgery, CSSS Trois-Rivière, Centre Hospitalier Affilié Universitaire Régional, Trois-Rivière, Québec, Canada Received 30 March 2017; received in revised form 30 June 2017; accepted 31 July 2017
Abstract Purpose: To report the safety and efficacy of mitomycin-C (MMC) injection followed by urethral dilatation for the treatment of recurrent vesicourethral anastomotic stenosis (VUAS) post-radical prostatectomy, and to report the outcome for patients treated for concomitant postprostatectomy incontinence. Materials and methods: A total of 29 patients with postprostatectomy incontinence and diagnosed with recurrent VUAS were recruited between March 2009 and January 2014 in this longitudinal case series. Under sedation, MMC was injected at the 3, 6, and 9 o’clock position, followed by urethral dilatation to 26 F. Cystoscopy was performed to evaluate for patency at set intervals. Patients had the possibility to receive a salvage MMC injection if recurrence was noted. Patients with resolved VUAS were offered an anti-incontinence surgery. Results: Median (interquartile range [IQR]) patient age was 67 years (63–72). Overall, 17 patients had ≥2 prior treatments for the VUAS (median ¼ 2, IQR: 1–3 treatments); 23 patients (79%) had a patent bladder neck at the 12 months follow-up cystoscopy after a single MMC injection and dilatation. Overall, 3 patients opted for a salvage MMC injection for recurrence, and 2 of those were salvaged, improving the success rate to 86%. No adverse events were reported. Overall, 20 patients (69%) opted for an anti-incontinence surgery, and all were either cured or improved of their incontinence after a median (IQR) follow-up of 58 months (48–77). Conclusions: MMC injection with urethral dilatation is a safe, effective, and minimally invasive treatment option for recurrent VUAS after radical prostatectomy. Favorable long-term results can be expected even after anti-incontinence procedures. r 2017 Elsevier Inc. All rights reserved.
Keywords: Dilatation; Male; Mitomycin; Urethral stricture; Urinary incontinence
1. Introduction The reported incidence of vesicourethral anastomotic stenosis (VUAS) after radical prostatectomy (RP) is 0.4% to 32% in contemporary series, and the incidence is decreasing with the rising use of laparoscopic and robotic-assisted techniques [1–4]. The Societe Internationale d’Urologie (SIU) has recently suggested replacing the commonly used, *
Corresponding author. E-mail address: [email protected] (M.W. Sourial). http://dx.doi.org/10.1016/j.urolonc.2017.07.031 1078-1439/r 2017 Elsevier Inc. All rights reserved.
but misleading term “bladder neck contracture” with “vesico-urethral anastomotic stenosis [5].” The exact underlying mechanism is unknown, but excessive fibrosis has been previously described [6]. Surgical technique and various patient-based factors such as age, obesity, and a propensity to hypertrophic scarring were also previously associated with a higher likelihood of VUAS [7,8]. Several authors have commented on VUAS and postprostatectomy incontinence (PPI), and VUAS has been shown to be an independent risk factor for PPI [9]. VUAS may impair the ability of a normally functioning external
672.e16
M.W. Sourial et al. / Urologic Oncology: Seminars and Original Investigations 35 (2017) 672.e15–672.e19
sphincter to close the bladder outlet. Concomitant VUAS and PPI is a rather challenging clinical scenario, and the VUAS must be aggressively treated and stabilized before any anti-incontinence surgery [8]. Various treatment options for VUAS are described in the literature, including scheduled dilatation or self-catheterization, endoscopic procedures, placement of a urethral stent, and open bladder neck reconstruction. There is no clear consensus on the management of recurrent VUAS. A graded approach is described in a recent SIU review article, beginning with endoscopic procedures, followed by more invasive procedures [10]. Although most VUAS will resolve after a single procedure, the management of patients with recurrent VUAS can be quite challenging. Mitomycin-C (MMC) is an antibiotic with antineoplastic and antiproliferative properties [11]. It has been shown to inhibit fibroblast proliferation, collagen deposit, and scar formation [12,13]. Its antiproliferative and antiscarring properties have been successfully used to treat glaucoma, laryngotracheal stenosis, and vaginal and anal strictures [11,14,15]. More recently, few series have looked at its use in the post-RP population with promising results [16–18]. The objectives of this study are to present our experience with intralesional MMC injection followed by urethral dilatation for recurrent VUAS post-RP, and to report on the outcome of patients treated for concomitant PPI. 2. Materials and methods 2.1. Patient selection After Institutional Review Board and Health Canada approval, we performed a prospective, longitudinal case series pilot study on patients with recurrent VUAS following RP. Between March 2009 and January 2014, 29 patients were recruited and followed until November 30, 2015. These patients were all evaluated in the context of PPI by a single urologic surgeon (L.M.T.). The diagnosis of VUAS was based on clinical voiding symptoms and confirmed by urethrocystoscopy as the inability to pass a 15 F flexible cystoscope through the anastomosis. Data collected included history and physical examination, RP technique, use of adjuvant therapy, number and type of prior treatment(s) for VUAS, and urethrocystoscopy findings using a 15 F flexible cystoscope. Baseline characteristics are outlined in Table 1. Inclusion criteria included men treated by RP and one or more prior treatment(s) for VUAS. Exclusion criteria included uncorrected coagulopathy, hypersensitivity to MMC, and active urinary tract infection. All patients had a sterile urine culture before MMC injection. 2.2. Operative technique Mild sedation and analgesia using intravenous midazolam and fentanyl were given to the patient along with
Table 1 Baseline characteristics of patients Characteristics
n (%)
Age (y), median (IQR) Radical retropubic prostatectomy, n (%) Open Laparoscopic Positive history of adjuvant external beam radiotherapy, n (%) Prior procedures for VUAS, n (%) Number of prior treatments, median (IQR) Type of proceduresa Urethral dilatation One time ≥ 2 times Cold-knife incision Laser incision Transurethral bladder neck resection Recurrence-free at 12 mo, n (%) After one salvage injection, n (%)
67 (63–72)
a
25 (86) 4 (14) 8 (28) 2 (1-3) 25 13 12 7 6 1 23 25
(86) (52) (48) (24) (21) (3) (79) (86)
Some patients had multiple procedures.
appropriate antibiotic prophylaxis before the procedure. The patient was placed in the dorsal lithotomy position, and a total of 0.1 mg of MMC in 2 ml of normal saline (i.e., a concentration of 0.05 mg/ml) was injected into the stricture with a 35 cm, 1.7-mm needle (Coloplast, Denmark) via a rigid cystoscope at the 3, 6, and 9 o’clock position. This concentration has been previously demonstrated to be safe and effective in a prospective, randomized clinical trial in patients with anterior urethral strictures [11]. A guidewire was then passed through the VUAS and serial dilatation up to 26 F was performed. A 16 F Council tip catheter was then introduced in the bladder and was kept in place for 3 days. 2.3. Postoperative evaluation Follow-up urethrocystoscopies were done at 2, 6, and 12 months, at the time of anti-incontinence surgery, and when dictated by clinical symptomatology. Success (patency) was defined as the ability to pass the 15 F flexible cystoscope or the passage of a 14 F Foley catheter thereafter on subsequent follow-up visits. If recurrence was noted during the first 12 months of follow-up, patients were given the opportunity to undergo either a salvage MMC injection followed by dilatation, or to undergo another treatment option for the VUAS. Once VUAS was stabilized for ≥12 months, patients were evaluated for their incontinence and offered anti-incontinence surgery. PPI was categorized as mild (0–2 ppd or 24-h pad weight o100 g), moderate (3–5 ppd or 24-h pad weight 100–400 g), or severe (45 ppd or 24-h pad weight 4400 g). Posttreatment incontinence status was defined as cured if the patients wore no pads, improved if he wore between 0 and 1 ppd or ≥50% daily pad reduction, and not improved if he had o50% daily pad reduction.
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2.4. Endpoints The primary objective was to report the patency rate at 12 months following MMC injection by urethrocystoscopy. Secondary objectives were to report (1) the long-term patency of the vesicourethral anastomosis at the time of anti-incontinence surgery and thereafter on subsequent follow-up visits (2) its safety, and (3) the outcome for patients treated for concomitant PPI. 2.5. Statistical analysis Descriptive statistics were used to characterize the clinical characteristics and outcome of the study cohort. Continuous variables were reported as medians (interquartile range [IQR]), while categorical variables were described with proportions. All data were recorded and statistical analyses were conducted using SAS v.9.3 (SAS Institute Inc., Cary, NC).
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further treatments. There were no reported adverse events in our series. The overall median (IQR) follow-up was 58 (48–77) months. Patients with a patent bladder neck at the 12 months follow-up visit were offered an anti-incontinence procedure. Overall, 20 patients (69%) opted for an antiincontinence procedure. Depending on the clinical evaluation and patient preference, initial implantation included the artificial urinary sphincter in 7 patients (35%), or various male slings in 13 patients (65%). All patients with an artificial urinary sphincter were cured of their incontinence. Of the 13 patients with a sling, 10 were cured or improved of their incontinence, and 3 had persistent incontinence requiring the implantation of the artificial urinary sphincter (all of whom were cured at their last follow-up visit). One patient had his male sling removed after an infection and refractory perineal pain, and remarkably remained continent.
4. Discussion 3. Results A total of 29 patients were recruited in the study. All patients had RP for localized prostate cancer and were initially evaluated in the context of PPI. Median (IQR) patient age was 67 years (63–72). Seventeen patients (59%) had ≥2 treatments before the MMC injection, with a median (IQR) of 2 (1–3) treatments. A summary of the cohort’s baseline characteristics can be found in Table 1. All 29 patients underwent cystoscopy at 2 months, and 5 were noted to have recurrence at that time. Two of these 5 recurrences were reinjected and restarted the follow-up schedule (cystoscopy at 2, 6, and 12 months). The 24 patients who did not recur underwent cystoscopy at 6 and 12 months per protocol (with 1 recurrence noted at 12 months, and the patient opted for reinjection). Six (21%) patients had a recurrence of VUAS during the first 12 months of follow-up. Recurrence was noted at the 2 months follow-up cystoscopy in 5 patients (17%), and at the 12 months follow-up cystoscopy in 1 patient (3%). Of these recurrences, 3 opted for a salvage MMC injection, while the other 3 opted for different treatment modalities such as direct vision cold knife or laser urethrotomy if it hasn’t been tried yet. Of the ones who received a salvage MMC injection, 2 were patent at their 12 months follow-up visit, improving the success rate after a salvage injection to 86% (25 of 29 patients). The three patients who received other treatments all developed recurrent VUAS. Of the 6 patients who had a recurrence after their first MMC injection, 4 were patients who had ≥2 treatments before the MMC injection. The one patient who recurred after the salvage injection had 9 treatments for VUAS before MMC injection, in addition to a rectourethral fistula repair, and multiple false passages. The patient refused
MMC is an antibiotic derived from Streptomyces caespitosus [11,14]. As an antiproliferative agent, it has been shown to inhibit fibroblast proliferation and decrease scar formation in vivo and in vitro [13]. Kunitomo and Mori first reported its use in the treatment of pterygium in 1963, and it has since been used to treat various medical conditions [11,14,15]. Its exact mechanism of action is unknown. Studies have shown that in addition to its inhibitory effect on fibroblasts, MMC cross-links DNA preferentially where genes are being induced. Its antiproliferative effect in fibroblasts is apparent at concentrations as low as 0.04 mg/ml [13]. In our study, we used the dosage of 0.1 mg of MMC diluted in 2 ml of normal saline (concentration of 0.05 mg/ml). The success rate using this protocol was 79% at the 12 months follow-up visit, with 23 of the 29 patients requiring only one MMC injection. The success rate improved to 86% (25 of 29 patients) after 1 salvage injection. The rationale to choose dilatation was two-fold. One is that cold-knife incision or other treatment modalities may be a confounding factor to the MMC injection, since those more invasive treatment options may salvage recurrent VUAS alone [19,20]. Secondly, dilatation is a less traumatic option and perhaps causes less recurrence of scarring than other procedures. We also injected MMC before performing the dilatation, and hypothesized that this allows the MMC to infuse into key areas immediately after the dilatation occurs. MMC was well tolerated and no adverse events were reported. The procedure is technically easy to perform, noninvasive, and can safely be carried out in a cystoscopy suite under mild sedation and analgesia, avoiding the general or regional anesthesia typically required for more invasive treatment options. Recurrent VUAS post-RP can be a particularly challenging complication with significant effect on quality of life.
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There is currently no consensus regarding management of this pathology [10]. Simple dilatation is often the first line of treatment, with initial success rates varying between 60% and 70% [21]. Other second-line treatments include endoscopic procedures such as cold-knife incision, laser incision, or transurethral resection of the bladder neck, with success rates up to 87% in some series [20,22]. Urethral stents have also been described in the literature, but their use is limited due to high failure rates and stent complications [23]. Combination of endoscopic procedures with a pharmacological agent has previously been described in the literature. Vanni et al. [16] published the first known series using MMC for recurrent VUAS. The authors evaluated the use of MMC injection following cold-knife incision for recurrent VUAS after RP. In all, 18 patients were treated with 3 or 4 cold-knife incisions, followed by 0.3 to 0.4 mg/ml of MMC at each incision site and bladder neck dilatation up to 26 F. Reported success rate was 72% after 1 injection, and 89% after 2 injections at a mean 9.4 months follow-up, comparable to results of the current series. More recently, a multi-institution series from the Trauma and Urologic Reconstruction Network of Surgeons study group showed the efficacy of intralesional injection of MMC at transurethral incision of the bladder neck (with Collins or cold knife) to be lower than previously reported (58% after 1 procedure; 75% after 2 procedures) in 55 patients analyzed, with 4 patients (7%) experiencing a serious adverse events [osteitis pubis
(2), rectourethral fistula with necrosis of bladder floor (1), and extensive necrosis of bladder neck (1)] [18]. The high rate of adverse events in their series may have been due to the higher doses of MMC used, ranging between 2 and 4.5 mg in those 4 patients (range: 0.4–10 mg in the entire series). The optimal dosing regimen for MMC injection has yet to be defined, but the dosage used in our series (0.1 mg of a 0.05 mg/ml solution) seems to be both safe and effective. Other series evaluating the use of similar endoscopic procedures and their results are summarized in Table 2. Concomitant PPI with VUAS is a particularly challenging scenario, and VUAS must be aggressively treated and stabilized before any anti-incontinence surgery is undertaken [8]. Twenty patients (69%) in the current series eventually had an anti-incontinence procedure, and all of these patients were cured or improved of their incontinence at their last follow-up visit, suggesting that MMC can help render patients with recurrent VUAS eligible for antiincontinence surgery, and also provide favorable long-term results with a median overall follow-up of 58 months. Limitations of this study include its small sample size and lack of a control arm where MMC was not used. In addition, due to the large referral base at our tertiary center, it is difficult to know how aggressively the VUAS were treated before the MMC injections. This, to our knowledge, is the largest series looking at MMC injection followed by dilatation alone, which avoids the more invasive procedures
Table 2 Series on recurrent VUAS treatment options and results Series
Treatment method
Giannarini et al. [20] Dilatation, followed by CKI at 4, 8, and 12 o’clock Ramirez et al. [19] Balloon dilatation (4 cm × 24 F), followed by deep transurethral incision (Collins knife) at 3 and 9 o’clock Eltahawy et al. [2] Ho-YAG laser incision at 3 and 9 o’clock, followed by triamcinolone injection Vanni et al. [16] CKI followed by dilatation to 26 F, followed by MMC injection × 3-4 incision site Lyon et al. [17] Bipolar transurethral incision of bladder neck with PK button electrode or Plasma-CISE, followed by MMC injection at 1, 4, 8, and 11 o’clock Redshaw et al. [18] Transurethral resection or incision of bladder neck (CKI or Collins knife), followed by MMC injection Nagpal et al. [24] CKI followed by dilatation to 26 F, followed by MMC injection × 3–4 incision site Farrell et al. [25]
Current series
N
Total dosage of MMC (concentration)
Adverse events n (%)
Results
43
–
N/R
74% success
50
–
N/R
24
–
N/R
72% success 86% after second procedure 83% success
18
N/R (0.3–0.4 mg/ml)
3 (16.7)
72% success
13
2 mg (40% solution)
1 (7.7)
55
0.4–10 mg (0.1–1 mg/ml)
4 (7)
40
N/R (0.3–0.4 mg/mL)
0
4 mg (0.4 mg/ml × 10 ml)
5/37a (13.5)
62% success 77% after other procedures 58% success 75% after second procedure 75% success 87.5% after second procedure 72.7% success
0.1 mg (0.05 mg/ml)
0
CKI at 12, 3, 6, and 9 o’clock, followed by MMC 11a injection at the incision sites, then daily CIC using MMC injection at 3, 6, 9 o’clock followed by 29 dilatation to 26 F
79% success 86% after second procedure
CIC ¼ clean intermittent catheterization; CKI ¼ cold-knife incision; N/R ¼ not reported. Total cohort included 37 patients with strictures in various locations, 11 of which were at the bladder neck. In all, 5 patients in the overall cohort had a complication. a
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and need for anesthesia. Future prospective studies comparing different MMC protocols, including different concentrations and number of injections, may help identify the best technique to maintain long-term bladder neck patency while avoiding adverse events.
5. Conclusion MMC injection combined with urethral dilatation is a safe, effective, and minimally invasive treatment option for recurrent VUAS after RP. Even if recurrence is noted after a first injection, a salvage MMC injection may potentially resolve the VUAS. MMC injection can safely be used to stabilize the VUAS before PPI surgery, and provides favorable long-term results even after anti-incontinence procedures. References [1] Bader MJ, Tilki D, Gratzke C, et al. Ho:YAG-laser: treatment of vesicourethral strictures after radical prostatectomy. World J Urol 2010;28:169. [2] Eltahawy E, Gur U, Virasoro R, et al. Management of recurrent anastomotic stenosis following radical prostatectomy using holmium laser and steroid injection. BJU Int 2008;102:796. [3] Surya BV, Provet J, Johanson KE, et al. Anastomotic strictures following radical prostatectomy: risk factors and management. J Urol 1990;143:755. [4] Buckley JC. Complications after radical prostatectomy: anastomotic stricture and rectourethral fistula. Curr Opin Urol 2011;21:461. [5] Latini JM, McAninch JW, Brandes SB, et al. SIU/ICUD consultation on urethral strictures: epidemiology, etiology, anatomy, and nomenclature of urethral stenoses, strictures, and pelvic fracture urethral disruption injuries. Urology 2014;83:S1. [6] 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. [7] 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. [8] King T, Almallah YZ. Post-radical-prostatectomy urinary incontinence: the management of concomitant bladder neck contracture. Adv Urol 2012;2012:295798. [9] Eastham JA, Kattan MW, Rogers E, et al. Risk factors for urinary incontinence after radical prostatectomy. J Urol 1996;156:1707.
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[10] Herschorn S, Elliott S, Coburn M, et al. SIU/ICUD consultation on urethral strictures: posterior urethral stenosis after treatment of prostate cancer. Urology 2014;83:S59. [11] Mazdak H, Meshki I, Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy. Eur Urol 2007;51:1089. [12] Simman R, Alani H, Williams F. Effect of mitomycin C on keloid fibroblasts: an in vitro study. Ann Plast Surg 2003;50:71. [13] Lee DA, Lee TC, Cortes AE, et al. Effects of mithramycin, mitomycin, daunorubicin, and bleomycin on human subconjunctival fibroblast attachment and proliferation. Invest Ophthalmol Vis Sci 1990;31:2136. [14] Rosseneu S, Afzal N, Yerushalmi B, et al. Topical application of mitomycin-C in oesophageal strictures. J Pediatr Gastroenterol Nutr 2007;44:336. [15] Mueller CM, Beaunoyer M, St-Vil D. Topical mitomycin-C for the treatment of anal stricture. J Pediatr Surg 2010;45:241. [16] 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. [17] Lyon TD, Ayyash OM, Ferroni MC, et al. Bipolar transurethral incision of bladder neck stenoses with mitomycin C injection. Adv Urol 2015;2015:758536. [18] 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 2015;193: 587. [19] 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;82:1430. [20] Giannarini G, Manassero F, Mogorovich A, et al. Cold-knife incision of anastomotic strictures after radical retropubic prostatectomy with bladder neck preservation: efficacy and impact on urinary continence status. Eur Urol 2008;54:647. [21] Popken G, Sommerkamp H, Schultze-Seemann W, et al. Anastomotic stricture after radical prostatectomy. Incidence, findings and treatment. Eur Urol 1998;33:382. [22] Yurkanin JP, Dalkin BL, Cui H. Evaluation of cold knife urethrotomy for the treatment of anastomotic stricture after radical retropubic prostatectomy. J Urol 2001;165:1545. [23] Magera JS Jr., Inman BA, Elliott DS. Outcome analysis of urethral wall stent insertion with artificial urinary sphincter placement for severe recurrent bladder neck contracture following radical prostatectomy. J Urol 2009;181:1236. [24] Nagpal K, Zinman LN, Lebeis C, et al. Durable results of mitomycin C injection with internal urethrotomy for refractory bladder neck contractures: multi-institutional experience. Urol Pract 2015;2:250–5. [25] 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.