RECONSTRUCTIVE SURGERY Long-term Effect of Colchicine Treatment in Preventing Urethral Stricture Recurrence After Internal Urethrotomy Orhun Sinanoglu,1* Fatih Osman Kurtulus,2 Feride Sinem Akgun3 Purpose: Urethral stricture, known as a scar formation leading to urethral lumen stricture in sub-epithelial tissue, is the most common late complication of transurethral prostate resection (TURP). The aim of study is to evaluate efficacy of colchicine treatment in preventing urethral stricture recurrence in patients after internal urethrotomy, and to determine whether colchicine treatment had a sustained effect in decreasing stricture recurrences in patients with concomitant diseases. Methods: Patient data with weak urine stream and/or voiding difficulty, and who had internal urethrotomy in Urology Department of Maltepe University Hospital between dates 01 January 2011 and December 2016 were collected. They were randomized to colchicine receiving, and non-receiving arms. Colchicine was given 1 g/day orally for two months, and primary efficacy point was defined as urethral stricture development in 3, 6, and 12 months after internal urethrotomy. Results: The study was conducted on 84 males with the mean age of 67.7 ± 7.5 years. The mean ages of colchicine receivers and non-receivers were 68.2 ± 7.6 and 67.1 ± 7.6 years, respectively. Recurrence rate of urethral stricture was significantly lower in colchicine receivers (P = .044) than non-receivers. In overall evaluation, recurrence rate of urethral stricture was significantly low, if there was only one comorbidity (P = .006), but rates were significantly higher in presence of three (P = .010) and four (P = .040) comorbidities. No significant difference in recurrence rates was determined in patients without comorbidities or with two comorbidities (P > .05). Conclusion: Combination of oral colchicine with internal urethrotomy reduces recurrence rates of urethral stric- ture significantly. Keywords: urethral stricture; colchicine; Peyronie’s disease; male; fibrosis; recurrence. INTRODUCTION Urethral stricture, the oldest and most difficult dis-ease to treat in urology, is known to be caused by scar formation leading to urethral lumen stenosis in sub-epithelial tissue. It is observed with the incidence of 2.7% in late phase of endourological interventions such as transurethral prostate resection.(1,2) It was first reported in 1974, and direct visual internal urethrotomy (DVIU) was performed more commonly than blinded urethrotomy methods such as periodic urethral dilation in urethral stricture treatment, because it was easy to perform and had a short recovery duration. The curative rate of internal urethrotomy was reported as 20% with the most common complication high recurrence rate. During the procedure, scarred tissue could not be taken, and thus internal urethrotomy might be curative in stric- tures shorter than 1 cm, and with minimal spongiofibro- sis.(1) Pansadoro and Heyns reported recurrence rates as 61%, 100% and 100% in their 4-year patient follow-up studies reciprocally.(3) On the other hand, studies indi- cated that mean recurrence rates of 68% after a single urethrotomy intervention, 58% after a bulbar stricture, and 89% after a penile urethral stricture.(3) In general, the usual disease initiation occurs after urethral mucosal 1Urology Department, Maltepe University Faculty of Medicine, Istanbul Turkey. 2Urology Clinic Kolan Hospital, Istanbul Turkey. 3Emergency Department, Maltepe University Faculty of Medicine, Istanbul Turkey. *Correspondence: Maltepe Universitesi, Uroloji AD, Feyzullah Cadesi No: 39 Maltepe Istanbul - Turkey. Tel: +90 216 444 06 20. E-mail: orhundr@hotmail.com. Received October 2017 & Accepted January 2018 lesion and infection which is followed by a scar tissue. Today, most urethral strictures are resulted from trauma such as endoscopic urological interventions. Although Peyronie’s disease is an uncommon condition in middle aged men, inflammation is observed in the tunica causing ultimately scarring and penile curvature. It is believed that fibrin intravasation occurs from blood circulation into tunica albuginea after a trauma. Fibrin reaching tunica albuginea stimulates profibrotic TGF-1 compound release, then induces formation of reactive oxygen species (ROS). Thus, irregular collagen accu- mulation is observed, and destruction of newly formed collagen mass is hindered, which leads eventually to plaque calcification.(4) It is assumed that etiopathogenesis of urethral stricture and Peyronie’s disease may have the common back- ground as trauma and fibrosis as well. Patients at early stages of Peyronie’s disease are candidates for medical treatment. In the literature, there are studies conduct- ed with various biological agents for the disease such as calcium channel blockers, corticosteroids, vitamin E, and colchicine.(5) Although the most effective treat- ment has not been determined for Peyronie’s disease yet, combination of verapamil with vitamin E and col- ID: 4198 chicine has shown better pain control while reducing penile curvature, dimensions of calcification and the degree of erectile dysfunction, thus improving the qual- ity of life.(5) Considering the similar etiological and pathophysiolog- ical backgrounds for both diseases, the present study was conducted to evaluate efficacy of colchicine treat- ment in preventing urethral stricture in patients after internal urethrotomy, and to determine whether colchi- cine treatment had a sustained effect in decreasing re- currence of urethral strictures in patients with multiple comorbidities. To our knowledge, colchicine treatment in the prevention of urethral stricture has not been in- vestigated yet, this is the first study evaluating the effect of oral colchicine against this common long-term com- plication of TURP. PATIENTS AND METHODS Study Population Medical data of patients who applied to Urology De- partment of Maltepe University Hospital with com- plaints of weak urine stream or difficulty on urination following a past TURP operation between dates 01 Jan- uary 2011 and December 2016 were collected, and after internal urethrotomy patients were randomized either to colchicine receiver or non-receiver study arms. Ran- dom numbers were obtained from computer software. The treatment modality for each patient was inserted in envelopes. When the eligible patient agreed to par- ticipation, the envelopes were opened by one of the re- searchers and allocated treatment started as described below. The outcomes were evaluated by investigators who were blind to treatment assignments. Colchicine receivers (n=41) Colchicine non-receivers (n=43) p Age (year) Min-Max (Median) 55-82 (66) 54-84 (66) a0.488 mean±SD 68.2 ± 7.6 67.1 ± 7.6 Etiology; n (%) TURP 31 (75.6) 38 (88.4) c0.127 Open prostatectomy 10 (24.4) 5 (11.6) Residual urine amount (cc) Min-Max (Median) 0-800 (160) 0-800 (160) b0.939 mean ± SD 224.88 ± 212.85 207.44 ± 179.60 Mean urine flow rate (ml/sec) Min-Max (Median) 0-8 (4) 1-8 (4) a0.754 mean ± SD 4.24 ± 1.93 4.12 ± 1.79 Maximum urine flow rate (ml/sec) Min-Max (Median) 0-14 (8) 3-13 (8) a0.729 mean ± SD 8.20 ± 3.33 7.95 ± 3.03 Table 1. Evaluation of Descriptive Characteristics According to Groups aStudent-t Test bMann Whitney U Test cPearson Chi-Square Test SD; Standard deviation Figure 1. Study flow diagram Colchicine effect against urethral stricture-Sinanoglu et al. Procedures Urethrography-uroflowmetry was performed to assess the presence and extent of urethral stricture. Colchicine was given 1 g/day orally (2x0.5 mg) for two months, and primary efficacy point was defined as whether ure- thral stricture recurrence was developed or not in 3, 6, and 12 months after internal urethrotomy in both study arms. Inclusion and exclusion criteria Patients undergoing TUR-P having urethral stricture complication which is shorter than 1.5 cm, treated with internal urethrotomy were included in the study. Patients who had urethral stricture longer than 1.5 cm and/or multiple urethral strictures, and developed ure- thral stricture after external trauma were excluded from the study. Patients who have previous history of hyper- sensitivity to colchicine, twice as high AST or ALT as the hospital's reference value, creatinine level of 2.0 mg/dL or higher, past history of malignant tumor, pep- tic ulcer, serious hematological disorder, serious cardi- ac disorder, aspirin induced asthma and patients who are ineligible for the study as judged by the investigator were exluded. Flow diagram of the study are summa- rized in Figure 1 . Evaluations Hospital Information Management Systems (MediPro Software and Pusula) determined medical information of eligible patients, such as demographic and investi- gation results, comorbidities, etiologies, preoperative IPSS scores, results of uroflowmetry, and stricture re- currences. Hospital Information Management Systems (MediPro Software and Pusula) determined medical in- formation of eligible patients, such as radiological and laboratory results, comorbidities, etiologies, preopera- tive IPSS scores, results of uroflowmetry, and stricture recurrences. The comorbidities were also confirmed by combining history taking, previous consultations. The study was initiated after obtaining approval of Local Ethics Committee (Maltepe University Medical Faculty Ethics Committee Number 2017/900/08). Statistical Analysis The external statistician remained blind to outcomes variables. NCSS (Number Cruncher Statistical System) 2007 (Kaysville, Utah, USA) program was used for sta- tistical analysis. The continuous variables; the urinary flow rate, residual urine and IPPS scores were measured to assess urethral stricture and were expressed as means and standard deviations. Variables in terms of comor- bidities between colchicine receiver and non-receiver groups were compared using Pearson Chi-Square Test and Fisher’s Exact Test. Comparisons of groups with normally distributed quantitative data were performed by using Student t test. If the distribution was abnormal, comparisons were performed by using Mann Whitney U test. The level of significance was determined as p < 0.05. RESULTS The study was conducted on 84 males with the mean age of 67.7 ± 7.5 (range = 54-84) years. The mean ages of colchicine receivers and non-receivers were 68.2 ± 7.6 and 67.1 ± 7.6 years, respectively (Table 1). Groups were age matched (P > .05). The average diameter of male urethra without stricture was 9-10 mm. In colchicine receiver group, TURP was performed in 75.6% (n = 31), and open prostatectomy was performed in 24.4% (n = 10) patients. In colchicine non-receiver group, TURP was performed in 88.4% (n = 38) patients, whereas open prostatectomy was performed in 11.6% (n = 5) patients. Residual urine amount, mean urine flow rate, and maximum urine flow rate were compared between the groups, and no significant difference was determined (P > .05) (Table 1). Recurrence rate of urethral stricture was significantly lower in colchicine receivers (14.6%) than non-receiv- ers (32.6%) (P = .044) (Table 2). The recurrence rates were significantly different ac- cording to number of comorbidities (P = .001). Ac- cording to paired comparisons to determine number of Table 2. Evaluation of Urethral Stricture Recurrence According to Groups Colchicine receivers (n=41) Colchicine non-receivers (n=43) cp Recurrence of urethral Recurrence (+) 6 (14.6) 14 (32.6) 0.044* stricture; n (%) Recurrence (-) 35 (85.4) 29 (67.4) cPearsonChi-Square Test *p < 0.05 Colchicine receivers (n = 41) Colchicine non-receivers (n = 43) US Recurrence p US Recurrence p (+) (-) (+) (-) Comorbidity Positive 3 (50.0) 24 (68.6) d0.393 14 (100) 18 (62.1) d0.008** Negative 3 (50.0) 11 (31.4) 0 (0) 11 (37.9) DM Positive 1 (16.7) 13 (37.1) d0.645 12 (85.7) 8 (27.6) c0.001** Negative 5 (83.3) 22 (62.9) 2 (14.3) 21 (72.4) COPD Positive 2 (33.3) 3 (8.6) d0.148 6 (42.9) 2 (6.9) d0.009** Negative 4 (66.7) 32 (91.4) 8 (57.1) 27 (93.1) HT Positive 3 (50.0) 20 (57.1) d1.000 12 (85.7) 12 (41.4) c0.006** Negative 3 (50.0) 15 (42.9) 2 (14.3) 17 (58.6) CAD Positive 2 (33.3) 6 (17.1) d0.578 7 (50.0) 2 (6.9) d0.003** Negative 4 (66.7) 29 (82.9) 7 (50.0) 27 (93.1) cPearsonChi-Square Test dFisher’sExact Test **p < 0.01 Abbreviations: US, Urinary stricture; DM, diabetes mellitus; COPD, chronic obstructive pulmonary disease; HT, hypertension; CAD, coronary arterial disease. Table 3. Evaluation of Relationship Between Comorbidity and Urethra Stricture Recurrence Rates According to Groups Colchicine effect against urethral stricture-Sinanoglu et al. comorbidity which caused difference, recurrence rate of urethra stricture was significantly low if there was only one comorbidity (P = .006), but the rates were signifi- cantly higher if there were three (P = .010) and four (P = .040) comorbidities. There was no significant differ- ence in the rates in patients without comorbidities and with two comorbidities (P > .05) (Table 3). DISCUSSION The average lifespan in elderly men has been extended with advances in diagnostic and treat-ment modalities in the past decades therefore, in recent years, the num- ber of elderly patients having benign prostate hyper- plasia (BPH) with several comorbidities who meet the criteria for recommended sur¬gery has increased.(2) However, surgical procedures including the widely used TURP have complications such as hemorrhage, electrolyte disturbances and long-term urethral stric- tures particularly in elderly patients with concomitant cardiovascular, pulmonary, and another organ diseases. (6) In the present study, we evaluated patients suffering from urethral stricture following prostatectomy proce- dures, and determined that colchicine may be an effec- tive option to decrease stricture recurrence rate after internal urethrotomy during 1-year follow-up. To the best of our knowledge this study is the first one, where combination of internal urethrotomy and oral colchi- cine treatment was employed to prevent recurrence of urethral stricture. The underlying conditions are still not clearly known how the process follows after inter- nal urethrotomy, but it is assumed by some authors that if epithelialization progresses completely before wound contraction, urethrotomy may be successful.(2,6) There- fore, if wound contraction is delayed by any drug or procedure, then the recurrence rate of urethral stricture will decrease. Mazdak et al.(1) conducted a prospective study on 50 patients with anterior urethral stricture, who underwent internal urethrotomy, and randomized to 40 mg sub- mucosal triamcinolone injection receivers and non-re- ceivers. After a mean follow-up of 13.7 ± 5.5 months, they reported that recurrence rate was significantly de- creased in triamcinolone receiving arm. The urethral stricture was (21.7 %) in the triamcinolone group and in 11 patients (50 %) in the control group. In our study recurrence rate of urethral stricture was significantly lower in colchicine receivers (14.6 %) compared to the studies combining urethrotomy with local medication. Corticosteroid injections are a well-established pharma- cological treatment for skin scars, mucosal strictures, and in a few cases of urethral strictures to decrease collagen production.(1,7) However, the reported success rates were not very promising especially for urethral stricture recurrence rates. Korhonen et al. indicated that total success rate was only 11 % at the end of the first year in patient group that received internal urethrotomy plus methylprednisolone.(8) Tavakkoli Tabassi K et al. performed a double-blind, randomized, placebo-controlled study in which experimental group (34 patients) received triamcinolone acetonide injection and the control group (36 patients) received an injection of sterile water after internal urethrotomy. Complica- tion and recurrence rates in experimental group were lower than the control group, but the difference was not statistically significant. However, time to recurrence Colchicine effect against urethral stricture-Sinanoglu et al. decreased significantly in triamcinolone group suggest- ing that intralesional corticosteroid injection may delay the recurrence.(10) These lower success rates with corticosteroids may be explained with the fact that routine urethral instrumen- tation destroys the wound and simultaneous subepithe- lial or intralesional medication with short duration of action may not reverse the fibrotic process. Moreover, Ye Tian et al. report that active surveillance is a better option for preventing stricture recurrence as compared with routine invasive manipulations as shearing force caused by them splits the epithelium. Urine extrava- sates through these fissures or ulcers leading to subepi- thelial fibrosis.(10) Therapeutic potential of colchicine was recently rec- ognized in Peyronie's disease. Its mechanism of action was described by blocking the path of arachidonic acid lipoxygenase, thus preventing leukotriene formation by reducing inflammation and chemotaxis and interferes with procollagen transcellular migration. Therefore, procollagen formation was decreased, and collagenase production was increased. Its mechanism of action would lead to antifibrotic, antimitotic and anti-inflam- matory effects.(4,5) In the present study, we inspired from promising results of colchicine in Peyronie’s disease treatment. Data of patients with anterior urethral stricture who underwent internal urethrotomy and received oral colchicine treat- ment in the subsequent 2 months were collected. It was most probable that significant decrease in recurrence rate of stricture in the colchicine receivers was related to antifibrotic and anti-inflammatory effects of colchi- cine. When demographic characteristics of our study group was considered, presence of multiple comorbidi- ties were expectable.(6) They could decrease the success rate of urethrotomy, and thus recurrent interventions would be required. Comorbidities in the study cohort were mainly diabetes mellitus, hypertension, chronic obstructive pulmonary disease, and coronary arterial disease. Combined treatment of internal urethrotomy with oral colchicine had positive influences in decreas- ing recurrence rates of urethral stricture in patients with three or four comorbidities. There are some limitations in our study. Firstly, the sam- ple size was small and could not be increased. However, it could be accepted as a pilot study, which would help to design new prospective randomized studies about the same issue. Secondly, we presented here 1-year fol- low-up results of the study. Five-year follow-up results would be more helpful in interpreting efficacy of this combination treatment, as it was frequently reported in the literature. Thirdly, data about cost-effectiveness and patient’s quality of life would show whether this treat- ment modality could reach secondary endpoints. CONCLUSIONS Combination of oral colchicine with internal urethrot- omy reduced the stricture recurrence rate significant- ly. Further prospective randomized studies with larg- er sample sizes are required to determine efficacy and safety of this new treatment approach in more detail. ACKNOWLEDGEMENT None CONFLICT OF INTEREST The authors report no conflict of interest. REFERENCES 1. Mazdak H, Izadpanahi MH, Ghalamkari A, et al. Internal urethrotomy and intraurethral submucosal injection of triamcinolone in short bulbar urethral strictures. Int Urol Nephrol 2010;42:565-8. 2. Jordan GH, Schlossberg SM. Surgery of penis and urethra. In: Wein AJ, Kavoussi LR, Novick AC (eds) Campbell-Walshurology, 9th edn. Saunders, Philadelphia, 2007. pp 1055–75. 3. Pansadoro V, Emiliozzi P. Internal urethrotomy in the management of anterior Urethral strictures: long-term follow up J Urol. 1996;156:73-5. 4. Tunuguntla HS. Management of Peyronie's disease: a review. World J Urol 2001;19:244- 50. 5. Halal AA, Geavlete P, Ceban E. Pharmacological therapy in patients diagnosed with Peyronie's disease. J MedLife 2012;5:192-5. 6. Sinanoglu O, Ekici S, Balci M.B.C, AHazar A I, Nuhoglu B. Comparison of plasmakinetic transurethral resection of the prostate with monopolar transurethral resection of the prostate in terms of urethral stricture rates in patients with comorbidities Prostate Int 2014;2:1-6 7. Geovannini UM. Treatment of scars by steroid injections. Wound Repair Regen 2002;10:116–7. 8. Korhonen P, Talja M, Ruutu M, Alfthan O. Intralesional corticosteroid injections in combination with internal urethrotomy in the treatment of urethral strictures. Int Urol Nephrol. 1990;22:263-9. 9. Tavakkoli Tabassi K, Yarmohamadi A, Mohammadi S. Triamcinolone injection following internal urethrotomy for treatment of urethral stricture. Urol J. 2011 ;8:132-6. 10. Tian Y, Wazir R, Wang J, Wang K, Li. Prevention of stricture recurrence following urethral internal urethrotomy: routine repeated dilations or active surveillance? H.Urol J. 2016 25;13:2794-6. Colchicine effect against urethral stricture-Sinanoglu et al.