Prevention of Stricture Recurrence Following Urethral Endoscopic Management: What Do We Have?

Abstract

Objective:

Strictures of the urethra are the most common cause of obstructed micturition in younger men and there is frequent recurrence after initial treatment. This review was performed to determine the best strategy for stricture recurrence prevention following urethral endoscopic management.

Methods:

We reviewed the published literature in PubMed, the Cochrane Library, and Google Scholar focusing on this intractable problem regardless of language restrictions. Outcomes of interest included the study methods and the applied strategy's efficacy. The level of evidence and grade of recommendations of included studies were appraised with an Oxford Centre for Evidence-Based Medicine Scale.

Results:

Currently, numerous techniques, including catheterization, repeated dilation, brachytherapy, and intraurethral use of various antifibrosis agents, have been employed to oppose the process of wound contraction or regulate the extracellular matrix. But unfortunately, none of these techniques or agents have demonstrated efficacy with enough evidence.

Conclusions:

Although lots of strategies are available, still, we do not have a suitable, single optimum solution for all the conditions. The clinical decision of stricture-recurrence-prevention techniques should be carefully tailored to every individual patient. As the studies are not sufficient, more efforts are warranted to address this interesting but challenging issue.

Introduction

Urethral stricture disease is the constriction of the urethral lumen due to fibrosis or scarring of the urethral epithelium and the surrounding tissues. It is a longstanding problem in urology, which can result from trauma, localized inflammation, and iatrogenic or idiopathic etiologies.^1,2 With popularization of transurethral manipulations, currently, iatrogenic reason is the leading etiology in the developed world.² The estimated urethral stricture prevalence in the United Kingdom ranges from 10/100,000 to 100/100,000 and even higher in the United States.^2,3 It produces voiding and storage urinary symptoms and can ultimately impair renal function, putting heavy financial and social burden on patient and the health services.^3,4

Treatment options for urethral strictures include dilation, urethrotomy, stent, and reconstructive surgical techniques. These can be selected according to the stricture sites, etiology, length, and patient condition, but no single technique is appropriate for all stricture diseases.^5,6 After a median follow-up of 6 months or a year, however, sizable proportion of patients who received urethral reconstructive treatments will eventually recur with more complicated length and severity.^5,7,8 Urethral constructions alone are just the beginning rather than the end of a definite treatment. Strategies for preventing scarring into the urethral lumen are even more important and challenging. In this article, we reviewed the published literature that focus on prevention of stricture recurrence following endoscopic surgery, with the aim of determining the best strategy for this intractable problem.

Materials and Methods

We provide a contemporary review of the available evidence regarding recurrence-preventing techniques and agents following urethral stricture internal urethrotomy using the PubMed database, the Cochrane Library, and Google Scholar with the following search terms: “male urethra,” “urethral stricture,” “urethral stenosis,” “internal urethrotomy,” “optical urethrotomy,” “stricture recurrence,” and “prevention” up to August 2013. We also used the reference lists of retrieved articles to identify additional relevant sources. Our search strategy yielded a total of 275 potentially relevant studies, and 57 were included in this review after evaluation of the titles, abstracts, and full texts. All selected articles were critically reviewed using the Cochrane Collaboration's tool for assessing risk of bias by two authors independently. In addition, the Oxford Centre for Evidence-Based Medicine Scale was used to assign a level of evidence and grade of recommendation to each publication by two reviewers (Tables 1 and 2).⁹ Discrepancies between the investigators were resolved by discussion or further consultation with a third author.

Table 1.

Levels of Evidence

Level	Type of evidence
1a	Evidence obtained from meta-analysis of randomized trials
1b	Evidence obtained from at least one randomized trial
2a	Evidence obtained from one well-designed controlled study without randomization
2b	Evidence obtained from at least one other type of well-designed quasi-experimental study
3	Evidence obtained from well-designed nonexperimental studies, such as comparative studies, correlation studies, and case reports
4	Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities

Modified from the Centre for Evidence-Based Medicine.⁹

Table 2.

Grades of Recommendation

Grade	Nature of recommendations
A	Based on clinical studies of good quality and consistency that addressed specific recommendations including at least one randomized trial
B	Based on well-conducted clinical studies but without randomized clinical trials
C	Made despite the absence of directly applicable clinical studies of good quality

Modified from the Centre for Evidence-Based Medicine.⁹

Postendoscopic Management Catheterization

Leaving an indwelling Foley catheter after urethral endoscopic surgery is well accepted and widely applied. It is hoped that the urethra will mold around the catheter as it heals. However, employing postendoscopic surgery catheterization and its optimal duration are still controversial. The recommended periods differ widely among studies (Table 3). Hjortrup et al. (Level 3, Grade C)¹⁰ reported urethral catheterization of 24 hours in 72 consecutive patients treated by internal urethrotomy. Mundy et al. and Desmond et al. (Level 4, Grade C and Level 3, Grade C, respectively)^11,12 believed that catheter should be left in for at least 3 days. Similarly, a silicon catheter left for ∼7 days postoperatively was considered optimal in the study of Lipsky et al. (Level 3, Grade C).¹³ Further, patients in study of Al-Ali et al. (Level 3, Grade C)¹⁴ were treated with a 16F catheter for 1 month and a 22F catheter for another 2 months. The authors suggested that leaving a silicone catheter indwelling for 3 months is optimal for epithelialization of the urethral tract. In Pansadoro et al. (Level 3, Grade C)¹⁵ study, however, no catheterizations were conducted. The failure rate of long-term catheterization after internal urethrotomy is similar to that seen with 3–7 days of catheterization, and even 6 weeks is not a sufficient time to oppose the forces of wound contraction. Meanwhile, Holm-Nielsen et al. (Level 3, Grade C) suggested that prolonged catheter treatment would not improve the final results.¹⁶ As evaluation of stricture recurrence among studies differs greatly, it remains unclear whether the period of catheterization affects the stricture recurrence rate, whereas it has been suggested that 3 days is the optimal period.¹⁷ In a small cohort, Gucuk et al. (Level 1b, Grade A)¹⁸ applied a steroid-coated (triamcinolone acetonide 1%) 18F hydrophilic catheter 2 weeks for patients after internal urethrotomy, showing slight improvement in maximum urinary flow rate. Ischemia is a common underlying cause or predisposing factor in stricture disease. Hammarsten et al. (Level 1b, Grade A)¹⁹ founded that the post-TURP (transurethral resection of the prostate) catheter (22F) plays an important role in stricture formation. Liss et al. (Level 3, Grade B)²⁰ indicated that reducing the size of the Foley catheter resulted in a statically significant reduction of fossa navicularis strictures. According to them, catheters that sized ≥22F could be associated with nearly a 10% risk of catheter-induced fossa navicularis strictures and consequently reduced the catheter size to virtually eliminate the incidence of strictures, implying that catheter should be carefully selected. Further, as latex catheters have been implicated in the etiology of urethral strictures, silicone catheters are preferred (Level 3, Grade B),²¹ if needed. Many urologists may consider leaving a catheter after internal urethrotomy as a solution to the problem; however, we are still ignorant regarding this issue. Whether a catheter is needed, the duration of catheterization, the optimal size, and material are still to be determined with persuasive evidence. Further comparative investigations, anyhow, are warranted.

Table 3.

Recommendations of Catheterization Periods Following Urethral Endoscopic Management

Studies	Study size	Primary surgery	Catheterization periods	Duration of follow-up	Recurrence rate (%)	LE	GR
Hjortrup et al.¹⁰	72	Internal urethrotomy	24 hours	29 months	18	3	C
Mundy et al.¹¹	NA	Internal urethrotomy	3 days	NA	NA	4	C
Desmond et al.¹²	52	Internal urethrotomy	≥3 days	13–86 weeks	51	3	C
Lipsky et al.¹³	32	Internal urethrotomy	7 days	6 months	17	3	C
Al-Ali et al.¹⁴	154	Optical urethral reconstruction	3 months	NA	65	3	C
Pansadoro et al.¹⁵	224	Internal urethrotomy	No catheterization	98 months	68	3	C
Holm-Nielsen et al.¹⁶	225	Internal urethrotomy	“A variable period of time”	≥6 months	23	3	C
Albers et al.¹⁷	937	Internal urethrotomy	≥3 days	4.6 years in Group 1	26.9 in Group 1	3	C
				3.2 years in Group 2	44.8 in Group 2
Gucuk et al.¹⁸	45	Internal urethrotomy	2 weeks	16.4 months	20 in Group 1	1b	A
					46.7 in Group 2
					60 in Group 3

LE=level of evidence; GR=grade of recommendations; NA=not available.

Repeated Urethral Dilation

Currently, routine repeated dilations including intermittent self-catheterization (ISC) have been popularized to reduce the risk of recurrent stricture. ICS is being routinely prescribed for urethral stricture recurrence prevention. As far as we know, however, there is no high-level supportive evidence from randomized controlled trials (RCTs) regarding on this issue. Matanhelia et al. (Level 1b, Grade A)²² analyzed a series of patients treated by internal urethrotomy in a prospective randomized study. They found no statistical difference in stricture recurrence rate between ISC group (with a 16F catheter) and the control group. However, it is far more commonly documented that repeated dilations are effective. Rouanet et al. (Level 3, Grade C)²³ claimed that ISC after internal urethrotomy improved IPSS score, QoL score of IPSS, and maximum flow rate significantly. Lauritzen et al. (Level 3, Grade B)²⁴ retrospectively evaluated 217 patients and showed that the median time until recurrence was 732 days in the ISC group and 167 days in the non-ISC group, while reducing the stricture recurrence rate significantly. Kjaergaard et al. (Level 1b, Grade A)²⁵ investigated the effect of weekly clean intermittent catheterization on prevention of urethral stricture recurrence after internal urethrotomy in a random controlled trial. They found that significantly fewer patients developed recurrence of urethral stricture compared with the control group.

ISC was mostly reported as a simple procedure and well tolerated^23,25
–27; however, Lubahn et al.²⁸ indicated that the overall QoL among urethral stricture patients treated with ISC was poor. As ISC is challenging, needing manual dexterity and cognitive ability, many patients simply stop using it because of the sheer inconvenience.²² Severe complications could result from repeated dilations, including urinary tract infections (UTIs), pain, hemorrhage, hematoma, false passage, extravasation, urethral perforation, rectal injury, and sexual dysfunction.^29
–31 In addition, recurrent urethral stricture after repeated interventions is usually more complex with worsening conditions, making a more difficult and definitive open-repair approach inevitable. Thus, indicating that not all the patients are candidates for this procedure. However, for those who need repeated dilations, regimens should follow the principle of initially frequent dilatations with a tapering schedule supplemented by techniques and practical tips being carefully offered.³²

Endourethral Brachytherapy

Ionizing radiation has been shown to prevent hypertrophic scarring and keloid formation. Olschewski et al. (Level 3, Grade C)³³ proposed that reduction of uncontrolled cell proliferation should be target of a successful approach. Ten men received internal urethrotomy included in their study and were treated with high-dose-rate (HDR) brachytherapy within 5 hours after the surgery. The radiation dose was 4×3 Gy to 4×4 Gy, which was prescribed at 3-mm tissue depth. During mean follow-up of 14.8 months, 9 of 10 patients remained relapse free. Accordingly, they concluded that endourethral HDR brachytherapy proved to be an effective method that can reduce urethral re-stricture. Similarly, Sun et al. (Level 3, Grade C)³⁴ recruited 17 patients with urethral stricture; they also applied endourethral brachytherapy following internal urethrotomy with single doses from 2.5 to 6 Gy and total doses from 10 to 15 Gy within two or three sessions. With mean follow-up of 20 months, they obtained a 93% stricture-free rate, confirming the efficacy of additional radiotherapy in preventing urethral re-strictures. Similar satisfactory results were also reported regarding the effect of endourethral radiotherapy in preventing urethral stricture recurrence (Level 3, Grade C).^5,35 HDR brachytherapy, however, may result in stricture formation of urethra with respect to the experience in prostate cancer radiotherapy.³⁶ Using the dosage of 16 Gy, radiation is unlikely to induce urethral scar formation or incontinence.³⁷ It has been accomplished with fractionated doses in the range of 10–20 Gy, which do not interfere with normal wound repair processes and do no harm to the deeper tissue.³⁸ The efficacy and safety of endourethral HDR brachytherapy in preventing urethral stricture recurrence following internal urethrotomy, nevertheless, should be interpreted within the preliminary results, the small size sample, and the single-arm study design. Whether the brachytherapy actually helped and if so, the ideal “dose and fractionation window,” long-term effects, as well as the indications are needed to be established.

Intraurethral Use of Steroid

Steroids are known for their antifibroblast and anticollagen properties. Transurethral use of steroid was proposed by Hebert in 1971 for urethral stricture treatment.³⁹ Currently, local administration of steroid is mostly employed as adjuvant therapy to urethral internal urethrotomy for decreasing collagen production and preventing wound contraction. But it was controversial when steroids were initially introduced for treating urethral strictures. Hradec et al. (Level 3, Grade C)⁴⁰ used a specially constructed needle for injection of triamcinolone acetonide after internal urethrotomy, which showed a recurrence rate of 4.3% compared with stricture recurrent rate of 19.4% in the group without corticoid injection. Korhonen and colleagues (Level 3, Grade C)⁴¹ studied 38 consecutive male urethral stricture patients, and they showed that intralesional corticosteroid injections with methylprednisolone did not offer any significant benefits in the treatment of urethral strictures. In the last decade, however, most scholars recommend the intraurethral use of steroid with relatively fair evidence. Hosseini et al. (Level 1b, Grade A)⁴² compared patients undergoing clean intermittent catheterization with or without triamcinolone ointment following internal urethrotomy. At a follow-up of 12 months, recurrence was noted in 30% in the triamcinolone group compared with 44% in the other. They believed that administration of triamcinolone ointment in patients after internal urethrotomy was effective although they failed to achieve a statistically significant difference between the two groups, which could be interpreted by the small cohort. Eltahawy et al. (Level 3, Grade C)⁴³ showed that Holmium laser bladder neck incision–combined steroid injection for anastomotic stenosis after radical prostatectomy had a success rate of 83% in a small series. Gucuk et al. (Level 1b, Grade A)¹⁸ presented short-term results of steroid-coated hydrophilic dilatation catheter usage in the management of urethral stricture. Either a steroid-coated (triamcinolone acetonide 1%) 18F hydrophilic dilatation catheter or an 18F hydrophilic dilatation catheter was applied to the patients for 2 weeks or an 18F silicone urethral catheter for 3 days. After 16.4-months of mean follow-up, they achieved no statistical difference regarding the postoperative maximum urinary flow rate and the failure rate. However, they optimistically suggested that this procedure was effortless, low in complications, and hopeful as an adjuvant treatment. Other scholars concluded similarly that intraurethral use of steroid is safe and effective, which could significantly reduce stricture recurrence or delay the recurrence of urethral stricture after urethral reconstruction (Level 1b, Grade A; Level 1b, Grade A; and Level 3, Grade C, respectively).^44
–46 Although studies of steroid usage showed encouraging results, they should be interpreted with caution due to the small study size and the insufficient follow-up period. These techniques deserve to be tested on large groups of patients with special emphasis on objective verification of the safety and efficacy profile in long-term observation.

Halofuginone

Histologically, urethral stricture presents as collagen-rich connective tissue and fibroblasts that replace the corpus spongiosum surrounding the urethra. This suggests that synthesis of collagen and other extracellular matrix proteins are involved in this process. Halofuginone, a plant alkaloid that was originally isolated from the plant Dichroa febrifuga, was identified as an effective antifibrotic agent by inhibiting collagen α1 gene expression and collagen synthesis in various tissues at extremely low concentrations.⁴⁷ In animal models, halofuginone was demonstrated with potential application prospects for prevention of scar formation after surgical incisions and cosmetic surgical intervention, keloid and hypertrophic scar formation after trauma, fibrosis post irradiation, liver posthepatitic cirrhosis, and fibrosis due to artificial implants.⁴⁷ Nagler et al.⁴⁸ administrated halofuginone into a urethral stricture rat model. Halofuginone was given to the animals either orally at 1 and 5 ppm in the diet or by injection of 0.03% halofuginone solution into the urethra. They found that halofuginone injected into the urethra or orally at 5 ppm normalized the urethrogram and prevented increases in collagen α1 gene expression and collagen content as well as inhibited the collagen secreted by fibroblasts derived from the rat male urethra. Jaidane et al.⁴⁹ conducted a two-phase study of halofuginone on urethral stricture. In the first phase, 20 rabbits of urethral stricture model induced by electrocoagulation were randomly assigned to 2 groups of 10 each, which received a diet containing halofuginone or a normal diet. Three weeks later, stricture developed in 2 study rabbits (20%) versus 10 controls (100%). In the second phase, electrocoagulation-induced stricture was treated with visual internal urethrotomy in halofuginone and a normal-diet group, respectively. Stricture evaluation was done 10 weeks thereafter; recurrent stricture was observed in 5 of the 18 study rabbits (27%) versus 14 of the 19 controls (73%). Krane et al.⁵⁰ used halofuginone-coated silicone catheters to prevent spongiofibrosis formation in a rat model. Following that, by urethral stricture induced by electrocoagulation, they compared periurethral type I collagen deposition between animals and placement of a halofuginone-coated catheter and uncoated silicone catheters for controls. It is showed that control animals had increased periurethral collagen type I deposition in this study. However, they did not confirm the inhibiting effect of halofuginone on urethral stricture formation with direct evidence, such as urethrography. It should be noticed that all these studies were performed on animals with limited study size. Halofuginone demonstrated the promising antifibrotic effects; however, the efficacy and safety should be further investigated in clinical settings.

Other Agents and Techniques

Most urologists routinely use antibiotic prophylaxis when performing internal urethrotomy. The use of perioperative antibiotics seems to reduce stricture recurrence rate (Level 3, Grade C),⁵¹ while untreated perioperative urinary infection increases the recurrence rate significantly.⁷ Bacterial infection may induce the squamous metaplasia, and then destroy the epithelium barrier and introduce scar formation. In Kumar et al. (Level 3, Grade C)⁴⁶ study, 5 out of 12 total recurrences had positive urine cultures (41.7%), whereas only 5 of 38 successful patients had positive urine cultures (13.2%). They found that UTI in the perioperative period was associated with urethral stricture recurrence. Boccon et al. (Level 3, Grade C)⁵² coincidentally reported that UTI was a risk factor affecting the outcome. Hammarsten et al. (Level 1b, Grade A)⁵³ carried out a prospective, randomized study that investigated the effect of norfloxacin prophylaxis on stricture formation after transurethral resection of the prostate. At follow-up of 6 to 12 months postoperatively, the number of strictures in the anterior urethra was 2 out of 135 in the norfloxacin group and 22 out of 130 in the control group (p<0.01). But the antibiotic prophylaxis effect on stricture formation or recurrence is still far from well understood.

As recognized that topical administration of mitomycin C inhibited fibroblast proliferation and prevented scar formation,⁵⁴ Ayyildiz et al.⁵⁵ investigated the intraurethral employment of low doses of mitomycin C on scar formation and fibrosis in experimental rat model. Compared with the control group, low-dose administration of mitomycin C downregulated hemosiderin-laden macrophages, mononuclear cell infiltration, and fibrosis significantly in the experiment groups. In 2007, Mazdak et al. (Level 1b, Grade A)⁵⁶ recruited 40 urethral stricture patients who were randomized to undergo internal urethrotomy with or without urethral submucosal mitomycin C injection. Urethral stricture recurred in 2 patients (10%) in the mitomycin C-treated group and in 10 patients (50%) in the other group with mean follow-up period of 15 months. This suggests that submucosal injection of mitomycin C significantly reduced the stricture recurrence rate after internal urethrotomy. This technique seems to be a potentially effective approach. However, this study was criticized for numerous flaws.^57
–59 Vanni et al. (Level 3, Grade C)⁶⁰ reported urethrotomy and intralesional mitomycin C for bladder neck contractures, which also yielded successful outcome.

Kim et al. (Level 3, Grade C)⁶¹ recently described their experience of hyaluronic acid (HA) instillation with visual internal urethrotomy for urethral stricture. They instilled HA via an 18-gauge tube catheter between the urethral lumen and Foley catheter after urethrotomy. Twelve months later, 52.9% of the patients were stricture free as followed up with retrograde urethrography, uroflowmetry, and postvoid residual urine showed. The authors claimed that the success rate of urethrotomy with HA instillation was not better than that observed in the literature for conventional urethrotomy. Following this retrospective, single-arm study, Chung et al. recently reported combination use of HA with carboxymethyl cellulose (CMC) in preventing recurrence of urethral stricture after internal urethrotomy (Level 1b, Grade A) and TURP (Level 1b, Grade A).^62,63 Recruited patients were randomly divided into two groups: either receiving HA/CMC instillation or lubricant instillation postoperatively. They found that HA/CMC instillation could effectively decrease the incidence of urethral stricture formation/recurrence postoperatively as compared with the control group. Extended follow-ups are warranted to confirm the long-term effects.

Other agents and techniques, including maintaining the temperature of the urethra during TURP (Level 2a, Grade B),⁶⁴ intraurethral use of captopril gel (Level 1b, Grade A),⁶⁵ and cyclooxygenase-2 inhibitor (Level 1b, Grade A),⁶⁶ are sporadically reported with satisfactory conclusions. Anyway, the efficacy of these agents and techniques are also far from well established.

Discussion and Future Trends

Urethral stricture recurrence after urethral reconstruction is one of the most challenging problems in urology. As far as we know, this is the first review that focuses on this challenging issue. Da-Silva et al. proposed the theoretical possibility that undesirable scar tissue could be prevented pharmacologically⁶⁷; together with the dismal success rate, numerous techniques and agents have been employed to oppose the process of wound contraction or regulate the extracellular matrix. But unfortunately, none of the discussed techniques or agents were demonstrated effectively with enough evidence (Table 4). More well-designed studies with extended follow-up are needed as a minimum follow-up of 5 years is recommend for assessing the results of treatment of urethral stricture.⁶⁸

Table 4.

Recommendation Summary

Recommendations
3-day-duration catheterization is likely the best choice of postinternal urethrotomy.
Silicone catheters are preferred.
Avoiding catheters larger than 22F to prevent fossa strictures in post-TURP patients.
Repeated urethral dilation could be selected either in clinics or ISC, for which should be carefully educated.
Evidence is inadequate on endourethral brachytherapy following internal urethrotomy.
Intraurethral use of steroid is effortless, low in complications, adjuvant treatment after endoscopic management, which could be considered. Its efficacy, however, should be further confirmed.
Halofuginone demonstrated efficacy on animals with limited study size, which is far from well understood in clinic.
Efficacy and safety of other agents and techniques regarding this issue are preliminary and undefined; thus, they should not be routinely prescribed.

ISC=intermittent self-catheterization; TURP=transurethral resection of the prostate.

The exact pathophysiology of the healing process following urethral reconstruction remains poorly understood. It is seen to be a process starting with inflammation, collagen, and other extracellular matrices synthesis, finally resulting in scar formation.^16,67 It is also assumed that if epithelialization progresses completely before wound contraction, then urethrotomy may be successful, but if wound contraction significantly narrows the lumen before completion of epithelialization, then the stricture recurs. Epithelium lining in the urethral lumen plays an important role in protecting subepithelial tissue from scaring.¹¹ One of the most important failure factors for reducing urethral stricture recurrence rate is that we neglect to recover the epithelium structure and function. We need more detailed studies to address the exact pathophysiology of scar development/remodeling and epithelialization progresses for defining new therapeutic targets. Developing new techniques, new tools, and new bioengineered materials is essential to effectively deal with this issue. Therapeutic approaches and agents for urethral stricture are changing rapidly, compelling surgeons to update their knowledge constantly, with newer minimally invasive procedures introduced regularly. In recent years, with success of cell cultures and various techniques for cell isolation, separation, selection, and optimized conditions for the proliferation of single cell types,⁶⁹ as well as the important developments of biomaterials and stem cell researches,⁷⁰ tissue engineering has become synonymous with physiological and functional reconstructive approaches in medicine. Despite the fact that this is a young field, it promises to influence urological treatment in the near future. New scaffolds that carry new cell sources and cytokines are under investigation, which are expected to substantially change this field.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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