Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis

Background

Urethral stricture often impairs quality of life and may result in a large economic burden¹. There are several procedures available for treating this condition, ranging from minimally invasive procedures like internal optical urethrotomy (IOU) to invasive procedure such as urethroplasty, with or without grafting, and tissue engineering². However, despite the methods available, urethral stricture often recurs. Several manipulations have been tried to prevent urethral stricture, such as indwelling catheter insertion, urethral calibration procedure, and home self-catheterization. Unfortunately, repeated instrumentation can cause scar formation. Moreover, it can also complicate subsequent reconstruction, which can lead to several complications^3,4. On the other hand, there have been several studies evaluating the effects of antifibrotic drugs such as glucocorticoid and mitomycin-C on urethral strictures. Mitomycin-C is an agent that has the potential to inhibit mitosis, fibroblast proliferation, formation of blood vessels, and synthesis of protein and collagen. This agent plays role in tissue healing process and scar formation by reducing the release of matrix proteins by inhibiting proliferative fibroblasts⁵.

To our knowledge, there have not been any systematic reviews or meta-analyses regarding the efficacy of mitomycin-C in treating anterior urethral stricture post internal urethrotomy. Thus, the present study aims to investigate the efficacy of mitomycin-C in treating anterior urethral stricture post internal urethrotomy. We hope that by conducting this review and analysis, a definite conclusion regarding the efficacy of such treatment could be achieved.

Methods

This systematic review was conducted based on guidelines from the Oxford University Center for Evidence-Based Medicine⁶. Our present study aims to determine whether mitomycin-C provide better efficacy compared to controls (without mitomycin-C) in adult patients with anterior urethral stricture after internal urethrotomy.

Results

Literature search

Searching process (searching strategy showed in Figure 1) by using six databases found 47 study articles. There were 28 articles eliminated after title and abstract screening. The remained 19 articles were reduced to six articles after eliminating duplicates, leaving six full text articles to be reviewed. Based on study design, we eliminated three articles, leaving three articles to be summarized in systematic review and meta-analysis.

Figure 1. Study flow diagram.

Results and heterogeneity of the studies

All selected articles stated that mitomycin-C had a significant effect on preventing or delaying urethral stricture recurrence post internal urethrotomy. All studies reported that the time-based recurrence rates in the two groups differed, where lower recurrence rates were found in the group given mitomycin-C^2,4,7. The forest plot in Figure 2 showed that recurrence rate are homogenous in all analyzed studies (I² <0.001, p=0.55). This was performed by using fixed effect model in the forest plot. This forest plot suggests that there were significant differences between cases and control group. The mean recurrence rate was 0.32 (95%CI=0.19 to 0.54).

Figure 2. Forest plot for recurrence rate.

Test for heterogeneity chi-square = 1.18; df(Q) = 2; p-value < 0.0001; I² < 0.001.

On the other hand, in stricture length, all studies showed that there were not significant differences between the groups that received and did not receive mitomycin-C administration (p=0.38). Figure 3 showed homogenous studies in stricture length (I² < 0,001; p=0.38) analysis. The mean difference was -0.02 (95%CI=-0.27 to 0.23).

Figure 3. Forest plot for stricture length after treatment.

Test for heterogeneity chi-square = 0.23; df(Q) = 2; p-value = 0.89; I² < 0.001.

Discussion

Urethral stricture is a serious complication in male patients, which causes great morbidity and considerable health-related costs. This condition often results in voiding dysfunction, which will affect quality of life. Moreover, this voiding disfunction can trigger chain of events leading to renal failure. Majority of the recommended treatment methods have low success rate⁸. A recent survey revealed that 86% of American urologists prefer internal urethrotomy when treating anterior urethral stricture⁹. However, internal urethrotomy is associated with a high rate of urethral stricture recurrence, ranging from 20 to 60%^10,11. Although several methods have been introduced to lower recurrence rate, including clean intermittent self-catheterization¹², numerous authors has labeled this a failure as it could not fully prevent recurrence of urethral stricture.

Despite unclear pathophysiology of urethral stricture, a pathophysiological mechanism suggested is fibrosis caused by excessive synthesis of collagen and altered extracellular matrix^13,14. Therefore, any drug or procedure which can delay fibrosis after internal urethrotomy would lead to an increase of surgical success rates and patient comfort, and therefore decrease treatment costs. Therefore, many studies have been performed to explore different molecules the can prevent fibrosis and urethral stricture recurrence^4,13–16.

Mitomycin-C is an alkylating antineoplastic antibiotic, produced by Streptomyces caespitosus. Mitomycin-C can inhibit DNA synthesis by linking adenine and guanine, resulting in DNA cross-linking. It can suppress cellular RNA and protein synthesis, and is not cell cycle specific⁸. Therefore, it can delay the healing process by preventing replication of fibroblasts and epithelial cells, as well as inhibiting collagen synthesis^6,14. It has been shown that mitomycin-C can improve the success rates of trabeculotomy and myringotomy by preventing proliferation of fibroblasts and development of fibrosis^18,19.

The anti-fibroblast activity mechanism of mitomycin-C is unknown. Experts have suggested that the reduction of fibroblast activity may be mediated by myofibroblasts apoptosis^2,4,11. As the wound closes, apoptosis of myofibroblast and vascular cells increases, indicating that this is the mechanism by which granulation tissue will lead to scarring^20,21.

All the studies included in this review treated the two groups equally and had relatively small loss-to-follow-up rates. A common problem with all the studies included in this review is that there was no clear blinding statement. In the study by Mazdak et al.⁴, it was not stated whether there was a randomization process in the study method. On the other hand, although Ali et al.² had randomized its subjects, age characteristics in the two groups were significantly different.

All studies support the use of mitomycin-C to prevent or delay anterior urethral stricture after internal urethrotomy. This was confirmed by a lower rate of recurrence rate in patients treated with mitomycin-C patients^2,4,7; we found that those who had mitomycin-C administered had lower incidence of recurrence during one year and 18 months of follow up (RR = 0.32, P < 0.001). This was also confirmed by a series of cases by Farrell et al.²², Farrell et al.²³, and Sourial et al.²⁴ Mazdak et al.¹¹ injected mitomycin-C into the submucosal layer of the urethra and reported lower rates of stricture recurrence in patients with mitomycin-C injection. On the other hand, some researchers proposed that submucosal injection might lead to an increase in complication rates and a decrease in the duration of the effective dose within the tissue¹⁹. Ayyildiz et al.²⁵ assessed the efficacy of mitomycin-C in preventing urethral scar by means of applying the agent topically to the traumatized region in rats. They concluded that mitomycin-C applied locally reduced fibrosis significantly in a dose-independent manner.

In stricture length, we found no statistically difference between the mitomycin-C-treated and control group in all studies. However, Mazdak et al. ⁴ and Moradi et al.⁷, even statistically showed no significant differences between these groups, the mitomycin-C-treated group showed a decrease in stricture length. The results of the study by Mazdak et al.⁴ were 0.76 mm (range:0.5-1 mm) in the mitomycin-C group compared to 0.84 mm (range:0.5-1 mm) in the control group after the procedure. Moradi et al.⁷ observed stricture lengths of 10.7±5.9 and 9.55±4.15 mm for the control and mitomycin-C groups, respectively.

Although all studies support the use of mitomycin-C to prevent or delay post-urethrotomy urethral stricture, the results of this review need to be followed up with caution. The limitation of this study can be seen from only a few studies that discuss this topic. Some of the existing studies are not enough to be applied to a wider population, given that selected studies were carried out only in Iran and Pakistan (and thus may not be representative of different ethnic groups)^2,4,7. Therefore, although the side effects reported in the studies reviewed are minimal, their application needs to be carried out wisely and cautiously. Research related to this in the future can still be done with different populations.

Due to short period of follow up time in all studies, some authors^2,4 concluded that the study of the use of mitomycin-C in this case needed firm results regarding long-term success. Mazdak et al.⁴ added that stricture may recur within two years after internal urethrotomy.

Conclusion

Mitomycin-C could be used as a potential additional treatment for anterior urethral strictures after internal urethrotomy. However, further studies are required to investigate the safety and efficacy of this method for treating anterior urethral strictures, as only a limited number of studies presently exist.

Data availability