The authors have declared that no competing interests exist.
Conceived and designed the experiments: YF SC. Performed the experiments: YF SC LX. Analyzed the data: YF SC JH. Contributed reagents/materials/analysis tools: YF YL SC. Wrote the paper: YF.
A number of published comparative studies have been conducted to evaluate the efficacy and safety of intraoperative mitomycin C (MMC) in endoscopic dacryocystorhinostomy (EN-DCR). However, results have not always been consistent. Therefore, we carried out a meta-analysis to compare the clinical results of EN-DCR with and without MMC.
A comprehensive literature search of Cochrane Library, PubMed and EMBASE to identify relevant trials comparing EN-DCR with and without MMC. Eleven studies including 574 eyes were included in this meta-analysis. The success was defined as patency of the nasolacrimal canal and symptomatic improvement. There was significantly higher success rate in the MMC group in comparison with control group [RR = 1.12, 95% CI (1.04, 1.20), P = 0.004]. A sensitivity analysis after the non-randomized controlled trials were excluded from the meta-analysis demonstrated no differences compared with the overall results. Subgroup analyses showed that MMC group had a significantly higher success rate than control group in primary and revision EN-DCR, and EN-DCR without silicone intubation, but no difference in the subgroup of with silicone intubation. The size of the osteotomy site was bigger in the MMC group compared to the control group at 3 months [WMD = 7.65, 95% CI (0.33, 14.98), P = 0.041] and 6 months [WMD = 9.28, 95% CI (2.45, 16.11), P = 0.008] after surgery. However, there was statistically significant difference in the osteotomy surface area between the two groups at 12 months after surgery [WMD = 11.63, 95% CI (−1.04, 24.29), P = 0.072].
Intraoperative MMC application seems to be a safe adjuvant that could reduce the closure rate of the osteotomy and enhance the success rate after both primary and revision EN-DCR.
ClinicalTrials.gov
Nasolacrimal duct obstruction (NLDO) is a common cause for ophthalmologic evaluation. The advent of dacryocystorhinostomy (DCR) provided a revolution in the management of tearing secondary to nasolacrimal duct obstruction. It can be performed through an external or endonasal approach. The endonasal approach was introduced by Caldwell in 1893
Mitomycin C (MMC) is an antineoplastic agent that inhibits the synthesis of DNA, cellular RNA, and protein by inhibiting the synthesis of collagen by fibroblasts
Recently, many controlled trials have investigated adjunctive MMC for primary or revision EN-DCR to augment the surgical success rate, but the results are not completely consistent
Following generally accepted methodology recommendations, this meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement (
Reports of clinical trials comparing EN-DCR with and without MMC were identified through a systematic search. The following electronic databases were searched: PubMed, Embase and the Cochrane Central Register of Controlled Trials from January 1, 1990 to December 30, 2012. A comprehensive search was conducted using the following terms “dacryocystorhinostomy”, “mitomycin C” and “nasolacrimal duct obstruction”. Language restrictions were not used. Retrieved studies from both PubMed and Embase were imported into Refworks (version 1.0; Refworks, Bethesda, MD) where duplicate articles were manually deleted. Titles and abstracts of the remaining studies were independently scanned by 2 authors (S.M.C. and Y.F.F.). The full texts of the potentially relevant reports were then read to determine whether they met our inclusion criteria. In addition, the reference lists from all identified studies were also examined.
The following selection criteria were used to identify published studies for inclusion in this meta-analysis: (1) comparative studies; (2) adult patients (>18 years) with NLDO undergoing primary or revision EN-DCR; and (3) all studies included were required to provide the success rates of both MMC and control groups, and the followed up time was more than 6 months. The following were excluded: (1) studies which did not provide the success rates; and (2) studies which included pediatric cases. Where multiple publications based on the same cohort were identified, the report with the largest number of patients was used.
Date extraction and quality assessment was performed according to the customized protocol by two reviewers (S.M.C. and Y.F.F.) independently. We extracted the following data from the eligible studies: (1) general characteristics (title, first author, journal and year of publication); (2) methodology (type of study, country of origin, sequence generation, allocation concealment, masking or blinding, incomplete outcome data, selective reporting and other sources of bias); (3) subjects (recruitment site, enrollment periods, inclusion criteria, exclusion criteria, general patient characteristics); (4) Interventions (concentration of MMC and expose time); (5) types of EN-DCR (primary and recurrent); (6) outcomes (measurement, follow-up time and loss of follow-up); (7) analysis (statistical methods); (8) results (quantitative results and qualitative results). Any disagreement was resolved by discussion or consensus involving a third reviewer (J.H.H.) when necessary.
The qualities of randomized controlled trials (RCTs) were assessed by two independent observers (S.M.C. and Y.F.F.) using a Jadad composite scale
The primary outcome measure was success rate, which was determined by the presence of any one of the following: (1) patent lacrimal passage on syringing, (2) symptomatic improvement, and (3) endoscopic visualisation of fluorescein dye at the nasal opening of the anastomoses. The secondary outcome measure that we have reviewed was the difference in ostium size between patients operated with EN-DCR with MMC and patients operated with EN-DCR without MMC. We also reviewed the most common adverse events that were reported such as haemorrhage, infection, granulation or wound dehiscence.
The meta-analysis was conducted using Stata software package (version 11.0; Stata Corp., College Station, TX). The success rate was treated as dichotomous variables, whereas ostium size was treated as continuous variable. Dichotomous data were presented as relative ratio (RR) with 95% confidence interval (CI). Weighted mean differences (WMD) with 95% CI were calculated for continuous variables. Both ORs and WMDs were considered statistically significant at the P<0.05 level.
Statistical heterogeneity was analyzed using a chisquare test
The selection of studies is summarized in
Selig |
USA | 8 | Yes | 88 | 10 | 0.4 mg/mL | 3 to 5 min |
Zilelioğlu |
Turkey | 64 | Yes | 80 | 11.3 (6–60) | 0.5 mg/mL | 2.5 min |
Yuen |
China | 99 | Yes | 80 | (17.6–25.6) | 0.4 mg/mL | 5 min |
Nemet |
Australia | 5 | Yes | 80 | 15.4 (8–19) | 0.3 mg/mL | unknown |
Dolmetsch |
Colombia | 224 | Yes | 95 | 18.2 (6–108) | 0.5 mg/mL | 10 min |
Apuhan |
Turkey | 22 | Yes | 91 | 18 (6–30) | 0.5 mg/mL | 2.5 min |
Görgülü |
Turkey | 20 | Yes | 90 | 17 (12–24) | 0.2 mg/mL | 5 min |
Mak |
China | 83 | Yes | 94 | 23.3 | 0.2 mg/mL | 3 to 10 min |
The studies were published between 1998 and 2012, and comprised a total of 574 eyes (291 in the MMC group and 283 in the control group). One study was divided into two comparative groups as it included both primary and revision DCRs. Three studies were done in India
Qin |
China | RCT | 0.4 mg/mL | 3 min | 73 (39/34) | 12∶23/9∶21 | 12 | Yes | Primary |
Ghosh |
India | RCT | 0.2 mg/mL | 2 min | 30 (15/15) | 12∶18 | 12 | No | Primary |
Prasannaraj |
India | RCT | 0.2 mg/mL | 10 min | 38 (17/21) | 16∶22 | 6 | No | Primary |
Mudhol |
India | RCT | 0.2 mg/mL | 5 min | 60 (30/30) | 15∶45 | 12 | No | Primary |
Tirakunwichcha |
Thailand | RCT | 0.5 mg/mL | 3 min | 50 (26/24) | 4∶22/5∶19 | 12 | Yes | Primary |
Farahani |
Iran | RCT | 0.2 mg/mL | 3 and 15 min | 92 (46/46) | 11∶35/13∶33 | 12.17±1.18/12.80±1.52 | Yes | Primary |
Penttilä |
Finland | RCT | 0.4 mg/mL | 5 min | 30 (15/15) | 2∶13/1∶14 | 6 | No | Recvison |
Özkiriş |
Turkey | RCT | 0.5 mg/mL | 5 min | 36 (18/18) | 11∶7/10∶8 | 11.5/12.7 | Yes | Recvison |
Ragab |
Egpty | RCT | 0.5 mg/mL | 10 min | 76 (38/38) | 27∶49 | 12 | Yes | Recvison |
Zilelioğlu |
Turkey | Non-RCT | 0.5 mg/mL; | 2.5 min | 40 (22/18) | 13∶26 | 18.2 | Yes | Primary and Recvison |
Özkiriş |
Turkey | Non-RCT | 0.5 mg/mL | 5 min | 54 (28/26) | 12∶16/12∶14 | 14.3/13.2 | No | Primary |
RCT = randomized-controlled trials; DCR = dacryocystorhinostomy; MMC = Mitomycin C.
The quality assessment of RCTs is shown in
Randomization | Appropriateness of Randomization | Single/Double Blind | Appropriateness of Blind | Withdrawals | ||
Qin |
1 | 0 | 0 | 0 | 1 | 2 |
Ghosh |
1 | 0 | 0 | 0 | 1 | 2 |
Prasannaraj |
1 | 1 | 1 | 1 | 1 | 5 |
Mudhol |
1 | 0 | 0 | 0 | 1 | 2 |
Tirakunwichcha |
1 | 1 | 1 | 1 | 1 | 5 |
Farahani |
1 | 0 | 1 | 1 | 1 | 4 |
Penttilä |
1 | 1 | 0 | 0 | 1 | 3 |
Özkiriş |
1 | 1 | 1 | 1 | 1 | 5 |
Ragab |
1 | 1 | 1 | 1 | 1 | 5 |
All of the eleven studies reported data for success rates. There was no statistical evidence of heterogeneity across these studies (I2 = 6.7%, P = 0.38), so the fix effect model was used for meta-analysis. The results are shown in
The four subgroups were used to produce the fix effect model for success rates. The results are as follows: Subgroup 1 (primary EN-DCR, eight studies
Three studies (recruiting 183 eyes)
No MMC-related complications were reported in all studies. Total seven cases of synechia were recorded in two studies
Publication bias is the term for what occurs when the research that appears in the published literature is systematically unrepresentative of the population of completed studies: The strongest and most positive studies are most likely to be published. An assessment using the Begg rank correction (
Findings from the present meta-analysis indicate that adjunctive intraoperative MMC application with EN-DCR surgery had a significantly higher success rate than EN-DCR surgery without MMC. Sensitivity and subgroup analysis also suggested that the results were comparatively reliable. Moreover, in three studies included in this meta-analysis, mean ostium size was significantly bigger in MMC group than that in control group at 3, 6 months postoperatively. However, the difference of mean ostium size was not significant between two groups at 12 months postoperatively.
The most common reason for the failure of this operation is the formation of scar or granulation tissue over the rhinostomy site
Only three trials compared the ostium size between MMC groups and control group after surgery
There is a difference of opinion as to whether a silicone tube should be inserted. To prevent obliteration of the intranasal lacrimal sac ostium, many surgeons prefer to insert either bi- or monocanalicular silicone tubes to stent the internal ostium. However, it has been postulated that silicone tubing itself may cause tissue granulation, predisposing the site to postoperative infection and adhesions, and canalicular lacerations, resulting in surgical failure
Some complications such as corneal ulcus, corneal perforations, scleral calcification, secondary cataract, endophthalmitis, hypotony and maculopathy have been reported from the use of MMC in pterygium and glaucoma surgery
After surgery, there is a natural tendency for the stoma to contract during the healing process, hence, the follow-up period must be adequate to accommodate completion of this healing process. An analysis by Boush and associates
This meta-analysis may have some limitations. First, two comparative studies included in the analysis were not randomized, which may leave them vulnerable to bias. Although the Begg and the Egger test demonstrated no evidence of publication bias, the results should be interpreted with caution publication bias. Second, a potential source of heterogeneity in the results was the different concentrations and exposure time of MMC application. In the current systematic review of eleven studies, the dose of MMC used ranged between 0.2 and 0.5 mg/mL and the exposure time from 2–15 minutes. Thus, a further controlled study with a large sample size is needed to evaluate the optimum concentration, as well as applied duration of MMC for EN-DCR. This may provide more conclusive information for determining whether intraoperative MMC in EN-DCR is a safe and effective adjuvant.
In summary, this meta-analysis suggests that intraoperative MMC application seems to be a safe adjuvant that could help achieve favorable success rates and reduce the closure rate of the osteotomy site after EN-DCR.
PRISMA checklist.
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