The Role of 5-Fluorouracil as an Adjuvant Antifibrotic Agent Post-Trabeculectomy : A Systematic Review of Randomized Controlled Trials and Primary Studies

Abstract

Introduction: Trabeculectomy remains the gold-standard surgical intervention for medically refractory glaucoma; however, long-term success is critically limited by excessive subconjunctival fibrosis. 5-Fluorouracil (5-FU), a pyrimidine antimetabolite inhibiting thymidylate synthase and fibroblast proliferation via S-phase arrest, has been employed as an adjuvant antifibrotic agent for over four decades. This systematic review consolidates evidence on ten primary clinical outcomes of 5-FU adjuvant therapy in trabeculectomy. Methods: The study strictly adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines. Inclusion criteria comprised RCTs, cohort studies, case-control studies, cross-sectional studies, and observational primary studies reporting ≥1 of ten pre-specified outcomes. Risk of bias was assessed using Cochrane RoB 2.0 for RCTs and Newcastle-Ottawa Scale for observational studies. PRISMA 2020 guidelines were followed. Results: Eighteen primary studies (3,847 eyes) were included. 5-FU consistently reduced mean postoperative IOP by 40–55% versus baseline. Cumulative 5-year success (IOP ≤21 mmHg) was 77.8% with 5-FU versus 62.2% without (P=0.02). 5-FU significantly reduced medication burden (0.7±1.1 vs. 1.8±1.4 agents; P<0.0001). Corneal epitheliotoxicity occurred in 29–55% of patients. Bleb-related infection rates were higher with 5-FU (11.5% vs. 2.7%; P=0.05). Long-term IOP control showed gradual attrition with comparable outcomes to placebo at 8 years (P=0.24). Discussion: 5-FU demonstrates robust antifibrotic activity through inhibition of Tenon's fibroblast proliferation and modulation of TGF-β-driven wound healing. Efficacy appears comparable to mitomycin C in primary trabeculectomy, though MMC confers superior IOP reduction in high-risk eyes. Special populations including uveitic glaucoma demonstrate favorable outcomes with 5-FU. Conclusion: 5-Fluorouracil remains a clinically effective, relatively safe, and cost-accessible adjuvant antifibrotic agent for trabeculectomy, significantly improving IOP control, surgical success rates, and medication independence, particularly in low-to-moderate risk primary glaucoma, necessitating vigilant monitoring for corneal toxicity and bleb-related infection.