Efficacy of 5-ALA Photodynamic Therapy in Dysplastic Oral Leukoplakia: Systematic Review and Meta-Analysis

Background: Oral leukoplakia (OL) with oral epithelial dysplasia (OED) carries an increased risk of malignant transformation and typically requires active management and long-term surveillance. Surgical excision remains the gold standard, yet recurrence is common and morbidity may be substantial, particularly in extensive or multifocal disease. Photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has emerged as a minimally invasive alternative. However, its effectiveness in dysplastic OL has not been quantified systematically. Methods: A systematic review and meta-analysis were conducted according to a prospectively registered protocol (PROSPERO: CRD420251249586) and reported in line with PRISMA 2020. PubMed, Scopus, and Web of Science were searched from inception to 15 December 2025 for clinical studies evaluating ALA-PDT as primary treatment for OL with histopathologically confirmed OED. Single-arm prospective or retrospective studies reporting clinical response were eligible. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Series. Pooled overall response rate (ORR) and complete response (CR) were estimated as proportions using random-effects models. Recurrence and malignant transformation were summarized as incidence rates per 100 person-years. Results: Six single-arm clinical studies including 109 patients with dysplastic oral leukoplakia treated with 5-ALA-mediated photodynamic therapy were eligible for quantitative synthesis. The pooled overall response rate was 0.85 (95% CI 0.74-0.93), whereas the pooled complete response rate reached 0.34 (95% CI 0.18-0.53), with moderate to substantial heterogeneity. Recurrence and malignant transformation outcomes were limited and analyzed descriptively, suggesting low but persistent long-term risk. The overall certainty of the evidence was rated as very low according to GRADE. Conclusions: 5-ALA-mediated photodynamic therapy appears to be an effective and minimally invasive treatment option for oral leukoplakia with epithelial dysplasia; however, the very low certainty of evidence, lack of standardized protocols, and persistent risk of recurrence and malignant transformation highlight the need for well-designed controlled studies and long-term clinical surveillance.