Efficacy and safety of ALA/MLA photodynamic therapy for superficial and nodular basal cell carcinoma: a systematic review and meta-analysis

Background: Basal cell carcinoma (BCC) is the most prevalent non-melanoma skin cancer, with surgical excision as the gold standard-though it carries risks of cosmetic scarring and functional impairment. Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) emerges as a non-invasive alternative, yet evidence on its relative efficacy across superficial (sBCC) and nodular (nBCC) subtypes remains inconsistent. Methods: This systematic review and meta-analysis adhered to PRISMA 2020 guidelines, with a comprehensive search of PubMed, Embase, Cochrane Library, and Web of Science up to December 31, 2025. Eligible studies included randomized controlled trials (RCTs) and single-arm studies evaluating ALA-PDT/MLA-PDT for histologically confirmed sBCC or nBCC. Study quality was assessed via the Methodological Index for Non-Randomized Studies (MINORS) scale, and statistical analyses were performed using Review Manager 5.4. Results: A comprehensive literature search identified 3832 records, with 55 eligible studies (41 for sBCC, 34 for nBCC) ultimately included, involving 2123 patients and 2995 lesions. For sBCC, the pooled complete response (CR) rate was 0.88 (95% CI: 0.85-0.91, p<0.00001) with high heterogeneity (I²=87%); no significant difference in CR rate was observed between ALA-PDT (0.87) and MAL-PDT (0.90) (p=0.47), and BF-200 ALA-PDT achieved a CR rate of 0.90. The pooled beauty effect rate for sBCC was 0.91 (95% CI: 0.87-0.95, p<0.00001), with a low pooled adverse event incidence of 0.08 (95% CI: 0.03-0.14, p=0.004) and a pooled recurrence rate of 0.13 (95% CI: 0.09-0.18, p<0.00001). For nBCC, the pooled CR rate was 0.75 (95% CI: 0.70-0.80, p<0.00001, I²=92%), with MAL-PDT (0.78) showing a statistically significant higher CR rate than ALA-PDT (0.69) (p=0.04); BF-200 ALA-PDT and AFL-MAL-PDT achieved CR rates of 0.89 and 0.84, respectively. The pooled beauty effect rate for nBCC was 0.90 (95% CI: 0.83-0.96, p<0.00001), with a pooled recurrence rate of 0.15 (95% CI: 0.10-0.20, p<0.00001); adverse event data were insufficient for pooling, with individual studies reporting mild, manageable local reactions. Subgroup analyses revealed that study design, light dose, and number of treatment sessions were the main factors contributing to heterogeneity in key outcomes. Conclusions: ALA/MAL-PDT is an effective and safe non-invasive therapeutic option for both sBCC and nBCC, with excellent cosmetic outcomes for both subtypes. MAL-PDT exhibits significantly superior efficacy in nBCC compared with ALA-PDT, while the two photosensitizers show comparable therapeutic effects in sBCC. Novel PDT formulations including BF-200 ALA-PDT and AFL-MAL-PDT demonstrate promising CR rates for BCC, providing new treatment alternatives for clinical practice. Standardization of treatment parameters (e.g., light dose, treatment sessions) and differentiation of study design types can effectively reduce heterogeneity in PDT efficacy evaluation, and ALA/MAL-PDT should be prioritized for patients seeking minimally invasive treatment, those with multiple lesions, or those with contraindications to surgical excision.