Efficacy and safety of 5-aminolevulinic acid-guided surgery versus white-light resection in newly diagnosed glioblastoma: a systematic review and meta-analysis.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour in adults, characterized by diffuse infiltration and poor prognosis despite multimodal therapy. Maximal safe surgical resection remains the cornerstone of management, as greater extent of resection (EOR) correlates with improved survival. However, conventional white-light microscopy often fails to distinguish tumour margins from surrounding functional brain tissue. 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery enhances intraoperative visualization by selectively accumulating protoporphyrin IX in tumour cells, allowing real-time delineation of malignant tissue. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of 5-ALA-guided resection compared with conventional white-light microsurgery in adults with newly diagnosed GBM. The review was conducted in accordance with PRISMA and Cochrane guidelines, and prospectively registered on PROSPERO (CRD420251160699). Comprehensive searches of PubMed, Embase, Scopus, Cochrane Library, and Google Scholar were performed from inception to July 2025. Randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs) comparing 5-ALA-guided and white-light surgery were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2.0 for RCTs and the Newcastle-Ottawa Scale for NRCTs. Meta-analyses were performed using random-effects models (RevMan 5.4), and outcomes were summarized as risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals (CIs). Certainty of evidence was graded using GRADE methodology. Seven studies involving 790 patients (three RCTs, four NRCTs) were included. Pooled analysis demonstrated that 5-ALA-guided surgery significantly improved gross total resection (GTR) compared with white-light microsurgery (RR = 1.54; 95% CI: 1.16-2.04; p = 0.003). Although 12-month overall survival (OS) did not differ significantly (RR = 1.31; 95% CI: 0.81-2.13; p = 0.27), mean OS was significantly prolonged with 5-ALA (MD = 2.89 months; 95% CI: 0.73-5.04; p = 0.009). Neurological morbidity was comparable between groups (RR = 1.31; 95% CI: 0.81-2.13; p = 0.27). Systematic evidence further supported higher EOR and lower subtotal resection rates with 5-ALA. Functional outcomes and progression-free survival (PFS) were generally similar, though some studies indicated modest PFS benefit. Safety analyses showed a low incidence of treatment-related adverse events, with photosensitization being the most frequent; neurological complication rates and perioperative mortality were comparable. 5-ALA-guided fluorescence surgery significantly enhances resection completeness in newly diagnosed GBM without increasing neurological morbidity and may confer modest survival benefit. Its favourable safety profile and reproducible efficacy support its integration into standard neurosurgical protocols aimed at maximizing safe tumour removal. Future trials should incorporate molecularly stratified cohorts, standardized definitions of EOR and PFS, and long-term functional outcomes to identify patient subgroups deriving the greatest benefit.