To compare the efficacy and safety of temozolomide– and lomustine–based chemotherapy regimens in glioblastoma multiforme through a systematic review and meta-analysis.

Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor survival despite multimodal therapy. Temozolomide (TMZ) remains standard under the Stupp protocol but offers limited benefit in patients lacking O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Lomustine (CCNU), an alkylating nitrosourea, has shown potential survival gains in MGMT-methylated GBM, yet its comparative efficacy and safety remain unclear.

A systematic search of PubMed, Google Scholar, ScienceDirect, and the Cochrane Library identified cohort studies and RCTs (up to October 6, 2025). Eligible studies included adult patients (≥18 years) with histologically confirmed GBM treated with TMZ- or CCNU-based regimens. Data on overall survival (OS), progression-free survival (PFS), and treatment-related hematological and neurological toxicities were extracted. Meta-analysis using Review Manager 5.4 estimated hazard ratios for OS and PFS and risk ratios for toxicities, with 95% confidence intervals.

Among 1,115 screened articles, six met inclusion criteria for the systematic review, and four (n = 793) were eligible for meta-analysis. Pooled analysis showed no significant difference in OS between CCNU- and TMZ-based regimens (HR = 0.88; 95% CI 0.60–1.29; p = 0.52). Sensitivity analysis excluding older trials revealed a survival advantage with CCNU-based therapy (HR = 0.64; 95% CI 0.55–0.74; p < 0.00001). No significant differences were found in PFS (HR = 1.15; 95% CI 0.84–1.59; p = 0.38), hematological toxicity (RR = 1.52; p = 0.10), or neurological toxicity (RR = 1.38; p = 0.13).

CCNU-based regimens may modestly improve survival over TMZ, particularly in MGMT-methylated, newly diagnosed GBM, without added toxicity. These findings support genotype-guided chemotherapy selection and highlight the need for biomarker-stratified trials to refine precision-based GBM treatment.