Survival Impact of Combined Biguanide and Temozolomide in Glioblastoma Preclinical Models: A Systematic Review and Meta-Analysis.

ABSTRACT

BACKGROUND: Glioblastoma (GBM) is an aggressive tumor known for its poor prognosis. Despite extensive research into its molecular and clinical aspects, the current management strategies have shown limited efficacy in improving survival rate. Despite some preclinical studies exploring the combination of temozolomide (TMZ) with biguanides such as metformin (MET) and others, the potential benefits of this combination remain uncertain. The aim of this study is to evaluate the overall survival (OS) in GBM murine-models treated with a combination of TMZ + biguanide compared to those treated with TMZ alone. METHODS: We systematically searched Medline, Embase, and Lilacs databases for studies comparing TMZ + biguanide versus TMZ alone in GBM models and reporting OS data. The mean difference (MD) with 95% confidence interval and random-effects model was adopted. RESULTS: Nine studies were included in this systematic review. The meta-analysis comprised 6 studies involving 85 rat-models, with 45 subjects undergoing combined-treatment. GBM-murine models treated with TMZ + biguanide exhibited notably superior OS rates compared to those who received TMZ alone, showing an MD of 21.0 days (6.9-35.0). Within the subgroup of orthotopic models, the OS was also significantly better in combination-therapy with an MD of 23.7 days (6.5-40.9). Similarly, in the subgroup where MET was used as biguanide therapy, TMZ + MET demonstrated a significant increase in OS, with an MD of 27.4 days (6.0-48.8). In immunocompromised models, the combination-therapy also exhibited higher survival rates, with an MD of 13 days (9.4-16.6). CONCLUSIONS: This systematic review and meta-analysis provide compelling evidence regarding the beneficial effects of TMZ + biguanide in GBM models compared with TMZ alone, resulting in a significant improvement in OS.