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

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. We systematically searched Medline, Embase, and Lilacs databases for studies comparing TMZ+Biguanide vs. TMZ-alone in GBM-models and reporting OS data. Mean difference (MD) with 95%-CI and random-effects model was adopted. 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 a 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 a 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 a MD of 27.4 days (6.0-48.8). In immunocompromised models, the combination-therapy also exhibited higher survival rates, with a MD of 13 days (9.4-16.6). 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.

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