Electric Fields at the Blood–Brain Barrier: Electrochemotherapy and Electroporation-Based Therapies for Brain Tumors—A Narrative Review and Clinical Perspective

The blood–brain barrier (BBB) limits systemic treatment of glioblastoma and brain metastases. Electroporation-based therapies apply short, high-intensity electric pulses that transiently permeabilize cell membranes or ablate tissue. Electrochemotherapy (ECT) combines reversible electroporation with chemotherapy, markedly enhancing bleomycin cytotoxicity, whereas irreversible electroporation (IRE) and its high-frequency variant (H-FIRE) induce non-thermal ablation and transiently disrupt the BBB in preclinical models. This narrative review critically examines the current evidence and identifies priorities for clinical translation. The available data remain predominantly preclinical. In rat gliomas, ECT delivered through a dedicated intracranial electrode achieved complete tumor eradication in 69% of treated animals, with effects largely confined to the target region. IRE and H-FIRE have proved technically feasible in dogs with spontaneous intracranial tumors, and H-FIRE has prolonged survival in rodent glioma models. Clinical experience is minimal: a non-invasive approach combining transcranial magnetic stimulation with bleomycin was withdrawn before patient enrollment, and the only identified trial of intracranial ECT for brain metastases was terminated for slow recruitment without published results. Major barriers include the lack of human safety and efficacy data, of intracranial electrodes approved for clinical use, and of validated treatment-planning workflows, together with uncertain recruitment feasibility. We also discuss how intracranial ECT might complement central nervous system (CNS)-active systemic therapies in patients with limited intracranial progression and controlled extracranial disease. Although most evidence derives from glioma models, we propose that selected patients with brain metastases recurring after stereotactic radiosurgery represent a rational population for initial pilot studies.