Radiation therapy (RT) is the cornerstone of management of malignant brain tumors, but its efficacy is limited in hypoxic tumors. Although numerous radiosensitizer compounds have been developed to enhance the effect of RT, progress has been stagnant. Through this systematic review, we provide an overview of radiosensitizers developed to date for malignant brain tumors, summarize their safety and efficacy, and evaluate areas for possible improvement.
Following PRISMA guidelines, PUBMED, EMBASE, Cochrane, and Web of Science were searched using terminology pertaining to radiosensitizers for brain tumor RT. Publications reporting clinical evidence of non-antineoplastic radiosensitizers with RT for malignant CNS tumors were included. Data of interest were presumed mechanism of action, median overall survival (OS), progression-free survival (PFS), and adverse events.
Twenty-two unique radiosensitizers were identified. Only 2/22 agents, fluosol with oxygen, and efaproxiral, showed improvement in OS in patients with glioblastoma and brain metastasis, respectively. A larger study was not able to confirm the latter. Improved PFS was reported with use of metronidazole, sodium glycididazole, and chloroquine. There was a wide range of toxicities which prompted change of schedule or complete discontinuation of 9 agents.
Progress in the field of radiosensitizers for malignant CNS tumors has been limited. Only 2 radiosensitizers have shown limited improvement in survival. Alternative strategies such as synthetic drug design, based on a mechanism of action that is independent of crossing the blood-brain barrier, may be necessary. Employing drug development strategies using new technologies to overcome past challenges is necessary.

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