Using a pre-radiation window to identify potentially active cytotoxic agents in adults with newly diagnosed glioblastoma.

Therapies shown to improve outcomes in patients with recurrent cancers are commonly used in the neoadjuvant setting to optimize surgery, reduce radiation fields, and treat micrometastatic disease. While the use of pre-radiation chemotherapy (PRC) has flourished in systemic cancers, it has not seen the same level of use in glioblastomas. This review documents these trajectories and highlights the potential of PRC to rapidly and safely screen cytotoxic drugs for efficacy in patients with newly diagnosed glioblastoma. Prospective trials of adults with newly diagnosed systemic and brain cancers treated with PRC published between 1980 and 2023 were identified in PubMed. The National Comprehensive Cancer Network guidelines were used to document the standard use of PRC in patients with systemic and brain cancers. Over 5000 prospective PRC trials in solid tumors were identified. These accrued  >1 million patients and resulted in neoadjuvant therapies being the standard of care in ~28 systemic cancers. Only 50 similar trials (2206 patients) were identified in high-grade gliomas. In 13 trials containing PRC temozolomide (n = 846), radiographic responses ranged from 6 to 53% with a median survival of ~13 months. Glioblastoma PRC trials were not associated with unexpected toxicities or major negative impacts on survival. Pre-radiation chemotherapy in patients with glioblastoma appears safe and feasible. The pre-radiation window is ideally suited to rapidly screen cytotoxic agents for efficacy. It permits radiographic response as a primary outcome, small sample sizes, and initiation of standard therapies a few months after diagnosis. Pre-radiation chemotherapy may be most appropriate for patients with glioblastoma who are unlikely to benefit from temozolomide.