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

This article discusses the potential role of pre-radiation chemotherapy (PRC) in selected patients with newly diagnosed glioblastoma, enabling early assessment of the efficacy of cytotoxic agents as viable therapeutic options. While neoadjuvant approaches have become standard in various systemic cancers, improving survival without increasing toxicity, this strategy was not observed in the treatment of glioblastomas, particularly since 2005, when temozolomide was recognized for achieving high response rates.

The authors conducted a comprehensive PubMed review of studies from 1980 to 2023 that focused on clinical trials involving PRC for patients with newly diagnosed systemic cancers and primary brain tumors. They identified only 50 PRC studies involving newly diagnosed high-grade gliomas, comprising a total of 2,206 patients, of whom 1,089 were diagnosed with glioblastoma. In contrast, over 5,000 trials have been conducted on neoadjuvant chemotherapy for systemic cancers.

Over the past 25 years, 13 trials have investigated the use of temozolomide in the PRC setting for high-grade gliomas, with seven reporting response rates. The median response rate observed was 39% and the median overall survival was 13 months. Patients received a median of three cycles of temozolomide, delaying radiation by 2 to 16 weeks. Patients were not well categorized in terms of IDH or MGMT status. 

Temozolomide given concurrently with radiation therapy is known to improve survival from 12 to 16 months, but most patients lacking MGMT methylation do not experience similar benefits. This highlights the need to investigate new agents that could improve prognoses for these patients. Unfortunately, most novel agents have been studied in patients with recurrent glioblastoma, at a stage when tumors exhibit significant resistance to treatment.

The central argument presented is the potential for utilizing novel cytotoxic agents in a PRC setting to assess their efficacy when tumors are more likely to respond. Radiological response rates could act as functional biomarkers for drug efficacy; if no response is observed within this short timeframe, the drug could be discontinued in favor of alternative agents or standard therapy. The authors advocate initiating PRC two weeks postoperatively, rather than waiting 4 to 6 weeks to start the standard therapy. A carefully selected group of patients, particularly those with unmethylated MGMT status and measurable contrast-enhancing tumors without significant mass effect, may derive substantial benefit from this approach.

The study is limited by several methodological issues. The review is not systematic and relies on heterogeneous historical trials spanning over four decades, many of which predate the adoption of critical molecular markers. Additionally, most included studies were small, underpowered, and inconsistent in reporting key outcomes such as toxicity and response rates. The lack of randomized controlled trials comparing PRC with standard post-surgical chemoradiotherapy limits the strength of the conclusions. Finally, the review does not sufficiently address the potential risks of delaying standard therapy.

New trials are essential to evaluate the use of cytotoxic agents in the pre-radiation window, aiming to ascertain the reliability, risks, and benefits of this strategy, its potential interference with standard therapy, and the identification of patients who would benefit most. Journal: Neuro-Oncology

Author: Bianca Gomes Wanderley, MD

Mini-CV: Neurological surgeon, Clinical fellow in Neurosurgical Oncology (SNOLA)