Translational Health Reports

Abstract Background: The established first-line treatment for newly diagnosed Glioblastoma Multiforme (GBM) involves maximal surgical removal of the tumor, followed by a regimen of radiotherapy (RT) together with concurrent and maintenance temozolomide (TMZ) chemotherapy. Patient response to this combined approach varies widely and is closely associated with the tumor's molecular characteristics.
Objective: This analysis compiles current research on how the RT/TMZ combination modifies crucial GBM biomarkers over time, focusing on therapy-induced alterations rather than their initial prognostic significance.
Methods: A systematic review of literature from January 2000 to July 2024 was performed using PubMed, Scopus, and Web of Science. Search keywords included "glioblastoma," "radiotherapy," "temozolomide," "MGMT," "IDH," "biomarker," and related terms. Emphasis was placed on clinical trials and key preclinical studies.
Results: The RT/TMZ protocol imposes significant selective pressure, dynamically influencing GBM biomarkers. MGMT promoter methylation is the primary predictor of TMZ efficacy, but treatment often leads to the expansion of MGMT-active, resistant tumor clones at recurrence. IDH1/2 mutations are strong prognostic indicators, and their associated metabolic changes may increase tumor sensitivity to DNA-damaging therapies. Treatment substantially reshapes the tumor immune microenvironment; RT can stimulate anti-tumor immune responses but also increase PD-L1 expression, while TMZ often causes severe lymphocyte depletion. Additionally, therapy promotes the selection of cells with enhanced DNA damage repair mechanisms and activates survival pathways such as EGFR, fostering treatment resistance.
Conclusion: RT and TMZ induce continuous, adaptive changes in GBM biomarkers. Recognizing this dynamic process is essential for personalizing treatment, assessing response, and developing new combination therapies to combat resistance.

Abstract Background: Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with a poor prognosis. Radiation therapy (RT) and temozolomide (TMZ) are standard treatments, but their impact on cognitive function is not well understood.

Objective: To investigate the effects of radiation dose and TMZ dose on cognitive function in patients with GBM treated with RT and TMZ.

Methods: This retrospective study included 162 patients with GBM treated with RT and TMZ between 2018 and 2023. Cognitive function was assessed using a comprehensive battery of neuropsychological tests, and MRI-based measures of cognitive function were obtained. Patients were categorized into three groups based on radiation dose received: low dose (< 50 Gy), moderate dose (50-60 Gy), and high dose (> 60 Gy). Follow ups were made up to 8 to 12 months after chemoradiotherapy.

Results: Patients in the high dose group performed significantly worse on executive function and memory tests, and had reduced white matter integrity and increased white matter hyperintensity volume compared to the low dose group. Higher TMZ doses were associated with poorer cognitive outcomes in executive function, memory, and reduced hippocampal volume. Linear regression analysis showed that higher radiation doses were associated with poorer cognitive outcomes in memory, and higher TMZ doses were associated with poorer cognitive outcomes in executive function, memory, and reduced hippocampal volume.

Conclusion: This study suggests that higher radiation doses and TMZ doses are associated with poorer cognitive outcomes in patients with GBM. These findings have important implications for the management of GBM, highlighting the need to minimize radiation dose and TMZ dose to prevent cognitive decline. Future studies are needed to confirm these findings and to explore strategies to mitigate the cognitive effects of RT and TMZ in patients with GBM.