Clinical and Genetic Markers of Vascular Toxicity in Glioblastoma Patients: Insights from NRG Oncology RTOG-0825

Academic Background

Glioblastoma (GBM) is a highly aggressive form of brain cancer, accounting for nearly 80% of malignant primary brain tumors. Despite standard treatments including surgical resection, radiotherapy, and chemotherapy, the survival period of patients remains short, with a median survival of only 12-15 months. During treatment, vascular toxicities such as thrombosis and hypertension are common side effects that may lead to treatment interruption or death. Specifically, thrombosis is associated with decreased survival in GBM patients, while hypertension is linked to longer progression-free survival and overall survival. Therefore, identifying risk factors for these vascular toxicities is crucial for improving clinical decision-making and treatment outcomes.

This study aims to explore the risk factors for thrombosis and hypertension in GBM patients during treatment through clinical and genetic markers, and to evaluate the role of these markers in predicting vascular toxicity.

Source of the Paper

This study was conducted by Joshua D. Strauss, Mark R. Gilbert, and other co-authors from several renowned institutions in the United States, including Baylor College of Medicine, National Institutes of Health, and MD Anderson Cancer Center. The paper was published in 2025 in the journal Neuro-Oncology, titled “Clinical and genetic markers of vascular toxicity in glioblastoma patients: insights from NRG Oncology RTOG-0825.”

Research Process

Study Population and Data Source

The data for this study were derived from the NRG Oncology RTOG-0825 clinical trial, a phase III randomized, double-blind, placebo-controlled trial investigating the efficacy of bevacizumab (Bev) combined with standard treatment in GBM patients. The study included 591 non-Hispanic white GBM patients, of whom 367 provided blood samples for genotyping.

Clinical Data Analysis

The researchers first analyzed the clinical data of the patients, assessing the incidence of thrombosis and hypertension and their relationship with patient survival. Thrombosis and hypertension were defined as events of grade ≥2 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Through univariate and multivariate regression analyses, the researchers identified clinical risk factors associated with thrombosis and hypertension.

Genome-Wide Association Study (GWAS)

A genome-wide association study (GWAS) was conducted on the 367 patients who provided blood samples to identify single nucleotide polymorphisms (SNPs) associated with thrombosis and hypertension. The researchers performed quality control on the genotyping data, retaining only samples with call rates ≥95%, minor allele frequency ≥5%, and in Hardy-Weinberg equilibrium. The significance threshold for GWAS was set at p ≤ 10^-7.

Integration of Clinical and Genetic Models

After identifying SNPs associated with thrombosis and hypertension, the researchers incorporated these SNPs as SNP-dose effect variables into the clinical risk prediction models, constructing the final genetic models. The predictive ability of the models was evaluated using 30-fold cross-validation and the area under the receiver operating characteristic curve (AUC).

Key Findings

Incidence of Thrombosis and Hypertension

Among the 591 patients, 11% experienced thrombosis, 10% experienced hypertension, and 1% experienced both vascular toxicities. The median time to thrombosis was 85 days after tumor resection, and the median time to hypertension was 115 days.

Survival Analysis

Patients with hypertension had significantly longer survival than those without hypertension (median overall survival: 25.72 months vs. 15.47 months, p = 0.002). In contrast, there was no significant difference in survival between patients with and without thrombosis (median overall survival: 14.03 months vs. 16.13 months, p = 0.20).

Clinical Risk Models

The clinical risk model for thrombosis showed that corticosteroid use (OR: 3.22, p = 0.01), absolute neutrophil count (ANC, OR: 1.009, p = 0.01), and body surface area (BSA, OR: 5.719, p = 0.002) were significant risk factors. In the clinical risk model for hypertension, bevacizumab use was the only significant predictor (OR: 2.45, p = 0.003).

Genetic Models

The genetic model for thrombosis included three SNPs (located on chromosomes 4, 7, and 18), and the dose effect of these SNPs significantly increased the risk of thrombosis (OR: 3.79, p < 0.0001). The genetic model for hypertension included six SNPs (located on chromosomes 2, 6, 9, 10, 12, and 13), and the dose effect of these SNPs significantly increased the risk of hypertension (OR: 4.44, p < 0.0001). The genetic model outperformed the clinical model in predicting hypertension (AUC: 0.820 vs. 0.614, p = 0.06).

Conclusions and Significance

By integrating clinical and genetic markers, this study successfully constructed models to predict vascular toxicity in GBM patients. The results indicate that corticosteroid use and body surface area are significant risk factors for thrombosis, while genetic variants have a significant advantage in predicting hypertension. Additionally, hypertension is associated with improved survival in GBM patients, suggesting that hypertension may be a positive prognostic marker.

The highlight of this study lies in the first-time incorporation of genetic markers into predictive models for vascular toxicity in GBM patients, revealing the important role of genetic variants in hypertension prediction. These findings not only provide new insights into personalized treatment for GBM patients but also offer references for bevacizumab treatment in other malignancies.

Research Value

This study provides important scientific evidence for the management of vascular toxicity in GBM patients, particularly through the use of genetic markers to predict the risk of hypertension, which may offer new tools for clinical decision-making. Furthermore, the findings suggest that hypertension during bevacizumab treatment may not be directly caused by the drug but rather related to the patient’s genetic background, which has important implications for the use of bevacizumab in other malignancies.

Other Valuable Information

The study also found that corticosteroid use is significantly associated with an increased risk of thrombosis, suggesting that corticosteroids should be used cautiously in GBM patients, and the possibility of prophylactic anticoagulation should be considered. Additionally, the study emphasizes the importance of collecting biological samples in clinical trials for future genetic analysis.

Through this study, the researchers not only provided new insights into the management of vascular toxicity in GBM patients but also offered important directions for future research, particularly in further exploring the relationship between genetic variants and vascular toxicity.