Heterogeneity phenotypes in recurrent glioblastoma: a multimodal MRI-based spatial mapping framework for precision treatment.

Background: To develop a multimodal magnetic resonance imaging (MRI)-based spatial mapping framework for quantitatively characterizing intratumoral heterogeneity in recurrent glioblastoma (rGBM), identifying distinct imaging subregions, and classifying heterogeneity phenotypes predictive of treatment response and survival outcomes.

Methods: A total of 140 rGBM patients were recruited and underwent standardized diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Pixel-wise colocalization of apparent diffusion coefficient (ADC) and DCE-MRI features identified four Multimodal Imaging Subregions (MIS). Entropy and Moran's I quantified heterogeneity, and hierarchical clustering defined imaging phenotypes. Treatment response to 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), bevacizumab (Bev) + stereotactic radiotherapy (SRT), and Bev + CCNU was assessed by volumetric and component-level changes. Survival analyses were performed using Kaplan-Meier and multivariate Cox models.

Results: MIS4, defined by low ADC and slow-rising enhancement, was consistently treatment-resistant. Three imaging phenotypes with distinct heterogeneity patterns demonstrated significant prognostic stratification across regimens. Phenotype A showed the best outcomes under Bev-based regimens, while Phenotype B responded better to CCNU. Imaging phenotypes independently predicted progression-free survival (PFS) and overall survival (OS).

Conclusion: This framework enables spatially resolved, phenotype-based analysis of rGBM heterogeneity using routine MRI. Imaging phenotypes serve as non-invasive biomarkers to guide personalized treatment planning and outcome prediction in recurrent glioblastoma.

Clinical trial registration number: Not applicable.