Imaging Patterns of Glioblastoma Progression: Comparative Analysis of Sequential Proton Boost versus Conventional Photon Therapy

Abstract Background Glioblastoma is the most aggressive brain tumor, with a 5-year survival rate of only 8%. Radiotherapy plays a crucial role in multimodal treatment. With novel therapy approaches emerging, we evaluated specific imaging patterns of progression in patients treated with a sequential proton boost after standard radiochemotherapy. Methods We analyzed data from 144 patients with histologically confirmed glioblastoma (CNS-WHO grade4), 94 received a sequential proton boost and 50 underwent conventional photon radiation. Tumor progression was confirmed histologically or according RANO criteria. MRI segmentation was automated using CE-marked AI software, tumor voxels were classified by location (inside or outside the CTV) and CBV-perfusion status (inclusion-zone). Results At progression, the proton group showed significantly larger contrast-enhancing tumor volumes outside the CTV (P = .007), focused in the CTV-PTV-transition-zone (P = .004) with no significant difference inside the CTV (P = .43). Subgroup analysis revealed greater extra-CTV volumes in MGMT-unmethylated (P = .019), TERT-mutant (P = .004), and RTK II subtype patients (P = .044). Metabolically active tumor tissue showed no significant differences between groups, inside or outside the CTV (P = .15 and P = .30). Conclusion Sequential proton boost therapy was associated with a distinct spatial pattern of radiographic progression, characterized by increased contrast enhancement beyond the CTV, especially in the CTV-PTV-transition-zone, without a corresponding rise in metabolic activity. These findings are hypothesis-generating and may reflect radiobiological range-edge effects or treatment-related tissue responses rather than true tumor progression. Prospective studies integrating dosimetric and metabolic data are warranted to elucidate underlying mechanisms.