Tumor Biology and Patterns of Recurrence in High-Grade Glioma: Implications for Radiation Target Delineation

Abstract: Purpose: Recurrence in high grade glioma (HGG) predominantly occurs within the high dose radiation field, raising the question of whether treatment failure reflects limitations in radiation target delineation or is driven by intrinsic tumor biology. This study evaluated recurrence patterns following standard chemoradiotherapy and their treatment implications. Material and Methods: This retrospective single center study included 41 patients with histologically confirmed HGG treated with surgery followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). Patients were followed through August 2018; those with recurrence were included in the analysis. Recurrence patterns were classified based on their spatial relationship to the 60 Gy isodose line as central, infield, marginal, or distant. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log rank test. Results: The most common pattern of recurrence was central (15 patients, 36.5%), followed by infield (11, 26.8%), distant (6, 14.6%), marginal (5, 12.1%), and multicentric (4, 9.8%). Central and in field recurrences (local failures) accounted for 26 patients (63%). Median overall survival (OS) was 27 months, and median progression-free survival (PFS) was 12 months. Survival differed significantly by recurrence pattern (log-rank p = 0.018), with marginal recurrence associated with more favorable outcomes. Conclusion: The predominance of central and infield recurrences within the high-dose region suggests that treatment failure in HGG is not solely explained by inadequate target delineation and may also be driven, in part, by intrinsic tumor biology, including radioresistant subpopulations and tumor heterogeneity. Future strategies may benefit from incorporating biologically guided approaches alongside optimization of radiation treatment parameters.