When Surgical Innovation Outpaces Evidence: Does Modern Maximal Resection Require Re-Evaluation of Postoperative Radiotherapy in Glioblastoma?

Postoperative radiotherapy (RT) improves survival in glioblastoma, and its role in standard management is not disputed. The randomized trials establishing this benefit, however, were conducted before computed tomography, magnetic resonance imaging (MRI), molecular classification, and temozolomide (TMZ), in heterogeneous populations of "operated malignant glioma" treated with whole-brain or large-field RT versus best supportive care. Their pooled survival benefit (risk ratio 0.81; 95% CI 0.74-0.88) robustly answers the historical question they were designed to address. Since then, advances in surgery, imaging, molecular diagnostics, and systemic therapy have created a modern best-prognosis subgroup-young patients with excellent performance status, MRI-confirmed complete or supramaximal resection of an IDH-wildtype glioblastoma, and median survival approaching or exceeding three years-for whom no clearly defined historical counterpart exists. This perspective provides a structured appraisal of the directness of the landmark randomized evidence using GRADE concepts and translates that appraisal into a graded roadmap for future de-escalation trial designs. Across population, intervention, comparator, and outcomes, the historical trials exhibit substantial indirectness, while the only randomized RT-versus-no-RT evidence from the modern era derives from elderly patients representing the opposite prognostic extreme. This is not an argument against RT. The infiltrative biology of glioblastoma, predominantly in-field recurrence, and radioresistant stem-cell populations strongly support continued benefit. Rather, the unresolved question concerns the magnitude of benefit after maximal contemporary therapy and whether selected de-escalation strategies merit prospective evaluation. Our thesis is one of collective scientific equipoise regarding an unresolved evidence question rather than individual clinician equipoise or refutation of current standard care.