“Early Imaging Marker of Progressive Glioblastoma: a window of opportunity”

ABSTRACT Background Therapeutic intervention at glioblastoma (GBM) progression, as defined by current assessment criteria, is arguably too late as second-line therapies fail to extend survival. Still, most GBM trials target recurrent disease. We propose integration of a novel imaging biomarker to more confidently and promptly define progression and propose a critical timepoint for earlier intervention to extend therapeutic exposure. Patients/Methods A retrospective review of 622 GBM patients between 2006-2019 yielded 135 meeting resection, clinical, and imaging inclusion criteria. We qualitatively and quantitatively analyzed 2000+ sequential brain MRIs (initial diagnosis to first progression) for development of T2 FLAIR signal intensity (SI) within the resection cavity (RC) compared to the ventricles (V) for quantitative inter-image normalization. PFS and OS were evaluated using Kaplan-Meier curves stratified by SI. Specificity and sensitivity were determined using a 2×2 table and pathology confirmation at progression. Multivariate analysis evaluated SI effect on the hazard rate for death after adjusting for established prognostic covariates. Recursive partitioning determined successive quantifiers and cutoffs associated with outcomes. Neurological deficits correlated with SI. Results Seventy-five percent of patients developed SI on average 3.4 months before RANO-assessed progression with 84% sensitivity. SI-positivity portended neurological decline and significantly poorer outcomes for PFS (median, 10 vs. 15 months) and OS (median, 20 vs. 29 months) compared to SI-negative. RC/V ratio ≥4 was the most significant prognostic indicator of death. Conclusions Implications of these data are far-reaching, potentially shifting paradigms for glioma treatment response assessment, altering timepoints for salvage therapeutic intervention, and reshaping glioma clinical trial design. KEYPOINTS Increased confidence in defining true tumor progression is of critical importance. Imaging markers preceding progression offer novel timepoints for salvage therapies. Earlier intervention might increase tumor therapy exposure and reshape clinical trial design. IMPORTANCE OF STUDY Therapeutic intervention at progression has failed to show benefit. Accurately defining progression impacts clinical decision-making, yet current response assessment criteria in glioblastoma remain unvalidated. The data presented identifies a highly sensitive brain tumor imaging biomarker, SI, which coincides with declining neurologic function and might supplement existing criteria to improve clinician confidence to declare GBM progression. Furthermore, as SI precedes current assessment guidelines by an average of 3.4 months, this finding might also offer an earlier window of opportunity for salvage therapeutic intervention and reshape glioma clinical trial design. This signal has been previously associated with glioma progression; however, prior studies were hampered by overly inclusive criteria and failed to make the innovative clinical and prognostic associations evidenced in our study. Prospective validation of the proposed imaging biomarker is currently underway as part of a centrally reviewed prospective interventional clinical trial for newly diagnosed GBM.