Combined PET imaging of tumor hypoxia and proliferation in Glioblastoma using a single injection of 18F‐FMISO and 18F‐FLT: Association with sites of subsequent recurrence

Abstract Background Glioblastoma (GBM) is characterized by intra‐tumoral heterogeneity, rapid proliferation, hypoxia‐driven radio‐resistance, and early recurrence. Gadolinium‐Enhanced MRI, the standard of care imaging modality for surgical and radiotherapy planning, lacks specificity for viable tumor burden, particularly in non‐enhancing regions. Purpose This pilot study aimed to evaluate whether preoperative dual‐tracer PET using a combined dose of 18 FMISO (hypoxia) and 18 FLT (proliferation) improves tumor delineation and predicts subsequent local recurrence compared with MRI. Methods Seven patients with WHO grade 4 gliomas (5 GBM, 2 IDH‐mutant astrocytomas) underwent preoperative dual‐[FMISO+FLT] static PET at 180 min post‐injection, and MRI. 6/7 patients underwent resection. Tumor volumes were segmented from PET, contrast‐enhanced T1 (T1‐Gd), and T2‐FLAIR. Postoperative resection cavities were delineated, and follow‐up MRI every 3 months was used to identify recurrence. PET‐defined tumor volumes extending beyond resection were correlated with subsequent recurrence sites. Results Thirteen lesions were analyzed; all showed [FMISO+FLT] uptake (mean activity concentration ratio 1.6 with the cerebellar cortex used as reference region). PET‐defined tumor volumes (9.2 cc) were slightly larger than T1‐Gd (7.9 cc) but smaller than T2‐FLAIR (28.8 cc). PET‐defined volumes frequently extended beyond MRI‐defined contours (mean non‐overlap 6.4 cc vs T1‐Gd; 1.5 cc vs. T2‐FLAIR). Of six patients undergoing resection, four developed local recurrence within 3.3 months. In all cases, recurrence arose within PET‐avid regions outside the resection cavity. The other two patients with complete resection of PET‐defined volumes showed a relatively prolonged progression‐free‐survival (PFS) and including one patient with overall survival exceeding 36 months. Conclusions Dual‐[FMISO+FLT] PET is feasible, safe, and can allow delineation of biologically viable tumor subregions, in particular within the MRI T2‐FLAIR volume. This approach prospectively identified sites of subsequent local recurrence and may improve surgical planning and radiotherapy dose escalation. Larger validation studies are warranted to establish dual‐tracer PET as a precision imaging paradigm in GBM.