ResPGlioma: Impact of PET-Guided Resection on Survival in High-Grade Gliomas - A Multicenter Prospective Study

Background and Scientific Rationale: Glioblastoma (GBM), classified as a CNS WHO grade 4 tumor under the 2021 WHO Classification of Central Nervous System Tumors, is the most common and aggressive primary brain malignancy. Despite the current standard of care-maximal surgical resection followed by radiotherapy and chemotherapy-its prognosis remains poor, with a mean overall survival (OS) of approximately 15 months. [11]Surgery plays a critical role in disease control, as the extent of resection (EOR) is one of the few modifiable prognostic factors. Traditionally, surgical resection is guided by magnetic resonance imaging (MRI), primarily through gadolinium contrast-enhanced T1-weighted (CE-T1) and Fluid-attenuated inversion recovery (FLAIR) T2-weighted sequences. Although there is no universally accepted definition of gross total resection (GTR), a near-complete removal (90-100%) of the contrast-enhancing tumor volume is associated with better outcomes. [5, 6]However, glioma cells frequently infiltrate areas beyond the contrast-enhanced margins, often extending into the FLAIR hyperintense region. Resection of these regions has been shown to confer a survival benefit, albeit at the potential cost of functional deficits, as FLAIR hyperintensity is non-specific and may also represent peritumoral edema. [1]This challenge has led to the exploration of additional imaging modalities, such as positron emission tomography (PET), magnetic resonance spectroscopy, and hybrid imaging techniques, to improve glioma delineation.[4, 8] PET imaging, particularly using amino acid tracers such as 18F-DOPA, has emerged as a valuable tool for identifying the true biological extent of gliomas. Unlike 18F-fluorodeoxyglucose (18F-FDG), which lacks specificity in brain imaging, radiolabeled amino acids offer superior tumor-to-background contrast due to their selective uptake via the L-type amino acid transporters (LAT). [7]Molecular imaging with 18F-DOPA PET allows for the delineation of the so-called biological tumor volume (BTV), highlighting metabolically active and potentially more aggressive tumor regions. Importantly, the BTV frequently extends beyond the contrast-enhancing margins and, in some cases, may identify tumor areas not detected by FLAIR.[3, 10] Evidence supporting the oncological relevance of PET-guided resection is growing. Several studies have demonstrated that PET-defined tumor volumes correspond to regions of viable neoplastic tissue, and surgical resection of these hypercaptant areas has been associated with improved OS. [2]Among the various amino acid radiotracers available, 18F-DOPA has shown particular promise not only in assessing tumor grade and aggressiveness but also in monitoring treatment response and distinguishing true progression from treatment-related changes. [9] Preliminary data from the study initial cohort of 24 patients further support this approach. In a subset of 5 patients, histopathological analyses of different tissue samples confirmed that PET hypercaptant areas outside the contrast-enhancing tumor region harbored a high mitotic index and a significant neoplastic component. Notably, these areas exhibited a higher proliferation rate compared to regions identified solely through FLAIR imaging. These findings, presented at national and international neurosurgical conferences, reinforce the hypothesis that PET-guided resection may enhance oncological outcomes and warrant further investigation through a dedicated multicenter study.

This study seeks to validate the clinical utility of PET-guided glioma resection by comparing outcomes in patients undergoing PET-RM integrated surgery versus standard MRI-guided resection. The authors hypothesize that PET-guided resection will yield superior survival benefits, as it enables more selective yet extensive tumor removal, providing a more precise target for supramaximal resection refining the balance between oncological efficacy and functional preservation.

Objectives: The authors hypothesize that 18F-DOPA PET can provide a more reliable and achievable surgical target than FLAIR hyperintensity in supramaximal resection, as it may differentiate infiltrative tumor tissue from peritumoral edema. Since PET-defined tumor volumes are larger than contrast-enhancing regions but smaller than FLAIR hyperintensity, PET-guided resection could optimize the balance between maximal tumor removal and functional preservation, enhancing the maximal safe resection approach.

Furthermore, the authors hypothesize-supported by the study preliminary data-that PET hypercaptant areas beyond the contrast-enhancing tumor harbor viable tumor cells and should be considered a biologically relevant resection target.

The main objectives of the present study are: