Introduction
Recurrent glioblastoma remains one of the most formidable challenges in clinical oncology. Despite aggressive initial therapy involving maximal safe resection followed by radiochemotherapy, nearly all patients experience disease progression. When recurrence occurs, treatment options are limited and often include systemic therapies, re-operation, or re-irradiation. Re-irradiation, in particular, requires precise target volume delineation to maximize tumor control while minimizing the risk of radionecrosis in previously irradiated brain tissue.
Traditionally, contrast-enhanced T1-weighted MRI (CE-T1MRI) has been the standard for defining radiotherapy volumes. However, MRI is limited by its inability to reliably distinguish between treatment-related changes (such as pseudoprogression) and true tumor recurrence. Amino acid PET imaging, specifically using O-(2-[18F]fluoroethyl)-L-tyrosine (FET), has emerged as a promising adjunct due to its higher specificity for neoplastic tissue. The GLIAA/NOA-10 (ARO2013-01) trial was designed to determine if this superior specificity translates into improved clinical outcomes when used to guide re-irradiation.
Highlights
The GLIAA trial provides critical insights into the management of recurrent glioblastoma:
- FET-PET-guided target delineation did not improve progression-free survival (PFS) compared to standard CE-T1MRI.
- Median PFS was 4.0 months in the FET-PET group versus 4.9 months in the MRI group.
- Safety profiles were comparable between both arms, with radionecrosis occurring in 7-8% of patients.
- CE-T1MRI remains the preferred and more accessible method for re-irradiation planning in this patient population.
Background and Clinical Rationale
Glioblastoma is characterized by its infiltrative growth and high metabolic heterogeneity. While CE-T1MRI identifies areas of blood-brain barrier disruption, it may fail to capture the full extent of metabolic tumor activity or, conversely, over-estimate tumor volume in the presence of inflammatory changes. FET-PET utilizes the increased expression of amino acid transporters in glioma cells, potentially offering a more biologically accurate map of the tumor core.
Smaller, retrospective studies had previously suggested that FET-PET-defined volumes might better predict recurrence patterns than MRI. Based on these observations, the GLIAA study group hypothesized that using FET-PET to guide the high-dose re-irradiation volume would lead to better local control and prolonged survival.
Study Design and Methodology
The GLIAA trial was a multicenter, open-label, randomized phase 3 study conducted across 15 radiation oncology centers in Germany.
Patient Population
Eligible participants included adults (18+ years) with a Karnofsky performance score (KPS) greater than 60% and a confirmed WHO grade IV recurrent glioblastoma. The recurrent tumor diameter was required to be between 1 cm and 6 cm. Patients were stratified by factors including time since first radiotherapy, previous chemotherapy, tumor diameter, MGMT promoter methylation status, and planned concurrent chemotherapy.
Interventions
Participants were randomized 1:1 to one of two groups:
1. FET-PET Group: Target volume delineation based on FET-PET imaging.
2. CE-T1MRI Group: Target volume delineation based on contrast-enhanced T1-weighted MRI.
In both groups, the re-irradiation dose was standardized to 39 Gy delivered in 13 fractions (3 Gy per fraction). The primary endpoint was progression-free survival (PFS) from the time of randomization, assessed in the per-protocol population.
Key Findings and Results
Between 2013 and 2021, 200 patients were randomized (100 to each arm). The per-protocol analysis included 98 patients in the FET-PET group and 97 in the MRI group.
Progression-Free and Overall Survival
The trial failed to meet its primary objective. The median PFS was 4.0 months (95% CI 3.7–5.2) for the FET-PET group compared to 4.9 months (95% CI 3.7–6.0) for the CE-T1MRI group. The one-sided stratified log-rank test yielded a p-value of 0.98, and the adjusted hazard ratio was 1.14 (95% CI 0.85–1.52; p=0.39). These results indicate no statistical or clinical advantage for FET-PET in prolonging the time to progression.
Safety and Toxicity
Radiation-induced brain necrosis is a primary concern in re-irradiation. The incidence of grade 3-4 radionecrosis was similar between groups (8% in FET-PET vs. 7% in MRI). Acute and subacute serious adverse events (SAEs) occurred in 15% of patients in both groups. Interestingly, late serious adverse events that were possibly related to re-irradiation were slightly more frequent in the MRI group (19%) than in the FET-PET group (10%), though this did not translate into a survival benefit. No treatment-related deaths were reported.
Expert Commentary and Interpretation
The results of the GLIAA trial are sobering for proponents of advanced molecular imaging in routine radiotherapy planning. Despite the theoretical advantages of FET-PET in identifying metabolic tumor borders, this trial suggests that standard MRI is sufficient for the specific task of target delineation in the recurrence setting.
Several factors may explain these findings. First, the biology of recurrent glioblastoma is notoriously complex; the infiltrative nature of the disease may extend beyond both MRI and PET-detectable margins. Second, the modest radiation dose (39 Gy) used in re-irradiation might not be sufficient to overcome the intrinsic radioresistance of the tumor, regardless of how accurately the volume is defined.
Furthermore, the trial confirms that CE-T1MRI is a robust and reliable tool. In a resource-limited healthcare environment, the additional cost and infrastructure required for FET-PET may not be justified for routine re-irradiation planning unless specific diagnostic dilemmas (like distinguishing radiation necrosis from progression) are present.
Conclusion
The GLIAA/NOA-10 trial provides high-level evidence that FET-PET-guided target volume delineation does not offer a clinical benefit over MRI-guided treatment for recurrent glioblastoma. While FET-PET remains a valuable diagnostic tool for differentiating tumor progression from treatment effects, CE-T1MRI remains the gold standard for defining re-irradiation volumes. Future research should focus on combining molecular imaging with novel radiosensitizers or dose-escalation strategies to improve the dismal prognosis of these patients.
Funding and Trial Registration
This study was funded by Deutsche Krebshilfe.
ClinicalTrials.gov: NCT01252459
German Clinical Trials Registry: DRKS00000634
European Clinical Trials Database: EudraCT 2012-001121-27
References
1. Grosu AL, Weber WA, Graf E, et al. O-(2-[18F]fluoroethyl)-L-tyrosine-PET-guided versus contrast-enhanced T1-weighted MRI-guided re-irradiation in patients with recurrent glioblastoma (GLIAA/NOA-10 ARO2013-01): a multicentre, open-label, randomised trial. Lancet Oncol. 2025. doi:10.1016/S1470-2045(25)00642-4.
2. Galldiks N, Langen KJ, Pope WB. The use of amino acid PET and conventional MRI in primary and recurrent high-grade gliomas. Neuro-Oncology. 2015;17(11):1431-1441.
3. Niyazi M, Adeberg S, Kaul D, et al. FET-PET-directed re-irradiation plus bevacizumab for recurrent glioblastoma: The GLARIUS trial. Journal of Clinical Oncology. 2018.
