Reconstruction matters: influence of EARL standards and BSREM in [18F]FET PET for distinguishing glioma progression from treatment-related changes

Differentiating progressive disease (PD) from treatment-related changes (TRC) in glioma remains challenging using magnetic resonance imaging (MRI) alone. Amino acid positron-emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([¹⁸F]FET) is increasingly applied in clinical practice, and the first guideline for PET-based Response Assessment in Neuro-Oncology (PET-RANO) has recently been developed. However, quantitative PET metrics are sensitive to image reconstruction, which may directly influence response classification and clinical interpretation. This study aimed to investigate how different reconstruction standards affect quantitative [¹⁸F]FET PET metrics and to what extent these differences impact clinical interpretation. Thirty-three patients with 42 lesions were analysed. In lesion‑based comparisons, both EANM Research Ltd. harmonization standard version 2.0 (EARL2) and block-sequential regularized expectation maximization using a β-value of 150 (BSREM150) yielded significantly higher standardized uptake values (SUV), tumour‑to‑background ratios (TBR), and biological tumour volumes (BTV) than EANM Research Ltd. harmonization standard version 1.0 (EARL1), and identified a greater number of lesions as measurable disease (MD). BTV differed across reconstructions; adapting the BSREM150 segmentation threshold to SUV ≥ 1.7 x mean background activity improved BTV concordance while preserving superior MD detection. Excellent discrimination between PD and TRC was observed for TBRmax across all reconstructions (area under the curve ≥ 0.94), although optimal thresholds were reconstruction‑specific (EARL1: 1.67; EARL2: 1.84; BSREM150: 2.39). At the patient level, EARL1 failed to identify three PD cases, whereas BSREM150 misclassified one TRC case as PD. Reconstruction standards substantially influence quantitative [¹⁸F]FET PET metrics and clinical interpretation. Applying universal thresholds across reconstructions risks misclassification, with EARL1 potentially underestimating tumour extent and BSREM150 increasing false-positive findings. Reconstruction-specific thresholds and neuro-oncology-specific harmonization frameworks are therefore essential for reliable [18F]FET PET assessment in routine clinical practice and PET-RANO implementation in multicentre trials.