Repeatability of quantitative ¹⁸F-FLT uptake measurements in solid tumors: an individual patient data multi-center meta-analysis

Introduction: 3′-deoxy-3′-[¹⁸F]fluorothymidine (¹⁸F–FLT) positron emission tomography (PET) provides a non-invasive method to assess cellular proliferation and response to antitumor therapy. Quantitative ¹⁸F–FLT uptake metrics are being used for evaluation of proliferative response in investigational setting, however multi-center repeatability needs to be established. The aim of this study was to determine the repeatability of ¹⁸F–FLT tumor uptake metrics by re-analyzing individual patient data from previously published reports using the same tumor segmentation method and repeatability metrics across cohorts. Methods: A systematic search in PubMed, EMBASE.com and the Cochrane Library from inception-October 2016 yielded five ¹⁸F–FLT repeatability cohorts in solid tumors. ¹⁸F–FLT avid lesions were delineated using a 50% isocontour adapted for local background on test and retest scans. SUV_max, SUV_mean, SUV_peak, proliferative volume and total lesion uptake (TLU) were calculated. Repeatability was assessed using the repeatability coefficient (RC = 1.96 × SD of test–retest differences), linear regression analysis, and the intra-class correlation coefficient (ICC). The impact of different lesion selection criteria was also evaluated. Results: Images from four cohorts containing 30 patients with 52 lesions were obtained and analyzed (ten in breast cancer, nine in head and neck squamous cell carcinoma, and 33 in non-small cell lung cancer patients). A good correlation was found between test–retest data for all ¹⁸F–FLT uptake metrics (R² ≥ 0.93; ICC ≥ 0.96). Best repeatability was found for SUV_peak (RC: 23.1%), without significant differences in RC between different SUV metrics. Repeatability of proliferative volume (RC: 36.0%) and TLU (RC: 36.4%) was worse than SUV. Lesion selection methods based on SUV_max ≥ 4.0 improved the repeatability of volumetric metrics (RC: 26–28%), but did not affect the repeatability of SUV metrics. Conclusions: In multi-center studies, differences ≥ 25% in ¹⁸F–FLT SUV metrics likely represent a true change in tumor uptake. Larger differences are required for FLT metrics comprising volume estimates when no lesion selection criteria are applied.