Kinetic analysis of 3'-deoxy-3'-18F-fluorothymidine in patients with gliomas

3'-Deoxy-3'-fluorothymidine (FLT), a thymidine analog, is under investigation for monitoring cellular proliferation in gliomas, a potential measure of disease progression and response to therapy. Uptake may result from retention in the biosynthetic pathway or leakage via the disrupted blood-tumor barrier. Visual analysis or static measures of F-18-FLT uptake are problematic as transport and retention cannot be distinguished. Methods: Twelve patients with primary brain tumors were imaged for 90 min of dynamic F-18-FLT PET with arterial blood sampling. Total blood activity was corrected for labeled metabolites to provide an FLT input function. A 2-tissue compartment, 4-rate-constant model was used to determine blood-to-tissue transport (K-1) and metabolic flux (K-FLT). Modeling results were compared with MR images of blood-brain barrier (BBB) breakdown revealed by gadolinium (Gd) contrast enhancement. Parametric image maps of K, and KFLT were produced by a mixture analysis approach. Results: Similar to prior work with C-11-thymidine, identifiability analysis showed that K, (transport) and KFLT (flux could be estimated independently for sufficiently high K, values. However, estimation of KFLT was less robust at low K, values, particularly those close to normal brain. K, was higher for MRI contrast-enhancing (CE) tumors (0.053 +/- 0.029 mLg/min) than noncontrast-enhancing (NCE) tumors (0.005 +/- 0.002 mLg/min; P < 0.02), and K-FLT was higher for high-grade tumors (0.018 +/- 0.008 mL/min, n = 9) than low-grade tumors (0.003 +/- 0.003 mLg/min, n = 3; P < 0.01). The flux in NCE tumors was indistinguishable from contralateral normal brain (0.002 +/- 0.001 mL/g/ min). For CE tumors, K, was higher than KFLT. Parametric images matched region-of-interest estimates of transport and flux. However, no patient has F-18-FLT uptake outside of the volume of increased permeability defined by MRI T1 + Gd enhancement. Conclusion: Modeling analysis of F-18-FLT PET data yielded robust estimates of K, and KFLT for enhancing tumors with sufficiently high K, and provides a clearer understanding of the relationship between transport and retention of F-18-FLT in gliomas. In tumors that show breakdown of the BBB, transport dominates F-18-FLT uptake. Transport across the BBB and modest rates of F-18-FLT phosphorylation appear to limit the assessment of cellular proliferation using F-18-FLT to highly proliferative tumors with significant BBB breakdown.