Purpose: To image pancreatic cancer, which is highly hypoxic, with 18F-FAZA and estimate the physiological parameters of the tracer.
Methods: 20 patients with pancreatic ductal adenocarcinoma underwent 55 min of dynamic 18F-FAZA scans. The dynamic tissue time activity curve (TACs) were analysed using graphical methods â€“ Patlak and Logan plot to determine the reversibility of the tracer and using standard two tissue compartment model (S2TCM) as well as our developed kinetic model, the flow modified two tissue compartment model (F2TCM). F2TCM incorporates mean transit time through the blood vessel, which could significantly affect parameter estimations. Multivariate logistic regression was used to find the optimal parameter set for distinguishing normal tissue from hypoxia tumors.
Results: Graphical analysis showed that the tracer was reversibly bound and distribution volume (DV) determined by Logan plot was correlated to volumes determined by S2TCM and F2TCM. According to Akaike Information Criteria, F2TCM was a better fit than S2TCM. Logistic regression determined that two F2TCM parameters â€“ DV and dissociation rate constant (k4) could classify normal tissue from hypoxic tissue with sensitivity and specificity of 57% and 95% respectively while it is lower - 43% and 79 % for Loganâ€™s DV.
Conclusion: Contrary to accepted notion that 18F-FAZA is irreversibly bound, both graphical and kinetic analysis showed that the binding is reversible. The proposed mechanism is that the reduced metabolite, amino-FAZA, is conjugated to glutathione (amino-FAZA-GS) which is usually trapped in cells due to its hydrophilicity, however, in the presence of elevated multidrug resistance protein (MRP-1) in pancreatic tumor, amino-FAZA-GS can be â€˜pumpedâ€™ out of the cells leading to radioactivity washout or reversible binding. Besides distinguishing normal pancreatic tissue from hypoxic tumor, kinetic modeling allows evaluation of k4 which can be associated with MRP-1 activity, while the binding rate constant (k3) can be associated with glutathione activity.