Image-guided PO2 probe measurements correlated with parametric images derived from 18F-fluoromisonidazole small-animal PET data in rats

Abstract

(18)F-fluoromisonidazole PET, a noninvasive means of identifying hypoxia in tumors, has been widely applied but with mixed results, raising concerns about its accuracy. The objective of this study was to determine whether kinetic analysis of dynamic (18)F-fluoromisonidazole data provides better discrimination of tumor hypoxia than methods based on a simple tissue-to-plasma ratio.

Methods: Eleven Dunning R3327-AT prostate tumor-bearing nude rats were immobilized in custom-fabricated whole-body molds, injected intravenously with (18)F-fluoromisonidazole, and imaged dynamically for 105 min. They were then transferred to a robotic system for image-guided measurement of intratumoral partial pressure of oxygen (Po(2)). The dynamic (18)F-fluoromisonidazole uptake data were fitted with 2 variants of a 2-compartment, 3-rate-constant model, one constrained to have K(1) equal to k(2) and the other unconstrained. Parametric images of the rate constants were generated. The Po(2) measurements were compared with spatially registered maps of kinetic rate constants and tumor-to-plasma ratios.

Results: The constrained pharmacokinetic model variant was shown to provide fits similar to that of the unconstrained model and did not introduce significant bias in the results. The trapping rate constant, k(3), of the constrained model provided a better discrimination of low Po(2) than the tissue-to-plasma ratio or the k(3) of the unconstrained model.

Conclusion: The use of kinetic modeling on a voxelwise basis can identify tumor hypoxia with improved accuracy over simple tumor-to-plasma ratios. An effective means of controlling noise in the trapping rate constant, k(3), without introducing significant bias, is to constrain K(1) equal to k(2) during the fitting process.

FIGURE 1

(A) Anesthetized rat immobilized in custom-fabricated foam mold, positioned on robot platform. Registration plate is centered over rat tumor. (B) Top image is rat tumor with OxyLite probe sampling PO₂ along predefined track. Bottom image is target region for sampling PO₂ as defined on 5-min static PET image.

FIGURE 2

Plots of data and fitted curve from single voxel of individual rat and corresponding partial-volume–corrected input function and fit from this same animal. (A) Data and fitted curve obtained using unconstrained model. (B) Data and fitted curve obtained using constrained model. (C) Partial-volume–corrected blood data and fit plotted on log linear scale such that peak of input function can be seen.

FIGURE 3

On left is image averaged over last 40 min, with ROI used to segment data for kinetic analysis overlaid in red and PO₂ probe trajectory overlaid in blue. Images on right are voxelwise kinetic maps for same slice and ROI shown on left. Overlaid onto each of these maps are corresponding PO₂ concentration measurements made at each of those corresponding voxel locations.

FIGURE 4

Registered histology images from single slice of rat tumor from each of 4 rats from which histology was obtained. Top row (blue-stained sections) shows histologic images of Hoescht 33342. Middle row (green-stained sections) shows histologic images of pimonidazole. Bottom row shows digital autoradiographs (DAR) of ¹⁸F-fluoromisonidazole.

FIGURE 5

Plots of Youden index vs. PO₂ threshold: unconstrained model (A) and constrained model (B).

FIGURE 6

Scatterplots of kinetic parameters estimated from constrained model (K₁ = k₂) vs. corresponding PO₂ measure. Red lines define optimal cut points selected by Youden indices. (A) k₃ vs. K₁. (B) k₃ vs. PO₂. (C) K₁ vs. PO₂. (D) T:P ratio vs. PO₂; blue line shows standard 1.4 threshold commonly applied in assessment of hypoxia.