Multiparametric Imaging of Tumor Hypoxia and Perfusion with¹⁸F-Fluoromisonidazole Dynamic PET in Head and Neck Cancer

Abstract

Tumor hypoxia and perfusion are independent prognostic indicators of patient outcome. We developed the methodology for and investigated the utility of multiparametric imaging of tumor hypoxia and perfusion with 18 F-fluoromisonidazole ( 18 F-FMISO) dynamic PET (dPET) in head and neck cancer. Methods: One hundred twenty head and neck cancer patients underwent 0-to 30-min 18 F-FMISO dPET in a customized immobilization mask, followed by 10-min static acquisitions starting at 93 6 6 and 160 6 13 min after injection. A total of 248 lesions ($2 cm 3 ) were analyzed. Voxelwise pharmacokinetic modeling was conducted using an irreversible 1-plasma 2-tissuecompartment model to calculate surrogate biomarkers of tumor hypoxia (k 3 ), perfusion (K 1 ), and 18 F-FMISO distribution volume. The analysis was repeated with truncated dPET datasets. Results: Substantial inter-and intratumor heterogeneity was observed for all investigated metrics. Equilibration between the blood and unbound 18 F-FMISO was rapid in all tumors. 18 F-FMISO distribution volume deviated from the expected value of unity, causing discrepancy between k 3 maps and total 18 F-FMISO uptake and reducing the dynamic range of total 18 F-FMISO uptake for quantifying the degree of hypoxia. Both positive and negative trends between hypoxia and perfusion were observed in individual lesions. All investigated metrics were reproducible when calculated from a truncated 20-min dataset. Conclusion: 18 F-FMISO dPET provides the data necessary to generate parametric maps of tumor hypoxia, perfusion, and radiotracer distribution volume. These data clarify the ambiguity in interpreting 18 F-FMISO uptake and improve the characterization of lesions. We show total acquisition times can be reduced to 20 min, facilitating the translation of 18 F-FMISO dPET into the clinic.

Monitoring early response to chemoradiotherapy with 18F-FMISO dynamic PET in head and neck cancer

“…Voxelwise pharmacokinetic modeling of FMISO dPET images was performed in PMOD v3.604 (PMOD Technologies GmbH), utilizing an irreversible one-plasma two-tissue compartment model [18]. The output of the pharmacokinetic modeling are three kinetic rate constants: K 1 , the kinetic rate constant describing transport from the vascular compartment to the extravascular tissue compartment and a surrogate biomarker of tumor perfusion, k 2 , the kinetic rate constant describing the transport of FMISO from the extravascular tissue compartment back to blood and k 3 , the kinetic rate constant approximating the rate of irreversible binding of FMISO and a surrogate for hypoxia-mediated entrapment.…”

“…DV represents the total FMISO distribution volume i.e., overall concentration of unbound FMISO relative to blood, and sets the threshold above which FMISO accumulation is due to hypoxia specific binding. DV was previously shown to be non-uniform across a tumor upon tracer equilibration [18]. The input function (IF) was delineated on ipsilateral (with respect to the lesion) jugular vein on the early dynamic frame with the highest image intensity, by selecting ~100 hottest voxels.…”

“…PET imaging with 18 F-fluoromisonidazole (FMISO), the most extensively studied hypoxia PET radiotracer, has been shown to be clinically feasible [14, 15] and reproducible [16, 17]. However, Tumor-to-Blood Ratio ( TBR ) or Tumor-to-Muscle Ratio ( TMR ), metrics derived from static FMISO acquisitions that are commonly used as surrogate biomarkers of tumor hypoxia, depend on the exact time point at which images are obtained; in addition, TBR and TMR also depend on the FMISO distribution volume that is non-uniform both within and between tumors [18]. Therefore, presence and extent of hypoxia may be over- or underestimated with this approach.…”

18F-Fluoromisonidazole Kinetic Modeling for Characterization of Tumor Perfusion and Hypoxia in Response to Antiangiogenic Therapy

“…18 F-fluoromisonidazole ( 18 F-FMISO) is the most widely used PET radiotracer for noninvasive, quantitative, reproducible, and clinically feasible imaging of tumor hypoxia (7)(8)(9)(10)(11). However, 18 F-FMISO PET scans are usually performed in static mode (9), which does not allow for the simultaneous assessment of blood flow and 18 F-FMISO distribution volume and may result in either underestimation or overestimation of the degree of tumor hypoxia (12). Multiparametric imaging presents an attractive opportunity for evaluating treatment response (13).…”

“…Simultaneous assessment of tumor perfusion and hypoxia can be achieved through kinetic modeling of dynamic 18 F-FMISO PET scans and carries several benefits. First, uncoupling the contribution of hypoxia-mediated entrapment to the total 18 F-FMISO signal results in a more accurate estimation of tumor hypoxia, since the variations in the 18 F-FMISO distribution volume combined with structurally and functionally abnormal vasculature may lead to low uptake in hypoxic regions or high uptake in normoxic regions even at later times after injection (12,16). Second, assessment of tumor perfusion is clinically relevant, as it is an indirect measure of angiogenesis and the delivery of nutrients and systemic agents to the tumor and may help in elucidating response mechanisms to both systemic and targeted treatments (17).…”