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

Abstract

Multiparametric imaging of tumor perfusion and hypoxia with dynamic ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) PET may allow for an improved response assessment to antiangiogenic therapies. Cediranib (AZD2171) is a potent inhibitor of tyrosine kinase activity associated with vascular endothelial growth factor receptors 1, 2, and 3, currently in phase II/III clinical trials. Serial dynamic ¹⁸F-FMISO PET was performed to investigate changes in tumor biomarkers of perfusion and hypoxia after cediranib treatment. <b>Methods:</b> Twenty-one rats bearing HT29 colorectal xenograft tumors were randomized into a vehicle-treated control group (0.5% methylcellulose daily for 2 d [5 rats] or 7 d [4 rats]) and a cediranib-treated test group (3 mg/kg daily for 2 or 7 d; 6 rats in both groups). All rats were imaged before and after treatment, using a 90-min dynamic PET acquisition after administration of 42.1 ± 3.9 MBq of ¹⁸F-FMISO by tail vein injection. Tumor volumes were delineated manually, and the input function was image-derived (abdominal aorta). Kinetic modeling was performed using an irreversible 1-plasma 2-tissue compartmental model to estimate the kinetic rate constants <i>K</i>₁, <i>K</i>₁/<i>k</i>₂, and <i>k</i>₃-surrogates for perfusion, ¹⁸F-FMISO distribution volume, and hypoxia-mediated entrapment, respectively. Tumor-to-blood ratios (TBRs) were calculated on the last dynamic frame (80-90 min). Tumors were assessed ex vivo by digital autoradiography and immunofluorescence for microscopic visualization of perfusion (pimonidazole) and hypoxia (Hoechst 33342). <b>Results:</b> Cediranib treatment resulted in significant reduction of mean voxelwise ¹⁸F-FMISO TBR, <i>K</i>₁, and <i>K</i>₁/<i>k</i>₂ in both the 2-d and the 7-d groups (<i>P</i> < 0.05). The <i>k</i>₃ parameter was increased in both groups but reached significance only in the 2-d group. In the vehicle-treated groups, no significant change in TBR, <i>K</i>₁, <i>K</i>₁/<i>k</i>₂, or <i>k</i>₃ was observed (<i>P</i> > 0.2). Ex vivo tumor analysis confirmed the presence of hypoxic tumor regions that nevertheless exhibited relatively lower ¹⁸F-FMISO uptake. <b>Conclusion:</b>¹⁸F-FMISO kinetic modeling reveals a more detailed response to antiangiogenic treatment than a single static image is able to reveal. The reduced mean <i>K</i>₁ reflects a reduction in tumor vascular perfusion, whereas the increased <i>k</i>₃ reflects a rise in hypoxia-mediated entrapment of the radiotracer. However, if only late static images are analyzed, the observed reduction in ¹⁸F-FMISO uptake after treatment with cediranib may be mistakenly interpreted as a global decrease, rather than an increase, in tumor hypoxia. These findings support the use of ¹⁸F-FMISO kinetic modeling to more accurately characterize the response to treatments that have a direct effect on tumor vascularization and perfusion.