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 ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) dynamic positron emission tomography (dPET) 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 ¹⁸F-FMISO dPET was performed to investigate changes in tumor biomarkers of perfusion and hypoxia following cediranib treatment. Methods: Rats bearing HT29 colorectal xenograft tumors were imaged pre-treatment (n = 21) and randomized into vehicle control (0.5% methylcellulose w/v, n = 9) and cediranib-treated cohorts (3mg/kg/day over 2 or 7 days (T2 and T7; n = 6 in both groups)). 90-min dPET acquisitions were performed after administering 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 carried out using an irreversible one-plasma two-tissue compartment model to estimate kinetic rate constants K1, K1/k2 and k3, surrogates for perfusion, ¹⁸F-FMISO distribution volume and hypoxia-mediated entrapment, respectively. Tumor-to-blood ratios (TBR) were calculated on the last dynamic frame (80-90min). Tumors were assessed ex vivo by digital autoradiography and immunofluorescence for microscopic visualization of perfusion (pimonidazole) and hypoxia (Hoechst 33342). Results: Cediranib treatment resulted in significant reduction of ¹⁸F-FMISO mean voxelwise TBR, K1 and K1/k2 in both treatment groups (p<0.05). The k3 parameter was increased in both treatment groups, but only reached significance for the T2 group. No significant change in TBR, K1, K1/k2 or k3 was observed in control animals (p>0.2). Ex vivo tumor analysis confirmed the presence of hypoxic tumor regions that nevertheless exhibit relatively lower ¹⁸F-FMISO uptake. Conclusion: ¹⁸F-FMISO kinetic modeling reveals a more detailed response to antiangiogenic treatment than a single static image. Reduced mean K1 reflects a reduction in tumor vascular perfusion, whilst increased k3 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 following treatment with cediranib could be mistakenly interpreted as a global decrease, rather than 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.