title: 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 dynamic18F-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 dynamic18F-FMISO PET was performed to investigate changes in tumor biomarkers of perfusion and hypoxia after cediranib treatment.Methods: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 of18F-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 constantsK1,K1/k2, andk3-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).Results:Cediranib treatment resulted in significant reduction of mean voxelwise18F-FMISO TBR,K1, andK1/k2in both the 2-d and the 7-d groups (P< 0.05). Thek3parameter was increased in both groups but reached significance only in the 2-d group. In the vehicle-treated groups, no significant change in TBR,K1,K1/k2, ork3was observed (P> 0.2). Ex vivo tumor analysis confirmed the presence of hypoxic tumor regions that nevertheless exhibited relatively lower18F-FMISO uptake.Conclusion:18F-FMISO kinetic modeling reveals a more detailed response to antiangiogenic treatment than a single static image is able to reveal. The reduced meanK1reflects a reduction in tumor vascular perfusion, whereas the increasedk3reflects a rise in hypoxia-mediated entrapment of the radiotracer. However, if only late static images are analyzed, the observed reduction in18F-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 of18F-FMISO kinetic modeling to more accurately characterize the response to treatments that have a direct effect on tumor vascularization and perfusion.
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Milan
authors.initials: M
authors.lastname: Grkovski
authors.affiliation: Imaging Team, Personalised Healthcare and Biomarkers, AstraZeneca, Macclesfield, United Kingdom; and.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Emmas
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York carlins@mail.med.upenn.edu.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Carlin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001775:Blood Circulation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007700:Kinetics; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000378:metabolism; D008954:Models, Biological; D049268:Positron-Emission Tomography; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D000072258:Tumor Hypoxia / Q000187:drug effects*; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D008920:Misonidazole; D011799:Quinazolines; C031843:fluoromisonidazole; C500926:cediranib; D007211:Indoles
keywords: 18F-FMISO; antiangiogenesis; cediranib; hypoxia; kinetic modeling; perfusion