(18)F-fluoromisonidazole kinetic modeling for characterization of tumor perfusion and hypoxia in response to antiangiogenic therapy Journal Article
| Authors: | Grkovski, M.; Emmas, S. A.; Carlin, S. D. |
| Article Title: | (18)F-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 F-18-fluoromisonidazole (F-18-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 F-18-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 of F-18-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 K-1, K-1/k(2), and k(3)-surrogates for perfusion, F-18-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 voxelwise F-18-FMISO TBR, K-1, and K-1/k(2) in both the 2-d and the 7-d groups (P, < 0.05). The k(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, K-1, K-1/k(2), or k(3) was observed (P >0.2). Ex vivo tumor analysis confirmed the presence of hypoxic tumor regions that nevertheless exhibited relatively lower F-18-FMISO uptake. Conclusion: F-18-FMISO kinetic modeling reveals a more detailed response to antiangiogenic treatment than a single static image is able to reveal. The reduced mean K-1 reflects a reduction in tumor vascular perfusion, whereas the increased k(3) reflects a rise in hypoxia-mediated entrapment of the radiotracer. However, if only late static images are analyzed, the observed reduction in F-18-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 F-18-FMISO kinetic modeling to more accurately characterize the response to treatments that have a direct effect on tumor vascularization and perfusion. |
| Keywords: | sunitinib; reproducibility; angiogenesis; hypoxia; cediranib; contrast-enhanced mri; pet; perfusion; positron-emission-tomography; neck-cancer; f-18-fmiso; head; fluoromisonidazole; kinetic modeling; antiangiogenesis; f-18; azd2171 |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 58 |
| Issue: | 10 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2017-10-01 |
| Start Page: | 1567 |
| End Page: | 1573 |
| Language: | English |
| ACCESSION: | WOS:000411985900011 |
| DOI: | 10.2967/jnumed.117.190892 |
| PROVIDER: | wos |
| PMCID: | PMC5632735 |
| PUBMED: | 28360207 |
| Notes: | Article -- Source: Wos |
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