title: The role of necrosis, acute hypoxia and chronic hypoxia in18F-FMISO PET image contrast: a computational modelling study.
abstract: Positron emission tomography (PET) using18F-fluoromisonidazole (FMISO) is a promising technique for imaging tumour hypoxia, and a potential target for radiotherapy dose-painting. However, the relationship between FMISO uptake and oxygen partial pressure ([Formula: see text]) is yet to be quantified fully. Tissue oxygenation varies over distances much smaller than clinical PET resolution (<100 μm versus  ∼4 mm), and cyclic variations in tumour perfusion have been observed on timescales shorter than typical FMISO PET studies (∼20 min versus a few hours). Furthermore, tracer uptake may be decreased in voxels containing some degree of necrosis. This work develops a computational model of FMISO uptake in millimetre-scale tumour regions. Coupled partial differential equations govern the evolution of oxygen and FMISO distributions, and a dynamic vascular source map represents temporal variations in perfusion. Local FMISO binding capacity is modulated by the necrotic fraction. Outputs include spatiotemporal maps of [Formula: see text] and tracer accumulation, enabling calculation of tissue-to-blood ratios (TBRs) and time-activity curves (TACs) as a function of mean tissue oxygenation. The model is characterised using experimental data, finding half-maximal FMISO binding at local [Formula: see text] of 1.4 mmHg (95% CI: 0.3-2.6 mmHg) and half-maximal necrosis at 1.2 mmHg (0.1-4.9 mmHg). Simulations predict a non-linear non-monotonic relationship between FMISO activity (4 hr post-injection) and mean tissue [Formula: see text] : tracer uptake rises sharply from negligible levels in avascular tissue, peaking at  ∼5 mmHg and declining towards blood activity in well-oxygenated conditions. Greater temporal variation in perfusion increases peak TBRs (range 2.20-5.27) as a result of smaller predicted necrotic fraction, rather than fundamental differences in FMISO accumulation under acute hypoxia. Identical late FMISO uptake can occur in regions with differing [Formula: see text] and necrotic fraction, but simulated TACs indicate that additional early-phase information may allow discrimination of hypoxic and necrotic signals. We conclude that a robust approach to FMISO interpretation (and dose-painting prescription) is likely to be based on dynamic PET analysis.
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Warren
authors.forename: Mike
authors.initials: M
authors.lastname: Partridge
mesh_terms: D003198:Computer Simulation; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000378:metabolism; D008962:Models, Theoretical; D009336:Necrosis; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology*
chemical_list: D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D008920:Misonidazole; D010100:Oxygen