¹⁸F-Fluoromisonidazole Quantification of Hypoxia in Human Cancer Patients Using Image-Derived Blood Surrogate Tissue Reference Regions

Abstract

18F-FMISO is the most widely used PET agent for imaging hypoxia, a condition associated with resistance to tumor therapy. 18F-FMISO equilibrates in normoxic tissues, but is retained under hypoxic conditions because of reduction and binding to macromolecules. A simple tissue-to-blood ratio (TB) is suitable for quantifying hypoxia. A threshold of TB ≥ 1.2 is useful in discriminating the hypoxic volume (HV) of tissue; TBmax is the maximum intensity of the hypoxic region and does not invoke a threshold. Because elimination of blood sampling would simplify clinical use, we tested the validity of using imaging regions as a surrogate for blood sampling. Methods Patients underwent 20 min 18F-FMISO scans during the 90–140 min interval post-injection with venous blood sampling. 223 18F-FMISO patient studies had detectable surrogate blood regions in the field-of-view. Quantitative parameters of hypoxia (TBmax, HV) derived from blood samples were compared to values using surrogate blood regions derived from heart, aorta and/or cerebellum. In a subset of brain cancer patients, parameters from blood samples and from cerebellum were compared for their ability to independently predict outcome. Results Vascular regions of heart showed the highest correlation to measured blood activity (R2 = 0.84). For brain studies, cerebellar activity was similarly correlated to blood samples. In brain cancer patients, Kaplan-Meier analysis showed that image-derived reference regions had nearly identical predictive power as parameters derived from blood, thus obviating the need for venous sampling in these patients. Conclusions Simple static analysis of 18F-FMISO PET captures both the intensity (TBmax) and spatial extent (HV) of tumor hypoxia. An image-derived region to assess blood activity can be used as a surrogate for blood sampling in quantification of hypoxia.

Prognostic value of dynamic hypoxia PET in head and neck cancer: Results from a planned interim analysis of a randomized phase II hypoxia-image guided dose escalation trial

“…This result is well in line with findings reported by other groups [4][5][6]16,19,28,32]. However, very different methodologies were applied in these studies in terms of hypoxia detection and quantification [5,6,10,16,23,32,[34][35][36]. In addition, hypoxia PET suffers from low signal-to-noise ratios, which makes the method prone to false classification of lesions [37].…”

ACRIN 6684: Assessment of Tumor Hypoxia in Newly Diagnosed Glioblastoma Using 18F-FMISO PET and MRI

“…Previous single institution 18 F-FMISO PET studies in newly diagnosed GBM had found that HV, the volume of hypoxic tumor below a particular threshold, was predictive of outcome. (13, 14, 35) Specific threshold values are harder to interpret when considering different centers and PET scanner types and the smaller tumor volumes in this study compared to the prior published studies are more sensitive to partial volume effects and likely explains why SUV performed more robustly than HV. Given that SUV is already a widely used tool for clinical 18 F-FDG PET imaging, using SUV will be a more easily implementable approach.…”

“…As FMISO is a freely diffusible tracer, the ROI was dilated to include regions of FMISO uptake beyond the FLAIR hyperintensity. (26, 27) Tumor ROIs ranged from 10 cc to 237 cc, so we did not therefore perform partial volume correction. The FMISO image data were normalized by the average blood activity to produce pixel level tissue-to-blood ratio (T/B) values for all image slices.…”

“…(28) HV determines the spatial extent of hypoxia in a tumor while TBmax reports the severity of hypoxia, both of which have been shown to be independent predictors of outcome in brain cancer. (13, 27) Conventional quantitative PET parameters, SUVmax and SUVpeak, were also extracted from the tumor regions, where SUVpeak was determined as the average SUV from a 1 cm circular ROI centered over the hottest pixel (cf. ACRIN 6668/RTOG 0235 protocol, page 21; http://www.acrin.org/Portals/0/Protocols/6668/ACRIN6668_Amend7_030210_ForONLINE.pdf).…”

Noninvasive PET Imaging and Tracking of Engineered Human Muscle Precursor Cells for Skeletal Muscle Tissue Engineering

“…Noninvasive methods include the use of bioreductive chemical markers such as 2-nitroimidazoles (37), which form adducts under hypoxic conditions and are irreversibly bound in hypoxic cells. 18 F-fluoromisonidazole is the most widely used PET radioligand for imaging hypoxia in humans (38)(39)(40).…”