Date Published: February 28, 2019
Publisher: Public Library of Science
Author(s): Markus Kroenke, Kenji Hirata, Andrei Gafita, Shiro Watanabe, Shozo Okamoto, Keiichi Magota, Tohru Shiga, Yuji Kuge, Nagara Tamaki, Thomas Pyka.
Hypoxia can induce radiation resistance and is an independent prognostic marker for outcome in head and neck cancer. As 18F-FMISO (FMISO), a hypoxia tracer for PET, is far less common than 18F-FDG (FDG) and two separate PET scans result in doubled cost and radiation exposure to the patient, we aimed to predict hypoxia from FDG PET with new techniques of voxel based analysis and texture analysis.
Thirty-eight patients with head-and-neck cancer underwent consecutive FDG and FMISO PET scans before any treatment. ROIs enclosing the primary cancer were compared in a voxel-by-voxel manner between FDG and FMISO PET. Tumour hypoxia was defined as the volume with a tumour-to-muscle ratio (TMR) > 1.25 in the FMISO PET and hypermetabolic volume was defined as >50% SUVmax in the FDG PET. The concordance rate was defined as percentage of voxels within the tumour which were both hypermetabolic and hypoxic. 38 different texture analysis (TA) parameters were computed based on the ROIs and correlated with presence of hypoxia.
Within the hypoxic tumour regions, the FDG uptake was twice as high as in the non-hypoxic tumour regions (SUVmean 10.9 vs. 5.4; p<0.001). A moderate correlation between FDG and FMISO uptake was found by a voxel-by-voxel comparison (r = 0.664 p<0.001). The average concordance rate was 25% (± 22%). Entropy was the TA parameter showing the highest correlation with hypoxia (r = 0.524 p<0.001). FDG uptake was higher in hypoxic tumour regions than in non-hypoxic regions as expected by tumour biology. A moderate correlation between FDG and FMISO PET was found by voxel-based analysis. TA yielded similar results in FDG and FMISO PET. However, it may not be possible to predict tumour hypoxia even with the help of texture analysis.
Hypoxic regions in tumours are known to be more radiation-resistant than normoxic tissues and hypoxia is an independent prognostic marker for patient outcome [1–5]. Most head-and-neck cancers have hypoxic regions, which vanish in the course of radiation therapy . The current gold standard to estimate hypoxic tissue is measuring the pO2 using the Eppendorf pO2 electrode , which not only is an invasive method but also can alter the local oxygen concentration. Fluorine-18-labeled fluoromisonidazole (FMISO) positron emission tomography (PET) is a known technique that allows visualisation of hypoxic areas with high reproducibility [8–10]. New therapeutic strategies have been proposed to treat hypoxic tumour areas, such as dose escalation and de-escalation of radiation therapy or dose painting (increased dosage in hypoxic regions of the tumour) [11–13], as well as inhibitors for hypoxia-inducible factor (HIF) . Fluorine-18-labeled fluorodeoxyglucose (FDG) is a common imaging agent used in the clinical routine to detect malignant tumours and to evaluate its degree of aggressiveness. Significant correlation was found between pO2 and FMISO-PET uptake in head-and-neck cancer, and a moderate correlation of FDG and FMISO uptake , while others reported that the FDG PET could not predict hypoxic areas . On the other side, no correlation between FDG- and FMISO-PET was found in lung cancer .
To our best knowledge, this study is the first trial to investigate voxel based analysis for predicting hypoxia by FDG PET and using texture analysis parameter to establish a better understanding of the relationship between hypoxia and increased glucose metabolism in tumours in a clinical setting. It was found that most head-and-neck tumours showed hypoxia which was moderately correlated to glycolysis both by SUVmax and voxel-wise. The concordance rate showed that 27% of the HMV was hypoxic. Vice versa the SUVmean in hypoxic tumour regions was twice as high as in the non-hypoxic regions.
Moderate correlations were found between FDG PET and FMISO PET in the voxel-based analysis, with a two-fold higher uptake in FDG PET for hypoxic areas compared to non-hypoxic areas. However, the concordance rate showed that the hypoxic fraction is a smaller than the high FDG uptake volume. No TA parameter of the FDG PET correlated well with Hypoxia, TMR, HV measured in the FMISO PETs.