Correlation between tumor oxygenation and ¹⁸F-fluoromisonidazole PET data simulated based on microvessel images

Abstract

Background. Assessing hypoxia with oxygen probes provides a sparse sampling of tumor volumes only, bearing a risk of missing hypoxic regions. Full coverage is achieved with positron emission tomography (PET) using the tracer ¹⁸F-fluoromisonidazole (FMISO). In this study, the correlation between different FMISO PET imaging parameters and the median voxel PO₂ (medianPO₂) was analyzed. A measure of the median PO₂ characterizes the microenvironment in consistency with probe measurements. Material and methods. Tissue oxygenations and FMISO diffusion-retention dynamics were simulated. Transport of FMISO and O₂ molecules into and out of tissue was modeled by vessel maps derived from histology of head-and-neck squamous cell cancer xenograft tumor lines. Parameter sets were evaluated for 300 distinct 2 × 2 mm² vessel configurations, including medianPO₂ and two FMISO PET parameters: F_H denotes the sub-regional signal four hours post injection (pi) and F_H/P denotes the ratio between F_H and the time-averaged signal 0–15 min pi. Correlations between O₂ and FMISO parameters were evaluated. A receiver operating characteristics (ROC) analysis was performed, regarding the accuracy of F_H and F_H/P in identifying voxels with medianPO₂ < 2.5 mmHg. Results. In hypoxic sub-regions, the correlation between F_H and medianPO₂ is low (R² = 0.37), while the correlation between F_H/P and median PO₂ is high (R² = 0.99). The ROC analysis showed that hypoxic regions can be identified using F_H/P with a higher diagnostic accuracy (YI = sensitivity+ specificity-1 = 1.0), than using F_H alone (YI = 0.83). Both FMISO parameters are moderately effective in identifying hypoxia on the microscopic length scale (YI = 0.63 and 0.60). Conclusions. A combination of two FMISO PET scans acquired 0–15 min and four hours pi may yield an accurate measure of the medianPO₂ in a voxel (F_H/P). This measure is comparable to averaged oxygen probe measurements and has the advantage of covering the entire tumor volume. Therefore, it may improve the prediction of radiotherapy outcome and facilitate individualized dose prescriptions.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This project was financially supported by the German Research Foundation (DFG), grant no. TH 1528/1-1 and by the European Social Fund and the Ministry of Science, Research and the Arts Baden-Württemberg.