Combined endogenous MR biomarkers to predict basal tumor oxygenation and response to hyperoxic challenge

Hypoxia is a common feature of solid tumors, which translates into increased angiogenesis, malignant phenotype cell selection, change in gene expression and greater resistance to radiotherapy and chemotherapy. Therefore, there is a need for markers of hypoxia to stratify patients, in order to personalize treatment to improve therapeutic outcome. However, no modality has yet been validated for the screening of hypoxia in routine clinical practice. Magnetic resonance imaging (MRI) R₁ and R₂ * relaxation parameters are sensitive to tissue oxygenation: R₁ is sensitive to dissolved oxygen and R₂ * is sensitive to intravascular deoxyhemoglobin content. Two rat tumor models with distinct levels of hypoxia, 9L-glioma and rhabdomyosarcoma, were imaged for R₁ and R₂ * under air and carbogen (95% O₂ and 5% CO₂ ) breathing conditions. It was observed that the basal tumor oxygenation level had an impact on the amplitude of response to carbogen in the vascular compartment (R₂ *), but not in the tissue compartment (R₁ ). In addition, the change in tissue oxygenation estimated by ΔR₁ correlated with the change in vascular oxygenation estimated by ΔR₂ *, which is consistent with an increase in oxygen supply generating an elevated tumor pO₂ . At the intra-tumoral level, we identified four types of voxel to which a hypoxic feature was attributed (mild hypoxia, severe hypoxia, normoxia and vascular steal), depending on the carbogen-induced change in R₁ and R₂ * values for each voxel. The results showed that 9L-gliomas present more normoxic fractions, whereas rhabdomyosarcomas present more hypoxic fractions, which is in accordance with a previous study using ¹⁸ F-fluoroazomycin arabinoside (¹⁸ F-FAZA) and electron paramagnetic resonance (EPR) oximetry. The response of the combined endogenous MRI contrasts to carbogen challenge could be a useful tool to predict different tumor hypoxic fractions.