Quantitative evaluation of oxygen metabolism in the intratumoral hypoxia: ¹⁸F-fluoromisonidazole and ¹⁵O-labelled gases inhalation PET

Background: Intratumoral hypoxia is one of the resistant factors in radiotherapy and chemotherapy for cancer. Although it is detected by ¹⁸F-fluoromisonidazole (FMISO) PET, the relationship between intratumoral hypoxia and oxygen metabolism has not been studied. The purpose of this study was to evaluate the intratumoral perfusion and oxygen metabolism in hypoxic regions using the rat xenograft model. Ten male Fischer rats with C6 glioma (body weight = 220 ± 15 g) were investigated with ¹⁸F-FMISO PET and steady-state inhalation method of ¹⁵O-labelled gases PET. The tumoral blood flow (TBF), tumoral metabolic rate of oxygen (TMRO₂), oxygen extraction fraction (OEF), and tumoral blood volume (TBV) were measured under artificial ventilation with ¹⁵O–CO₂, ¹⁵O–O₂, and ¹⁵O–CO gases. Multiple volumes of interest (1-mm diameter sphere) were placed on the co-registered ¹⁸F-FMISO (3 h post injection) and functional ¹⁵O-labelled gases PET images. The TBF, TMRO₂, OEF, and TBV values were compared among the three groups classified by the ¹⁸F-FMISO uptake as follows: group Low (L), less than 1.0; group Medium (M), between 1.0 and 2.0; and group High (H), more than 2.0 in the ¹⁸F-FMISO standardized uptake value (SUV). Results: There were moderate negative correlations between ¹⁸F-FMISO SUV and TBF (r = −0.56 and p < 0.01), and weak negative correlations between ¹⁸F-FMISO SUV and TMRO₂ (r = −0.38 and p < 0.01) and ¹⁸F-FMISO SUV and TBV (r = −0.38 and p < 0.01). Quantitative values were as follows: TBF, (L) 55 ± 30, (M) 32 ± 17, and (H) 30 ± 15 mL/100 mL/min; OEF, (L) 33 ± 14, (M) 36 ± 17, and (H) 41 ± 16%; TMRO₂, (L) 2.8 ± 1.3, (M) 1.9 ± 1.0, and (H) 2.1 ± 1.1 mL/100 mL/min; and TBV, (L) 5.7 ± 2.1, (M) 4.3 ± 1.9, and (H) 3.9 ± 1.2 mL/100 mL, respectively. Intratumoral hypoxic regions (M and H) showed significantly lower TBF, TMRO₂, and TBV values than non-hypoxic regions (L). OEF showed significant increase in the severe hypoxic region compared to non-hypoxic and mild hypoxic regions. Conclusions: This study demonstrated that intratumoral hypoxic regions showed decreased blood flow with increased oxygen extraction, suggesting the need for a treatment strategy to normalize the blood flow for oxygen-avid active tumor cells in hypoxic regions.