Evaluation of intratumoral perfusion pressure and its relation to hypoxia: ¹⁵O-labeled gases and ¹⁸F-FMISO studies.

Objectives: Perfusion pressure is considered as a key factor in cerebral ischemia, but little is known about oncology, especially its relation to hypoxia. Our previous study reported decreased tumoral blood flow (TBF) was related to intratumoral hypoxia. However, there was a wide variety of TBF due to the tumor heterogeneity and intratumoral perfusion pressure (IPP) can be used as another indicator to define intratumoral hypoxia. The purpose of this study was to evaluate the IPP and its relation to hypoxia by comparing ¹⁵O-labeled gases and ¹⁸F-FMISO PET.

Methods: 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-labeled gases PET. The 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 labeled gases. Multiple volumes of interest (1 mm diameter sphere) were placed on the co-registered ¹⁸F-FMISO (3 hrs post injection) and functional ¹⁵O-labeled gases PET images. IPP was calculated as the ratio of TBF to TBV and its correlation to ¹⁸F-FMISO uptake was evaluated by Spearman’s correlation coefficient (r). The IPP, TBF, TMRO₂, OEF, and TBV values were compared among the three groups classified by the ¹⁸F-FMISO uptake as follows: group Low, less than 1.0; group Moderate, between 1.0 and 2.0; and group High, more than 2.0 in the ¹⁸F-FMISO standardized uptake value (SUV).

Results: There were significant but weak correlations between IPP and ¹⁸F-FMISO SUV (r=-0.274, p<0.01), IPP and OEF (r=-0.314, p<0.01), and IPP and TMRO₂ (r=0.365, p<0.01). Quantitative values in the Low (L), Moderate (M), and High (H) groups were as follows: IPP, (L) 11.3 ± 11.1, (M) 8.43 ± 6.42, and (H) 8.15 ± 4.11 /min; TBF, (L) 54.7 ± 30.3, (M) 31.8 ± 16.5, and (H) 30.0 ± 14.8 mL/100 mL/min; OEF, (L) 33.1 ± 13.6, (M) 35.7 ± 17.1 and (H) 40.8 ± 16.2 %; TMRO₂, (L) 2.82 ± 1.29, (M) 1.87 ± 1.03, and (H) 2.07 ± 1.13 mL/100 mL/min; and TBV, (L) 5.66 ± 2.11, (M) 4.34 ± 1.86, and (H) 3.90 ± 1.24 mL/100 mL, respectively. Intratumoral hypoxic regions (group Moderate and High) showed significantly lower IPP, TBF, TMRO₂, and TBV values than non-hypoxic regions (group Low). OEF showed significant increase in the severe hypoxic region compared to non-hypoxic and mild hypoxic regions. In comparison between group Moderate and High, significant differences were observed only in OEF and TBV, but not in IPP. It was suggested that oxygen extraction and vascular density rather than perfusion pressure reflected the severity of intratumoral hypoxia.

Conclusion: This study demonstrated IPP was decreased in the intratumoral hypoxia compared to non-hypoxic region, but failed to show the difference between moderate and severe hypoxia. Oxygen extraction and vascular density were considered as key factors to define the severity of intratumoral hypoxia.