Multiparametric analysis of the relationship between tumor hypoxia and perfusion using ¹⁸F-FAZA and ¹⁵O-H₂O PET

Abstract

¹⁸F-fluoroazomycin-arabinoside (¹⁸F-FAZA) is a positron emission tomography (PET) tracer of tumor hypoxia. However, as hypoxia often is associated with decreased perfusion, delivery of ¹⁸F-FAZA might be compromised, potentially disturbing the association between tissue hypoxia and ¹⁸F-FAZA uptake. The aim of this study was to gain insight in the relationship between tumor perfusion and ¹⁸F-FAZA uptake. Methods: Ten patients diagnosed with advanced non-small cell lung cancer (NSCLC) underwent subsequent dynamic ¹⁵O-H₂O and ¹⁸F-FAZA PET scans with arterial sampling. Parametric images of both ¹⁵O-H₂O derived perfusion (TBF) and volume of distribution (V_T) of ¹⁸F-FAZA were generated. Next, multiparametric classification was performed using lesional and global thresholds. Voxels were classified as low or high TBF and ¹⁸F-FAZA V_T, respectively. Finally, by combining these initial classifications, voxels were allocated to four categories (lowTBF-lowV_T, lowTBF-highV_T, highTBF-lowV_T and highTBF-highV_T). Results: A total of thirteen malignant lesions were identified in the ten patients. Average TBF and ¹⁸F-FAZA V_T across all lesions were 0.45±0.20 mL·cm^-3·min^-1 and 0.94±0.31 mL·cm^-3, respectively. The average of all lesional median values were 0.37±0.15 mL·cm^-3·min^-1 and 0.85±0.18 mL·cm^-3 for TBF and ¹⁸F-FAZA V_T, respectively. Multiparametric analysis showed that classified voxels were clustered rather than randomly distributed. Several intralesional areas could be identified where ¹⁸F-FAZA V_T was inversely related to TBF. On the other hand, there were also distinct areas where TBF as well as ¹⁸F-FAZA V_T were decreased or increased. Conclusion: The present data indicate that spatial variation of ¹⁸F-FAZA uptake is not necessarily inversely related with TBF. This suggests that decreased TBF may result in flow limited delivery of ¹⁸F-FAZA. Areas with both high ¹⁸F-FAZA uptake and high TBF suggest that high ¹⁸F-FAZA uptake, possibly suggesting hypoxia, may occur in regions despite having high TBF. In conclusion, multiparametric evaluation of the spatial distribution of both TBF and ¹⁸F-FAZA uptake may be helpful for understanding the ¹⁸F-FAZA signal.