title: Multiparametric Analysis of the Relationship Between Tumor Hypoxia and Perfusion with ¹⁸F-Fluoroazomycin Arabinoside and ¹⁵O-H₂O PET.
abstract: (18)F-fluoroazomycin arabinoside ((18)F-FAZA) is a PET tracer of tumor hypoxia. However, as hypoxia often is associated with decreased perfusion, the delivery of (18)F-FAZA may be compromised, potentially disturbing the association between tissue hypoxia and (18)F-FAZA uptake. The aim of this study was to gain insight into the relationship between tumor perfusion and (18)F-FAZA uptake.
  
  
  METHODS
  Ten patients diagnosed with advanced non-small cell lung cancer underwent subsequent dynamic (15)O-H2O and (18)F-FAZA PET scans with arterial sampling. Parametric images of both (15)O-H2O-derived perfusion (tumor blood flow [TBF]) and volume of distribution (V(T)) of (18)F-FAZA were generated. Next, multiparametric classification was performed using lesional and global thresholds. Voxels were classified as low or high TBF and (18)F-FAZA V(T), respectively. Finally, by combining these initial classifications, voxels were allocated to 4 categories: lowTBF-lowV(T), lowTBF-highV(T), highTBF-lowV(T), and highTBF-highV(T).
  
  
  RESULTS
  A total of 13 malignant lesions were identified in the 10 patients. The TBF and (18)F-FAZA V(T) values (average ± SD) across all lesions were 0.45 ± 0.20 mL·cm(-3)·min(-1) and 0.94 ± 0.31 mL·cm(-3), respectively. The averages of all lesional median values for TBF and (18)F-FAZA V(T) were 0.37 ± 0.15 mL·cm(-3)·min(-1) and 0.85 ± 0.18 mL·cm(-3), respectively. Multiparametric analysis showed that classified voxels were clustered rather than randomly distributed. Several intralesion areas were identified where (18)F-FAZA V(T) was inversely related to TBF. On the other hand, there were also distinct areas where TBF as well as (18)F-FAZA V(T) were decreased or increased.
  
  
  CONCLUSIONS
  The present data indicate that spatial variation of (18)F-FAZA uptake is not necessarily inversely related to TBF. This suggests that decreased TBF may result in flow-limited delivery of (18)F-FAZA. Areas with both high (18)F-FAZA uptake and high TBF values suggest that high (18)F-FAZA uptake, possibly suggesting hypoxia, may occur despite high TBF values. In conclusion, multiparametric evaluation of the spatial distributions of both TBF and (18)F-FAZA uptake may be helpful for understanding the (18)F-FAZA signal.
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; and r.iqbal@vumc.nl.
authors.forename: Ramsha
authors.initials: R
authors.lastname: Iqbal
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; and.
authors.forename: Gem M
authors.initials: GM
authors.lastname: Kramer
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; and.
authors.forename: Eline E
authors.initials: EE
authors.lastname: Verwer
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; and.
authors.forename: Marc C
authors.initials: MC
authors.lastname: Huisman
authors.affiliation: Department of Pulmonology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Adrianus J
authors.initials: AJ
authors.lastname: de Langen
authors.affiliation: Department of Pulmonology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Idris
authors.initials: I
authors.lastname: Bahce
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; and.
authors.forename: Floris H P
authors.initials: FH
authors.lastname: van Velden
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; and.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; and.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; and.
authors.forename: Otto S
authors.initials: OS
authors.lastname: Hoekstra
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands; and.
authors.forename: Ronald
authors.initials: R
authors.lastname: Boellaard
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging; D016000:Cluster Analysis; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008175:Lung Neoplasms / Q000000981:diagnostic imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging* / Q000378:metabolism; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D010104:Oxygen Radioisotopes; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D012039:Regional Blood Flow; D014867:Water / Q000737:chemistry*
chemical_list: D009593:Nitroimidazoles; D010104:Oxygen Radioisotopes; D019275:Radiopharmaceuticals; D014867:Water; C498052:fluoroazomycin arabinoside
keywords: 18F-FAZA; PET; hypoxia; non–small cell lung cancer; perfusion