title: Dynamic contrast-enhanced computed tomography to assess antitumor treatment effects: comparison of two contrast agents with different pharmacokinetics.
abstract: OBJECTIVE
  Dynamic contrast-enhanced computed tomography (CT) is a sensitive method to evaluate functional changes of the tumor microvasculature after antitumor therapy by monitoring the kinetics of the contrast agent (CA) passage. Therefore, the pharmacokinetic properties of the CA possess a central role: iodinated x-ray CAs are small molecules that distribute rapidly within the extravascular extracellular space, whereas larger macromolecular compounds have a prolonged vascular phase and a restricted volume of distribution. The aim of this animal study was to compare the x-ray CA iopromide and the experimental gadolinium-based dendrimeric Gadomer in the assessment of early therapy response after a single dose of the novel multikinase inhibitor regorafenib.
  
  
  METHODS
  For the study, an experimental GS9L rat glioma model was used. For each CA, the animals were divided randomly into a therapy (n = 8) and a placebo group (n = 4). All animals underwent a baseline CT and a second examination 24 hours after therapy with regorafenib (10 mg/kg body weight, oral) and placebo, respectively. The CAs were administered intravenously at a dosage of 0.5 g I or Gd per kg body weight and dynamic CT scans (80 kV, 160 mAseff, no table feed) of the tumor region were performed up to 404 seconds post injection (p.i.). Image evaluation was done by analyzing tumor time-density curves, the area under the curve (AUC), and the results of the 2-compartment Patlak modeling.
  
  
  RESULTS
  Significant differences in the time-density curves, the AUC, and the Patlak transfer constant (Ktrans) were observed 24 hours after the regorafenib therapy but not after the placebo treatment. The treatment effects visualized with iopromide were most pronounced at early time points (<100 seconds p.i.), whereas imaging with Gadomer was most effective at a later time window (300-404 seconds p.i.). Comparable reductions of the AUC to 0.69 ± 0.12 (iopromide) and 0.76 ± 0.11 (Gadomer) were found 24 hours after the therapy. A significant higher Ktrans was detected with iopromide (14.3 ± 2.7 mL per 100 mL/min) compared with Gadomer (1.8 ± 0.2 mL per 100 mL/min). However, the relative reduction in Ktrans to 67% ± 11% (iopromide) and to 68% ± 7% (Gadomer) 24 hours after the therapy was similar.
  
  
  CONCLUSIONS
  Dynamic contrast-enhanced CT detects early treatment effects on tumor microvasculature after a single dose of regorafenib, independently of the used CA. Gadomer showed a later optimal imaging window than iopromide did. However, the efficacy of Gadomer- and iopromide-enhanced imaging is equivalent. The results demonstrate the potential of dynamic contrast-enhanced CT using clinically available x-ray CA in the assessment of early treatment response after administration of novel antitumor therapeutic agents.
authors.affiliation: MR and CT Contrast Media Research, Bayer Healthcare, 178 13353 Berlin, Germany. gregor.jost@bayer.com
authors.forename: Gregor
authors.initials: G
authors.lastname: Jost
authors.forename: Hubertus
authors.initials: H
authors.lastname: Pietsch
authors.forename: Lars
authors.initials: L
authors.lastname: Grenacher
mesh_terms: D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics; D005682:Gadolinium / Q000493:pharmacokinetics*; D005910:Glioma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D007472:Iohexol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D011379:Prognosis; D011725:Pyridines / Q000627:therapeutic use*; D011856:Radiographic Image Enhancement / Q000379:methods; D011857:Radiographic Image Interpretation, Computer-Assisted / Q000379:methods; D051381:Rats; D011916:Rats, Inbred F344; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014057:Tomography, X-Ray Computed / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003287:Contrast Media; D010671:Phenylurea Compounds; D011725:Pyridines; C402765:gadomer 17; C559147:regorafenib; D007472:Iohexol; C038192:iopromide; D005682:Gadolinium