title: Factors affecting the unexpected failure of DCE-MRI to determine the optimal biological dose of the vascular targeting agent NGR-hTNF in solid cancer patients.
abstract: BACKGROUND
  To understand which factors could affect the assessment of anti-vascular treatment by DCE-MRI, we investigated possible causes that could have hampered the selection of an optimal biological dose in humans of the vascular targeted agent NGR-hTNF by DCE-MRI: (1) insufficient reproducibility of DCE-MRI; (2) less specific targeting of NGR-hTNF; (3) interference of vessel characteristics with NGR-hTNF efficacy; (4) interfering pharmacodynamic effects.
  
  
  METHODS
  In a phase I study NGR-hTNF, DCE-MRI was performed at baseline and 2 h after NGR-hTNF administration in 31 patients with advanced solid cancer. Reproducibility measurements were performed in 5 other non-treated patients with metastatic disease. Mean kep, Ktrans values and their histogram distribution were determined in metastases and healthy liver tissue. The correlation between tumour size and DCE-MRI parameters was determined. Kinetics of soluble TNF receptors and the development of anti-TNF antibodies were assessed.
  
  
  RESULTS
  Reproducibility of the DCE-MRI technique was adequate. Mean DCE-MRI parameters did not significantly change after NGR-hTNF administration, but histogram analyses showed significant changes in metastases and healthy liver tissue in some patients. The anti-vascular effects of NGR-hTNF were larger in smaller tumours, which have less mature neovasculature. Soluble TNF receptors were released.
  
  
  CONCLUSIONS
  The difficulty to find an optimal biological dose of NGR-TNF by DCE-MRI is likely caused by a combination of factors: (i) different profiles of early anti-vascular effects in tumours and healthy liver tissue, (ii) dependence of the magnitude of the anti-vascular effect of NGR-hTNF on tumour size and (iii) shedding kinetics of soluble TNFα receptors.
authors.affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Centre, The Netherlands. i.desar@aig.umcn.nl
authors.forename: Ingrid M E
authors.initials: IM
authors.lastname: Desar
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
authors.forename: Jack J A
authors.initials: JJ
authors.lastname: van Asten
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marreaud
authors.forename: Johanna N H
authors.initials: JN
authors.lastname: Timmer-Bonte
authors.forename: Edwin G W
authors.initials: EG
authors.lastname: ter Voert
authors.forename: Antonio
authors.initials: A
authors.lastname: Lambiase
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Arend
authors.initials: A
authors.lastname: Heerschap
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Laarhoven
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage; D004360:Drug Therapy, Computer-Assisted / Q000379:methods*; D005260:Female; D006801:Humans; D007089:Image Enhancement / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D017211:Treatment Failure; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C464839:tumor necrosis factor-alpha, CNGRC fusion protein, human