TY - JOUR
T1 - 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
AU - Desar, Ingrid M. E.
AU - van Herpen, Carla M. L.
AU - van Asten, Jack J. A.
AU - Fiedler, Walter
AU - Marreaud, Sandrine
AU - Timmer-Bonte, Johanna N. H.
AU - ter Voert, Edwin G. W.
AU - Lambiase, Antonio
AU - Bordignon, Claudio
AU - Heerschap, Arend
AU - van Laarhoven, Hanneke W. M.
PY - 2011
Y1 - 2011
N2 - 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. 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. 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. 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
AB - 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. 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. 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. 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
U2 - https://doi.org/10.1016/j.ejrad.2010.08.045
DO - https://doi.org/10.1016/j.ejrad.2010.08.045
M3 - Article
C2 - 20863638
SN - 0720-048X
VL - 80
SP - 655
EP - 661
JO - European Journal of Radiology
JF - European Journal of Radiology
IS - 3
ER -