Improved Evaluation of Antivascular Cancer Therapy Using Constrained Tracer-Kinetic Modeling for Multiagent Dynamic...

Dynamic contrast-enhanced MRI (DCE-MRI) is a promising technique for assessing the response of tumor vasculature to antivascular therapies. Multiagent DCE-MRI employs a combination of low and high molecular weight contrast agents, which potentially improves the accuracy of estimation of tumor hemodynamic and vascular permeability parameters. In this study, we used multiagent DCE-MRI to assess changes in tumor hemodynamics and vascular permeability after vascular-disrupting therapy. Multiagent DCE-MRI (sequential injection of G5 dendrimer, G2 dendrimer, and Gd-DOTA) was performed in tumor-bearing mice before, 2 and 24 hours after treatment with vascular disrupting agent DMXAA or placebo. Constrained DCE-MRI gamma capillary transit time modeling was used to estimate flow F, blood volume fraction v_b, mean capillary transit time t_c, bolus arrival time t_d, extracellular extravascular fraction v_e, vascular heterogeneity index α^-1 (all identical between agents) and extraction fraction E (reflective of permeability), and transfer constant K^trans (both agent-specific) in perfused pixels. F, v_b, and α^-1 decreased at both time points after DMXAA, whereas t_c increased. E (G2 and G5) showed an initial increase, after which, both parameters restored. K^trans (G2 and Gd-DOTA) decreased at both time points after treatment. In the control, placebo-treated animals, only F, t_c, and K^trans Gd-DOTA showed significant changes. Histologic perfused tumor fraction was significantly lower in DMXAA-treated versus control animals. Our results show how multiagent tracer-kinetic modeling can accurately determine the effects of vascular-disrupting therapy by separating simultaneous changes in tumor hemodynamics and vascular permeability.Significance: These findings describe a new approach to measure separately the effects of antivascular therapy on tumor hemodynamics and vascular permeability, which could help more rapidly and accurately assess the efficacy of experimental therapy of this class. Cancer Res; 78(6); 1561-70. ©2018 AACR.