Multiparametric characterization of response to anti-angiogenic therapy using USPIO contrast-enhanced MRI in combination with dynamic contrast-enhanced MRI.

Background: Steady state susceptibility contrast (SSC)-MRI provides information on vascular morphology but is a rarely used method. Purpose: To investigate the utility of the ultrasmall superparamagnetic iron oxide particles (USPIOs) GEH121333 for measuring tumor response to bevacizumab and compare this with gadolinium-based DCE-MRI. Study Type: Prospective preclinical animal model study. ANIMAL MODEL: Mice bearing subcutaneous TOV-21G human ovarian cancer xenografts treated with bevacizumab (n=9) or saline (n=9). Field Strength/Sequence: Imaging was performed on a 7T Bruker Biospec. For SSC-MRI with GEH121333 we acquired R-1-maps (RARE-sequence with variable TR), R-2-maps (multi-spin echo), and R2*-maps (multi-gradient echo). Additionally, R-1 and R-2 maps were measured on the days after USPIO injection. For DCE-MRI with gadodiamide we acquired 200T(1)-weighted images (RARE-sequence). Assessment: Delta R-1, Delta R-2, and Delta R2* maps were computed from SSC-MRI. DCE-MRI was analysed using the extended Tofts model. Statistical Tests: Results from pre- and 3 days posttreatment SSC-MRI were compared using paired-sample t-tests. Treatment and control groups were compared using independent sample t-tests. Performance of SSC- and DCE-MRI was compared using multivariate partial least squares discriminant analysis. Results: Already one day after treatment and USPIO injection, R-1 and R-2 values were lower in treated (R-1=0.49 +/- 0.03s(-1), R-2=23.07 +/- 1.49s(-1)) compared with control tumors (R-1=0.52 +/- 0.02s(-1), R-2=24.98 +/- 1.01s(-1)), indicating lower USPIO accumulation. Posttreatment SSC-MRI displayed significantly decreased tumor blood volume (change in Delta R-2=-0.43 +/- 0.26s(-1), P=0.001) and vessel density (change in Q=-0.032 +/- 0.020s(-1/3), P=0.002). DCE-MRI showed among others lower K-trans in treated tumors (control=0.064 +/- 0.011min(-1), tx=0.046 +/- 0.008min(-1), P=0.002). Multivariate analysis suggests that SSC-MRI was slightly inferior to DCE-MRI in distinguishing treated from control tumors (accuracy=75%, P=0.058 versus 80%, P=0.028), but a combination of both was best (accuracy=85%; P=0.003). Data Conclusion: SSC-MRI with GEH121333 is sensitive to early (<24h) and late changes in tumor vasculature. SSC-MRI and DCE-MRI provide complementary information and can be used to assess different aspects of vascular responses to anti-angiogenic therapies. Technical Efficacy: Stage 2