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 R₁ -maps (RARE-sequence with variable TR), R₂ -maps (multi-spin echo), and R2*-maps (multi-gradient echo). Additionally, R₁ and R₂ maps were measured on the days after USPIO injection. For DCE-MRI with gadodiamide we acquired 200 T₁ -weighted images (RARE-sequence).

Assessment: ΔR₁ , ΔR₂ , and ΔR2* 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, R₁ and R₂ values were lower in treated (R₁ = 0.49 ± 0.03s^-1 , R₂ = 23.07 ± 1.49s^-1 ) compared with control tumors (R₁ = 0.52 ± 0.02s^-1 , R₂ = 24.98 ± 1.01s^-1 ), indicating lower USPIO accumulation. Posttreatment SSC-MRI displayed significantly decreased tumor blood volume (change in ΔR₂ = -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 (<24 h) 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.

Level of evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1589-1600.