DCE-MRI is more sensitive than IVIM-DWI for assessing anti-angiogenic treatment-induced changes in colorectal liver metastases

Abstract

Background: Diffusion weighted imaging (DWI) with intravoxel incoherent motion (IVIM) modelling can inform on tissue perfusion without exogenous contrast administration. Dynamic-contrast-enhanced (DCE) MRI can also characterise tissue perfusion, but requires a bolus injection of a Gadolinium-based contrast agent. This study compares the use of DCE-MRI and IVIM-DWI methods in assessing response to anti-angiogenic treatment in patients with colorectal liver metastases in a cohort with confirmed treatment response.

Methods: This prospective imaging study enrolled 25 participants with colorectal liver metastases to receive Regorafenib treatment. A target metastasis > 2 cm in each patient was imaged before and at 15 days after treatment on a 1.5T MR scanner using slice-matched IVIM-DWI and DCE-MRI protocols. MRI data were motion-corrected and tumour volumes of interest drawn on b=900 s/mm2 diffusion-weighted images were transferred to DCE-MRI data for further analysis. The median value of four IVIM-DWI parameters [diffusion coefficient D (10-3 mm2/s), perfusion fraction f (ml/ml), pseudodiffusion coefficient D* (10-3 mm2/s), and their product fD* (mm2/s)] and three DCE-MRI parameters [volume transfer constant Ktrans (min-1), enhancement fraction EF (%), and their product KEF (min-1)] were recorded at each visit, before and after treatment. Changes in pre- and post-treatment measurements of all MR parameters were assessed using Wilcoxon signed-rank tests (P<0.05 was considered significant). DCE-MRI and IVIM-DWI parameter correlations were evaluated with Spearman rank tests. Functional MR parameters were also compared against Response Evaluation Criteria In Solid Tumours v.1.1 (RECIST) evaluations.

Results: Significant treatment-induced reductions of DCE-MRI parameters across the cohort were observed for EF (91.2 to 50.8%, P<0.001), KEF (0.095 to 0.045 min-1, P<0.001) and Ktrans (0.109 to 0.078 min-1, P=0.002). For IVIM-DWI, only D (a non-perfusion parameter) increased significantly post treatment (0.83 to 0.97 × 10-3 mm2/s, P<0.001), while perfusion-related parameters showed no change. No strong correlations were found between DCE-MRI and IVIM-DWI parameters. A moderate correlation was found, after treatment, between Ktrans and D* (r=0.60; P=0.002) and fD* (r=0.67; P<0.001). When compared to RECIST v.1.1 evaluations, KEF and D correctly identified most clinical responders, whilst non-responders were incorrectly identified.

Conclusion: IVIM-DWI perfusion-related parameters showed limited sensitivity to the anti-angiogenic effects of Regorafenib treatment in colorectal liver metastases and showed low correlation with DCE-MRI parameters, despite profound and significant post-treatment reductions in DCE-MRI measurements.

Trial registration: NCT03010722 clinicaltrials.gov; registration date 6th January 2015.

Keywords: Clinical trial.; Colorectal liver metastasis; Dynamic contrast enhanced MRI (DCE-MRI); Intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI); Perfusion.

Conflict of interest statement

MF received honoraria for consulting, advisory role, speaker bureau, and/or research funding from Astellas Pharma, QED Therapeutics, Diaceutics, Tesaro, Roche, Eli Lilly and Novartis.

NV received honoraria from Merck Serono, Pfizer, Bayer and Eli-Lilly.

DCum received honoraria from Bayer.

The remaining authors of this manuscript declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

Flowchart of the MR cohort

Fig. 2

VOI-based data processing (example of one slice out of the 8 evaluated) for a 48 year old female patient with a lesion in segments 7/8 of the liver. VOI was drawn on the highest-b-value image (a), then transferred to the DCE-MRI subtraction image (b). The subtraction image was calculated as the difference between the dynamic image with peak enhancement within the liver parenchyma (dynamic 9/40) and the first pre-contrast image (dynamic 1/40). The VOIs were used in conjunction with each of the computed maps to derive the median values of parameters of interest: D (c) and Ktrans (d) are shown here. Note that Ktrans map is shown overlaid on the last dynamic image of the DCE-MRI acquisition (dynamic 40/40)

Fig. 3

Pre/post-treatment overlapped Ladder/Box plots of MR parameters from 25 liver metastases patients demonstrating significant response for all DCE-MRI parameters and D, but no significance for the three other IVIM-DWI parameters. Wilcoxon P-values are listed within the header

Fig. 4

Example MR parametric maps from a 59 year old male patient with liver metastasis before (top row) and after 15 days of treatment (bottom row); coronal plane

Fig. 5

Scatter plots for IVIM-DWI perfusion parameters (D*, f and fD*) versus the DCE-MRI parameter (Ktrans) showing little correlation. Spearman’s rank correlation coefficient r and its corresponding P-value are shown for each plot. Only the four cases within a box framed with a solid line (i.e. D* and fD* versus Ktrans) were statistically significant. Pre- and post-treatment data from the main cohort of 25 patients with liver metastases

Fig. 6

Bland-Altman plots for each IVIM-DWI parameter presenting values for the mean bias (and its P value), upper and lower limits of agreement and coefficient of variation. Data derived from the 5 patient repeatability cohort

Fig. 7

Waterfall plots for the four most sensitive MR parameters: Ktrans (a), EF (b), KEF (b) and D (d) demonstrating a good identification of responders when using KEF and D parameters. The percentage change (relative to baseline value) for each MR parameter was calculated at day 15 post-treatment (25 patients), while the RECIST was performed at week 8 (21 patients)