Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies

Abstract

About 100 early-phase clinical trials and investigator-led studies of targeted antivascular therapies—both anti-angiogenic and vascular-targeting agents—have reported data derived from T1-weighted dynamic contrast-enhanced (DCE)-MRI. However, the role of DCE-MRI for decision making during the drug-development process remains controversial. Despite well-documented guidelines on image acquisition and analysis, several key questions concerning the role of this technique in early-phase trial design remain unanswered. This Review describes studies of single-agent antivascular therapies, in which DCE-MRI parameters are incorporated as pharmacodynamic biomarkers. We discuss whether these parameters, such as volume transfer constant (Ktrans), are reproducible and reliable biomarkers of both drug efficacy and proof of concept, and whether they assist in dose selection and drug scheduling for subsequent phase II trials. Emerging evidence indicates that multiparametric analysis of DCE-MRI data offers greater insight into the mechanism of drug action than studies measuring a single parameter, such as Ktrans. We also provide an overview of current data and appraise the future directions of this technique in oncology trials. Finally, major hurdles in imaging biomarker development, validation and qualification that hinder a wide application of DCE-MRI techniques in clinical trials are addressed.

Key Points

  • Changes in dynamic contrast-enhanced (DCE)-MRI parameters are necessary, but not sufficient, to demonstrate efficacy of monoclonal antibodies targeting VEGF, tyrosine kinase inhibitors and vascular-targeting agents

  • DCE-MRI assists in dose selection; preliminary evidence suggests that the technique also helps to decide drug scheduling

  • Multiparametric analysis of DCE-MRI data offers greater insight into mechanisms of drug action than studies measuring only one parameter, such as volume transfer constant, Ktrans

  • Application of DCE-MRI in phase II studies of combination of antivascular therapies with chemotherapy, radiotherapy or other targeted agents provides new challenges regarding trial design and data interpretation

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Figure 1: DCE-MRI data acquisition and analysis.
Figure 2: Example of three Ktrans parameter maps.

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All authors contributed to the discussion of content, and reviewed and edited the manuscript before submission. J. P. B. O'Connor researched data for the article and contributed significantly to the writing of the manuscript before submission. A. Jackson, G. J. M. Parker, G. C Jayson contributed to the writing of the article before submission.

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Correspondence to James P. B. O'Connor.

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Supplementary information

Supplementary Table 1

Anti-VEGF ligand compounds, VEGFR inhibitors and vascular disrupting agents evaluated by DCE-MRI in studies of single agent therapy (PDF 135 kb)

Supplementary Table 2

Miscellaneous anti-vascular agents evaluated by DCE-MRI in studies of single agent (PDF 52 kb)

Supplementary Table 3

Anti-vascular agents evaluated by DCE-MRI in combination therapy regimens (PDF 42 kb)

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O'Connor, J., Jackson, A., Parker, G. et al. Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies. Nat Rev Clin Oncol 9, 167–177 (2012). https://doi.org/10.1038/nrclinonc.2012.2

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