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  • Review Article
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Vessel calibre—a potential MRI biomarker of tumour response in clinical trials

Nature Reviews Clinical Oncology volume 11, pages 566–584 (2014)Cite this article

Subjects

Key Points

  • Negative phase III trials suggest that administration of antiangiogenic therapies in unselected patient groups does not result in optimal outcomes, owing to diversity in cancer biology and natural history

  • Antivascular and antiangiogenic therapies are not directly cytotoxic and, therefore, traditional assessment of MRI-based tumour volume change alone can no longer be considered an adequate biomarker of therapeutic response

  • Intravascular paramagnetic contrast agents induce small and local magnetic field variations in tissue that scale with the blood vessel calibre (the cross-sectional width of the vessel)

  • MRI is exquisitely sensitive to these magnetic field perturbations and, therefore, provides a means for in vivo assessment of tumour vessel calibre

  • Depending on drug and dose administration, initial experiences with antivascular and antiangiogenic therapies and vessel-calibre MRI suggest that pruning of abnormal tumour vessels is often non-uniform

  • Collectively, vessel-calibre MRI and emerging MRI-based assessments, such as vessel architectural imaging, can provide insights into vessel type and oxygenation status—creating new possibilities for clinical trial design and monitoring therapeutic response and outcomes

Abstract

Our understanding of the importance of blood vessels and angiogenesis in cancer has increased considerably over the past decades, and the assessment of tumour vessel calibre and structure has become increasingly important for in vivo monitoring of therapeutic response. The preferred method for in vivo imaging of most solid cancers is MRI, and the concept of vessel-calibre MRI has evolved since its initial inception in the early 1990s. Almost a quarter of a century later, unlike traditional contrast-enhanced MRI techniques, vessel-calibre MRI remains widely inaccessible to the general clinical community. The narrow availability of the technique is, in part, attributable to limited awareness and a lack of imaging standardization. Thus, the role of vessel-calibre MRI in early phase clinical trials remains to be determined. By contrast, regulatory approvals of antiangiogenic agents that are not directly cytotoxic have created an urgent need for clinical trials incorporating advanced imaging analyses, going beyond traditional assessments of tumour volume. To this end, we review the field of vessel-calibre MRI and summarize the emerging evidence supporting the use of this technique to monitor response to anticancer therapy. We also discuss the potential use of this biomarker assessment in clinical imaging trials and highlight relevant avenues for future research.

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Figure 1: Vessel calibres in solid cancers.
Figure 2: Vessel-calibre MRI.
Figure 3: Vessel-calibre MRI during antiangiogenic therapy.
Figure 4: Advanced MRI assessments might inform optimal dose scheduling.

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Acknowledgements

The authors thank J. Martin (Department of Chemical Engineering, Massachusetts Institute of Technology and the Edwin L. Steele Laboratory of Tumor Biology, Massachusetts General Hospital) and T. Stylianopoulos (Department of Mechanical and Manufacturing Engineering, University of Cyprus) for help with this manuscript. The authors apologize to the authors whose work we could not cite owing to limits on the number of references that we were able to include. The authors acknowledge funding support from the National Cancer Institute, NIH, US Department of Human and Health Services (grants NCT00254943 to K.E.E., T32-CA009502 to C.T.F., NCT00756106 to E.R.G., NCT00662506 to T.T.B., S10 RR021110-01A1 to B.R.R., NCT00254943 to A.G.S. and P01CA80124 to R.K.J.), and the South-Eastern Norway Regional Health Authority (grant 2013069 to K.E.E.). In addition, R.J.H.B. acknowledges funding from the Sigrid Juselius Foundation, the Instrumentarium Research Foundation, the Academy of Finland, the Paulo Foundation and the Finnish Medical Foundation.

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Authors and Affiliations

  1. The Intervention Centre, Oslo University Hospital, Sognsvannsveien 20, Oslo, 0372, Norway

    Kyrre E. Emblem

  2. Department of Radiology and Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, MA, USA

    Christian T. Farrar, Ronald J. H. Borra & Bruce R. Rosen

  3. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, 02114, MA, USA

    Elizabeth R. Gerstner & Tracy T. Batchelor

  4. Department of Radiation Oncology, Edwin L. Steele Laboratory of Tumor Biology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, 02114, MA, USA

    Rakesh K. Jain

  5. Siemens Healthcare Health Services, 51 Valley Stream Parkway, Malvern, 19355, PA, USA

    A. Gregory Sorensen

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Competing interests

K.E.E. has intellectual property rights with NordicNeuroLab. T.T.B. is a consultant and/or is an advisory board member for Advance Medical, Agenus, Champions Biotechnology, Kirin Pharmaceuticals, Merck & Co. Inc., Novartis, Proximagen and Roche, and has received research funding from AstraZeneca, Millenium and Pfizer. B.R.R is a consultant and an advisory board member for Siemens Medical. A.G.S. is the Chief Executive Officer for Siemens HealthCare USA. R.K.J. is on the Board of Directors of Xtuit; holds equity in Enlight, SynDevRx and Xtuit; and has received research funding from Dyax, Medimmune and Roche. C.T.F., E.R.G. and R.J.H.B. declare no competing interests.

Supplementary information

Supplementary Figure 1

PMID-based reports on vessel-calibre MRI. (DOC 53 kb)

Supplementary Figure 2

MRI-based vessel calibre measurements in 14 patients with newly diagnosed glioblastomas undergoing chemoradiation therapy, but not antiangiogenic therapy with the VEGF receptor inhibitor cediranib, for 6 weeks (including day 43). (DOC 127 kb)

Supplementary Figure 3

MRI and VAI of healthy kidneys. (DOC 179 kb)

Supplementary Methods

(DOC 326 kb)

Supplementary Table 1

Abbreviations and terminology relating to vessel-calibre MRI (DOC 91 kb)

Supplementary Table 2

Conventional imaging response criteria (DOC 49 kb)

Supplementary Table 3

Vessel-calibre MRI validation studies (DOC 284 kb)

Supplementary Table 4

PMID articles reporting animal or human vessel-calibre MRI data (DOC 136 kb)

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Emblem, K., Farrar, C., Gerstner, E. et al. Vessel calibre—a potential MRI biomarker of tumour response in clinical trials. Nat Rev Clin Oncol 11, 566–584 (2014). https://doi.org/10.1038/nrclinonc.2014.126

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