Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies

Nature Reviews Clinical Oncology volume 9, pages 167–177 (2012)Cite this article

Subjects

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

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Collins, J. M. Functional imaging in phase I studies: decorations or decision making? J. Clin. Oncol. 21, 2807–2809 (2003).

    PubMed  Google Scholar 

  2. O'Connor, J. P., Jackson, A., Parker, G. J. & Jayson, G. C. DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. Br. J. Cancer 96, 189–195 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Zweifel, M. & Padhani, A. R. Perfusion MRI in the early clinical development of antivascular drugs: decorations or decision making tools? Eur. J. Nucl. Med. Mol. Imaging 37 (Suppl. 1), 164–182 (2010).

    CAS  Google Scholar 

  4. Tofts, P. S. et al. Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols. J. Magn. Reson. Imaging 10, 223–232 (1999).

    CAS  PubMed  Google Scholar 

  5. Dowlati, A. et al. A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res. 62, 3408–3416 (2002).

    CAS  PubMed  Google Scholar 

  6. Galbraith, S. M. et al. Effects of 5,6-dimethylxanthenone-4-acetic acid on human tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. J. Clin. Oncol. 20, 3826–3840 (2002).

    CAS  PubMed  Google Scholar 

  7. Jayson, G. C. et al. Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. J. Natl Cancer Inst. 94, 1484–1493 (2002).

    CAS  PubMed  Google Scholar 

  8. Galbraith, S. M. et al. Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. J. Clin. Oncol. 21, 2831–2842 (2003).

    CAS  PubMed  Google Scholar 

  9. Leach, M. O. et al. The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations. Br. J. Cancer 92, 1599–1610 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Tofts, P. S. & Kermode, A. G. Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn. Reson. Med. 17, 357–367 (1991).

    CAS  PubMed  Google Scholar 

  11. Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nat. Med. 9, 669–676 (2003).

    CAS  PubMed  Google Scholar 

  12. Thorpe, P. E. Vascular targeting agents as cancer therapeutics. Clin. Cancer Res. 10, 415–427 (2004).

    PubMed  Google Scholar 

  13. McPhail, L. D., Griffiths, J. R. & Robinson, S. P. Assessment of tumor response to the vascular disrupting agents 5, 6-dimethylxanthenone-4-acetic acid or combretastatin-a4-phosphate by intrinsic susceptibility magnetic resonance imaging. Int. J. Radiat. Oncol. Biol. Phys. 69, 1238–1245 (2007).

    CAS  PubMed  Google Scholar 

  14. Koh, D. M. et al. Reproducibility and changes in the apparent diffusion coefficients of solid tumours treated with combretastatin A4 phosphate and bevacizumab in a two-centre phase I clinical trial. Eur. Radiol. 19, 2728–2738 (2009).

    PubMed  Google Scholar 

  15. Padhani, A. R. & Miles, K. A. Multiparametric imaging of tumor response to therapy. Radiology 256, 348–364 (2010).

    PubMed  Google Scholar 

  16. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83–95 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. O'Connor, J. P. et al. Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging. Clin. Cancer Res. 15, 6674–6682 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wong, C. I. et al. Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies. J. Clin. Oncol. 27, 4718–4726 (2009).

    CAS  PubMed  Google Scholar 

  19. Dingemans, A. M. et al. First-line erlotinib and bevacizumab in patients with locally advanced and/or metastatic non-small-cell lung cancer: a phase II study including molecular imaging. Ann. Oncol. 22, 559–566 (2011).

    PubMed  Google Scholar 

  20. Barboriak, D. P. et al. Treatment of recurrent glioblastoma multiforme with bevacizumab and irinotecan leads to rapid decreases in tumor plasma volume and Ktrans. Presented at the Radiological Society of North America (RSNA) meeting, SST09–05 (Chicago, 2007).

  21. Padhani, A. R. et al. DCE-MRI demonstration of antivascular effects of combretastatin A4 phosphate (CA4P) given in combination with bevacizumab to human subjects with advanced solid tumours. In Proc. 16th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM) 16, 773 (Toronto, 2008).

    Google Scholar 

  22. Mitchell, C. L. et al. A two-part phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics. Cancer Chemother. Pharmacol. 68, 631–641 (2011).

    CAS  PubMed  Google Scholar 

  23. Wedam, S. B. et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J. Clin. Oncol. 24, 769–777 (2006).

    CAS  PubMed  Google Scholar 

  24. Gutin, P. H. et al. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int. J. Radiat. Oncol. Biol. Phys. 75, 156–163 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang, W. et al. Acute effects of bevacizumab on glioblastoma vascularity assessed with DCE-MRI and relation to patient survival. In Proc. 17th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM) 17, 282 (Honolulu, 2009).

    Google Scholar 

  26. Hahn, O. M. et al. Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma. J. Clin. Oncol. 26, 4572–4578 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Flaherty, K. T. et al. Pilot study of DCE-MRI to predict progression-free survival with sorafenib therapy in renal cell carcinoma. Cancer Biol. Ther. 7, 496–501 (2008).

    CAS  PubMed  Google Scholar 

  28. Zhu, A. X. et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J. Clin. Oncol. 27, 3027–3035 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Mross, K. et al. Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin. Cancer Res. 16, 311–319 (2010).

    CAS  PubMed  Google Scholar 

  30. Hurwitz, H. I. et al. Phase I trial of pazopanib in patients with advanced cancer. Clin. Cancer Res. 15, 4220–4227 (2009).

    CAS  PubMed  Google Scholar 

  31. Spratlin, J. L. et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J. Clin. Oncol. 28, 1780–1787 (2010).

    Google Scholar 

  32. de Bono, J. S. & Ashworth, A. Translating cancer research into targeted therapeutics. Nature 467, 543–549 (2010).

    CAS  PubMed  Google Scholar 

  33. Galbraith, S. M. et al. Reproducibility of dynamic contrast-enhanced MRI in human muscle and tumours: comparison of quantitative and semi-quantitative analysis. NMR Biomed. 15, 132–142 (2002).

    PubMed  Google Scholar 

  34. Jackson, A. et al. Reproducibility of quantitative dynamic contrast-enhanced MRI in newly presenting glioma. Br. J. Radiol. 76, 153–162 (2003).

    CAS  PubMed  Google Scholar 

  35. Mross, K. et al. DCE-MRI assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal cancer and liver metastases: a randomized phase I study. J. Angiogenes. Res. 1, 5 (2009).

    PubMed  PubMed Central  Google Scholar 

  36. Messiou, C. et al. An exploratory open-label, non-randomised, single centre methodology study to compare dynamic contrast enhanced CT and MRI as markers of changes in vascular activity mediated by a positive control agent (cediranib), a potent inhibitor of VEGF-driven angiogenesis in patients with advanced solid tumours. In Proc. 19th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM) 19, 3143 (Montréal, 2011).

    Google Scholar 

  37. US National Library of Medicine. ClinicalTrials.gov [online],.

  38. Li, S. P. et al. Evaluating the early effects of anti-angiogenic treatment in human breast cancer with intrinsic susceptibility-weighted and diffusion-weighted MRI: initial observations. In Proc. 19th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM) 19, 342 (Montréal, 2011).

    Google Scholar 

  39. Gururangan, S. et al. Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a pediatric brain tumor consortium study. J. Clin. Oncol. 28, 3069–3075 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kreisl, T. N. et al. A phase II trial of single-agent bevacizumab in patients with recurrent anaplastic glioma. Neuro. Oncol. 13, 1143–1150 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Siegel, A. B. et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J. Clin. Oncol. 26, 2992–2998 (2008).

    CAS  PubMed  Google Scholar 

  42. Lockhart, A. C. et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J. Clin. Oncol. 28, 207–214 (2010).

    CAS  PubMed  Google Scholar 

  43. Gollob, J. et al. Interim safety and pharmacodynamic results for ALN-VSP02, a novel RNAi therapeutic for solid tumors with liver involvement [abstract]. J. Clin. Oncol. 28 (Suppl. 15), a3042 (2010).

    Google Scholar 

  44. Drevs, J. et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 25, 3045–3054 (2007).

    CAS  PubMed  Google Scholar 

  45. Kelly, R. J. et al. Evaluation of KRAS mutations, angiogenic biomarkers, and DCE-MRI in patients with advanced non-small-cell lung cancer receiving sorafenib. Clin. Cancer Res. 17, 1190–1199 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kloos, R. T. et al. Phase II trial of sorafenib in metastatic thyroid cancer. J. Clin. Oncol. 27, 1675–1684 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Lam, E. T. et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J. Clin. Oncol. 28, 2323–2330 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Rosen, M. A. et al. DCE-MRI demonstrates antivascular properties of sorafenib in metastatic hormone-resistant prostate cancer. In Proc. 18th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM) 18, 4845 (Stockholm, 2010).

    Google Scholar 

  49. Machiels, J. P. et al. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006–2001. J. Clin. Oncol. 28, 21–28 (2010).

    CAS  PubMed  Google Scholar 

  50. Bjarnason, G. A. et al. Microbubble ultrasound (DCE-US) compared to DCE-MRI and DCE-CT for the assessment of vascular response to sunitinib in renal cell carcinoma (RCC) [abstract]. J. Clin. Oncol. 29 (Suppl.), a4627 (2011).

    Google Scholar 

  51. Desar, I. M. et al. Assessment of early vascular effects of the angiogenesis inhibitor sunitinib (SU) in renal cell carcinoma (RCC) by dynamic contrast enhanced MRI (DCE-MRI) and diffusion weight MRI (DWI) at 3 tesla (T) [abstract]. J. Clin. Oncol. 28 (Suppl. 15), a3051 (2010).

    Google Scholar 

  52. Rosen, M. A. et al. Sunitinib induces reductions in tumor vascular permeability and intra-tumor vascular volume in renal cell carcinoma. In Proc. 19th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM), 19, 3137 (Montréal, 2011).

    Google Scholar 

  53. Murphy, P. S. et al. Vascular response of hepatocellular carcinoma to pazopanib measured by dynamic contrast-enhanced MRI: pharmacokinetic and clinical activity correlations. In Proc. 18th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM) 18, 2720 (Stockholm, 2010).

    Google Scholar 

  54. Iwamoto, F. M. et al. Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North American Brain Tumor Consortium Study 06–02). Neuro. Oncol. 12, 855–861 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Stevenson, J. P. et al. Phase I trial of the agent combretastatin A4 phosphate on a 5-day schedule to patients with cancer: magnetic resonance imaging evidence for altered tumor blood flow. J. Clin. Oncol. 21, 4428–4438 (2003).

    CAS  PubMed  Google Scholar 

  56. Akerley, W. L. et al. A randomized phase II trial of combretatstatin A4 phosphate (CA4P) in combination with paclitaxel and carboplatin to evaluate safety and efficacy in subjects with advanced imageable malignancies [abstract]. J. Clin. Oncol. 25 (Suppl. 18), a14060 (2007).

    Google Scholar 

  57. Medved, M. et al. Semiquantitative analysis of dynamic contrast enhanced MRI in cancer patients: variability and changes in tumor tissue over time. J. Magn. Reson. Imaging 20, 122–128 (2004).

    PubMed  Google Scholar 

  58. O'Donnell, A. et al. A phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points. Br. J. Cancer 93, 876–883 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Dowlati, A. et al. Novel phase I dose de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416. Clin. Cancer Res. 11, 7938–7944 (2005).

    CAS  PubMed  Google Scholar 

  60. Miller, K. D. et al. A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin. Cancer Res. 11, 3369–3376 (2005).

    CAS  PubMed  Google Scholar 

  61. Annunziata, C. M. et al. Vandetanib, designed to inhibit VEGFR2 and EGFR signaling, had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of VEGFR2. Clin. Cancer Res. 16, 664–672 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Conrad, C. et al. A phase I/II trial of single-agent PTK 787/ZK 222584 (PTK/ZK), a novel, oral angiogenesis inhibitor, in patients with recurrent glioblastoma multiforme (GBM) [abstract]. J. Clin. Oncol. 22 (Suppl. 14), a1512 (2004).

    Google Scholar 

  63. Morgan, B. et al. Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: results from two phase I studies. J. Clin. Oncol. 21, 3955–3964 (2003).

    CAS  PubMed  Google Scholar 

  64. Mross, K. et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur. J. Cancer 41, 1291–1299 (2005).

    CAS  PubMed  Google Scholar 

  65. Thomas, A. L. et al. Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. J. Clin. Oncol. 23, 4162–4171 (2005).

    CAS  PubMed  Google Scholar 

  66. Morgan, B. et al. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a biomarker for the effect of PTK787/ZK 222584 (PTK/ZK) as second-line mono-therapy in patients with stage IIIB or stage IV non-small cell lung cancer (NSCLC) [abstract]. J. Clin. Oncol. 25 (Suppl. 18), a7676 (2007).

    Google Scholar 

  67. Drevs, J. et al. A phase IA, open-label, dose-escalating study of PTK787/ZK 222584 administered orally on a continuous dosing schedule in patients with advanced cancer. Anticancer Res. 30, 2335–2339 (2010).

    CAS  PubMed  Google Scholar 

  68. Hecht, J. R. et al. Randomized, placebo-controlled, phase III study of first-line oxaliplatin-based chemotherapy plus PTK787/ZK 222584, an oral vascular endothelial growth factor receptor inhibitor, in patients with metastatic colorectal adenocarcinoma. J. Clin. Oncol. 29, 1997–2003 (2011).

    CAS  PubMed  Google Scholar 

  69. Ellis, L. M. Antiangiogenic therapy: more promise and, yet again, more questions. J. Clin. Oncol. 21, 3897–3899 (2003).

    CAS  PubMed  Google Scholar 

  70. van Laarhoven, H. W. et al. Phase I clinical and magnetic resonance imaging study of the vascular agent NGR-hTNF in patients with advanced cancers (European Organisation for Research and Treatment of Cancer Study 16041). Clin. Cancer Res. 16, 1315–1323 (2010).

    CAS  PubMed  Google Scholar 

  71. Liu, G. et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J. Clin. Oncol. 23, 5464–5473 (2005).

    CAS  PubMed  Google Scholar 

  72. Jonker, D. J. et al. A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors. Ann. Oncol. 22, 1413–1419 (2011).

    CAS  PubMed  Google Scholar 

  73. Strumberg, D. et al. Phase I dose escalation study of telatinib (BAY 57–9352) in patients with advanced solid tumours. Br. J. Cancer 99, 1579–1585 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Eskens, F. A. et al. Phase I dose escalation study of telatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet-derived growth factor receptor beta, and c-Kit, in patients with advanced or metastatic solid tumors. J. Clin. Oncol. 27, 4169–4176 (2009).

    CAS  PubMed  Google Scholar 

  75. Rosen, L. S. et al. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 25, 2369–2376 (2007).

    CAS  PubMed  Google Scholar 

  76. Michaelis, L. C. & Ratain, M. J. Measuring response in a post-RECIST world: from black and white to shades of grey. Nat. Rev. Cancer 6, 409–414 (2006).

    CAS  PubMed  Google Scholar 

  77. Karrison, T. G., Maitland, M. L., Stadler, W. M. & Ratain, M. J. Design of phase II cancer trials using a continuous endpoint of change in tumor size: application to a study of sorafenib and erlotinib in non small-cell lung cancer. J. Natl Cancer Inst. 99, 1455–1461 (2007).

    CAS  PubMed  Google Scholar 

  78. Ton, N. C. et al. Phase I evaluation of CDP791, a PEGylated Di-Fab' conjugate that binds vascular endothelial growth factor receptor 2. Clin. Cancer Res. 13, 7113–7118 (2007).

    CAS  PubMed  Google Scholar 

  79. Jamin, Y. et al. Native T1 is a generic imaging biomarker of response to chemotherapy in neuroblastoma. In Proc. 19th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM), 19, 987 (Montréal, 2011).

    Google Scholar 

  80. Roberts, C. et al. The effect of blood inflow and B(1)-field in homogeneity on measurement of the arterial input function in axial 3D spoiled gradient echo dynamic contrast-enhanced MRI. Magn. Reson. Med. 65, 108–119 (2011).

    PubMed  Google Scholar 

  81. Buckley, D. L. Uncertainty in the analysis of tracer kinetics using dynamic contrast-enhanced T1-weighted MRI. Magn. Reson. Med. 47, 601–606 (2002).

    PubMed  Google Scholar 

  82. Eder, J. P., Jr. et al. Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily. J. Clin. Oncol. 20, 3772–3784 (2002).

    CAS  PubMed  Google Scholar 

  83. McKeage, M. J. et al. 5, 6-Dimethylxanthenone-4-acetic acid in the treatment of refractory tumors: a phase I safety study of a vascular disrupting agent. Clin. Cancer Res. 12, 1776–1784 (2006).

    CAS  PubMed  Google Scholar 

  84. Sledge, G. W., Jr What is targeted therapy? J. Clin. Oncol. 23, 1614–1615 (2005).

    PubMed  Google Scholar 

  85. Hayes, C., Padhani, A. R. & Leach, M. O. Assessing changes in tumour vascular function using dynamic contrast-enhanced magnetic resonance imaging. NMR Biomed. 15, 154–163 (2002).

    PubMed  Google Scholar 

  86. Baar, J. et al. A vasculature-targeting regimen of preoperative docetaxel with or without bevacizumab for locally advanced breast cancer: impact on angiogenic biomarkers. Clin. Cancer Res. 15, 3583–3590 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lankester, K. J. et al. Effects of platinum/taxane based chemotherapy on acute perfusion in human pelvic tumours measured by dynamic MRI. Br. J. Cancer 93, 979–985 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Vriens, D. et al. Chemotherapy response monitoring of colorectal liver metastases by dynamic Gd-DTPA-enhanced MRI perfusion parameters and 18F-FDG PET metabolic rate. J. Nucl. Med. 50, 1777–1784 (2009).

    CAS  PubMed  Google Scholar 

  89. Overmoyer, B. et al. Inflammatory breast cancer as a model disease to study tumor angiogenesis: results of a phase IB trial of combination SU5416 and doxorubicin. Clin. Cancer Res. 13, 5862–5868 (2007).

    CAS  PubMed  Google Scholar 

  90. Akisik, M. F. et al. Pancreatic cancer: utility of dynamic contrast-enhanced MR imaging in assessment of antiangiogenic therapy. Radiology 256, 441–449 (2010).

    PubMed  Google Scholar 

  91. Hsu, C. Y. et al. Dynamic contrast-enhanced magnetic resonance imaging biomarkers predict survival and response in hepatocellular carcinoma patients treated with sorafenib and metronomic tegafur/uracil. J. Hepatol. 55, 858–865 (2011).

    CAS  PubMed  Google Scholar 

  92. de Lussanet, Q. G. et al. Dynamic contrast-enhanced magnetic resonance imaging of radiation therapy-induced microcirculation changes in rectal cancer. Int. J. Radiat. Oncol. Biol. Phys. 63, 1309–1315 (2005).

    PubMed  Google Scholar 

  93. Cao, Y. et al. Early prediction of outcome in advanced head-and-neck cancer based on tumor blood volume alterations during therapy: a prospective study. Int. J. Radiat. Oncol. Biol. Phys. 72, 1287–1290 (2008).

    PubMed  PubMed Central  Google Scholar 

  94. Ceelen, W. et al. Noninvasive monitoring of radiotherapy-induced microvascular changes using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in a colorectal tumor model. Int. J. Radiat. Oncol. Biol. Phys. 64, 1188–1196 (2006).

    PubMed  Google Scholar 

  95. Roe, K. et al. Longitudinal magnetic resonance imaging-based assessment of vascular changes and radiation response in androgen-sensitive prostate carcinoma xenografts under androgen-exposed and androgen-deprived conditions. Neoplasia 12, 818–825 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. Benjaminsen, I. C., Melas, E. A., Mathiesen, B. S. & Rofstad, E. K. Limitations of dynamic contrast-enhanced MRI in monitoring radiation-induced changes in the fraction of radiobiologically hypoxic cells in human melanoma xenografts. J. Magn. Reson. Imaging 28, 1209–1218 (2008).

    PubMed  Google Scholar 

  97. Jackson, A., O'Connor, J. P., Parker, G. J. & Jayson, G. C. Imaging tumor vascular heterogeneity and angiogenesis using dynamic contrast-enhanced magnetic resonance imaging. Clin. Cancer Res. 13, 3449–3459 (2007).

    PubMed  Google Scholar 

  98. Herbst, R. S. et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 377, 1846–1854 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Azad, N. S. et al. Dual targeting of vascular endothelial growth factor (VEGF) with sorafenib and bevacizumab: clinical and translational results [abstract]. J. Clin. Oncol. 25 (Suppl. 18), a3542 (2007).

    Google Scholar 

  100. Kummar, S. et al. Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas. Eur. J. Cancer 47, 997–1005 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Posey, J. A. et al. A phase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma. Clin. Cancer Res. 9, 1323–1332 (2003).

    CAS  PubMed  Google Scholar 

  102. Padhani, A. R. et al. Dynamic MRI evaluation of the triple receptor tyrosine kinase inhibitor BIBF 1120 in patients with advanced solid tumours. In Proc. 18th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM) 14, 765 (Seattle, 2006).

    Google Scholar 

  103. Xiong, H. Q. et al. A phase I study of AEE788, a multitargeted inhibitor of ErbB and VEGF receptor family tyrosine kinases, to determine safety, PK and PD in patients (pts) with advanced colorectal cancer (CRC) and liver metastases [abstract]. J. Clin. Oncol. 25 (Suppl. 18), a4065 (2007).

    Google Scholar 

  104. Zweifel, M. et al. Serial R2* MRI to evaluate response to tumour vascular disruptive treatment in a clinical phase I trial. In Proc. 18th Annual Scientific Meeting of International Society for Magnetic Resonance in Medicine (ISMRM) 18, 2718 (Stockholm, 2010).

    Google Scholar 

  105. Mita, M. M. et al. Phase 1 first-in-human trial of the vascular disrupting agent plinabulin(NPI-2358) in patients with solid tumors or lymphomas. Clin. Cancer Res. 16, 5892–5899 (2010).

    CAS  PubMed  Google Scholar 

  106. Rischin, D. et al. Clinical, pharmacodynamic, and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation. Clin. Cancer Res. 17, 5152–5160 (2011).

    CAS  PubMed  Google Scholar 

  107. Ricart, A. D. et al. A phase I study of MN-029 (denibulin), a novel vascular-disrupting agent, in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 68, 959–970 (2011).

    CAS  PubMed  Google Scholar 

  108. Lickliter, J. D. et al. Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent. Br. J. Cancer 103, 597–606 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. LoRusso, P. M. et al. Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors. Invest. New Drugs 26, 159–167 (2008).

    CAS  PubMed  Google Scholar 

  110. Gregorc, V. et al. Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours. Eur. J. Cancer 46, 198–206 (2010).

    CAS  PubMed  Google Scholar 

  111. Zucali, P. A. et al. Phase I and pharmacodynamic study of high-dose NGR-hTNF in patients with solid tumors [abstract]. J. Clin. Oncol. 29 (Suppl. 15), a2522 (2011).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Imaging, Genomics and Proteomics Research Group, School of Cancer and Enabling Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

    James P. B. O'Connor, Alan Jackson, Geoff J. M. Parker & Caleb Roberts

  2. Cancer Research UK Department of Medical Oncology, Christie Hospital, Wilmslow Road, Manchester, M20 4BX, UK

    Gordon C. Jayson

Authors
  1. James P. B. O'Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Geoff J. M. Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Caleb Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gordon C. Jayson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to James P. B. O'Connor.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2012.2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer