The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

Leach, Martin O.; Brindle, Kevin M.; Evelhoch, Jeffrey L.; Griffiths, John R.; Horsman, Michael R.; Jackson, Alan; Jayson, Gordon C; Judson, Ian; Knopp, Michael V.; Maxwell, Ross J.; McIntyre, Dominick J.O.; Padhani, Anwar R.; Price, Pat; Rathbone, Richard; Rustin, G. J. S.; Tofts, PS; Tozer, Gillian M.; Vennart, W.; Waterton, John C.; Williams, S. R.; Workman, Paul

doi:10.1038/sj.bjc.6602550

Cited by 480 publications

(391 citation statements)

References 69 publications

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“…R͑t͒ ϭ E.e Ϫ EF ve ͑tϪTc͒ , t Ն T c [5] with T c defining the mean capillary transit time. Finally, the capillary permeability-surface area product PS (mL s Ϫ1 g Ϫ1 ) is calculated according to the Crone formula (29) as:…”

Section: Image Analysismentioning

confidence: 99%

“…Assessing tumor perfusion and transvascular/interstitial transport with dynamic contrast-enhanced MRI is increasingly performed for determining the accumulation of cytotoxic drugs or evaluating the response to antiangiogenic treatments (3)(4)(5)(6). The effect of antiangiogenic and antivascular treatments on perfusion and transvascular and interstitial transport is complex and depends on the tumor, the type and dose of the treatment, and the timing after the start of the treatment (7).…”

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confidence: 99%

“…Recently, Leach et al (5), on behalf of the Pharmacodynamic/Pharmacokinetic Technologies Advisory Committee of the Cancer Research UK, recommended using K trans with the simple Kety model as the primary endpoint of antiangiogenesis therapeutics. The authors considered that K trans was the most widely accepted kinetic parameter, describing the transendothelial transport into the extravascular extracellular space by diffusion (20).…”

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confidence: 99%

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Transvascular and interstitial transport in rat hepatocellular carcinomas: Dynamic contrast‐enhanced MRI assessment with low‐ and high‐molecular weight agents

Michoux

Huwart

Abarca‐Quinones

et al. 2008

Magnetic Resonance Imaging

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Purpose:To assess which MRI-derived kinetic parameters reflect decreased transvascular and interstitial transport when low-and high-molecular-weight agents are used in rat hepatocellular carcinomas. Materials and Methods:Dynamic MRI after injection of a low-molecular-weight contrast agent of 0.56 kDa (Gd-DOTA, gadoterate) and two high-molecular-weight contrast agents of 6.47 kDa (P792, gadomelitol) and 52 kDa (P717, carboxymethyldextran Gd-DOTA) was performed in rats with chemically induced hepatocellular carcinomas. The data were analyzed with the Kety compartmental model, the extended Kety compartmental model in which it is assumed that the tissue voxels contain a vascular component, and the St Lawrence and Lee distributed-parameter model. Results:The extravascular extracellular space accessible to the contrast agent v e and the extraction fraction E decreased with increasing molecular weight of the contrast agent. In contrast, the volume transfer constant Ktrans did not differ significantly when low-or high-molecular-weight agents were used. Conclusion:In this animal model the results suggest that the accessible extravascular extracellular space and the extraction fraction are more sensitive indicators of decreased transvascular and interstitial transport with highmolecular-weight agents than the volume transfer constant, which is a lumped representation of blood flow and permeability.

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Section: Image Analysismentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Transvascular and interstitial transport in rat hepatocellular carcinomas: Dynamic contrast‐enhanced MRI assessment with low‐ and high‐molecular weight agents

Michoux

Huwart

Abarca‐Quinones

et al. 2008

Magnetic Resonance Imaging

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“…The main heuristic parameters include peak enhancement, rate of enhancement, and terminal slope. These parameters, which are extracted from the DCE-MRI signal curve without any requirement for further measurement, are simple and straightforward but vary greatly with different protocols, contrast agent injection, and scanners (22). Therefore, between-patient and between-system comparisons are difficult.…”

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confidence: 99%

DCE‐MRI pixel‐by‐pixel quantitative curve pattern analysis and its application to osteosarcoma

Guo

Reddick

2009

Magnetic Resonance Imaging

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Purpose: To present a novel curve pattern analysis (CPA) method to characterize and quantify signal curves from the dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) data without any prerequisites such as arterial input function (AIF) or T 1 measurement. Materials and Methods:CPA parameters represent characteristics of the scaled DCE signal curve. Simulations were performed to investigate the dependence of CPA parameters on T 1 , TR, and flip angle. In vivo studies were performed on five pediatric patients with osteosarcoma. Parametric maps were generated using the CPA method and a pharmacokinetic model-based method for comparison.Results: Simulations show that CPA parameters varied less than 2% when T 1 changed from 300 msec to 1500 msec, and less than 10% when the flip angle changed from 30°to 40°. Various curve patterns can be qualitatively identified and recognized from CPA parameter maps. Simulation and in vivo studies showed that the CPA parameter had a strong correlation with k ep , with correlation coefficients of 0.9983 in the simulation and 0.95 in the in vivo studies. Conclusion:A novel CPA method is presented. Simulations and in vivo studies showed that the CPA method provides a feasible alternative to quantifying DCE-MRI studies with possibly higher repeatability by minimizing variations potentially induced by AIF and T 1 estimations and model dependence.

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“…In clinical studies, the quality of data is frequently inadequate for quantitative analysis. 43 There is also considerable intrapatient variability of the quantitative parameters; two pre-therapy baseline scans are currently recommended to assess the reproducibility of measurements in clinical trials. 43 It is also unclear whether DCE-MRI will be as successful as existing imaging techniques for the assessment of the effects of drugs that are less potent inhibitors of vascular permeability than are VEGF inhibitors.…”

Section: Measuring Target Inhibitionmentioning

confidence: 99%

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

et al. 2008

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SUMMARYTargeted drugs hold great promise for the treatment of malignant tumors; however, there are several challenges for efficient evaluation of these drugs in preclinical and clinical studies. These challenges include identifying the 'correct', biologically active concentration and dose schedule, selecting the patients likely to benefit from treatment, monitoring inhibition of the target protein or pathway, and assessing the response of the tumor to therapy. Although anatomic imaging will remain important, molecular imaging provides several new opportunities to make the process of drug development more efficient. Various techniques for molecular imaging that enable noninvasive and quantitative imaging are now available in the preclinical and clinical settings, to aid development and evaluation of new drugs for the treatment of cancer. In this Review, we discuss the integration of molecular imaging into the process of drug development and how molecular imaging can address key questions in the preclinical and clinical evaluation of new targeted drugs. Examples include imaging of the expression and inhibition of drug targets, noninvasive tissue pharmacokinetics, and early assessment of the tumor response.

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The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

Cited by 480 publications

References 69 publications

Transvascular and interstitial transport in rat hepatocellular carcinomas: Dynamic contrast‐enhanced MRI assessment with low‐ and high‐molecular weight agents

Transvascular and interstitial transport in rat hepatocellular carcinomas: Dynamic contrast‐enhanced MRI assessment with low‐ and high‐molecular weight agents

DCE‐MRI pixel‐by‐pixel quantitative curve pattern analysis and its application to osteosarcoma

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

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