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Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials

Pharmacodynamic/Pharmacokinetic Technologies Advisory Committee (PTAC), Drug Development Office, Cancer Research UK, London, UK

Correspondence: Prof. Martin O Leach, Cancer Research UK Clinical Magnetic Resonance Research Group, The Institute of Cancer Research and The Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK

	Introduction

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
MRI is increasingly being used to evaluate antiangiogenic and antivascular agents in early stage clinical trials. The measurement and analysis methodology required for robust application of MRI to such trials has been considered by specialist panels in a workshop, resulting in recommendations for the design and analysis of trials, and identification of areas requiring further development. The following document is the text of the poster presented by Cancer Research UK Pharmacodynamic/Pharmacokinetic Technologies Advisory Committee (PTAC) on the use of MRI for the evaluation of antiangiogenic and antivascular cancer drugs presented at the American Association for Cancer Research, Washington (2003) and at the International Society of Magnetic Resonance in Medicine, 11th Scientific meeting, Toronto, 2003 [1, 2].

	Need for recommended guidelines

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
With the increasing pace of target discovery and new therapeutic development, there is a need to evaluate the effects of drugs on their therapeutic targets in vivo, and to perform clinical trials more effectively. To aid this process in the UK, proposed trial designs submitted to Cancer Research UK are evaluated by PTAC to obtain information on therapeutic delivery and action on the intended molecular target in hypothesis-testing trials. An increasing number of proposals aim to assess antiangiogenic and antivascular agents using dynamic contrast medium enhanced magnetic resonance imaging (DCE-MRI). These proposals often provide little methodological detail, or demonstrate considerable variation in approach, resulting in a need for detailed advice from PTAC. Given the evident value of DCE-MRI in assessing antiangiogenic and antivascular agents [3–7], it was thought timely to consider the methodological and analysis requirements for such studies.

A workshop was held at the Novartis Foundation, London in March 2002, to provide recommendations for future trials. In developing these recommendations, the views of pharmacologists, clinical trialists, the pharmaceutical industry and MR radiologists and scientists were considered. The workshop considered the types of therapeutics and their effects; the requirements of clinicians and the pharmaceutical industry; the potential MRI approaches, the information provided and the reproducibility of the data. Panels then considered the important issues involved in applying MRI to antivascular and antiangiogenic therapies, and guidelines for such use. The recommended guidelines below summarize the presentations and conclusions of the panels. The panels and workshop also considered requirements for further research and development to improve methodology, analysis and the design of clinical trials.

	1. Effects of therapeutics

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
Antiangiogenic therapy

• Inhibition of growth factor support of neovasculature
  
• Reduced permeability
  
• Reduced perfusion
  
• Reduced blood volume
  

Antivascular therapy

• Collapse of proliferating vasculature
  
• Possible collapse of mature tumour vasculature
  
• Loss of permeable vasculature
  
• Reduced perfusion, flow
  
• Reduced blood volume
  
• Reduced vascular tortuosity
  

	2. Issues relating to therapeutic drug development

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
It was considered important to know if the drug is:

• Reaching the required concentration
  
• Affecting the desired molecular target
  
• Modulating the biochemical pathway
  
• Achieving the desired biological effect
  

There is a requirement for non-invasive assays—particularly when timing of the peak biological activity is not known.

Hypothesis testing trials should aim to:

• Support go/no go decisions
  
• Kill failures early
  
• Provide confidence to go forward to expensive large scale trials
  
• Accelerate drug development
  
• Establish dose and time response (scheduling)
  
• Examine drug combinations
  

It was thought less important to provide surrogate endpoints to regulatory bodies.

Studies should operate at a level of evidence between publication standard quality assurance and GCP (good clinical practice).

Studies should have realistic guidelines (resource issues – who pays to develop methods and maintain facilities).

	3. Clinical issues

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 

• Antiangiogenic therapies may have most effect on small tumours – not those traditionally monitored in Phase I/II clinical trials – this can be challenging for MRI.
  
• In the absence of volume response, functional measurement information or biopsy may be required to gain the confidence to go to Phase III studies.
  
• What is the correct timing for measurements?
  
• To what extent can information from pre-clinical models guide clinical measurements?
  
• Can a dose response be identified?
  

	4. Pharmaceutical industry view

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 

• MR endpoints may aid selection of leads from many targets and molecules, for eventual Phase III trials, reducing lead-time and costs.
  
• Ideally identify markers of biological efficacy, guiding effective dose, scheduling and combinations.
  
• The MR effect may not give a dose response?
  
• Alternative methods of interest including PET, infrared imaging, perfusion CT, Doppler and contrast enhanced ultrasound (US) should be considered.
  
• Studies should be feasible and analysis methods should be robust.
  
• The approach should have widely accepted validity.
  
• The method should enable standardized implementation across several centres.
  
• Clear primary MR endpoint(s) should be established prospectively.
  
• The type of analysis should be specified prospectively.
  
• There is recognition of a tension between trials conducted at GCP and publication standards, the funding required to meet these standards and who should fund this activity.
  

	5. Recommendations for MR measurement methods and endpoints for use in Phase 1/2a trials of anticancer therapeutics

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
Type of measurement
Pharmacodynamic assessment should use T₁ weighted studies with low molecular weight gadolinium chelates as contrast agents.

T₂* weighted DCE-MRI studies may provide further information relating to tumour blood flow.

Non-contrast enhanced MRI methods such as blood oxygen level dependent (BOLD) and arterial spin tagging may provide additional information.

High molecular weight contrast agents may prove more sensitive than small molecular weight MRI in the longer term but the former are not readily available and are not yet recommended for routine use.

Primary endpoints
The primary endpoint should be either transfer constant (K^trans (s^–1) or IAUGC (mMGd.s)) as defined by Tofts et al [8].

Vascularized tumour volume can be obtained by summing voxels with values above a pre-determined threshold.

Ideally measurements of K^trans or IAUGC should be made voxel-wise.

In tissues with substantial motion, averaged region of interest (ROI) measurements may be appropriate.

As far as possible, 3D (multislice) measurements are preferred because single slice measurements (in theory) may be prone to bias.

Tumour volume/size should be measured.

All data including ROI definition and analysis should be recorded and traceable to support external review.

Measurement requirements to assess K^trans and IAUGC
Both K^trans and IAUGC require calculation of instantaneous tumour contrast agent concentration, based on the change in relaxivity due to contrast agent uptake (R1). This requires:

• An estimate of contrast agent relaxivity in tumour vasculature and tissues.
  
• Measurement of tumour T₁ relaxation rate immediately prior to contrast uptake.
  
• An accurate T₁ measurement method verified for all spatial locations, coils and scanners used.
  
• Cardiac output (or arterial input function) measurements.
  
• Reproducible injection (ideally an MR compatible power injector).
  

Secondary endpoints
Simplified methods of characterizing contrast–time curves in DCE-MRI are not recommended. They may be less sensitive than transfer constant (K^trans) or initial area under the gadolinium concentration time curve (IAUGC) and are harder to compare between centres.

Semi-quantitative techniques are limited as they:

• May not accurately reflect tissue contrast agent concentration.
  
• May be influenced by contrast injection procedure, scanner settings, adjustment and coil behaviour.
  
• May be influenced by cardiac output.
  
• Have a poorly defined relationship to underlying physiological processes.
  
• Comparison between patients and between systems is difficult.
  

Other endpoints derived from compartmental models and DCE-MRI such as v_b (blood volume), v_e (leakage space), k_ep (rate constant) may be of added value [8].

More elaborate pharmacokinetic models [9] may improve evaluation of dynamic data but are not yet supported by sufficient evidence to warrant use as primary endpoints. Non DCE-MRI secondary endpoints include T₁, T₂ and T₂* relaxation rates, diffusion, perfusion from arterial spin tagging.

	6. Trial design

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
Entry criteria should consider tumour size in relation to pharmacological mechanisms, MRI resolution and potential confounding from rapid tumour growth rates (see clinical issues).

Investigators might consider dose escalation in individual patients, allowing each subject to act as their own control.

	7. Nomenclature and analysis

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
Nomenclature
Standardized terms should be employed as defined in Tofts et al [8].

Primary endpoints

• K^trans or transfer constant reflects contrast delivery (perfusion) and transport across the vascular endothelium (permeability), with the dominant factor depending on whether delivery is flow or permeability limited. Converting DCE-MRI data are converted to contrast concentration and fitting derived values are fitted to a pharmacokinetic model.
  
• IAUGC (Initial area under the gadolinium concentration–time curve) does not require a model, but does not have a simple relationship to physiology. It is a relatively robust and simple technique [10].
  

Secondary endpoints based on quantitative techniques

• v_b (blood volume) can be derived from T₂* first pass studies, or from T₁ weighted modelling techniques.
  
• k_ep is a function of K^trans and v_e.
  
• v_e (extravascular–extracellular space) may reflect cellular density.
  

Macromolecular contrast agents, although not yet recommended for trials of new therapeutic agents, are of value for pre-clinical experimental work. They can measure PS (endothelial permeability) and v_p (fractional plasma volume) without flow contamination.

Measurements of PS may be hindered by low vascular leak into tumours, requiring long measurement times and images may show poor signal to noise (particularly for T₁ weighted measurements).

Analysis
Model analysis should be based on the well-accepted Tofts or equivalent models [9], but with inclusion of arterial input normalization (where possible), blood volume, and classification of fit failures.

Estimates of uncertainty should monitor model fitting and chi-squared error, mapping this factor and including it in error analysis.

Fit failures should be categorised as enhancing model fit failure (possibly multiple classes), no enhancement, or noise.

Data analysis
ROI analysis, based on whole tumour mean values, may not evaluate tumour heterogeneity, although it may be robust to motion. It may not reflect small areas of rapid change and so may be insensitive to therapeutic effects.

Pixel mapping allows all data to be evaluated, allowing description and evaluation of regional change. Individual pixels will have a relatively poor signal to noise ratio.

Analysis techniques, such as histogram and principal components analysis, may yield sensitive assessment of change.

ROI placement needs to be supported by method of definition, and recorded to permit re-evaluation.

	8. Recommendations for analysis of DCE-MRI data in ROI

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
Before placement of an ROI, individual images should be examined for the presence of patient motion, best seen on subtraction images. Ideally dynamic image datasets should be spatially registered before analysis. Both early (60–120 s after contrast medium) and late (more than 5 min after contrast medium) subtraction images should be generated. Ideally the early subtraction images will determine the position for ROI placement. If early enhancement is low the late subtraction dataset should be used. If no enhancement is seen, the baseline data (non-enhanced) aided by conventional images should be used for ROI placement.

The outer limit of the lesion should act as a boundary of the ROI to minimize partial volume effects.

Areas of necrosis, adjacent blood vessels and artefacts should be excluded. The ROI should be constant in position and size for each image in the series under analysis.

The position of the ROIs, corresponding graphs and table of enhancement values should be recorded, ideally in digital and hard copy form for future reference.

In the event of significant motion, it may be necessary to adjust the ROI position on each image, measuring only a mean value.

Analysis should take account of potential partial volume and ROI shape.

	9. Standardization, validation and reproducibility

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
Validation of MRI in relation to endpoints of action
Requires correlation between lesion size and type of biological effect to the relevant MR parameter; performed firstly in animal models and supported by clinical biopsy data. The time course of effects of rapidly acting agents needs to be defined.

Require hypothesis-driven relationships between imaging and specific biological endpoints.

Biological endpoints should relate to the mechanism of activity of the compound. It would be desirable to be able to predict the magnitude of the MR effect based on animal models, allowing trial design to monitor dose related change.

What validation/evidence of reproducibility is required?
Centres should define reproducibility of data that is traceable, for individuals and intergroup comparisons, allowing the power of studies to be defined prospectively for a defined endpoint.

Where possible, and in the absence of existing reproducibility data specific to the method, two baseline measurements should be incorporated to allow assessment of individual patient reproducibility.

A standardized minimum statistical approach for reproducibility analysis should be defined.

Standardization of measurement methods
Basic standards for measurements of T₁ relaxation rate should be established and adhered to. They should be tested against relevant phantoms, and reproducibility established. New techniques need to demonstrate specific advantages over existing methods, providing comparison data that defines the benefit.

In multicentre trials using identical (preferred), similar or different methods, comparison of precision and accuracy should be determined on phantoms, to provide a basis for pooling data, with account taken of correction for machine specific factors, and for sensitivity to motion effects not seen in phantoms.

Studies should include routine measurement and analysis quality assurance.

Validation of analysis methods
Standardized data sets need to be made available to allow testing and comparison of analysis approaches.

Research groups should make analysis methods available, either as open source code or by specific agreements where there are confidential or commercial issues. Standardization of software for analysis would be desirable.

Analysis of dynamic contrast enhanced data in any multicentre trial should be performed at a single centre using validated software.

Performance of measurements at each site should be validated at the analysis site, prior to recruitment using standardized data from each site.

	10. The need for further development

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 
Short term
Commercial equipment needs to provide rapid robust methods for measuring T₁ as standard, with means of validation.

Generally applicable methods of measuring arterial input function appropriate for all tumour sites of interest are required.

Validated statistical tools for histogram analysis are needed.

A generally available database of anonymized standard DCE-MRI studies, with full information on the acquisition method and related diagnostic and clinical data is needed. More scientific work to define the relationship between MR changes and the action of therapeutics is required.

Long term
Clinically applicable macromolecular contrast agents are required.

Improved and more specific contrast agents are required for clinical use, including agents specifically designed for given targets/compounds.

Application of effective motion correction and registration techniques should be incorporated into measurement methods.

Arterial spin tagging as an independent means of assessing perfusion should be investigated.

The incorporation of simultaneous morphological, physiological and functional information into clinical studies may strengthen such investigations.

Future requirements for clinical trials
Methods of supporting the MR developments required to underpin clinical trials need to be established.

Trials using the MR techniques recommended here need the support of a physicist and radiologist at all stages.

For multicentre trials this should include establishing and effecting cross-site standardization of measurements and evaluation.

	Acknowledgments

 
We are grateful to Cancer Research UK for supporting this workshop.

	References

Top Introduction Need for recommended guidelines 1. Effects of therapeutics 2. Issues relating to... 3. Clinical issues 4. Pharmaceutical industry view 5. Recommendations for MR... 6. Trial design 7. Nomenclature and analysis 8. Recommendations for analysis... 9. Standardization, validation... 10. The need for... References

 

1. Leach MO, Brindle KM, Evelhoch JL, et al. Assessment of anti-angiogenic and anti-vascular therapeutics using magnetic resonance imaging: recommendations for appropriate methodology for clinical trials. In: Proceedings of the 94th Annual Meeting of the American Association for Cancer Research. Washington, DC, 2003:504.
2. Leach MO, Brindle KM, Evelhoch JL, et al. Assessment of anti-angiogenic and anti-vascular therapeutics using magnetic resonance imaging: recommendations for appropriate methodology for clinical trials. In: Proceedings of the International Society of Magnetic Resonance in Medicine, 11th Scientific meeting. Toronto, 2003:1268.
3. Galbraith SM, Maxwell RJ, Lodge MA, et al. Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. J Clin Oncol 2003;21:2831–42.[Abstract/Free Full Text]
4. Galbraith SM, Rustin GJ, Lodge MA, 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 2002;20:3826–40.[Abstract/Free Full Text]
5. Morgan B, Thomas AL, Drevs J, 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 2003;21:3955–64.[Abstract/Free Full Text]
6. Gossmann A, Helbich TH, Kuriyama N, et al. Dynamic contrast-enhanced magnetic resonance imaging as a surrogate marker of tumor response to anti-angiogenic therapy in a xenograft model of glioblastoma multiforme. J Magn Reson Imaging 2002;15:233–40.[CrossRef][Medline]
7. Jayson GC, Zweit J, Jackson A, et al. Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. J Natl Cancer Inst 2002;94:1484–93.[Abstract/Free Full Text]
8. Tofts PS, Brix G, Buckley DL, 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 1999;10:223–32.[CrossRef][Medline]
9. Tofts PS. Modeling tracer kinetics in dynamic Gd-DTPA MR imaging. J Magn Reson Imaging 1997;7:91–101.[Medline]
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