Selecting the Right Technique

Very often, similar measurements of biological and disease processes are provided by multiple imaging modalities or even distinct approaches within a single modality. In selecting the right technique for a given problem, it is important to consider the range of possible biomarkers (both imaging and nonimaging), as well as the varying technical requirements and available resources, any significant differences between hardware platforms, and the limitations of specific modalities. Here we illustrate the considerations for selecting a particular imaging biomarker for the problem of assessing tumor vascularity.

Example: Studying Aspects of Tissue Vascularity Let us assume that we wish to evaluate the tumor response to a new antiangiogenic agent for the purposes of defining the lower limit of biological effectiveness across a dose range. What parameters need consideration when deciding on the appropriate methodology?

The advantages and disadvantages of techniques are seldom reviewed comprehensively, and more specifically, there are few studies actually comparing methodologies for their potential to study therapy. De Langen et al. provide an insightful comparison of [15O]H2O-PET versus DCE-MRI for tumor blood flow measurements [168]. The review focuses on both the practical aspects of the two techniques and the ability of the different techniques to probe flow. The conclusion from the comparison is that both approaches are viable methods for the study of flow, yet important differences need to be considered for each study. Goh and Padhani compare the merits of DCE-CT versus DCE-MRI in the study of tumor angiogenesis [169]. Again, it is concluded that both techniques should be considered, but a number of factors should determine selection, including drug mechanism of action, tumor location, patient characteristics, and available infrastructure and expertise [169].

The potential techniques able to define tumor vascular characteristics include the following:

Dynamic Contrast-Enhanced CT

• Endpoints. DCE-CT can measure blood flow, blood volume, permeability, and mean transit time.

• Tumor localization. Multidetector CT technology enables a significant coverage of the tumor during the dynamic assessment, overcoming previous limitations of the approach. Furthermore, CT offers some key advantages when imaging certain anatomical regions, as summarized by Goh and Padhani [169].

• Clinical trial practicalities. The technique is widely available, although it is preferable that sites have previous expertise in dynamic CT. However, training imaging centers with a standard protocol is achievable. Also, since CT is generally required for RECIST assessment of disease burden, the use of CT for a pharmacodynamic investigation may result in fewer scanning sessions.

• Risks. Dynamic CT may add a significant radiation dose burden that may become problematic in many patient populations. This is particularly true if these subjects are already receiving regular CT scans for standard radiological assessment, perhaps also with nuclear medicine investigations accumulating a significant dose. This is likely to limit the number of time points that are measurable within a short clinical trial, particularly compared to DCE-MRI and microbubble ultrasound.

• Quantification. The straightforward relationship between CT contrast agent concentration and tissue enhancement is often cited as a significant advantage that DCE-CT has over DCE-MRI, making absolute quantification of perfusion achievable. For analysis, the availability of commercial software on the scanning platform holds a significant advantage relative to other methods, although centralized analysis is often required anyway, so this advantage may be limited.

In summary, DCE-CT is a widely available, robust methodology for providing perfusion quantification [170] . However, the associated radiation dose is likely to limit the use of CT in certain patient populations and certainly keep the number of time points low.

Dynamic Contrast-Enhanced MRI

• Endpoints. DCE-MRI typically provides indices relating to permeability and flow (Ktrans and IAUC) in addition to indices relating to the tissue microenvironment (ve).

• Tumor localization. The localization can be similar to CT in that a single level is typically scanned using multiple slices. However, coronal scanning, for example, may facilitate greater coverage if multiple lesions require measurement. Compared to DCE-CT, DCE-MRI is not optimal for all lesions and may often suffer from artifacts rendering measurement impossible (e.g., in the mediastinum).

• Clinical trial practicalities. The equipment required to perform DCE-MRI is widely available, yet the expertise in quantitative MRI measurement is limited. This can often be overcome by working closely with the imaging center and providing rapid feedback on data generated. In many instances, willingness of a site to adhere to a consistent imaging protocol is preferable to a site with extensive experience, insisting that the measurement be performed a particular way. The number of time points available from DCE-MRI is one advantage, with many publications demonstrating five measurements or more are feasible. However, recent concerns regarding NSF are likely to limit the number of time points, especially in patient populations with compromised renal function.

• Risks. The only significant risk to the subject is from the exposure to gadolinium-containing contrast media. These risks can be minimized, but in patient populations with compromised renal function an alternative imaging technique may be deemed appropriate.

• Quantification. With the lack of consistent and widely available image analysis platforms for DCE-MRI, central analysis of multicenter data is paramount. A significant limitation is the inability to define flow separately from permeability. Although Ktrans and IAUC may provide useful general indicators of vascular pharmacology, interpretation can be challenging.

Without the radiation dose burden and the ability to perform multiple post-therapy time points, DCE-MRI remains attractive for many studies. However, the challenge to implement across multiple centers with the associated cost and time should not be overlooked. Furthermore, ambiguity of the imaging parameters needs to be considered carefully to ensure that DCE-MRI will contribute sufficient insight into the pharmacology.

Microbubble Ultrasound

• Endpoints. The reported endpoints are varied and include parameters such as area under the enhancement curve, arrival time, time to peak enhancement, and counting of identified vessels.

• Tumor localization. Bone and air attenuation sets significant limits on accessibility of this technique to some lesions. This is a fundamental limitation that should be considered when establishing the appropriate patient population to study.

• Clinical trialpracticalities. Ultrasound remains widely available, although centers experienced in quantitative microbubble techniques remain limited. Furthermore, differences in techniques at those centers need harmonizing before a clinical trial can begin. Several repeat measurements are possible [171] - This could allow studies in multiple lesions or repeat measurement in the event of failure or repeated measurements averaged to minimize variability. The technique is likely to be favorable to the patient, requiring relatively quick examination times, and comfort during the examination is likely to be high. The low cost may also be an important factor, and if implemented appropriately would constitute only a small fraction of a total study budget. A frequently quoted criticism of quantitative ultrasound is the operator dependence of the measurement. However, it has been shown that with careful implementation, such dependence can be controlled [172]. How this would translate into large multicenter studies, however, is yet to be established.

• Risks. No significant risks are expected with repeated microbubble ultrasound investigations. Microbubble contrast media are considered generally safe, with serious adverse events rarely observed [173].

• Quantification. Analysis is currently limited to empirical analyses of the microbubble dynamics. As such, there is likely to be significant variability of measurement from one scanner to the next where different performance characteristics and software implementations will affect measurement. A cross- s ite calibration exercise combined with central analysis could overcome many of the limitations. Understanding the relationship of the ultrasound parameters to the biology may be challenging.

Microbubble ultrasound remains a quick, low-cost, highly accessible methodology for gauging vascular change [174]. Further understanding is needed of the multisite performance together with more insight into the biological linkage. For single or small multisite studies it could provide a useful method to enable many repeat measurements over a short period of time to understand relationships between pharmacokinetics and pharmacodynamic response.

[15O]H2O-PET

• Endpoints. Flow and distribution volume are typically derived. Since the tracer is rapidly diffusible, permeability is not extracted.

• Tumor localization. The poor spatial resolution of PET will limit the study of small lesions. Even if such lesions are identifiable, partial volume effects are likely to make robust quantification challenging [175]. Careful screening of subjects is required to ensure that there exist, for example, at least 2-cm lesions prior to entering into the study.

• Clinical trialpracticalities. Owing to the short half-life of 15O (2 minutes), an onsite cyclotron is required to generate the tracer and facilitate rapid administration. Even sites with a cyclotron may not produce [1 5O]H2O

routinely. If this technique is required at multiple sites, the infrastructure and expertise of potential sites must be assessed carefully. One benefit of the short half-life is that repeat examinations can be performed within 10 minutes of each other. This allows either repeat perfusion assessments early after therapy or use of correlative imaging such as [18F]FDG-PET without interference. Since an arterial input function needs to be defined for quantification, rapid arterial blood sampling is required during the study. This adds significant complexity onto an imaging examination, and the practicalities need consideration when selecting this technique.

• Risks. Although the effective radiation dose is lower than an extensive CT scan or an [18F]FDG -PET scan, the additional radiation dose this brings to a subject who has been scanned extensively should be considered carefully. This is particularly true where there may be no direct benefit to the subject of such a pharmacodynamic endpoint versus a diagnostic CT or PET scan.

• Quantification. A significant body of work exists on quantification of dynamic PET data, particularly from the brain and heart. Adaptation of such analyses can facilitate robust measurement of tumor pathophysiol-ogy [176]. Owing to different implementation options, central analysis is required if data are obtained from multiple centers.

PET provides a robust technique to quantify absolute tumor perfusion, and the quantification has many advantages over other methodologies. However, the limited availability across sites, the relatively complex patient setup, and limited performance in small lesions need careful consideration.

As outlined above, there exist many practical and basic differences between measurement techniques able to study different aspects of the same phenomenon. All decisions will be dependent on the study question being asked. For example, if analysis of lung tumor perfusion across multiple centers is required, DCE-CT is likely to be an appropriate technology. If multiple time points are required to assess relative vascular change of liver lesions, microbubble ultrasound may be an appropriate methodology.

The following parameters will define the appropriateness of the various techniques: the ability to perform centralized analysis; the patient characteristics (radiation dose considerations and sensitivity to both MR and CT contrast media), the number of subjects and study centers required for delivery of the primary study endpoint, the number of time points required to fully assess the pharmacodynamics, the drug mechanism, and the probable importance of perfusion analysis versus a measure also sensitive to permeability.

There is no single technique ideally suited to address all questions in all types of clinical trials. DCE-MRI has tended to receive considerable attention for studies of anti-angiogenics. This is probably because although it has limitations in terms of the quantification, it comes with high-resolution robust measurement in a variety of tumor types, and multiple repeat measurements are possible in most patient populations. Despite these advantages, the limitations of DCE-MRI should be evaluated and all measurement options considered.

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