SPECIFIC IMAGING STUDIES FOR ANGIOGENESIS

The need for specific tools to assess anti-angiogenic response emerges from the lack of quantitative studies to track early changes in angiogenesis.

Perfusion Cross-Sectional Imaging

Hepatic perfusion imaging can be used for monitoring the response of anti-angiogenic therapy and depends predominantly on the vascular burden of the tumor. Perfusion imaging is obtained using contrast-enhanced studies with quantification of the blood flow at the capillary level per unit time, depending on the hemodynamic circulation of the contrast agent. Quantitative studies are shown to be more sensitive in detecting response to anti-angiogenic therapy in the form of vascular burden changes, compared to RECIST and also detects changes much earlier than mRECIST.^66,80

Hepatic Perfusion CT scan (pCT) includes a pre-contrast series followed by sequential scanning of the tumor in two phases: an early phase within 40–60 seconds from the time of contrast administration (30–60 mL of iodine-based contrast agent must be injected rate ≥5 mL/sec followed by 50 mL saline flush) and a delayed phase within 2–10 mins. Perfusion CT requires a multi-detector scanner (≥16 detector configuration) with high temporal resolution (one image per second) to ensure proper extraction of the perfusion parameters.^81,82

Perfusion MRI (pMRI) of the liver is a dynamic T1W imaging technique that can provide quantitative data of tumor microvasculature, detecting vasculature changes in the tumor, prior to and after therapy. Pre-contrast T1 mapping is usually performed in the oblique axis (to include all vessels) followed by gadolinium-based extracellular contrast injection. Contrast enhancement is evaluated on the late arterial, portal venous and delayed dynamic phases. 3D gradient echo techniques such as fast spoiled gradient echo, fast low angle shot (FLASH) with variable flip angles with parallel imaging are recommended for image acquisition due to a higher signal-to-noise ratio and less scan time.^83,84 In either modality, the scan should include the main portal vein, aorta and the region of interest (HCC under therapy in our case).

Quantification of the perfusion parameters can be obtained by either model-free approach or model-based approach; model-free approach depends on capturing tissue enhancement rate in relation to contrast passage through the tissues.

Perfusion parameters are extracted from the maximum slope of time-to-intensity curve of hepatic artery and portal vein to derive only hepatic perfusion index (HPI). Model-based approach built according to tracer kinetic physiological models. The most commonly used models in liver perfusion images are dual compartmental model (deconvolution analysis) and distributed parameter model (for further details about these kinetic models, see reference⁸⁵). The difference between both models depends on the contrast concentration gradient between the intravascular and interstitial space.

The “Dual Compartment Model” assumed an equal distribution of the contrast between both spaces while the “Distributed Parameter Model” takes into consideration the tracer concentration gradient between both spaces, especially in cases of HCC due to the presence of immature tumoral vessels. Being computationally simpler, the Dual Compartment Model is more commonly used with the main drawbacks being the underestimation of the permeability surface area product and inability to calculate the mean transit time (MTT), which is an important parameter for monitoring anti-angiogenic therapy.^85–87

Perfusion studies have recently been shown to be valid for assessment of response to anti-angiogenic drugs using the parametric perfusion maps and extracting parameters from the kinetic model (Table 2). These values reflect the flow of contrast between the extracellular and intracellular compartments, thus indicating tumoral blood flow and vascular permeability.^88–91

Generally in both pCT and pMRI, there is a trend for a significant decrease in the levels of blood flow (BF), BV, HPI and ALP with significant increase in MTT.^80,81

K-trans is the most important parameter extracted from pMRI, which is independently affected by blood flow, vessel surface area, and vessel permeability. In pre-clinical & clinical trials, K-trans is associated with higher microvascular density and its level is correlated with the aggressive nature of the liver nodules being highest in HCC compared with regenerative nodules.^92–96

Research in perfusion imaging is ongoing in preclinical and clinical trials and is a promising radiological marker for monitoring response to anti-angiogenic therapy.

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