Monitoring treatment response with color and power Doppler
Introduction
Nowadays color and power Doppler ultrasonography (US) are widely used in monitoring the results of drug or US-guided treatments thanks to technologic advances and the growing use of echo-enhancing agents 1, 2, 3, 4, 5, 6. In particular, monitoring the response to tumor treatment is increasingly important in cancer radiology because, although cancer frequency is increasing, major advances in treatment allow more cancer patients to survive. Treatment response is assessed as the volume of post-treatment necrosis and changes in local vascularity indicate a successful outcome 3, 7. Optimization of equipment settings in color and power Doppler US is an essential requisite for the evaluation of treatment response.
Low PRF and long US pulses, with consequently decreased ‘frame rate’, should be used because of the slow flow of the parenchymas. Furthermore, the units equipped with ‘steering’ are very useful because different slants of the color Doppler component can be selected while keeping the direction of the two-dimensional component of the image unchanged 8, 9, 10, 11, 12.
Power Doppler has shown a higher sensitivity in the detection of blood flow than conventional color Doppler. Power Doppler images are repeatedly described in the recent literature as depicting ‘blood flow’ or ‘perfusion’. However, basic physical principles suggest that the amount of color in these images should be independent of blood flow. These results support the hypothesis that power Doppler reflects the relative vascular volume of detectable moving blood, regardless of perfusion, while color Doppler images reflect perfusion more closely 1, 13, 14, 15.
US contrast agents allow the enhancement of both normal and tumoral vessels and markedly improve the depiction of abnormal residual vascularization after therapy 6, 16, 17, 18. Echo-enhancing agents are particularly well suited for the units equipped with harmonic imaging because they make blood more conspicuous in both B-mode and Doppler imaging. The effect of contrast agents in color Doppler US is dramatic; signals from flow in vessels which are too small or too deep and therefore previously undetectable, are clearly depicted on color Doppler images.
Blood flow velocity decreases as vessels become smaller, approaching that of the normal pulsatile motion of soft tissue at about the arteriolar level. At this point, the clutter signal from moving tissue has a Doppler shift frequency comparable to that of moving blood itself. On the other hand, the amplitude of the clutter signal remains ∼1000 times higher than that of the blood echo. The conventional method for eliminating the clutter component—the wall filter— is of no use since there is no difference in frequency between the two components. Attempts to use Doppler in such instances fail because of the overwhelming signal from tissue movement—the ‘flash artifact’ in color or the ‘thump artifact’ in spectral Doppler. Thus a contrast agent, though improving the signal-to-noise ratio in a Doppler study, will not solve the problem of small vessel flow detection.
How then might contrast agents be used to improve the conspicuity of small vessels? A method identifying the echo from the contrast agent and suppressing that from solid tissue would provide real-time ‘subtraction’ for contrast-enhanced B-mode imaging. Would it also permit the suppression of Doppler clutter with no need for a velocity dependent filter in spectral and color modes? The answer is yes and harmonic imaging actually detects flow in very small and otherwise undetectable vessels [19].
Few literature reports deal with color and power Doppler in monitoring treatment outcome and the latest clinical trials are mainly focused on the treatment of hepatocellular carcinoma, hyperfunctioning nodules of the thyroid and parathyroid glands and neoadjuvant chemotherapy of breast carcinomas 20, 21, 22, 23, 24.
Pathological findings and color Doppler patterns indicate that the growth of particularly malignant tumors is associated with major neovascularization. This process is similar in all organs except for the features specific to some abnormal processes.
Most tumors would never exceed 1–2 mm in size if they could not make new blood vessels and there is a strong correlation between vascularization and tumor growth. Neovascularization is due to tumor angiogenetic factors (TAF) secreted by cancer cells. It is initiated from a starting vessel, usually at a terminal arteriole, the new vessel anastomoses with host capillaries resulting in a rich network of tumor vessels. As the lesion grows, the blood pressure in the starting vessel increases while the already existing postcapillaries become deformed and dilated, causing a decrease in blood pressure. Reduced capillary blood pressure is likely to disturb capillary exchange. Neovascularization occurs particularly at the tumor periphery, while low-pressure capillaries inside the tumor are reduced or occluded, which eventually results in central necrosis. Thus, the degree of vascularization differs in different parts of the tumor, being high at the periphery and low in the center. Angiographic studies have also demonstrated different vascular patterns in the center and at the periphery of tumors. Numerous abnormal and chaotically arranged vessels, representing abnormally proliferated capillaries, are seen in the lesion center, while arteries enter more or less at a right angle, together with the accompanying veins, at the periphery of malignant tumors. Arteriovenous (AV) shunts may also be present [25].
Since tumor vascularization patterns are so variable, the color and power Doppler examinations performed to monitor treatment response should be compared with those performed before the beginning of the therapy, preferably with the use of echo-enhancing agents in both cases.
This review will briefly describe the role and potentials of color and power Doppler imaging in monitoring treatment outcome in some major pathologic conditions.
Section snippets
Hepatocellular carcinoma (HCC)
US is usually used for HCC identification, characterization and staging. The introduction of color Doppler has improved the differentiation between HCC and the other focal liver lesions. HCC is a hypervascular tumor and therefore color signals, with high velocity arterial Doppler spectrum, are usually visualized.
Arterial flow is easy to differentiate from venous flow. Indeed venous flow, when present, is continuous, directed toward hepatic hilum and reversed relative to normal portal flow.
At
Thyroid and parathyroid glands
PEI is a well-established method in the treatment of autonomously functioning thyroid nodules (Plummer's disease) or in hyperparathyroidism sustained by functioning adenomas 28, 33.
The toxic effects of ethanol injected into solid tissues are referable to its intracellular spread and its high concentration in local vessels. Ethanol diffusion causes direct damage—cell dehydration followed by immediate coagulation, necrosis and subsequent fibrotic changes. The vascular distribution causes indirect
The breast
The role of postoperative adjuvant therapy in patients with stage I and II breast cancer is well established. The concept of treating tumors with chemotherapy and/or endocrine therapy as first-line treatment before local treatment (known as primary therapy or neoadjuvant therapy) is relatively new. The goals of this first-line treatment are to debulk the tumor and to allow conservative surgery in the patients not requiring mastectomy 34, 35.
Considering the limitations of conventional methods,
Conclusions
The increasing use of color Doppler US in monitoring treatment outcome has been allowed by progressive technologic improvements and by the increasing application of echo-enhancing agents which, together with second armonic imaging, improve the unit sensitivity.
To date the results are very encouraging and correlate well with the changes in tumor vascularity determined by treatment, which suggests that color and power Doppler will be increasingly used in monitoring treatment outcome.
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