In daily practice contrast-enhanced ultrasound (CEUS) has proven to be helpful for
detection and characterisation of liver tumours [EFSUMB-Guidelines and Good Clinical
Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) - Update 2008. Ultraschall
in Med 2008; 29:28-44], ultrasound guided biopsy, and postablative monitoring after
radio frequency ablation (RFA). With the introduction of second generation ultrasound
contrast agents allowing real time imaging it is possible to describe the change of
brightness over time as a function of ultrasound contrast agents in- and outflow in
a certain region of interest, especially when used with current software methods allowing
analysing signals of blood pool ultrasound contrast agents without disturbances of
underlying tissue background information. In the literature there are many topics
in which time intensity curves (TIC) may add substantial information to the information
gained by conventional contrast enhanced ultrasound.
Assessment of tumour response
Assessment of tumour response
It is of special interest that time intensity curves may serve as a predictor of tumor
response to medical treatment, e.g., to the tyrosine kinase inhibitor Imatinib [Am
J Roentgenol 2006;187:1267-1273. Ultraschall in Med 2008; 5:S276-S277]. But it is
also of interest that published guidelines so far have not recognized ultrasound as
a recommended imaging method in the diagnosis and follow up of gastrointestinal stroma
tumours (GIST). The panelists of the 2005 published guidelines agreed that currently
available imaging techniques to evaluate GIST include computed tomography (CT), magnetic
resonance imaging (MRI) and fluorine-18-fluoro-deoxyglucose (FDG) positron emission
tomography (PET). It is also stated that the role of ultrasound is currently under
investigation and CEUS was not mentioned at all [Consensus meeting for the management
of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21
March 2004, under the auspices of ESMO. Ann Oncol 2005;16:566]. This might be due
to a so-called subjectivity of the ultrasound examination technique ("subjectivity"
is certainly also true also for CT and MRI but this might be less obvious). Similarly,
in the RECIST (Response Evaluation Criteria In Solid Tumors) criteria used in cancer
trials only CT and MR are allowed, ultrasound is not (for more details on RECIST see
http://www.eortc.be/).
Assessing hypervascularity and response to antiangiogenetic drugs
Assessing hypervascularity and response to antiangiogenetic drugs
In contrast to most published reports focussing mainly on CT and PET it could be recently
shown in some patients that ultrasound can be the only imaging method depicting small
hypervascularized metastases and is, therefore, also the only imaging method in the
follow up. In addition the early functional evaluation to optimize therapeutical strategies
is a main goal of tumour evaluation using antiangiogenetic treatment. Treatment response
can be predicted analyzing the vascularization before any volume reduction can be
observed using the RECIST-criteria. CEUS might also be the only method identifying
small lesions before and after treatment in patients with no evidence of metastases
using CT, MRI and PET [Ultraschall in Med 2008; 29: S276-S277]. In an experimental
animal study changes in vascularity could be detected within the first 24 hours after
administration of an antiangiogenetic drug [Lavisse et al. Invest Radiol 2008; 43:
100-111]. Recognizing these patterns on CEUS in tumor response evaluation is important,
since often, response in tumor size, particularly of the hepatic metastasis, is not
apparent until late in therapy. The analysis of time intensity curves is, therefore,
a promising method to overcome the subjectivity of contrast enhanced ultrasound.
Several of the parameters in time intensity curves correspond statistically with microvessel
density, especially the area under the curve [Du et al, J Ultrasound Med 2008; 27:
821-31].
Parameters used in Time Intensity Curves
Parameters used in Time Intensity Curves
TIC-parameters used are summarised in Table [1].
Table 1 Parameters calculated from the time intensity curve and their explanation
Reproducibility
Reproducibility
When a new technique is applied to clinical indications and questions, basic research
has to be performed including the validity of the parameters analysed (intra-observer
stability, stability against external factors, reproducibility) and the comparability
of different software sources used.
Very few studies on the subject are available. The area under the curve may be less
reproducible than other measurements; inter- and intra-observer variation of 20-30
% have been observed (Grossjohann HS, unpublished observations).
So far the amount of deviation for measuring TIC values at different depths is still
remarkable. Rise time and time to peak seem to be the most stable parameters for depth
positioning variations. For different sizes of the region of interest a reported mean
deviation of 11 % is acceptable. For different shapes of the region of interest (circular,
square, irregular) again time to peak, area under the curve and rise time are the
most stable parameters when the mean deviation published is 6 %. Although there is
a tendency for certain parameters (time to peak, area under the curve and rise time)
to be more stable than others, all parameters had good values. It could be shown that
when comparing more than one region of interest, e.g. in a tumour versus representative
parenchyma they must be compared in the same depth [Ignee A, Jedrejczyk M, Schuessler
G, Jakubowski W, Dietrich CF. Quantitative contrast enhanced ultrasound of the liver
for time intensity curves-Reliability and potential sources of errors. Eur J Radiol
2009, epub in advance]. The size of the region of interest (ROI) could also have influence
on the reproducibility of the time intensity curves; theoretically a small ROI would
show larger variation than a large (but it could be shown in the
mentioned study that the size of ROI does not significantly influence results). Proximity
to vessels will also have influence. In patient studies it is therefore very difficult
to standardize the size and the location of the ROI. Figure [1a-c ] reproducibility studies during different phases of contrast enhancement illustrating
the problem of surrounding vessels.
Fig. 1a-c Reproducibility studies during different phases of contrast enhancement
illustrating the problem of surrounding vessels.
Some authors stress the use of raw data files as a basic source for analysing perfusion
kinetics. Conventional video data files are non-linearly compressed and discretisised
on an 8 bit base with 256 grey levels. Therefore the original data are thought to
be more accurate in the time intensity curve analysis. Up to now the access to raw
data in commercially available ultrasound machines is limited. In addition, not all
parameters are theoretically influenced by the compression like pure temporal parameters
like time to peak, rise time, and mean transit time. Further investigations are necessary
to define the real impact of raw data analysis in direct comparison with conventional
data files.
In conclusion
In conclusion
Concerning the work done so far we postulate that multicentre studies are needed in
order to obtain large series of patients. Before multicentre studies on strictly defined
issues are performed the standardisation of time intensity curves analysis is crucial.
Among the necessary topics of the standardisation are:
Time intensity curves analysis is a promising tool with plenty of potential applications.
Nevertheless not much basic work has been done so far although this is important before
analysing clinical questions. Please feel free and be even more encouraged to perform
studies or contact us and participate on this new technology.
Cordially,
Christoph F. Dietrich,
EFSUMB Honorary Secretary
Michael Bachmann Nielsen,
Chairman EFSUMB Publications Committee
