Download Dynamic Contrast Enhanced Ultrasonography (DCE-US)

VISIONS 11 . 07 ULTRASOUND
The usefulness of
raw data in perfusion
quantification for
assessment of new
targeted therapies in
oncology
Dynamic Contrast
Enhanced
Ultrasonography
(DCE-US)
N Lassau,
P Péronneau,
Institut Gustave Roussy,
Villejuif, France
60
Early functional evaluation of new treatments in
oncology is of major importance. Overall survival
rate is the best criterion for assessing treatment,
but unfortunately it calls for lengthy follow-up
whereas treatment efficacy must be ascertained
as soon as possible. The morphological criteria
normally used (WHO or RECIST) do not lend
themselves easily to new therapies which often
induce lesion necrosis without reducing tumor
volume.
In international oncology and radiology conferences it has been realized more and more that these
measurement techniques for solid tumors and response criteria are no longer pertinent to the currently evolving imaging techniques. With the advent
of new technologies offering functional evaluation
of changes in tumor vascularity before any decrease
in tumor volume is detected, this purely morphological evaluation should be re-assessed1,2. For several
years, functional imaging (ultrasound, CT, MRI, or
PET) could quantify tumor perfusion, and thus
provide early evaluation well suited to this type of
therapy, before any volumetric changes became
detectable.
With recent advances in technology, Doppler
ultrasound also offers the option of functional imaging, thus not only permitting the study of tumor
morphology but also tumor vascularity3,4.
Combined with innovative signal processing, the
development of ultrasound contrast agents has
greatly increased the efficacy of detecting intratumoral vascularity. Computerized quantification of
this intratumoral vascular bed yields a more objective and consistent analysis. Over the last few years,
experimental studies on small animals have been
demonstrating that real-time Doppler ultrasound
with high frequency probes can visualize in vivo angiogenesis, thereby detecting microvessels with diameters down to 100 microns5.
The first studies were carried out on animals in
the late 1990s6,7 and on humans after the turn of the
century8; phase I and II trials demonstrated that early decrease in tumor vascularity, as assessed by
Doppler ultrasound, reflected the efficacy of the targeted treatment before any decrease in tumor volume could be observed.
The arrival of first generation contrast agents,
approved in France in 1999 (Levovist, Schering), considerably improved the sensitivity of this detection
so that vessels with diameters down to 40 microns
could be visualized9. This class of contrast agents
was used in destructive mode with a high mechanical index on the order of 100%. The detection
threshold of microvascularity thus improved significantly providing "tissue type" visualization. This
type of functional imaging has been used in 49
patients with extremity sarcoma to predict the response as early as 24 hours after initiating isolated
limb perfusion with TNF10. When compared with
functional MRI and the histopathology after surgical resection, the results demonstrated that with
contrast enhanced Doppler ultrasound the response
could be predicted from D+1, before any changes in
the size of the lesions were detected, with a sensitivity, specificity, PPV and NPV of 89, 100, 100, and
90% respectively. It has been suggested by surgeons
that this imaging method could possibly help modify the timetable of surgery11.
Together with the second generation of contrast
agents (Sonovue, Bracco), recent technical advances
in ultrasound, in particular combining harmonic
imaging techniques with signal processing, have further increased the signal-to-noise ratio and thus
have refined the detection of microvascularity.
Several studies on different types of tumor undergoing targeted therapy have confirmed that
these second generation contrast agents provide
early prediction of the response to treatment12,13. All
perfusion programs of the various manufacturers
use this characteristic in either the temporal or spatial domain, adding the phase-inverted signals from
the fundamental and harmonic imaging of the tissues and microbubbles.
The first study using this new type of signal processing was carried out in patients with gastrointestinal stromal tumors treated with Imatinib
(Glivec). These gastrointestinal stromal tumors
Fig 1: Ultrasound
signal acquisition
and processing:
Radio frequency
signals, raw data,
video images.
Fig. 2: Early
evaluation of a
new drug in small
animals: comparison
of perfusion curves
acquired from raw
data and video
data respectively.
derived from the interstitial cells of Cajal in the gastrointestinal tract14 and the prognosis was extremely unfavorable15. The arrival of Glivec, targeted on the
c-kit receptor, fundamentally changed the prognosis of these patients with an objective response rate
of about 80%. This treatment induces considerable
parenchymal changes in the tumor, accompanied by
decreased vascularity and the advent of necrosis
without changing the volume of the tumor.16
Since the WHO or RECIST criteria are based on tumor size, they do not lend themselves to evaluating
the response to this treatment. Thus, imaging techniques combining morphological and functional criteria should be the preferred modality for assessing
the response to this type of treatment17,18. A contrast-enhanced ultrasound study of 30 patients with
metastatic GIST demonstrated that a drop in contrast uptake after day 7 could reliably differentiate
between good and poor responders19. This technique
is suitable for any type of hypervascular tumor accessible to ultrasound. Indeed, it has also been
shown in patients with metastatic renal cancer receiving anti-angiogenic treatment (Sorafenib, Bayer) that a reduction in perfusion observed after three
weeks and confirmed at six weeks correlated significantly with no-progress survival and with overall
survival20.
These three published studies on soft tissue sarcoma, GIST, and metastatic renal cancer demonstrated the considerable potential of contrast ultrasound for early prediction of the response to new
targeted treatments in several types of tumor.
Nevertheless, parametric objective quantification
has to be finalized in order for this technique to be
recognized, validated, and systematically included in
therapeutic trials. At present, several manufacturers
are providing access to raw data, i.e. before compression (generally of a logarithmic type) of the data into
the video format (Fig. 1). This methodological aspect
during signal acquisition is crucial. By enhancing raw
data, contrast uptake can be clearly objectified with
acquisition of the tumor perfusion curve.
It is important to emphasize that any quantitative analysis of perfusion must be based on these
raw data before compression if perfusion parameters
equivalent to the DCE-MRI are to be calculated. In
fact, data compression considerably modifies perfusion curves and therefore parameter calculation (Fig.
61
VISIONS 11 . 07 ULTRASOUND
Fig 3: Patient with
pelvic metastasis from
GIST treated by an
inhibitor of thysosine
kinase in phase 2.
a
The evaluations were
performed before
treatment (a), and at
Day 7 (b), 14 (c) and
1 Month (d). The graph
shows the corresponding contrast uptake
curves from the raw
linear data (e).
Fig. 3a: before
treatment
Fig. 3b:
After day 7
62
b
c
Fig. 3c:
After day 14
d
Fig. 3d:
After 1 month
2)21,22. For evaluating the efficacy of new treatment
modalities, this type of quantification is currently
being undertaken very early on in animals after the
first minutes23, and also in several therapeutic clinical trials (Fig. 3) after the first days of treatment24.
Quantification programs allow regions of interest
to be set, with real-time acquisition of raw data
over several minutes and thus complete acquisition
of the signal enhancement curve. In humans, the
lesion can be monitored with this type of program
while the patient breathes normally, thereby reducing the problems of motion artefacts described
in other functional imaging techniques25. After
modelling of the perfusion curves, it is thus possible to calculate various parameters, e.g. maximum
intensity of the peak, mean transit time, wash-in
curve coefficient, and the area under the curve26. It
should be remembered that only intravascular ultrasound contrast agents are employed which,
when compared with DCE-MRI, simplifies model-
63
VISIONS 11 . 07 ULTRASOUND
e
7.
ling of the curves, particularly as there is a linear
relationship between the concentrations used. On
the other hand, it is not possible to calculate the
coefficient of permeability.
In conclusion, the advent of contrast agents has
turned ultrasonography into a functional imaging
modality permitting early assessment of new targeted treatments which often induce necrosis of lesions without altering their volume.
With the development of perfusion modules as
part of quantification programs it is possible to objectively quantify the perfusion of a tumor and calculate perfusion parameters, for example, the maximum
intensity of enhancement, mean transit time, and the
wash-in slope coefficient. Thus, DCE US is a new tool
permitting very early prediction of the response to
treatment, based on changes in vascularity well before any changes in tumor volume become evident. It
also seems to be very promising24 for dosage adjustment in phase I trials of new treatment modalities.
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64
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