You are on page 1of 7

Pe d i a t r i c I m a g i n g O r i g i n a l R e s e a r c h

McCarville et al.
Ultrasound Assessment of Response to Antiangiogenic Therapy

Pediatric Imaging
Original Research
Use of Quantitative Dynamic
Contrast-Enhanced Ultrasound
to Assess Response to
Downloaded from by on 05/18/17 from IP address Copyright ARRS. For personal use only; all rights reserved

Antiangiogenic Therapy in Children


and Adolescents With Solid

Malignancies: A Pilot Study
M. Beth McCarville1 OBJECTIVE. The purpose of this study was to investigate contrast-enhanced ultrasound
Jamie L. Coleman1 assessment of tumor response to antiangiogenic therapy in children and adolescents with sol-
Junyu Guo1 id malignancies.
Yimei Li2 SUBJECTS AND METHODS. Children with recurrent solid tumors who were en-
Xingyu Li2 rolled in an institutional phase 1 study of antiangiogenic therapy underwent contrast-en-
hanced ultrasound of target lesions before therapy, on therapy days 3 and 7, and at the end
Patricia J. Honnoll1
of course 1. Acoustic data from target lesion ROIs were used to measure peak enhancement,
Andrew M. Davidoff 3 time to peak, rate of enhancement, total AUC, AUC during wash-in (AUC1), and AUC dur-
Fariba Navid 4,5 ing washout (AUC2). The Cox regression model was used to assess the association between
McCarville MB, Coleman JL, Guo J, et al.
changes in parameters from baseline to follow-up time points and time to tumor progression.
Values of p 0.050 were considered significant.
RESULTS. Target lesion sites included liver (n= 3), pleura (n= 2), and supraclavicular
mass, soft-tissue component of bone metastasis, lung, retroperitoneum, peritoneum, lymph
node, muscle mass, and perineum (n= 1 each). Hazard ratios for changes from baseline to end
Keywords: antiangiogenic, contrast-enhanced
of course 1 for peak enhancement (1.17, p= 0.034), rate of enhancement (3.25, p= 0.029), and
ultrasound, pediatric, tumor response
AUC1 (1.02, p= 0.040) were significantly associated with time to progression. Greater de-
DOI:10.2214/AJR.15.15789 creases in these parameters correlated with longer time to progression.
CONCLUSION. Contrast-enhanced ultrasound measurements of tumor peak enhance-
Received November 4, 2015; accepted after revision ment, rate of enhancement, and AUC1 were early predictors of time to progression in a cohort
December 31, 2015.
of children and adolescents with recurrent solid tumors treated with antiangiogenic therapy.
Based on a presentation at the Society for Pediatric Further investigation of these findings in a larger population is warranted.
Radiology 2015 annual meeting, Bellevue, WA.
ngiogenesis plays a critical role in giogenic cancer therapy. Children are ideally

Supported in part by the American Lebanese Syrian
Associated Charities and Cancer Center core grant tumor growth, metastasis, and suited for ultrasound because their small size
027165. M. B. McCarville receives product support from survival, and targeted antiangio- facilitates placement of the transducer near
GE Healthcare. genic therapies are being increas- the structure of interest, thus reducing arti-
ingly used in cancer clinical trials. Unlike fact. Furthermore, ultrasound does not re-
Department of Diagnostic Imaging (MS 220), St. Jude
conventional cytotoxic chemotherapy, these quire sedation and, most important, does not
Childrens Research Hospital, 262 Danny Thomas Pl,
Memphis, TN 38105. Address correspondence to agents are cytostatic and may be effective entail ionizing radiation, an issue of consider-
M.B.McCarville ( without causing tumors to shrink. Therefore, able concern in the care of children.
traditional methods that depend on changes We previously reported that tumor en-
in tumor size are not suitable for assessing re- hancement measured with CEUS as early
Department of Biostatistics, St. Jude Childrens
Research Hospital, Memphis, TN.
sponse to antiangiogenic agents, and tech- as 24 hours after initiation of antiangiogen-
Department of Surgery, St. Jude Childrens Research niques that provide quantitative measure- ic therapy is statistically significantly asso-
Hospital, Memphis, TN. ments of tumor perfusion are needed. ciated with the degree of tumor vascularity
Dynamic contrast-enhanced ultrasound in murine models of pediatric malignancies
Department of Oncology, St. Jude Childrens Research
(CEUS) findings are emerging as a reliable [1215]. We have also found that ultrasound
Hospital, Memphis, TN.
indicator of tumor response to antiangiogenic contrast agents are safe and well tolerated in
Present address: McLean, VA. therapy in adults with hepatocellular carcino- children with underlying solid malignancies
ma, renal cell carcinoma, malignant melano- and can improve visualization of tumor mar-
AJR 2016; 206:933939 ma, and gastrointestinal stromal tumor [1 gins [16, 17]. The purpose of this pilot study
11]. To our knowledge, however, there have was to build on our preclinical and clinical
been no reports of the value of this modality experience and to investigate the value of
American Roentgen Ray Society in children and adolescents receiving antian- quantitative dynamic CEUS in the assess-

AJR:206, May 2016 933

McCarville et al.

ment of tumor response in children and ado- ment) were investigated. In this study, we report course was 21 days in duration. Tumor response
lescents with recurrent or refractory solid tu- on six parameters from a larger cohort. To be eli- was assessed with the original Response Evalua-
mors treated in an institutional phase 1 trial gible for CEUS, patients had to have a target le- tion Criteria in Solid Tumors (RECIST) with pro-
of antiangiogenic therapy. sion (residual primary tumor or metastasis) that gression defined as a 20% or greater increase in
was visible with gray-scale sonography. Because sum of diameters of target lesions compared with
Subjects and Methods of a theoretic risk of microemboli caused by mi- the smallest sum of diameters achieved or the
Downloaded from by on 05/18/17 from IP address Copyright ARRS. For personal use only; all rights reserved

Patient Population and Outcome Measures crosphere contrast agent bypassing the pulmonary presence of new disease [19]. Time to progression
Our cohort comprised a subset of patients 21 circulation, all subjects were required to undergo was defined as the time in days between the on-
years old or younger at the time of diagnosis of a complete history and physical examination, 12- study date and the date of tumor progression.
a solid malignancy, with recurrent or refractory lead ECG, and echocardiography. Those with a
disease, and enrolled in an institutional phase 1 history of ultrasound contrast allergy, a right-to- Contrast-Enhanced Ultrasound Technique,
study of bevacizumab, sorafenib, and low-dose left or intracardiac shunt, pulmonary hyperten- Image Analysis, and Timing
cyclophosphamide ( identifi- sion, or oxygen saturation less than 92% on room The choice of target lesion was based on
er, NCT00665990) between December 2008 and air were not eligible for CEUS. Eligible patients ease of visibility at gray-scale sonography and
April 2013. The study was approved by our insti- and guardians signed informed assent and consent identification of landmarks to ensure similar trans-
tutional review board, was HIPAA compliant, and for CEUS at the time of enrollment in the phase ducer placement during follow-up (Figs. 1A and
was performed under U.S. Food and Drug Ad- 1 study. Subjects were monitored with continuous 2A). In general, the largest tumor area was identi-
ministration investigational new drug application pulse oximetry and three-lead ECG (Propaq mon- fied in the transverse or longitudinal plane, and the
62,852. Treatment study design, eligibility and itor, Welch Allyn) immediately before, during, and transducer was held in that position throughout a
exclusion criteria, preliminary study results, and for 30 minutes after contrast injection. 60-second recording (rate, 10 Hz) begun just before
initial CEUS findings in four subjects have been Conventional imaging was performed at base- contrast administration. All subjects received per-
reported [18]. In that report only two CEUS pa- line, at the ends of courses 1 and 2, and after ev- flutren protein type A microsphere contrast mate-
rameters (peak enhancement and rate of enhance- ery other course until disease progression. Each rial (Optison, GE Healthcare). One subject was re-

Fig. 115-year-old girl with recurrent synovial sarcoma.

A, Color Doppler sonogram of largest transverse area of left supraclavicular tumor
(T) shows common carotid artery (arrow) used as landmark to ensure similar
transducer placement on follow-up contrast-enhanced ultrasound (CEUS) studies.
B, Baseline transverse CEUS image shows ROI (solid line) drawn just inside tumor
margins. Vertical line in inset time-intensity curve indicates that this image was
obtained at peak enhancement of 28.9 dB.
C, Transverse CEUS image obtained on day 7 after initiation of therapy at peak
enhancement of 2.0 dB shows 93% reduction compared with baseline. Time to
progression was 242 days. Solid line indicates ROI.


934 AJR:206, May 2016

Ultrasound Assessment of Response to Antiangiogenic Therapy

moved from the protocol but continued the same ization. Tumor ROI analysis was performed online line values were generated for measurement of the
treatment outside of the study and received perfl- with the CPS Auto-Tracking Contrast Quantifica- AUC in arbitrary units. The AUC was divided into
utren lipid microsphere contrast agent (Definitiy, tion system, which corrects for respiratory motion. wash-in (AUC1) and washout (AUC2). Because
Lantheus) during follow-up because the protein Because video-compressed data are known to be maximal enhancement was seen approximately 10
type A agent was available only for the phase 1 less reliable than noncompressed data for quanti- seconds after arrival of the contrast agent, we de-
study participants. Subjects weighing less than 20 tation of tumor perfusion, the CPS system operates fined wash-in as the first 10 seconds and washout as
Downloaded from by on 05/18/17 from IP address Copyright ARRS. For personal use only; all rights reserved

kg received 0.3 mL and those weighing 20 kg or with noncompressed, acoustic data [20]. The princi- the subsequent 10 seconds of the AUC (Fig. 3B). All
more received 0.50.6 mL through an indwelling pal investigator, blinded to RECIST response, drew subjects underwent initial CEUS within an average
central venous line. The one exception was a patient an ROI on the target lesion keeping inside tumor of 1 day (range, 06 days) before treatment initia-
who preferred peripheral IV access. Bolus hand in- margins to avoid including adjacent, normal tissue tion. On the basis of our preclinical data, we per-
jections were administered by the principal investi- (Figs. 1B, 1C, 2B, and 2C). If the tumor did not en- formed follow-up on days 3 and 7 (2 days) after
gator or radiologist coinvestigator and followed by hance at least 5 dB at baseline, the contrast dose was the start of study therapy and then at conventional
a 5-mL sterile saline flush. doubled, and the injection was repeated after a wait imaging response assessment time points until dis-
All examinations were performed with an Acu- of 10 minutes for the first dose to clear. If the tumor ease progression [1215]. To assess interobserver
son Sequoia ultrasound machine (Siemens Health- did not enhance at least 5 dB after the second, high- variability, three reviewers (two radiologists with
care) with a 6C2 or 15L8 MHz transducer and the er dose, the subject was not eligible for follow-up. 11 and 5 years of CEUS experience, one sonogra-
vendors Contrast Pulse Sequencing (CPS) soft- The ROI time-intensity curve data were used to pher with 7 years of CEUS experience) drew ROIs
ware. Scanning parameters were preset by the CPS measure peak enhancement (PE), time to PE, and on each tumor at the baseline, day 3 and 7, and end
system and included a low mechanical index of 0.2 rate of enhancement as shown in Figure 3A. Raw of course 1 time points. To assess intraobserver
to avoid contrast agent destruction. The focal zone, data were exported to Microsoft Excel, 2003 files, variability, each reviewer repeated the ROI mea-
depth, and gain were optimized for tumor visual- and time-intensity curves normalized to their base- surements for each tumor at each time point.

Fig. 221-month-old girl with recurrent rhabdoid tumor.

A, Transverse gray-scale sonogram shows peritoneal tumor (T) posterior to liver
(L) and medial to right kidney (K). Tumoral calcification (arrow) and adjacent
organs were used as landmarks for transducer placement.
B, Baseline transverse contrast-enhanced ultrasound (CEUS) image obtained at
peak enhancement of 33.5 dB shows ROI (solid line) inside tumor margins.
C, Transverse CEUS image obtained on day 7 after initiation of therapy at
peak enhancement of 30.6 dB shows 8.7% reduction compared with baseline.
Progression occurred before end of course 1, at 22 days. Solid line indicates ROI.


AJR:206, May 2016 935

McCarville et al.

Normalized Signal Intensity (AU)

Downloaded from by on 05/18/17 from IP address Copyright ARRS. For personal use only; all rights reserved


0 10 20 30 40
10 s 10 s Time (s)

Fig. 3Use of ROI time-intensity curve data to measure peak enhancement (PE), time to PE (TTP), and rate of enhancement.
A, Screen shot shows time-intensity curve and parameters obtained from ROI analysis within tumor shown in Figure 1A. A= baseline unenhanced signal intensity in
decibels, B= maximal enhancement (PE= B A in decibels), C= time of arrival of contrast agent into ROI in seconds, D= time of maximal enhancement in seconds (TTP=
D C in seconds), E= rate of change in enhancement calculated as PE / TTP in decibels per second.
B, Graph shows normalized time-intensity curve for measurement of AUC generated offline from exported raw data for patient in Figure 1. AUC1= wash-in, AUC2=
washout, AUC= AUC1+ AUC2.

Statistical Analysis Because of the small sample size, multiple regres- Results
Statistical analyses were performed with SAS sion models were not explored. Subjects who had Twenty-five patients underwent CEUS
software (version 9.3, SAS Institute). We used progression on day 42 or sooner (end of course 2) screening. Four of them had lesions that were
the Cox regression model on the first ROI mea- were considered nonresponders, and those who had not adequately visualized with gray-scale ul-
surements made by reviewer 1 to assess the as- progression after 42 days were considered respond- trasound (skull metastasis, middle medias-
sociation between each of the CEUS parame- ers. We compared the baseline values and percent- tinal mass, pleural nodule, and orbital apex
ters (PE, time to PE, rate of enhancement, AUC age change of each parameter at the early follow-up nodule), two had visible lesions but declined
(AUC1+ AUC2), AUC1, and AUC2) at baseline time points for responders versus nonresponders. participation, one had a cystic mass that was
and changes in these parameters from baseline Values of p 0.050 were considered significant. not suitable for CEUS, and one signed con-
to early follow-up time points (days 3 and 7, end The variability of ROI measurements was in- sent for CEUS but became ineligible before
of course 1) and time to progression separately. vestigated with an ANOVA model to obtain in- starting therapy because of clinical deteriora-
We also investigated the association between the terobserver and intraobserver reliability coef- tion. Four of the remaining 17 consenting sub-
time, in days, between the maximal and minimal ficients that characterize the consistency and jects were excluded: two because they had no
values of each parameter, caliber of change be- reproducibility of measurements made by differ- baseline study (one, missed appointment; one,
tween baseline and maximal change, and cali- ent observers and by the same observer at review equipment failure), one because of oxygen sat-
ber of change between the maximal and minimal 1 or 2. Reliability coefficients vary between 0 and uration less than 92% on room air, and one
values for each parameter at any time point with 1, higher values indicating greater consistency and because the target lesion enhanced less than 5
time to progression separately. reproducibility in repeated measurements. dB even after the contrast dose was doubled.

TABLE 1: Values of Contrast-Enhanced Ultrasound Parameters at Baseline and Changes in Parameters at Various
Time Points During and at the End of Course 1
Peak Rate of
Time Point n Enhancement (dB) Enhancement (dB/s) Time to Peak (s) AUC (AU) AUC1 (AU) AUC2 (AU)
Baseline 13 17.30 1.54 11.21 175.99 90.15 80.89
(4.47 to 33.4) (0.20 to 10.26) (3.21 to 33.59) (55.13 to 447.60) (18.69 to 290.12) (30.71 to 275.13)
Day 3 11 2.08 0.23 1.03 6.62 5.58 11.14
(12.37 to 5.88) (4.14 to 1.54) (16.9 to 2.97) (184.9 to 86.31) (97.96 to 26.93) (147.83 to 59.38)
Day 7 12 4.59 0.48 2.11 49.25 32.69 30.45
(26.83 to 3.84) (6.64 to 1.49) (7.37 to 12.73) (427.42 to 52.86) (161.72 to 15.46) (265.70 to 37.41)
End of course 1 12 3.24 0.85 0.65 31.81 5.26 13.62
(24.15 to 10.64) (2.73 to 2.31) (16.08 to 19.38) (385.21 to 124.7) (147.10 to 54.30) (238.11 to 70.41)
NoteData are median with range in parentheses. AU= arbitrary units.

936 AJR:206, May 2016

TABLE 2: Hazard Ratios for Risk of Progression Associated With Changes in Contrast-Enhanced Ultrasound
Parameters at Baseline Assessment
and Early of Response
Follow-Up to Antiangiogenic Therapy
Time Points
Peak Rate of
Time Point Enhancement p Enhancement p Time to Peak p AUC p AUC1 p AUC2 p
Baseline 0.96 0.38 1.18 0.47 1.03 0.53 0.995 0.18 1.00 0.96 0.99 0.17
(0.871.05) (0.761.83) (0.941.13) (0.991.0) (0.991.01) (0.981.0)
Day 3 1.26 0.051 0.97 0.92 0.99 0.87 1.01 0.12 1.03 0.15 1.02 0.15
Downloaded from by on 05/18/17 from IP address Copyright ARRS. For personal use only; all rights reserved

(0.991.59) (0.491.89) (0.831.16) (1.01.03) (0.991.07) (0.991.05)

Day 7 1.24 0.072 1.23 0.56 0.99 0.83 1.01 0.14 1.03 0.065 1.02 0.17
(0.981.57) (0.612.46) (0.901.09) (1.01.03) (1.01.06) (0.991.04)
End of course 1 1.17 0.034 3.25 0.029 0.95 0.28 1.00 0.06 1.02 0.04 1.02 0.059
(1.011.35) (1.139.35) (0.861.04) (0.991.02) (1.01.04) (1.01.03)
NoteValues in parentheses are 95% CI.

Of the 13 evaluable subjects, four were on days 3 and 7, change in AUC1 on day 7, The baseline values of parameters, time be-
girls and nine were boys (mean age, 13 years; and changes in AUC and AUC2 at the end of tween the maximal and minimal values of
range, 1.819.8 years). The primary diagno- course 1 approached statistical significance. each parameter, caliber of change between
ses were rhabdomyosarcoma (n= 2), rhab-
doid tumor (n= 2), Wilms tumor (n= 2), and TABLE 3: Median Baseline Contrast-Enhanced Ultrasound Parameter Values
renal cell carcinoma, hepatocellular carci- and Percentage Change in Median Values at Early Follow-Up Time
noma, osteosarcoma, synovial sarcoma, ep- Points in Responders and Nonresponders
ithelioid sarcoma, and Ewing sarcoma (n=
Parameter Nonresponders (n= 4) Responders (n= 9)
1 each). Target lesion sites included liver
(n= 3), pleura (n= 2), and supraclavicular Baseline value
mass, soft-tissue component of a bone me- Peak enhancement (dB) 16.78 17.30
tastasis, lung, retroperitoneum, peritoneum,
Rate of enhancement (dB/s) 2.82 1.54
lymph node, muscle mass, and perineum
(n= 1 each). A total of 74 CEUS examina- Time to peak enhancement (s) 8.50 11.21
tions were performed at the following time AUC (AU) 175.99 188.92
points: baseline (n= 13), day 3 (n= 11), day AUC1 (AU) 102.96 53.81
7 (n= 12), end of course 1 (n= 12), end of
AUC2 (AU) 80.89 116.94
course 2 (n= 8), end of course 4 (n= 8), end
of course 6 (n= 5), end of course 8 (n= 3), Percentage change day 3
and end of courses 10 and 12 (n= 1 each). Peak enhancement 9.63 40.17
End of course 1 AUC and AUC2 data were Rate of enhancement 53.86 29.93
excluded for one nonresponder and one re-
Time to peak enhancement 16.95 25.42
sponder because of inadequate AUC2 data.
One subject reported brief taste alteration AUC 3.51 41.78
after contrast injection during three of five AUC1 15.89 27.58
examinations. There were no other adverse AUC2 60.93 37.28
events. There were nine responders and four
Percentage change day 7
nonresponders. The median time to progres-
sion for all 13 subjects was 95 days (range, Peak enhancement 10.34 59.97
22242 days), for responders was 142 days Rate of enhancement 24.25 54.37
(range, 61242 days), and for nonresponders Time to peak enhancement 10.30 35.33
was 23 days (range, 2227 days).
AUC 36.54 65.42
Table 1 summarizes descriptive data for
CEUS parameters at baseline and changes AUC1 20.68 39.15
from baseline to each early follow-up time AUC2 7.19 66.04
point. Table 2 summarizes results with the Percentage change end of course 1
Cox regression model, showing hazard ratios
Peak enhancement 8.49 49.31
for the association between time to progres-
sion and changes in parameters from base- Rate of enhancement 1.37 55.16
line to early follow-up time points. Nota- Time to peak enhancement 1.47 8.03
bly, changes in PE, rate of enhancement, and AUC 15.99 35.49
AUC1 at the end of course 1 were significant-
AUC1 5.60 28.28
ly associated with time to progression; great-
er decreases were predictive of longer time AUC2 21.58 35.08
to progression (Figs. 1 and 2). Changes in PE NoteAU= arbitrary units.

AJR:206, May 2016 937

McCarville et al.

baseline and maximal change, and caliber of main within the vascular space and, because good response, but they found no signifi-
change between the maximal and minimal they contain a gas, are highly reflective at ul- cant change in patients with a poor response.
values at any time point were not predictive trasound imaging, allowing detection at the However, our findings differ slightly from a
of time to progression, with the exception of capillary level [25]. These contrast agents subsequent study by Lassau and colleagues
caliber change between maximal and mini- therefore are ideal surrogate markers of tu- [2] that assessed 42 adults with hepatocellular
mal PE (p = 0.018), such that subjects with mor blood flow and can be quantitated with carcinoma treated with bevacizumab. In that
Downloaded from by on 05/18/17 from IP address Copyright ARRS. For personal use only; all rights reserved

larger differences had longer time to progres- modern CEUS software. Dynamic quantita- study, changes in AUC, AUC1, AUC2, time
sion. There were too few subjects to reach sta- tive CEUS is becoming an important meth- to PE, and mean transit time on day 3 trended
tistical power for a comparison of respond- od of monitoring the effects of antiangiogen- toward significant correlation with RECIST
ers with nonresponders. However, the median ic therapies in adults. The current challenge response, but there was no correlation be-
baseline values for each group were similar is to define which CEUS parameters are pre- tween PE and RECIST response or patient
(with the exception of AUC1 and AUC2), al- dictive of tumor response and patient out- survival. The reason for these differences is
though responders had substantially greater come, the ideal timing for assessment, and not clear but could be related to differences
percentage reductions in all parameters by with regard to children, which malignancies in the perfusion pattern of liver lesions com-
day 3, day 7, or the end of course 1 compared are most suitable for this technique. pared with other tumor sites and differences
with nonresponders (Table 3). PE, AUC, Our findings show that CEUS depicts in biologic behavior of the tumor types.
AUC1, and AUC2 had consistently greater re- changes in blood flow in a variety of solid ma- We found a high degree of interobserver
ductions in responders than in nonresponders lignancies in children very early in the course and intraobserver reliability for measurement
at all early time points. Interobserver and in- of antiangiogenic therapy and that these of all parameters at most time points. Impor-
traobserver reliability was generally high for changes can be predictive of time to progres- tantly, this was especially true of PE, which
all parameters at all time points with a few sion. Importantly, this imaging modality may had excellent reproducibility both within a
exceptions. The parameter with the best re- help identify poor responders before conven- single reviewer and between reviewers. These
liability was PE; interobserver reliability tional RECIST values do, thus affording the findings further support the suitability of PE
ranged from 0.87 to 0.99 and intraobserver opportunity for early intervention and tailored as a meaningful parameter for assessing tu-
reliability from 0.91 to 1.0. management. This approach could avoid use mor response to antiangiogenic therapy.
of toxic and ineffective maintenance therapy Our study had several limitations. Our
Discussion for weeks or months before conventional im- sample size was small, precluding statisti-
With the increasing number of molecular- aging shows morphologic changes that indi- cal comparison of responders and nonre-
ly targeted agents being evaluated in clini- cate tumor progression. In our study, subjects sponders. Although our findings suggest that
cal trials, there is a growing need for imag- with greater decreases in PE, rate of enhance- CEUS can be predictive of time to progres-
ing methods that go beyond an assessment ment, and AUC1 at the end of course 1 had sion very early in the course of antiangiogen-
of anatomic change yet yield quantitative significantly longer times to progression. In ic treatment, they should be interpreted with
measurements of tumor response. Numerous addition, reductions in PE on day 3, PE and caution. Our cohort comprised patients with
functional and metabolic imaging modalities AUC1 on day 7, and AUC and AUC2 at the a wide variety of solid malignancies, and
are being incorporated into clinical trials, end of course 1 were marginally significant. CEUS may be more valuable in some than in
and each has unique indications, merits, and Although our cohort was too small to at- others. In our phase 1 study, all patients had
limitations. In addition to dynamic CEUS, tain statistical power, there were substantial recurrent or refractory disease, and many
promising methods of assessing tumor vas- differences in percentage changes in all pa- had numerous metastatic sites. Because ul-
cularity include dynamic contrast-enhanced rameters at early time points in responders trasound contrast agents are not U.S. Food
CT and MRI and 15O-labeled water PET [21 compared with nonresponders. Among the and Drug Administration approved for pe-
24]. Dynamic CT and PET expose patients six parameters that we investigated, PE ap- diatric use, we limited our analysis to a sin-
to ionizing radiation and therefore are less pears to be the most robust indicator of tu- gle target lesion to minimize the cumulative
attractive for the pediatric population. Dy- mor response. We found that the early per- contrast dose. It is possible that performing
namic contrast-enhanced MRI avoids expo- centage decreases in PE relative to baseline multiple contrast injections to assess several
sure to radiation but is technically challeng- were 56 times greater in responders than in target lesions would better represent total tu-
ing. Because MRI contrast agents diffuse nonresponders. This is perhaps not surpris- mor burden and overall response to therapy.
freely across the vascular membrane, com- ing because PE depends on tumor perfusion, In addition, because of limitations in current
plex pharmacokinetic models are needed to and tumors that respond well to antiangio- software, we imaged only a single slice of
analyze gadolinium concentration time-in- genic therapies will have substantially re- tumor. Because tumor composition is often
tensity curves [23]. Furthermore, sedation is duced blood flow and contrast enhancement. heterogeneous, it may be preferable to assess
often required for young patients who can- Our findings agree with those of Lassau et the entire tumor volume or numerous slices
not lie still for lengthy MRI acquisitions. In al. [4], who investigated the value of CEUS throughout the tumor mass [26, 27].
contrast, dynamic CEUS is an ideal modal- in 24 adults with gastrointestinal stromal tu-
ity for children because it is well tolerated, mors treated with imatinib. Those investi- Conclusion
does not require sedation, and has the impor- gators found a strong correlation (p < 10 4) The results of our pilot study suggest that
tant attribute of not exposing this vulnerable between changes in percentage of contrast several quantitative CEUS parameters ob-
population to radiation. Ultrasound contrast uptake within tumors from baseline to days tained very early in the course of antiangio-
agents are composed of microspheres that re- 7 and 14 and at 2 months in patients with a genic therapy are statistically significant pre-

938 AJR:206, May 2016

Ultrasound Assessment of Response to Antiangiogenic Therapy

dictors of time to progression in children and 4. Lassau N, Lamuraglia M, Chami L, et al. Gastro- 15. McCarville MB, Streck CJ, Dickson PV, Li CS,
adolescents with solid malignancies. Although intestinal stromal tumors treated with imatinib: Nathwani AC, Davidoff AM. Angiogenesis inhibitors
our cohort was too small to achieve statistical monitoring response with contrast-enhanced so- in a murine neuroblastoma model: quantitative assess-
power, we found substantial differences in per- nography. AJR 2006; 187:12671273 ment of intratumoral blood flow with contrast-en-
centage reductions in all parameters as early 5. Escudier B, Lassau N, Angevin E, et al. Phase I hanced gray-scale US. Radiology 2006; 240:7381
as days 3 and 7 in responders versus nonre- trial of sorafenib in combination with IFN alpha- 16. McCarville MB, Kaste SC, Hoffer FA, et al. Contrast-
Downloaded from by on 05/18/17 from IP address Copyright ARRS. For personal use only; all rights reserved

sponders. In this patient population PE appears 2a in patients with unresectable and/or metastatic enhanced sonography of malignant pediatric abdomi-
to be the most robust and reproducible param- renal cell carcinoma or malignant melanoma. Clin nal and pelvic solid tumors: preliminary safety and
eter. Our findings require validation in larger Cancer Res 2007; 13:18011809 feasibility data. Pediatr Radiol 2012; 42:824833
clinical trials with closer-to-homogeneous pa- 6. De Giorgi U, Aliberti C, Benea G, Conti M, 17. Coleman JL, Navid F, Furman WL, McCarville
tient populations. We are currently investigat- Marangolo M. Effect of angiosonography to mon- MB. Safety of ultrasound contrast agents in the
ing the value of CEUS in children with Ewing itor response during imatinib treatment in patients pediatric oncologic population: a single-institu-
sarcoma who are being treated at our institu- with metastatic gastrointestinal stromal tumors. tion experience. AJR 2014; 202:966970
tion with a mammalian target of rapamycin Clin Cancer Res 2005; 11:61716176 18. Navid F, Baker SD, McCarville MB, et al. Phase I
(mTOR) inhibitor in combination with cyto- 7. Lassau N, Lamuraglia M, Vanel D, et al. Doppler and clinical pharmacology study of bevacizumab,
toxic chemotherapy. Because tumor microen- US with perfusion software and contrast medium sorafenib, and low-dose cyclophosphamide in chil-
vironments involve complex interactions be- injection in the early evaluation of isolated limb dren and young adults with refractory/recurrent
tween angiogenesis, tissue hypoxia, altered perfusion of limb sarcomas: prospective study of solid tumors. Clin Cancer Res 2013; 19:236246
metabolism, cell proliferation, and apoptosis, 49 cases. Ann Oncol 2005; 16:10541060 19. Therasse P, Arbuck SG, Eisenhauer EA, et al. New
the best approach to assessing tumor response 8. Goetti R, Reiner CS, Knuth A, et al. Quantitative guidelines to evaluate the response to treatment in
will likely require a multimodality and mul- perfusion analysis of malignant liver tumors: dy- solid tumors. European Organization for Research
tiparametric approach that includes imaging namic computed tomography and contrast-en- and Treatment of Cancer, National Cancer Insti-
technologies that can quantify these various hanced ultrasound. Invest Radiol 2012; 47:1824 tute of the United States, National Cancer Institute
processes [24]. Dynamic CEUS appears to 9. Averkiou M, Lampaskis M, Kyriakopoulou K, et of Canada. JNatl Cancer Inst 2000; 92:205216
be an ideal modality for assessing solid tumor al. Quantification of tumor microvascularity with 20. Peronneau P, Lassau N, Leguerney I, Roche A, Cos-
vascularity in pediatric patients. respiratory gated contrast enhanced ultrasound grove D. Contrast ultrasonography: necessity of lin-
for monitoring therapy. Ultrasound Med Biol ear data processing for the quantification of tumor
Acknowledgments 2010; 36:6877 vascularization. Ultraschall Med 2010; 31:370378
We thank Stacey Glass for technical as- 10. Frhlich E, Muller R, Cui XW, Schreiber-Dietrich 21. Specht JM, Kurland BF, Montgomery SK, et al.
sistance in performing CEUS, Kim Johnson D, Dietrich CF. Dynamic contrast-enhanced ultra- Tumor metabolism and blood flow as assessed by
for data management, the sedation nursing sound for quantification of tissue perfusion. positron emission tomography varies by tumor
team at our institution for patient monitor- JUltrasound Med 2015; 34:179196 subtype in locally advanced breast cancer. Clin
ing, Erika Thompson and Adrianne Mat- 11. Lassau N, Chami L, Benatsou B, Peronneau P, Cancer Res 2010; 16:28032810
thews for administrative assistance, and Roche A. Dynamic contrast-enhanced ultraso- 22. Eary JF, Link JM, Muzi M, et al. Multiagent PET
GE Healthcare for product support. nography (DCE-US) with quantification of tumor for risk characterization in sarcoma. JNucl Med
perfusion: a new diagnostic tool to evaluate the 2011; 52:541546
References early effects of antiangiogenic treatment. Eur 23. Winfield JM, Payne GS, deSouza NM. Functional
1. Lassau N, Chebil M, Chami L, Bidault S, Girard Radiol 2007; 17(suppl 6):F89F98 MRI and CT biomarkers in oncology. EurJ Nucl
E, Roche A. Dynamic contrast-enhanced ultraso- 12. Sims TL, McGee M, Williams RF, et al. IFN-beta Med Mol Imaging 2015; 42:562578
nography (DCE-US): a new tool for the early restricts tumor growth and sensitizes alveolar 24. Padhani AR, Miles KA. Multiparametric imaging
evaluation of antiangiogenic treatment. Target rhabdomyosarcoma to ionizing radiation. Mol of tumor response to therapy. Radiology 2010;
Oncol 2010; 5:5358 Cancer Ther 2010; 9:761771 256:348364
2. Lassau N, Koscielny S, Chami L, et al. Advanced 13. Dickson PV, Hamner JB, Sims T, et al. Bevaci- 25. Greis C. Quantitative evaluation of microvascular
hepatocellular carcinoma: early evaluation of re- zumab-induced transient remodeling of the vascu- blood flow by contrast-enhanced ultrasound (CEUS).
sponse to bevacizumab therapy at dynamic con- lature in neuroblastoma xenografts results in im- Clin Hemorheol Microcirc 2011; 49:137149
trast-enhanced US with quantificationprelimi- proved delivery and efficacy of systemically 26. Miles KA, Ganeshan B, Hayball MP. CT texture
nary results. Radiology 2011; 258:291300 administered chemotherapy. Clin Cancer Res analysis using the filtration-histogram method:
3. Lamuraglia M, Escudier B, Chami L, et al. To pre- 2007; 13:39423950 what do the measurements mean? Cancer Imaging
dict progression-free survival and overall survival 14. Dickson PV, Hamner JB, Streck CJ, et al. Continu- 2013; 13:400406
in metastatic renal cancer treated with sorafenib: ous delivery of IFN-beta promotes sustained 27. Hoyt K, Sorace A, Saini R. Quantitative mapping of
pilot study using dynamic contrast-enhanced Dop- maturation of intratumoral vasculature. Mol tumor vascularity using volumetric contrast-en-
pler ultrasound. EurJ Cancer 2006; 42:24722479 Cancer Res 2007; 5:531542 hanced ultrasound. Invest Radiol 2012; 47:167174

AJR:206, May 2016 939