metastatic renal cell carcinoma treated with sunitinib ... · the utility of dce-us with...

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Published OnlineFirst February 15, 2010; DOI: 10.1158/1078-0432.CCR-09-2175

Imaging, Diagnosis, Prognosis Clinical
Cancer
Research
Metastatic Renal Cell Carcinoma Treated with Sunitinib:Early Evaluation of Treatment Response Using DynamicContrast-Enhanced Ultrasonography
Nathalie Lassau1, Serge Koscielny2, Laurence Albiges3, Linda Chami1, Baya Benatsou1,Mohamed Chebil1, Alain Roche1, and Bernard J. Escudier3

Abstract

Authors' AEpidemioloVillejuif Ced

Corresponrue Camille11-60-14; F

doi: 10.115

©2010 Am

Clin Canc

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Purpose: To determine the utility of dynamic contrast-enhanced ultrasonography (DCE-US) as a prog-nostic tool for metastatic renal cell carcinoma patients receiving sunitinib and to identify DCE-USparameters that correlate with early treatment response.Experimental Design: Thirty-eight patients received 50 mg/d sunitinib on schedule 4/2 (4 weeks on

followed by 2 weeks off treatment). After two cycles, response evaluation criteria in solid tumors wereused to classify patients as responders or nonresponders. DCE-US evaluations were done before treatmentand at day 15; variations between days 0 and 15 were calculated for seven DCE-US functional parametersand were compared for responders and nonresponders. The correlation between DCE-US parameters anddisease-free survival (DFS) and overall survival (OS) was assessed.Results: The ratio between DCE-US examinations at baseline and day 15 significantly correlated with

response in five of the seven DCE-US parameters. Two DCE-US parameters (time to peak intensity andslope of the wash-in) were significantly associated with DFS; time to peak intensity was also significantlyassociated with OS.Conclusions: DCE-US is a useful tool for predicting the early efficacy of sunitinib in metastatic renal

cell carcinoma patients. Robust correlations were observed between functional parameters and classic assess-ments, including DFS and OS. Clin Cancer Res; 16(4); 1216–25. ©2010 AACR.

The introduction of targeted therapies, including theoral, multitargeted receptor tyrosine kinase inhibitor suni-tinib malate (SUTENT; Pfizer, Inc.), has substantially im-proved the prognosis of patients with metastatic renal cellcarcinoma (mRCC; ref. 1).Sunitinib is approved multinationally for the first- or

second-line treatment of mRCC and is recognized as a ref-erence standard of care for the first-line treatment ofmRCC based on results of a pivotal phase III trial compar-ing sunitinib with interferon-α (IFN-α) in patients withoutprior systemic therapy (1). In this study, sunitinib resultedin median progression-free survival (PFS) more than dou-ble that observed for IFN-α (11 months versus 5 months,respectively; P < 0.001) and a significantly higher objectiveresponse rate (47% versus 12%, respectively; P < 0.001;refs. 1, 2). Of note, median overall survival (OS) >2 yearswas observed with sunitinib in this study (26.4 months withsunitinib versus 21.8 months with IFN-α; P = 0.051; ref. 2).

ffiliations: 1Imaging Department, 2Service of Biostatistics andgy, and 3Medical Department, Institut Gustave Roussy,ex, France

ding Author: Nathalie Lassau, Institut Gustave-Roussy, 39Desmoulins, 94805 Villejuif Cedex, France. Phone: 33-1-42-ax: 33-1-42-11-60-29; E-mail: [email protected].

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Although OS and PFS remain the ideal criteria for asses-sing treatment success, early evaluation of response totreatment, and the ability to predict the duration of benefitwith targeted therapies, would be valuable for optimizingtreatment. In the era of targeted therapy for mRCC, andthe associated improved survival rates, substantial treat-ment duration is usually required to reach median valuesfor PFS and OS. In addition, as targeted agents often in-duce tumor necrosis before reduction in tumor volume,morphologic criteria such as Response Evaluation Criteriain Solid Tumors (RECIST; ref. 3) may be insensitive to earlyimprovements with these agents.Dynamic contrast-enhanced ultrasonography (DCE-US)

is a technique that can be used to detect microvessels andquantitatively assess solid tumor perfusion using raw lin-ear data (4). It involves Doppler ultrasound after injectionwith a contrast agent, which enhances the vessel signal(5, 6). Doppler ultrasonography can accurately detectand characterize blood flow in vessels with a diameter aslow as 100 μm (3). Doppler signals provide functional in-formation on neovascularity by indicating the maximal ve-locity in tumor supply vessels (5). The addition ofperfusion software and microbubble contrast agents hasfurther improved the technique, enabling the visualizationof vessels with a diameter as small as 40 μm (6).To date, DCE-US has been used in a number of clinical

trials with receptor tyrosine kinase inhibitors. These studies

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Translational Relevance

Targeted therapies such as sunitinib have substan-tially improved the prognosis of patients with metastaticrenal cell carcinoma (mRCC). Although measures ofprogression-free survival (PFS) and overall survival(OS) remain the ideal criteria for assessing treatmentsuccess, earlier evaluation of response to therapy wouldallow physicians to gauge the likelihood of treatmentefficacy sooner, helping them to decide when to switchto a different therapy. However, as targeted agents ofteninduce tumor necrosis before reduction in tumor vol-ume, classic criteria such as response evaluation crite-ria in solid tumors (RECIST) can be insensitive to earlyimprovements with these agents. This study showedthat dynamic contrast-enhanced ultrasonography(DCE-US) is a more sensitive measure for predictingthe early efficacy of sunitinib in mRCC patients. Robustcorrelations were observed between DCE-US functionalparameters just 15 days after the beginning of treatmentand RECIST response after 3 months, as well as OS andPFS. Further studies are warranted to confirm thesefindings.

Use of DCE-US in Renal Cancer


have indicated that DCE-US parameters may be correlatedwith tumor responses, for example in RCC with sorafenib(7, 8) or in gastrointestinal stromal tumors (GIST) treatedby imatinib (9).The aim of this study was to prospectively determine

the utility of DCE-US with quantification as a prognostictool for patients with mRCC treated with sunitinib andidentify DCE-US quantitative parameters that correlatewith disease-free survival (DFS) and OS.

Patients and Methods

Patients. Thirty-eight patients were enrolled in the studybetween November 7, 2006, and February 12, 2008. DCE-US is a routine part of the monitoring of patients who re-ceive antiangiogenic drugs at our institute. All patientswere informed of the technique and provided written in-formed consent. The human investigations were done afterapproval by a local Human Investigations Committee andin accordance with an assurance filed with and approvedby the Department of Health and Human Services, whereappropriate. Eligibility criteria included patients treatedwith sunitinib for mRCC, who had tumors accessible toultrasonography and who accepted follow-up with DCE-US. Patients were excluded if the tumor was not accessiblefor ultrasonography or the tumor was not vascularized atbaseline DCE-US. One tumor per patient was studied; thetumor was selected based on size (>2 cm), percentage ofnecrosis (<50% of total tumor volume), and site (selectedfor the best acoustic window enabling acquisition over3 min without losing the tumor).

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Study treatment. Sunitinib (50 mg/d) was administeredin repeated 6-wk cycles of daily therapy for 4 wk, followedby 2 wk off treatment (schedule 4/2). Sunitinib was self-administered orally once daily, without regard to meals.Evaluation. Baseline evaluations included usual eval-

uations for patients with mRCC receiving targeted agents,including past history, current medications, physical ex-amination, and blood biological and hematologic param-eters. In addition, baseline chest and abdominopelviccomputed tomography (CT) scans were done.Assessment of efficacy. Responses to sunitinib were as-

sessed by investigators according to RECIST (3), using CTscans done before treatment and after two treatment cycles.Patients were classified as responders (confirmed partial re-sponse) or nonresponders (confirmed stable disease orprogressive disease). DFS and OS were also assessed.Dynamic contrast-enhanced ultrasonography. DCE-US ex-

aminations were done before treatment (day 0) and at day15. The examinations were done with a sonograph Apliofrom Toshiba equipped with several different softwares:vascular recognition imaging perfusion software that en-ables enhanced detection of the signal generated by micro-bubbles, software enabling access to the raw data, andultrasonograph quantification software (CHI-Q) enablingdetermination of the region of interest (ROI).The probes used were selected by target depth: a 3.5-MHz

convex-array abdominal probe was used for deep targets ora 12-MHz linear-array probe for superficial targets. For eachprobe, the settings were predefined with, in particular, gainand acoustic power. The field depth and incidence of theinvestigation was determined initially for each patientand reproduced for each investigation.For each investigation, a morphologic study was initial-

ly conducted in B mode with measurement of the threelargest diameters of the lesion for volume calculation. Sub-sequently, a functional study was conducted with injectionof the contrast medium. The peripheral venous access con-sists of a length of tubing (maximum of 10-cm long), to theend of which a three-way tap for contrast medium injectionis fixed. A 4.8 mL bolus injection of SonoVue (Bracco) isadministered into the tube for less than 3 s, and thenflushed immediately with 5 mL of normal saline. Investiga-tion recording and timing are triggered as soon as the Sono-Vue has been injected. The acquisition time is 3min, duringwhich time the raw data are acquired. Once the invest-igation has been completed, the raw data are recorded ona workstation. Initial quantification is taken using theCHI-Q software.The 3-min acquisition time necessitates set up of a pro-

cedure for ROI follow-up as a function of the patient'srespiration. The procedure is semiautomatic and imple-mented by interpolation. After each examination, a ROIincluding the tumor was defined surrounding the lesion.The time-intensity curve of the total surface delimitedwas calculated with the sum of the time-intensity curveof all the pixels using linear raw data obtained with theCHI-Q software. The calculation is formed by summingthe intensity of the various pixels of the ROI over time.

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The addition, conducted on the raw linear data, is propor-tional to the real perfusion of the tumor (arithmetic oper-ation conducted on the 720 images acquired duringpatient investigation, four images per second for 3 min).The tumor perfusion quantification obtained from the

raw linear data is different from that derived from the im-age data obtained after data compression. In the lattercase, the quantification is derived from a sum of loga-rithms, which is different from the arithmetic mean andthus completely falsifies the results because the operationis nonlinear. In fact, (log a + log b + log c)/3 = log (a × b × c)/3is very different from log (a + b + c)/3. It is therefore funda-mental and indispensable to conduct quantification on theraw linear data.Quantitative analyses of the time-intensity curve were

done to determine seven DCE-US functional parametersthat are sufficient to characterize the time-intensity curves:peak intensity, area under the curve, area under the wash-in,area under the wash-out (all the above corresponding toblood volume), time to peak intensity, slope of the wash-in(both corresponding to blood flow), and mean transittime (10, 11).At each examination, the radiologist described the lesion

in terms of size and anatomic region. The ultrasonographyplane (longitudinal or transversal), including the center ofthe lesion, was then chosen and images were captured. Thedefinition of the plane according to the words “longitu-dinal” or “transversal”does not warrant that the ultrasonog-raphy plane is exactly the same for all the examinations.However, whereas the choice of the ultrasonography planeis radiologist dependent, variations in the position of theultrasonography plane are limited and do not exceed afew millimeter difference in the majority of cases. TheROI is defined on the captured images on a dedicated work-station; this definition is also operator dependent, as areRECIST measurements on a CT scan.Statistical analysis. Variations between day 0 and day 15

were calculated for each of the seven DCE-US functionalparameters. The variation was calculated as the ratio be-tween the value of the parameter evaluated on day 15and the value on day 0 (day 15/day 0). Variations werecompared between responders and nonresponders usinga nonparametric Kruskal-Wallis test. For each parameter,two categories of patients were defined according to themedian parameter variation. The median was chosen asa cutoff to maximize the number of patients in the twogroups. A cutoff maximizing the difference between thetwo groups was not sought because the number of patientswas not considered sufficient. DFS and OS were comparedbetween the two groups using log-rank tests.

Results

Patient characteristics. A total of 38 patients were treatedwith sunitinib. Patient characteristics at baseline are listedin Table 1. Most patients had clear-cell histology (74%)with Eastern Cooperative Oncology Group performancestatus ≤1 (84%). Most patients had not received prior sys-

Clin Cancer Res; 16(4) February 15, 2010


temic therapy with either targeted agents (76%) or cyto-kines (81%).Efficacy. Overall, 13 patients were classified as respon-

ders and 25 were considered nonresponders according toRECIST. Among the responders, all 13 patients (34%) hada confirmed partial response. Clinical examples of re-sponder patients with mRCC who were treated with50 mg/d sunitinib on schedule 4/2 are presented in Figs. 1and 2. In these examples, the patients were evaluated withDCE-US before treatment on day 0 and again at day 15.CT scans were done before treatment and at two and fourtreatment cycles. The DCE-US and CT images, plus con-trast uptake time-intensity curves constructed from theDCE-US data, are shown in both figures.

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Table 1. Patient characteristics at baseline

Characteristic

Clinical Cance

2020. © 2010 American Association for Ca

No. (%)

Total
38 (100) Sex Male 28 (74) Female 10 (26)
Histology
Clear cell 28 (74) Papillary 8 (21) Others 2 (5)
ECOG PS
PS ≤1 32 (84) PS ≥2 6 (16)
MSKCC score
Favorable 17 (45) Intermediate 15 (39) Poor 6 (16)
Metastatic sites
1 5 (13) 2 19 (50) ≥3 14 (37)
Targeted lesion in DCE-US
Liver 11 (29) Other 27 (71)
Previous targeted therapy
None 29 (76) Sorafenib 8 (21) Missing 1 (3)
Previous cytokine therapy
None 31 (81) Interferon 1 (3) Interferon + interleukin-2 4 (10) Interferon + temsirolimus 1 (3) Missing 1 (3)
Abbreviations: ECOG PS, Eastern Cooperative OncologyGroupperformance status;MSKCC,Memorial Sloan-KetteringCancer Center.

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Among the 25 nonresponders, 16 patients (42%) hadstable disease, whereas 9 patients (24%) had progressivedisease. A clinical example of a nonresponder is presentedin Fig. 3.At the time of the analysis, 22 patients had progressed

and 12 had died.



Dynamic contrast-enhanced ultrasonography. The meanlesion volume was 44.6 cm3. DCE-US parameters in re-sponders and nonresponders are listed in Table 2. The ratiobetween DCE-US examinations at baseline and day 15 wassignificantly different in responders and nonresponders infive of the seven DCE-US parameters: peak intensity, area

Fig. 1. Clinical example of good responder patient with an abdominal lesion treated with sunitinib. DCE-US before treatment with contrast-enhancedsonogram with (A) a strong vascularized lesion and (B) with mode B (47 × 35 × 28 mm). C, a CT scan before treatment (red circle shows the same lesionas selected in DCE-US). D, DCE-US at day 15, showing a dramatic decrease in vascularization. CT scans at two cycles (E) and at four cycles (F).G, contrast uptake curves corresponding to the DCE-US data.




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under the curve, area under the wash-out, time to peakintensity, and slope of the wash-in (Table 2).The correlation between the seven DCE-US parameters

and DFS and OS is shown in Table 3. Two of the DCE-USparameters were significantly associated with DFS (time topeak intensity, P = 0.0002; slope of the wash-in, P = 0.02);



time to peak intensity was also significantly associated withOS (P = 0.007). An increase in time to peak intensityof more than 29% and a decrease in slope of the wash-inof more than 76% were associated with increased DFS(Table 3; Fig. 4A) and OS (Table 3; Fig. 4B). Mean transittime was significantly correlated with OS but not with DFS.

Fig. 2. Clinical example of good responder patient with neck metastasis treated with sunitinib. DCE-US before treatment (baseline) with superficialprobe showing (A) a metastatic lymph node measuring 35 mm for the longest axis and (B) strong vascularization after 4.8 mL bolus injection of SonoVue.C, the same vascular recognition imaging view at day 15 showing a dramatic decrease of vascularization. CT scan before treatment (D) and afterat two cycles (E). F, contrast uptake curves corresponding to the DCE-US data.

Clinical Cancer Research





Fig. 3. Clinical example of a poor responder patient with a hepatic lesion (segment IV) treated with sunitinib. DCE-US (A) and CT scan (B) before treatment.The same vascular recognition imaging view (C) and CT scan (D) at day 15 showing no modification of vascularization (C). E, contrast uptake curvesconstructed from the DCE-US data.

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Discussion

This study showed that DCE-US functional parametervalues, corresponding to blood volume and flow, were ingood agreement with classic efficacy measures of antitumortreatments, RECIST response, DFS, and OS. Five of sevenDCE-US parameters at day 15 of treatment were significantlycorrelatedwith RECIST response after two cycles (∼3months)of treatment with 50 mg/d sunitinib on schedule 4/2. In ad-dition, the blood-flow parameters, time to peak intensity andslope of the wash-in, were good predictors of OS and DFS.The RECIST (3) and WHO (12) morphologic criteria,

which are the most commonly used assessments of tumorresponse, are both based on tumor size measurements(unidimensional and bidimensional, respectively). Thesecriteria were originally designed to evaluate cytotoxic



drugs, which have a different mechanism of action fromtargeted agents. Targeted agents induce changes in the tu-mor structure, such as decreased tumor vascularity, de-creased density, or necrosis, which are consistent with atherapeutic response, but which may not be accompaniedby a change in tumor volume (13). When changes in tu-mor volume occur, it tends to be some time after the startof treatment. For example, a median interval of ∼4 monthselapses before significant shrinkage of tumor volume hasbeen observed with RECIST criteria (14). Thus, the devel-opment of targeted agents for cancer has created the needfor more sensitive measures for evaluating tumor response.Several examples are available of alternative assessment

tools/criteria for determining response to targeted agents,including a number of studies in patients with GIST. In2004, the following criteria for an optimal tumor response

Table 2. DCE-US parameters by responder status

Parameter
Median
Clinical Cancer

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P*

All patients(n = 38)

Responders(n = 13)

Nonresponders(n = 25)

Peak intensity (linear intensity)
Day 0 124.39 218.85 115.24 0.21 Day 15 15.36 8.21 44.96 0.27 Ratio 0.22 0.08 0.37 0.008†
Slope of wash-in (coefficient)
Day 0 30.86 67.41 29.25 0.14 Day 15 3.35 0.60 5.30 0.08 Ratio 0.24 0.05 0.40 0.0006†
Mean transit time (s)
Day 0 16.25 13.90 16.80 0.31 Day 15 17.60 14.80 22.80 1.00 Ratio 1.00 1.24 0.85 0.24
Time to peak intensity (s)
Day 0 6.25 5.40 6.40 0.21 Day 15 9.2 12.20 9.00 0.27 Ratio 1.29 1.88 1.19 0.008†
Area under the curve(linear intensity)
Day 0 3,492.27 4,562.44 3,150.60 0.46 Day 15 803.30 374.21 1,550.60 0.25 Ratio 0.25 0.09 0.31 0.008†
Area under the wash-in(linear intensity)
Day 0 542.56 549.74 542.56 0.54 Day 15 134.38 74.30 240.67 0.53 Ratio 0.30 0.15 0.42 0.10
Area under the wash-out(linear intensity)
Day 0 2,861.82 4,012.70 2,798.71 0.47 Day 15 588.59 304.55 1,224.83 0.19 Ratio 0.21 0.09 0.29 0.01†
*Kruskal-Wallis test.†Statistically significant.

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to vascular targeting treatment were decided at the GIST Con-sensusConference (15) organized by the European Society forMedical Oncology: stabilization/reduction in morphologicsize and decrease in tumor density (Hounsfield units) onCT scan, the Choi et al. criteria (reduction inmorphologic sizeby 10% or 15%HU; ref. 16), and decrease in fluorodeoxyglu-cose (FDG) uptake on positron emission tomography (PET).The European Organization for Research and Treatment

of Cancer PET study group has recommended criteria fortumor response monitoring by measurement of 18F-FDGuptake to aid the comparison of results from different clin-ical trials using this method (17). FDG PET was validatedin patients with GIST as a sensitive method for evaluatingan early response to imatinib treatment (18, 19). In onestudy, 18F-FDG PET response 8 days after the start of treat-ment was a good predictor of RECIST response as assessedbyCTafter 8weeks (18). In another study comparing 18F-FDGPET to CT, PET was the superior method for predictingresponse to 2 months of treatment with imatinib (20).Dual-modality 18F-FDG PET/CT was found to be the op-

timal method of evaluating response to imatinib in astudy comparing PET, CT, and dual-modality imaging(21). Tumor response was correctly characterized in 95%patients after 1 month and 100% after 3 and 6 monthswith PET/CT. PET alone was accurate in 85% of patientsat 1 month and 100% at 3 and 6 months, while CT alonewas accurate in 44% of patients at 1 month, 60% at3 months, and 57% at 6 months. The study concludedthat tumor response to imatinib should be assessed by acombination of functional and morphologic imaging.



Both morphologic and functional perfusion data areprovided by DCE-US. One of the major advantages ofDCE-US for the evaluation of new antitumor treatmentsis that the cost of the examination is low (70 per vial ofcontrast agent) and it can be repeated without adverse ef-fects. In addition, it has been previously shown that thistechnique is not operator dependent (22). Recent develop-ments, such as the use of raw linear data and perfusionand quantification software, have improved the accuracyand sensitivity of DCE-US. These techniques allow theevaluation of tumoral perfusion and the collection ofquantitative data, such as mean transit time, peak intensity,time to peak intensity, and area under the curve.Amethod of detecting responses to treatment earlier is im-

portant for optimizing cancer treatment. Physicians cangauge the likelihood of treatment efficacy sooner, helpingthem to decide when to switch to a different therapy or toadjust the dosage schedule, and patients can avoid wastingtime on an expensive treatment from which they may notbe deriving maximum benefit. The results from this studysupport the use of DCE-US at an early stage to identify pa-tients who may respond well to treatment. However, furtherstudies with larger sample sizes are warranted to confirmthese findings. The French National Program for the Evalua-tion of DCE-US, a 2-year study that is due to conclude in2009, will further evaluate the use of DCE-US. The study isrunning at 18 centers in France andwill include a total of 650patients with metastases from breast cancer, melanoma, co-lon cancer, GIST, RCC, and hepatocellular carcinoma. Cur-rently, 479 patients have been recruited. The study will

Table 3. Correlation between DCE-US parameters and DFS and OS

Ratio parameters
≤Median >Median
Clin

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Relative risk(95% CI)*

Cancer Res; 16(4) Februar

ican Association for Canc

P†

1-y estimate (95% CI)

Overall survival
Peak intensity 0.71 (0.36-0.91) 0.63 (0.32-0.86) 1.4 (0.54-3.4) 0.25 Slope of wash-in 0.79 (0.41-0.96) 0.50 (0.24-0.77) 3.2 (1.2-8.8) 0.06 Mean transit time 0.49 (0.24-0.75) 0.84 (0.37-0.98) 0.7 (0.29-1.7) 0.04‡
Time to peak intensity
0.40 (0.19-0.66) 0.94 (0.36-1.00) 0.14 (0.05-0.45) 0.007‡
Area under the curve
0.62 (0.32-0.85) 0.73 (0.38-0.92) 1.6 (0.63-4.0) 0.73 Area under the wash-in 0.60 (0.30-0.84) 0.72 (0.38-0.92) 1.1 (0.46-2.7) 0.90 Area under the wash-out 0.65 (0.34-0.87) 0.72 (0.37-0.92) 2.1 (0.78-5.6) 0.62
Disease-free survival
Peak intensity 0.45 (0.23-0.69) 0.28 (0.09-0.61) 2.1 (0.58-7.4) 0.51 Slope of wash-in 0.57 (0.30-0.81) 0.14 (0.02-0.57) 3.3 (0.86-13) 0.02‡
Mean transit time
0.27 (0.10-0.55) 0.50 (0.24-0.76) 0.22 (0.05-1.0) 0.43 Time to peak intensity 0.10 (0.01-0.51) 0.67 (0.33-0.90) 0.10 (0.01-0.79) 0.0002‡
Area under the curve
0.50 (0.25-0.74) 0.25 (0.08-0.57) 1.24 (0.36-4.3) 0.32 Area under the wash-in 0.39 (0.18-0.64) 0.39 (0.19-0.63) 0.92 (0.27-3.2) 0.81 Area under the wash-out 0.52 (0.28-0.76) 0.17 (0.03-0.60) 1.4 (0.39-4.8) 0.14
*Relative risk is estimated with ratio parameter ≤ median as the reference group.†Log-rank test.‡Statistically significant.

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help to extend the use of DCE-US using quantification fromraw linear data, show the feasibility of using DCE-US in gen-eral hospitals in France, determine the best parameter andtiming to assess antiangiogenesis and antivascular treatment,and investigate the cost and ease of use of DCE-US.In summary, this study found correlations between DCE-

US functional parameters just 15 days after the beginning oftreatment with sunitinib and RECIST response inmRCCpa-tients after 3 months of therapy. The classic assessments re-lating directly to survival, such as OS and PFS, remain themost important measures of efficacy and thus it was impor-tant that these indications of early antivascular effectswere also correlated with DFS and OS. The introductionof quantitative assessment of short-term efficacy will bean important tool for improving cancer treatment.



Disclosure of Potential Conflicts of Interest

N. Lassau, honoraria from Roche, Pfizer, Wyeth, and Novartis;B. Escudier, honoraria from Bayer, Roche, Pfizer, Wyeth, and Novarts. S.Koscielny, L. Albiges, L. Chami, B. Benatsou, M. Chebil, and A. Roche haveno potential conflicts of interest.

Grant Support

Medical writing support was provided by ACUMED (Tytherington,United Kingdom), with funding from Pfizer, Inc.

The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely toindicate this fact.

Received 8/14/09; revised 12/2/09; accepted 12/15/09; publishedOnlineFirst 2/9/10.

Fig. 4. Disease-free survival (A) and overallsurvival (B) according to time to peakintensity at day 15.

Clinical Cancer Research





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2010;16:1216-1225. Published OnlineFirst February 15, 2010.Clin Cancer Res Nathalie Lassau, Serge Koscielny, Laurence Albiges, et al. Contrast-Enhanced UltrasonographyEvaluation of Treatment Response Using Dynamic Metastatic Renal Cell Carcinoma Treated with Sunitinib: Early

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