Purpose: To determine the utility of dynamic contrast-enhanced ultrasonography (DCE-US) as a prognostic tool for metastatic renal cell carcinoma patients receiving sunitinib and to identify DCE-US parameters 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 were used to classify patients as responders or nonresponders. DCE-US evaluations were done before treatment and at day 15; variations between days 0 and 15 were calculated for seven DCE-US functional parameters and were compared for responders and nonresponders. The correlation between DCE-US parameters and disease-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 and slope of the wash-in) were significantly associated with DFS; time to peak intensity was also significantly associated 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 assessments, including DFS and OS. Clin Cancer Res; 16(4); 1216–25

Translational Relevance

Targeted therapies such as sunitinib have substantially improved the prognosis of patients with metastatic renal cell carcinoma (mRCC). Although measures of progression-free survival (PFS) and overall survival (OS) remain the ideal criteria for assessing treatment success, earlier evaluation of response to therapy would allow physicians to gauge the likelihood of treatment efficacy sooner, helping them to decide when to switch to a different therapy. However, as targeted agents often induce tumor necrosis before reduction in tumor volume, classic criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) can be insensitive to early improvements with these agents. This study showed that dynamic contrast-enhanced ultrasonography (DCE-US) is a more sensitive measure for predicting the early efficacy of sunitinib in mRCC patients. Robust correlations were observed between DCE-US functional parameters just 15 days after the beginning of treatment and RECIST response after 3 months, as well as OS and PFS. Further studies are warranted to confirm these findings.

The introduction of targeted therapies, including the oral, multitargeted receptor tyrosine kinase inhibitor sunitinib malate (SUTENT; Pfizer, Inc.), has substantially improved the prognosis of patients with metastatic renal cell carcinoma (mRCC; ref. 1).

Sunitinib is approved multinationally for the first- or second-line treatment of mRCC and is recognized as a reference standard of care for the first-line treatment of mRCC based on results of a pivotal phase III trial comparing sunitinib with interferon-α (IFN-α) in patients without prior systemic therapy (1). In this study, sunitinib resulted in median progression-free survival (PFS) more than double that observed for IFN-α (11 months versus 5 months, respectively; P < 0.001) and a significantly higher objective response rate (47% versus 12%, respectively; P < 0.001; refs. 1, 2). Of note, median overall survival (OS) >2 years was observed with sunitinib in this study (26.4 months with sunitinib versus 21.8 months with IFN-α; P = 0.051; ref. 2).

Although OS and PFS remain the ideal criteria for assessing treatment success, early evaluation of response to treatment, and the ability to predict the duration of benefit with targeted therapies, would be valuable for optimizing treatment. In the era of targeted therapy for mRCC, and the associated improved survival rates, substantial treatment duration is usually required to reach median values for PFS and OS. In addition, as targeted agents often induce tumor necrosis before reduction in tumor volume, morphologic criteria such as Response Evaluation Criteria in Solid Tumors (RECIST; ref. 3) may be insensitive to early improvements with these agents.

Dynamic contrast-enhanced ultrasonography (DCE-US) is a technique that can be used to detect microvessels and quantitatively assess solid tumor perfusion using raw linear data (4). It involves Doppler ultrasound after injection with a contrast agent, which enhances the vessel signal (5, 6). Doppler ultrasonography can accurately detect and characterize blood flow in vessels with a diameter as low as 100 μm (3). Doppler signals provide functional information on neovascularity by indicating the maximal velocity in tumor supply vessels (5). The addition of perfusion software and microbubble contrast agents has further improved the technique, enabling the visualization of 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 have indicated that DCE-US parameters may be correlated with tumor responses, for example in RCC with sorafenib (7, 8) or in gastrointestinal stromal tumors (GIST) treated by imatinib (9).

The aim of this study was to prospectively determine the utility of DCE-US with quantification as a prognostic tool for patients with mRCC treated with sunitinib and identify DCE-US quantitative parameters that correlate with disease-free survival (DFS) and OS.

Patients

Thirty-eight patients were enrolled in the study between November 7, 2006, and February 12, 2008. DCE-US is a routine part of the monitoring of patients who receive antiangiogenic drugs at our institute. All patients were informed of the technique and provided written informed consent. The human investigations were done after approval by a local Human Investigations Committee and in accordance with an assurance filed with and approved by the Department of Health and Human Services, where appropriate. Eligibility criteria included patients treated with sunitinib for mRCC, who had tumors accessible to ultrasonography and who accepted follow-up with DCE-US. Patients were excluded if the tumor was not accessible for ultrasonography or the tumor was not vascularized at baseline DCE-US. One tumor per patient was studied; the tumor was selected based on size (>2 cm), percentage of necrosis (<50% of total tumor volume), and site (selected for the best acoustic window enabling acquisition over 3 min without losing the tumor).

Study treatment

Sunitinib (50 mg/d) was administered in repeated 6-wk cycles of daily therapy for 4 wk, followed by 2 wk off treatment (schedule 4/2). Sunitinib was self-administered orally once daily, without regard to meals.

Evaluation

Baseline evaluations included usual evaluations for patients with mRCC receiving targeted agents, including past history, current medications, physical examination, and blood biological and hematologic parameters. In addition, baseline chest and abdominopelvic computed tomography (CT) scans were done.

Assessment of efficacy

Responses to sunitinib were assessed by investigators according to RECIST (3), using CT scans done before treatment and after two treatment cycles. Patients were classified as responders (confirmed partial response) or nonresponders (confirmed stable disease or progressive disease). DFS and OS were also assessed.

Dynamic contrast-enhanced ultrasonography

DCE-US examinations were done before treatment (day 0) and at day 15. The examinations were done with a sonograph Aplio from Toshiba equipped with several different softwares: vascular recognition imaging perfusion software that enables enhanced detection of the signal generated by microbubbles, software enabling access to the raw data, and ultrasonograph quantification software (CHI-Q) enabling determination 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 or a 12-MHz linear-array probe for superficial targets. For each probe, the settings were predefined with, in particular, gain and acoustic power. The field depth and incidence of the investigation was determined initially for each patient and reproduced for each investigation.

For each investigation, a morphologic study was initially conducted in B mode with measurement of the three largest diameters of the lesion for volume calculation. Subsequently, a functional study was conducted with injection of the contrast medium. The peripheral venous access consists of a length of tubing (maximum of 10-cm long), to the end of which a three-way tap for contrast medium injection is fixed. A 4.8 mL bolus injection of SonoVue (Bracco) is administered into the tube for less than 3 s, and then flushed immediately with 5 mL of normal saline. Investigation recording and timing are triggered as soon as the SonoVue has been injected. The acquisition time is 3 min, during which time the raw data are acquired. Once the investigation has been completed, the raw data are recorded on a workstation. Initial quantification is taken using the CHI-Q software.

The 3-min acquisition time necessitates set up of a procedure for ROI follow-up as a function of the patient's respiration. The procedure is semiautomatic and implemented by interpolation. After each examination, a ROI including the tumor was defined surrounding the lesion. The time-intensity curve of the total surface delimited was calculated with the sum of the time-intensity curve of all the pixels using linear raw data obtained with the CHI-Q software. The calculation is formed by summing the intensity of the various pixels of the ROI over time. The addition, conducted on the raw linear data, is proportional to the real perfusion of the tumor (arithmetic operation conducted on the 720 images acquired during patient 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 image data obtained after data compression. In the latter case, the quantification is derived from a sum of logarithms, which is different from the arithmetic mean and thus completely falsifies the results because the operation is nonlinear. In fact, (log a + log b + log c)/3 = log (a × b × c)/3 is very different from log (a + b + c)/3. It is therefore fundamental and indispensable to conduct quantification on the raw linear data.

Quantitative analyses of the time-intensity curve were done to determine seven DCE-US functional parameters that 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 to blood volume), time to peak intensity, slope of the wash-in (both corresponding to blood flow), and mean transit time (10, 11).

At each examination, the radiologist described the lesion in terms of size and anatomic region. The ultrasonography plane (longitudinal or transversal), including the center of the lesion, was then chosen and images were captured. The definition of the plane according to the words “longitudinal” or “transversal” does not warrant that the ultrasonography plane is exactly the same for all the examinations. However, whereas the choice of the ultrasonography plane is radiologist dependent, variations in the position of the ultrasonography plane are limited and do not exceed a few millimeter difference in the majority of cases. The ROI is defined on the captured images on a dedicated workstation; this definition is also operator dependent, as are RECIST measurements on a CT scan.

Statistical analysis

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

Patient characteristics

A total of 38 patients were treated with sunitinib. Patient characteristics at baseline are listed in Table 1. Most patients had clear-cell histology (74%) with Eastern Cooperative Oncology Group performance status ≤1 (84%). Most patients had not received prior systemic therapy with either targeted agents (76%) or cytokines (81%).

Table 1.

Patient characteristics at baseline

CharacteristicNo. (%)
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) 
CharacteristicNo. (%)
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 Oncology Group performance status; MSKCC, Memorial Sloan-Kettering Cancer Center.

Efficacy

Overall, 13 patients were classified as responders and 25 were considered nonresponders according to RECIST. Among the responders, all 13 patients (34%) had a confirmed partial response. Clinical examples of responder patients with mRCC who were treated with 50 mg/d sunitinib on schedule 4/2 are presented in Figs. 1 and 2. In these examples, the patients were evaluated with DCE-US before treatment on day 0 and again at day 15. CT scans were done before treatment and at two and four treatment cycles. The DCE-US and CT images, plus contrast uptake time-intensity curves constructed from the DCE-US data, are shown in both figures.

Fig. 1.

Clinical example of good responder patient with an abdominal lesion treated with sunitinib. DCE-US before treatment with contrast-enhanced sonogram 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 lesion as 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.

Fig. 1.

Clinical example of good responder patient with an abdominal lesion treated with sunitinib. DCE-US before treatment with contrast-enhanced sonogram 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 lesion as 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.

Close modal
Fig. 2.

Clinical example of good responder patient with neck metastasis treated with sunitinib. DCE-US before treatment (baseline) with superficial probe 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 after at two cycles (E). F, contrast uptake curves corresponding to the DCE-US data.

Fig. 2.

Clinical example of good responder patient with neck metastasis treated with sunitinib. DCE-US before treatment (baseline) with superficial probe 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 after at two cycles (E). F, contrast uptake curves corresponding to the DCE-US data.

Close modal

Among the 25 nonresponders, 16 patients (42%) had stable disease, whereas 9 patients (24%) had progressive disease. A clinical example of a nonresponder is presented in Fig. 3.

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 curves constructed from the DCE-US data.

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 curves constructed from the DCE-US data.

Close modal

At the time of the analysis, 22 patients had progressed and 12 had died.

Dynamic contrast-enhanced ultrasonography

The mean lesion volume was 44.6 cm3. DCE-US parameters in responders and nonresponders are listed in Table 2. The ratio between DCE-US examinations at baseline and day 15 was significantly different in responders and nonresponders in five of the seven DCE-US parameters: peak intensity, area under the curve, area under the wash-out, time to peak intensity, and slope of the wash-in (Table 2).

Table 2.

DCE-US parameters by responder status

ParameterMedianP*
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 
ParameterMedianP*
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.

The correlation between the seven DCE-US parameters and DFS and OS is shown in Table 3. Two of the DCE-US parameters were significantly associated with DFS (time to peak intensity, P = 0.0002; slope of the wash-in, P = 0.02); time to peak intensity was also significantly associated with OS (P = 0.007). An increase in time to peak intensity of more than 29% and a decrease in slope of the wash-in of more than 76% were associated with increased DFS (Table 3; Fig. 4A) and OS (Table 3; Fig. 4B). Mean transit time was significantly correlated with OS but not with DFS.

Table 3.

Correlation between DCE-US parameters and DFS and OS

Ratio parameters≤Median>MedianRelative risk (95% CI)*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 
Ratio parameters≤Median>MedianRelative risk (95% CI)*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.

Fig. 4.

Disease-free survival (A) and overall survival (B) according to time to peak intensity at day 15.

Fig. 4.

Disease-free survival (A) and overall survival (B) according to time to peak intensity at day 15.

Close modal

This study showed that DCE-US functional parameter values, corresponding to blood volume and flow, were in good agreement with classic efficacy measures of antitumor treatments, RECIST response, DFS, and OS. Five of seven DCE-US parameters at day 15 of treatment were significantly correlated with RECIST response after two cycles (∼3 months) of treatment with 50 mg/d sunitinib on schedule 4/2. In addition, the blood-flow parameters, time to peak intensity and slope 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 tumor response, are both based on tumor size measurements (unidimensional and bidimensional, respectively). These criteria were originally designed to evaluate cytotoxic drugs, which have a different mechanism of action from targeted agents. Targeted agents induce changes in the tumor structure, such as decreased tumor vascularity, decreased density, or necrosis, which are consistent with a therapeutic response, but which may not be accompanied by a change in tumor volume (13). When changes in tumor volume occur, it tends to be some time after the start of treatment. For example, a median interval of ∼4 months elapses before significant shrinkage of tumor volume has been observed with RECIST criteria (14). Thus, the development of targeted agents for cancer has created the need for 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. In 2004, the following criteria for an optimal tumor response to vascular targeting treatment were decided at the GIST Consensus Conference (15) organized by the European Society for Medical Oncology: stabilization/reduction in morphologic size and decrease in tumor density (Hounsfield units) on CT scan, the Choi et al. criteria (reduction in morphologic size by 10% or 15% HU; ref. 16), and decrease in fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET).

The European Organization for Research and Treatment of Cancer PET study group has recommended criteria for tumor response monitoring by measurement of 18F-FDG uptake to aid the comparison of results from different clinical trials using this method (17). FDG PET was validated in patients with GIST as a sensitive method for evaluating an early response to imatinib treatment (18, 19). In one study, 18F-FDG PET response 8 days after the start of treatment was a good predictor of RECIST response as assessed by CT after 8 weeks (18). In another study comparing 18F-FDG PET to CT, PET was the superior method for predicting response to 2 months of treatment with imatinib (20).

Dual-modality 18F-FDG PET/CT was found to be the optimal method of evaluating response to imatinib in a study 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 months with PET/CT. PET alone was accurate in 85% of patients at 1 month and 100% at 3 and 6 months, while CT alone was accurate in 44% of patients at 1 month, 60% at 3 months, and 57% at 6 months. The study concluded that tumor response to imatinib should be assessed by a combination of functional and morphologic imaging.

Both morphologic and functional perfusion data are provided by DCE-US. One of the major advantages of DCE-US for the evaluation of new antitumor treatments is that the cost of the examination is low (70 per vial of contrast agent) and it can be repeated without adverse effects. In addition, it has been previously shown that this technique is not operator dependent (22). Recent developments, such as the use of raw linear data and perfusion and quantification software, have improved the accuracy and sensitivity of DCE-US. These techniques allow the evaluation of tumoral perfusion and the collection of quantitative data, such as mean transit time, peak intensity, time to peak intensity, and area under the curve.

A method of detecting responses to treatment earlier is important for optimizing cancer treatment. Physicians can gauge the likelihood of treatment efficacy sooner, helping them to decide when to switch to a different therapy or to adjust the dosage schedule, and patients can avoid wasting time on an expensive treatment from which they may not be deriving maximum benefit. The results from this study support the use of DCE-US at an early stage to identify patients who may respond well to treatment. However, further studies with larger sample sizes are warranted to confirm these findings. The French National Program for the Evaluation of DCE-US, a 2-year study that is due to conclude in 2009, will further evaluate the use of DCE-US. The study is running at 18 centers in France and will include a total of 650 patients with metastases from breast cancer, melanoma, colon cancer, GIST, RCC, and hepatocellular carcinoma. Currently, 479 patients have been recruited. The study will help to extend the use of DCE-US using quantification from raw linear data, show the feasibility of using DCE-US in general hospitals in France, determine the best parameter and timing 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 of treatment with sunitinib and RECIST response in mRCC patients after 3 months of therapy. The classic assessments relating directly to survival, such as OS and PFS, remain the most important measures of efficacy and thus it was important that these indications of early antivascular effects were also correlated with DFS and OS. The introduction of quantitative assessment of short-term efficacy will be an important tool for improving cancer treatment.

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 have no potential conflicts of interest.

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 the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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