Use of Quantitative Dynamic Contrast-Enhanced Ultrasound to Assess Response to Antiangiogenic Therapy in Children and Adolescents With Solid Malignancies: A Pilot Study

Abstract

Objective: The purpose of this study was to investigate contrast-enhanced ultrasound assessment of tumor response to antiangiogenic therapy in children and adolescents with solid malignancies.

Subjects and methods: Children with recurrent solid tumors who were enrolled in an institutional phase 1 study of antiangiogenic therapy underwent contrast-enhanced ultrasound of target lesions before therapy, on therapy days 3 and 7, and at the end of course 1. Acoustic data from target lesion ROIs were used to measure peak enhancement, time to peak, rate of enhancement, total AUC, AUC during wash-in (AUC1), and AUC during washout (AUC2). The Cox regression model was used to assess the association between 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 of course 1 for peak enhancement (1.17, p = 0.034), rate of enhancement (3.25, p = 0.029), and AUC1 (1.02, p = 0.040) were significantly associated with time to progression. Greater decreases in these parameters correlated with longer time to progression.

Conclusion: Contrast-enhanced ultrasound measurements of tumor peak enhancement, rate of enhancement, and AUC1 were early predictors of time to progression in a cohort of children and adolescents with recurrent solid tumors treated with antiangiogenic therapy. Further investigation of these findings in a larger population is warranted.

Trial registration: ClinicalTrials.gov NCT00665990.

Keywords: antiangiogenic; contrast-enhanced ultrasound; pediatric; tumor response.

Figures

Fig. 1

15 year old girl with recurrent synovial sarcoma. A) Transverse color Doppler grey-scale sonogram of the largest transverse area of a left supraclavicular tumor (T). Common carotid artery (arrow) was used as a landmark to insure similar transducer placement on follow-up contrast enhanced ultrasound (CEUS) studies. B) Baseline transverse CEUS with region-of-interest (ROI, solid line) drawn just inside tumor margins. Vertical line in the inset time intensity curve (TIC) indicates that this image was obtained at peak enhancement (PE) of 28.9 dB. C) Day 7 after initiation of therapy, transverse CEUS image obtained at PE of 2.0 dB giving a 93% reduction compared to baseline. This subject’s time to progression was 242 days.

Fig. 1

15 year old girl with recurrent synovial sarcoma. A) Transverse color Doppler grey-scale sonogram of the largest transverse area of a left supraclavicular tumor (T). Common carotid artery (arrow) was used as a landmark to insure similar transducer placement on follow-up contrast enhanced ultrasound (CEUS) studies. B) Baseline transverse CEUS with region-of-interest (ROI, solid line) drawn just inside tumor margins. Vertical line in the inset time intensity curve (TIC) indicates that this image was obtained at peak enhancement (PE) of 28.9 dB. C) Day 7 after initiation of therapy, transverse CEUS image obtained at PE of 2.0 dB giving a 93% reduction compared to baseline. This subject’s time to progression was 242 days.

Fig. 1

15 year old girl with recurrent synovial sarcoma. A) Transverse color Doppler grey-scale sonogram of the largest transverse area of a left supraclavicular tumor (T). Common carotid artery (arrow) was used as a landmark to insure similar transducer placement on follow-up contrast enhanced ultrasound (CEUS) studies. B) Baseline transverse CEUS with region-of-interest (ROI, solid line) drawn just inside tumor margins. Vertical line in the inset time intensity curve (TIC) indicates that this image was obtained at peak enhancement (PE) of 28.9 dB. C) Day 7 after initiation of therapy, transverse CEUS image obtained at PE of 2.0 dB giving a 93% reduction compared to baseline. This subject’s time to progression was 242 days.

Figure2

21 month old girl with recurrent rhabdoid tumor. A) Transverse grey-scale sonogram shows a peritoneal tumor (T) located posterior to the liver (L) and medial to the right kidney (K). Tumoral calcification (arrow) and adjacent organs were used as landmarks for transducer placement. B) Baseline transverse CEUS image with ROI inside tumor margins, obtained at PE of 33.5 dB. C) Day 7 after initiation of therapy, transverse CEUS image obtained at PE of 30.6 dB giving a 8.7% reduction compared to baseline. This subject progressed before the end of course 1, at 22 days.

Figure2

21 month old girl with recurrent rhabdoid tumor. A) Transverse grey-scale sonogram shows a peritoneal tumor (T) located posterior to the liver (L) and medial to the right kidney (K). Tumoral calcification (arrow) and adjacent organs were used as landmarks for transducer placement. B) Baseline transverse CEUS image with ROI inside tumor margins, obtained at PE of 33.5 dB. C) Day 7 after initiation of therapy, transverse CEUS image obtained at PE of 30.6 dB giving a 8.7% reduction compared to baseline. This subject progressed before the end of course 1, at 22 days.

Figure2

21 month old girl with recurrent rhabdoid tumor. A) Transverse grey-scale sonogram shows a peritoneal tumor (T) located posterior to the liver (L) and medial to the right kidney (K). Tumoral calcification (arrow) and adjacent organs were used as landmarks for transducer placement. B) Baseline transverse CEUS image with ROI inside tumor margins, obtained at PE of 33.5 dB. C) Day 7 after initiation of therapy, transverse CEUS image obtained at PE of 30.6 dB giving a 8.7% reduction compared to baseline. This subject progressed before the end of course 1, at 22 days.

Fig. 3

A = baseline, pre-contrast signal (dB) B = maximal enhancement: Peak enhancement (PE) = B – A in dB C = time of arrival of contrast agent into region of interest (sec) D = time of maximal enhancement (sec): Time to peak (TTP) = D – C (sec) E = rate of change in enhancement (RE) calculated as PE/TTP in dB/sec AUC1 = wash-in AUC2 = wash-out AUC = AUC1 + AUC2 A) Time intensity curve and parameters obtained from a region of interest analysis within the tumor shown in Figure 1A. B) Normalized time intensity curve for measurement of the area under the curve (AUC), created off-line from exported raw data for the same patient.

Fig. 3

A = baseline, pre-contrast signal (dB) B = maximal enhancement: Peak enhancement (PE) = B – A in dB C = time of arrival of contrast agent into region of interest (sec) D = time of maximal enhancement (sec): Time to peak (TTP) = D – C (sec) E = rate of change in enhancement (RE) calculated as PE/TTP in dB/sec AUC1 = wash-in AUC2 = wash-out AUC = AUC1 + AUC2 A) Time intensity curve and parameters obtained from a region of interest analysis within the tumor shown in Figure 1A. B) Normalized time intensity curve for measurement of the area under the curve (AUC), created off-line from exported raw data for the same patient.