Quantitative Dynamic Contrast Enhanced Ultrasound to Assess Response to Anti-Angiogenic Therapy in Children and Adolescents with Solid Malignancies: A Pilot Study

Objective— To investigate contrast enhanced ultrasound (CEUS) assessment of tumor response to anti-angiogenic therapy in children and adolescents with solid malignancies. Methods & Materials— After IRB approval, 4 girls and 9 boys, mean age 13 years (range, 1.8 to 19.8 years) with recurrent solid tumors enrolled on an institutional phase I study of antiangiogenic therapy, underwent CEUS of target lesions before therapy, on days 3 and 7 and end of course 1. Acoustic data from target lesion regions of interest were used to measure peak enhancement (PE), time to peak (TTP), rate of enhancement (RE), total area under the curve (AUC), AUC during wash-in (AUC1) and AUC during wash-out (AUC2). Using Cox regression analysis we assessed the association between changes in parameters from baseline to follow-up time points and time to tumor progression. P-values ≤ 0.050 were considered significant. Results— Target lesion sites included: liver (n=3), pleura (n=2), and supraclavicular mass, soft tissue component of a bone metastasis, lung, retroperitoneum, peritoneum, lymph node, muscle mass and perineum (n=1 each). Hazard ratios for changes from baseline to end course 1 in PE (1.17, p=0.034), RE (3.3, p=0.029) and AUC1 (1.023, p=0.040) were significantly associated with time to progression. Greater decreases in these parameters correlated with longer time to progression. to progression in our cohort of children and adolescents with recurrent solid tumors treated with anti-angiogenic therapy. Further these to 19.8 years). Primary diagnoses were rhabdomyosarcoma (n=2), rhabdoid tumor (n=2), Wilms tumor (n=2), renal cell carcinoma, hepatocellular carcinoma, osteosarcoma, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma (n=1 each). Target lesion sites included; liver (n=3), pleura (n=2) and supraclavicular mass, soft-tissue component of a bone metastasis, lung, retroperitoneum, peritoneum, lymph node, muscle mass and perineum (n=1 each). A total of 74 CEUS examinations were performed at the following time points: baseline (n=13), day 3 (n=11), day 7 (n=12), end course 1 (n=12), end course 2 (n=8), end course 4 (n=8), end course 6 (n=5), end course 8 (n=3), and end courses 10 and 12 (n=1 each). End of course 1 AUC and AUC2 data were excluded for 1 non-responder and 1 responder due to inadequate AUC2 data. One subject reported brief taste alteration after contrast injection during 3 of 5 examinations. There were no other adverse events. There were 9 responders and 4 non-responders. The median time to progression for all 13 was 95 days (range, 22 to 242 days), for responders it was 142 days (range, 61 to 242 days) and for non-responders, 23 days (range, 22 to 27 days). Our findings show that CEUS detects changes in blood flow in a variety of solid malignancies in children very early in the course of anti-angiogenic therapy and that these changes can predict time to progression. Importantly, this imaging modality may identify poor responders before conventional RECIST criteria, thus affording the opportunity for early intervention and tailored management. This approach could avoid maintaining patients on toxic and ineffective therapy for weeks or months before conventional imaging identifies morphologic changes that indicate tumor progression. In our study, subjects with greater decreases in PE, RE and AUC 1 at the end of course 1 had significantly longer time to progression. Additionally, reductions in PE at day 3, PE and AUC1 at day 7 and the AUC and AUC2 at the end of course 1 were marginally significant. Although our cohort was too small to attain statistical power, there were substantial differences in percent changes in all parameters at early time points in responders compared to non-responders. Among the 6 parameters that we investigated, the PE appears to be the most robust indicator of tumor response. We found that the early percentage decreases of PE, relative to baseline, were 5 to 6 times greater in responders than non-responders. This is perhaps not surprising since the PE depends on tumor perfusion and tumors that respond well to anti-angiogenic therapies will have substantially reduced blood flow and contrast enhancement. Our findings agree with those of Lassau et al who investigated the value of CEUS in 24 adults with gastrointestinal stromal tumors treated with imatinib. Those investigators found a strong correlation (p < 10 -4 ) between changes in percent of contrast uptake within tumors from baseline to day 7, day 14 and at 2 months in patients with a good response but no significant change in poor responders (4). However, our findings differ slightly from a subsequent study by Lassau and colleagues that assessed 42 adults with hepatocellular carcinoma treated with bevacizumab (2). In that study changes in AUC, AUC1, AUC2, TTP and mean transit time at day 3 trended toward a significant correlation with RECIST response, but there was no correlation between PE and RECIST response