Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US)

Abstract

Purpose: Dynamic contrast-enhanced ultrasound (DCE-US) was used to monitor early response to sorafenib therapy in patients with liver metastases from uveal melanoma.

Methods: In total, 21 patients with liver metastases were recruited within a prospective trial and underwent daily sorafenib therapy. DCE-US of a target lesion was performed before initiation of treatment, on day 15 and 56. Two independent blinded investigators performed software analysis for DCE-US parameters and inter-observer-correlation was calculated. Response to treatment was evaluated on day 56. DCE-US parameters were correlated with clinical response and RECIST1.1 criteria.

Results: Inter-observer-correlation (r) of DCE-US parameters [time-to-peak (TTP), mean-transit-time (MTT), peak intensity (PI), regional blood volume (RBV), regional blood flow (RBF)] at baseline, day 15, and day 56 was highly significant (r-range 0.73-0.97, all p < 0.001). Out of 17 evaluable patients, 12 patients survived day 56 (clinical responders, cRE), whereas, five patients died before day 56 and were classified as non-responders (cNR). TTP values significantly increased in the cRE group 15 days after initiation of treatment for investigator 1 (p = 0.034) and at day 56 for both investigators (p = 0.028/0.028). MTT had increased significantly in the cRE group on day 56 (p = 0.037/0.022). In the cNR group changes for TTP and MTT remained insignificant. Thus, increase of the DCE-US parameters TTP and MTT are associated with response to treatment and prognosis.

Conclusion: An increase of TTP and MTT at frequent intervals could serve as a surrogate marker for early response evaluation to anti-angiogenic treatment of metastatic uveal melanoma.

Keywords: CEUS; Dynamic contrast-enhanced ultrasound (DCEUS); Functional imaging; Response prediction; Sorafenib; Uveal melanoma.

Fig. 1

Contrast-enhanced ultrasound examinations: The first image showing the dual window mode with the lesion in grey scale ultrasonography and at the beginning of contrast agent wash-in. Image series of two patients after initiation of sorafenib therapy at baseline (d0) and after 2 weeks of treatment (d15). a Patient with response to sorafenib treatment. A decline of signal intensity within the tumor and the occurrence of avascular areas (remaining black) in the lesion (*) are visible. The tumor size is unchanged. b Patient without response to treatment. The lesion (↑) remains well vascularized throughout the arterial wash-in phase. Again, the lesion size is constant

Fig. 2

Time-intensity-curves of two patients, responder and non-responder, at baseline (Day 0) and after two weeks of sorafenib therapy (Day 15). Blue line showing the raw image data of absolute signal intensity. On that basis, the green line (fitted curve) is calculated and DCE-US parameters are obtained

Fig. 3

a Time-to-peak (TTP) and b Mean-transit-time (MTT) values of both readers at baseline, day 15 and day 56. Each box represents the interquartile range and the median. Error bars mark minimum and maximum values (range) and small circles and stars mark outliers