Early Prediction of Treatment Response to Sorafenib with Elastosonography in a Mice Xenograft Model of Hepatocellular Carcinoma: A Proof-of-Concept Study

Abstract

Purpose: Sorafenib is the reference therapy for advanced hepatocellular carcinoma (HCC). There is no method for predicting in the early period subsequent individual response. Starting from the clinical experience in humans that subcutaneous metastases may rapidly change consistency under sorafenib and that elastosonography allows assessment of tissue elasticity, we investigated the role of this ultrasound-based technique in the early prediction of tumor response to sorafenib in a HCC mice model.

Materials and Methods: HCC subcutaneous xenografting in mice was utilized. Mice were randomized to vehicle (17 mice) or treatment with sorafenib (19 mice). Strain elastosonography (Esaote, Italy) of the tumor mass was performed at different time points (day 0, + 2 and + 14 from treatment start) until the mice were sacrificed (day + 14). At the same time points, the volume was calculated with ultrasonography.

Results: Sorafenib-treated mice showed a smaller increase in tumor size on day + 14 in comparison to vehicle-treated mice (tumor volume increase + 175 % vs. + 382 %, p = 0.009). The median tumor elasticity increased in both groups on day + 2 (+ 5.65 % and + 3.86 %, respectively) and decreased on day + 14 (–3.86 % and –3.63 %, respectively). However, among Sorafenib-treated tumors, 13 mice with a growth percentage delta < 200 % (considered as good treatment response) showed an increase in elasticity on day + 2 (+ 8.9 %, range –12.6 – + 64) while the other 6 with a growth percentage delta > 300 % (considered as poor treatment response) showed a decrease in elasticity (–17 %, range –30.2 – + 15.3) (p = 0.044).

Conclusion: Elastosonography appears to be a promising noninvasive new technique for the early treatment prediction of HCC tumor response to sorafenib. Specifically, an early increase in tumor elasticity (corresponding to tumors becoming softer) is associated with a good response.

Zusammenfassung

Ziel: Sorafenib ist die Referenz-Therapie für das fortgeschrittene hepatozelluläre Karzinom (HCC). In der Frühphase gibt es keine Methode, um das individuelle Ansprechen auf die Therapie vorherzusagen. Ausgehend von der klinischen Erfahrung beim Menschen, dass subkutane Metastasen ihre Konsistenz unter Sorafenib sehr schnell verändern können und dass die Elastosonografie die Bewertung der Gewebe-Elastizität ermöglicht, untersuchten wir diese Technik zur Untersuchung des frühen Ansprechens des Tumors auf Sorafenib im HCC-Mausmodell.

Material und Methoden: Es wurde ein subkutanes HCC-Xenotransplantat in Mäusen durchgeführt. Die Mäuse wurden randomisiert und entweder mit Trägersubstanz (17 Mäuse) oder Sorafenib (19 Mäuse) behandelt. Die Strain-Elastosonografie (Esaote, Italy) der Tumormasse erfolgte zu bestimmten Zeitpunkten (Tag 0, + 2 und + 14 ab Therapiebeginn) bis Autopsie der Mäuse (Tag + 14). Jeweils zum gleichen Zeitpunkt wurde auch das Volumen sonografisch errechnet.

Ergebnisse: Sorafenib-behandelte Mäuse zeigten eine geringere Zunahme der Tumorgröße am Tag + 14 im Vergleich zu Mäusen, die Trägersubstanz erhielten (+ 175 % vs. + 382 %, p = 0,009). In beiden Gruppen stieg der Median der Tumor-Elastizität am Tag + 2 an (+ 5,65 % mit Sorafenib, + 3,86 % mit Trägersubstanz) und sank am Tag + 14 ab (–3,86 % mit Sorafenib, –3,63 % mit Trägersubstanz). Allerdings zeigten 13 Mäuse aus der Gruppe der sorafenib-behandelten Tumore mit einer Größenzunahme delta < 200 % (als gutes Therapieansprechen zu bewerten) eine Erhöhung der Elastizität am Tag + 2 (+ 8,9 %, Bereich – 12,6 – + 64), während die 6 anderen Mäuse eine Wachstumszunahme von delta > 300 % (entsprechend einem schlechten Therapieansprechen) eine Verminderung der Elastizität (–17 %, Bereich –30,2 – + 15,3) (p = 0,044) aufwiesen.

Schlussfolgerung: Die Elastosonografie scheint eine viel versprechende, nicht-invasive neue Methode zu sein, die ein frühes Ansprechen der Behandlung eines HCC auf Sorafenib ermöglicht. Insbesondere geht ein früher Anstieg der Elastizität des Tumors (in Übereinstimmung mit Tumoren, die weicher werden) mit einem guten Ansprechen einher.

Key words

ultrasound - animal investigations - treatment effects - tumor

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