Value of Contrast-Enhanced Ultrasound Quantification Criteria for Identifying Patients not Responding to Bevacizumab-Based Therapy for Colorectal Liver Metastases

Abstract

Purpose To evaluate changes in tumor vascularization parameters based on contrast-enhanced ultrasound (CEUS) quantification criteria of at least one visible liver metastasis as an early predictor of non-response to chemotherapy, including bevacizumab for colorectal cancer (CRC) liver metastases.

Materials and Methods This multicenter prospective study included patients who received first-line bevacizumab-based chemotherapy. Tumor enhancement measured using CEUS within one liver metastasis and in relation to the surrounding healthy liver was quantified within 8 days before the first infusion of bevacizumab (E0), 24 hours after the end of the first infusion of bevacizumab (E1), in the 24 hours before the 2nd and 3 rd infusion of bevacizumab on day 15 (E2) and day 30 (E3), respectively, and after 2 months of treatment (E4). Endpoints were tumor response using RECIST criteria at 2 months, progression-free survival (PFS) and overall survival (OS).

Results Among the 137 patients included in this study, 109 were analyzed. Only CEUS parameters calculated in relation to healthy liver were significant. High wash-in and wash-out rates at baseline were significantly associated with a better tumor response. Increases over time E2-E0 and E3-E0 for peak enhancement were significantly associated with shorter progression-free survival. Increases over time E2-E0 and E3-E0 for peak enhancement and wash-in area under the curve were significantly associated with a shorter overall survival.

Conclusion This large study demonstrated that early dynamic changes in the vascularity of liver metastases evaluated by quantified CEUS are associated with outcome in patients receiving first-line bevacizumab-based treatment for metastatic CRC.

Zusammenfassung

Ziel Bewertung der Veränderungen der Tumorvaskularisations-Parameter anhand der Quantifizierungskriterien des kontrastverstärkten Ultraschalls (CEUS) bei mindestens einer sichtbaren Lebermetastase als früher prädiktiver Marker für ein Nicht-Ansprechen auf die Chemotherapie mit Bevacizumab bei Lebermetastasen des kolorektalen Karzinoms (CRC).

Material und Methoden Diese multizentrische, prospektive Studie umfasste Patienten, die eine Chemotherapie mit Bevacizumab als Mittel der ersten Wahl erhalten hatten. Die mittels CEUS gemessene Kontrastverstärkung des Tumors innerhalb einer Lebermetastase und in Relation zur umgebenden gesunden Leber wurde innerhalb von 8 Tagen vor der ersten Infusion von Bevacizumab (E0), 24 Stunden nach Ende der ersten Bevacizumab-Infusion (E1), 24 Stunden vor der 2. und 3. Bevacizumab-Infusion an Tag 15 (E2) bzw. Tag 30 (E3) sowie nach 2 Monaten Behandlung (E4) quantifiziert. Endpunkte waren das Ansprechen des Tumors mittels RECIST-Kriterien nach 2 Monaten, das progressionsfreie Überleben (PFS) und die Gesamtüberlebenszeit (OS).

Ergebnisse Von den 137 in dieser Studie eingeschlossenen Patienten wurden 109 analysiert. Nur diejenigen CEUS-Parameter, die relativ zur gesunden Leber berechnet wurden, waren signifikant. Bei Behandlungsbeginn waren hohe Wash-in und Wash-out Raten signifikant mit einem besseren Ansprechens des Tumors assoziiert. Die Anstiege über die Zeit von E2-E0 und E3-E0 für das Peak-Enhancement waren signifikant mit einem kürzeren progressionsfreien Überleben assoziiert. Die Anstiege über die Zeit von E2-E0 und E3-E0 für das Peak-Enhancement und der „area-under the curve“ des Wash-in zeigten einen signifikanten Zusammenhang mit einer geringeren Gesamtüberlebenszeit.

Schlussfolgerung Diese große Studie zeigte einen Zusammenhang zwischen den frühen dynamischen Veränderungen der Vaskularisierung von Lebermetastasen mittels quantifizierter CEUS und dem Erfolg einer Bevacizumab-basierten First-Line-Therapie bei Patienten mit metastasierendem CRC.

Key words

ultrasound - colorectal cancer - bevacizumab

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