Transarterial chemoembolization plus or minus intravenous bevacizumab in the treatment of hepatocellular cancer: a pilot study

Abstract

Background: Stimulation of vascular endothelial growth factor (VEGF) has been observed following transarterial chemoembolization (TACE) in hepatocellular cancer (HCC) and may contribute to tumor regrowth. This pilot study examined whether intravenous (IV) bevacizumab, a monoclonal antibody against VEGF, could inhibit neovessel formation after TACE.

Methods: 30 subjects with HCC undergoing TACE at a single academic institution were randomized with a computer-generated allocation in a one to one ratio to either bevacizumab at a dose of 10 mg/kg IV every 14 days beginning 1 week prior to TACE (TACE-BEV arm) or observation (TACE-O arm). Angiography was performed with TACE at day 8, and again at weeks 10 and 14. Repeat TACE was performed at week 14 if indicated. TACE-BEV subjects were allowed to continue bevacizumab beyond week 16. TACE-O subjects were allowed to cross-over to bevacizumab at week 16 in the setting of progressive disease. The main outcome measure was a comparison of neovessel formation by serial angiography. Secondary outcome measures were progression free survival (PFS) at 16 weeks, overall survival (OS), bevacizumab safety, and an analysis of VEGF levels before and after TACE with and without bevacizumab.

Results: Among the 30 subjects enrolled, 9 of 15 randomized to the TACE-O arm and 14 of 15 randomized to the TACE-BEV arm completed all 3 angiograms. At week 14, 3 of 9 (33%) TACE-O subjects and 2 of 14 (14%) TACE-BEV subjects demonstrated neovascularity. The PFS at 16 weeks was 0.19 in the TACE-O arm and 0.79 in the TACE-BEV arm (p = 0.021). The median OS was 61 months in the TACE-O arm and 49 months in the TACE-BEV arm (p = 0.21). No life-threatening bevacizumab-related toxicities were observed. There were no substantial differences in bevacizumab pharmacokinetics compared to historical controls. Bevacizumab attenuated the increase in VEGF observed post-TACE.

Conclusions: IV bevacizumab was well tolerated in selected HCC subjects undergoing TACE, and appeared to diminish neovessel formation at week 14.

Trial registration: ClinicalTrials.gov NCT00049322.

Figures

Figure 1

Study design.

Figure 2

Disposition of subjects.

Figure 3

Serial angiograms from a subject on the observation arm demonstrating neovascularity: a) pre-TACE angiogram on Day 8 demonstrating tumor blush; b) post-TACE angiogram on Day 8 demonstrating successful embolization of vessels supplying the tumor; and c) Week 10 angiogram demonstrating 2+ neovascularity and recanalization.

Figure 4

Kaplan-Meier plot for progression free survival (PFS). The PFS at 16 weeks was 0.79 in the TACE-BEV arm (solid line) and 0.19 in the TACE-O arm (dashed line), with a p-value of 0.021

Figure 5

Kaplan-Meier plot for overall survival (OS). The median OS was 49 months in the TACE-BEV arm (solid line) and 61 months in the TACE-O arm (dashed line), with a p-value of 0.21

Figure 6

Effect of TACE on serum VEGF levels. Fold-change in VEGF levels over time are depicted for observation and bevacizumab arms. One-sided t-test values for each timepoint are as follows: 1 h, 0.053; 24 h, 0.167; 48 h, 0.161; 72 h, 0.048; 360 h, 0.039; 528 h, 0.063; 696 h, 0.06