Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma

Abstract

Objective: Hepatocellular carcinoma (HCC) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis. We assessed the safety, efficacy, and potential biomarkers of activity of bevacizumab in patients with advanced HCC.

Methods: In this phase II trial, eligible patients received bevacizumab, 5 mg/kg or 10 mg/kg every 2 weeks. The disease-control rate at 16 weeks (16W-DCR) was the primary endpoint. Circulating endothelial cells (CECs) and plasma cytokines and angiogenic factors (CAFs) were measured at baseline and throughout treatment.

Results: The 16W-DCR was 42% (95% confidence interval, 27%-57%). Six of the 43 patients who received bevacizumab achieved a partial response (objective response rate [ORR], 14%). Grade 3-4 asthenia, hemorrhage, and aminotransferase elevation occurred in five (12%), three (7%), and three (7%) patients, respectively. During treatment, placental growth factor markedly increased, whereas vascular endothelial growth factor (VEGF)-A dramatically decreased (p < .0001); soluble VEGF receptor-2 (p < .0001) and CECs (p = .03) transiently increased on day 3. High and increased CEC counts at day 15 were associated with the ORR (p = .04) and the 16W-DCR (p = .02), respectively. Lower interleukin (IL)-8 levels at baseline (p = .01) and throughout treatment (p ≤ .04) were associated with the 16W-DCR. High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times (p ≤ .04).

Conclusion: Bevacizumab is active and well tolerated in patients with advanced HCC. The clinical value of CECs, IL-6, and IL-8 warrants further investigation.

Trial registration: ClinicalTrials.gov NCT00162669.

Conflict of interest statement

Disclosures: David Malka: Roche (C/A); Amgen (RF); Michel Ducreux: Roche, Merck (C/A); Roche, Merck, Pfizer, Novartis, Amgen, Sanofi (H); Pfizer, Roche (RF). The other authors indicated no financial relationships.

Figures

Figure 1.

Changes in tumor area and serum alphafoetoprotein level over time in patients with advanced hepatocellular carcinoma treated with bevacizumab. Waterfall plot of maximum percentage changes in tumor size of index lesions (A) and maximum changes in α-fetoprotein (AFP) levels from baseline (B). Evaluable patients (n = 38) are categorized according to Response Evaluation Criteria in Solid Tumors (version 1.0) as having an objective response (white bars), stable disease (dashed bars), or disease progression (purple bars). Eight patients with a <20% increase in the sum of the largest dimensions of the target lesions were categorized as having disease progression because of the appearance of new lesions. *0% decrease or increase.

Figure 2.

Kaplan-Meier estimates of overall survival and progression-free survival. (A): Progression-free survival probability. (B): Overall survival probability.

Figure 3.

Prognostic value of plasma interleukin (IL)-8 and IL-6 in patients with advanced hepatocellular carcinoma treated with bevacizumab. Overall (A) and progression-free (B) survival probabilities according to whether baseline plasma interleukin (IL)-8 levels were <80 pg/mL or ≥80 pg/mL. Overall (C) and progression-free (D) survival probabilities according to whether baseline plasma IL-6 levels were <8 pg/mL or ≥8 pg/mL.