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.

Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging

“…Prospective single arm phase Ⅱ Sunitinib Decease Better TTP Boige et al [98] CEC 36 Prospective single arm phase Ⅱ Bevacizumab Early increase Better OR CEC level was not associated with prognosis in this study.…”

“…In the SHARP trial, the increase of VEGF-A plasma concentration during sorafenib treatment observed in patients with advanced HCC did not predict OS or tumor response [63] . Similarly, no association between VEGF-A plasma level changes and outcome was observed in patients treated with bevacizumab for advanced HCC [98] . Accordingly, the VEGF-A could serve as a pharmacodynamic marker of exposure to antiangiogenic agents but did not have prognostic or predictive value [85] .…”

Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade

“…When treated with bevacizumab plus a chemotherapeutic regimen, a better outcome was reported for metastatic colorectal cancer (mCRC) patients with a signature that included lower than average baseline IL6 serum levels (44), whereas in another study of mCRC, a worse outcome was associated with a signature that included lower than average IL6 serum levels (45). High baseline IL6 levels were also reported to predict shorter progression-free survival (PFS) and overall survival (OS) in patients with advanced hepatocellular carcinomas (46). In line with these later studies, we observed in an ovarian cancer trial that aflibercept-treated patients with high IL6 had poorer survival than patients with low IL6 serum levels.…”

New modalities of treatment for hepatocellular carcinoma

“…ORR was 13% and 14% interestingly, but this drug failed to develop because of safety concerns. 133,134 Ramucirumab. It is a human IgG1 monoclonal antibody.…”