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


CONCLUSIONS
Bevacizumab is active and well tolerated in patients with advanced HCC. The clinical value of CECs, IL-6, and IL-8 warrants further investigation.
Department of Oncologic Medicine, Institut de Cancérologie Gustave-Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France. boige@igr.fr
Valérie
V
Boige
David
D
Malka
Abderrahmane
A
Bourredjem
Clarisse
C
Dromain
Charlotte
C
Baey
Nathalie
N
Jacques
Jean-Pierre
JP
Pignon
Nadege
N
Vimond
Nathalie
N
Bouvet-Forteau
Thierry
T
De Baere
Michel
M
Ducreux
Françoise
F
Farace
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043925:Angiogenesis Inducing Agents / Q000097:blood; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab; D054316:Biomarkers, Pharmacological / Q000097:blood*; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D012449:Safety
D043925:Angiogenesis Inducing Agents; D061067:Antibodies, Monoclonal, Humanized; D054316:Biomarkers, Pharmacological; D015850:Interleukin-6; D016209:Interleukin-8; D000068258:Bevacizumab