Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma.
OBJECTIVE
To determine the clinical and biologic effects of bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in unresectable hepatocellular carcinoma (HCC).


METHODS
Adults with organ-confined HCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and compensated liver disease were eligible. Patients received bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicity. The primary objective was to determine whether bevacizumab improved the 6-month progression-free survival (PFS) rate from 40% to 60%. Secondary end points included determining the effects of bevacizumab on arterial enhancement and on plasma cytokine levels and the capacity of patients' plasma to support angiogenesis via an in vitro assay.


RESULTS
The study included 46 patients, of whom six had objective responses (13%; 95% CI, 3% to 23%), and 65% were progression free at 6 months. Median PFS time was 6.9 months (95% CI, 6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 years, and 23% at 3 years. Grade 3 to 4 adverse events included hypertension (15%) and thrombosis (6%, including 4% with arterial thrombosis). Grade 3 or higher hemorrhage occurred in 11% of patients, including one fatal variceal bleed. Bevacizumab was associated with significant reductions in tumor enhancement by dynamic contrast-enhanced magnetic resonance imaging and reductions in circulating VEGF-A and stromal-derived factor-1 levels. Functional angiogenic activity was associated with VEGF-A levels in patient plasma.


CONCLUSIONS
We observed significant clinical and biologic activity for bevacizumab in nonmetastatic HCC and achieved the primary study end point. Serious bleeding complications occurred in 11% of patients. Further evaluation is warranted in carefully selected patients.
Department of Medicine, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032-3784, USA. aas54@columbia.edu
Abby B
AB
Siegel
Emil I
EI
Cohen
Allyson
A
Ocean
Deborah
D
Lehrer
Alec
A
Goldenberg
Jennifer J
JJ
Knox
Helen
H
Chen
Sean
S
Clark-Garvey
Alan
A
Weinberg
John
J
Mandeli
Paul
P
Christos
Madhu
M
Mazumdar
Elizabeta
E
Popa
Robert S
RS
Brown
Shahin
S
Rafii
Jonathan D
JD
Schwartz
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000098:blood supply* / Q000188:drug therapy*; D054377:Chemokine CXCL12 / Q000097:blood; D018572:Disease-Free Survival; D006801:Humans; D007262:Infusions, Intravenous; D008113:Liver Neoplasms / Q000097:blood / Q000098:blood supply* / Q000188:drug therapy*; D018810:Magnetic Resonance Angiography / Q000379:methods; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D054377:Chemokine CXCL12; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab