title: Hepatocellular Carcinoma: A Phase II Randomized Controlled Double-Blind Trial of Transarterial Chemoembolization in Combination with Biweekly Intravenous Administration of Bevacizumab or a Placebo.
abstract: OBJECTIVE
  To investigate the efficacy and safety of conventional transarterial chemoembolization (TACE) (cTACE) in combination with bevacizumab or a placebo in patients with hepatocellular carcinoma (HCC) in a randomized controlled double-blind phase II trial.
  
  
  METHODS
  This study was approved by the institutional review board, and written informed consent was obtained prior to inclusion. A total of 40 patients (20 patients per group, all 18 years or older) with histologically confirmed early- or intermediate-stage HCC and Child-Pugh class A or B cirrhosis were scheduled for inclusion. The primary endpoint was radiologic progression at 12 months according to European Association for the Study of the Liver criteria. Secondary endpoints were safety and overall survival (OS). Patients underwent cTACE with doxorubicin and intravenous administration of a placebo (cTACE-C) or bevacizumab (cTACE-B) (5 mg per kilogram of body weight) every 2 weeks for 52 weeks. After the first TACE procedure, TACE was repeated twice in 4-week intervals if indicated and technically feasible and on demand thereafter. Statistical analyses were performed with statistical software. P < .05 indicated a significant difference.
  
  
  RESULTS
  Thirty-two patients were recruited between January 2006 and December 2009 (29 male, three female; mean age, 61 years ± 8 [standard deviation]; Barcelona Clinic Liver Cancer stage A, n = 4; Barcelona Clinic Liver Cancer stage B, n = 28; predominant cause, alcohol [n = 15]; Child-Pugh class A disease, n = 22; Child-Pugh class B disease, n = 10; 16 patients received bevacizumab; 16 patients received a placebo). Patients underwent a median of three TACE cycles and received 13 infusions of bevacizumab versus 11 infusions of the placebo before the trial was stopped prematurely for safety reasons. Severe (grade 3-5) septic (n = 8 vs n = 3) and vascular (n = 9 vs n = 0) side effects were observed almost exclusively in the cTACE-B group. Median survival was worse in the cTACE-B group than in the cTACE-C group (5.3 vs 13.7 months; hazard ratio [HR], 1.7; 95% confidence interval [CI]: 0.8, 3.6; P = .195) and reached significance in patients with Child-Pugh class A cirrhosis (7.3 vs 26.5 months; HR, 2.6; 95% CI: 1.0, 6.6; P = .049). The primary endpoint was not met, since there was no difference in radiologic response between the groups at 3, 6, or 12 months.
  
  
  CONCLUSIONS
  No improvement in radiologic tumor response or OS was observed in patients with HCC who received cTACE and bevacizumab, but severe and even lethal septic and vascular side effects occurred. Thus, bevacizumab cannot be recommended as an adjuvant treatment to cTACE.
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Matthias
authors.initials: M
authors.lastname: Pinter
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Gregor
authors.initials: G
authors.lastname: Ulbrich
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sieghart
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Claus
authors.initials: C
authors.lastname: Kölblinger
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiberger
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Shuren
authors.initials: S
authors.lastname: Li
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Arnulf
authors.initials: A
authors.lastname: Ferlitsch
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Johannes
authors.initials: J
authors.lastname: Lammer
authors.affiliation: From the Division of Gastroenterology & Hepatology (M. Pinter, G.U., W.S., T.R., A.F., C.M., M. Peck-Radosavljevic), Division of Interventional Radiology (C.K., J.L.), and Division of Nuclear Medicine (S.L.), Medical University of Vienna, Vienna, Austria; Medical Division, Krankenhaus Hietzing, Vienna, Austria (G.U.); and Vienna Liver Cancer Study Group, Vienna, Austria (M. Pinter, W.S., M. Peck-Radosavljevic).
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
mesh_terms: D061605:Administration, Intravenous; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000628:therapy*; D016461:Chemoembolization, Therapeutic / Q000379:methods*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011859:Radiography
chemical_list: D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab