title: Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group.
abstract: OBJECTIVE
  To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival.
  
  
  METHODS
  This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate.
  
  
  RESULTS
  Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1α/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment.
  
  
  CONCLUSIONS
  The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, A445A Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43212, USA, kristen.ciombor@osumc.edu.
authors.forename: Kristen K
authors.initials: KK
authors.lastname: Ciombor
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Al Bowen
authors.initials: AB
authors.lastname: Benson
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Su
authors.forename: Linda
authors.initials: L
authors.lastname: Horton
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Short
authors.forename: John Sae Wook
authors.initials: JS
authors.lastname: Kauh
authors.forename: Charles
authors.initials: C
authors.lastname: Staley
authors.forename: Mary
authors.initials: M
authors.lastname: Mulcahy
authors.forename: Mark
authors.initials: M
authors.lastname: Powell
authors.forename: Katayoun I
authors.initials: KI
authors.lastname: Amiri
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
authors.forename: Jordan
authors.initials: J
authors.lastname: Berlin
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000069286:Bortezomib; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy*; D018946:Chemokine CCL5 / Q000097:blood; D016207:Cytokines / Q000097:blood; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D055815:Young Adult
chemical_list: D001897:Boronic Acids; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D016207:Cytokines; D011719:Pyrazines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069286:Bortezomib; D004317:Doxorubicin