title: An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma.
abstract: OBJECTIVE
  Bortezomib (PS-341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitin-proteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients.
  
  
  METHODS
  The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted.
  
  
  RESULTS
  Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months.
  
  
  CONCLUSIONS
  This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.
authors.affiliation: Mayo Clinic Florida, Jacksonville, FL, USA. kim.george@mayo.edu
authors.forename: George P
authors.initials: GP
authors.lastname: Kim
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Mahoney
authors.forename: Daniel
authors.initials: D
authors.lastname: Szydlo
authors.forename: Tony S K
authors.initials: TS
authors.lastname: Mok
authors.forename: Robert
authors.initials: R
authors.lastname: Marshke
authors.forename: Kyle
authors.initials: K
authors.lastname: Holen
authors.forename: Joel
authors.initials: J
authors.lastname: Picus
authors.forename: Michael
authors.initials: M
authors.lastname: Boyer
authors.forename: Henry C
authors.initials: HC
authors.lastname: Pitot
authors.forename: Joseph
authors.initials: J
authors.lastname: Rubin
authors.forename: Philip A
authors.initials: PA
authors.lastname: Philip
authors.forename: Anna
authors.initials: A
authors.lastname: Nowak
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009656:North America; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease