title: Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin.
abstract: OBJECTIVE
  The study objective was to compare the overall survival (OS) of patients with unresectable or metastatic hepatocellular carcinoma (HCC) treated with nolatrexed (NOL) or doxorubicin (DOX).
  
  
  METHODS
  Patients from North America, Europe, and South Africa (N = 445) with HCC were randomly assigned to receive NOL or DOX. Eligible patients had Karnofsky performance status (KPS) > or = 60%, Cancer of the Liver Italian Program (CLIP) score < or = 3, and adequate organ function. Primary end point was OS. Secondary end points included progression-free survival (PFS), objective response rates, and safety. The treatment groups were well-balanced with regards to age, sex, ethnic origin, and underlying liver disease. Randomization was stratified according to KPS and CLIP score.
  
  
  RESULTS
  At the time of the final analysis, 377 patients had died. Median OS was 22.3 weeks for NOL and 32.3 weeks for DOX (P = .0068). The hazard ratio was 0.753 in favor of DOX. Objective response rate (complete response [CR] plus partial response [PR]) was 1.4% for NOL and 4.0% for DOX. Median PFS was 12 weeks for NOL and 10 weeks for DOX (P = .7091). Median time to treatment failure was 8.4 weeks for NOL and 9.1 weeks for DOX (P = .0969). Grade 3 and 4 stomatitis, vomiting, diarrhea, and thrombocytopenia were more common in the NOL arm. Alopecia was more common in the DOX arm. More patients were withdrawn from study for toxicity in the NOL arm than in the DOX arm.
  
  
  CONCLUSIONS
  NOL showed minimal activity in this phase III trial. Further exploration at this dose and schedule in HCC is not warranted.
authors.affiliation: California Pacific Medical Center, San Francisco, CA 94115, USA. gishr@sutterhealth.org
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gish
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.forename: Lucian
authors.initials: L
authors.lastname: Lazar
authors.forename: Paul
authors.initials: P
authors.lastname: Ruff
authors.forename: Ronald
authors.initials: R
authors.lastname: Feld
authors.forename: Adina
authors.initials: A
authors.lastname: Croitoru
authors.forename: Lynn
authors.initials: L
authors.lastname: Feun
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jeziorski
authors.forename: John
authors.initials: J
authors.lastname: Leighton
authors.forename: José
authors.initials: J
authors.lastname: Gallo
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Kennealey
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D010166:Palliative Care / Q000379:methods; D011788:Quality of Life; D011799:Quinazolines / Q000627:therapeutic use*; D018570:Risk Assessment; D016019:Survival Analysis; D019452:Terminally Ill
chemical_list: D011799:Quinazolines; D004317:Doxorubicin; C099178:nolatrexed