title: Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma.
abstract: OBJECTIVE
  It is well known that hepatocellular carcinoma (HCC) is an arginine auxotroph due to argininosuccinate synthetase I deficiency. This study's purpose was to evaluate the effects of pegylated arginine deiminase (ADI) in terms of toxicity, tumor response, alpha-fetoprotein (AFP) levels, and serum arginine levels.
  
  
  METHODS
  Eighty patients were randomly assigned to receive either 80 IU/m(2) or 160 IU/m(2) of ADI weekly for up to 6 months. Adverse events, serum arginine, AFP levels, and antibody production against ADI were measured on a regular basis. In addition, disease response and time to progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) and survival rates were evaluated.
  
  
  RESULTS
  Four patients were excluded from the survival analysis because they developed exclusion criteria after randomization, but before first treatment. The number of patients in the two cohorts were similar (n = 37 in the low-dose cohort, n = 39 in the high-dose cohort). Mean (+/-SE) survival for all subjects was 15.8 months (474 days +/- 39 days) from time of diagnosis of unresectable disease. Arginine levels remained below baseline for 50 days while antibodies against ADI reached a plateau at approximately the same time. There were no deaths attributed to ADI treatment. Only two patients were withdrawn for immunogenic-related adverse events. Grade 2, 3, or 4 toxicities were recorded in 92, 19, and 0 patients, respectively.
  
  
  CONCLUSIONS
  Pegylated ADI is a promising drug that capitalizes on a significant enzymatic deficiency in HCC. It is safe, well tolerated, and may benefit patients with unresectable HCC.
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Evan S
authors.initials: ES
authors.lastname: Glazer
authors.forename: Mauro
authors.initials: M
authors.lastname: Piccirillo
authors.forename: Vittorio
authors.initials: V
authors.lastname: Albino
authors.forename: Raimondo
authors.initials: R
authors.lastname: Di Giacomo
authors.forename: Raffaele
authors.initials: R
authors.lastname: Palaia
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Mastro
authors.forename: Gerardo
authors.initials: G
authors.lastname: Beneduce
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castello
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Rosa
authors.forename: Antonella
authors.initials: A
authors.lastname: Petrillo
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.forename: Steven A
authors.initials: SA
authors.lastname: Curley
authors.forename: Francesco
authors.initials: F
authors.lastname: Izzo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D001120:Arginine / Q000097:blood; D015415:Biomarkers / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D007273:Injections, Intramuscular; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome; D000509:alpha-Fetoproteins / Q000378:metabolism
chemical_list: C097353:AFP protein, human; D000906:Antibodies; D000970:Antineoplastic Agents; D015415:Biomarkers; D000509:alpha-Fetoproteins; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20