title: Pharmacokinetic Study of Adjuvant Gemcitabine Therapy for Biliary Tract Cancer following Major Hepatectomy (KHBO1101).
abstract: BACKGROUND
  Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m2 on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects.
  
  
  METHODS
  We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2',2'-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800-1,000 mg/m2. Physical examination and adverse events were monitored for 12 weeks.
  
  
  RESULTS
  Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43-83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy.
  
  
  CONCLUSIONS
  Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU.
  
  
  BACKGROUND
  UMIN-CTR in (JPRN) UMIN000005109.
authors.affiliation: Division of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.|Department of Experimental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.affiliation: Outpatient Oncology Unit, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Etsuo
authors.initials: E
authors.lastname: Hatano
authors.affiliation: Division of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Toyoda
authors.affiliation: Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ajiki
authors.affiliation: Department of Clinical Pharmacology, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takashima
authors.affiliation: Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Clinical Pharmacology, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
authors.affiliation: Division of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.affiliation: Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ioka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000601:surgery; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006498:Hepatectomy; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine