Abstract 4650: Pharmacokinetic and pharmacodynamic study of adjuvant gemcitabine therapy of biliary tract cancer following major hepatectomy (KHBO1101)

Abstract

Abstract Background: Gemcitabine at a standard dose of 1000 mg/m2 on Day 1, 8 and 15 every 4 weeks is not tolerated in biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy determined that the recommended dose is 1000 mg/m2 on Day 1 and 15 every 4 weeks. Here, we evaluated the pharmacokinetics and pharmacodynamics of gemcitabine at this recommended dose. Methods: This study evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by postoperative gemcitabine therapy. Pharmacokinetic evaluation of gemcitabine and 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 to 1000 mg/m2. Physical examination and adverse events were assessed for two weeks. Results: Thirteen patients were enrolled from August 2011 to January 2013, with 12 completing the study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had distal extrahepatic cholangiocarcinoma. Median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43-83 days). In the twelve patients, the following disorders at all grades of severity were observed: leukopenia (83.3%), neutropenia (66.7%), and thrombocytopenia (50.0%). Further, Grade 3 of neutropenia was observed in 16.7% of these patients. The dose-normalized AUC of gemcitabine and dFdU in patients with major hepatectomy was 10.22 ± 2.54 and 94.38 ± 45.38 mg/L/hr, respectively. These values were generally similar to those of patients with pancreatic cancer who did not undergo hepatectomy in a previous study. Conclusion: This study demonstrated that major hepatectomy did not affect the pharmacokinetics of gemcitabine and dFdU, despite an increase in hematological toxicity. Citation Format: Yutaka Fujiwara, Shogo Kobayashi, Hiroaki Nagano, Masashi Kanai, Etsuo Hatano, Masanori Toyoda, Tetsuo Ajiki, Yuki Takashima, Akinobu Hamada, Hironobu Minami, Tatsuya Ioka. Pharmacokinetic and pharmacodynamic study of adjuvant gemcitabine therapy of biliary tract cancer following major hepatectomy (KHBO1101). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4650. doi:10.1158/1538-7445.AM2014-4650