Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study

Shogo Kobayashi, Hiroaki Nagano, Daisuke Sakai, Hidetoshi Eguchi, Etsuro Hatano, Masashi Kanai, Satoru Seo, Kojiro Taura, Yutaka Fujiwara, Tetsuo Ajiki, Shigekazu Takemura, Shoji Kubo, Hiroaki Yanagimoto, Hideyoshi Toyokawa, Akihito Tsuji, Hiroaki Terajima, Satoshi Morita, Tatsuya Ioka

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Abstract

Background: Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy. Methods: Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800-1,000 mg/m2 gemcitabine on days 1, 8, and 15 and then every 3-4 weeks or 40-80 mg/m2/day S-1 on days 1-28 and every 3-6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm. Results: Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10 % of DLT, the recommended dose was 1,000 mg/m2 gemcitabine biweekly and 80 mg/m2/day S-1 on days 1-28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted. Conclusion: We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10 %.

Original languageEnglish
Pages (from-to)699-709
Number of pages11
JournalCancer chemotherapy and pharmacology
Volume74
Issue number4
DOIs
Publication statusPublished - Jul 30 2014

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gemcitabine
Biliary Tract Neoplasms
Chemotherapy
Toxicity
Adjuvant Chemotherapy
Ducts
Intrahepatic Bile Ducts
Extrahepatic Bile Ducts
Febrile Neutropenia
Neutropenia
Drug-Related Side Effects and Adverse Reactions
Liver
Multicenter Studies
Urinary Bladder
Safety

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy : KHBO1003 study. / Kobayashi, Shogo; Nagano, Hiroaki; Sakai, Daisuke; Eguchi, Hidetoshi; Hatano, Etsuro; Kanai, Masashi; Seo, Satoru; Taura, Kojiro; Fujiwara, Yutaka; Ajiki, Tetsuo; Takemura, Shigekazu; Kubo, Shoji; Yanagimoto, Hiroaki; Toyokawa, Hideyoshi; Tsuji, Akihito; Terajima, Hiroaki; Morita, Satoshi; Ioka, Tatsuya.

In: Cancer chemotherapy and pharmacology, Vol. 74, No. 4, 30.07.2014, p. 699-709.

Research output: Contribution to journalArticle

Kobayashi, S, Nagano, H, Sakai, D, Eguchi, H, Hatano, E, Kanai, M, Seo, S, Taura, K, Fujiwara, Y, Ajiki, T, Takemura, S, Kubo, S, Yanagimoto, H, Toyokawa, H, Tsuji, A, Terajima, H, Morita, S & Ioka, T 2014, 'Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study', Cancer chemotherapy and pharmacology, vol. 74, no. 4, pp. 699-709. https://doi.org/10.1007/s00280-014-2543-4
Kobayashi, Shogo ; Nagano, Hiroaki ; Sakai, Daisuke ; Eguchi, Hidetoshi ; Hatano, Etsuro ; Kanai, Masashi ; Seo, Satoru ; Taura, Kojiro ; Fujiwara, Yutaka ; Ajiki, Tetsuo ; Takemura, Shigekazu ; Kubo, Shoji ; Yanagimoto, Hiroaki ; Toyokawa, Hideyoshi ; Tsuji, Akihito ; Terajima, Hiroaki ; Morita, Satoshi ; Ioka, Tatsuya. / Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy : KHBO1003 study. In: Cancer chemotherapy and pharmacology. 2014 ; Vol. 74, No. 4. pp. 699-709.
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abstract = "Background: Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy. Methods: Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800-1,000 mg/m2 gemcitabine on days 1, 8, and 15 and then every 3-4 weeks or 40-80 mg/m2/day S-1 on days 1-28 and every 3-6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm. Results: Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10 {\%} of DLT, the recommended dose was 1,000 mg/m2 gemcitabine biweekly and 80 mg/m2/day S-1 on days 1-28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted. Conclusion: We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10 {\%}.",
author = "Shogo Kobayashi and Hiroaki Nagano and Daisuke Sakai and Hidetoshi Eguchi and Etsuro Hatano and Masashi Kanai and Satoru Seo and Kojiro Taura and Yutaka Fujiwara and Tetsuo Ajiki and Shigekazu Takemura and Shoji Kubo and Hiroaki Yanagimoto and Hideyoshi Toyokawa and Akihito Tsuji and Hiroaki Terajima and Satoshi Morita and Tatsuya Ioka",
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T1 - Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy

T2 - KHBO1003 study

AU - Kobayashi, Shogo

AU - Nagano, Hiroaki

AU - Sakai, Daisuke

AU - Eguchi, Hidetoshi

AU - Hatano, Etsuro

AU - Kanai, Masashi

AU - Seo, Satoru

AU - Taura, Kojiro

AU - Fujiwara, Yutaka

AU - Ajiki, Tetsuo

AU - Takemura, Shigekazu

AU - Kubo, Shoji

AU - Yanagimoto, Hiroaki

AU - Toyokawa, Hideyoshi

AU - Tsuji, Akihito

AU - Terajima, Hiroaki

AU - Morita, Satoshi

AU - Ioka, Tatsuya

PY - 2014/7/30

Y1 - 2014/7/30

N2 - Background: Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy. Methods: Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800-1,000 mg/m2 gemcitabine on days 1, 8, and 15 and then every 3-4 weeks or 40-80 mg/m2/day S-1 on days 1-28 and every 3-6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm. Results: Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10 % of DLT, the recommended dose was 1,000 mg/m2 gemcitabine biweekly and 80 mg/m2/day S-1 on days 1-28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted. Conclusion: We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10 %.

AB - Background: Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy. Methods: Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800-1,000 mg/m2 gemcitabine on days 1, 8, and 15 and then every 3-4 weeks or 40-80 mg/m2/day S-1 on days 1-28 and every 3-6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm. Results: Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10 % of DLT, the recommended dose was 1,000 mg/m2 gemcitabine biweekly and 80 mg/m2/day S-1 on days 1-28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted. Conclusion: We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10 %.

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