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

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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 %.

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Abbreviations

BTC:

Biliary tract cancer

CA19-9:

Carbohydrate antigen 19-9

CEA:

Carcinoembryonic antigen

CRM:

Continual reassessment method

CTCAE:

Common toxicity criteria adverse events

DLT:

Dose-limited toxicity

IDSMC:

Independent data and safety monitoring committee

KHBO:

Kansai hepato-biliary oncology group

RD:

Recommended dose

ULN:

Upper limit of normal

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Acknowledgments

We are grateful to Professor Michiaki Unno, Department of Surgery, Tohoku University, and Professor Minoru Takada, Department of Medical Oncology, Sakai Hospital, Kinki University, who served as the Independent Data and Safety Monitoring Committee (IDSMC). The authors acknowledge all physicians for their contribution to this research, Ms. Masami Kashibou and Ms. Hiromi Oura for their data management, and the Independent Data Center. Other KHBO affiliations (authors not included): Kyoto Prefectural University of Medicine, Kyoto Prefectural Yosanoumi Hospital, National Hospital Organization Kyoto Medical Center, National Hospital Organization Osaka National Hospital, Osaka City General Hospital, and Osaka Medical College. This work was funded by Independent Research and Development.

Conflict of interest

Tatsuya Ioka received research funding from Yakult Honsha, Taiho Pharmaceutical Co. Akihito Tsuji received a lecture fee from Taiho Pharmaceutical Co. All remaining authors have no conflict of interests to declare.

Author information

Authors and Affiliations

  1. Department of Surgery, Graduate School of Medicine, Osaka University, Suita, Japan

    Shogo Kobayashi, Hiroaki Nagano, Daisuke Sakai & Hidetoshi Eguchi

  2. Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

    Shogo Kobayashi

  3. Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Japan

    Daisuke Sakai

  4. Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Etsuro Hatano, Satoru Seo & Kojiro Taura

  5. Department of Clinical Oncology and Pharmacogenomics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Masashi Kanai

  6. Division of Medical Oncology/Hematology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

    Yutaka Fujiwara

  7. Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan

    Yutaka Fujiwara

  8. Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan

    Tetsuo Ajiki

  9. Department of Hepato-biliary Pancreatic Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Shigekazu Takemura & Shoji Kubo

  10. Department of Surgery, Kansai Medical University, Hirakata, Japan

    Hiroaki Yanagimoto & Hideyoshi Toyokawa

  11. Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan

    Akihito Tsuji

  12. Department of Gastroenterological Surgery and Oncology, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Osaka, Japan

    Hiroaki Terajima

  13. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Satoshi Morita

  14. Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

    Tatsuya Ioka

  15. Kansai Hepato-Biliary Oncology Group, Osaka, Japan

    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

Authors
  1. Shogo Kobayashi
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Corresponding author

Correspondence to Shogo Kobayashi.

Additional information

Trail reregistration ClinicalTrials.gov NCT01291615 and UMIN-CTR UMIN000004682.

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Kobayashi, S., Nagano, H., Sakai, D. et al. Phase I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study. Cancer Chemother Pharmacol 74, 699–709 (2014). https://doi.org/10.1007/s00280-014-2543-4

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  • DOI: https://doi.org/10.1007/s00280-014-2543-4

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