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A phase I study for adjuvant chemotherapy of gemcitabine plus S-1 in patients with biliary tract cancer undergoing curative resection without major hepatectomy (KHBO1202)

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Abstract

Purpose

To determine the recommended dose (RD) of gemcitabine (GEM) plus S-1 (GS) in curatively resected biliary tract cancer (BTC) patients without major hepatectomy.

Methods

A standard 3 + 3 dose-escalation design was used with planned dose levels (mg/m2) of GEM (administered intravenously on days 1 and 8) and S-1 (administered orally twice daily on days 1–14, with a 1-week rest, every 3 weeks for up to 24 weeks) of 1000/80 (Level 2), 1000/65 (Level 1), 800/65 (Level − 1), and 800/50 (Level − 2).

Results

Thirty-one patients (17 men and 14 women; median age, 70 years) were enrolled. Level 1 was chosen as the starting dose. Three of seven patients developed dose-limiting toxicities at Level 1 and the dose was de-escalated to Level − 1. Five of 12 patients developed Grade 4 neutropenia at Level − 1 and the dose was de-escalated to Level − 2. One patient developed Grade 4 neutropenia at Level − 2. Another patient was unable to receive the day 8 dose due to Grade 3 neutropenia at Level − 2. Level − 1 was confirmed as the maximum tolerated dose and Level − 2 the RD for this regimen. The 1- and 2-year recurrence-free survival rates were 77.0 and 54.0%, respectively. The recurrence-free survival rate of patients in the GS completion group was significantly higher than that of the GS discontinuation group.

Conclusions

Level − 2 was confirmed as the RD (GEM 800 mg/m2 and S-1 50 mg/m2) for GS adjuvant chemotherapy in curatively resected BTC patients without major hepatectomy.

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Acknowledgements

Acknowledgments we thank all the people related to this study, patients, caregivers, physicians, medical workers, data manager, Ms. Masami Kashibou for data management. This work was Independent Research and Development.

Funding

No funding was received for this work.

Author information

Authors and Affiliations

  1. Department of Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, 573-1010, Japan

    Hiroaki Yanagimoto, Hideyoshi Toyokawa, Sohei Satoi & Tomohisa Yamamoto

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

    Daisuke Sakai

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

    Hiroshi Wada & Hiroaki Nagano

  4. Department of Digestive Surgery and Surgical Oncology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan

    Hiroaki Nagano

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

    Masanori Toyoda

  6. Division of Hepato‑Biliary‑Pancreatic Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Kobe, Japan

    Tetsuo Ajiki

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

    Hironaga Satake

  8. Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Akihito Tsuji

  9. Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan

    Atsushi Miyamoto

  10. Department of Gastroenterological Surgery, Kindai University Nara Hospital, Ikoma, Japan

    Masanori Tsujie

  11. Department of Hepatobiliary Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan

    Shigekazu Takemura

  12. Department of Medical Oncology, Kansai Electric Power Hospital, Osaka, Japan

    Kazuhiro Yanagihara

  13. Department of Clinical Oncology, Kansai Electric Power Medical Research Institute, Osaka, Japan

    Kazuhiro Yanagihara

  14. Department of Cancer Survey and Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan

    Tatsuya Ioka

  15. Kansai Hepato-Biliary Oncology Group (KHBO), Osaka, Japan

    Hiroaki Yanagimoto, Hideyoshi Toyokawa, Daisuke Sakai, Hiroshi Wada, Sohei Satoi, Tomohisa Yamamoto, Hiroaki Nagano, Masanori Toyoda, Tetsuo Ajiki, Hironaga Satake, Akihito Tsuji, Atsushi Miyamoto, Masanori Tsujie, Shigekazu Takemura, Kazuhiro Yanagihara & Tatsuya Ioka

Authors
  1. Hiroaki Yanagimoto
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  2. Hideyoshi Toyokawa
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  6. Tomohisa Yamamoto
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  7. Hiroaki Nagano
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  8. Masanori Toyoda
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  9. Tetsuo Ajiki
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  11. Akihito Tsuji
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  12. Atsushi Miyamoto
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  13. Masanori Tsujie
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  14. Shigekazu Takemura
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  15. Kazuhiro Yanagihara
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  16. Tatsuya Ioka
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Corresponding author

Correspondence to Hiroaki Yanagimoto.

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Conflict of interest

Tatsuya Ioka received research funding from Taiho Pharmaceutical Co. All remaining authors declare that they have no conflict of interest.

Human and animal rights

This article does not contain any studieswith animals performed by any of the authors.

Ethical approval

All procedures performed in studies involvinghuman participants were in accordance with the ethical standards ofthe institutional research committee and with the 1964 Declaration ofHelsinki and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from allstudy participants.

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Yanagimoto, H., Toyokawa, H., Sakai, D. et al. A phase I study for adjuvant chemotherapy of gemcitabine plus S-1 in patients with biliary tract cancer undergoing curative resection without major hepatectomy (KHBO1202). Cancer Chemother Pharmacol 81, 461–468 (2018). https://doi.org/10.1007/s00280-017-3513-4

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  • DOI: https://doi.org/10.1007/s00280-017-3513-4

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