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Phase I trial of oral S-1 combined with hepatic arterial infusion of gemcitabine in unresectable biliary tract cancer

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Abstract

Purpose

S-1 and gemcitabine (GS) combination therapy is a promising treatment for advanced biliary tract cancer (BTC). However, systemic administration of GS is associated with a high rate of grade 3 and 4 neutropenia. Hepatic arterial infusion (HAI) of gemcitabine may overcome this problem. We conducted a prospective phase 1 trial to determine the maximum tolerated dose (MTD) of S-1 and rates of dose-limiting toxicities (DLTs) associated with HAI of gemcitabine in patients with unresectable BTC.

Methods

BTC patients were treated with 21-day cycles of HAI of gemcitabine (1000 mg/m2 on days 1 and 8) and oral S-1 (60, 70, or 80 mg/m2 on days 1–14) until disease progression occurred.

Results

Fifteen patients were enrolled in the study. Grade 3 and 4 neutropenia occurred in five of 15 (33 %) patients. Among six patients who were treated with 60 mg/m2 S-1, one developed grade 4 neutropenia. DLTs (grade 4 neutropenia and bladder infection) occurred in two of six patients who were treated with 70 mg/m2 S-1. Two of the three patients who were treated with 80 mg/m2 S-1 experienced DLTs (grade 4 leukopenia and neutropenia and grade 3 febrile neutropenia). Thus, 80 mg/m2 was defined as the MTD of S-1.

Conclusion

The MTD of oral S-1 in GS therapy is 80 mg/m2. Furthermore, HAI of gemcitabine may reduce the rate of grade 3 and 4 neutropenia in BTC patients receiving GS therapy.

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Acknowledgments

We would like to thank Drs. Yutaka Okagawa, Wataru Jomen, and Ikumi Umeda for their assistance with data collection.

Conflict of interest

There are no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543, Japan

    Hirotoshi Ishiwatari, Tsuyoshi Hayashi, Makoto Yoshida, Michihiro Ono, Tsutomu Sato, Koji Miyanishi, Yasushi Sato, Rishu Takimoto, Masayoshi Kobune & Junji Kato

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  1. Hirotoshi Ishiwatari
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  2. Tsuyoshi Hayashi
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  3. Makoto Yoshida
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  7. Yasushi Sato
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Correspondence to Hirotoshi Ishiwatari.

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Ishiwatari, H., Hayashi, T., Yoshida, M. et al. Phase I trial of oral S-1 combined with hepatic arterial infusion of gemcitabine in unresectable biliary tract cancer. Cancer Chemother Pharmacol 75, 805–812 (2015). https://doi.org/10.1007/s00280-015-2704-0

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