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Multi-center clinical evaluation of streptozocin-based chemotherapy for advanced pancreatic neuroendocrine tumors in Japan: focus on weekly regimens and monotherapy

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Abstract

Purpose

Streptozocin (STZ) is a key agent for treating advanced pancreatic neuroendocrine tumors (pNET). Most STZ regimens for pNET are daily and also include 5-fluorouracil (5FU), whereas STZ monotherapy and weekly regimens have also been applied in daily practice in Japan. The present study aimed to evaluate responses to weekly regimens and to STZ monotherapy, and to identify a predictive marker of a response to STZ.

Methods

Clinical data regarding STZ-based chemotherapy for pNET were collected between 2015 and 2017 at 25 facilities. We analyzed the effects, safety, progression-free survival (PFS), and factors that correlate with responses to STZ.

Results

The overall objective response rate (ORR) of 110 patients who underwent STZ-based chemotherapy (monotherapy, 81.8%; weekly regimen 46.4%) was 21.8%, and PFS was 9.8 months. The ORR of weekly vs. daily regimens was 21.6 vs. 22.0% (P = 1.000), and that of monotherapy vs. combination therapy was 21.1 vs. 25.0% (P = 0.766). A Ki67 proliferation index (Ki67) of > 5% was a predictive marker of a response to STZ (P = 0.017), whereas regimen type, mono- or combination therapy, treatment line and liver tumor burden were not associated with responses. The frequencies of Grade ≥ 3 nausea and hematological adverse events were significantly lower for monotherapy than combination therapy (P = 0.032).

Conclusions

The effects of weekly STZ monotherapy on pNET are comparable to those previously reported and the toxicity profile was acceptable. Ki67 > 5% was the sole predictive marker of an objective response.

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Acknowledgements

We are grateful to Drs. Yuichi Tachibana, Nozomu Machida, and Yutaka Kawano for cooperation and helpful discussions.

Funding

This work received no outside funding.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan

    Hitoshi Shibuya, Susumu Hijioka & Kazuo Hara

  2. Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

    Hitoshi Shibuya

  3. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Susumu Hijioka, Yasunari Sakamoto & Takuji Okusaka

  4. Neuroendocrine Tumor Center, Fukuoka Sanno Hospital, Fukuoka, Japan

    Tetsuhide Ito

  5. Internal University of Health and Welfare, Fukuoka, Japan

    Tetsuhide Ito

  6. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Keijiro Ueda

  7. Department of Surgery, Kansai Electric Power Hospital, Osaka, Japan

    Izumi Komoto & Masayuki Imamura

  8. Department of Oncology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan

    Noritoshi Kobayashi

  9. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Atsushi Kudo

  10. Division of Gastroenterology and Hepatology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Hiroaki Yasuda & Hayato Miyake

  11. Hepato-Biliary and Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Junichi Arita & Sho Kiritani

  12. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan

    Masafumi Ikeda & Hiroshi Imaoka

  13. Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Kanagawa, Japan

    Makoto Ueno & Satoshi Kobayashi

  14. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan

    Mitsuhiro Furuta

  15. Department of Hepato-Biliary-Pancreatology, National Kyushu Cancer Center, Fukuoka, Japan

    Yoshikuni Nagashio

  16. Department of Gastroenterology, Seirei Hamamatsu General Hospital, Shizuoka, Japan

    Gou Murohisa

  17. Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan

    Taku Aoki

  18. Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Shigemi Matsumoto

  19. Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Masayo Motoya

  20. Department of Gastroenterology, Shikoku Cancer Center, Matsuyama, Japan

    Nobuaki Azemoto

  21. Department of Gastrointestinal, Breast and Endocrine Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan

    Jun Itakura

  22. Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama, Japan

    Shigeru Horiguchi

  23. Department of Infectious, Respiratory, and Digestive Medicine, Control and Prevention of Infectious Diseases, Faculty of Medicine, University of the Ryukyu, Okinawa, Japan

    Tatsuji Yogi

  24. Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo, Japan

    Tetsuro Kawagoe

  25. Department of Endoscopy, Shimane Prefectural Central Hospital, Shimane, Japan

    Youichi Miyaoka

  26. Hitachi, Ltd., Hitachinaka General Hospital, Ibaraki, Japan

    Fumito Imamura

  27. Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

    Michio Senju

  28. Department of Medical Oncology, Yokohama Rosai Hospital, Kanagawa, Japan

    Hitoshi Arioka

Authors
  1. Hitoshi Shibuya
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  2. Susumu Hijioka
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  3. Yasunari Sakamoto
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  4. Tetsuhide Ito
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  5. Keijiro Ueda
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  6. Izumi Komoto
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  7. Noritoshi Kobayashi
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  8. Atsushi Kudo
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  9. Hiroaki Yasuda
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  10. Hayato Miyake
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  11. Junichi Arita
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  12. Sho Kiritani
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  13. Masafumi Ikeda
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  15. Makoto Ueno
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  18. Yoshikuni Nagashio
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  20. Taku Aoki
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  21. Shigemi Matsumoto
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  29. Fumito Imamura
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  30. Michio Senju
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  31. Hitoshi Arioka
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  32. Kazuo Hara
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  33. Masayuki Imamura
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  34. Takuji Okusaka
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Corresponding author

Correspondence to Susumu Hijioka.

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Conflict of interest

Author Masafumi Ikeda has received research grants from Ono Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Merck Serono, Yakult, Kyowa Hakko Kirin, Eisai, Eli Lilly Japan, Baxter, ASLAN Pharmaceuticals, Chugai Pharmaceutical; speaker honoraria from Bayer Yakuhin, Taiho Pharmaceutical, Novartis Pharma, Bristol-Myers Squibb, Eli Lilly Japan. Author Susumu Hijioka has received speaker honoraria from Novelpharma, Novartis Pharma and Teijin Pharma. Author Hiroshi Imaoka has received a speaker honorarium from Novartis Pharma. The other authors have no conflicts of interest to declare.

Ethical approval

All procedures involving human participants proceeded in accordance with the ethical standards of each institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Formal consent is not required for this type of study.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Shibuya, H., Hijioka, S., Sakamoto, Y. et al. Multi-center clinical evaluation of streptozocin-based chemotherapy for advanced pancreatic neuroendocrine tumors in Japan: focus on weekly regimens and monotherapy. Cancer Chemother Pharmacol 82, 661–668 (2018). https://doi.org/10.1007/s00280-018-3656-y

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  • DOI: https://doi.org/10.1007/s00280-018-3656-y

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