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Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): a placebo-controlled, double-blind, randomized phase III study

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Abstract

Background

Peripheral sensory neurotoxicity is a frequent adverse effect of oxaliplatin therapy. Calcium and magnesium (Ca/Mg) infusions are frequently used as preventatives, but a recent phase III trial failed to show that they prevent neurotoxicity. We therefore conducted a multicenter randomized phase III trial to compare fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with and without Goshajinkigan (GJG), a traditional Japanese herbal medicine (Kampo), to determine GJG’s potential for reducing peripheral neuropathy in patients with colorectal cancer.

Methods

Patients with colon cancer who were undergoing adjuvant therapy with infusional mFOLFOX6 were randomly assigned to GJG (7.5 mg three times daily) or placebo in a double-blind manner. The primary endpoint was the time to grade 2 or greater neuropathy, which was determined at any point during or after oxaliplatin-based therapy using version 3 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

Findings

An interim analysis was performed when 142 of the planned 310 patients had been enrolled and the safety assessment committee recommended that the study be discontinued. One hundred eighty-two patients were evaluable for response. They included 89 patients in the GJG group and 93 patients in the placebo group. The incidence of grade 2 or greater neurotoxicity was 50.6 % in the GJG group and 31.2 % in the placebo group. A Cox proportional hazards analysis indicated that the use of GJG was significantly associated with the incidence of neuropathy (hazard ratio, 1.908; p = 0.007).

Conclusion

Goshajinkigan did not prevent oxaliplatin-associated peripheral neuropathy in this clinical trial. The clinical study was therefore terminated.

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Acknowledgments

We thank all patients who participated in this trial and their families. We are indebted to the physicians and all clinical study teams at the participating institutions. The following departments and hospitals participated in the trial: Department of Surgery and Science, Kyuhsu University (Fukuoka, Japan); Department of Surgery, Saiseikai Fukuoka General Hospital (Fukuoka, Japan); Department of Surgery, Minoh City Hospital, Minoh, Japan; Department of Gastroenterological Surgery, Aichi Cancer Center, Aichi Hospital (Nagoya, Japan);Division of Lower GI Department of Surgery, Hyogo College of Medicine (Nishinomiya, Japan); Department of Surgery, Kitasato University School of Medicine (Kanagawa, Japan); Kochi University Department of Surgery (Nankoku, Japan); Department of Surgery, Kurume University Medical Center (Kurume, Japan); Division of Gastroenterological Surgery, Chiba Cancer Center (Chiba, Japan); Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University (Kumamoto, Japan); Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University (Kagoshima, Japan); Department of Surgery, Aomori Prefectural Central Hospital (Aomori City, Japan); Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences (Nagasaki, Japan); Department of Surgery, University of Tokushima (Tokushima, Japan); Asahikawa Medical University Hospital (Asahikawa, Japan); Department of Surgery, Gifu Municipal Hospital (Gifu, Japan); Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine (Nagoya, Japan); Department of Surgery I, Dokkyo University School of Medicine (Shimotsuga, Japan); Department of Gastroenterological Surgery, Kyushu National Medical Center (Fukuoka, Japan); Japanese Red Cross Kanazawa Hospital (Kanazawa, Japan); First Department of Surgery, University of Fukui (Fukui, Japan); Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University (Osaka, Japan); First Department of Surgery, Ryukyu University, School of Medicine (Okinawa, Japan); Aichi Cancer Center Aichi Hospital; Department of Surgery, Fujita Health University (Toyoake, Japan); Department of General Surgery, Kawasaki Medical School (Okayama, Japan); Department of Surgical Oncology and Gastroenterological Surgery, Sapporo Medical University (Sapporo, Japan); Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science (Okayama, Japan); Department of Surgical Oncology, Gifu University Graduate School of Medicine (Gifu, Japan); Hamamatsu University School of Medicine (Shizuoka, Japan); Department of Surgery, Kyoto University Graduate School of Medicine (Kyoto, Japan); Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine (Hirosaki, Japan); Osaka Medical　College (Osaka, Japan); Department of Surgery, Kansai Medical University (Osaka, Japan); Nihon University Itabashi Hospital (Tokyo, Japan); Kanazawa Medical University, Department of Surgical Oncology (Ishikawa, Japan); Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical School (Saitama, Japan); Kansai Rosai Hospital (Amagasaki, Japan); Department of Gastrointestinal Surgery, Kobe University (Kobe, Japan). This clinical trial was totally supported by a Ministry of Health, Labour and Welfare Grant-in-Aid for Scientific Research in Japan (Tokyo, Japan). We also thank Ms. Satomi Abe and Ms. Masako Yamashita from the Kyushu University Data Center and the EPS Corporation (Tokyo, Japan) for their excellent secretarial assistance.

Conflict of interest

Yoshihiko Maehara received a research grant from Yakult Honsha and Tsumura & Co.; Toru Kono received a research Grant from Tsumura & Co; Eiji Oki and Takeshi Kato received lecture fees from Yakult Honsha; the other authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

    Eiji Oki, Hiroshi Saeki, Ken Shirabe & Yoshihiko Maehara

  2. Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan

    Yasunori Emi

  3. Department of Gastroenterological Surgery, Aichi Cancer Center Aichi Hospital, Nagoya, Japan

    Hiroshi Kojima

  4. Department of Digestive and Pediatric Surgery, Faculty of Medicine, University of Tokushima, Tokushima, Japan

    Jun Higashijima

  5. Department of Surgery, Kansai Rosai Hospital, Amagasaki, Japan

    Takeshi Kato

  6. Department of Surgery, Minoh City Hospital, Minoh, Japan

    Yasuhiro Miyake

  7. Department of Surgery, Kansai Medical University, Osaka, Japan

    Masanori Kon

  8. Department of Surgery, Kurume University Medical Center, Kurume, Japan

    Yutaka Ogata

  9. Department of Surgery, Aomori Prefectural Central Hospital, Aomori, Japan

    Kenichi Takahashi

  10. Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical School, Saitama, Japan

    Hideyuki Ishida

  11. Department of Gastroenterological Surgery, Kyushu National Medical Center, Fukuoka, Japan

    Yoshihisa Sakaguchi

  12. Department of Biostatistics, Yokohama City University, Yokohama, Japan

    Takeharu Yamanaka

  13. Sapporo Higashi Tokushukai Hospital, Sapporo, Japan

    Toru Kono

  14. Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan

    Naohiro Tomita

  15. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Hideo Baba

  16. Department of Gastrointestinal Surgery, Kobe University, Kobe, Japan

    Yoshihiro Kakeji

Authors
  1. Eiji Oki
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  2. Yasunori Emi
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  3. Hiroshi Kojima
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  4. Jun Higashijima
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  6. Yasuhiro Miyake
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  7. Masanori Kon
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  8. Yutaka Ogata
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  9. Kenichi Takahashi
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  10. Hideyuki Ishida
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  11. Hiroshi Saeki
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  12. Yoshihisa Sakaguchi
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  13. Takeharu Yamanaka
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  14. Toru Kono
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  15. Naohiro Tomita
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  16. Hideo Baba
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  17. Ken Shirabe
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  18. Yoshihiro Kakeji
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  19. Yoshihiko Maehara
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Corresponding author

Correspondence to Yoshihiko Maehara.

Electronic supplementary material

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10147_2015_784_MOESM1_ESM.pptx

Supplementary material 1. Time to grade 2 or greater sensory neuropathy (TTN), as measured according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3.0) and the Neurotoxicity Criteria of Debiopharm (DEB-NTC).

Fig. S1. A and B are the findings from the interim analysis. C and D are the findings from the final analysis. The black and dotted lines represent the Goshajinkigan (GJG) group and the placebo group, respectively

Fig. S2. A Time to grade 1 sensory neuropathy, reported by course. B Time to grade 2 sensory neuropathy, reported by course. C Time to grade 3 sensory neuropathy, reported by course. (PPTX 145 kb)

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Oki, E., Emi, Y., Kojima, H. et al. Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): a placebo-controlled, double-blind, randomized phase III study. Int J Clin Oncol 20, 767–775 (2015). https://doi.org/10.1007/s10147-015-0784-9

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  • DOI: https://doi.org/10.1007/s10147-015-0784-9

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