International Journal of Clinical Oncology

, Volume 20, Issue 4, pp 767–775

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

  • Eiji Oki
  • Yasunori Emi
  • Hiroshi Kojima
  • Jun Higashijima
  • Takeshi Kato
  • Yasuhiro Miyake
  • Masanori Kon
  • Yutaka Ogata
  • Kenichi Takahashi
  • Hideyuki Ishida
  • Hiroshi Saeki
  • Yoshihisa Sakaguchi
  • Takeharu Yamanaka
  • Toru Kono
  • Naohiro Tomita
  • Hideo Baba
  • Ken Shirabe
  • Yoshihiro Kakeji
  • Yoshihiko Maehara
Original Article

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.

Keywords

Adjuvant chemotherapy Colon cancer Colorectal cancer Goshajinkigan Herbal medicine, Kampo Peripheral neuropathy 

Supplementary material

10147_2015_784_MOESM1_ESM.pptx (146 kb)
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, respectivelyFig. 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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Copyright information

© Japan Society of Clinical Oncology 2015

Authors and Affiliations

  • Eiji Oki
    • 1
  • Yasunori Emi
    • 2
  • Hiroshi Kojima
    • 3
  • Jun Higashijima
    • 4
  • Takeshi Kato
    • 5
  • Yasuhiro Miyake
    • 6
  • Masanori Kon
    • 7
  • Yutaka Ogata
    • 8
  • Kenichi Takahashi
    • 9
  • Hideyuki Ishida
    • 10
  • Hiroshi Saeki
    • 1
  • Yoshihisa Sakaguchi
    • 11
  • Takeharu Yamanaka
    • 12
  • Toru Kono
    • 13
  • Naohiro Tomita
    • 14
  • Hideo Baba
    • 15
  • Ken Shirabe
    • 1
  • Yoshihiro Kakeji
    • 16
  • Yoshihiko Maehara
    • 1
  1. 1.Department of Surgery and Science, Graduate School of Medical ScienceKyushu UniversityFukuokaJapan
  2. 2.Department of SurgerySaiseikai Fukuoka General HospitalFukuokaJapan
  3. 3.Department of Gastroenterological SurgeryAichi Cancer Center Aichi HospitalNagoyaJapan
  4. 4.Department of Digestive and Pediatric Surgery, Faculty of MedicineUniversity of TokushimaTokushimaJapan
  5. 5.Department of SurgeryKansai Rosai HospitalAmagasakiJapan
  6. 6.Department of SurgeryMinoh City HospitalMinohJapan
  7. 7.Department of SurgeryKansai Medical UniversityOsakaJapan
  8. 8.Department of SurgeryKurume University Medical CenterKurumeJapan
  9. 9.Department of SurgeryAomori Prefectural Central HospitalAomoriJapan
  10. 10.Department of Digestive Tract and General Surgery, Saitama Medical CenterSaitama Medical SchoolSaitamaJapan
  11. 11.Department of Gastroenterological SurgeryKyushu National Medical CenterFukuokaJapan
  12. 12.Department of BiostatisticsYokohama City UniversityYokohamaJapan
  13. 13.Sapporo Higashi Tokushukai HospitalSapporoJapan
  14. 14.Department of SurgeryHyogo College of MedicineNishinomiyaJapan
  15. 15.Department of Gastroenterological Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
  16. 16.Department of Gastrointestinal SurgeryKobe UniversityKobeJapan

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