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



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.


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).


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).


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


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)


  1. 1.
    Fuchs CS, Marshall J, Mitchell E et al (2007) Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol 25:4779–4786PubMedCrossRefGoogle Scholar
  2. 2.
    Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRefGoogle Scholar
  3. 3.
    Tournigand C, Andre T, Achille E et al (2004) FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 22:229–237PubMedCrossRefGoogle Scholar
  4. 4.
    Van Cutsem E, Kohne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417PubMedCrossRefGoogle Scholar
  5. 5.
    Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664PubMedCrossRefGoogle Scholar
  6. 6.
    Andre T, Boni C, Mounedji-Boudiaf L et al (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351PubMedCrossRefGoogle Scholar
  7. 7.
    Tournigand C, Cervantes A, Figer A et al (2006) OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer––a GERCOR study. J Clin Oncol 24:394–400PubMedCrossRefGoogle Scholar
  8. 8.
    Wen F, Zhou Y, Wang W et al (2013) Ca/Mg infusions for the prevention of oxaliplatin-related neurotoxicity in patients with colorectal cancer: a meta-analysis. Ann Oncol 24:171–178PubMedCrossRefGoogle Scholar
  9. 9.
    Gamelin L, Boisdron-Celle M, Delva R et al (2004) Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res 10:4055–4061Google Scholar
  10. 10.
    Gamelin L, Boisdron-Celle M, Morel A et al (2008) Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol 26:1188–1189 (author reply 1189–1190)PubMedCrossRefGoogle Scholar
  11. 11.
    Von Delius S, Eckel F, Wagenpfeil S et al (2007) Carbamazepine for prevention of oxaliplatin-related neurotoxicity in patients with advanced colorectal cancer: final results of a randomised, controlled, multicenter phase II study. Invest New Drugs 25:173–180CrossRefGoogle Scholar
  12. 12.
    Milla P, Airoldi M, Weber G et al (2009) Administration of reduced glutathione in FOLFOX4 adjuvant treatment for colorectal cancer: effect on oxaliplatin pharmacokinetics, Pt-DNA adduct formation, and neurotoxicity. Anticancer Drugs 20:396–402PubMedCrossRefGoogle Scholar
  13. 13.
    Tawata M, Kurihara A, Nitta K et al (1994) The effects of goshajinkigan, a herbal medicine, on subjective symptoms and vibratory threshold in patients with diabetic neuropathy. Diabetes Res Clin Pract 26:121–128PubMedCrossRefGoogle Scholar
  14. 14.
    Qin B, Nagasaki M, Ren M et al (2004) Gosha-jinki-gan (a herbal complex) corrects abnormal insulin signaling. Evid Based Complement Altern Med 1:269–276CrossRefGoogle Scholar
  15. 15.
    Imamura T, Ishizuka O, Aizawa N et al (2008) Gosha-jinki-gan reduces transmitter proteins and sensory receptors associated with C fiber activation induced by acetic acid in rat urinary bladder. Neurourol Urodyn 27:832–837PubMedCrossRefGoogle Scholar
  16. 16.
    Nishizawa M, Sutherland WH, Nukada H (1995) Gosha-jinki-gan (herbal medicine) in streptozocin-induced diabetic neuropathy. J Neurol Sci 132:177–181PubMedCrossRefGoogle Scholar
  17. 17.
    Kaku H, Kumagai S, Onoue H et al (2012) Objective evaluation of the alleviating effects of goshajinkigan on peripheral neuropathy induced by paclitaxel/carboplatin therapy: a multicenter collaborative study. Exp Ther Med 3:60–65PubMedCentralPubMedGoogle Scholar
  18. 18.
    Ushio S, Egashira N, Sada H et al (2012) Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents. Eur J Cancer 48:1407–1413PubMedCrossRefGoogle Scholar
  19. 19.
    Kono T, Mamiya N, Chisato N et al (2011) Efficacy of goshajinkigan for peripheral neurotoxicity of oxaliplatin in patients with advanced or recurrent colorectal cancer. Evid Based Complement Altern Med 2011:418481CrossRefGoogle Scholar
  20. 20.
    Japanese Society for Cancer of the Colon and Rectum (2009) Japanese Classification of Colorectal Carcinoma, 7th edn. Kanehara & Co., Ltd., TokyoGoogle Scholar
  21. 21.
    Inoue N, Ishida H, Sano M et al (2012) Discrepancy between the NCI-CTCAE and DEB-NTC scales in the evaluation of oxaliplatin-related neurotoxicity in patients with metastatic colorectal cancer. Int J Clin Oncol 17:341–347PubMedCrossRefGoogle Scholar
  22. 22.
    Sakurai M, Egashira N, Kawashiri T et al (2009) Oxaliplatin-induced neuropathy in the rat: involvement of oxalate in cold hyperalgesia but not mechanical allodynia. Pain 147:165–174PubMedCrossRefGoogle Scholar
  23. 23.
    Wu Z, Ouyang J, He Z et al (2012) Infusion of calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in colorectal cancer: a systematic review and meta-analysis. Eur J Cancer 48:1791–1798PubMedCrossRefGoogle Scholar
  24. 24.
    Grothey A, Nikcevich DA, Sloan JA et al (2011) Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol 29:421–427PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Loprinzi CL, Qin R, Dakhil SR et al (2014) Phase III randomized, placebo-controlled, double-blind study of intravenous calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (N08CB/Alliance). J Clin Oncol 32:997–1005PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Uno T, Ohsawa I, Tokudome M et al (2005) Effects of goshajinkigan on insulin resistance in patients with type 2 diabetes. Diabetes Res Clin Pract 69:129–135PubMedCrossRefGoogle Scholar
  27. 27.
    Usuki Y, Usuki S, Hommura S (1991) Successful treatment of a senile diabetic woman with cataract with goshajinkigan. Am J Chin Med 19:259–263PubMedCrossRefGoogle Scholar
  28. 28.
    Mizuno K, Kono T, Suzuki Y et al (2014) Goshajinkigan, a traditional Japanese medicine, prevents oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels in rat. J Pharmacol Sci 125(1):91–98PubMedCrossRefGoogle Scholar
  29. 29.
    Kono T, Mishima H, Shimada M et al (2009) Preventive effect of goshajinkigan on peripheral neurotoxicity of FOLFOX therapy: a placebo-controlled double-blind randomized phase II study (the GONE Study). Jpn J Clin Oncol 39:847–849PubMedCrossRefGoogle Scholar
  30. 30.
    Hochster HS, Grothey A, Childs BH (2007) Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol 25:4028–4029PubMedCrossRefGoogle Scholar

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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