International Journal of Colorectal Disease

, Volume 27, Issue 12, pp 1645–1650 | Cite as

Neuroprotective effect of neurotropin on chronic oxaliplatin-induced neurotoxicity in stage II and stage III colorectal cancer patients: results from a prospective, randomised, single-centre, pilot clinical trial

Original Article



Oxaliplatin is effective in adjuvant and first-line colorectal cancer chemotherapy. Oxaliplatin-induced severe chronic neurotoxicity is the main dose-limiting adverse event. No standard treatment for oxaliplatin-induced chronic neurotoxicity has been identified.

Materials and methods

We conducted a prospective pilot clinical trial to explore whether neurotropin has neuroprotective effects on chronic neurotoxicity. From May 1, 2010 to May 1, 2011, 80 stage II and III colorectal cancer patients who were eligible to receive oxaliplatin-based chemotherapy voluntarily enrolled in the trial. The patients were randomly divided into two groups, one of which received neurotropin treatment.


The patients in the control group experienced significantly ≥ grade 2 and ≥ grade 3 neurotoxicity (by NCI CTCAE grading) than those in the neurotropin group (60.9 vs. 21.1 %, for at least grade 2 neurotoxicity, P = 0.001; 39 vs. 2.7 %, for at least grade 3 neurotoxicity, P < 0.001). If neurotoxicity was assessed by oxaliplatin-specific neurotoxicity grading, the patients in the control group also experienced significantly more ≥ grade 2 neurotoxicity (51.2 vs. 12.5 %, P = 0.001). Neurotropin was the only factor that affected the incidence of ≥ grade 2 neurotoxicity in the multivariate Cox proportional hazards regression analysis.


Neurotropin combined with oxaliplatin decreases chronic neurotoxicity effectively and safely.


Adverse event Oxaliplatin Management Neurotoxicity Neurotropin 



We are grateful to Dr. Zhi-Heng Peng and Dr. Wen-Hua Fan for collecting data. This study was supported by the Chinese Society of Clinical Oncology Research Funding.


  1. 1.
    Jemal A, Siegel R, Ward E et al (2008) Cancer statistics. CA Cancer J Clin 58:71–96PubMedCrossRefGoogle Scholar
  2. 2.
    Rixe O, Ortuzar W, Alvarez M et al (1996) Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute's anticancer drug screen panel. Biochem Pharmacol 52:1855–1865PubMedCrossRefGoogle Scholar
  3. 3.
    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
  4. 4.
    De Gramont A, Figer A, Seymour M et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947PubMedGoogle Scholar
  5. 5.
    Schmoll H-J, Cartwright T, Tabernero J et al (2007) Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol 25:102–108PubMedCrossRefGoogle Scholar
  6. 6.
    Kweekel DM, Gelderblom H, Guchelaar HJ (2005) Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy. Cancer Treat Rev 31:90–105PubMedCrossRefGoogle 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.
    Wang W-S, Lin J-K et al (2007) Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist 12:312–319PubMedCrossRefGoogle Scholar
  9. 9.
    Extra JM, Marty M, Brienza S et al (1998) Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol 25:13–22PubMedGoogle Scholar
  10. 10.
    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 10:4055–4061PubMedCrossRefGoogle Scholar
  11. 11.
    Lersch C, Schmelz R, Eckel F et al (2002) Prevention of oxaliplatin-induced peripheral sensory neuropathy by carbamazepine in patients with advanced colorectal cancer. Clin Colorectal Cancer 2:54–58PubMedCrossRefGoogle Scholar
  12. 12.
    Penz M, Kornek GV, Raderer M (2001) Subcutaneous administration of amifostine: a promising therapeutic option in patients with oxaliplatin-related peripheral sensitive neuropathy. Ann Oncol 12:421–422PubMedCrossRefGoogle Scholar
  13. 13.
    Cascinu S, Catalano V, Cordella L et al (2002) Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 20:3478–3483PubMedCrossRefGoogle Scholar
  14. 14.
    Kawashiri T, Egashira N, Watanabe H, Ikegami Y, Hirakawa S, Mihara Y, Yano T, Ikesue H, Oishi R (2011) Prevention of oxaliplatin-induced mechanical allodynia and neurodegeneration by neurotropin in the rat model. Eur J Pain 15(4):344–50PubMedCrossRefGoogle Scholar
  15. 15.
    Gamelin E, Gamelin L, Bossi L, Quasthoff S (2002) Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures. Semin Oncol 29:21–33PubMedCrossRefGoogle Scholar
  16. 16.
    Extra JM, Espie M, Calvo F, Ferme C, Mignot L, Marty M (1990) Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 25:299–303PubMedCrossRefGoogle Scholar
  17. 17.
    Torbersen T, Stalberg E, Brautaset NJ (1996) Generator sites for spontaneous activity in neuromyotonia. An EMG study. Electroencephalogr Clin Neurophysiol 101:69–98CrossRefGoogle Scholar
  18. 18.
    Van Dijk JG, Lammers GJ, Wintzen AR, Molenaar PC (1996) Repetitive CMAPs: mechanisms of neural and synaptic genesis. Muscle Nerve 19:1127–1133PubMedCrossRefGoogle Scholar
  19. 19.
    Vincent A, Beeson D, Lang B (2000) Molecular targets for autoimmune and genetic disorders of neuromuscular transmission. Eur J Biochem 267:6717–6728PubMedCrossRefGoogle Scholar
  20. 20.
    Adelsberger H, Quasthoff S, Grosskreutz J, Lepier A, Eckel F, Lersch C (2000) The chemotherapeutic oxaliplatin alters voltage-gated Na-channel kinetics on rat sensory neurons. Eur J Pharmacol 406:25–32PubMedCrossRefGoogle Scholar
  21. 21.
    Wilson RH, Lehky T, Thomas RR, Quinn MG, Floeter MK, Grem JL (2002) Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 20:1767–1774PubMedCrossRefGoogle Scholar
  22. 22.
    Hartmann JT, Lipp HP (2003) Toxicity of platinum compounds. Expert Opin Pharmacother 4:889–901PubMedCrossRefGoogle Scholar
  23. 23.
    Lahrmann H, Albrecht G, Drlicek M, Oberndorfer S, Urbanits S, Wanschitz J, Zifko UA, Grisold W (2001) Acquired neuromyotonia and peripheral neuropathy in a patient with Hodgkin's disease. Muscle Nerve 24:834–838PubMedCrossRefGoogle Scholar
  24. 24.
    Bai J, Nakamura H, Kwon YW et al (2003) Critical roles of thioredoxin in nerve growth factor-mediated signal transduction and neurite outgrowth in PC12 cells. J Neurosci 23:503–9PubMedGoogle Scholar
  25. 25.
    Price SA, Gardiner NJ, Duran-Jimenez B, Zeef LA, Obrosova IG, Tomlinson DR (2006) Thioredoxin interacting protein is increased in sensory neurons in experimental diabetes. Brain Res 1116:206–14PubMedCrossRefGoogle Scholar
  26. 26.
    Kawashiri T, Egashira N, Itoh Y et al (2009) Neurotropin reverses paclitaxel-induced neuropathy without affecting anti-tumour efficacy. Eur J Cancer 45:154–163PubMedCrossRefGoogle Scholar
  27. 27.
    Baek KK, Lee J, Park SH, Park JO et al (2010) Oxaliplatin-induced chronic peripheral neurotoxicity: a prospective analysis in patients with colorectal cancer. Cancer Res Treat 42(4):185–90PubMedCrossRefGoogle Scholar
  28. 28.
    Kato K, Inaba Y, Tsuji Y et al (2011) A multicenter phase-II study of 5-FU, leucovorin and oxaliplatin (FOLFOX6) in patients with pretreated metastatic colorectal cancer. Jpn J Clin Oncol 41(1):63–8PubMedCrossRefGoogle Scholar
  29. 29.
    Axel Grothey, Nikcevich DA (2011) Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer. NCCTG N04C7 29(4):421–427Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of Colorectal SurgerySun Yat-sen University Cancer CentreGuangzhouPeople’s Republic of China

Personalised recommendations