Role of Metformin in Oxaliplatin-Induced Peripheral Neuropathy in Patients With Stage III Colorectal Cancer: Randomized, Controlled Study

Int J Colorectal Dis. 2018 Dec;33(12):1675-1683. doi: 10.1007/s00384-018-3104-9. Epub 2018 Jun 21.


Purpose: Peripheral sensory neuropathy is the most prominently reported adverse effect of oxaliplatin. The purpose of this study was to evaluate metformin role in oxaliplatin-induced neuropathy.

Patients and methods: From November 2014 to May 2016, 40 patients with stage III colorectal cancer completed 12 cycles of FOLFOX-4 regimen. Twenty patients in the control arm received FOLFOX-4 regimen only, and 20 patients in the metformin arm, received the same regimen along with metformin 500 mg three times daily. The metformin efficacy was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0), a12-item neurotoxicity questionnaire (Ntx-12) from the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group and, the brief pain inventory short form "worst pain" item. In addition to neurotensin, malondialdehyde and interleukin-6 serum levels assessment.

Results: At the end of the 12th cycle, there were less patients with grade 2 and 3 neuropathy in metformin arm as compared to control arm. (60 versus 95%, P = 0.009) In addition, metformin arm showed significantly higher total scores of Ntx-12 questionnaire than control arm (24.0 versus 19.2, P < 0.001). Furthermore, the mean pain score in metformin arm was significantly lower than those of control arm, (6.7 versus 7.3, P = 0.005). Mean serum levels of malondialdehyde and neurotensin were significantly lower in metformin arm after the 6th and the 12th cycles.

Conclusion: Metformin may be a promising drug in protecting colorectal cancer patients against oxaliplatin-induced chronic peripheral sensory neuropathy.

Keywords: Colorectal cancer; Metformin; Oxaliplatin; Peripheral neuropathy.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Egypt
  • Fluorouracil / adverse effects
  • Humans
  • Leucovorin / adverse effects
  • Metformin / adverse effects
  • Metformin / therapeutic use*
  • Neoplasm Staging
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / therapeutic use*
  • Organoplatinum Compounds / adverse effects
  • Oxaliplatin / adverse effects*
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / diagnosis
  • Peripheral Nervous System Diseases / drug therapy*
  • Peripheral Nervous System Diseases / physiopathology
  • Prospective Studies
  • Risk Factors
  • Time Factors
  • Treatment Outcome


  • Neuroprotective Agents
  • Organoplatinum Compounds
  • Oxaliplatin
  • Metformin
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol