Skip to main content

Advertisement

SpringerLink
Log in

Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kuebler JP, Wieand HS, O'Connell MJ, Smith RE, Colangelo LH, Yothers G, Petrelli NJ, Findlay MP, Seay TE, Atkins JN, Zapas JL, Goodwin JW, Fehrenbacher L, Ramanathan RK, Conley BA, Flynn PJ, Soori G, Colman LK, Levine EA, Lanier KS, Wolmark N (2007) Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 25(16):2198–2204. https://doi.org/10.1200/JCO.2006.08.2974

    Article  CAS  PubMed  Google Scholar 

  2. Andre T, Iveson T, Labianca R, Meyerhardt JA, Souglakos I, Yoshino T et al (2013) The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) collaboration: prospective combined analysis of phase III trials investigating duration of adjuvant therapy with the FOLFOX (FOLFOX4 or modified FOLFOX6) or XELOX (3 versus 6 months) regimen for patients with stage III Colon Cancer: trial design and current status. Curr Colorectal Cancer Rep 9:261–269. https://doi.org/10.1007/s11888-013-0181-6

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zedan AH, Hansen TF, Fex Svenningsen A, Vilholm OJ (2014) Oxaliplatin-induced neuropathy in colorectal cancer: many questions with few answers. Clin Colorectal Cancer 13(2):73–80. https://doi.org/10.1016/j.clcc.2013.11.004

    Article  PubMed  Google Scholar 

  4. Tofthagen C, Donovan KA, Morgan MA, Shibata D, Yeh Y (2013) Oxaliplatin-induced peripheral neuropathy’s effects on health-related quality of life of colorectal cancer survivors. Support Care Cancer 21:3307–3313

    Article  PubMed  PubMed Central  Google Scholar 

  5. Drott JE (2014) Oxaliplatin induced neurotoxicity among patients with colorectal cancer: documentation in medical records—a pilot study. Open Journal of Nursing 4:265–274. https://doi.org/10.4236/ojn.2014.44031

    Article  Google Scholar 

  6. Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, Chauhan C, Gavin P, Lavino A, Lustberg MB, Paice J, Schneider B, Smith ML, Smith T, Terstriep S, Wagner-Johnston N, Bak K, Loprinzi CL, American Society of Clinical Oncology (2014) Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32(18):1941–1967. https://doi.org/10.1200/JCO.2013.54.0914

    Article  CAS  PubMed  Google Scholar 

  7. Hoff PM, Saad ED, Costa F, Coutinho AK, Caponero R, Prolla G, Gansl RC (2012) Literature review and practical aspects on the management of oxaliplatin-associated toxicity. Clin Colorectal Cancer 11(2):93–100. https://doi.org/10.1016/j.clcc.2011.10.004

    Article  CAS  PubMed  Google Scholar 

  8. Zanardelli M, L M, Cinci L, Failli P, Ghelardini C et al (2014) Oxaliplatin neurotoxicity involves peroxisome alterations. PPARc agonism as preventive pharmacological approach. PLoS One 9(7):e102758. https://doi.org/10.1371/journal.pone.0102758.g001.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chakraborty A, Chowdhury S, Bhattacharyya M (2011) Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res Clin Pract 93(1):56–62. https://doi.org/10.1016/j.diabres.2010.11.030

    Article  CAS  PubMed  Google Scholar 

  10. Mao-Ying QL, Kavelaars A, Krukowski K, Huo XJ, Zhou W, Price TJ, Cleeland C, Heijnen CJ (2014) The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS One 9(6):e100701. https://doi.org/10.1371/journal.pone.0100701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hou X, Song J, Zhang L, Wang X, Chen L, Shen YH (2010) Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun 396(2):199–205. https://doi.org/10.1016/j.bbrc.2010.04.017

    Article  CAS  PubMed  Google Scholar 

  12. Correia S, C C, Santos MS et al (2008) Metformin protects the brain against the oxidative imbalance promoted by type 2 diabetes. Med Chem 4:358–364

    Article  CAS  PubMed  Google Scholar 

  13. Ma J, Liu J, Yu H, Chen Y, Wang Q, Xiang L (2015) Beneficial effect of metformin on nerve regeneration and functional recovery after sciatic nerve crush injury in diabetic rats. Neurochem Res 41:1130–1137

    Article  PubMed  Google Scholar 

  14. Melemedjian O, Asiedu M, Tillu D, Sanoja R, Yan J, Lark A et al (2011) Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol Pain 7:70–84. https://doi.org/10.1186/1744-8069-7-70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Melemedjian OK, Khoutorsky A, Sorge RE, Yan J, Asiedu MN, Valdez A, Ghosh S, Dussor G, Mogil JS, Sonenberg N, Price TJ (2013) mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. Pain 154(7):1080–1091. https://doi.org/10.1016/j.pain.2013.03.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang W, Sun XF, Bo JH, Zhang J, Liu XJ, Wu LP, Ma ZL, Gu XP (2013) Activation of mTOR in the spinal cord is required for pain hypersensitivity induced by chronic constriction injury in mice. Pharmacol Biochem Behav 111:64–70. https://doi.org/10.1016/j.pbb.2013.07.017

    Article  CAS  PubMed  Google Scholar 

  17. Tillu DV, Melemedjian OK, Asiedu MN, Qu N, De Felice M, Dussor G et al (2012) Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain. Mol Pain 8:1–12. https://doi.org/10.1186/1744-8069-8-5

    Article  CAS  Google Scholar 

  18. Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17(6):1471–1474

    Article  PubMed  Google Scholar 

  19. Lami L, Areces F, Lence JJ, Arbesú MA (2009) FOLFOX-4 regimen as a first-line therapy for Cuban patients with metastatic colorectal cancer. MEDICC Rev 11:34–38

    PubMed  Google Scholar 

  20. National Cancer Institue. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed 9 February 2018

  21. Kopec JA, Land SR, Cecchini RS, Ganz PA, Cella D, Costantino JP et al (2006) Validation of a self-reported neurotoxicity scale in patients with operable colon cancer receiving oxaliplatin. J Support Oncol 4(8):W1–W8

    Google Scholar 

  22. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed 25 Augest 2017.

  23. Kidwell KM, Yothers G, Ganz PA, Land SR, Ko CY, Cecchini RS, Kopec JA, Wolmark N (2012) Long-term neurotoxicity effects of oxaliplatin added to fluorouracil and leucovorin as adjuvant therapy for colon cancer: results from National Surgical Adjuvant Breast and Bowel Project trials C-07 and LTS-01. Cancer 118(22):5614–5622. https://doi.org/10.1002/cncr.27593

    Article  CAS  PubMed  Google Scholar 

  24. Tan G, Jensen MP, Thornby JI, Shanti BF (2004) Validation of the brief pain inventory for chronic nonmalignant pain. J Pain 5(2):133–137

    Article  PubMed  Google Scholar 

  25. Cleeland C The breif pain inventory user guide. http://www.mdanderson.org/education-and-research/departments-programs-and-labs/departments-and-divisions/symptom-research/symptom-assessment-tools/BPI_UserGuide.pdf. Accessed 25 Augest 2017.

  26. Atkinson TM, Mendoza TR, Sit L, Passik S, Scher HI, Cleeland C, Basch E (2010) The brief pain inventory and its “pain at its worst in the last 24 hours” item: clinical trial endpoint considerations. Pain Med 11(3):337–346

    Article  PubMed  Google Scholar 

  27. Dworkin RH, Turk DC, Peirce-Sandner S, Baron R, Bellamy N, Burke LB, Chappell A, Chartier K, Cleeland CS, Costello A, Cowan P, Dimitrova R, Ellenberg S, Farrar JT, French JA, Gilron I, Hertz S, Jadad AR, Jay GW, Kalliomäki J, Katz NP, Kerns RD, Manning DC, McDermott MP, McGrath PJ, Narayana A, Porter L, Quessy S, Rappaport BA, Rauschkolb C, Reeve BB, Rhodes T, Sampaio C, Simpson DM, Stauffer JW, Stucki G, Tobias J, White RE, Witter J (2010) Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain 149(2):177–193

    Article  PubMed  Google Scholar 

  28. Durand J, Deplanque G, Montheil V, Gornet J, Scotte F, Mir O, Cessot A, Coriat R, Raymond E, Mitry E, Herait P, Yataghene Y, Goldwasser F (2011) Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol 23(1):200–205

    Article  PubMed  Google Scholar 

  29. Zimmerman C, Atherton PJ, Pachman D, Seisler D, Wagner-Johnston N, Dakhil S, Lafky JM, Qin R, Grothey A, Loprinzi CL (2016) MC11C4: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy. Support Care Cancer 24(3):1071–1078

    Article  PubMed  Google Scholar 

  30. Burcelin R (2014) The antidiabetic gutsy role of metformin uncovered? Gut 63(5):706–707

    Article  CAS  PubMed  Google Scholar 

  31. Ma J, Yu H, Liu J, Chen Y, Wang Q, Xiang L (2015) Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin. Eur J Pharmacol 764:599–606

    Article  CAS  PubMed  Google Scholar 

  32. Taylor A, Westveld AH, Szkudlinska M, Guruguri P, Annabi E, Patwardhan A, Price TJ, Yassine HN (2013) The use of metformin is associated with decreased lumbar radiculopathy pain. J Pain Res 6:755–763

    PubMed  PubMed Central  Google Scholar 

  33. Moore MN (2015) A retrospective descriptive study of pain scores in pre-diabetic patients on metformin. faculty of the University Graduate School in partial fulfillment of the requirements for the degree Doctor of Philosophy in the School of Health and Rehabilitation Sciences, Indiana University. https://scholarworks.iupui.edu/bitstream/handle/1805/7988/Moore_iupui_0104D_10036.pdf?sequence=1; Accessed 13 March 2017

  34. Smith B, Ang D (2015) Metformin: potential analgesic? Pain Med 16(12):2256–2260

    Article  PubMed  Google Scholar 

  35. Kleczkowska P, Lipkowski AW (2013) Neurotensin and neurotensin receptors: characteristic, structure-activity relationship and pain modulation--a review. Eur J Pharmacol 716(1–3):54–60. https://doi.org/10.1016/j.ejphar.2013.03.004

    Article  CAS  PubMed  Google Scholar 

  36. Plaza-Manzano G, Molina-Ortega F, Lomas-Vega R, Martinez-Amat A, Achalandabaso A, Hita-Contreras F (2014) Changes in biochemical markers of pain perception and stress response after spinal manipulation. J Orthop Sports Phys Ther 44(4):231–239. https://doi.org/10.2519/jospt.2014.4996

    Article  PubMed  Google Scholar 

  37. Theoharides T, Stewart J, Panagiotidou S, Melamed I (2016) Mast cells, brain inflammation and autism. Eur J Pharmacol 778:96–102

    Article  CAS  PubMed  Google Scholar 

  38. Al Moundhri MS, Al-Salam S, Al Mahrouqee A, Beegam S, Ali BH (2013) The effect of curcumin on oxaliplatin and cisplatin neurotoxicity in rats: some behavioral, biochemical, and histopathological studies. J Med Toxicol 9(1):25–33. https://doi.org/10.1007/s13181-012-0239-x

    Article  CAS  PubMed  Google Scholar 

  39. Kocer D, Bayram F, Diri H (2014) The effects of metformin on endothelial dysfunction, lipid metabolism and oxidative stress in women with polycystic ovary syndrome. Gynecol Endocrinol 30(5):367–371

    Article  CAS  PubMed  Google Scholar 

  40. Yilmaz M, Bukan N, Ayvaz G, Karakoç A, Törüner F, Çakir N et al (2005) The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome. Hum Reprod 20(12):3333–3340

    Article  CAS  PubMed  Google Scholar 

  41. Cerles O, Benoit E, Chéreau C, Chouzenoux S, Morin F, Guillaumot M-A et al (2016) Niclosamide inhibits oxaliplatin neurotoxicity while improving colorectal cancer therapeutic response. Mol Cancer Ther 16:300–311

    Article  PubMed  Google Scholar 

  42. Kadoglou N, Kapelouzou A, Tsanikidis H, Vitta I, Liapis C, Sailer N (2011) Effects of rosiglitazone/metformin fixed-dose combination therapy and metformin monotherapy on serum vaspin, adiponectin and IL-6 levels in drug-naïve patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 119(2):63–68

    Article  CAS  PubMed  Google Scholar 

  43. Fidan E, Ersoz HO, Yilmaz M, Yilmaz H, Kocak M, Karahan C et al (2011) The effects of rosiglitazone and metformin on inflammation and endothelial dysfunction in patients with type 2 diabetes mellitus. Acta Diabetol 48(4):297–302

    Article  CAS  PubMed  Google Scholar 

  44. Areti A, Yerra VG, Naidu V, Kumar A (2014) Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biol 2:289–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG (2008) Insulin-lowering effects of metformin in women with early breast cancer. Clinical breast cancer 8(6):501–505

    Article  CAS  PubMed  Google Scholar 

  46. Osama H, Hussein HAE, Abdelrahim ME, Salem HF (2016) Screening the effect of metformin on serum vitamin B12 and blood homocysteine levels in patients with type 2 diabetes mellitus. Medicine Science| International Medical Journal 5(1):46–56

    Article  Google Scholar 

  47. Russo G, Giandalia A, Romeo E, Scarcella C, Gambadoro N, Zingale R et al (2016) Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR C677T mutation in type 2 diabetic outpatients taking metformin. J Endocrinol Investig 39(3):305–314

    Article  CAS  Google Scholar 

  48. Holmes D (2016) Diabetes: metformin linked to vitamin B12 deficiency. Nat Rev Endocrinol 12(6):312

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Tanta, Egypt

    Basma Mahrous El-fatatry, Osama Mohamed Ibrahim & Tarek Mohamed Mostafa

  2. Department of Clinical Oncology, Faculty of Medicine, Tanta University, Tanta, Egypt

    Fatma Zakaria Hussien

Authors
  1. Basma Mahrous El-fatatry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Osama Mohamed Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fatma Zakaria Hussien
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tarek Mohamed Mostafa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Basma Mahrous El-fatatry.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of Tanta University Research Ethical Committee, with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El-fatatry, B.M., Ibrahim, O.M., Hussien, F.Z. et al. Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study. Int J Colorectal Dis 33, 1675–1683 (2018). https://doi.org/10.1007/s00384-018-3104-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-018-3104-9

Keywords

Search

Navigation