Supportive Care in Cancer

, Volume 22, Issue 7, pp 1999–2007 | Cite as

A systematic review on chronic oxaliplatin-induced peripheral neuropathy and the relation with oxaliplatin administration

  • A. J. M. Beijers
  • F. Mols
  • G. VreugdenhilEmail author
Review Article



The aim of this study was to systematically review the literature on the influence of oxaliplatin administration (e.g. cumulative dose, dose intensity, number of cycles and combination regimen) on the long-term prevalence of oxaliplatin-induced peripheral neuropathy (O-IPN) at least 12 months after termination of chemotherapy.


A computerized search of literature on databases PubMed and Cochrane was performed. Published original articles were included if they reported about long-term O-IPN and gave concomitant information about oxaliplatin therapy given to the patients. All articles were assessed for quality.


We included 14 articles (n = 3,869 patients), and the majority of these studies were of high quality. All included patients who were treated for colorectal cancer, mainly with oxaliplatin in combination with 5-fluorouracil/leucovorin. Median cumulative doses and dose intensity varied between 676 and 1,449 mg/m2 and 30.8 and 42.6 mg/m2/week, respectively. Neuropathy assessment differed between studies, and the National Cancer Institute-Common Terminology Criteria (NCI-CTC) was used most often. The degree of neuropathy ranged from grade 0 to 3. Only six studies directly assessed the relationship between oxaliplatin administration and neuropathy. Of these studies, five did find a relation between neuropathy and higher cumulative dose, while one study did not find a relation.


O-IPN is still present in a great amount of patients in ≥12 months after termination of therapy. A higher cumulative dose is likely to have an influence on the development of long-term O-IPN. More studies are needed that assess long-term neuropathy and oxaliplatin administration by means of validated neuropathy assessments.


Cancer Chronic Chemotherapy Neurotoxicity Oxaliplatin Peripheral neuropathy 



Floortje Mols was supported by a VENI grant (no. 451-10-041) from the Netherlands Organization for Scientific Research (The Hague, The Netherlands).

Conflict of interest



  1. 1.
    de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18(16):2938–2947PubMedGoogle Scholar
  2. 2.
    André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer I (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350(23):2343–2351. doi: 10.1056/NEJMoa032709 PubMedCrossRefGoogle Scholar
  3. 3.
    André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, Bonetti A, Clingan P, Bridgewater J, Rivera F, de Gramont A (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27(19):3109–3116. doi: 10.1200/JCO.2008.20.6771 PubMedCrossRefGoogle Scholar
  4. 4.
    Haller DG, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Gilberg F, Rittweger K, Schmoll HJ (2011) Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 29(11):1465–1471. doi: 10.1200/JCO.2010.33.6297 PubMedCrossRefGoogle Scholar
  5. 5.
    Ducreux M, Bennouna J, Hebbar M, Ychou M, Lledo G, Conroy T, Adenis A, Faroux R, Rebischung C, Bergougnoux L, Kockler L, Douillard JY, Centers GIGotFA-C (2011) Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) as first-line treatment for metastatic colorectal cancer. Int J Cancer 128(3):682–690. doi: 10.1002/ijc.25369 PubMedCrossRefGoogle Scholar
  6. 6.
    Krishnan AV, Goldstein D, Friedlander M, Kiernan MC (2005) Oxaliplatin-induced neurotoxicity and the development of neuropathy. Muscle Nerve 32(1):51–60. doi: 10.1002/mus.20340 PubMedCrossRefGoogle Scholar
  7. 7.
    Pietrangeli A, Leandri M, Terzoli E, Jandolo B, Garufi C (2006) Persistence of high-dose oxaliplatin-induced neuropathy at long-term follow-up. Eur Neurol 56(1):13–16. doi: 10.1159/000094376 PubMedCrossRefGoogle Scholar
  8. 8.
    Pasetto LM, D’Andrea MR, Rossi E, Monfardini S (2006) Oxaliplatin-related neurotoxicity: how and why? Criti Rev Oncol Hematol 59(2):159–168. doi: 10.1016/j.critrevonc.2006.01.001 CrossRefGoogle Scholar
  9. 9.
    Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC (2011) Dose effects of oxaliplatin on persistent and transient Na+conductances and the development of neurotoxicity. PLoS One 6(4):e18469. doi: 10.1371/journal.pone.0018469 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, Dib-Hajj S, Drenth JP, Waxman SG, Merkies IS (2012) Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 71(1):26–39. doi: 10.1002/ana.22485 PubMedCrossRefGoogle Scholar
  11. 11.
    Faber CG, Lauria G, Merkies IS, Cheng X, Han C, Ahn HS, Persson AK, Hoeijmakers JG, Gerrits MM, Pierro T, Lombardi R, Kapetis D, Dib-Hajj SD, Waxman SG (2012) Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A 109(47):19444–19449. doi: 10.1073/pnas.1216080109 PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Beijers AJ, Jongen JL, Vreugdenhil G (2012) Chemotherapy-induced neurotoxicity: the value of neuroprotective strategies. Neth J Med 70(1):18–25PubMedGoogle Scholar
  13. 13.
    Grothey A (2003) Oxaliplatin-safety profile: neurotoxicity. Semin Oncol 30(4 Suppl 15):5–13PubMedCrossRefGoogle Scholar
  14. 14.
    Ocean A, Vahdat L (2004) Chemotherapy-induced peripheral neuropathy: pathogenesis and emerging therapies. Support Care Cancer 12(9):619–625PubMedGoogle Scholar
  15. 15.
    Quasthoff S, Hartung H (2002) Chemotherapy-induced peripheral neuropathy. J Neurol 249(1):9–17PubMedCrossRefGoogle Scholar
  16. 16.
    Mols F, Beijers T, Lemmens V, van den Hurk CJ, Vreugdenhil G, van de Poll-Franse LV (2013) Chemotherapy-induced neuropathy and its association with quality of life among 2- to 11-year colorectal cancer survivors: results from the population-based PROFILES registry. J Clin Oncol 31(21):2699–2707. doi: 10.1200/JCO.2013.49.1514 PubMedCrossRefGoogle Scholar
  17. 17.
    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(12):3307–3313. doi: 10.1007/s00520-013-1905-5 PubMedCrossRefGoogle Scholar
  18. 18.
    Cavaletti G, Tredici G, Petruccioli MG, Donde E, Tredici P, Marmiroli P, Minoia C, Ronchi A, Bayssas M, Etienne GG (2001) Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J Cancer 37(18):2457–2463PubMedCrossRefGoogle Scholar
  19. 19.
    Velasco R, Bruna J, Briani C, Argyriou AA, Cavaletti G, Alberti P, Frigeni B, Cacciavillani M, Lonardi S, Cortinovis D, Cazzaniga M, Santos C, Kalofonos HP (2013) Early predictors of oxaliplatin-induced cumulative neuropathy in colorectal cancer patients. J Neurol Neurosurg Psychiatry 85(4):392–398. doi: 10.1136/jnnp-2013-305334 PubMedCrossRefGoogle Scholar
  20. 20.
    Vatandoust S, Joshi R, Pittman KB, Esterman A, Broadbridge V, Adams J, Singhal N, Yeend S, Price TJ (2013) A descriptive study of persistent oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer. Support Care Cancer 22(2):513–518. doi: 10.1007/s00520-013-2004-3 CrossRefGoogle Scholar
  21. 21.
    Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Colangelo LH, Lopa SH, Petrelli NJ, Goldberg RM, Atkins JN, Seay TE, Fehrenbacher L, O’Reilly S, Chu L, Azar CA, Wolmark N (2009) Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol 27(20):3385–3390. doi: 10.1200/JCO.2009.21.9220 PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Brouwers EE, Huitema AD, Boogerd W, Beijnen JH, Schellens JH (2009) Persistent neuropathy after treatment with cisplatin and oxaliplatin. Acta Oncol 48(6):832–841. doi: 10.1080/02841860902806609 PubMedCrossRefGoogle Scholar
  23. 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. doi: 10.1002/cncr.27593 PubMedCrossRefGoogle Scholar
  24. 24.
    Land SR, Kopec JA, Cecchini RS, Ganz PA, Wieand HS, Colangelo LH, Murphy K, Kuebler JP, Seay TE, Needles BM, Bearden JD 3rd, Colman LK, Lanier KS, Pajon ER Jr, Cella D, Smith RE, O’Connell MJ, Costantino JP, Wolmark N (2007) Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07. J Clin Oncol 25(16):2205–2211. doi: 10.1200/JCO.2006.08.6652 PubMedCrossRefGoogle Scholar
  25. 25.
    Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC (2011) Long-term neuropathy after oxaliplatin treatment: challenging the dictum of reversibility. Oncologist 16(5):708–716. doi: 10.1634/theoncologist.2010-0248 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG (2003) Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21(11):2059–2069. doi: 10.1200/JCO.2003.11.126 PubMedCrossRefGoogle Scholar
  27. 27.
    Yothers G, O’Connell MJ, Allegra CJ, Kuebler JP, Colangelo LH, Petrelli NJ, Wolmark N (2011) Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol 29(28):3768–3774. doi: 10.1200/JCO.2011.36.4539 PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Lee P, Park YS, Ji JF, Fu YT, Ratanatharathorn V (2009) Safety and tolerability of FOLFOX4 in the adjuvant treatment of colon cancer in Asian patients: the MASCOT study. Asia Pac J Clin Oncol 5:101–110CrossRefGoogle Scholar
  29. 29.
    Matsumoto S, Nishimura T, Kanai M, Mori Y, Nagayama S, Kawamura J, Nomura A, Miyamoto S, Kitano T, Ishiguro H, Yanagihara K, Teramukai S, Sakai Y, Chiba T, Fukushima M (2008) Safety and efficacy of modified FOLFOX6 for treatment of metastatic or locally advanced colorectal cancer. A single-institution outcome study. Chemotherapy 54(5):395–403. doi: 10.1159/000154921 PubMedCrossRefGoogle Scholar
  30. 30.
    Petrioli R, Pascucci A, Francini E, Marsili S, Sciandivasci A, Tassi R, Civitelli S, Tanzini G, Lorenzi M, Francini G (2008) Neurotoxicity of FOLFOX-4 as adjuvant treatment for patients with colon and gastric cancer: a randomized study of two different schedules of oxaliplatin. Cancer Chemother Pharmacol 61(1):105–111. doi: 10.1007/s00280-007-0454-3 PubMedCrossRefGoogle Scholar
  31. 31.
    Storey DJ, Sakala M, McLean CM, Phillips HA, Dawson LK, Wall LR, Fallon MT, Clive S (2010) Capecitabine combined with oxaliplatin (CapOx) in clinical practice: how significant is peripheral neuropathy? Ann Oncol 21(8):1657–1661. doi: 10.1093/annonc/mdp594 PubMedCrossRefGoogle Scholar
  32. 32.
    Mols F, Vingerhoets AJ, Coebergh JW, van de Poll-Franse LV (2005) Quality of life among long-term breast cancer survivors: a systematic review. Eur J Cancer 41(17):2613–2619. doi: 10.1016/j.ejca.2005.05.017 PubMedCrossRefGoogle Scholar
  33. 33.
    Vandenbroucke JP, von Elm E, Altman DG, Gotzsche PC, Mulrow CD, Pocock SJ, Poole C, Schlesselman JJ, Egger M, Initiative S (2007) Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Epidemiology 18(6):805–835. doi: 10.1097/EDE.0b013e3181577511 PubMedCrossRefGoogle Scholar
  34. 34.
    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. doi: 10.1200/JCO.2006.08.2974 PubMedCrossRefGoogle Scholar
  35. 35.
    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. doi: 10.1016/j.clcc.2011.10.004 PubMedCrossRefGoogle Scholar
  36. 36.
    Argyriou AA, Velasco R, Briani C, Cavaletti G, Bruna J, Alberti P, Cacciavillani M, Lonardi S, Santos C, Cortinovis D, Cazzaniga M, Kalofonos HP (2012) Peripheral neurotoxicity of oxaliplatin in combination with 5-fluorouracil (FOLFOX) or capecitabine (XELOX): a prospective evaluation of 150 colorectal cancer patients. Ann Oncol 23(12):3116–3122. doi: 10.1093/annonc/mds208 PubMedCrossRefGoogle Scholar
  37. 37.
    Postma TJ, Heimans JJ, Muller MJ, Ossenkoppele GJ, Vermorken JB, Aaronson NK (1998) Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann Oncol 9(7):739–744PubMedCrossRefGoogle Scholar
  38. 38.
    Argyriou AA, Cavaletti G, Antonacopoulou A, Genazzani AA, Briani C, Bruna J, Terrazzino S, Velasco R, Alberti P, Campagnolo M, Lonardi S, Cortinovis D, Cazzaniga M, Santos C, Psaromyalou A, Angelopoulou A, Kalofonos HP (2013) Voltage-gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin-induced peripheral neurotoxicity: results from a prospective multicenter study. Cancer 119(19):3570–3577. doi: 10.1002/cncr.28234 PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Internal MedicineMáxima Medical CentreVeldhovenThe Netherlands
  2. 2.Center of Research on Psychology in Somatic Diseases (CoRPS), Department of Medical and Clinical PsychologyTilburg UniversityTilburgThe Netherlands
  3. 3.Comprehensive Cancer Centre Netherlands (CCCN)Eindhoven Cancer RegistryEindhovenThe Netherlands
  4. 4.Department of Medical OncologyMaastricht University Medical CentreMaastrichtThe Netherlands

Personalised recommendations