Skip to main content

Advertisement

SpringerLink
Log in

Update on Chemotherapy-Induced Peripheral Neuropathy

  • Nerve and Muscle (LH Weimer, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The purpose of this study was to briefly discuss chemotherapy-induced peripheral neuropathy (CIPN) and detail the most important and most recent chemotherapeutic agents implicated. This review will examine neuropathy mechanisms, risk factors, and clinical patterns; novel and prospective drugs with similar effects that are less well known to neurologists are discussed.

Recent Findings

CIPN is increasingly recognized for its clinical importance and effect on patient quality of life. Identification of risk factors is ongoing and may enable future risk stratification. Newer classes of agents and new members of existing classes are continually recognized, notably immune check point inhibitors, other monoclonal antibody treatments, novel immunomodulatory agents, and proteasome inhibitors. Advances regarding established classes including taxanes, platins, and vinca alkaloids are also reviewed.

Summary

CIPN is an important often dose-limiting toxicity. Multiple agents cause neuropathy; various clinical patterns are described. Future studies should aim at improved understanding of toxicity mechanisms and development of preventive and therapeutic strategies.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain. 2014;155(12):2461–70.

    Article  PubMed  Google Scholar 

  2. • Kolb NA, Smith AG, Singleton JR, Beck SL, Stoddard GJ, Brown S, et al. The association of chemotherapy-induced peripheral neuropathy symptoms and the risk of falling. JAMA Neurol. 2016;73(7):860–6. Good identification of importance of underappreciated CIPN manifestations.

    Article  PubMed  Google Scholar 

  3. Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32(18):1941–67.

    Article  CAS  PubMed  Google Scholar 

  4. Griffith KA, Merkies IS, Hill EE, Cornblath DR. Measures of chemotherapy-induced peripheral neuropathy: a systematic review of psychometric properties. J Peripher Nerv Syst. 2010;15(4):314–25.

    Article  PubMed  Google Scholar 

  5. Hershman DL, Weimer LH, Wang A, Kranwinkel G, Brafman L, Fuentes D, et al. Association between patient reported outcomes and quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors treated with adjuvant paclitaxel chemotherapy. Breast Cancer Res Treat. 2011;125(3):767–74.

    Article  CAS  PubMed  Google Scholar 

  6. Bober BG, Shah SB. Paclitaxel alters sensory nerve biomechanical properties. J Biomech. 2015;48(13):3559–67.

    Article  PubMed  Google Scholar 

  7. Chiba T, Oka Y, Kambe T, Koizumi N, Abe K, Kawakami K, et al. Paclitaxel-induced peripheral neuropathy increases substance P release in rat spinal cord. Eur J Pharmacol. 2016;770:46–51.

    Article  CAS  PubMed  Google Scholar 

  8. Bobylev I, Joshi AR, Barham M, Ritter C, Neiss WF, Hoke A, et al. Paclitaxel inhibits mRNA transport in axons. Neurobiol Dis. 2015;82:321–31.

    Article  CAS  PubMed  Google Scholar 

  9. Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, et al. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016;17(3):345–56.

    Article  CAS  PubMed  Google Scholar 

  10. Peng L, Bu Z, Ye X, Zhou Y, Zhao Q. Incidence and risk of peripheral neuropathy with nab-paclitaxel in patients with cancer: a meta-analysis. Eur J Cancer Care (Engl). 2015.

  11. Donehower RC, Rowinsky EK. An overview of experience with TAXOL (paclitaxel) in the U.S.A. Cancer Treat Rev. 1993;19(Suppl C):63–78.

    Article  PubMed  Google Scholar 

  12. Pereira S, Fontes F, Sonin T, Dias T, Fragoso M, Castro-Lopes JM, et al. Chemotherapy-induced peripheral neuropathy after neoadjuvant or adjuvant treatment of breast cancer: a prospective cohort study. Support Care Cancer. 2016;24(4):1571–81.

    Article  PubMed  Google Scholar 

  13. Eckhoff L, Knoop A, Jensen MB, Ewertz M. Persistence of docetaxel-induced neuropathy and impact on quality of life among breast cancer survivors. Eur J Cancer. 2015;51(3):292–300.

    Article  CAS  PubMed  Google Scholar 

  14. Kus T, Aktas G, Kalender ME, Demiryurek AT, Ulasli M, Oztuzcu S, et al. Polymorphism of CYP3A4 and ABCB1 genes increase the risk of neuropathy in breast cancer patients treated with paclitaxel and docetaxel. Onco Targets Ther. 2016;9:5073–80.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Boora GK, Kulkarni AA, Kanwar R, Beyerlein P, Qin R, Banck MS, et al. Association of the Charcot-Marie-Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance). J Neurol Sci. 2015;357(1–2):35–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schneider BP, Li L, Radovich M, Shen F, Miller KD, Flockhart DA, et al. Genome-wide association studies for taxane-induced peripheral neuropathy in ECOG-5103 and ECOG-1199. Clin Cancer Res. 2015;21(22):5082–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Apellaniz-Ruiz M, Lee MY, Sanchez-Barroso L, Gutierrez-Gutierrez G, Calvo I, Garcia-Estevez L, et al. Whole-exome sequencing reveals defective CYP3A4 variants predictive of paclitaxel dose-limiting neuropathy. Clin Cancer Res. 2015;21(2):322–8.

    Article  CAS  PubMed  Google Scholar 

  18. Beutler AS, Kulkarni AA, Kanwar R, Klein CJ, Therneau TM, Qin R, et al. Sequencing of Charcot-Marie-Tooth disease genes in a toxic polyneuropathy. Ann Neurol. 2014;76(5):727–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bergmann TK, Filppula AM, Launiainen T, Nielsen F, Backman J, Brosen K. Neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60-year-old Caucasian woman with ovarian carcinoma. Br J Clin Pharmacol. 2016;81(2):313–5.

    Article  CAS  PubMed  Google Scholar 

  20. Topp KS, Tanner KD, Levine JD. Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat. J Comp Neurol. 2000;424(4):563–76.

    Article  CAS  PubMed  Google Scholar 

  21. Casey EB, Jellife AM, Le Quesne PM, Millett YL. Vincristine neuropathy. Clinical and electrophysiological observations. Brain. 1973;96(1):69–86.

    Article  CAS  PubMed  Google Scholar 

  22. Sandler SG, Tobin W, Henderson ES. Vincristine-induced neuropathy. A clinical study of fifty leukemic patients. Neurology. 1969;19(4):367–74.

    Article  CAS  PubMed  Google Scholar 

  23. • Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. 1996;77(7):1356–62. Classic initial description of this association. Many additional cases later reported.

    Article  CAS  PubMed  Google Scholar 

  24. Nakamura T, Hashiguchi A, Suzuki S, Uozumi K, Tokunaga S, Takashima H. Vincristine exacerbates asymptomatic Charcot-Marie-Tooth disease with a novel EGR2 mutation. Neurogenetics. 2012;13(1):77–82.

    Article  CAS  PubMed  Google Scholar 

  25. Diouf B, Crews KR, Lew G, Pei D, Cheng C, Bao J, et al. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA. 2015;313(8):815–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Barzegar-Fallah A, Alimoradi H, Mehrzadi S, Barzegar-Fallah N, Zendedel A, Abbasi A, et al. The neuroprotective effect of tropisetron on vincristine-induced neurotoxicity. Neurotoxicology. 2014;41:1–8.

    Article  CAS  PubMed  Google Scholar 

  27. Geisler S, Doan RA, Strickland A, Huang X, Milbrandt J, DiAntonio A. Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain. 2016;139(Pt 12):3092–108.

    Article  PubMed  Google Scholar 

  28. • Johnstone TC, Suntharalingam K, Lippard SJ. The next generation of platinum drugs: targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) prodrugs. Chem Rev. 2016;116(5):3436–86. Comprehensive review of current and anticipated agents in this established class.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. de Carvalho Barbosa M, Kosturakis AK, Eng C, Wendelschafer-Crabb G, Kennedy WR, Simone DA, et al. A quantitative sensory analysis of peripheral neuropathy in colorectal cancer and its exacerbation by oxaliplatin chemotherapy. Cancer Res. 2014;74(21):5955–62.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lucchetta M, Lonardi S, Bergamo F, Alberti P, Velasco R, Argyriou AA, et al. Incidence of atypical acute nerve hyperexcitability symptoms in oxaliplatin-treated patients with colorectal cancer. Cancer Chemother Pharmacol. 2012;70(6):899–902.

    Article  CAS  PubMed  Google Scholar 

  31. Beijers AJ, Mols F, Tjan-Heijnen VC, Faber CG, van de Poll-Franse LV, Vreugdenhil G. Peripheral neuropathy in colorectal cancer survivors: the influence of oxaliplatin administration. Results from the population-based PROFILES registry. Acta Oncol. 2015;54(4):463–9.

    Article  CAS  PubMed  Google Scholar 

  32. Padman S, Lee J, Kumar R, Slee M, Hakendorf P, Richards A, et al. Late effects of oxaliplatin-induced peripheral neuropathy (LEON)—cross-sectional cohort study of patients with colorectal cancer surviving at least 2 years. Support Care Cancer. 2015;23(3):861–9.

    Article  PubMed  Google Scholar 

  33. Makker PG, Duffy SS, Lees JG, Perera CJ, Tonkin RS, Butovsky O, et al. Characterisation of immune and neuroinflammatory changes associated with chemotherapy-induced peripheral neuropathy. PLoS One. 2017;12(1):e0170814.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bobylev I, Joshi AR, Barham M, Neiss WF, Lehmann HC. Depletion of mitofusin-2 causes mitochondrial damage in cisplatin-induced neuropathy. Mol Neurobiol. 2017.

  35. Albers JW, Chaudhry V, Cavaletti G, Donehower RC. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev. 2014;3:CD005228.

    Google Scholar 

  36. Kelley MR, Wikel JH, Guo C, Pollok KE, Bailey BJ, Wireman R, et al. Identification and characterization of new chemical entities targeting apurinic/apyrimidinic endonuclease 1 for the prevention of chemotherapy-induced peripheral neuropathy. J Pharmacol Exp Ther. 2016;359(2):300–9.

    Article  CAS  PubMed  Google Scholar 

  37. Zhu J, Carozzi VA, Reed N, Mi R, Marmiroli P, Cavaletti G, et al. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity. Sci Rep. 2016;6:28861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Saifee TA, Elliott KJ, Rabin N, Yong KL, D'Sa S, Brandner S, et al. Bortezomib-induced inflammatory neuropathy. J Peripher Nerv Syst. 2010;15(4):366–8.

    Article  PubMed  Google Scholar 

  39. Thawani SP, Tanji K, De Sousa EA, Weimer LH, Brannagan 3rd TH. Bortezomib-associated demyelinating neuropathy—clinical and pathologic features. J Clin Neuromuscul Dis. 2015;16(4):202–9.

    Article  PubMed  Google Scholar 

  40. Peng L, Ye X, Zhou Y, Zhang J, Zhao Q. Meta-analysis of incidence and risk of peripheral neuropathy associated with intravenous bortezomib. Support Care Cancer. 2015;23(9):2813–24.

    Article  PubMed  Google Scholar 

  41. Hu B, Zhou Q, Wu T, Zhuang L, Yi L, Cao J, et al. Efficacy and safety of subcutaneous versus intravenous bortezomib in multiple myeloma: a meta-analysis. Int J Clin Pharmacol Ther. 2017.

  42. Liu H, Xu R, Huang H. Peripheral neuropathy outcomes and efficacy of subcutaneous bortezomib when combined with thalidomide and dexamethasone in the treatment of multiple myeloma. Exp Ther Med. 2016;12(5):3041–6.

    PubMed  PubMed Central  Google Scholar 

  43. Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, et al. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010;11(11):1057–65.

    Article  CAS  PubMed  Google Scholar 

  44. Magrangeas F, Kuiper R, Avet-Loiseau H, Gouraud W, Guerin-Charbonnel C, Ferrer L, et al. A genome-wide association study identifies a novel locus for bortezomib-induced peripheral neuropathy in European patients with multiple myeloma. Clin Cancer Res. 2016;22(17):4350–5.

    Article  CAS  PubMed  Google Scholar 

  45. Ale A, Bruna J, Calls A, Karamita M, Haralambous S, Probert L, et al. Inhibition of the neuronal NFkappaB pathway attenuates bortezomib-induced neuropathy in a mouse model. Neurotoxicology. 2016;55:58–64.

    Article  CAS  PubMed  Google Scholar 

  46. Wang J, Udd KA, Vidisheva A, Swift RA, Spektor TM, Bravin E, et al. Low serum vitamin D occurs commonly among multiple myeloma patients treated with bortezomib and/or thalidomide and is associated with severe neuropathy. Support Care Cancer. 2016;24(7):3105–10.

    PubMed  Google Scholar 

  47. • Dalla Torre C, Zambello R, Cacciavillani M, Campagnolo M, Berno T, Salvalaggio A, et al. Lenalidomide long-term neurotoxicity: clinical and neurophysiologic prospective study. Neurology. 2016;87(11):1161–6. Prospective study of this agent using better neuropathy ascertainment methods.

    Article  CAS  PubMed  Google Scholar 

  48. Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, et al. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016;128(4):497–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lopus M, Smiyun G, Miller H, Oroudjev E, Wilson L, Jordan MA. Mechanism of action of ixabepilone and its interactions with the betaIII-tubulin isotype. Cancer Chemother Pharmacol. 2015;76(5):1013–24.

    Article  CAS  PubMed  Google Scholar 

  50. Saura C, Tseng LM, Chan S, Chacko RT, Campone M, Manikhas A, et al. Neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early stage breast cancer and evaluation of betaIII-tubulin expression as a predictive marker. Oncologist. 2013;18(7):787–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ebenezer GJ, Carlson K, Donovan D, Cobham M, Chuang E, Moore A, et al. Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients. Ann Clin Transl Neurol. 2014;1(9):639–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. McCourt CK, Deng W, Dizon DS, Lankes HA, Birrer MJ, Lomme MM, et al. A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2017;144(1):101–6.

    Article  CAS  PubMed  Google Scholar 

  53. Heigener DF, von Pawel J, Eschbach C, Brune A, Schmittel A, Schmelter T, et al. Prospective, multicenter, randomized, independent-group, open-label phase II study to investigate the efficacy and safety of three regimens with two doses of sagopilone as second-line therapy in patients with stage IIIB or IV non-small-cell lung cancer. Lung Cancer. 2013;80(3):319–25.

    Article  PubMed  Google Scholar 

  54. Wozniak KM, Wu Y, Farah MH, Littlefield BA, Nomoto K, Slusher BS. Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy. Neurotox Res. 2013;24(3):338–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Puhalla S, Wilks S, Brufsky AM, O'Shaughnessy J, Schwartzberg LS, Berrak E, et al. Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: results from a phase II, single-arm, multicenter study. Breast Cancer (Dove Med Press). 2016;8:231–9.

    Google Scholar 

  56. Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, et al. Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/leucovorin vs. FOLFOX-bevacizumab in colorectal cancer. Clin Colorectal Cancer. 2012;11(2):101–11.

    Article  CAS  PubMed  Google Scholar 

  57. Herbst RS, Kelly K, Chansky K, Mack PC, Franklin WA, Hirsch FR, et al. Phase II selection design trial of concurrent chemotherapy and cetuximab versus chemotherapy followed by cetuximab in advanced-stage non-small-cell lung cancer: Southwest Oncology Group study S0342. J Clin Oncol. 2010;28(31):4747–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Beydoun SR, Shatzmiller RA. Chronic immune-mediated demyelinating polyneuropathy in the setting of cetuximab treatment. Clin Neurol Neurosurg. 2010;112(10):900–2.

    Article  PubMed  Google Scholar 

  59. Aya F, Ruiz-Esquide V, Viladot M, Font C, Prieto-Gonzalez S, Prat A, et al. Vasculitic neuropathy induced by pembrolizumab. Ann Oncol. 2016.

  60. • Hottinger AF. Neurologic complications of immune checkpoint inhibitors. Curr Opin Neurol. 2016;29(6):806–12. Informative review of various neurotoxicity forms associated with this relatively new class of agents.

    Article  CAS  PubMed  Google Scholar 

  61. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro-Oncology. 2014;16(4):589–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tanaka R, Maruyama H, Tomidokoro Y, Yanagiha K, Hirabayashi T, Ishii A, et al. Nivolumab-induced chronic inflammatory demyelinating polyradiculoneuropathy mimicking rapid-onset Guillain-Barre syndrome: a case report. Jpn J Clin Oncol. 2016;46(9):875–8.

    Article  PubMed  Google Scholar 

  63. Loochtan AI, Nickolich MS, Hobson-Webb LD. Myasthenia gravis associated with ipilimumab and nivolumab in the treatment of small cell lung cancer. Muscle Nerve. 2015;52(2):307–8.

    Article  PubMed  Google Scholar 

  64. Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8(1):e53745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S, Thomas I, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:210–25.

    Article  CAS  PubMed  Google Scholar 

  66. Pastorelli F, Derenzini E, Plasmati R, Pellegrini C, Broccoli A, Casadei B, et al. Severe peripheral motor neuropathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin. Leuk Lymphoma. 2013;54(10):2318–21.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The editors would like to thank Dr. John Brust for taking the time to review this manuscript.

Author information

Authors and Affiliations

  1. Neurological Institute of New York, Columbia University Medical Center, 710 W168th Street, New York, NY, 10032, USA

    Comana Cioroiu & Louis H. Weimer

Authors
  1. Comana Cioroiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Louis H. Weimer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Louis H. Weimer.

Ethics declarations

Conflict of Interest

Comana Cioroiu and Louis H. Weimer declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Nerve and Muscle

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cioroiu, C., Weimer, L.H. Update on Chemotherapy-Induced Peripheral Neuropathy. Curr Neurol Neurosci Rep 17, 47 (2017). https://doi.org/10.1007/s11910-017-0757-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-017-0757-7

Keywords

Search

Navigation