Incidence of peripheral neuropathy associated with eribulin mesylate versus vinorelbine in patients with metastatic breast cancer: sub-group analysis of a randomized phase III study

Abstract

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most significant neurologic complications of chemotherapy, impacting patient’s behavior and quality of life. CIPN is mostly sensory, with rare incidences of autonomic dysfunction and other neuropathy.

Methods

We conducted a single-center sub-group analysis of patients with metastatic breast cancer enrolled in a phase III study (NCT02225470) set up to compare eribulin mesylate (1.4 mg/m2 on days 1 and 8 every 21 days) with vinorelbine (25 mg/m2 on days 1, 8, and 15 every 21 days). The analysis investigated incidence of peripheral neuropathy, time to onset of neuropathy, and safety.

Results

Our analysis included 110 women with a mean age of 50.7 (SD = 10.9). The median accumulated dose of eribulin was 11.2 mg/m2 and 125.0 mg/m2 for vinorelbine. Among patients in the eribulin group, a performance status (ECOG PS) of 2 was correlated with peripheral sensory neuropathy (p = 0.015), and accumulated eribulin dose (≥ 10 mg/m2) was associated with all neuropathy and peripheral sensory neuropathy (p = 0.003 and p = 0.007, respectively). In the vinorelbine group, patient age (≥ 65 years) was positively associated with all neuropathy (p = 0.043). The time to onset of neuropathy appeared to be longer for eribulin versus vinorelbine (35.3 vs. 34.6 weeks; p = 0.046), with a significantly higher incidence of autonomic neuropathy at weeks 2 and 10 observed among patients receiving vinorelbine (p = 0.008 and p = 0.043, respectively).

Conclusion

Vinorelbine is associated with a higher incidence of autonomic neuropathy than eribulin in patients with metastatic breast cancer. Furthermore, the onset of neurotoxicity appears to occur earlier with vinorelbine than eribulin.

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

Fig. 1

Abbreviations

CIPN:

Chemotherapy-induced peripheral neuropathy

OS:

Overall survival

TPC:

Treatment of physician’s choice

MBC:

Metastatic breast cancer

PN:

Peripheral neuropathy

ORR:

Overall response rates

CR:

Complete response

PR:

Partial response

PFS:

Progress free survival

AE:

Adverse event

CTCAE:

Common Terminology Criteria for Adverse Events

ECOG:

Eastern Cooperative Oncology Group

EMBRACE:

Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389

FISH:

Fluorescence in situ hybridization

HER2:

Human epidermal growth factor receptor 2

PgR:

Progesterone receptor

PNQ:

Patient-reported neurotoxicity questionnaire

VPT:

Vibration perception threshold

FACT-Taxane:

Functional assessment of cancer therapy-taxane

EORTC:

European Organization for Research and Treatment of Cancer

QLQ:

Quality of Life Questionnaire

References

  1. 1.

    Faneyte IF, Kristel PM, van de Vijver MJ (2004) Multidrug resistance associated genes MRP1, MRP2 and MRP3 in primary and anthracycline exposed breast cancer. Anticancer Res 24(5a):2931–2939

    CAS  PubMed  Google Scholar 

  2. 2.

    Chien AJ, Moasser MM (2008) Cellular mechanisms of resistance to anthracyclines and taxanes in cancer: intrinsic and acquired. Semin Oncol 35(2 Suppl 2):S1–S14 quiz S39

    CAS  PubMed  Google Scholar 

  3. 3.

    Li Q, Yang Z, Fan J, He J, Zhang B, Yang H, Xie X, Tang Z, Li H, Qiao Y, Zhang P (2017) A nation-wide multicenter 10-year (1999-2008) retrospective study of chemotherapy in Chinese breast cancer patients. Oncotarget 8(44):75864–75873

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Network NCC: NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2018. 2018.

  5. 5.

    (2011) Eribulin mesylate (Halaven) for breast cancer. Med Lett Drugs Ther 53(1362):30–31

  6. 6.

    Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Dieras V, Delozier T et al (2011) Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 377(9769):914–923

    CAS  Google Scholar 

  7. 7.

    Fumoleau P, Delgado FM, Delozier T, Monnier A, Gil Delgado MA, Kerbrat P, Garcia-Giralt E, Keiling R, Namer M, Closon MT et al (1993) Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol 11(7):1245–1252

    CAS  PubMed  Google Scholar 

  8. 8.

    Garcia-Conde J, Lluch A, Martin M, Casado A, Gervasio H, De Oliveira C, De Pablo JL, Gorostiaga J, Giron GC, Cervantes A et al (1994) Phase II trial of weekly IV vinorelbine in first-line advanced breast cancer chemotherapy. Ann Oncol 5(9):854–857

    CAS  PubMed  Google Scholar 

  9. 9.

    Romero A, Rabinovich MG, Vallejo CT, Perez JE, Rodriguez R, Cuevas MA, Machiavelli M, Lacava JA, Langhi M, Romero Acuna L et al (1994) Vinorelbine as first-line chemotherapy for metastatic breast carcinoma. J Clin Oncol 12(2):336–341

    CAS  PubMed  Google Scholar 

  10. 10.

    Staff NP, Grisold A, Grisold W, Windebank AJ (2017) Chemotherapy-induced peripheral neuropathy: a current review. Ann Neurol 81(6):772–781

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Addington J, Freimer M: Chemotherapy-induced peripheral neuropathy: an update on the current understanding. F1000Res 2016, 5.

  12. 12.

    Chaudhry V, Rowinsky EK, Sartorius SE, Donehower RC, Cornblath DR (1994) Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol 35(3):304–311

    CAS  PubMed  Google Scholar 

  13. 13.

    Kautio AL, Haanpaa M, Kautiainen H, Kalso E, Saarto T (2011) Burden of chemotherapy-induced neuropathy--a cross-sectional study. Support Care Cancer 19(12):1991–1996

    PubMed  Google Scholar 

  14. 14.

    Pachman DR, Barton DL, Watson JC, Loprinzi CL (2011) Chemotherapy-induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther 90(3):377–387

    CAS  PubMed  Google Scholar 

  15. 15.

    Speck RM, DeMichele A, Farrar JT, Hennessy S, Mao JJ, Stineman MG, Barg FK (2012) Scope of symptoms and self-management strategies for chemotherapy-induced peripheral neuropathy in breast cancer patients. Support Care Cancer 20(10):2433–2439

    PubMed  Google Scholar 

  16. 16.

    Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA (2004) Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res 64(16):5760–5766

    CAS  PubMed  Google Scholar 

  17. 17.

    de Bono JS, Molife LR, Sonpavde G, Maroto JP, Calvo E, Cartwright TH, Loesch DM, Feit K, Das A, Zang EA, Wanders J, Agoulnik S, Petrylak DP (2012) Phase II study of eribulin mesylate (E7389) in patients with metastatic castration-resistant prostate cancer stratified by prior taxane therapy. Ann Oncol 23(5):1241–1249

    PubMed  Google Scholar 

  18. 18.

    Galano G, Caputo M, Tecce MF, Capasso A (2011) Efficacy and tolerability of vinorelbine in the cancer therapy. Curr Drug Saf 6(3):185–193

    CAS  PubMed  Google Scholar 

  19. 19.

    Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J (2015) Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 33(6):594–601

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Martin M, Ruiz A, Munoz M, Balil A, Garcia-Mata J, Calvo L, Carrasco E, Mahillo E, Casado A, Garcia-Saenz JA et al (2007) Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol 8(3):219–225

    CAS  PubMed  Google Scholar 

  21. 21.

    Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B (2019) Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: a randomised clinical trial. Eur J Cancer 112:57–65

    CAS  PubMed  Google Scholar 

  22. 22.

    Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, Lyman GH, Pettengell R, Tjan-Heijnen VC, Walewski J, Weber DC, Zielinski C, European Organisation for Research and Treatment of Cancer (2011) 2010 Update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 47(1):8–32

    CAS  PubMed  Google Scholar 

  23. 23.

    Cavaletti G, Jann S, Pace A, Plasmati R, Siciliano G, Briani C, Cocito D, Padua L, Ghiglione E, Manicone M et al (2006) Multi-center assessment of the Total Neuropathy Score for chemotherapy-induced peripheral neurotoxicity. J Peripher Nerv Syst 11(2):135–141

    CAS  PubMed  Google Scholar 

  24. 24.

    Polomano RC, Bennett GJ (2001) Chemotherapy-evoked painful peripheral neuropathy. Pain Med 2(1):8–14

    CAS  PubMed  Google Scholar 

  25. 25.

    Hausheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F (2006) Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol 33(1):15–49

    CAS  PubMed  Google Scholar 

  26. 26.

    Argyriou AA, Polychronopoulos P, Iconomou G, Chroni E, Kalofonos HP (2008) A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat Rev 34(4):368–377

    CAS  PubMed  Google Scholar 

  27. 27.

    Wilkes G (2007) Peripheral neuropathy related to chemotherapy. Semin Oncol Nurs 23(3):162–173

    PubMed  Google Scholar 

  28. 28.

    Shemesh OA, Spira ME (2010) Paclitaxel induces axonal microtubules polar reconfiguration and impaired organelle transport: implications for the pathogenesis of paclitaxel-induced polyneuropathy. Acta Neuropathol 119(2):235–248

    CAS  PubMed  Google Scholar 

  29. 29.

    Wozniak KM, Nomoto K, Lapidus RG, Wu Y, Carozzi V, Cavaletti G, Hayakawa K, Hosokawa S, Towle MJ, Littlefield BA et al (2011) Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice. Cancer Res 71(11):3952–3962

    CAS  PubMed  Google Scholar 

  30. 30.

    Inoue K, Saito T, Okubo K, Kimizuka K, Yamada H, Sakurai T, Ishizuna K, Hata S, Kai T, Kurosumi M (2016) Phase II clinical study of eribulin monotherapy in Japanese patients with metastatic breast cancer who had well-defined taxane resistance. Breast Cancer Res Treat 157(2):295–305

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Goodin S, Barbour S, Song J, Berrak E, Cox D (2015) Safety and tolerability of eribulin mesylate in patients with pretreated metastatic breast cancer. Am J Health Syst Pharm 72(24):2150–2156

    CAS  PubMed  Google Scholar 

  32. 32.

    Aftimos P, Polastro L, Ameye L, Jungels C, Vakili J, Paesmans M, van den Eerenbeemt J, Buttice A, Gombos A, de Valeriola D et al (2016) Results of the Belgian expanded access program of eribulin in the treatment of metastatic breast cancer closely mirror those of the pivotal phase III trial. Eur J Cancer 60:117–124

    CAS  PubMed  Google Scholar 

  33. 33.

    Dranitsaris G, Beegle N, Kalberer T, Blau S, Cox D, Faria C (2015) A comparison of toxicity and health care resource use between eribulin, capecitabine, gemcitabine, and vinorelbine in patients with metastatic breast cancer treated in a community oncology setting. J Oncol Pharm Pract 21(3):170–177

    CAS  PubMed  Google Scholar 

  34. 34.

    Dybdal-Hargreaves NF, Risinger AL, Mooberry SL (2015) Eribulin mesylate: mechanism of action of a unique microtubule-targeting agent. Clin Cancer Res 21(11):2445–2452

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L (2005) The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther 4(7):1086–1095

    CAS  PubMed  Google Scholar 

  36. 36.

    Stanton RA, Gernert KM, Nettles JH, Aneja R (2011) Drugs that target dynamic microtubules: a new molecular perspective. Med Res Rev 31(3):443–481

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Chaudhry V, Chaudhry M, Crawford TO, Simmons-O’Brien E, Griffin JW (2003) Toxic neuropathy in patients with pre-existing neuropathy. Neurology 60(2):337–340

    CAS  PubMed  Google Scholar 

  38. 38.

    Hilkens PH, Verweij J, Stoter G, Vecht CJ, van Putten WL, van den Bent MJ (1996) Peripheral neurotoxicity induced by docetaxel. Neurology 46(1):104–108

    CAS  PubMed  Google Scholar 

  39. 39.

    Chauvenet AR, Shashi V, Selsky C, Morgan E, Kurtzberg J, Bell B (2003) Pediatric Oncology Group S: Vincristine-induced neuropathy as the initial presentation of Charcot-Marie-Tooth disease in acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Pediatr Hematol Oncol 25(4):316–320

    PubMed  Google Scholar 

  40. 40.

    Balayssac D, Ferrier J, Descoeur J, Ling B, Pezet D, Eschalier A, Authier N (2011) Chemotherapy-induced peripheral neuropathies: from clinical relevance to preclinical evidence. Expert Opin Drug Saf 10(3):407–417

    CAS  PubMed  Google Scholar 

  41. 41.

    Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD (1996) Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer 77(7):1356–1362

    CAS  PubMed  Google Scholar 

  42. 42.

    Vahdat LT, Garcia AA, Vogel C, Pellegrino C, Lindquist DL, Iannotti N, Gopalakrishna P, Sparano JA (2013) Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized phase II study comparing the incidence of peripheral neuropathy. Breast Cancer Res Treat 140(2):341–351

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M (2014) Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain 155(12):2461–2470

    PubMed  Google Scholar 

  44. 44.

    Izycki D, Niezgoda A, Kazmierczak M, Nowak-Markwitz E (2016) Chemotherapy-induced peripheral neuropathy - epidemiology and pathogenesis. Ginekol Pol 87(4):293–299

    PubMed  Google Scholar 

  45. 45.

    Devriese LA, Witteveen PO, Marchetti S, Mergui-Roelvink M, Reyderman L, Wanders J, Jenner A, Edwards G, Beijnen JH, Voest EE, Schellens JH (2012) Pharmacokinetics of eribulin mesylate in patients with solid tumors and hepatic impairment. Cancer Chemother Pharmacol70(6):823–832

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the patients and investigators who participated in this study. Editorial support for this manuscript was provided by Jake Burrell, PhD (Rude Health Consulting).

Funding

The study was funded by Eisai Co., Ltd., Japan. Preparation assistance by Oxford PharmaGenesis was funded by Eisai Inc.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Xichun Hu.

Ethics declarations

The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and the institutional review board/ethics committee at each site.

Disclaimer

The sponsor played a role in designing the study, interpreting the data, and reviewing the draft manuscripts.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the institutional ethical committee and the patient signed an informed consent to participate in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, Y., Wang, Q., Zhang, J. et al. Incidence of peripheral neuropathy associated with eribulin mesylate versus vinorelbine in patients with metastatic breast cancer: sub-group analysis of a randomized phase III study. Support Care Cancer 28, 3819–3829 (2020). https://doi.org/10.1007/s00520-019-05112-5

Download citation

Keywords

  • Eribulin mesylate
  • Vinorelbine
  • Peripheral neuropathy
  • Metastatic breast cancer