Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Epidemiology

Persistent neuropathy among early-stage breast cancer survivors in a population-based cohort

Abstract

Background

The prevalence of persistent peripheral neuropathy (PN) in early-stage breast cancer (ESBC) survivors is largely unknown. We explored the occurrence and risk factors of PN among long-term ESBC survivors treated with taxane chemotherapy.

Methods

A population-based cohort of 884 recurrence-free ESBC survivors diagnosed 2010–2015 in the South East Health Care region, Sweden and 1768 control women without prior cancer received a postal questionnaire that included the European Organisation for Research and Treatment of Cancer chemotherapy-induced peripheral neuropathy (CIPN20) items. Prevalence, relative risks (RRs) (Poisson regression) and risk factors (binomial regression) were calculated. Adjustments were made for confounding factors (e.g. age, body mass index, comorbidities).

Results

The response rate was 79% for survivors and 59% for controls. The median time post taxane was 3.6 years (1.5–7.3 years). The adjusted RR was highest (RR 1.8) for “tingling/numbness of toes/feet”. Individual sensory symptoms occurred in 8.9–48.4% and motor symptoms in 7.2–61.3% of survivors; the most prevalent symptoms were “difficulty opening jar” and “cramps in feet”. Paclitaxel, older age, overweight, diabetes mellitus, vibrating hand tools, autoimmune disease and smoking were independent risk factors.

Conclusions

PN was more common among ESBC survivors than control women and many symptoms persisted over time. Risk factors should be considered when treatment decisions are made.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2: Self-reported symptoms of peripheral neuropathy (EORTC QLQ-CIPN20) among early-stage breast cancer survivors and control women.

References

  1. 1.

    Peto, R., Davies, C., Godwin, J., Gray, R., Pan, H. C., Clarke, M. et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379, 432–444 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Bedard, P. L., Di Leo, A. & Piccart-Gebhart, M. J. Taxanes: optimizing adjuvant chemotherapy for early-stage breast cancer. Nat. Rev. Clin. Oncol. 7, 22–36 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Mols, F., Beijers, T., Vreugdenhil, G. & van de Poll-Franse, L. Chemotherapy-induced peripheral neuropathy and its association with quality of life: a systematic review. Support. Care Cancer 22, 2261–2269 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Tanabe, Y., Hashimoto, K., Shimizu, C., Hirakawa, A., Harano, K., Yunokawa, M. et al. Paclitaxel-induced peripheral neuropathy in patients receiving adjuvant chemotherapy for breast cancer. Int. J. Clin. Oncol. 18, 132–138 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Nitz, U., Gluz, O., Huober, J., Kreipe, H. H., Kates, R. E., Hartmann, A. et al. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. Ann. Oncol. 25, 1551–1557 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Ewertz, M., Qvortrup, C. & Eckhoff, L. Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives. Acta Oncol. 54, 587–591 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Bandos, H., Melnikow, J., Rivera, D. R., Swain, S. M., Sturtz, K., Fehrenbacher, L. et al. Long-term peripheral neuropathy in breast cancer patients treated with adjuvant chemotherapy: NRG Oncology/NSABP B-30. J. Natl Cancer Inst. 110, https://doi.org/10.1093/jnci/djx162 (2018).

  9. 9.

    Speck, R. M., Sammel, M. D., Farrar, J. T., Hennessy, S., Mao, J. J., Stineman, M. G. et al. Impact of chemotherapy-induced peripheral neuropathy on treatment delivery in nonmetastatic breast cancer. J. Oncol. Pract. 9, e234–e240 (2013).

    PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Pachman, D. R., Barton, D. L., Swetz, K. M. & Loprinzi, C. L. Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain. J. Clin. Oncol. 30, 3687–3696 (2012).

    PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Rivera, D. R., Ganz, P. A., Weyrich, M. S., Bandos, H. & Melnikow, J. Chemotherapy-Associated peripheral neuropathy in patients with early-stage breast cancer: a systematic review. J. Natl Cancer Inst. 110, https://doi.org/10.1093/jnci/djx140 (2018).

  12. 12.

    Seretny, M., Currie, G. L., Sena, E. S., Ramnarine, S., Grant, R., MacLeod, M. R. et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain 155, 2461–2470 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Greenlee, H., Hershman, D. L., Shi, Z., Kwan, M. L., Ergas, I. J., Roh, J. M. et al. BMI, lifestyle factors and taxane-induced neuropathy in breast cancer patients: the Pathways Study. J. Natl Cancer Inst. 109, https://doi.org/10.1093/jnci/djw206 (2017).

  14. 14.

    Bao, T., Basal, C., Seluzicki, C., Li, S. Q., Seidman, A. D. & Mao, J. J. Long-term chemotherapy-induced peripheral neuropathy among breast cancer survivors: prevalence, risk factors, and fall risk. Breast Cancer Res. Treat. 159, 327–333 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Julian, T., Glascow, N., Syeed, R. & Zis, P. Alcohol-related peripheral neuropathy: a systematic review and meta-analysis. J. Neurol. 266, 2907–2919 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Hanewinckel, R., van Oijen, M., Ikram, M. A. & van Doorn, P. A. The epidemiology and risk factors of chronic polyneuropathy. Eur. J. Epidemiol. 31, 5–20 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Rolke, R., Rolke, S., Vogt, T., Birklein, F., Geber, C., Treede, R. D. et al. Hand-arm vibration syndrome: clinical characteristics, conventional electrophysiology and quantitative sensory testing. Clin. Neurophysiol. 124, 1680–1688 (2013).

    PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Heaver, C., Goonetilleke, K. S., Ferguson, H. & Shiralkar, S. Hand-arm vibration syndrome: a common occupational hazard in industrialized countries. J. Hand Surg. Eur. Vol. 36, 354–363 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Mols, F., van de Poll-Franse, L. V., Vreugdenhil, G., Beijers, A. J., Kieffer, J. M., Aaronson, N. K. et al. Reference data of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 Questionnaire in the general Dutch population. Eur. J. Cancer 69, 28–38 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Barlow, L., Westergren, K., Holmberg, L. & Talbäck, M. The completeness of the Swedish Cancer Register: a sample survey for year 1998. Acta Oncol. 48, 27–33 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J. et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J. Natl Cancer Inst. 85, 365–376 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Zigmond, A. S. & Snaith, R. P. The hospital anxiety and depression scale. Acta Psychiatr. Scand. 67, 361–370 (1983).

    CAS  Article  Google Scholar 

  23. 23.

    Postma, T. J., Aaronson, N. K., Heimans, J. J., Muller, M. J., Hildebrand, J. G., Delattre, J. Y. et al. The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20. Eur. J. Cancer 41, 1135–1139 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Kieffer, J. M., Postma, T. J., van de Poll-Franse, L., Mols, F., Heimans, J. J., Cavaletti, G. et al. Evaluation of the psychometric properties of the EORTC chemotherapy-induced peripheral neuropathy questionnaire (QLQ-CIPN20). Qual. Life Res. 26, 2999–3010 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Cavaletti, G., Cornblath, D. R., Merkies, I. S., Postma, T. J., Rossi, E., Frigeni, B. et al. The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings. Ann. Oncol. 24, 454–462 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Lavoie Smith, E. M., Barton, D. L., Qin, R., Steen, P. D., Aaronson, N. K. & Loprinzi, C. L. Assessing patient-reported peripheral neuropathy: the reliability and validity of the European Organization for Research and Treatment of Cancer QLQ-CIPN20 Questionnaire. Qual. Life Res. 22, 2787–2799 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Smith, E. M. L., Banerjee, T., Yang, J. J., Bridges, C. M., Alberti, P., Sloan, J. A. et al. Psychometric Testing of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20-Item Scale Using Pooled Chemotherapy-Induced Peripheral Neuropathy Outcome Measures Standardization and Alliance for Clinical Trials in Oncology A151408 Study Data. Cancer Nurs. 42, 179–189 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Olsson, S. J., Ekblom, Ö., Andersson, E., Börjesson, M. & Kallings, L. V. Categorical answer modes provide superior validity to open answers when asking for level of physical activity: a cross-sectional study. Scand. J. Public Health 44, 70–76 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Bush, K., Kivlahan, D. R., McDonell, M. B., Fihn, S. D. & Bradley, K. A. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. Arch. Intern. Med. 158, 1789–1795 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    McNutt, L. A., Wu, C., Xue, X. & Hafner, J. P. Estimating the relative risk in cohort studies and clinical trials of common outcomes. Am. J. Epidemiol. 157, 940–943 (2003).

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Winters-Stone, K. M., Horak, F., Jacobs, P. G., Trubowitz, P., Dieckmann, N. F., Stoyles, S. et al. Falls, functioning, and disability among women with persistent symptoms of chemotherapy-induced peripheral neuropathy. J. Clin. Oncol. 35, 2604–2612 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Mustafa Ali, M., Moeller, M., Rybicki, L. & Moore, H. C. F. Long-term peripheral neuropathy symptoms in breast cancer survivors. Breast Cancer Res. Treat. https://doi.org/10.1007/s10549-017-4437-8 (2017).

  33. 33.

    Lavoie Smith, E. M., Haupt, R., Kelly, J. P., Lee, D., Kanzawa-Lee, G., Knoerl, R. et al. The content validity of a chemotherapy-induced peripheral neuropathy patient-reported outcome measure. Oncol. Nurs. Forum 44, 580–588 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Wang, M., Cheng, H. L., Lopez, V., Sundar, R., Yorke, J. & Molassiotis, A. Redefining chemotherapy-induced peripheral neuropathy through symptom cluster analysis and patient-reported outcome data over time. BMC Cancer 19, 1151 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Molassiotis, A., Cheng, H. L., Lopez, V., Au, J. S. K., Chan, A., Bandla, A. et al. Are we mis-estimating chemotherapy-induced peripheral neuropathy? Analysis of assessment methodologies from a prospective, multinational, longitudinal cohort study of patients receiving neurotoxic chemotherapy. BMC Cancer 19, 132 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Frisina, R. D., Wheeler, H. E., Fossa, S. D., Kerns, S. L., Fung, C., Sesso, H. D. et al. Comprehensive audiometric analysis of hearing impairment and tinnitus after cisplatin-based chemotherapy in survivors of adult-onset cancer. J. Clin. Oncol. 34, 2712–2720 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Hanewinckel, R., Drenthen, J., van Oijen, M., Hofman, A., van Doorn, P. A. & Ikram, M. A. Prevalence of polyneuropathy in the general middle-aged and elderly population. Neurology 87, 1892–1898 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Pérez-Fidalgo, J. A., Roselló, S., García-Garré, E., Jordá, E., Martín-Martorell, P., Bermejo, B. et al. Incidence of chemotherapy-induced amenorrhea in hormone-sensitive breast cancer patients: the impact of addition of taxanes to anthracycline-based regimens. Breast Cancer Res. Treat. 120, 245–251 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Gonnelli, S. & Petrioli, R. Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer. Clin. Interv. Aging 3, 647–657 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Neuhouser, M. L., Aragaki, A. K., Prentice, R. L., Manson, J. E., Chlebowski, R., Carty, C. L. et al. Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the women’s health initiative randomized clinical trials. JAMA Oncol. 1, 611–621 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Hershman, D. L., Till, C., Wright, J. D., Awad, D., Ramsey, S. D., Barlow, W. E. et al. Comorbidities and risk of chemotherapy-induced peripheral neuropathy among participants 65 years or older in southwest oncology group clinical trials. J. Clin. Oncol. 34, 3014–3022 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Bhattacharyya, S. & Helfgott, S. M. Neurologic complications of systemic lupus erythematosus, Sjögren syndrome, and rheumatoid arthritis. Semin. Neurol. 34, 425–436 (2014).

    PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Brydøy, M., Oldenburg, J., Klepp, O., Bremnes, R. M., Wist, E. A., Wentzel-Larsen, T. et al. Observational study of prevalence of long-term Raynaud-like phenomena and neurological side effects in testicular cancer survivors. J. Natl Cancer Inst. 101, 1682–1695 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Jordan, B., Margulies, A., Cardoso, F., Cavaletti, G., Haugnes, H. S., Jahn, P. et al. Systemic anticancer therapy-induced peripheral and central neurotoxicity: ESMO-EONS-EANO Clinical Practice Guidelines for diagnosis, prevention, treatment and follow-up. Ann. Oncol. 31, 1306–1319 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Hershman, D. L., Weimer, L. H., 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. 125, 767–774 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

We wish to thank all the study participants, Marika Wenemark for assistance in developing the questionnaire and Rasmus Mikiver for cancer register assistance.

Author information

Affiliations

Authors

Contributions

Conceptualisation; data curation; formal analysis; methodology; resources; software; supervision; validation; visualisation; roles/writing—original draft: K.E., M.F., H.G. and E.Å.-L. Funding acquisition; investigation; project administration; writing—review and editing: K.E., H.G. and E.Å.L.

Corresponding author

Correspondence to Kristina Engvall.

Ethics declarations

Ethics approval and consent to participate

The Regional Ethics Committee in Linköping approved the study (Ref. no. 2016/548-31). All women who participated in the study gave informed consent by returning the questionnaire. The study was performed in accordance with the Declaration of Helsinki.

Consent to publish

This study contained no individual person’s data.

Data availability

The dataset analysed during the current study is available from the corresponding author on reasonable request.

Competing interests

The funding sources played no role in the study. The authors declare no competing interests.

Funding information

This work was supported by the Swedish Cancer Society (190224); the Medical Research Council of Southeast Sweden (FORSS-932359); Futurum—The Academy for Health and Care, Jönköping County Council (575361); Forsknings-ALF (LIO-901261).

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Engvall, K., Gréen, H., Fredriksson, M. et al. Persistent neuropathy among early-stage breast cancer survivors in a population-based cohort. Br J Cancer (2021). https://doi.org/10.1038/s41416-021-01429-3

Download citation

Search

Quick links