Skip to main content

Advertisement

SpringerLink
Log in

Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial

  • Original Article
  • Published:
Supportive Care in Cancer Aims and scope Submit manuscript

Abstract

Purpose

Over half of all cancer patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which includes numbness, tingling, pain, cold sensitivity, and motor impairment in the hands and feet. CIPN is a dose-limiting toxicity, potentially increasing mortality. There are no FDA-approved drugs to treat CIPN, and behavioral interventions such as exercise are promising yet understudied. This secondary analysis of our nationwide phase III randomized controlled trial of exercise for fatigue examines (1) effects of exercise on CIPN symptoms, (2) factors that predict CIPN symptoms, and (3) factors that moderate effects of exercise on CIPN symptoms.

Methods

Cancer patients (N = 355, 56 ± 11 years, 93% female, 79% breast cancer) receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy were randomized to chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP©®). EXCAP is a standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance exercise program. Patients reported CIPN symptoms of numbness and tingling and hot/coldness in hands/feet (0–10 scales) pre- and post-intervention. We explored baseline neuropathy, sex, age, body mass index, cancer stage, and cancer type as possible factors associated with CIPN symptoms and exercise effectiveness.

Results

Exercise reduced CIPN symptoms of hot/coldness in hands/feet (−0.46 units, p = 0.045) and numbness and tingling (− 0.42 units, p = 0.061) compared to the control. Exercise reduced CIPN symptoms more for patients who were older (p = 0.086), male (p = 0.028), or had breast cancer (p = 0.076).

Conclusions

Exercise appears to reduce CIPN symptoms in patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy. Clinicians should consider prescribing exercise for these patients.

Trial registration

Clinical Trials.gov, # NCT00924651, http://www.clinicaltrials.gov.

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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. 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. https://doi.org/10.1016/j.pain.2014.09.020

    Article  PubMed  Google Scholar 

  2. Postma TJ, Aaronson NK, Heimans JJ, Muller MJ, Hildebrand JG, Delattre JY, Hoang-Xuan K, Lanteri-Minet M, Grant R, Huddart R, Moynihan C, Maher J, Lucey R, E.Q.o.L. Group (2005) The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20. Eur J Cancer 41(8):1135–1139. https://doi.org/10.1016/j.ejca.2005.02.012

    Article  CAS  PubMed  Google Scholar 

  3. Staff NP, Grisold A, Grisold W, Windebank AJ (2017) Chemotherapy-induced peripheral neuropathy: a current review. Ann Neurol 81(6):772–781. https://doi.org/10.1002/ana.24951

    Article  CAS  PubMed  Google Scholar 

  4. Lyman GH (2009) Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Cancer Netw 7(1):99–108. https://doi.org/10.6004/jnccn.2009.0009

    Article  Google Scholar 

  5. Beijers A, Mols F, Dercksen W, Driessen C, Vreugdenhil G (2014) Chemotherapy-induced peripheral neuropathy and impact on quality of life 6 months after treatment with chemotherapy. J Community Support Oncol 12(11):401–406. https://doi.org/10.12788/jcso.0086

    Article  PubMed  Google Scholar 

  6. 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. https://doi.org/10.1080/02841860902806609

    Article  CAS  PubMed  Google Scholar 

  7. Sisignano M, Baron R, Scholich K, Geisslinger G (2014) Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain. Nat Rev Neurol 10(12):694–707. https://doi.org/10.1038/nrneurol.2014.211

    Article  CAS  PubMed  Google Scholar 

  8. Lees JG, Makker PG, Tonkin RS, Abdulla M, Park SB, Goldstein D, Moalem-Taylor G (2017) Immune-mediated processes implicated in chemotherapy-induced peripheral neuropathy. Eur J Cancer 73:22–29. https://doi.org/10.1016/j.ejca.2016.12.006

    Article  CAS  PubMed  Google Scholar 

  9. Wang XM, Lehky TJ, Brell JM, Dorsey SG (2012) Discovering cytokines as targets for chemotherapy-induced painful peripheral neuropathy. Cytokine 59(1):3–9. https://doi.org/10.1016/j.cyto.2012.03.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Flatters SJ, Bennett GJ (2006) Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 122(3):245–257. https://doi.org/10.1016/j.pain.2006.01.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Costigan M, Scholz J, Woolf CJ (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 32(1):1–32. https://doi.org/10.1146/annurev.neuro.051508.135531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cathcart-Rake EJ, Hilliker DR, Loprinzi CL (2017) Chemotherapy-induced neuropathy: central resolution of a peripherally perceived problem? Cancer 123(11):1898–1900. https://doi.org/10.1002/cncr.30650

    Article  PubMed  Google Scholar 

  13. Majithia N, Temkin SM, Ruddy KJ, Beutler AS, Hershman DL, Loprinzi CL (2016) National Cancer Institute-supported chemotherapy-induced peripheral neuropathy trials: outcomes and lessons. Support Care Cancer 24(3):1439–1447. https://doi.org/10.1007/s00520-015-3063-4

    Article  PubMed  Google Scholar 

  14. 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, O. American Society of Clinical (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 

  15. Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, Bressler LR, Fadul CE, Knox C, Le-Lindqwister N, Gilman PB, Shapiro CL, O. Alliance for Clinical Trials in (2013) Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA 309(13):1359–1367. https://doi.org/10.1001/jama.2013.2813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tham A, Jonsson U, Andersson G, Soderlund A, Allard P, Bertilsson G (2016) Efficacy and tolerability of antidepressants in people aged 65 years or older with major depressive disorder—a systematic review and a meta-analysis. J Affect Disord 205:1–12. https://doi.org/10.1016/j.jad.2016.06.013

    Article  CAS  PubMed  Google Scholar 

  17. Brami C, Bao T, Deng G (2016) Natural products and complementary therapies for chemotherapy-induced peripheral neuropathy: a systematic review. Crit Rev Oncol Hematol 98:325–334. https://doi.org/10.1016/j.critrevonc.2015.11.014

    Article  PubMed  Google Scholar 

  18. Mols F, Beijers AJ, Vreugdenhil G, Verhulst A, Schep G, Husson O (2015) Chemotherapy-induced peripheral neuropathy, physical activity and health-related quality of life among colorectal cancer survivors from the PROFILES registry. J Cancer Surviv 9(3):512–522. https://doi.org/10.1007/s11764-015-0427-1

    Article  PubMed  Google Scholar 

  19. Stevinson C, Steed H, Faught W, Tonkin K, Vallance JK, Ladha AB, Schepansky A, Capstick V, Courneya KS (2009) Physical activity in ovarian cancer survivors: associations with fatigue, sleep, and psychosocial functioning. Int J Gynecol Cancer 19(1):73–78. https://doi.org/10.1111/IGC.0b013e31819902ec

    Article  PubMed  Google Scholar 

  20. Courneya KS, McKenzie DC, Mackey JR, Gelmon K, Friedenreich CM, Yasui Y, Reid RD, Vallerand JR, Adams SC, Proulx C, Dolan LB, Wooding E, Segal RJ (2014) Subgroup effects in a randomised trial of different types and doses of exercise during breast cancer chemotherapy. Br J Cancer 111(9):1718–1725. https://doi.org/10.1038/bjc.2014.466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Streckmann F, Kneis S, Leifert JA, Baumann FT, Kleber M, Ihorst G, Herich L, Grussinger V, Gollhofer A, Bertz H (2014) Exercise program improves therapy-related side-effects and quality of life in lymphoma patients undergoing therapy. Ann Oncol 25(2):493–499. https://doi.org/10.1093/annonc/mdt568

    Article  CAS  PubMed  Google Scholar 

  22. Zimmer P, Trebing S, Timmers-Trebing U, Schenk A, Paust R, Bloch W, Rudolph R, Streckmann F, Baumann FT (2017) Eight-week, multimodal exercise counteracts a progress of chemotherapy-induced peripheral neuropathy and improves balance and strength in metastasized colorectal cancer patients: a randomized controlled trial. Support Care Cancer. https://doi.org/10.1007/s00520-017-3875-5

  23. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA (2011) The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 11(9):607–615. https://doi.org/10.1038/nri3041

    Article  CAS  PubMed  Google Scholar 

  24. Holschneider DP, Yang J, Guo Y, Maarek JM (2007) Reorganization of functional brain maps after exercise training: importance of cerebellar-thalamic-cortical pathway. Brain Res 1184:96–107. https://doi.org/10.1016/j.brainres.2007.09.081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schutzer KA, Graves BS (2004) Barriers and motivations to exercise in older adults. Prev Med 39(5):1056–1061. https://doi.org/10.1016/j.ypmed.2004.04.003

    Article  PubMed  Google Scholar 

  26. McCorkle R, Ercolano E, Lazenby M, Schulman-Green D, Schilling LS, Lorig K, Wagner EH (2011) Self-management: enabling and empowering patients living with cancer as a chronic illness. CA Cancer J Clin 61(1):50–62. https://doi.org/10.3322/caac.20093

    Article  PubMed  PubMed Central  Google Scholar 

  27. Marcus BH, Selby VC, Niaura RS, Rossi JS (1992) Self-efficacy and the stages of exercise behavior change. Res Q Exerc Sport 63(1):60–66. https://doi.org/10.1080/02701367.1992.10607557

    Article  CAS  PubMed  Google Scholar 

  28. American College of Sports Medicine (2010) ACSM’s guidelines for exercise testing and prescription. Lippincott, Williams, & Wilkins, Baltimore

    Google Scholar 

  29. Mendoza TR, Zhao F, Cleeland CS, Wagner LI, Patrick-Miller LJ, Fisch MJ (2013) The validity and utility of the M. D. Anderson symptom inventory in patients with breast cancer: evidence from the symptom outcomes and practice patterns data from the eastern cooperative oncology group. Clin Breast Cancer 13(5):325–334. https://doi.org/10.1016/j.clbc.2013.02.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bao T, Basal C, Seluzicki C, Li SQ, Seidman AD, Mao JJ (2016) Long-term chemotherapy-induced peripheral neuropathy among breast cancer survivors: prevalence, risk factors, and fall risk. Breast Cancer Res Treat 159(2):327–333. https://doi.org/10.1007/s10549-016-3939-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. R Core Team (2013) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

    Google Scholar 

  32. Mustian KM, Sprod LK, Janelsins M, Peppone LJ, Palesh OG, Chandwani K, Reddy PS, Melnik MK, Heckler C, Morrow GR (2013) Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors. J Clin Oncol 31(26):3233–3241. https://doi.org/10.1200/JCO.2012.43.7707

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hui D, Glitza I, Chisholm G, Yennu S, Bruera E (2013) Attrition rates, reasons, and predictive factors in supportive care and palliative oncology clinical trials. Cancer 119(5):1098–1105. https://doi.org/10.1002/cncr.27854

    Article  PubMed  Google Scholar 

  34. Yoshikawa T, Takano M, Miyamoto M, Yajima I, Shimizu Y, Aizawa Y, Suguchi Y, Moriiwa M, Aoyama T, Soyama H, Goto T, Hirata J, Suzuki A, Sasa H, Nagaoka I, Tsuda H, Furuya K (2017) Psoas muscle volume as a predictor of peripheral neurotoxicity induced by primary chemotherapy in ovarian cancers. Cancer Chemother Pharmacol 80:555. https://doi.org/10.1007/s00280-017-3395-5

  35. Kleckner IR, Zhang J, Touroutoglou A, Chanes L, Xia C, Simmons WK, Quigley KS, Dickerson BC, Barrett LF (2017) Evidence for a Large-Scale Brain System Supporting Allostasis and Interoception in Humans. Nat Hum Behav 1. Article 0069. https://doi.org/10.1038/s41562-017-0069

  36. Khalsa SS, Rudrauf D, Tranel D (2009) Interoceptive awareness declines with age. Psychophysiology 46(6):1130–1136. https://doi.org/10.1111/j.1469-8986.2009.00859.x

    Article  PubMed  PubMed Central  Google Scholar 

  37. Mendes WB (2010) Weakened links between mind and body in older age: the case for maturational dualism in the experience of emotion. Emot Rev 2(3):240–244. https://doi.org/10.1177/1754073910364149

    Article  Google Scholar 

  38. Damoiseaux JS, Beckmann CF, Arigita EJ, Barkhof F, Scheltens P, Stam CJ, Smith SM, Rombouts SA (2008) Reduced resting-state brain activity in the “default network” in normal aging. Cereb Cortex 18(8):1856–1864. https://doi.org/10.1093/cercor/bhm207

    Article  CAS  PubMed  Google Scholar 

  39. Bakkour A, Morris JC, Wolk DA, Dickerson BC (2013) The effects of aging and Alzheimer’s disease on cerebral cortical anatomy: specificity and differential relationships with cognition. NeuroImage 76:332–344. https://doi.org/10.1016/j.neuroimage.2013.02.059

    Article  PubMed  PubMed Central  Google Scholar 

  40. Huang P, Fang R, Li BY, Chen SD (2016) Exercise-related changes of networks in aging and mild cognitive impairment brain. Front Aging Neurosci 8:47

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Vandervelde A, Miller H, Younts J (2014) Impact on medicare payments of shift in site of care for chemotherapy administration. Berkeley Research Group. https://www.communityoncology.org/UserFiles/BRG_340B_SiteofCare_ReportF_6-9-14.pdf

  42. McCrary JM, Goldstein D, Boyle F, Cox K, Grimison P, Kiernan MC, Krishnan AV, Lewis CR, Webber K, Baron-Hay S, Horvath L, Park SB, I.F.D.w. party (2017) Optimal clinical assessment strategies for chemotherapy-induced peripheral neuropathy (CIPN): a systematic review and Delphi survey. Support Care Cancer 25:3485. https://doi.org/10.1007/s00520-017-3772-y

  43. Nam S, Dobrosielski DA, Stewart KJ (2012) Predictors of exercise intervention dropout in sedentary individuals with type 2 diabetes. J Cardiopulm Rehabil Prev 32(6):370–378. https://doi.org/10.1097/HCR.0b013e31826be485

    Article  PubMed  PubMed Central  Google Scholar 

  44. Gewandter JS, Freeman R, Kitt RA, Cavaletti G, Gauthier LR, McDermott MP, Mohile NA, Mohlie SG, Smith AG, Tejani MA, Turk DC, Dworkin RH (2017) Chemotherapy-induced peripheral neuropathy clinical trials: review and recommendations. Neurology 89(8):859–869. https://doi.org/10.1212/WNL.0000000000004272

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Drs. Susan Rosenthal and Amber Kleckner for their support on this project. We extend special thanks to the cancer patients, as well as the research staff in the University of Rochester Cancer Center NCORP Research Base at each of the NCI NCORP affiliates who recruited and followed participants in this study. We also thank the staff of the PEAK Human Performance Laboratory and the Cancer Control Psychoneuroimmunology Laboratory. We thank the National Cancer Institute and the Division of Cancer Prevention for their funding support of this project.

Funding

Funding was provided by the National Cancer Institute, including funds from NCORP (formerly CCOP) parent grant U10 CA037420, NCORP (formerly CCOP) supplement U10 CA037420, and R25 CA102618.

Author information

Authors and Affiliations

  1. James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA

    Ian R. Kleckner, Charles Kamen, Jennifer S. Gewandter, Nimish A. Mohile, Charles E. Heckler, Eva Culakova, Chunkit Fung, Michelle C. Janelsins, Matthew Asare, Po-Ju Lin & Karen M. Mustian

  2. Cancer Control Center, Department of Surgery, University of Rochester Medical Center, 265 Crittenden Blvd., Box CU 420658, Rochester, NY, 14642, USA

    Ian R. Kleckner

  3. Wichita NCI Community Oncology Research Program (NCORP), Wichita, KS, USA

    Pavan S. Reddy

  4. Greenville NCORP, Greenville, SC, USA

    Jeffrey Giguere

  5. Hawaii NCORP, Honolulu, HI, USA

    Jeffrey Berenberg

  6. MD Anderson Cancer Center, Houston, TX, USA

    Shelli R. Kesler

Authors
  1. Ian R. Kleckner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles Kamen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jennifer S. Gewandter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nimish A. Mohile
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Charles E. Heckler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eva Culakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chunkit Fung
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michelle C. Janelsins
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Matthew Asare
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Po-Ju Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Pavan S. Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jeffrey Giguere
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jeffrey Berenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shelli R. Kesler
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Karen M. Mustian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian R. Kleckner.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(PDF 606 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kleckner, I.R., Kamen, C., Gewandter, J.S. et al. Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial. Support Care Cancer 26, 1019–1028 (2018). https://doi.org/10.1007/s00520-017-4013-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00520-017-4013-0

Keywords

Search

Navigation