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, access via your institution.



References
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
American College of Sports Medicine (2010) ACSM’s guidelines for exercise testing and prescription. Lippincott, Williams, & Wilkins, Baltimore
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
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
R Core Team (2013) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Corresponding author
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
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00520-017-4013-0
Keywords
- CIPN
- Exercise
- Neuropathy