Abstract
Purpose:
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect of neurotoxic chemotherapy. Exercise activates neuromuscular function and may improve CIPN. We examined the association between exercise and CIPN symptoms in breast cancer survivors.
Methods:
In a retrospective cross-sectional study, we included patients completing a survey assessing exercise exposure and neuropathy symptoms in a tertiary cancer center survivorship clinic. We evaluated exercise duration and intensity using a standardized questionnaire quantified in metabolic equivalent tasks (MET-h/wk). We defined exercisers as patients meeting the National Physical Activity Guidelines’ criteria. We used multivariable logistic regressions to examine the relationship between exercise and CIPN and if this differed as a function of chemotherapy regimen adjusting for age, gender, and race.
Results:
We identified 5,444 breast cancer survivors post-chemotherapy (median age 62 years (interquartile range [IQR]: 55, 71); median 4.7 years post-chemotherapy (IQR: 3.3, 7.6)) from 2017–2022. CIPN overall prevalence was 34% (95% confidence interval [CI]: 33%, 36%), 33% for non-taxane and 37% for taxane-based chemotherapy. CIPN prevalence was 28% (95% CI: 26%, 30%) among exercisers and 38% (95% CI: 37%, 40%) among non-exercisers (difference 11%; 95% CI: 8%, 13%; p<0.001). Compared to patients with low (<6 MET-h/wk) levels of exercise (42%), 11% fewer patients with moderate (6–20.24 MET-h/wk) to high (>20.25 MET-h/wk) levels of exercise reported CIPN. Exercise was associated with reduced prevalence of all CIPN symptoms regardless of chemotherapy type.
Conclusion:
CIPN may persist several years following chemotherapy among patients with breast cancer but is significantly reduced by exercise in a dose-dependent manner.
Keywords: chemotherapy-induced peripheral neuropathy, physical exercise, symptom management, breast cancer survivors
INTRODUCTION
Chemotherapy remains a mainstay anticancer treatment for primary breast cancer. Unfortunately, chemotherapy-induced peripheral neuropathy (CIPN) is a common, and often debilitating, side effect of neurotoxic chemotherapy such as taxanes, platinums, and vinca alkaloids.[1] Up to 68% of patients receiving chemotherapy will develop CIPN during or immediately after treatment, with 30–40% of patients still experiencing symptoms six months post-chemotherapy.[2–7]
CIPN causes pain, numbness, and tingling in the extremities, resulting in balance difficulties and an increased risk of falls.[8, 9] CIPN can lead to dose reduction or discontinuation altogether of chemotherapy for those undergoing treatment, resulting in lower treatment efficacy and higher overall mortality.[3] Among cancer survivors, CIPN can lower quality of life by interfering with basic daily activities such as walking and driving.[10–12] Despite its prevalence, strategies to treat CIPN are limited; 2020 American Society of Clinical Oncology (ASCO) guidelines recommend only duloxetine for CIPN treatment.[10] Duloxetine has been demonstrated to reduce neuropathy pain and numbness in two recent clinical trials among patients with a wide variety of cancer diagnoses.[13, 14]
Exercise may be one behavioral strategy to reduce CIPN symptoms among breast cancer survivors. Prior trials have demonstrated that higher exercise is associated with lower sensory and motor symptoms of CIPN,[15, 16] and can improve balance, and quality of life[15] among patients with a variety of cancer types (predominantly breast and colorectal) three to 19 months following the completion of chemotherapy. However, little is known about the prevalence of CIPN long term post-chemotherapy and the association between exercise and CIPN within this population.
Leveraging data from a survivorship clinic at a National Cancer Institute-Designated Comprehensive Cancer Center, we examined the prevalence of CIPN among breast cancer survivors and the association between exercise and CIPN in 5,444 patients with primary breast cancer previously treated with adjuvant chemotherapy. We hypothesized that patients who reported higher levels of exercise intensity and duration would report lower CIPN severity.
METHODS
Study Design and Inclusion Criteria
We used a retrospective study design. Eligible patients were diagnosed between 1965 and 2021 with histologically confirmed early-stage (ductal carcinoma in situ, stage I, IIA, IIB, or IIIA) breast cancer; completed a self-reported assessment as an aspect of standard intake at each Breast Survivorship Clinic visits at Memorial Sloan Kettering Cancer Center (MSK) between 2017 and 2022; and previously treated with chemotherapy. The protocol was approved by the MSK Institutional Review Board (IRB#20–101). Written informed consent was waived as the IRB identified our study involved minimal risk to the participants. This manuscript is reported consistent with STROBE recommendations.
Exercise Assessment
Exercise history was evaluated using the Godin Leisure Time Exercise Questionnaire (GLTEQ), a validated survey instrument for breast cancer patients.[17] All survey responses included in this analysis were completed via a web application called MSK Engage. The GLTEQ contains three questions that assess the average frequency of mild, moderate, and strenuous-intensity exercise sessions of at least 15 minutes/session in a typical seven-day period during leisure time. We modified the GLTEQ to assess average session duration in minutes.
Exercise exposure was calculated using two methods, both of which have been previously described.[18] First, exercise across intensity categories was weighted by an estimate of the metabolic equivalent of the task (MET) then summed to calculate total MET hours per week (MET-h/wk). The standard MET weights for each exercise intensity are mild (3 METs), moderate (5 METs), and strenuous (9 METs). Dose-response was evaluated using tertiles of MET-h/wk. Second, exercise was dichotomized as either meeting or not meeting the Department of Health and Human Services Physical Activity Guidelines for Americans.[19] “Exercisers” were defined as those who did moderate-intensity aerobic exercise ≥ three times per week, with each session, on average, ≥30 minutes in duration or strenuous-intensity exercise ≥ three times per week, with each session, on average, ≥20 minutes in duration or an equivalent combination. “Non- exercisers” are defined as those not meeting the guidelines.
CIPN Assessment
Peripheral neuropathy symptoms were assessed using questions from the Breast Survivorship Patient Self-Assessment.[20] Participants were asked if they currently had numbness or tingling in their hands and feet over the last month, indicating peripheral neuropathy. CIPN was further defined as those experiencing peripheral neuropathy following neurotoxic chemotherapy. Participants described the severity of the numbness or tingling at its worst, measured on a Likert scale ranging from (1) none to (5) very severe, and how much these symptoms interfere with their usual or daily activities, measured on a Likert scale from (1) not at all to (5) very much. Pain at its worst in the last month was also reported on a 0–10 pain scale, with (0) no pain to (10) extreme pain. Pain was subsequently grouped into none (0), mild (1–3), moderate (4–6), and severe pain (7–10).
Statistical Analyses
Demographic and clinical characteristics were summarized using descriptive statistics. Bivariate analyses were used to evaluate associations between CIPN and multiple predictors (i.e. exercise, employment, and mental health comorbidities) using Chi-square tests, Mann-Whitney U-tests, and Kendall’s rank correlations at a p-value threshold of 0.05. A multivariable analysis was then performed using logistic regression with CIPN as the outcome variable and exercise, age, race, gender, ethnicity, chemotherapy type, and time since last chemotherapy as model predictors. Tertiles of GLTEQ scores in MET-h/wk were used to examine exercise dose response. To assess whether the association between exercise and CIPN differs by type of chemotherapy, the interaction between chemotherapy type and exercise was tested in the multivariable logistic regression. All statistical analyses were performed using R 4.2.1.[21]
We collected demographic factors including age, race, ethnicity, employment status, and mental health comorbidities through patient self-report.
RESULTS
A total of 11,233 patients completed the Breast Survivorship Patient Self-Assessment between 2017 and 2022. Of these, 356 (3%) patients were excluded due to missing treatment data and 5,433 (50%) were excluded as they did not receive chemotherapy, leaving a final analytic dataset of 5,444 (Figure 1).
Figure 1.
Study design flow chart: demonstrates the overall study design and number of participants included and excluded in each step
Chemo = Chemotherapy
The median age was 62 years (interquartile range [IQR]: 55, 71), and the median time between the last chemotherapy treatment and survey completion was 4.7 years (IQR: 3.3, 7.6). The majority of our patients were female (99.6%), white (80%), and non-Hispanic (94%). 2,248 participants (41%) received taxane-based chemotherapy and 3,196 (59%) participants received non-taxane chemotherapy such as cyclophosphamide/methotrexate/5-fluorouracil (CMF) and Adriamycin/cyclophosphamide (AC) alone (Table 1).
Table 1.
Participant characteristics
| Characteristicsa | Overall | Non-Taxane Chemotherapy | Taxane-Based Chemotherapy |
|---|---|---|---|
| n | 5,444 | 3,196 (59%) | 2,248 (41%) |
| Age b | 62 (55, 71) | 64 (56, 71) | 61 (54, 69) |
| Time Since Diagnosis (years)b | 8 (5.5, 11.6) | 7.4 (5.1, 10.8) | 8.7 (6.1, 12.5) |
| Time Since Last Chemo | 4.7 (3.3, 7.6) | 4.5 (3.1, 7.1) | 5.1 (3.5, 8.4) |
| Time Between Diagnosis and Last Chemo Treatment (years)b | 1.4 (0.6, 5.2) | 1.5 (0.7, 4.9) | 1.0 (0.5, 5.4) |
| Gender c | |||
| Female | 5,421 (99.6%) | 3,181 (99.5%) | 2,240 (99.6%) |
| Male | 23 (0.4%) | 15 (0.5%) | 8 (0.4%) |
| Race c | |||
| White | 4,237 (80%) | 2,525 (81%) | 1,712 (78%) |
| Black | 551 (10%) | 286 (9.2%) | 265 (12%) |
| Asian | 425 (8%) | 250 (8.0%) | 175 (8.0%) |
| Native | 5 (<0.1%) | 2 (<0.1%) | 3 (0.1%) |
| Other | 79 (1.5%) | 48 (1.5%) | 31 (1.4%) |
| Ethnicity c | |||
| Hispanic/Latinx | 339 (6.4%) | 185 (6.0%) | 154 (7.1%) |
| Non-Hispanic/Latinx | 4,917 (94%) | 2,915 (94%) | 2,002 (93%) |
Values may not equal 100% due to missing data;
Median (IQR);
n (%)
CIPN Prevalence
The overall prevalence of CIPN is 34% (95% confidence interval [CI]: 33%, 36%) in breast cancer individuals who completed adjuvant chemotherapy (n=5,444), including 33% and 37% of patients experience CIPN following non-taxane (n=3,151) or taxane (n=2,212) treatment, respectively. The prevalence of CIPN was 28% (95% CI: 26%, 30%) among exercisers and 38% (95% CI: 37%, 40%) among non-exercisers (difference of 11%; 95% CI: 8%, 13%; p<0.001).
Exercise and CIPN
Compared to patients who reported CIPN as characterized by numbness or tingling by self-report (median MET-h/wk 9, IQR 2, 22), patients without CIPN (median MET-h/wk 13, (IQR 5, 27)) had four points higher MET-h/wk scores (p<0.001). For patients reporting different levels of interference in daily life by CIPN symptoms, there is a significant difference in MET-h/wk (p<0.001) with patients who reported no CIPN symptom interference also having higher MET-h/wk (median 11, (IQR 4, 25)) compared to patients reporting “somewhat” interference (8 (2, 21)), “quite a bit” interference (7 (1, 15)), or “very much” interference (5 (0, 20)). The differences in MET-h/wk across CIPN severity subgroups were statistically significant (p<0.001), with patients who described mild CIPN symptoms also reporting higher MET-h/wk (11 (3, 25)) than those with more severe CIPN symptoms (7, (1, 16)). (Figure 2) These results are consistent across chemotherapy subgroups (taxane, non-taxane based).
Figure 2.
Association between GLTEQ exercise amount (MET-h/wk) and CIPN
This figure demonstrates the association between exercise amount, standardized in MET-h/wk from the GLTEQ instrument, and various CIPN-related symptoms including numbness and tingling of the hands and feet, pain severity, and interference of symptoms on daily life.
GLTEQ = Godin Leisure Time Exercise Questionnaire, a validated questionnaire to evaluate exercise type and amount
MET-h/wk = metabolic equivalent hours per week, a standardized measure of physical activity
CIPN = Chemotherapy-induced peripheral neuropathy
Note: Colors are for improved visualization only; does not have other significance.
We also evaluated findings based on National Exercise Guidelines. Among patients defined as “exercisers,” the prevalence of CIPN was 28% (95% CI: 26%, 30%) and 38% (95% CI: 37%, 40%) among non-exercisers (difference of 11%; 95% CI: 8%, 13%; p<0.001). For exercisers versus non-exercisers, interference in daily life was 50% vs. 60%, (p<0.001), and the mean pain rating was 1.3 vs. 2.1, (p<0.001), respectively. The same association was seen across chemotherapy groups (taxane and non-taxane). Associations appeared dose-dependent. We defined patients with low exercise as the first tertile (T1, <6 MET-h/wk), medium exercise as the second tertile (T2, 6–20.24 MET-h/wk) and high exercise as the third tertile (T3, >20.25 MET-h/wk). Overall CIPN prevalence was 42% for T1, 33% for T2, and 29% for T3. (Table 2)
Table 2.
CIPN symptoms by exercise tertiles (MET-h/wk) and by meeting Department of Health and Human Services Physical Activity Guidelines (exercisers vs. non-exercisers)
| MET-h/wk Tertiles | P-value | Non-Exercisers a,b | Exercisersa | P-value | |||
|---|---|---|---|---|---|---|---|
| T1a | T2a | T3a | |||||
| n | 1,758 | 1,885 | 1,801 | 3,416 | 2,028 | ||
| Numbness or Tingling in Hands or Feet | <0.001U | <0.001χ2 | |||||
| Yes | 724 (42%) | 609 (33%) | 511 (29%) | 1,290 (38%) | 554 (28%) | ||
| No | 999 (58%) | 1,251 (67%) | 1,269 (71%) | 2,065 (62%) | 1,454 (72%) | ||
| Severity at its worst | <0.001τ | <0.001U | |||||
| None | 11 (1.5%) | 8 (1.3%) | 5 (1.0%) | 20 (1.6%) | 4 (0.7%) | ||
| Mild | 319 (44%) | 302 (50%) | 280 (55%) | 593 (46%) | 308 (56%) | ||
| Moderate | 287 (40%) | 217 (36%) | 181 (36%) | 491 (38%) | 194 (35%) | ||
| Severe | 88 (12%) | 69 (11%) | 35 (6.9%) | 156 (12%) | 36 (6.5%) | ||
| Very Severe | 12 (1.7%) | 10 (1.7%) | 8 (1.6%) | 21 (1.6%) | 9 (1.6%) | ||
| Interfere with daily life | <0.001τ | <0.001U | |||||
| Not at all | 263 (37%) | 276 (46%) | 246 (48%) | 511 (40%) | 274 (50%) | ||
| A little bit | 224 (31%) | 164 (27%) | 149 (29%) | 380 (30%) | 157 (28%) | ||
| Somewhat | 146 (20%) | 101 (17%) | 85 (17%) | 245 (19%) | 87 (16%) | ||
| Quite a bit | 65 (9.0%) | 54 (8.9%) | 21 (4.1%) | 114 (8.9%) | 26 (4.7%) | ||
| Very much | 21 (2.9%) | 9 (1.5%) | 10 (2.0%) | 32 (2.5%) | 8 (1.4%) | ||
| Pain rating at its worst | <0.001τ | <0.001U | |||||
| None (0) | 763 (49%) | 944 (55%) | 996 (61%) | 1,569 (51%) | 1,134 (62%) | ||
| Mild (1–3) | 356 (23%) | 394 (23%) | 372 (23%) | 704 (23%) | 418 (23%) | ||
| Moderate (4–6) | 259 (17%) | 209 (12%) | 157 (9.7%) | 454 (15%) | 171 (9.3%) | ||
| Severe (7–10) | 189 (12%) | 163 (9.5%) | 100 (6.2%) | 345 (11%) | 107 (5.8%) | ||
n (%);
Did not meet physical activity guidelines;
Mann-Whitney U-test;
Kendall’s rank correlation;
Chi-square test
These results were consistent when adjusting for age, gender, race, ethnicity, chemotherapy group, and time since the last chemotherapy treatment (Table 3). According to the multivariable analysis, exercise was significantly associated with CIPN (p<0.001). Specifically, an increase of one MET-h/wk was associated with 1% reduced odds of CIPN symptoms (OR: 0.993, 95% CI: 0.989, 0.996). The interaction term between chemotherapy type and exercise was not significant (p=0.7) in the multivariable logistic regression, indicating that the association between exercise and CIPN does not differ by chemotherapy type.
Table 3.
Multivariable analysis results from the logistic regression model for CIPN symptoms
| Characteristic | Odds Ratio | 95% Confidence Interval | P-value |
|---|---|---|---|
| Chemo Group | <0.001 | ||
| Non-Taxane | -- | -- | |
| Taxane | 1.253 | 1.110, 1.415 | |
| GLTEQ (MET-h/wk) | 0.993 | 0.989, 0.996 | <0.001 |
| Age | 1.025 | 1.019, 1.032 | <0.001 |
| Time Since Last Chemo (years) | 0.981 | 0.970, 0.992 | <0.001 |
| Gender | 0.5 | ||
| Female | -- | -- | |
| Male | 0.735 | 0.260, 1.827 | |
| Race | <0.001 | ||
| White | -- | -- | |
| Black/African American | 1.737 | 1.438, 2.097 | |
| Asian/Far East/Indian Sub-Continent | 1.275 | 1.024, 1.583 | |
| Native | 1.509 | 0.195, 9.294 | |
| Other | 0.925 | 0.536, 1.551 | |
| Ethnicity | 0.1 | ||
| Non-Hispanic/Latinx | -- | -- | |
| Hispanic/Latinx | 1.244 | 0.960, 1.607 |
DISCUSSION
This study examined the association between the amount of exercise and CIPN severity among breast cancer survivors. We found 34% percent of breast cancer survivors reported CIPN symptoms, with a median of five years after treatment completion. Among breast cancer survivors, exercise was significantly associated with lower CIPN occurrence and less severe symptom severity including pain, tingling and numbness in a dose-dependent manner, regardless of chemotherapy type. This finding is consistent with prior literature.[22]
Our study results suggest that exercise might be a useful lifestyle factor for CIPN management. Duloxetine has been shown to be effective for improving CIPN pain and numbness, but patients have concerns about unwanted side effects.[10, 13] The most recent 2022 ASCO guideline recommends regular aerobic and resistance exercise during active treatment to mitigate cancer treatment-related side effects. It does not mention using exercise for CIPN specifically.[23] Our study results suggest exercise might be useful for CIPN treatment.
Our results are consistent with findings from Mols et al: their 2015 cross-sectional study among 1,648 colorectal cancer survivors found that of 506 patients treated with chemotherapy, 154 (30%) reported tingling in their hands or feet.[24] This is similar to our finding of 34% of patients reporting CIPN symptoms. Mols et al. found that patients meeting exercise guidelines also reported improved sensory and motor scores, lower pain, and higher physical function.[24] Similar to our own methods, Mols et al. evaluated exercise using MET-h/wk and a dichotomized variable as meeting exercise guidelines or not.[24] A major difference between the two studies, however, is that our patients were primarily treated with taxane-based chemotherapy. In contrast, Mols et al.’s patients were primarily treated with platinum-based agents, a common treatment for colon cancer, the primary cancer type evaluated in their study. [24]
Similarly, McCrary et al. evaluated an eight-week exercise program for breast, colorectal, and ovarian cancer survivors with CIPN in 2019.[15] The intervention consisted of three hours of weekly resistance, balance, and cardiovascular training.[15] Their prospective pilot intervention demonstrated improvement in CIPN symptoms, balance, mobility, and quality of life after the exercise intervention.[15] This prospective study provides further evidence for the ability of increased exercise to lower CIPN symptoms.[15] In addition, their study expands these findings to patients with additional cancer types as our study only included breast cancer survivors.[15]
For patients with CIPN, sensorimotor training is a critical aspect alongside endurance exercise as a key component of treatment.[25] Our results, in conjunction with these previous studies, strongly suggest increased exercise is associated with lower CIPN symptomology. However, given the unclear side effects and clinical importance, exercise should be used as an important lifestyle factor to assist CIPN management. It is important that patients need to pursue proper medical attention from their healthcare team to address their specific symptom management needs. Patients with cancer history might benefit from working with a fitness professional to guide their exercise plans, as this patient population often has treatment and disease adverse effects that can impact their ability to exercise.[26] Patients with CIPN may experience unique challenges to exercising: when proprioception is compromised due to impaired sensory nerve function, strength may also be limited. Patients with CIPN also may experience decreased balance function which can limit their ability to perform certain exercises. [27]
The mechanism of CIPN is multifactorial and chemotherapy agent-specific. Taxane-based therapeutics cause microtubule disruption, mitochondrial dysfunction, and axonal degeneration, leading to peripheral nerve damage.[28] CIPN can also involve neuropathic pain, likely due to alterations in brain areas needed for pain processing, including the somatosensory cortex and the insula.[29], [30–32] Exercise has been shown to reduce chronic inflammation by breaking down visceral fat and promoting an anti-inflammatory environment by increasing circulating IL-10.[33] In addition to reducing inflammation, exercise in animal models increases sensorimotor processing, aid in nerve regeneration through increased blood flow and brain-derived neurotrophic factors and release endogenous opioids to manage neuropathic pain.[34–38]
This study has limitations. First, this retrospective survey study is subject to recall bias. We do not know exercise’s specificity in relieving taxane or non-taxane-based CIPN. Verifications of our findings in a rigorous randomized clinical trial with objective exercise and clinical outcomes assessments are needed address the specificity of exercise on CIPN and inform clinical practice. Second, given the nature of the cross-sectional analysis, we have data from a single point in time for a patient population that had already completed cancer treatment. As such, we do not know the directionality of the association between exercise and CIPN. It is possible that participants who exercised more experienced less CIPN because of the exercise. However, we also must consider that the participants who exercised more were perhaps also those with fewer CIPN symptoms initially, thus allowing them to engage in a higher dosage of physical activity.[39, 40] Third, omitted confounding variables bias is possible, such as drugs, toxins, disease states [41],[42], socioeconomic status, pre-diagnosis exercise states, and non-leisure exercise forms.[43] Fourth, our p-values were not corrected for multiple comparisons. Finally, despite our large sample size, our patients were primarily white, non-Hispanic women with a history of breast cancer, likely due to the clinic location in Manhattan and the surveys only being provided in English. Our study results are therefore limited in generalizability to other genders, races, ethnicities, and cancer types.
CONCLUSION
Among breast cancer survivors treated with taxane- and non-taxane-based chemotherapy, CIPN is persistent several years following chemotherapy cessation but higher exercise is associated with decreased intensity of symptoms. To further determine the causality of this relationship, we recommend future randomized trials testing whether treatment with exercise therapy can treat CIPN.
Acknowledgements:
The authors thank the study participants for their time. Please see “Statements and Declarations” section below for funding and grant information.
Funding:
This work is supported in part by a National Institutes of Health/National Cancer Institute (NIH/NCI) Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. Dr. Bao is supported by NCI R37 CA248563 and R01 CA251470. Alexie Lessing is supported in part by NIH/NCI award number 5R25 CA020449. The funder played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.
Footnotes
Statements and Declarations:
Competing interests: Dr. Jones reports stock ownership in Pacylex Inc. and Illumisonics Inc. Dr. Bao reports a consultation role in Eisai Inc. All other authors declare no financial or non-financial competing interests.
Ethics approval: The protocol was approved by the MSK Institutional Review Board (IRB#20–101).
Consent to participate: Written informed consent was waived as the MSK Institutional Review Board identified our study involved minimal risk to the participants.
Data availability:
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code availability:
The underlying code for this study [and training/validation datasets] is not publicly available but may be made available to qualified researchers on reasonable request from the corresponding author.
REFERENCES
- 1.Windebank AJ, Grisold W: Chemotherapy-induced neuropathy. J Peripher Nerv Syst 2008, 13(1):27–46. [DOI] [PubMed] [Google Scholar]
- 2.Pachman DR, Barton DL, Watson JC, Loprinzi CL: Chemotherapy-induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther 2011, 90(3):377–387. [DOI] [PubMed] [Google Scholar]
- 3.Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, Colvin LA, Fallon M: Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain 2014, 155(12):2461–2470. [DOI] [PubMed] [Google Scholar]
- 4.Hershman DL, Weimer LH, Wang A, Kranwinkel G, Brafman L, Fuentes D, Awad D, Crew KD: 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):767–774. [DOI] [PubMed] [Google Scholar]
- 5.Tanabe Y, Hashimoto K, Shimizu C, Hirakawa A, Harano K, Yunokawa M, Yonemori K, Katsumata N, Tamura K, Ando M et al. : Paclitaxel-induced peripheral neuropathy in patients receiving adjuvant chemotherapy for breast cancer. Int J Clin Oncol 2013, 18(1):132–138. [DOI] [PubMed] [Google Scholar]
- 6.Richardson PG, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D et al. : Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol 2009, 144(6):895–903. [DOI] [PubMed] [Google Scholar]
- 7.Kautio AL, Haanpää M, Kautiainen H, Kalso E, Saarto T: Burden of chemotherapy-induced neuropathy--a cross-sectional study. Support Care Cancer 2011, 19(12):1991–1996. [DOI] [PubMed] [Google Scholar]
- 8.Park SB, Goldstein D, Krishnan AV, Lin CS, Friedlander ML, Cassidy J, Koltzenburg M, Kiernan MC: Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin 2013, 63(6):419–437. [DOI] [PubMed] [Google Scholar]
- 9.Autissier E: Chemotherapy-Induced Peripheral Neuropathy: Association With Increased Risk of Falls and Injuries. Clin J Oncol Nurs 2019, 23(4):405–410. [DOI] [PubMed] [Google Scholar]
- 10.Loprinzi CL, Lacchetti C, Bleeker J, Cavaletti G, Chauhan C, Hertz DL, Kelley MR, Lavino A, Lustberg MB, Paice JA et al. : Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J Clin Oncol 2020, 38(28):3325–3348. [DOI] [PubMed] [Google Scholar]
- 11.Staff NP, Grisold A, Grisold W, Windebank AJ: Chemotherapy-induced peripheral neuropathy: A current review. Ann Neurol 2017, 81(6):772–781. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Pike CT, Birnbaum HG, Muehlenbein CE, Pohl GM, Natale RB: Healthcare costs and workloss burden of patients with chemotherapy-associated peripheral neuropathy in breast, ovarian, head and neck, and nonsmall cell lung cancer. Chemother Res Pract 2012, 2012:913848. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Farshchian N, Alavi A, Heydarheydari S, Moradian N: Comparative study of the effects of venlafaxine and duloxetine on chemotherapy-induced peripheral neuropathy. Cancer Chemother Pharmacol 2018, 82(5):787–793. [DOI] [PubMed] [Google Scholar]
- 14.Hirayama Y, Ishitani K, Sato Y, Iyama S, Takada K, Murase K, Kuroda H, Nagamachi Y, Konuma Y, Fujimi A et al. : Effect of duloxetine in Japanese patients with chemotherapy-induced peripheral neuropathy: a pilot randomized trial. Int J Clin Oncol 2015, 20(5):866–871. [DOI] [PubMed] [Google Scholar]
- 15.McCrary JM, Goldstein D, Sandler CX, Barry BK, Marthick M, Timmins HC, Li T, Horvath L, Grimison P, Park SB: Exercise-based rehabilitation for cancer survivors with chemotherapy-induced peripheral neuropathy. Support Care Cancer 2019, 27(10):3849–3857. [DOI] [PubMed] [Google Scholar]
- 16.Kneis S, Wehrle A, Müller J, Maurer C, Ihorst G, Gollhofer A, Bertz H: It’s never too late - balance and endurance training improves functional performance, quality of life, and alleviates neuropathic symptoms in cancer survivors suffering from chemotherapy-induced peripheral neuropathy: results of a randomized controlled trial. BMC Cancer 2019, 19(1):414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Amireault S, Godin G, Lacombe J, Sabiston CM: Validation of the Godin-Shephard Leisure-Time Physical Activity Questionnaire classification coding system using accelerometer assessment among breast cancer survivors. J Cancer Surviv 2015, 9(3):532–540. [DOI] [PubMed] [Google Scholar]
- 18.Bliss JW, Lavery JA, Underwood WP, Chun SS, Fickera GA, Lee CP, Corcoran S, Maloy MA, Polubriaginof FC, Kelly DW et al. : Impact of Exercise on Susceptibility and Severity of COVID-19 in Patients with Cancer: A Retrospective Study. Cancer Epidemiol Biomarkers Prev 2022, 31(5):1036–1042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, George SM, Olson RD: The Physical Activity Guidelines for Americans. JAMA 2018, 320(19):2020–2028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Bao T, Basal C, Seluzicki C, Li SQ, Seidman AD, Mao JJ: Long-term chemotherapy-induced peripheral neuropathy among breast cancer survivors: prevalence, risk factors, and fall risk. Breast Cancer Res Treat 2016, 159(2):327–333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Computing RCTAlaefscRFfS: R Core Team (2022): A language and environment for statistical computing. R Foundation for Statistical Computing. In. Vienna, Austria. ; 2022. [Google Scholar]
- 22.Núñez de Arenas-Arroyo S, Cavero-Redondo I, Torres-Costoso A, Reina-Gutiérrez S, Lorenzo-García P, Martínez-Vizcaíno V: Effects of exercise interventions to reduce chemotherapy-induced peripheral neuropathy severity: a meta-analysis. Scand J Med Sci Sports 2023. [DOI] [PubMed] [Google Scholar]
- 23.Ligibel JA, Bohlke K, May AM, Clinton SK, Demark-Wahnefried W, Gilchrist SC, Irwin ML, Late M, Mansfield S, Marshall TF et al. : Exercise, Diet, and Weight Management During Cancer Treatment: ASCO Guideline. J Clin Oncol 2022, 40(22):2491–2507. [DOI] [PubMed] [Google Scholar]
- 24.Mols F, Beijers AJ, Vreugdenhil G, Verhulst A, Schep G, Husson O: Chemotherapy-induced peripheral neuropathy, physical activity and health-related quality of life among colorectal cancer survivors from the PROFILES registry. J Cancer Surviv 2015, 9(3):512–522. [DOI] [PubMed] [Google Scholar]
- 25.Streckmann F, Balke M, Cavaletti G, Toscanelli A, Bloch W, Décard BF, Lehmann HC, Faude O: Exercise and Neuropathy: Systematic Review with Meta-Analysis. Sports Med 2022, 52(5):1043–1065. [DOI] [PubMed] [Google Scholar]
- 26.Campbell KL, Winters-Stone KM, Wiskemann J, May AM, Schwartz AL, Courneya KS, Zucker DS, Matthews CE, Ligibel JA, Gerber LH et al. : Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable. Med Sci Sports Exerc 2019, 51(11):2375–2390. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Guo S, Han W, Wang P, Wang X, Fang X: Effects of exercise on chemotherapy-induced peripheral neuropathy in cancer patients: a systematic review and meta-analysis. J Cancer Surviv 2023, 17(2):318–331. [DOI] [PubMed] [Google Scholar]
- 28.Zajączkowska R, Kocot-Kępska M, Leppert W, Wrzosek A, Mika J, Wordliczek J: Mechanisms of Chemotherapy-Induced Peripheral Neuropathy. Int J Mol Sci 2019, 20(6). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Kleckner IR, Kamen C, Gewandter JS, Mohile NA, Heckler CE, Culakova E, Fung C, Janelsins MC, Asare M, Lin PJ et al. : Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial. Support Care Cancer 2018, 26(4):1019–1028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Colvin LA: Chemotherapy-induced peripheral neuropathy: where are we now? Pain 2019, 160 Suppl 1:S1–S10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Boland EG, Selvarajah D, Hunter M, Ezaydi Y, Tesfaye S, Ahmedzai SH, Snowden JA, Wilkinson ID: Central pain processing in chronic chemotherapy-induced peripheral neuropathy: a functional magnetic resonance imaging study. PLoS One 2014, 9(5):e96474. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Nudelman KN, McDonald BC, Wang Y, Smith DJ, West JD, O’Neill DP, Zanville NR, Champion VL, Schneider BP, Saykin AJ: Cerebral Perfusion and Gray Matter Changes Associated With Chemotherapy-Induced Peripheral Neuropathy. J Clin Oncol 2016, 34(7):677–683. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA: The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 2011, 11(9):607–615. [DOI] [PubMed] [Google Scholar]
- 34.Andersen Hammond E, Pitz M, Shay B: Neuropathic Pain in Taxane-Induced Peripheral Neuropathy: Evidence for Exercise in Treatment. Neurorehabil Neural Repair 2019, 33(10):792–799. [DOI] [PubMed] [Google Scholar]
- 35.Holschneider DP, Yang J, Guo Y, Maarek JM: Reorganization of functional brain maps after exercise training: Importance of cerebellar-thalamic-cortical pathway. Brain Res 2007, 1184:96–107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Armada-da-Silva PA, Pereira C, Amado S, Veloso AP: Role of physical exercise for improving posttraumatic nerve regeneration. Int Rev Neurobiol 2013, 109:125–149. [DOI] [PubMed] [Google Scholar]
- 37.Park JS, Hoke A: Treadmill exercise induced functional recovery after peripheral nerve repair is associated with increased levels of neurotrophic factors. PLoS One 2014, 9(3):e90245. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Stagg NJ, Mata HP, Ibrahim MM, Henriksen EJ, Porreca F, Vanderah TW, Philip Malan T Jr.: Regular exercise reverses sensory hypersensitivity in a rat neuropathic pain model: role of endogenous opioids. Anesthesiology 2011, 114(4):940–948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Zhang YH, Hu HY, Xiong YC, Peng C, Hu L, Kong YZ, Wang YL, Guo JB, Bi S, Li TS et al. : Exercise for Neuropathic Pain: A Systematic Review and Expert Consensus. Front Med (Lausanne) 2021, 8:756940. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Santa Mina D, van Rooijen SJ, Minnella EM, Alibhai SMH, Brahmbhatt P, Dalton SO, Gillis C, Grocott MPW, Howell D, Randall IM et al. : Multiphasic Prehabilitation Across the Cancer Continuum: A Narrative Review and Conceptual Framework. Front Oncol 2020, 10:598425. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Castelli G, Desai KM, Cantone RE: Peripheral Neuropathy: Evaluation and Differential Diagnosis. Am Fam Physician 2020, 102(12):732–739. [PubMed] [Google Scholar]
- 42.Delanian S, Lefaix JL, Pradat PF: Radiation-induced neuropathy in cancer survivors. Radiother Oncol 2012, 105(3):273–282. [DOI] [PubMed] [Google Scholar]
- 43.Volaco A, Cavalcanti AM, Filho RP, Précoma DB: Socioeconomic Status: The Missing Link Between Obesity and Diabetes Mellitus? Curr Diabetes Rev 2018, 14(4):321–326. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.