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Exercise Effects on Chemotherapy-Induced Peripheral Neuropathy

A Comprehensive Integrative Review

Kanzawa-Lee, Grace A. PhD, RN; Larson, Janet L. PhD, RN, FAAN; Resnicow, Kenneth PhD; Smith, Ellen Marie Lavoie PhD, APRN, AOCN, FAAN

Author Information
doi: 10.1097/NCC.0000000000000801
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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is among the most prevalent and debilitating adverse effects of cancer treatment. Approximately 60% of cancer survivors develop CIPN from neurotoxic chemotherapies, such as taxanes (paclitaxel, docetaxel), platinums (oxaliplatin, cisplatin, carboplatin), vinca alkaloids (vincristine, vinblastine, vinorelbine), bortezomib, and antiangiogenesis agents (thalidomide, lenalidomide).1,2 These chemotherapies can damage the peripheral sensory, motor, and autonomic nerves and lead to CIPN manifestations, most commonly numbness, tingling, burning or shooting pain, extremity weakness, and loss of proprioception and deep tendon reflexes. Long-term pain and sensorimotor deficits associated with CIPN increase risk of falls and impair physical function and quality of life (QOL).3,4 Thus, CIPN is a primary dose-limiting factor for patients who are receiving neurotoxic chemotherapy for the treatment of their cancer.5

Currently, there are no evidence-based preventive or curative treatments for CIPN6,7; however, some studies suggest exercise may be beneficial for other types of peripheral neuropathy8,9 and in treating other cancer treatment–associated symptoms: pain, fatigue, mood, emotional distress, sleep disturbance, balance, and decreased QOL.10,11 Large observational trials have also shown links between higher physical activity levels and less severe CIPN.12,13 Exercise may attenuate CIPN through its influence on blood circulation/oxidative stress,14,15 inflammation,16–18 pain-inhibiting neurotransmitters,19 endogenous opioids,20 growth factors,21 neuroplasticity,22 and coping and symptom interaction mechanisms.23–25 Although exercise is recommended for cancer survivors,26 little is known about specific exercise prescriptions’ effectiveness in reducing CIPN and feasibility among individuals who have received neurotoxic chemotherapy.

Purpose

The purpose of this integrative review was to synthesize research literature published since 2006, reporting the effects of exercise interventions on CIPN and other relevant outcomes among previously or currently neurotoxic chemotherapy-receiving people of all age groups. In this population, the specific aims were to (a) investigate the effects of exercise and physical therapy on CIPN severity and related outcomes, (b) identify the exercise type, delivery mode, and dosage associated with superior participant adherence rates and effects on CIPN, and (c) explore feasibility, including the rates and influencing factors of exercise intervention trial enrollment and completion, and adverse events. This review will add to the existing systematic reviews27–29 by providing critical appraisal and numerical synthesis of the most recent literature to identify patterns among the sample characteristics: exercise types, dosages, and delivery settings and CIPN and other relevant outcomes.

Methods

Search Method

PubMed, CINAHL, Scopus, PsycINFO, and SPORTDiscus were searched for all trials and meta-analyses that evaluated the effects of exercise on CIPN. Two reiterations of the full search were conducted: first between May and November 2016 to evaluate the literature published from 2006 to 2017 and then in April 2019 to evaluate the literature published from 2017 to 2019. The authors preliminarily reviewed all literature published since database inception before conducting the full search and had identified that only the studies published since 2006 had evaluated peripheral neuropathy outcomes of exercise. Article references, ScienceDirect recommendations, PEDro, and select journals and gray-literature databases were hand-searched, including American College of Sports Medicine’s Health & Fitness Journal, Advances in Physiotherapy, human kinetics and neurology journals, clinicaltrials.gov, opengrey.eu, ProQuest Dissertations and Theses, and eric.edu.gov. The following keywords were used to find relevant studies: exercise, physical activity, physical therapy, physiotherapy, peripheral neuropathy, polyneuropathy, and neurotoxicity.

Inclusion and Exclusion Criteria

Articles were considered if they met all of the following inclusion criteria: (1) randomized controlled trial (RCT), meta-analysis, or quasi-experimental (QE) design; (2) published within 2006 to 2019; (3) human subjects of any age; (4) most (≥50%) participants had received or were receiving neurotoxic chemotherapy; (5) at least 10 participants; (6) tested exercise interventions, including physical therapy and exercise counseling; (7) measured CIPN outcomes; and (8) published in English. Articles were excluded if they (1) were an abstract or protocol only; (2) tested passive exercise interventions (eg, whole-body vibration, passive range of motion, splinting); and (3) tested concurrent nonexercise physiological interventions (eg, drugs, supplements, transcutaneous electrical nerve stimulation).

Data Abstraction and Measurement Strategy

The following information was abstracted from the studies: (1) study design; (2) sample size; (3) sample characteristics (neuropathy and cancer type and grade/stage, age, gender, body mass index (BMI), and fitness/activity level); (4) intervention characteristics—type, prescribed dose and intensity, duration, and delivery settings; (5) control condition; (6) CIPN and related outcomes; (7) long-term postintervention outcomes; (8) intervention adherence; (9) enrollment and completion rates; (10) reasons for participation refusal or discontinuation; and (11) adverse effects.

Analysis/Quality Appraisal Methods

All n’s refer to the number of studies being quantified/described, except the Ns in Table 1 refer to the study sample sizes. Descriptive analyses were used to describe the sample and intervention characteristics. Multiarm trials that lacked a true control condition (eg, evaluated side-by-side physical interventions or compared the intervention only to healthy controls) were analyzed as pretest-posttest QE studies. Those classified as mixed sample studies included participants with mixed cancer types and/or who were receiving various chemotherapy regimens. In cases where the articles provided only ranges (and no means), the average of that range was used in this review’s descriptive analysis (eg, 40 minutes per day was used in the analysis for prescriptions of 30–50 min/d).

Table 1
Table 1:
Exercise Trials Among Patients With Peripheral Neuropathy Published 2006–2019

Regarding the exercise type, studies of functional and sensorimotor training were grouped in with balance training because of the similarity in their methods and intentions. One intervention focused on elastic band training and increasing step counts was categorized as an aerobic + strength training intervention.

The efficacy of the interventions on/among various outcomes and populations were evaluated based on the percentage of studies that showed clinically (≥30% difference)30 and statistically (P ≤ .05) significant effects for each outcome. Effect sizes were considered in the synthesized outcome discussion if provided by the studies. This review presents only results on outcomes that were evaluated in at least 3 studies. Two studies—from which only pretest-posttest results were gleanable in active neurotoxic chemotherapy-receiving individuals with no baseline CIPN—were excluded from the dichotomous quantification of outcomes (1, significant improvement; 0, no improvement), because they had no room for improvement. Description and further explanation for the exclusion of these studies are provided in the Outcome Measures and Results section.

CRITICAL APPRAISAL

The articles were critically appraised by the primary author using the CONSORT (Consolidated Standards of Reporting Trials) checklist.31 The author categorized studies as having a low or moderate risk of bias if the study met key CONSORT criteria and did not present with other critical confounding factors. No studies met 100% of the criteria; thus, the in-depth critical appraisal and results from all eligible studies are described below.

Results

The Figure is a flowchart of the literature search. The search yielded 758 results from the databases and 4 from hand-searching. Studies were mostly excluded because they did not evaluate a CIPN outcome or did not test an active exercise intervention. Ultimately, 13 studies (7 RCTs32–38 and 6 QE studies39–45) remained and are summarized in Table 1.

Figure
Figure:
Flowchart of the literature search.

Table 2 presents the critical appraisal results of the studies’ risks of scientific bias. Chemotherapy-induced peripheral neuropathy was the primary outcome in 5 studies.32,36,38,42,43 All but 2 studies36,42 had a high risk of bias. The first study rated to have a moderate risk of bias by McCrary et al42 tested an aerobic + strength + balance training intervention. The second “moderate-risk” study by Streckmann et al36 tested a sensorimotor (balance) training intervention. The strengths of these “moderate-risk” studies included employment of both clinical and patient-reported outcome (PRO) measures to assess CIPN as the primary outcome and enrollment of individuals who had established clinically and patient report–confirmed chronic CIPN. Despite small sample sizes (40 participants split into 4 groups,36 and 29 participants42), both studies found significant CIPN benefits.

Table 2
Table 2:
Risk of Scientific Bias of the Studies

However, the studies of both McCrary et al42 and Streckmann et al36 had significant limitations. The QE study of McCrary et al42 lacked report of the qualification and blinding of the individual who performed the clinical CIPN assessments.42 The study of Streckmann et al36 lacked report of interrater reliability for the CIPN clinical assessments.36 Instead of using a validated measure such as the Total Neuropathy Score (TNS),46–48 clinical signs of CIPN (eg, tendon reflexes) were evaluated separately without clear use of an established, reproducible, grading rubric.36 Finally, their PRO neuropathic pain (PainDETECT) data are likely unreliable because of missing data (likely from individuals who had no pain per the authors).36

Most other studies lacked assessor blinding32–34,37–45 and sufficient power.33,35–37,39,41,43,45 Few studies utilized either a strong PRO37–39 or clinical assessment41 CIPN measure; even fewer used both a strong PRO and clinical assessment CIPN measure.32,36,42 No studies of CIPN as a secondary/exploratory outcome reported error rate adjustment to avoid the risk of statistical fishing bias.33–35,37,39–41,44,45 All 13 studies lacked control for potential confounding factors, including peripheral neuropathy–related comorbidities (eg, diabetes, peripheral arterial disease, and vitamin B deficiency); heterogeneity of the sample in CIPN presence, severity, and stability at baseline; chemotherapy status, regimen, and duration; and other psychological mediators/moderators (eg, mood). Further, all the studies lacked report of or control for the participants’ intervention adherence and/or outside exercise/physical activity.

Sample Characteristics

The study sample sizes ranged from 21 to 355 participants. Average participant age was 55.6 years (range, 18–81 years) (n = 12); BMI, 25.62 kg/m2 (n = 7); and percent male, 27% (n = 12). All studies were conducted in adults, whose physical activity or fitness was generally below average. Study participants had stage I to IV (mostly breast) cancer and had received36,39,41,42 or were actively receiving32–35,37,38,43–45 primarily taxane-32,37,40,43,44 or platinum-based33,38,39 or mixed types of chemotherapy.34–36,42,45 Few studies focused on 1 type of cancer and chemotherapy.33,35,37,38,40,44,45 Baseline CIPN was chronic and moderate-severe (n = 4),36,39,41,42 absent/mild (n = 3),34,37,40,44 or mixed/acute/unclearly specified (n = 5).32,33,35,38,43,45

Exercise Interventions

Six different types of exercise were tested in the 13 studies: yoga,39 and exercise with aerobic (n = 7),33–35,38,40,42–45 strength (n = 9),32–35,37,38,40,42–45 and balance (n = 7)32,35–38,41,42,45 training components. The interventions in all but 3 studies—1 yoga39 and 2 balance training alone36,41—were multimodal: varied combinations of aerobic, strength, and balance training. Aerobic + strength,33,34,40,43,44 and aerobic + strength + balance35,38,42,45 exercises were the most common interventions.

DOSAGES

The mean (range) exercise prescription characteristics included 107.61 min/wk (23–210 min/wk), over 3.42 d/wk (1–7 d/wk), for a duration of 11.68 weeks (3–36 weeks). Seven interventions encouraged moderate- to vigorous-intensity (50%–80% heart rate maximum/reserve [HRmax/HRreserve], 40%–75% VO2peak, or Borg rating of perceived exertion of 13–15) exercise.33,35,37,38,40,42–44

The most common aerobic exercise dosages prescribed were 20 to 30 minutes per session of moderate- to vigorous-intensity physical activity, 2 to 5 d/wk. The total prescribed weekly doses (20–165 min/wk) and durations (6–36 weeks) of the aerobic interventions varied. The strength training dosages ranged from 4 strength training tasks (3 sets of 10 repetitions per task)33 to 14 tasks (4 sets of 15 repetitions per task)34 performed at light to moderate intensity 2 to 7 d/wk.32–35,37,38,40,42–44 Balance training sessions were most commonly 10 to 12 minutes in duration32,35,36,41 and involved 4,32,35,36,38,42 15- to 30-second35,36,42 balance training tasks repeated 2 to 3 times each.35,36,38,41,42

DELIVERY SETTING

All but 4 studies32,34,42,45 were conducted in a clinical setting. One intervention was delivered by group.39

Control Conditions

The most common control conditions were no exercise/usual care32–36 or health education.37,39 One 4-arm study evaluated a balance training intervention compared to whole-body vibration, no intervention, and age- and gender-matched healthy controls,36 and another 4-arm study evaluated yoga compared to reiki, meditation, or health education.39 One 3-arm study evaluated 3 exercise interventions alone.40,44

Outcome Measures and Results

Table 3 contains a list of the most common outcome variables evaluated, the number that evaluated that outcome, and the percentage of studies that showed outcome improvement. Balance, fitness, and CIPN outcomes improved most consistently. Given the dichotomous quantification (improvement or no improvement) in the tables, 2 pretest-posttest QE studies of individuals in active neurotoxic chemotherapy treatment without baseline CIPN were excluded, because the participants had no room for improvement.44,45

Table 3
Table 3:
Outcomes Measured and Frequency of Positive Effects in the Studies

CIPN OUTCOMES

Table 4 lists the number and percentage of studies that demonstrated statistically significant (P < .05) outcome improvement by sample characteristic. Five studies (83%) demonstrated clinically significant (≥30%) intervention group–favoring intergroup differences in PRO-surveyed32–34,38 and clinically assessed CIPN35 among patients with32,35 and without33,34,38 baseline CIPN. Clinically significant pretest-posttest intervention CIPN improvements were also demonstrated, using clinical assessments36,41 and PRO surveys32,36 in patients with baseline CIPN.32,36,41 Although not clinically significant, 2 studies showed moderate statistically significant improvements in CIPN, measured by the TNS-Clinical version (24.29% improvement; P = .001),42 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire CIPN20 module (27.17% improvement; P < .001),42 and Leeds assessment of neuropathic symptoms and signs (no effect size reported).43 Nerve conduction studies—often considered a diagnostic tool for peripheral neuropathy—did not show significant effects, even though clinical assessment and PRO surveys of CIPN did.32,36,42 One study among individuals with baseline chronic CIPN showed that clinically assessed CIPN values recovered to a level that matched healthy age- and gender-matched controls after the intervention.36

Table 4
Table 4:
Synthesis of Outcomes by Sample Characteristic (n = 11)a

Among individuals actively receiving chemotherapy, those with acute baseline CIPN showed no progression38,45 or significant improvement of CIPN (P < .05),32,43 but those with no baseline CIPN demonstrated significant development/worsening of CIPN over time.33,34,44 Regardless of baseline CIPN status, intergroup outcomes were often better in the intervention than the control groups in individuals receiving chemotherapy.32–35,38

Table 5 lists the number and percentage of studies that demonstrated statistically significant outcome improvement by exercise intervention characteristic. Statistically significant CIPN benefits were found in all studies of home-based interventions32,34,42 and those with an aerobic exercise component,33,35,37,38,42,43 exercise dosages of ≥100 min/wk,32,34,35,38,42 and/or durations of 8 to 12 weeks.32,33,38,42,43 All interventions with only balance training led to large clinically significant improvements in established CIPN.36,41 However, some studies of clinic-based33,35,36,38,41,43 interventions and those of doses less than 100 min/wk (as low as 22.66 min/wk) also demonstrated statistically significant CIPN benefits33,36,41,43 Finally, balance training for as low as 3 weeks41 and aerobic + strength training for as low as 6 weeks in duration resulted in statistically significant CIPN benefits.34

Table 5
Table 5:
Synthesis of the Outcomes by Exercise Intervention Characteristic (n = 11)a

Focusing on the 8 aerobic intervention studies, moderate-large intergroup33–35,38 and small pretest-posttest38,42 CIPN benefits—measured by PRO33,34,38,42,43 and clinical assessments35,42—were demonstrated among patients mostly in active treatment with various neurotoxic chemotherapy types.33–35,38,43 The interventions that led to large intervention-favoring CIPN benefits (40%–141% difference between groups) all were of moderate-vigorous intensity (55%–70% HRreserve or 60%–80% HRmax). The 1 home, step-count prescription-based intervention led to moderate intervention-favoring CIPN benefits (34% difference) between groups.34 Various doses (20–60 min/wk; 8–30 min/d), frequencies (2–5 d/wk), and durations (6–36 weeks) of aerobic exercise led to moderate-large clinically significant benefits. No studies tested (in comparison to a control condition) an aerobic exercise dose greater than 60 min/wk. Of note, 1 study found no differences in Functional Assessment of Cancer Therapies-Taxane–measured CIPN outcomes between prescriptions of 25 to 30 min/d and 50 to 60 min/d of vigorous-intensity aerobic exercise 3 d/wk throughout chemotherapy (over 16–32 weeks).40,44

Finally, the 2 studies with a moderate risk of bias showed small-moderate (19%–35%) statistically significant pretest-posttest benefits. Specifically, aerobic + strength + balance and solely balance training alleviated established moderate-severe clinical signs and symptoms of CIPN, measured by the TNSc and CIPN20,42 and deep tendon reflexes and vibration sensibility.36 Specifically, the QE study (29 participants) suggested that 8 weeks of individualized combined home- and clinic-based moderate-vigorous aerobic + strength + balance training (60 min/d, 3 d/wk) may alleviate CIPN and improve physical function, balance, and QOL in individuals with breast, colorectal, ovarian, and other cancers who have completed paclitaxel, oxaliplatin, or other types of neurotoxic chemotherapy treatment.42 The 4-arm RCT (40 participants) showed that 6 weeks of clinic-based sensorimotor training (2 d/wk, <30 min/wk) may effectively treat chronic CIPN in individuals 1 to 5 years post–taxane- platinum or vinca alkaloid treatment; it may restore tendon reflexes and vibration sensibility to normal levels exhibited by age- and gender-matched healthy controls. Brief sensorimotor training may also improve balance and subjective CIPN; however, a higher dose may be required to induce significant benefit.

OTHER KEY OUTCOMES

Balance and fitness improved significantly in all the studies, regardless of exercise type, dosage, or setting, but pain, physical function, and QOL improvement varied. Higher weekly doses (>100 min) and frequencies (≥3 days) resulted in more consistent holistic outcome benefits.

LONG-TERM OUTCOMES

Two studies reported long-term follow-up 1 month38 and 3 months45 after intervention completion. Eight weeks of clinic-based moderate-vigorous aerobic + strength + balance training (60 min twice weekly) led to sustained improvements in subjective CIPN and objectively measured balance and strength at 1-month follow-up in colorectal cancer survivors receiving oxaliplatin; the control group simultaneously exhibited declines in all the outcomes.38 The other study did not provide meaningful long-term follow-up results because it lacked intent-to-treat analysis and only had 3-month follow-up data on 12 participants (40%) who complied with the intervention and had no medical complications.45

ADHERENCE AND COMPLETION RATES

Eleven studies reported outcome assessment completion rates ranging from 70%45 to 99%.40,44 Seven studies reported adherence rates (65%35 to 88.3%38), defined as the percent of intervention sessions attended or time completed38,40,42,44 or percent of participants who met a specified exercise dose/criteria.32,34,35,45 Participants adhered to 64 to 120 min/wk (SD =17–39 min/wk) of moderate- to vigorous-intensity aerobic exercise (65.2%–68.4% VO2peak) in a clinic-supervised setting40,44 and 196 min/wk (SD =138 min/wk) of aerobic + strength + balance exercise self-reported in a home-based setting.45 Participants averaged 4820 steps per day in another home-based aerobic + strength training study.34 These adherence levels were all obtained from patients in active chemotherapy treatment.

The studies with the lowest adherence rates were conducted in individuals actively receiving treatment;32,34,35,45 2 studies also had high standards for their definition of adherence: percent that averaged ≥12035 or 150 min/wk32 of exercise. The studies with the lowest completion rates evaluated low-dosage/intensity interventions and small sample sizes,33,39,45 lacked rigor,39,45 and/or were conducted in stage III to IV cancer survivors receiving treatment.33,45 The primary reasons reported by participants for study discontinuation included loss of interest/unknown reasons (20%–100%), medical complications (11%–100%), noncompliance (5%–59%), death (11%–35%), and time concerns (33%). One study reported that 3 (33%) of the patients who withdrew did so because of chemotherapy adverse effects.45 No other patterns were found between the intervention characteristics and adherence or completion rates.

The studies with an adherence and completion rate ≥80%38,40,42,44 tested clinic-based aerobic, balance, and multimodal training interventions performed 2 to 3 d/wk. The intervention and sample characteristics were otherwise heterogeneous in these studies.

ENROLLMENT RATES

On average, 53.16% (range, 33%–76.3%) of patients enrolled out of the 233 (range, 48–728) mean patients approached for the studies.32,34,35,37,40,42,44,45 Recruitment occurred over a mean period of 28.89 months (range, 6–84 months) and most often in clinics or hospital settings.32–35,37,38,40,42,44,45 The oncologists usually referred potentially eligible patients. All the studies with enrollment rates of less than 55% had attempted to recruit patients before and/or shortly after chemotherapy initiation.34,35,37,40,44 However, the 2 studies with the highest enrollment rates (63%45 and 76.3%32) recruited participants midway through chemotherapy treatment. The top reasons for declining participation (and the percentage of patients who cited the reason) included lack of interest or response (15%–100%), living too far away/transportation issues (11%–54%; highest in supervised intervention studies), time concerns (22%–28%), and medical complications (6%–28%). One study reported that 6.02% of patients refused participation because of chemotherapy adverse effects.40,44

ADVERSE EFFECTS

No exercise adverse effects were found.32,35,36,38,40,44,45 However, nearly half of the studies lacked report about adverse effects.

Discussion

This integrative review identified 13 clinical trials that reported the effects of an exercise or physical therapy intervention on CIPN and other key outcomes. The following key findings emerged:

  1. All the studies had a moderate-high risk of bias and were conducted in adults.
  2. Chemotherapy-induced peripheral neuropathy, balance, and fitness improved consistently after the exercise interventions.
  3. All the aerobic exercise–containing interventions led to significant CIPN benefits; however, no studies have tested just aerobic exercise to reduce CIPN.
  4. Adherence, completion, and enrollment rates were the lowest among patients who were just starting chemotherapy treatment.
  5. The samples and intervention types, dosages, and delivery settings were otherwise highly heterogeneous.

These findings are consistent with prior systematic reviews of exercise interventions among patients with CIPN.27–29 The general consensus is that exercise may lead to improvements in balance, fitness, and CIPN among adults with and/or at risk of CIPN; however, the evidence is limited in abundance and quality. Further, the current studies have been too heterogeneous to identify the most effective exercise prescriptions to target CIPN.27 One review highlighted the importance of balance training for reducing CIPN but ultimately proposed that moderate-intensity aerobic + strength + balance training (2–5 d/wk; ≤60 minutes per session) for at least 36 weeks may be most beneficial for individuals receiving neurotoxic chemotherapy.28

This integrative review supports the value of combined aerobic + strength + balance training (≥100 minutes, ≥3 d/wk) for individuals with CIPN32,34,35,38,42; however, this review found that interventions 8 to 12 weeks in duration led to the most consistent32,33,38,42,43 and potentially sustainable CIPN benefits.38

Further, this review’s numerical evidence synthesis suggests that aerobic exercise is a key modality to reduce CIPN,33–35,38,42,43 particularly during active neurotoxic chemotherapy treatment.33–35,38,43 Various aerobic exercise doses (20–60 min/wk; 8–30 min/d), frequencies (2–5 d/wk), intensities (Borg rating of perceived exertion 11–15; 40%–80% VO2peak, HRmax, or HRreserve), and durations (6–36 weeks) were beneficial. However, no studies have tested the effects of aerobic exercise alone and/or in doses ≥60 min/wk on CIPN, compared with control.

Overall, few studies have tested unimodal, national guideline prescription-compliant, and home- and group-based exercise interventions for CIPN. Sole aerobic exercise and balance training interventions appear most promising for CIPN, but no studies have evaluated their individual long-term effects on acute, chronic, and painful CIPN at various dosages. Finally, only 3 studies tested a home-based intervention—all of which showed improved CIPN outcomes32,34,45—and 1 study tested a group-based intervention (yoga).39

Patterns between adherence, completion, and enrollment rates and CIPN outcomes and sample characteristics were difficult to identify. Seven studies reported variable exercise adherence rates (65%–88.3%) based on variable definitions of adherence;32,34,35,38,40,42,44,45 6 studies reported adverse effects data.32,35,36,38,40,44,45 No studies comprehensively described the recruitment process (eg, timing, location, and medium); however, the studies that recruited patients before and/or just after beginning chemotherapy treatment exhibited the lowest enrollment, completion, and adherence rates. Lack of interest/personal reasons, living far away/transportation issues especially in supervised intervention studies, and time concerns were also common reasons for declining participation.

Few studies employed strong CIPN assessment methods. No studies rigorously controlled for peripheral neuropathy–related comorbidities (eg, diabetes), potential mediating or moderating psychological confounders (eg, mood), intervention adherence; outside physical activity (in non–home-physical activity–based interventions); and sample heterogeneity in baseline CIPN presence, severity, and stability and chemotherapy status, regimen, and duration. Lastly, few studies reported key participant characteristics (eg, baseline BMI, physical activity level, and motivational traits) that could have biased participant enrollment, completion, and benefit from the exercise interventions.

Limitations

Definitive conclusions about the most effective intervention types and dosages cannot be drawn from this review, because a small number of studies with moderate-high risk of bias have been published, and the tested interventions were highly heterogeneous. These review findings can only be used to inform future studies among adults, given that no studies in this review had evaluated pediatric populations. Additionally, the study samples may not fully represent the population of patients with or at risk of CIPN, because some study samples were mixed and included some participants who were and some who were not receiving/had not received any neurotoxic chemotherapy. For example, some participants in the study of Courneya et al44 received nonneurotoxic regimens (eg, adriamycin and doxorubicin), and some received paclitaxel or other neurotoxic chemotherapies. Finally, 1 author primarily reviewed and synthesized the literature; however, the coauthors were consulted to develop the eligibility criteria and settle confusion regarding the inclusion of questionable articles.

Conclusions and Recommendations for Further Research

Considering the findings and limitations of this review along with prior systematic reviews of exercise for CIPN, the following can be concluded:

  1. Exercises, particularly aerobic exercise and balance training, are promising preventive interventions and treatments for CIPN and should be further investigated individually.
  2. Higher-quality studies are needed to provide more definitive results on the effects of specific exercise types, dosages, and delivery methods on specific types of CIPN.
  3. Studies are needed to evaluate the effects of exercise on CIPN among children.

No cures or preventive interventions for CIPN have been found.6,7 Yet, preliminary empirical evidence suggests that exercise may be effective in preventing and treating CIPN. Thus, research is needed to evaluate the mechanisms that mediate the protective or treatment effects of specific exercise types—first focusing on aerobic and balance training—on CIPN in homogeneous samples. For example, studies should control for neurotoxic drug class, dose, and schedule; coasting effects (time since last chemotherapy dose); and baseline CIPN severity. Further, future studies should control (through eligibility criteria or statistics) for potential confounding factors, such as peripheral neuropathy–related comorbidities, use of medications intended to reduce peripheral neuropathy (eg, duloxetine), cumulative chemotherapy dose received, and outside physical activity levels.

Second, studies are needed to evaluate the feasibility of specific exercise prescriptions in patients with or at risk of developing CIPN. Future studies should report the participants’ baseline BMI, physical activity level, and motivational traits to contribute to the understanding of the best individualized exercise prescriptions for specific populations. Studies should also evaluate the interactions among the exercise prescription, participant adherence, changes in outside physical activity and lifestyle, and CIPN outcomes. Finally, future studies should test and compare the efficacy and feasibility (eg, cost/labor effectiveness) of home- and group-based interventions versus standard individually supervised, in-clinic interventions.

IMPLICATIONS FOR PRACTICE

Chemotherapy-induced peripheral neuropathy is among the most common, debilitating, and treatment-resistant adverse effects of neurotoxic chemotherapy. However, a growing body of evidence has shown that appropriately prescribed exercise is safe, feasible, and a potentially effective intervention for patients with CIPN.9,23,33,35,49 Various exercise types and dosages and increased physical activity have demonstrated broad benefits at every stage of cancer survivorship33,35,38,40,41; however, identifying exercise prescriptions to utilize as nonpharmacological symptom treatment requires rigorous research. This review highlights the importance of critically evaluating the literature before using the findings. Ultimately, the practice implications that can be drawn from the current studies of exercise for CIPN are limited, because all but 2 studies had critical limitations.

However, nurses can encourage and educate cancer survivors about the safety and importance (particularly in bolstering balance and fitness and possibly alleviating symptoms) of exercise throughout cancer survivorship. Patients in active chemotherapy treatment with baseline CIPN and poorer functional status may require additional support to promote adherence to exercise programs. Although no definitive conclusions can be made about exercise as a treatment for CIPN, nurses can empower patients to promote their own well-being by staying physically active.

ACKNOWLEDGMENTS

The authors acknowledge John C. Krauss, MD; Robert J. Ploutz-Snyder, PhD, PStat; Athena Lievense; and Lauren Kavanagh for their contributions to the conceptualization of this review.

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Keywords:

Cancer; Chemotherapy-induced peripheral neuropathy; Endurance training; Exercise; Neurotoxicity; Physical activity; Physical therapy; Review; Sensorimotor training; Strength training

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