Persistent Cancer-Related Fatigue After Breast Cancer Treatment Predicts Postural Sway and Postexertional Changes in Sit-to-Stand Strategy : Rehabilitation Oncology

Secondary Logo

Journal Logo

Advanced Search
RESEARCH REPORTS

Persistent Cancer-Related Fatigue After Breast Cancer Treatment Predicts Postural Sway and Postexertional Changes in Sit-to-Stand Strategy

Wechsler, Stephen PT, DPT, PhD1; Kneiss, Janet PT, DPT, PhD2; Adams, Benjamin PT, DPT3; Wood Magee, Lisa J. PhD, RN, FAAN4

Author Information

1Board-Certified Neurologic Clinical Specialist, PhD Program in Rehabilitation Sciences, MGH Institute of Health Professions, Charlestown, MA

2Professor, Department of Physical Therapy, College of Saint Mary, Omaha, NE

3Board-Certified Orthopedic Clinical Specialist, PhD Candidate, PhD Program in Rehabilitation Sciences, MGH Institute of Health Professions, Charlestown, MA

4Professor, William F. Connell School of Nursing, Boston College, Chestnut Hill, MA

Correspondence: Stephen Wechsler, PT, DPT, PhD, PhD Program in Rehabilitation Sciences, MGH Institute of Health Professions, 36 1st Ave, Charlestown, MA 02129 ([email protected]).

This study was supported by grant R21AG055149 from the National Institute on Aging.

The authors have no conflicts of interest to declare that are relevant to the content of the article.

Online Publication date: June 28, 2022

Rehabilitation Oncology 40(4):p 162-171, October 2022. | DOI: 10.1097/01.REO.0000000000000308
  • Free

Abstract

Background: 

Chemotherapy-induced peripheral neuropathy (CIPN) is considered a primary mechanism of imbalance among women diagnosed with breast cancer. Recent evidence, however, suggests that cancer-related fatigue (CRF) may also influence balance.

Purpose: 

Examine the contributions of CRF and CIPN to static and dynamic balance before and after a period of fatiguing exercise.

Methods: 

This is a secondary analysis of data examining functional differences between women with breast cancer with and with no persistent CRF. Postural sway was measured during static standing and the rising phase of an instrumented sit-to-stand before and after exercise. Regression analyses were performed to determine how CRF and severity of CIPN predicted sway and how much variance was attributable to each.

Results: 

Greater CRF predicted increased pre-, P = .04, and postexertional, P = .02, static sway in the anterior-posterior plane. Cancer-related fatigue accounted for 10.5% and 9.5% of the variance in pre- and postexertional sway (respectively) compared with the 0.9% and 1.4% accounted for by CIPN severity, which was not a significant predictor. After exercise, greater CRF predicted smaller, more conservative, anterior weight shifting during the instrumented sit-to-stand, P = .01, and accounted for 6.6% of the variance in sway compared with 3% attributed to CIPN, which was not a significant predictor.

Limitations: 

This analysis is limited by its small and demographically homogenous sample.

Conclusions: 

These results suggest that CRF may influence balance independent of CIPN symptoms. While CIPN remains a risk factor for imbalance in this population, CRF warrants consideration in clinical practice and research as a mechanism of postural instability.

Breast cancer is the most commonly diagnosed cancer among women with an estimated 281 550 new cases in 2021.1 Because of advances in screening, diagnosis, and treatment, the 5-year survival rate of breast cancer is 90%.1 As a result, there are nearly 4 million women with a history of breast cancer living in the United States.2 In contrast to these advances, as many as two-thirds of these women report experiencing at least 1 long-term adverse side effect related to their cancer or treatment.3 For many of these women, side effects include physical or functional performance limitations, imbalance, impaired gait, and an increased risk of falls.4–6 Imbalance and falls among individuals with a history of cancer are linked to decreased quality of life7,8 and may have severe consequences in this population due to comorbidities and risk of subsequent physical decline.9,10

To date, chemotherapy-induced peripheral neuropathy (CIPN), a common long-term side effect of treatment, has been thoroughly investigated as the primary mechanism of imbalance among women diagnosed with breast cancer.7,11–14 A recent scoping review found that two-thirds of studies that have assessed balance, gait, and falls after chemotherapy exposure identified CIPN as the key process leading to functional impairments.15 However, recent evidence highlights the possible contribution of persistent cancer-related fatigue (CRF), another highly prevalent side effect of cancer and its treatments,16,17 to limitations in functional performance and balance among women with breast cancer. Specifically, women with a history of breast cancer and persistent CRF (5.6 [3.9] years postdiagnosis) demonstrate worse performance on functional tests and report twice the rate of falls compared with their nonfatigued counterparts, even after controlling for severity of CIPN sensory symptoms in the feet.6 Comparably, in a recent study, after controlling for symptoms of CIPN, women with a history of breast cancer and persistent CRF (3.5 [2.1] years posttreatment) demonstrated decreased lower extremity rate of force production and power following exercise.18 These variables are associated with postexertional imbalance, gait impairments, and falls.19–25 Taken together, this evidence suggests that CRF may have a distinct effect on balance, though this relationship has not been quantified.

To our knowledge, no studies have objectively measured the discrete influence of CRF on balance and this relationship remains unclear. This is particularly relevant, given the recently updated American College of Sports Medicine's exercise guidelines for cancer survivors that recommend moderate- to vigorous-intensity exercise for individuals with fatigue.26,27 A clearer illustration of CRF's effect on periexertional balance, and its relative contribution to that of CIPN, would improve clinicians' ability to screen for balance deficits and to personalize exercise recommendations while optimizing safety. Therefore, the purpose of this study was to examine the contributions of CRF and CIPN to static and dynamic balance before and after a period of fatiguing exercise. We hypothesized that greater CRF and severity of CIPN sensory symptoms would predict greater static and dynamic postural sway (ie, worse balance) before and after exercise.

METHODS

Data Source/Design

This is a secondary analysis of data from an ongoing study, henceforth referred to as the parent study. The Institutional Review Board–approved parent study is a cross-sectional study, which uses patient-reported outcomes and functional testing in a laboratory to examine group differences between women diagnosed with breast cancer with and with no persistent CRF before, during, and after a period of moderate-intensity exercise. The parent study's primary outcomes are measures of fatigability (endurance, perceived exertion, lower extremity rate of force development and power) and function (standing balance, gait speed).

Participants

The parent study's participants were recruited from a high-volume breast cancer center at a large urban hospital. The sample consists of female participants, 30 to 85 years of age, who have completed cytotoxic chemotherapy with or with no radiation therapy for stage I–III breast cancer at least 12 months prior to study involvement (antihormone therapies permitted). Participants are excluded if they report any injury or functional limitation that would prohibit being able to safely perform a repeated sit-to-stand task for up to 15 minutes (eg, cardiac condition, arthritis) without upper extremity support. To minimize confounding of CRF-related effects, participants are also excluded if they report any of the following conditions that typically include a component of fatigue: precancer diagnosis of fibromyalgia, posttreatment Lyme disease syndrome, chronic fatigue syndrome, hypothyroidism without replacement therapy, anemia with hemoglobin levels less than 12 g/dL, or positive screens for major depression or an anxiety disorder.

Procedure

All participants underwent standardized functional testing (static standing balance and instrumented sit-to-stand [ISTS] on a force plate) before performing a repeated sit-to-stand task. This repeated sit-to-stand task represented a moderate-intensity lower extremity exercise that has been used in prior studies to examine the effect of lower extremity fatigue on functional outcomes including balance and gait characteristics.24,25 Following this bout of exercise, the participants repeated the same functional testing at 1 minute postexercise.

Static Standing Balance

To assess pre- and postexertional static standing balance, the participants were asked to stand as still as possible for 30 seconds on a single force plate mounted in the floor with arms by their sides, directing their head and eyes forward, while postural sway was measured in the medial-lateral (ML) and anterior-posterior (AP) planes.

Dynamic Balance

To assess pre- and postexertional dynamic balance, postural sway was measured in the ML and AP planes during the rising phase of an ISTS. Each participant began seated with feet hip-width apart and arms crossed over their chest. The participant's feet were placed on the same force plate used to assess static balance with ankles at approximately 15° of dorsiflexion. They were then instructed to stand up as quickly as possible without falling. Rising phase of the ISTS begins at the point at which peak vertical force is measured (seat-off) and ends when the vertical force reaches body weight after decreasing (due to the participant's momentum in the superior direction) and increasing again (Figure 1).28 During the rising phase, the participants are fully unsupported and are actively transitioning from sitting to standing. Therefore, we considered postural sway during the rising phase of the ISTS a measure of dynamic balance.29–31 The participants performed 3 ISTS repetitions prior to the bout of exercise to establish a baseline of rising phase sway.

F1
Fig. 1.:
Vertical ground reaction force during instrumented sit-to-stand. BW indicates body weight; MGRF, maximum ground reaction force; T1, initiation of movement; T1-T2, preparation phase; T2, seat-off; T2-T3, rising phase; T3, standing position assumed; T3-T4, stabilization phase; T4, stable standing achieved; WF/L, weight of feet and legs at rest prior to transfer.

Repeated Sit-to-Stand Task

For the repeated sit-to-stand task, the participants transitioned sitting to standing and standing to sitting without upper extremity support at a metronome-standardized pace of 30 cycles per minute. Objective data were not collected during this task. The participants were given 2 verbal cues if their sit-to-stand speed dropped below 30 cycles per minute. If the participant was unable to maintain the selected speed after verbal cues, if the participant stated that he or she was unable to continue, or if a duration of 15 minutes was achieved, then the task was terminated.

Outcome Measures

Dependent Variable: Postural Sway

Our primary outcome for this study was postural sway, measured in Newton-seconds via force plates (Bertec Corporation model 4060NC) and recorded through Motion Monitor Software (Innsport Training, Inc, Chicago, Illinois) at a sampling rate of 1000 Hz. Postural sway was operationally defined as the amplitude of displacement of the participant's center of pressure. This measure is a reliable parameter that has been used widely to analyze postural deficits among patients with neuromotor disorders.32,33 Greater values of amplitude of center of pressure displacement (ie, greater postural sway) indicate worse balance.

Independent Variables: Clinical, Behavioral, and Demographic Data

Survey response participant-level data included (1) self-reported CRF; (2) severity of CIPN in the feet; (3) self-reported hours of moderate-intensity activity per week; and (4) standard demographic and comorbidity data.

Self-Reported CRF

Our primary independent variable was self-reported level of CRF, as measured by the 36-Item Short Form Health Survey (SF-36) Vitality Subscale (VS). The SF36-VS is commonly used to assess CRF in cancer populations.34–37 Among individuals with cancer, the SF-36-VS has well-established internal consistency (Cronbach α = 0.72-0.81)35,38 and the SF-36 demonstrates good construct validity with measures such as the European Organisation for Research and Treatment of Cancer (r = 0.83).35 Minimally clinically important difference (MCID) and minimal detectable change (MDC) values are unavailable. The 4-item VS assesses fatigue during the past 4 weeks, and responses are scored on a 0 to 100 scale, with higher scores corresponding to less fatigue. Level of CRF was treated as a continuous variable to determine whether greater CRF predicted greater postural sway.

Severity of CIPN

The presence and severity of sensory neuropathy in the lower extremities were assessed in all participants using the sensory neuropathy items on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx-4 v4). This measure, validated and applied in samples of patients with breast cancer,39,40 is highly recommended by the Academy of Oncologic Physical Therapy of the American Physical Therapy Association (APTA Oncology) Task Force on Breast Cancer Outcomes.41 Although MCID/MDC values are unavailable,41 it has good internal consistency (Cronbach α = 0.62-0.90) and moderate-to-strong convergent validity with objective measures of peripheral neuropathy (r = 0.39-0.64).39 Severity of CIPN was treated as a continuous variable (range: 0-8), with higher scores representing greater severity.

Self-Reported Hours of Moderate-Intensity Activity per Week

Given the clear relationship between physical activity level and physical function among individuals with a history of cancer,26,42,43 habitual physical activity level was assessed using the Community Health Activity Model Program for Seniors (CHAMPS) questionnaire. The CHAMPS asks about sedentary, low-, moderate-, and vigorous-intensity activities during the last 4 weeks and calculates weekly energy expended in each activity (kcal/wk).44 The questionnaire does not have established MCID/MDC values but demonstrates good reliability (ICC = 0.66) and known-groups validity, able to discriminate between inactive, somewhat active, and active groups, P value less than .001.44 Frequency per week of moderate-intensity physical activities correlates moderately with self-reported physical functioning (r = 0.30) among older adults.44 Self-reported hours of moderate-intensity activity per week was treated as a continuous variable.

Demographic and Clinical Data

A standard demographic survey was used to collect data including age, racial background, marital status, education, employment, occupation, the number of adults and children younger than 12 years living in the home, and income. Treatment details, including time since treatment, were extracted from the medical record. The presence of chronic medical conditions was measured using the Functional Comorbidity Index, an 18-item self-report measure designed to examine the effect of comorbidities on physical function.45

Statistical Analysis

Frequency distributions and descriptive statistics were examined for all study variables. Rising phase sway values from the 3 pretest ISTS trials were averaged to represent a single pretest value for each participant, and reliability across the 3 trials was assessed via intraclass correlation coefficient to ensure a stable baseline prior to exercise. Correlation coefficients were examined for all independent variables to assess for multicollinearity. To adjust for outliers, skewness, and to better fit regression assumptions, static postural sway data were log-transformed. Rising phase sway data met all assumptions and therefore did not require transformation. To improve interpretability, self-report CRF scores were centered and reversed so that higher values represent higher levels of fatigue.

Analyses were conducted in R46 and figures were produced using the package ggplot2.47 Regression assumptions and diagnostics were assessed for all final models. Final model results were not significantly different with multivariate outliers and influential cases removed, so these cases were included to preserve sample size. All other assumptions were within acceptable limits. All estimates of log-transformed variables were exponentiated and effects are presented as percentages to improve interpretability. Since rising phase sway was not log-transformed, regression estimates and values are reported in Newton-seconds.

Pre- and Postexertional Postural Sway

To determine whether CRF predicts greater pre- and postexertional postural sway, we separately regressed pretest and 1-minute posttest values of static AP sway, static ML sway, rising phase AP sway, and rising phase ML sway on CRF level. For all postexertional analyses, pretest sway values were included to control for variation in baseline sway. Severity of CIPN symptoms, which was moderately correlated with fatigue level (r = 0.59, P value less than.001), was then added to each model to determine how much additional variability was accounted for by CIPN. Finally, due to moderate correlations with fatigue level and the potential to impact balance, participant age (r = −0.33, P = .03) and hours of moderate-intensity activity per week (r = −0.41, P = .06) were included in all analyses to control for these covariates.

RESULTS

Participants

Table 1 provides baseline data for our sample of 43 women with a history of breast cancer. The average age of women in our sample was 57.28 (10.17) years, while the average time since treatment was 3.5 (2.1) years. All participants had been treated with chemotherapy, while 69.8% of the sample also received radiation therapy and 53.5% were still taking an antiestrogen at the time of study involvement. The average fatigue level (after reversal) was 43.15 (25.6), with scores ranging from 0 to 100. In addition, 53.5% of the participants reported the presence of sensory symptoms of CIPN in their feet, which is at the upper range of previously documented prevalence at and beyond 6 months following chemotherapy (6.4-53.5).13 Participants with CIPN symptoms reported an average severity of 2.3 (1.5), with responses ranging from 1 to 6. Overall prevalence of comorbidities was low, with no participants reporting congestive heart failure or peripheral vascular disease.

TABLE 1 - Participant Demographic and Clinical Characteristics
Characteristic M (SD) or %
N 43
Fatigue levela 43.15 (25.6)
Age, y 57.28 (10.17)
Race
White 90.6
Black 4.7
Asian 4.7
Time since treatment, y 3.5 (2.1)
Treatment type
Chemotherapy only 30.2
Chemotherapy + Radiation 69.8
Chemotherapy type
AC or AC-T 58.1
TC 27.9
Other 14.0
Antiestrogens
None 34.9
Tamoxifen 23.2
Aromatase inhibitors 41.9
Still taking antiestrogens 53.5
Surgery type
Lumpectomy 30.2
Single mastectomy 39.6
Double mastectomy 30.2
Sensory symptoms CIPN
CIPN + 53.5
Severity if + 2.3 (1.5)
Self-report physical activity
Hours in all activity per week 15.9 (10.1)
Hours of MVPA per week 7.4 (7.3)
BMI 26.4 (5.5)
Falls in past 6 mo, % 2.3
Comorbidities (per person)
Mean (SD) 1.8 (1.7)
Median (range) 1.0 (0-6)
Abbreviations: AC, Adriamycin and Cytoxan; AC-T, Adriamycin and Cytoxan plus Taxol; BMI, body mass index; CIPN, chemotherapy-induced peripheral neuropathy; MVPA, moderate to vigorous physical activity; TC, docetaxel and Cytoxan.
aScores on the SF-36 Vitality Scale (0-100, scores reversed, so higher scores indicate higher fatigue).

Static Standing Balance

Preexertional Static Sway

Before engaging in moderate-intensity exercise, level of CRF was a statistically significant predictor of postural sway in the AP plane, P = .04, with greater CRF predicting greater AP sway. Level of CRF accounted for 10.5% of the variance in pre-exertional AP sway and remained a significant predictor after controlling for CIPN severity, age, and hours of moderate-intensity activity per week, P = .04 (Table 2). In comparison, CIPN severity accounted for only 0.9% of additional variance in AP sway after controlling for CRF and was not a statistically significant predictor. In the fully adjusted model, a participant who reported CRF 1 standard deviation (25.6) above average (43.15) demonstrated 1.15% (95% confidence interval [CI], 1.01-1.31) greater sway in the AP plane than a participant with average CRF (Figure 2).

TABLE 2 - Regression Results Predicting Static and Rising-Phase AP Swaya
Static Standing AP Swayb Rising-Phase AP Swayc
Pre-exercise Postexercise Pre-exercise Postexercise
Intercept 1.66d 0.84d 119.48d −20.46
Pre-exercise sway ... 0.45d ... 1.11d
Fatigue 0.006e 0.006e 0.21 −0.601e
CIPN severity −0.03 −0.03 −1.74 5.66
Age, y 0.01 0.01 −0.12 0.2
Moderate-intensity activity per week, h −0.001 −0.001 −1.13 0.16
Adjusted R 2 0.17 0.42 0.15 0.61
F statistic 1.74 4.98d 1.61 11.31d
Abbreviations: AP, anterior-posterior; CIPN, chemotherapy-induced peripheral neuropathy.
aValues are standardized β-coefficients.
bEstimates are log-values.
cEstimates are in Newton-seconds.
dP < .01.
eP < .05.

F2
Fig. 2.:
Pre- and postexertional static anterior-posterior postural sway by fatigue level. Before and after exercise, participants with greater fatigue demonstrated greater postural sway in the anterior-posterior plane. Each data point represents a single participant; darker points indicate overlap. r = Pearson correlation coefficient. Higher fatigue score indicates greater fatigue. This figure is available in color online (www.rehabonc.com).

Level of CRF was not a statistically significant predictor of pre-exertional sway in the ML plane, P = .28. No other variables were statistically significant predictors of pre-exertional postural sway.

Postexertional Static Sway

There were positive trends between level of CRF and change in ML (r = 0.21, P = .19) and AP (r = 0.19, P = .24) standing postural sway from pre- to postexertion. As level of CRF increased, there was a greater increase in both ML and AP sway from pre- to postexertion. After controlling for pretest postural sway, CRF was a statistically significant predictor of postexertional sway in the AP plane, P = .02, however, not in the ML plane, P = .21. Level of CRF accounted for an additional 9.5% of the variance in postexertional AP sway after controlling for pretest sway and remained a significant predictor after controlling for CIPN severity, age, and hours of moderate-intensity activity per week, P = .03 (Table 2). In the fully adjusted model, a participant who reported CRF 1 SD greater than the average demonstrated 1.17% (95% CI, 1.02-1.33) greater postexertional AP sway compared with a participant with average fatigue (Figure 2). No other predictors of postexertional ML or AP sway were statistically significant.

Dynamic Balance

Preexertional Rising Phase Sway

Before engaging in moderate-intensity exercise, level of CRF was a statistically significant predictor of rising phase postural sway in the ML plane, β = 0.12, P = .03; however, this effect was lost after controlling for CIPN. Level of CRF was not a statistically significant predictor of pre-exertional rising phase sway in the AP plane, P = .11. No other variables were statistically significant predictors of pre-exertional rising phase postural sway (Table 2).

Postexertional Rising Phase Sway

There were small to moderate negative correlations between level of CRF and change in ML (r = −0.17, P = .28) and AP (r = −0.36, P = .02) rising phase postural sway from pre- to postexertion. As level of CRF increased, there was a greater decrease in both ML and AP sway from pre- to postexertion and the decrease in AP sway was significantly correlated with the level of CRF (Figure 3). After controlling for pretest rising phase sway, CRF was a statistically significant predictor of postexertional rising phase sway in the AP plane, P = .016, but not in the ML plane, P = .96, with greater CRF predicting less rising phase AP sway. Level of CRF accounted for 6.6% of the variance in postexertional rising phase AP sway after controlling for pretest sway, while CIPN severity accounted for an additional 3% of the variance but was not a statistically significant predictor, P = .07. Level of CRF remained a significant predictor after controlling for CIPN severity, age, and hours of moderate-intensity activity per week, P = .01 (Table 2). In this fully adjusted model, a participant who reported CRF 1 SD greater than average demonstrated 15.23 N-s (95% CI, 4.18-26.28) less rising phase sway in the AP plane compared with a participant with average fatigue. To confirm our analysis, we also regressed the change in rising phase AP sway from pre- to postexercise on level of CRF and found that, after controlling for all covariates, greater CRF significantly predicted a greater decrease from pre to post, β = −0.71, P = .006.48

F3
Fig. 3.:
Pre- to postexertional change in anterior weight shift during instrumented sit-to-stand by fatigue level. Postexercise, participants with greater fatigue demonstrated greater decreases in anterior weight shifting during a sit-to-stand transfer. Each data point represents a single participant; darker points indicate overlap. r = Pearson correlation coefficient. Higher fatigue score indicates greater fatigue.

DISCUSSION

This study begins to address the gap identified in the recent scoping review that, while substantial evidence exists linking CIPN to imbalance and falls, there has been a severe lack of investigation to quantify CRF's influence on balance.15 Among the women in this study, the contribution of CRF to balance compared with the relative lesser contribution of CIPN is evident. Under both static and dynamic conditions, CRF accounted for greater variability in postural sway and remained a significant predictor of sway even after controlling for CIPN symptoms. Our results, which support prior evidence linking CRF to patient-reported falls,6,49 indicate that CRF, even several years following exposure to chemotherapy, may distinctly influence balance independent of a patient's CIPN status. This finding is important since persistent CRF affects up to 30% of individuals well beyond 1 year following completion of primary cancer treatment.16,17 Although CIPN remains a significant risk factor for imbalance, impaired gait, and falls in this population, CRF warrants further consideration in research and in clinical practice as a possible causal pathway between cancer treatment and impairments in balance.

In contrast to our hypothesis, women in our sample with greater CRF demonstrated significantly less rising phase sway in the AP plane following the bout of exercise. In other words, postexercise, participants with greater CRF demonstrated significantly smaller anterior weight shifts while transitioning from sitting to standing. Counterintuitively, the smaller weight shift may still be indicative of impaired dynamic balance, as this sit-to-stand pattern, known as a stabilization strategy (SS), has been observed among known fallers and populations with balance impairments.50–52 This pattern is contrasted with the conventional sit-to-stand pattern known as a momentum-transfer (MT) strategy observed in younger populations and elderly nonfallers.50,51

The MT sit-to-stand strategy uses momentum generated by the rapid forward motion of the trunk and depends on sufficient postural control as the momentum developed must be large enough to reach but not overshoot the standing position.51 In contrast, the SS uses little anterior momentum, requiring less postural control, and instead relying more heavily on the lower extremity musculature (Figure 4).51 If balance is compromised, an individual may transition from an MT strategy to an SS sit-to-stand transfer. This may be particularly relevant for individuals with increased postural sway in the AP plane, as was demonstrated statically by participants with greater CRF, since this is the same plane in which an individual rises from sitting to standing.

F4
Fig. 4.:
Momentum transfer versus stabilization strategy transfer. BOS indicates base of support; COM, center of mass; COP, center of pressure; LE, lower extremity.

The implementation of an SS by women with breast cancer and greater CRF in our sample may represent a compensatory strategy. Given the chronicity of CRF observed in this sample, associated balance impairments may have been long-standing, leading to gradual incorporation of a self-protective strategy. This may be mirrored by evidence of an SS among elderly fallers, possibly due to slow onset of age-related imbalance.52 Future longitudinal studies should explore the temporal relationship between CRF and balance with assessments before, during, and after cancer treatment. A greater understanding of the temporal relationship between CRF and balance would improve our ability to monitor for and address changes in balance throughout the continuum of care.

Clinical Implications and Future Research

The postexertional change in sit-to-stand strategy among participants with greater CRF suggests that a lower extremity fatiguing task may cause or exacerbate impairments in dynamic balance. In everyday life, women with breast cancer and CRF may encounter such fatiguing tasks through performing activities of daily living, negotiating stairs or the community, or participating in a recommended exercise program. The vast majority of falls occur during dynamic tasks and transitional movements.53,54 Therefore, potential changes in the ability of individuals with CRF to perform these dynamic tasks following activity must be taken seriously.

Rehabilitation clinicians and exercise specialists must consider the potential implications of balance impairments among individuals with CRF when prescribing exercise according to the American College of Sports Medicine's exercise guidelines for cancer survivors. Although these guidelines suggest that the efficacy of exercise to reduce CRF is independent of supervision or setting,26 safety must be a foremost consideration when recommending exercise. Given our study's findings, patients with CRF should be assessed for imbalance independent of their CIPN status. Furthermore, the order of an objective examination of a patient with CRF should be considered, as balance may vary based on whether it is tested before or after physically fatiguing tasks. Clinicians are encouraged to consider the recent systematic review of balance outcome measures for adult survivors of cancer to identify measures of static and dynamic balance with good clinical utility.55 Although several recommended measures, such as the Fullerton Advanced Balance Scale and gait speed, have been validated among individuals with CIPN,55 to our knowledge, no balance measures have been validated among individuals with CRF. Future studies should seek to validate clinical outcome measures that are sensitive to CRF-related imbalance.

A greater understanding of how postexertional changes in balance are experienced in the context of daily life may enhance our ability to provide individualized activity recommendations for individuals with CRF following cancer treatment. These individuals may benefit from balance-related education regarding safety and coping or compensatory strategies. Future studies should also assess the efficacy of multimodal exercise and balance training, effective for individuals with CIPN,56,57 among patients experiencing CRF-related imbalance.

Limitations

The primary limitation of this secondary analysis was the small and demographically homogenous sample. A relative strength of our sample, however, was the variation in fatigue scores among participants, ranging from 0 to 100 with normal distribution, suggesting that our small sample represented the spectrum of persistent CRF. As several trends were noted in our results, this investigation will benefit from continued enrollment and analysis. The complex nature of CRF should also be acknowledged and results should be interpreted with the understanding that, while our study was designed to exclude and control for confounding factors, it is possible that subclinical medical conditions or external factors influenced our results. The cross-sectional design of our study also limits our ability to draw conclusions. As detailed previously, longitudinal studies with assessments of CRF and balance before, during, and after cancer treatment would greatly enhance our understanding of the effect of CRF on balance.

The average severity of CIPN symptoms (2.3 [1.5] with possible range of 0-8) suggests a mild to moderate level of CIPN among participants. This relatively low level of CIPN may have affected the degree to which severity of CIPN symptoms accounted for variability in postural sway. However, research has shown an association between mild CIPN symptoms and impaired balance,58 as well as a linear relationship between CIPN symptoms and higher fall risk,11 suggesting that the severity of CIPN symptoms in our sample was likely sufficient to influence postural sway.

Limitations that may have restricted the change in static standing balance from pre- to postexercise also warrant consideration. Compared with dynamic balance, which changed following exercise, static balance is a less complex task and may have been less susceptible to change. Patients with a history of cancer demonstrate worse balance when performing more complex or challenging tasks such as those requiring dual tasking or divided attention.58–60 Therefore, our quiet static standing protocol may not have provided a great enough challenge to the participants' balance to observe significant differences postexercise. Future studies may benefit from assessing static balance on compliant surfaces or underaltered visual conditions. It is also possible that the bout of exercise, though similar to protocols used to elicit changes in gait characteristics in older adults,24 was not performed at a high enough intensity to provoke changes in static balance. Future studies may benefit from more intense fatiguing tasks, though participant tolerance may be compromised.

figure5

REFERENCES

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33. doi:10.3322/caac.21654.
2. American Cancer Society. Breast Cancer Facts & Figures 2019-2020. Atlanta, GA: American Cancer Society; 2019.
3. Cheville AL, Troxel AB, Basford JR, Kornblith AB. Prevalence and treatment patterns of physical impairments in patients with metastatic breast cancer. J Clin Oncol. 2008;26(16):2621–2629. doi:10.1200/JCO.2007.12.3075.
4. Cheville AL, Mustian K, Winters-Stone K, Zucker DS, Gamble GL, Alfano CM. Cancer rehabilitation: an overview of current need, delivery models, and levels of care. Phys Med Rehabil Clin N Am. 2017;28(1):1–17. doi:10.1016/j.pmr.2016.08.001.
5. Hsieh KL, Wood TA, An R, Trinh L, Sosnoff JJ. Gait and balance impairments in breast cancer survivors: a systematic review and meta-analysis of observational studies. Arch Rehabil Res Clin Transl. 2019;1(1-2):100001. doi:10.1016/j.arrct.2018.12.001.
6. Wood LJ, Winters-Stone KM, Kneiss JA, Fox AB, Walker RK. Women with clinically significant fatigue after breast cancer treatment report increased falls and perform poorly on objective measures of physical fitness and function. Rehabil Oncol. 2020;38(2):92–99. doi:10.1097/01.REO.0000000000000193.
7. Miaskowski C, Mastick J, Paul SM, et al. Impact of chemotherapy-induced neurotoxicities on adult cancer survivors' symptom burden and quality of life. J Cancer Surviv. 2018;12(2):234–245.
8. Kandula T, Farrar MA, Cohn RJ, et al. Chemotherapy-induced peripheral neuropathy in long-term survivors of childhood cancer: clinical, neurophysiological, functional, and patient-reported outcomes. JAMA Neurol. 2018;75(8):980–988. doi:10.1001/jamaneurol.2018.0963.
9. Winters-Stone KM, Nail L, Bennett JA, Schwartz A. Bone health and falls: fracture risk in breast cancer survivors with chemotherapy-induced amenorrhea. Oncol Nurs Forum. 2009;36(3):315–325. doi:10.1188/09.ONF.315-325.
10. Chen Z, Maricic M, Bassford TL, et al. Fracture risk among breast cancer survivors: results from the Women's Health Initiative Observational Study. Arch Intern Med. 2005;165(5):552–558. doi:10.1001/archinte.165.5.552.
11. Winters-Stone KM, Horak F, Jacobs PG, et al. Falls, functioning, and disability among women with persistent symptoms of chemotherapy-induced peripheral neuropathy. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(23):2604–2612. doi:10.1200/JCO.2016.71.3552.
12. 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:10.1007/s10549-016-3939-0.
13. Seretny M, Currie GL, Sena ES, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: a systematic review and meta-analysis. Pain. 2014;155(12):2461–2470. doi:10.1016/j.pain.2014.09.020.
14. Kneis S, Wehrle A, Freyler K, et al. Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy. Clin Neurophysiol. 2016;127(2):1481–1490. doi:10.1016/j.clinph.2015.07.022.
15. Wechsler S, Wood L. The effect of chemotherapy on balance, gait, and falls among cancer survivors: a scoping review. Rehabil Oncol. 2021;39(1):6–22. doi:10.1097/01.REO.0000000000000238.
16. Jones JM, Olson K, Catton P, et al. Cancer-related fatigue and associated disability in post-treatment cancer survivors. J Cancer Surviv. 2016;10(1):51–61. doi:10.1007/s11764-015-0450-2.
17. Goedendorp MM, Gielissen MFM, Verhagen CAHHVM, Bleijenberg G. Development of fatigue in cancer survivors: a prospective follow-up study from diagnosis into the year after treatment. J Pain Symptom Manage. 2013;45(2):213–222. doi:10.1016/j.jpainsymman.2012.02.009.
18. Wood Magee LJ, Kneiss J, Wechsler S, et al. Increased fatigability in women with persistent cancer-related fatigue after breast cancer treatment: a pilot study. Rehabil Oncol. 2022. doi:10.1097/01.REO.0000000000000305.
19. Skelton DA. Explosive power and asymmetry in leg muscle function in frequent fallers and non-fallers aged over 65. Age Ageing. 2002;31(2):119–125. doi:10.1093/ageing/31.2.119.
20. Portegijs E, Sipilä S, Pajala S, et al. Asymmetrical lower extremity power deficit as a risk factor for injurious falls in healthy older women. J Am Geriatr Soc. 2006;54(3):551–553. doi:10.1111/j.1532-5415.2006.00643_6.x.
21. Adlerton AK, Moritz U, Moe-Nilssen R. Forceplate and accelerometer measures for evaluating the effect of muscle fatigue on postural control during one-legged stance. Physiother Res Int J Res Clin Phys Ther. 2003;8(4):187–199. doi:10.1002/pri.289.
22. Foulis SA, Jones SL, van Emmerik RE, Kent JA. Post-fatigue recovery of power, postural control and physical function in older women. PLoS One. 2017;12(9):e0183483. doi:10.1371/journal.pone.0183483.
23. Pinsault N, Vuillerme N. Differential postural effects of plantar-flexor muscle fatigue under normal, altered and improved vestibular and neck somatosensory conditions. Exp Brain Res. 2008;191(1):99–107. doi:10.1007/s00221-008-1500-z.
24. Helbostad JL, Leirfall S, Moe-Nilssen R, Sletvold O. Physical fatigue affects gait characteristics in older persons. J Gerontol Ser A. 2007;62(9):1010–1015. doi:10.1093/gerona/62.9.1010.
25. Helbostad JL, Sturnieks DL, Menant J, Delbaere K, Lord SR, Pijnappels M. Consequences of lower extremity and trunk muscle fatigue on balance and functional tasks in older people: a systematic literature review. BMC Geriatr. 2010;10:56. doi:10.1186/1471-2318-10-56.
26. Campbell KL, Winters-Stone KM, Wiskemann J, et al. Exercise guidelines for cancer survivors: consensus statement from international multidisciplinary roundtable. Med Sci Sports Exerc. 2019;51(11):2375–2390. doi:10.1249/MSS.0000000000002116.
27. Campbell KL, Winters-Stone KM, Patel AV, et al. An executive summary of reports from an international multidisciplinary roundtable on exercise and cancer: evidence, guidelines, and implementation. Rehabil Oncol. 2019;37(4):144–152. doi:10.1097/01.REO.0000000000000186.
28. Lindemann U, Claus H, Stuber M, et al. Measuring power during the sit-to-stand transfer. Eur J Appl Physiol. 2003;89(5):466–470. doi:10.1007/s00421-003-0837-z.
29. Heller B, Senior T, Wheat J. The Smartfloor: a large area force-measuring floor for investigating dynamic balance and motivating exercise. Procedia Eng. 2014;72:226–231. doi:10.1016/j.proeng.2014.06.040.
30. Winter DA, Patla AE, Frank JS. Assessment of balance control in humans. Med Prog Technol. 1990;16(1-2):31–51.
31. Goldie PA, Bach TM, Evans OM. Force platform measures for evaluating postural control: reliability and validity. Arch Phys Med Rehabil. 1989;70(7):510–517.
32. Paillard T, Noé F. Techniques and methods for testing the postural function in healthy and pathological subjects. BioMed Res Int. 2015;2015:1–15. doi:10.1155/2015/891390.
33. Vieira MF, de Avelar IS, Silva MS, Soares V, Lobo da Costa PH. Effects of four days hiking on postural control. PLoS One. 2015;10(4):e0123214. doi:10.1371/journal.pone.0123214.
34. Catania G, Bell C, Ottonelli S, et al. Cancer-related fatigue in Italian cancer patients: validation of the Italian version of the Brief Fatigue Inventory (BFI). Support Care Cancer. 2013;21(2):413–419. doi:10.1007/s00520-012-1539-z.
35. Rogers SN, Humphris G, Lowe D, Brown JS, Vaughan ED. The impact of surgery for oral cancer on quality of life as measured by the Medical Outcomes Short Form 36. Oral Oncol. 1998;34(3):171–179. doi:10.1016/S1368-8375(97)00069-9.
36. Fang FM, Chiu HC, Kuo WR, et al. Health-related quality of life for nasopharyngeal carcinoma patients with cancer-free survival after treatment. Int J Radiat Oncol. 2002;53(4):959–968. doi:10.1016/S0360-3016(02)02838-9.
37. Karvonen-Gutierrez CA, Ronis DL, Fowler KE, Terrell JE, Gruber SB, Duffy SA. Quality of life scores predict survival among patients with head and neck cancer. J Clin Oncol. 2008;26(16):2754–2760. doi:10.1200/JCO.2007.12.9510.
38. Mosconi P, Cifani S, Crispino S, Fossati R, Apolone G. The performance of SF-36 health survey in patients with laryngeal cancer. Head Neck. 2000;22(2):175–182. doi:10.1002/(SICI)1097-0347(200003)22:2<175::AID-HED10>3.0.CO;2-V.
39. Calhoun EA, Welshman EE, Hunt TL, Cella D. Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group—neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer. 2003;13(6):741–748.
40. Shimozuma K, Ohashi Y, Takeuchi A, et al. Feasibility and validity of the Patient Neurotoxicity Questionnaire during taxane chemotherapy in a phase III randomized trial in patients with breast cancer: N-SAS BC 02. Support Care Cancer 2009;17(12):1483–1491. doi:10.1007/s00520-009-0613-7.
41. Hile E, Levangie P, Ryans K, Gilchrist L. Oncology section task force on breast cancer outcomes: clinical measures of chemotherapy-induced peripheral neuropathy—a systematic review. Rehabil Oncol. 2015;33(3):32.
42. Winters-Stone KM, Dobek J, Bennett JA, Nail LM, Leo MC, Schwartz A. The effect of resistance training on muscle strength and physical function in older, postmenopausal breast cancer survivors: a randomized controlled trial. J Cancer Surviv. 2012;6(2):189–199. doi:10.1007/s11764-011-0210-x.
43. Granger CL, McDonald CF, Irving L, et al. Low physical activity levels and functional decline in individuals with lung cancer. Lung Cancer Amst Neth. 2014;83(2):292–299. doi:10.1016/j.lungcan.2013.11.014.
44. Stewart AL, Mills KM, King AC, Haskell WL, Gillis D, Ritter PL. CHAMPS physical activity questionnaire for older adults: outcomes for interventions. Med Sci Sports Exerc. 2001;33(7):1126–1141. doi:10.1097/00005768-200107000-00010.
45. Groll DL, To T, Bombardier C, Wright JG. The development of a comorbidity index with physical function as the outcome. J Clin Epidemiol. 2005;58(6):595–602. doi:10.1016/j.jclinepi.2004.10.018.
46. R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing. https://www.r-project.org/. Published 2017. Accessed January 26, 2021.
47. Wickham H. Ggplot2: Elegant Graphics for Data Analysis. New York, NY: Springer-Verlag; 2009. http://ggplot2.org. Accessed January 26, 2021.
48. van Breukelen GJP. ANCOVA versus CHANGE from baseline in nonrandomized studies: the difference. Multivar Behav Res. 2013;48(6):895–922. doi:10.1080/00273171.2013.831743.
49. Huang MH, Blackwood J, Godoshian M, Pfalzer L. Factors associated with self-reported falls, balance or walking difficulty in older survivors of breast, colorectal, lung, or prostate cancer: results from Surveillance, Epidemiology, and End Results–Medicare Health Outcomes Survey linkage. PLoS One. 2018;13(12):e0208573. doi:10.1371/journal.pone.0208573.
50. Scarborough DM, McGibbon CA, Krebs DE. Chair rise strategies in older adults with functional limitations. J Rehabil Res Dev. 2007;44(1):33–42. doi:10.1682/JRRD.2005.08.0134.
51. Hughes MA, Weiner DK, Schenkman ML, Long RM, Studenski SA. Chair rise strategies in the elderly. Clin Biomech. 1994;9(3):187–192. doi:10.1016/0268-0033(94)90020-5.
52. Chorin F, Cornu C, Beaune B, Frère J, Rahmani A. Sit to stand in elderly fallers vs non-fallers: new insights from force platform and electromyography data. Aging Clin Exp Res. 2016;28(5):871–879. doi:10.1007/s40520-015-0486-1.
53. Piano L, Geri T, Testa M. Raising and stabilization phase of the sit-to-stand movement better discriminate healthy elderly adults from young subjects: a pilot cross-sectional study. Arch Physiother. 2020;10(1):7. doi:10.1186/s40945-020-00078-8.
54. Galli M, Cimolin V, Crivellini M, Campanini I. Quantitative analysis of sit to stand: experimental set up definition and evaluation of adults with hemiplegia. Gait Posture. 2006;24:S46. doi:10.1016/j.gaitpost.2006.09.064.
55. Huang MH, Hile E, Croarkin E, et al. Academy of oncologic physical therapy EDGE Task force: a systematic review of measures of balance in adult cancer survivors. Rehabil Oncol. 2019;37(3):92–103. doi:10.1097/01.REO.0000000000000177.
56. McCrary JM, Goldstein D, Trinh T, et al. Balance deficits and functional disability in cancer survivors exposed to neurotoxic cancer treatments. J Natl Compr Canc Netw. 2019;17(8):949–955. doi:10.6004/jnccn.2019.7290.
57. Kneis S, Wehrle A, MĂ¼ller J, et al. 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:10.1186/s12885-019-5522-7.
58. Monfort SM, Pan X, Loprinzi CL, Lustberg MB, Chaudhari AMW. Exploring the roles of central and peripheral nervous system function in gait stability: preliminary insights from cancer survivors. Gait Posture. 2019;71:62–68. doi:10.1016/j.gaitpost.2019.04.002.
59. Blackwood J. Physical mobility and balance performance differs in older cancer survivors with impaired executive function. Rehabil Oncol. 2021;39(1):31–37.
60. Blackwood J. The influence of cognitive function on balance, mobility, and falls in older cancer survivors. Rehabil Oncol. 2019;37(2):77–82. doi:10.1097/01.REO.0000000000000128.
Keywords:

chemotherapy-induced peripheral neuropathy; dynamic balance; static balance; survivorship

© 2022 Academy of Oncologic Physical Therapy, APTA.