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RESEARCH REPORT

Increased Fatigability in Women With Persistent Cancer-Related Fatigue After Breast Cancer Treatment: A Pilot Study

Wood Magee, Lisa J. PhD, RN, FAAN1; Kneiss, Janet DPT, PhD2; Wechsler, Stephen PT, DPT3; Singh, Ayesha Bani NP4; Fox, Annie B. PhD5; Peppercorn, Jeffrey MD, MPH6; Pirl, William F. MD, MPH7

Author Information
Rehabilitation Oncology: April 28, 2022 - Volume - Issue - 10.1097/01.REO.0000000000000305
doi: 10.1097/01.REO.0000000000000305
  • Open
  • PAP

Abstract

Breast cancer (BC) is the most common cancer and leading cause of cancer death in women living in the United States.1 Advances in BC diagnosis and the use of taxane and anthracycline-based chemotherapy regimens have greatly improved BC survival.2 Consequently, there are currently over 3 million survivors of breast cancer (SBC) in the United States.3 Among SBC in the United States, over 50% are older than 60 years.3 Despite these improvements in survival, cancer treatment's long-term effects pose a considerable problem for many survivors of cancer. Cancer-related fatigue (CRF) is defined as “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”4 CRF is one of the most commonly experienced symptoms in patients undergoing treatment for BC, affecting 60% to 100% of patients.5,6 For most women with BC, CRF gradually declines in the months after treatment has ended.7 However, for a significant percentage of women (up to 30%), CRF can become persistent, lasting for more than 6 months post-treatment,8–13 and in some cases, for several years after treatment has ended.8,14

CRF has a profoundly negative effect on self-report physical functioning and quality of life.15–17 In a recent study, we found that SBC with fatigue (5.6 ± 3.9 years post-diagnosis) reported twice the rate of falls and performed more poorly on objectively measured functional tests compared with SBC without fatigue.14 In that study, SBC with fatigue took an average of 13 seconds to complete the 5-time sit-to-stand test and had gait speeds 0.1 m/s slower compared with SBC without fatigue.14 These findings are clinically significant because a 5-time sit-to-stand test longer than 12 seconds predicts a 2.4-fold increase in fall risk in people 74 years and older,18 and 0.1 m/s is a minimal clinically significant difference in gait speed.19 Of note, in this latter study, muscle strength and gross balance were not significantly different between the 2 fatigue groups, suggesting that other factors contributed to the functional deficits seen in SBC with fatigue.14

Lower extremity muscle fatigability is associated with functional impairments and increased risk of falls in older adults,20 and may explain why women with persistent CRF perform more poorly on functional tests and report twice the number of falls compared with women without CRF.14 Fatigability is a broad term used to describe a specific set of functional deficits, including poor endurance, greater perceived exertion, and lower muscle force and power during muscular exercise. Among people 65 years and oler, fatigability is a significant predictor of immobility, is associated with higher scores on the Short Physical Performance Battery,21 and associated with an increased relative risk of falls.22,23 A few studies have examined fatigability in survivors of cancer,24–28 but only one compared measures of fatigability in those with and without CRF.29 These prior studies were limited by their focus on the fatigability of isolated small muscle groups (ie, forearm flexors or ankle plantar flexor muscles) under isometric conditions (ie, static position).24–29 No studies to date have examined fatigability of the larger muscles of the lower extremities (ie, quadruceps) that is more closely linked to balance and gait impairments during aging.30,31

The purpose of this pilot study was to determine whether SBC with CRF have greater fatigability compared with SBC without CRF during and after a functional task that targets the large muscles of the lower extremities and includes a balance component. We hypothesized that compared with SBC without CRF, SBC with CRF will show reduced endurance, increased perceived effort, lower muscle force and power, and longer sit-to-stand times (STSTs) during and after muscular exercise.

METHODS

Population and Sample

Participants were women, 35 to 80 years of age, who had completed cytotoxic chemotherapy with or without radiation therapy for stage I to III BC 12 months or more post-treatment (antihormone therapies, ie, tamoxifen or anastrozole permitted). Participants were recruited from the Gillette Center for Breast Cancer at Massachusetts General Hospital (MGH). We did not recruit participants within 12 months post-treatment to minimize the effect of acute treatment-related effects on fatigue level, including anxiety and depression.32 Eligible participants were able to undergo the testing protocol, speak and read English at a minimum of a sixth-grade level, and be functionally independent (ie, able to perform activities of daily living independently without an assistive device). Participants also met CRF or non-CRF criteria based on their responses on the SF-36 vitality scale33; a score of 50 or less indicated CRF and 50 or more indicated non-CRF.14,34–37 Exclusion criteria were (1) any injury or functional limitation that would prohibit being able to perform the sit-to-stand maneuver safely for up to 15 minutes (ie, a cardiac condition), (2) precancer diagnosis of fibromyalgia or chronic fatigue syndrome, (3) diagnosis of hypothyroidism, (4) a hemoglobin level less than 12 g/dL or receiving treatment for anemia in the last 3 months, and (5) positive screens for major depression or anxiety on the Patient Health Questionnaire-4.38 All procedures performed in this study were in accordance with the ethical standards of the Dana Faber Cancer Institute and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants in the study.

Overview of Study Visit

Study participants were met by staff at the Biomotion Laboratory at the MGH Institute for Health Professions. First, participants completed study surveys electronically using a browser-based research electronic data capture (REDCap) and study iPADs. Participants then underwent tests to measure lower extremity muscle force and power (instrumented sit-to-stand [ISTS]). The total time needed for all procedures, including the sit-to-stand fatigue (STSF) task, was approximately 75 minutes. As an incentive, participants received a small remuneration for their time and were provided with on-site parking.

Primary Study Outcomes

The primary study outcomes were 4 measures of fatigability: (1) perceived exertion during the STSF task, (2) endurance during the STSF task, (3) change in lower extremity muscle force from before to immediately after the STSF task, and (4) change in lower extremity muscle power from before to immediately after the STSF task. Potential covariates were also assessed including age, comorbidities, level of moderate to vigorous physical activity (MVPA), and the severity of sensory symptoms of chemotherapy-induced peripheral neuropathy (CIPN) in the lower extremities. We included these covariates in the analyses because each has the potential to impact fatigability outcomes independent of the CRF group.

Demographic and Clinical Data

An 8-item standard demographic survey was used to collect data, including age, racial background, marital status, education, employment, occupation, the number of adults and children <12 living in the home, and income. Cancer stage, treatment type, and time since diagnosis were extracted from the medical record. The purpose of collecting this data was to describe the population under study.

Comorbidities

The presence of chronic medical conditions that may affect fatigue and physical functioning was measured using the Functional Comorbidity Index (FCI), a validated and reliable self-administered 18-item list of diagnoses that was developed to specifically examine the effect of comorbidities on physical function.39 Diagnoses included on the FCI checklist include asthma, arthritis, diabetes type 2 or 2, etc. The FCI has been used in previous studies to document comorbidities that could impact physical function in survivors of cancer, and in other studies, comorbidities were associated with higher fatigue levels in women with BC.40,41 The FCI score consists of the total number of comorbidities identified, with a minimum score of 0 (no comorbidities) and a maximum score of 18 (18 comorbidities).

Sensory Neuropathy Symptoms

Survivors of BC frequently report sensory symptoms of CIPN as a result of exposure to neurotoxic chemotherapy agents.42 Sensory symptoms include numbness, tingling, or discomfort in the hands and feet. The presence or absence of sensory neuropathy in the feet was assessed using the sensory neuropathy items on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity43 (FACT/GOG-Ntx-4 v4) that ask about sensory neuropathy symptoms. The 4-item FACT/GOG-Ntx-4 has shown excellent internal reliability (α > 0.80) and criterion validity (α > 0.90) in the assessment of CIPN.43 For the purposes of this study, we chose to focus on assessing sensory symptoms of CIPN only in the feet. Participants were asked how strongly they agree with the following statements: “I have numbness and tingling in my feet” and “I feel discomfort in my feet” on a 0- to 4-point scale, where 0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = very much. Responses on these 2 items were summed (possible range 0-8).44 Higher scores represent more severe symptoms of sensory neuropathy in the feet. This 2-item summary score has been used to quantify sensory symptoms of CIPN in the feet in 2 prior studies of SBC.14,45 In these prior studies, higher scores were associated with poorer performance on several objective tests of physical function (all P < .05), poorer self-report functioning (P < .05), more disability (P < .05), and nearly twice the rate of falls (odds ratio 1.46) compared with women who did not report these symptoms.14,45

Self-report Physical Activity

The Community Health Activity Model Program for Seniors (CHAMPS) questionnaire was used to assess the weekly duration of low and moderate to vigorous physical activity (MVPA).46 The 41-item CHAMPS questionnaire asks about the weekly frequency and duration of physical activity including of various intensities (light to vigorous) including walking, running, hiking, swimming, bicycling, dancing, tennis, aerobics, yoga/tai chi, gardening, and housework in people. The CHAMPS has demonstrated acceptable reliability and validity for the assessment of physical activity in individuals 50 years and older (α > 0.8).46 We have used this tool in a prior study of SBC and found it to have excellent internal consistency (α > 0.8) and moderate convergent validity with the 6-minute walk test (Spearman's ρ = .373).

Instrumented Sit-to-Stand

The ISTS is a measurement of hip, knee, and ankle force and power during a sit-to-stand. Bilateral force of hip, knee, and ankle extensors is measured, as a push on a force plate, during the transition from sit to stand. The ISTS has been validated and used in previous studies to assess lower extremity strength and muscle power.23,47,48 The ISTS was used to evaluate lower extremity muscle force and power and STST. Each participant performed the ISTS 4 times during the visit: 3 times before the STSF task (preexercise trials) and once within 1 minute after completing the STSF task (postexercise trial). As described previously, participants were seated upright on a chair with arms folded across their chest, feet in line with the hips, an approximate hip/knee angle of 90°, and ankles placed at approximately 15° of dorsiflexion.47 The chair was placed on top of a force plate (Bertec Corporation model 4060NC) embedded in the floor that recorded the forces acting through the chair (vGRFChair), while an identical force plate under the feet recorded the forces acting through the feet (vGRFFeet). Participants were instructed to move from a seated to a standing position as “quickly as possible without falling” on the count of “1, 2, Go!”. Upon standing, participants were asked to remain standing until told to sit down. The time between each ISTS trial was approximately 2 minutes. One practice trial was performed before recording data from 3 preexercise baseline ISTS trials. The vertical ground reaction force (vGRF) during the ISTS was recorded at a sampling rate of 1000 Hz and the Motion Monitor Software (Innsport Training, Inc, Chicago, Illinois). A separate digital video camera (model DCR-TRV240, Sony) synchronized with the force plate data, frame rate = 30 samples/second, was used to acquire a side view video of participants during the sit-to-stand task. As detailed in previous studies,47,49 2 phases of the sit-to-stand task were identified from the vGRF: the preparation phase and the rising phase (see the Figure). The preparation phase begins when the vGRFfeet decreases by 5 newtons (N), and ends at the beginning of the rising phase when the buttocks leave the chair (vGRFChair < 5 N). The rising phase ends when vGRFfeet reaches the participant's body weight after the first peak of vGRFfeet. The STST is the time from the beginning of the preparation phase to the end of the rising phase. During the preparation phase, the rate of force development (RFD), measured in newtons per second (N/s), was calculated as the slope between 25% and 50% of the vGRF achieved at seat off. From the vGRF and digital video data, the average power during the rising phase was calculated as described previously.47,48

F1
Fig.:
A representation of a single instrumented sit-to-stand (ISTS) for 1 study participant. The vertical ground reaction forces (vGRF) under the feet (vGRFFeet) and the chair (vGRFChair) are shown during a sit-to-stand maneuver. Two phases of the sit-to-stand task can be identified from the vGRF: the preparation phase and the rising phase. The preparation phase begins when the vGRFfeet decreases by 5 N, and ends at the beginning of the rising phase when the buttocks leave the chair (vGRFChair < 5 N). The rising phase ends when the vGRFfeet reaches the participant's body weight after the first peak of vGRFfeet. Sit-to-stand time (STST) is the time from the beginning of the preparation phase to the end of the rising phase. During the preparation phase, the rate of force development (RFD), measured in newtons per second (N/s), is calculated as the slope between 25% and 50% of the vGRF achieved at seat off.

Sit-to-Stand Fatigue Task

The STSF was used to induce lower extremity muscle fatigue. Two measures of fatigability were retrieved from this task; endurance time and perceived exertion (see later for more detail). The STSF has been used in prior studies to examine the effect of lower extremity fatigue on functional outcomes, including postural stability and changes in gait characteristics.50,51 Additionally, the repeated STSF test has a stronger association with health status than leg strength and a 1 repetition sit-to-stand.52 Participants were asked to fold their arms across their chest while performing repeated sit-to-stands at a speed of 30 cycles/min guided by a metronome with equal weight-bearing on the right and left sides. Participants sat on the same chair with the same body positioning used in the ISTS test. They were told that the purpose of the test was to induce fatigue in the muscles of their legs and to keep performing the maneuver at the indicated speed as long as they were able. Before the STSF task and every 2 minutes during the task, participants were asked to rate their level of perceived exertion based on the 6- to 20-point Borg rating scale,53 where 6 indicates “no exertion at all” and 20 indicates “maximal exertion.” The Borg perceived exertion scale is a widely used 15-point measure of perceived exertion during physical exercise that correlates highly with physiological measures of exercise intensity including heart rate and blood lactate level.54

The task was continued until participants stated that they could not continue at the required rate, or if they rated their exertion level 17 or more on the Borg scale, or until a duration of 15 minutes was achieved. The time to performance fatigue and the final Borg rating was recorded as endurance and perceived exertion measures, respectively.

Statistical Analysis

All analyses were conducted in SPSS v26 (IBM, Chicago, Illinois). We examined frequency distributions and descriptive statistics for all study variables.55 The t test, 1-way analysis of variance (ANOVA), and χ2 analyses were conducted on demographic and clinical variables to identify variables that differed between the 2 groups. ANOVA or analysis of covariance (ANCOVA) was used to examine group differences in RFD, power, and STST before and immediately after the STSF task and perceived exertion and endurance during the STSF task, controlling for covariates (see results for a description of covariates included in the analyses). The test-retest reliability of the 3 ISTS pretrials was determined using the intraclass correlation coefficient (ICC) for RFD, power, and STST. Effect sizes and 95% confidence intervals were calculated for all comparisons.

RESULTS

Study Participant Characteristics

Table 1 shows the demographic and clinical factors for women with and without CRF. Compared with women without CRF, those with CRF were younger (P < .006), reported more anxiety and depressive symptoms (P =.008), had a higher body mass index (P = .031), were more than twice as likely to report the presence of sensory symptoms of CIPN in their feet (P = .012) and reported engaging in significantly fewer hours of MVPA compared with their nonfatigued counterparts (P = .002). Groups were similar on race, employment, marital status, education, income, cancer treatment type, time since treatment, current antiestrogen use, the severity of sensory symptoms of CIPN in their feet if CIPN was present, the number of hours spent in low-level physical activities, and the number of comorbidities.

TABLE 1 - Participant Demographic and Clinical Characteristicsa
Characteristic Fatigue+
(n = 21)
Mean (SD) or %
Fatigue–
(n = 22)
Mean (SD) or %
Pb
Fatigue levelc 33.6 (13.0) 78.4 (9.8) .000
Age, y 53.1 (8.4) 61.3 (10.2) .006
Time since treatment, y 3.3 (2.5) 3.7 (1.7) .519
Treatment type .817
Chemotherapy only 28.6 31.8
Radiation and chemotherapy 71.4 68.2
Chemotherapy type .601
AC or AC-T 57.1 59.1
TC 23.8 31.8
Other 19.0 9.1
Antiestrogens .613
None 28.6 40.9
Tamoxifen 28.5 18.2
Aromatase inhibitors 42.8 40.9
Still taking antiestrogens 93.0 69.2 .097
Surgery type .776
Lumpectomy 27.2 27.2
Single mastectomy 36.4 45.6
Double mastectomy 36.4 27.2
FCI 2.1 (1.7) 1.4 (1.6) .152
Sensory symptoms CIPN
CIPN+ (%) 75.0 36.4 .012
Severity 2.6 (1.7) 1.8 (1.0) .209
Self-report physical activity
Hours in all activity/wk 10.9 (7.7) 20.4 (10.0) .001
Hours in low activity/wk 6.8 (5.2) 9.3 (5.4) 131
Hours of MVPA/wk 4.0 (4.5) 10.6 (8.0) .002
BMI 28.2 (6.8) 24.6 (3.2) .031
Fallen in past 6 mo, % 5 0 .300
Abbreviations: AC, Adriamycin-Cytoxan; AC-T, Adriamycin-Cytoxan-Taxol; BMI, body mass index; CIPN, chemotherapy-induced peripheral neuropathy; CIPN+, evidence of sensory symptoms of CIPN; FCI, Functional Comorbidity Index; MVPA, moderate to vigorous physical activity; TC, Taxotere-Cytoxan.
aData represent means and SD or percent of the sample.
bGroup comparisons (fatigued+ vs fatigue–) were performed using t tests or χ2 tests.
cScores on the SF-36 vitality scale (0-100, lower scores indicate higher fatigue).

Group Differences in Preexercise Lower Extremity Force, Power, and Sit-to-Stand Times

Table 2 shows the ICC for the baseline ISTS values for RFD, power, and STST, which ranged from 0.78 to 0.93. Table 3 shows group differences in RFD, power, and STST before exercise. Because women were significantly younger in the CRF group, and increasing age is associated with poorer lower extremity RFD and power,31 we controlled for age in all analyses. Compared with women without CRF, those with CRF had lower RFD (P = .031, ηp2 = 0.112) and power (P = .012, ηp2 = 0.148), and slower STSTs (P = .014, ηp2 = 0.142) (model 1). In model 2, we further controlled for CIPN severity since we reasoned that women with more severe symptoms would be more cautious when moving from a seated to a standing position and move more slowly. Group differences in RFD, power, and STST were all lost after controlling for CIPN severity and in fully adjusted models that further controlled for the number of hours per week engaged in MVPA (model 3).

TABLE 2 - Intraclass Correlation Coefficients (95% CI) of Sit-to-Stand Outcomes
Variable All Participants Fatigue+ Fatigue–
Preparation phase
RFD, (N/s)/kg 0.795 (0.659-0.882) 0.783 (0.552-0.905) 0.801 (0.596-0.911)
Rising phase
Power, W/kg 0.921 (0.865-0.955) 0.929 (0.853-0.969) 0.904 (0.805-0.957)
STS time, s 0.912 (0.855-0.950) 0.932 (0.859-0.970) 0.873 (0.742-0.943)
Abbreviations: CI, confidence interval; RFD, rate of force development; STS, sit-to-stand.

TABLE 3 - Group Differences in Preexercise Fatigability Outcomesa
Model 1 Model 2 Model 3
Outcome Fatigability Fatigue–Mean
(95% CI)
Fatigue+Mean
(95% CI)
P ηp 2 Fatigue–Mean
(95% CI)
Fatigue+Mean
(95% CI)
P ηp 2 Fatigue–Mean
(95% CI)
Fatigue+Mean
(95% CI)
P ηp 2
RFD, (N/s)/kg 101.8 (87.0-116.6) 82.2 (67.0-97.4) .031 0.112 98.0 (82.2-113.6) 87.3 (70.6-103.9) .191 0.045 93.3 (78.2-108.4) 92.3 (76.3-108.4) .266 0.033
Power, w/kg 5.2 (4.8-5.7) 4.3 (3.8-4.9) .012 0.148 5.2 (4.6-5.7) 4.4 (3.9-5.0) .078 0.079 5.1 (4.6-5.7) 4.5 (3.9-5.0) .144 0.057
STST, s 0.59 (0.52-0.67) 0.73 (0.66-0.80) .014 0.142 0.61 (0.53-0.69) 0.71 (0.62-0.79) .093 0.074 0.63 (0.55-0.71) 0.69 (0.60-0.77) .195 0.045
Abbreviations: CI, confidence interval; RFD, rate of force development; STST, sit-to-stand time; ηp2, partial eta squared, a measure of effect size, where 0.01, 0.09, and 0.25 represent small, medium, and large effect sizes, respectively.
aData are presented as means with 95% CI. P values refer to univariate analyses performed with normally distributed data. Model 1 is adjusted for age, model 2 is further adjusted for the severity of chemotherapy-induced peripheral neuropathy symptoms, and model 3 is fully adjusted, including all prior covariates plus self-reported hours spent in all moderate-vigorous intensity physical activity.

Group Differences in Fatigability Outcomes

Group differences in fatigability outcomes immediately post-exercise were examined with ANCOVA. Controlling for age, women in the CRF group had poorer endurance (P = .003, ηp2 = 0.205) and greater perceived exertion (P < .001, ηp2 = 0.284) compared with women without CRF (Table 4; model 1). Controlling for age and preexercise values, which differed between the CRF groups, we found that women with CRF also had lower postexertional RFD (P = .035, ηp2 = 0.109), and power (P = .001, ηp2 = 0.242), and slower STST (P = .001, ηp2 = 0.258) compared with women without CRF (Table 4; model 1). Group differences in endurance, perceived exertion, power, and STST time remained after further controlling for the severity of sensory symptoms of CIPN (model 2, P < .05), while group differences in RFD were weakened (P = .058, ηp2 = 0.094). Group differences in perceived exertion, power, and STST remained after further controlling for self-reported levels of MVPA, but were lost for RFD and endurance (P > .05).

TABLE 4 - Group Differences in Fatigability and Functional Outcomes Post-exercisea
Model 1 Model 2 Model 3
Outcome Fatigability Fatigue–Mean
(95% CI)
Fatigue+Mean
(95% CI)
P ηp 2 Fatigue–Mean
(95% CI)
Fatigue+Mean
(95% CI)
P ηp 2 Fatigue–Mean
(95% CI)
Fatigue+Mean
(95% CI)
P ηp 2
Endurance, min 12.7 (10.6-14.6) 7.9 (5.9-9.9) .003 0.205 12.4 (10.3-14.5) 8.5 (6.2-10.7) .026 0.124 12.0 (9.8-14.2) 8.9 (6.6-11.3) .096 0.073
Exertion 13.0 (11.8-14.1) 16.4 (15.2-17.6) .000 0.284 13.1 (11.9-14.4) 16.1 (14.8-17.5) .005 0.193 13.5 (12.3-14.8) 15.7 (14.4-17.1) .037 0.113
RFD, (N/s)/kg 110.9 (88.1-133.8) 85.7 (62.2-109.1) .035 0.109 110.4 (85.8-134.9) 87.4 (61.4-113.4) .058 0.094 102.2 (78.6-125.7) 96.4 (71.4-121.5) .355 0.024
Power, W/kg 5.2 (4.9-5.6) 4.3 (4.0-4.7) .001 0.242 5.2 (4.9-5.6) 4.4 (4.0-4.8) .008 0.173 5.1 (4.8-5.4) 4.5 (4.2-4.9) .049 0.104
STST, s 0.59 (0.54-0.64) 0.73 (0.68-0.78) .001 0.258 0.59 (0.54-0.65) 0.71 (0.66-0.77) .006 0.185 0.60 (0.55-0.66) 0.70 (0.64-0.75) .031 0.122
Abbreviations: CI, confidence interval; RFD, rate of force development; STST, sit-to-stand time; ηp2, partial eta squared, a measure of effect size, where 0.01, 0.09, and 0.25 represent small, medium, and large effect sizes, respectively.
aData are presented as means with 95% CI of untransformed dependent variables. Preexercise RFD, power, and STST were included in all models as a covariate. Model 1 is further adjusted for age, model 2 is further adjusted for the severity of chemotherapy-induced peripheral neuropathy symptoms, and model 3 is fully adjusted including all prior covariates plus self-reported hours spent in all moderate-vigorous intensity physical activity.

DISCUSSION

This study is the first to demonstrate a relationship between clinically important CRF and fatigability using a functionally relevant fatiguing protocol that targets the larger muscle groups of the lower extremities and includes a balance component.20 Our study is one of the few that have specifically examined fatigability in people with a history of cancer24–28 and only the second to compare fatigability measures in survivors of cancer with and without CRF.29 Our focus on disease-free SBC with and without CRF allowed us to circumvent limitations of prior studies that compared fatigability outcomes between cancer-free controls and fatigued individuals with advanced cancer where muscle loss and weakness are key features.56,57

The American College of Sports Medicine (ACSM) recently developed exercise guidelines for survivors of cancer, recommending MVPA for those with CRF.58 Although the ACSM guidelines acknowledge the potential need to modify exercise recommendations for survivors based on individual tolerance,58 guidance for how exercise should be modified for those with persistent CRF remains unclear. Our finding that women with CRF have lower postexertional force and power provides guidance for how clinicians may individually tailor rehabilitative or exercise programs for these individuals. Clinicians should screen for and provide education concerning the potential for postexertional lower extremity fatigability. If individuals with CRF demonstrate transient declines in lower extremity force or power following exercise, they may benefit from additional guidance regarding energy conservation or structuring their exercise routine in the context of their daily life. Additionally, clinicians should consider the order of an objective examination of an individual with CRF, as objective tests of strength may vary based on whether they are administered before or after a fatiguing task (eg, submaximal exercise test, 6-minute walk test, and 30-second sit-to-stand test). Furthermore, our findings suggest that exercise programs for SBC with persistent CRF should include activities that increase lower limb muscle RFD and power, such as heavy resistance training and explosive-type strength training.59–61

Consistent with our recent study, we found that women with CRF were twice as likely to report sensory symptoms of CIPN in their feet.14 This finding suggests that CRF and CIPN could share an etiological mechanism (ie, neurotoxicity) or that sensory neuropathy may indirectly influence the perception of CRF through its association with pain.62 Moving from a seated to a standing position is a complex maneuver requiring lower extremity muscle force, power, and postural control. Sensory neuropathies in the lower extremities decrease postural stability and increase fear of falling in individuals with a history of cancer.42,63,64 While CIPN severity likely explained group differences in force plate measures before exercise, it had little effect on group differences in RFD, power, and STST after exercise, which suggests that factors other than CIPN contribute to the increased fatigability observed in women with CRF. The multifactorial nature of CRF and its multisystem morbidities make identification of such contributing factors challenging. Central fatigue processes, while beyond the scope of this study, may warrant further investigation, as motor fatigue among individuals with CRF has been found to be more of central than peripheral origin during intermittent motor tasks.24 Peripheral processes such as CIPN-related motor neuropathies or differences in muscle strength also deserve consideration, although results of our prior study showed no difference in maximal leg press strength between individuals with BC with and without fatigue; hence, we did not objectively measure strength in this sample.14

Like prior studies, we found that CRF was linked to greater perceived exertion and lower endurance. Reduced motivation has been documented in survivors of cancer with CRF and may explain poorer endurance in women with CRF performing the STSF task.65,66 Reduced motivation can also impact engagement in routine physical exercise and may explain why women with CRF reported fewer hours spent engaged in MVPA than women without CRF. While the reduced motivation to perform the STSF task could have explained lower endurance and greater perceived exertion in women with CRF, it would not explain why RFD and power were lower, and STSTs longer immediately post-exercise, despite exercising for shorter times. Similarly, group differences in several of the fatigability outcomes (power, STST, and perceived exertion) remained after controlling for the reported level of MVPA, although RFD and endurance were lost. Although we did not ask participants about challenges they face engaging in MVPA, prior studies have shown that survivors of cancer fear that exercise will worsen CRF,67,68 and many survivors of cancer report a coping strategy of avoiding activities that cause energy loss.69 The STSF task, which consists of repeated sit-to-stand maneuvers for up to 15 minutes, is a challenging and particularly fatiguing task. Reduced endurance and greater perceived exertion observed in women with CRF may reflect their conscious or subconscious effort to minimize the effect of this strenuous exercise on their postexertional fatigue and function. Indeed, one-third of survivors of cancer with CRF enrolled in a recent study by Twomey and colleagues70 experienced a significant worsening of fatigue, weakness, joint pain, muscle soreness, changes in mood, difficulty with memory/concentration, and a need to modify their daily routines, with some participants experiencing these symptoms for several days following a single bout of exercise. We did not evaluate postexertional symptoms in the present study, but future work should include this assessment so that exercise recommendations for women with CRF can be further refined.

In summary, our findings add to the growing evidence that SBC with persistent CRF may respond differently to exercise, and as such, their treatment history and current fatigue level should be considered when recommending or prescribing exercise. The results of this study suggest that CRF remains an imperative consideration in exercise prescription and symptom management, even years following the completion of primary cancer treatment. Clinicians should be encouraged to screen for CRF, monitor patient symptoms during and after physical exertion, and modify exercise prescriptions accordingly.

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Keywords:

cancer-related fatigue; endurance; fatigability; instrumented sit-to-stand; lower extremity muscle force and power

© 2022 The Authors. Published by Wolters Kluwer Health, Inc.