Abstract
Background:
Up to 75% of patients experience cancer-related cognitive impairment (CRCI) during treatment. CRCI often co-occurs with mental fatigue. Chemotherapy may cause cognitive impairment and mental fatigue by compromising systemic inflammatory responses, whereas exercise may induce a self-regulating inflammatory response and promote immunocompetence. Exercise-induced immunocompetence may lead to improvements in CRCI and mental fatigue. We examined the effects of exercise on CRCI and mental fatigue, as well as the relationships between exercise and CRCI and between inflammatory responses and CRCI, in patients receiving chemotherapy in a multicenter phase III randomized controlled trial.
Patients and Methods:
Patients diagnosed with any cancer type and scheduled to start chemotherapy were randomized to either a 6-week home-based, individually tailored exercise intervention—Exercise for Cancer Patients (EXCAP)—or usual care. The Functional Assessment of Cancer Therapy–Cognitive Function and the Multidimensional Fatigue Symptom Inventory were used to assess cognitive impairment and mental fatigue, respectively. Blood samples were collected to assess inflammation (i.e., IL-1β, IL-6, IL-8, IL-10, IFN-γ, and sTNFR1). Analysis of covariance (ANCOVA) was used to examine between-group differences in CRCI and mental fatigue. Structural equation modeling was conducted to examine the relationships between exercise and CRCI and between inflammatory responses and CRCI.
Results:
Compared with participants receiving usual care, EXCAP participants undergoing chemotherapy on 2-week cycles reported less overall cognitive impairment (mean difference [SE], 7.0 [3.3]; P5.04), perceived cognitive impairment (4.1 [2.1]; P5.05), comments from others identifying cognitive impairment (0.6 [0.2]; P5.02), and mental fatigue (21.6 [0.5]; P,.01). All EXCAP participants, regardless of chemotherapy cycle duration, reported less mental fatigue compared with participants receiving usual care (20.7 [0.3]; P5.02). Suppressed inflammatory responses were associated with CRCI in participants receiving chemotherapy (0.2 [0.1]; P,.01).
Conclusions:
EXCAP may reduce CRCI and mental fatigue, particularly in patients receiving 2-week cycles of chemotherapy. A healthy inflammatory response, characterized by increases in both proinflammatory and anti-inflammatory cytokines, is associated with less cognitive impairment during chemotherapy.
Background
Up to 75% of patients report cancer-related cognitive impairment (CRCI) during treatment and up to 10 years posttreatment.1–4 CRCI manifests as deficits in attention, verbal memory, executive function, and processing speed.5 CRCI frequently co-occurs with mental fatigue.6 These deficits severely impact treatment adherence, resulting in poor prognosis and increased morbidity and mortality.7–9 Additionally, patients with CRCI and mental fatigue experience considerable difficulty completing activities of daily living (eg, managing medicines and money, driving, shopping, traveling, maintaining the household).10–13 Currently, there are no gold-standard treatments for CRCI or mental fatigue.5
Chemotherapy may cause cognitive impairment and mental fatigue by compromising healthy systemic inflammatory responses.14–17 Evidence suggests that cytotoxic chemotherapy disrupts immune function, specifically the balance between proinflammatory and anti-inflammatory responses, resulting in a persistent proinflammatory state driven by an inadequate anti-inflammatory reaction. This imbalance impairs patients’ immune function, leading to immunodeficiency. For example, dysregulated immune function within the tumor necrosis factor (TNF) signaling axis—characterized by alterations in markers such as IFN-γ, IL-1β, IL-6, IL-8, IL-10, and sTNFR1—is often seen in patients with CRCI and mental fatigue.17–21
Exercise is a promising nonpharmacologic intervention for CRCI and mental fatigue. It induces a self-regulating inflammatory response that promotes immunocompetence, whereby an initial release of proinflammatory cytokines (eg, IFN-γ, IL-1β, IL-8) is followed by the release of anti-inflammatory cytokines (eg, IL-10, sTNFR1), thereby attenuating the initial proinflammatory response.22 IL-6 is generally classified as a proinflammatory cytokine, especially in the context of cancer and chemotherapy.23 However, exercise can induce a differential effect, whereby IL-6 derived from skeletal muscle exerts anti-inflammatory effects through its myokine function. This differential effect of IL-6 response decreases the proinflammatory response of the immune system24 in favor of an anti-inflammatory status that promotes immunocompetence, which is critical for improving health outcomes.25
The immunocompetence elicited by exercise is posited to improve CRCI and mental fatigue.26 We previously showed that patients who received the Exercise for Cancer Patients (EXCAP) intervention exhibited higher immunocompetence, demonstrated by (1) an anti-inflammatory status with lower IFN-γ and IL-1β, and (2) stronger correlations between changes in IL-6 and IL-10, IL-1β and IL-10, and sTNFR1 and IL-10, suggesting stronger coupling between proinflammatory and anti-inflammatory responses and greater immunocompetence.22 Based on our prior work, it is important to understand the collective influence of both proinflammatory and anti-inflammatory cytokines and immunocompetence on CRCI.
Research evaluating the effects of exercise on CRCI while receiving treatment is limited, with no nationwide, multicenter, phase III randomized controlled trials (RCTs).27–37 Only a handful of studies tested an intervention that combined aerobic and anaerobic exercises, and the effects of exercise on CRCI are inconsistent.30,31,36–39 In light of this, experts in the field of CRCI and patient advocates recommend moving forward with testing promising behavioral interventions, such as exercise, in large-scale (eg, phase III RCTs) clinical trials to advance CRCI research.40
Herein, we report secondary outcomes examining the effects of exercise on CRCI and mental fatigue from a nationwide, multicenter, phase III RCT. To our knowledge, this is the first nationwide, multicenter, phase III RCT to examine (1) the effectiveness of a home-based, individually tailored progressive exercise prescription, including walking and resistance bands, for treating CRCI and mental fatigue, and (2) the relationships between exercise, CRCI, and inflammation in patients receiving chemotherapy. We hypothesized that EXCAP participants would experience less CRCI and mental fatigue than those receiving usual care, and that suppressed immunocompetence contributes to CRCI in patients undergoing chemotherapy.
Patients and Methods
Study Design
This nationwide, multicenter, phase III RCT (ClinicalTrials.gov identifier: NCT00924651) was conducted through the University of Rochester Cancer Center National Cancer Institute (NCI) Community Oncology Research Program (URCC NCORP) Research Base. Patients were recruited from 20 NCI-funded NCORP community oncology practices across the United States from 2009 through 2014. The Institutional Review Board at each NCORP community oncology practice approved the study before patients were enrolled. All participants provided written informed consent. Participants were randomized to receive either EXCAP or usual care while receiving chemotherapy. Randomization was stratified by NCORP community oncology practices, chemotherapy cycle length, sex, and degree of fatigue (2 levels: ≤5 or >5 on an 11-point scale) reported at preintervention. A computer-generated random number table with an equal probability of block size 4 or 6 was used to determine intervention assignment in the ratio 1:1. Study coordinators received the randomization allocation after completion of participant registration. Participants were not informed of their randomization assignment until all preintervention assessments were completed. For the analyses performed in this study, the principal investigator was blinded to the allocation.
Participant Eligibility
Participant were eligible in they (1) were aged ≥21 years; (2) had any cancer diagnosis except leukemia or cancer with distant metastases; (3) were chemotherapy naïve; (4) were scheduled to begin chemotherapy with cycles of 2, 3, or 4 weeks; (5) had a Karnofsky performance status score ≥70; and (6) were able to read English. Patients were excluded if they (1) were scheduled to receive concurrent radiation therapy; (2) had physical limitations (eg, cardiorespiratory, orthopedic, central nervous system conditions) that contraindicated participation in low- to moderate-intensity exercise; or (3) were in the active or maintenance stage of exercise behavior, as assessed by the Exercise Stages of Change.41
Exercise Intervention
EXCAP is a 6-week, home-based, individually tailored walking and resistance band exercise program designed by Dr. Mustian and American College of Sports Medicine (ACSM)–certified exercise professionals at the University of Rochester Medical Center. Each NCORP community oncology practice staff member completed EXCAP training, led by ACSM-certified exercise professionals from the University of Rochester PEAK Human Performance Science Clinical Research Lab and URCC NCORP Research Base, to deliver the exercise prescription. EXCAP participants received a kit containing a bag, an EXCAP manual, resistance bands, a pedometer, and individualized exercise prescriptions, which was introduced during a single 60-minute in-person session conducted by the trained community oncology practice staff in the clinic on the day of the participant’s first chemotherapy treatment.
One component of EXCAP is an individualized walking prescription, which provides instructions for daily low- to moderate-intensity aerobic exercise for 6 weeks (60%–85% of heart rate reserve; 3–5 on the rating of perceived exertion [RPE] visual analog scale, where 0 = no exertion and 10 = maximal exertion). The other component of EXCAP is a resistance band prescription, which provides instructions for daily low- to moderate-intensity resistance exercises (RPE 3–5) for 6 weeks.42 During the initial EXCAP delivery session, the teach-back method was used; study staff first demonstrated the proper form for each exercise, and participants then performed the exercises to demonstrate correct technique. After the initial EXCAP teaching session, participants received phone calls every 2 weeks from the study staff to remind them to do the exercises and help them troubleshoot any barriers to adherence. A detailed description of the EXCAP prescription is provided in Appendix 1 (available in the supplementary materials).
Usual Care
Participants randomized to the usual care did not receive the EXCAP intervention during the intervention period. Participants assigned to usual care received the same time and attention from study staff, except for the 60-minute EXCAP teaching session. These participants were not instructed to change or modify their usual exercise behavior in any way. To increase retention and reduce exercise contamination, the EXCAP kit and prescriptions were offered to usual care participants after they completed all study requirements.
Measures
Clinical and demographic information was collected by NCORP community oncology practice staff using medical records and study-specific forms.
Baseline levels of steps walked, minutes of resistance band training, and exercise intensity, as well as adherence to the EXCAP intervention and exercise contamination in the usual care group, were assessed using a standard daily diary, pedometer, and RPE scale.43 The diary used to monitor exercise behavior is a standard tool commonly employed to collect and analyze exercise data at the group level.44–48 Participants were instructed to record their daily steps (measured via pedometer), minutes of resistance band exercise, and RPE during exercise in the daily diary. The diary is a valid and reliable tool in exercise research for collecting data and monitoring exercise behavior at the group level, especially when used in combination with an activity monitor.44,49–52 Details regarding pedometer wearing are provided in Appendix 1.
We assessed CRCI using the Functional Assessment of Cancer Therapy–Cognitive Function (FACT-Cog, version 2)53 at pre- and postintervention. The FACT-Cog contains 50 questions to measure overall cognitive function. The total score is the sum of 4 subscales: perceived cognitive impairment, perceived cognitive abilities, comments from others regarding cognitive impairment, and the impact of cognitive impairments on quality of life. A higher score indicates less cognitive impairment.
We assessed mental fatigue using the 6-item mental fatigue subscale of the Multidimensional Fatigue Symptom Inventory (MFSI)54 at pre- and postintervention. A higher score indicates higher fatigue.
Serum levels of the cytokines IFN-γ, IL-1β, IL-6, IL-8, and IL-10 and the cytokine receptor sTNFR1 were measured at pre- and postintervention using standard high-sensitivity Luminex multiplex assays. We have previously reported the effects of EXCAP on inflammatory profiles in patients receiving chemotherapy.22 In the present study, we focus on examining the relationships among exercise, CRCI, and inflammation using structural equation modeling (SEM).
All participants also completed a 6-item feedback questionnaire at the end of the study to provide their perspectives on exercise and their feedback regarding the study procedure and intervention.
Adverse Events
Adverse events were monitored using CTCAE version 4.0 and reviewed by members of the URCC Data Safety Monitoring Committee. All serious adverse events were reported.
Statistical Analyses
Enrolling 693 patients, and allowing for up to 30% without fully evaluable data, provided sufficient power (80%–95%) to detect a 15% to 20% improvement in CRCI in the intervention group compared with the usual care group. Fisher exact and chi-square tests were used to examine between-group differences at preintervention. Analysis of covariance (ANCOVA) was performed to compare means in FACT-Cog and MFSI Mental Fatigue scores between the 2 groups at postintervention, and effect sizes were also calculated. The ANCOVA model was adjusted for preintervention value, chemotherapy cycle duration, and the interaction term (intervention group with chemotherapy cycle duration).
To capture each participant’s overall inflammation profile, we did not examine individual cytokines separately. Instead, we used SEM to construct a latent variable, “inflammatory response,” representing changes in 6 measured cytokines: IL-1β, IL-6, IL-8, IFN-γ, IL-10, and sTNFR1. See Appendix 1 for SEM details.
All analyses were based on intent-to-treat. Analyses were performed using SAS 9.3 (SAS Institute Inc) and R version 3.2.2 (R Foundation for Statistical Computing). Missing data were examined and found to be missing completely at random.55 All outcomes were assessed at a 0.05 significance level.
Results
Participants
Among 693 patients who consented to participate in the study, 6 were excluded due to ineligibility, and 687 eligible patients were randomized to EXCAP (n=354) or usual care (n=333) (Figure 1). Complete preintervention FACT-Cog data were provided by 638 participants, and 547 participants provided complete pre- and postintervention FACT-Cog data. A total of 140 participants (EXCAP, n=82; usual care, n=58) did not provide complete FACT-Cog data due to medical issues such as disease progression (n=42), personal issues (n=56), death (n=1), or unknown reasons (n=41). Of the 547 participants who provided complete FACT-Cog data, 348 also provided blood samples. The dropout rate did not differ significantly between EXCAP (23%) and usual care (17%) participants (chi-square, P>.05). Similarly, there were no significant between-group differences in demographic or clinical characteristics (all P>.05; Table 1).
Figure 1.
CONSORT diagram.
Abbreviations: EXCAP, Exercise for Cancer Patients intervention; FACT-Cog, Functional Assessment of Cancer Therapy–Cognitive Function.
Citation: Journal of the National Comprehensive Cancer Network 24, 3; 10.6004/jnccn.2025.7118
Table 1.
Demographic and Clinical Characteristics
| Characteristic | Total n (%) | EXCAP n (%) | Usual Care n (%) | P Value |
|---|---|---|---|---|
| Total, N | 687 | 354 | 333 | |
| Age, mean [SD], y | 55.2 [11.1] | 55.4 [11.1] | 55.0 [11.1] | .62 |
| Karnofsky performance status, mean [SD] | 94.5 [6.9] | 94.3 [6.9] | 94.8 [6.9] | .48 |
| Sex | ||||
| Female | 646 (94) | 329 (93) | 317 (95) | .21 |
| Male | 41 (6) | 25 (7) | 16 (5) | |
| Race | .74 | |||
| White | 585 (85) | 303 (86) | 282 (85) | |
| Black | 68 (10) | 35 (10) | 33 (10) | |
| Asian | 23 (3) | 12 (3) | 11 (3) | |
| Othera | 11 (2) | 4 (1) | 7 (2) | |
| Ethnicity | 1.00 | |||
| Non-Hispanic | 665 (97) | 343 (97) | 322 (97) | |
| Hispanic | 20 (3) | 10 (3) | 10 (3) | |
| Unknown | 2 (<1) | 1 (<1) | 1 (<1) | |
| Currently employed | .72 | |||
| Yes | 476 (69) | 241 (68) | 235 (71) | |
| No | 208 (30) | 112 (31) | 96 (29) | |
| Marital status | .42 | |||
| Partnered (married/committed relationship) | 475 (69) | 250 (71) | 225 (68) | |
| Single | 209 (30) | 103 (29) | 106 (32) | |
| Education | .36 | |||
| College and beyond | 465 (68) | 245 (69) | 220 (66) | |
| High school | 217 (32) | 107 (30) | 110 (33) | |
| Cancer type | .63 | |||
| Breast | 572 (83) | 291 (82) | 281 (84) | |
| Lymphoma | 26 (4) | 17 (5) | 9 (3) | |
| Colon | 37 (5) | 20 (6) | 17 (5) | |
| Lung | 18 (3) | 8 (2) | 10 (3) | |
| Otherb | 33 (5) | 18 (5) | 15 (5) | |
| Cancer stage | .93 | |||
| I | 175 (25) | 87 (25) | 88 (26) | |
| II | 306 (45) | 160 (45) | 146 (44) | |
| III | 174 (25) | 90 (25) | 84 (25) | |
| IV | 13 (2) | 6 (2) | 7 (2) | |
| Previous treatment | ||||
| Surgery | 607 (88) | 316 (89) | 291 (87) | .44 |
| Chemotherapy | 6 (<1) | 2 (<1) | 4 (1) | .44 |
| Radiation therapy | 15 (2) | 8 (2) | 7 (2) | .89 |
| Hormone therapy | 22 (3) | 14 (4) | 8 (2) | .25 |
Group differences were compared using t tests for continuous variables and chi-square or Fisher exact tests for categorical variables, as appropriate.
Abbreviation: EXCAP, Exercise for Cancer Patients intervention.
Native Hawaiian or Other Pacific Islander, American Indian or Alaskan Native, and Unknown.
Endometrial, ovarian, testicular, uterine, brain, head/neck, cervical, renal, pancreatic, and peritoneal.
EXCAP Intervention Adherence
At preintervention, EXCAP participants walked a mean [SE] of 4,351 [314] steps per day, and usual care participants walked 4,076 [287] steps per day, corresponding to approximately 2 miles of walking daily prior to initiating chemotherapy. After 6 weeks of intervention, EXCAP participants maintained their daily steps (−358 [362]; P=.32), whereas usual care participants significantly reduced their daily steps by 53% (−2,171 [352]; P<.01), corresponding to <1 mile of walking daily. At postintervention, EXCAP participants walked 1,882 [310] more steps daily than usual care participants (P<.01).
EXCAP participants reported performing resistance band exercises 3 times per week for an average of 25 minutes per session at moderate intensity (RPE 4). Exercise contamination in the usual care group was minimal; 18 usual care participants (6%) reported performing resistance exercises a total of 3 times during the 6-week intervention.
Adverse Events
A total of 10 adverse events were reported, 5 of which were graded as serious adverse events (SAEs). Of these, 4 were due to lymphopenia or neutropenia, and 1 was due to multiple organ failure resulting in death. The participant who experienced multiple organ failure and subsequently died during the study was unable to complete it. The remaining 4 participants with SAEs completed the study.
Effects of EXCAP on CRCI
From preintervention to postintervention, all participants, on average, reported cognitive declines (Table 2, Figure 2). EXCAP participants receiving 2-week chemotherapy cycles demonstrated significantly less cognitive decline than usual care participants. Specifically, EXCAP participants reported less overall cognitive impairment (7.0 [3.3]; P=.04), lower perceived cognitive impairment (4.1 [2.1]; P=.05), and fewer comments from others identifying cognitive impairment (0.6 [0.2]; P=.02) at postintervention. No significant differences were observed between EXCAP and usual care participants receiving 3- or 4-week chemotherapy cycles.
Table 2.
Adaptation of Table 3 in Maximal-Setting Guideline
| Deficit | Basic | Limited (to add to Basic) | Enhanced (to add to Limited plus Basic) |
|---|---|---|---|
| Physical function/falls | Check orthostatic blood pressure and adjust medications Provide fall prevention and general physical activity/exercise handouts Weigh risk and benefits of cancer treatment options incorporating information about physical performance Encourage home-based exercises to improve strength and stability |
Consider outpatient physical/occupational therapy | Consider home-based physical therapy Request gait/assistive device evaluation, lower extremity strength, and balance training Referral for home safety evaluation |
| Functional status | Consider treatment modifications, particularly in the noncurative treatment setting: single agent rather than doublet, modified (reduced) dosage (dose de-escalation), treatment schedule modification Consider more frequent toxicity checks Encourage regular physical activity (eg, walking, light stretching) |
Consider outpatient physical therapy Provide guidance on safe exercise routines to maintain mobility and independence |
Consider home-based physical therapy Request gait/assistive device evaluation, lower extremity strength, and balance training Consider occupational therapy |
| Nutrition/weight loss | Discuss concerns related to nutrition and how potential treatment may affect nutrition Consider recommendations and/or handouts for nutritional supplements, liberalize calorie restricted diets, small frequent meals and/or high protein snacks Use caution with highly emetogenic regimens Use aggressive antiemetic therapy Education on nausea and vomiting Educate on hydration importance and strategies to maintain fluid intake Encourage weight monitoring to track unintentional weight loss |
Referral to a nutritionist/dietitian Referral to a dentist (for oral health issues affecting nutrition, eg, mucositis) Referral to physical therapy Offer guidance on easy-to-prepare, nutrient-dense foods suitable for patients with limited energy |
Referral to speech therapy for issues affecting chewing or swallowing Meals-on-wheels or social work for food assistance at home Referral to occupational therapy Consider medications for loss of appetite |
| Social support | Discuss the availability of social support at home Discuss who to contact in case of emergency Confirm documented health care proxy Identify primary caregiver or family member responsible for daily support Provide education on patient and caregiver rights (eg, advanced directives) Review available community supports such as peer support groups and faith-based organizations |
Referral to social work Facilitate connection to local or remote support resources for patients and caregivers Assist with transportation needs |
Visiting community nursing services In-person lifeline emergency services |
| Depression/anxiety | Review history of psychiatric disorders Initiate pharmacologic therapy Assess suicide risk or elder abuse Provide emotional support through family/caregiver involvement Link to community resources (including spiritual) |
Referral to a psychologist Referral to a social worker Referral to psychiatry Referral to palliative care |
Referral to a psychooncologist Referral to health care organization-provided spiritual counseling/chaplaincy Integrated care plans tailored to comorbid conditions and cancer treatment |
| Comorbidity | Discuss how comorbidities affect risks and benefits of treatment choices Initiate direct communication and management with primary care clinicians about comorbidities and medication Modify schedule if there are concerns about tolerability If history of diabetes, avoid neurotoxic agents (use steroids with caution) If history of heart disease, consider minimizing volume of agents If history of liver or kidney disease, adjust medication as appropriate Ensure wearing glasses Review the medication list |
Referral for hearing aid evaluation, if clinically indicated Referral for a vision specialist, if clinically indicated Review medication list, referral to another clinician (geriatrician), assess adherence and minimize medications as much as possible |
Test for glaucoma, if clinically indicated Consider involving a clinical pharmacist |
| Cognition | Provide explicit and written instruction for appointments, medications, and treatments Identify the primary caregiver or family member responsible for daily support and elicit input from caregivers regarding the patient’s cognition Assess decision-making capacity Assess for potential elder abuse |
Referral to a geriatrician or neurologist for follow-up Referral to occupational therapy referral |
Referral to a cognitive specialist Neuropsychological testing |
| Abnormal geriatric screening | Consider using the CARG chemotherapy toxicity2 calculator to assess the risk of toxicity and guide decision-making Considering administering a GA |
Administer a GA | Administer a GA |
| Intermediate or high risk of chemotherapy toxicity according to CARG score | Consider administering a GA Consider treatment modifications, particularly in the noncurative treatment setting: single agent rather than doublet, modified dosage, treatment schedule modification Consider more frequent toxicity checks |
Administer a GA | Administer a GA |
Figure 2.
Changes in cognitive impairment among patients receiving 2-week chemotherapy cycles: (A) perceived cognitive impairment, (B) perceived cognitive ability, (C) comments from others identifying cognitive impairment, (D) impact of cognitive impairment on quality of life, and (E) overall cognitive impairment.
Abbreviations: EXCAP, Exercise for Cancer Patients intervention; FACT-Cog, Functional Assessment of Cancer Therapy–Cognitive Function; PCA, perceived cognitive abilities; PCI, perceived cognitive impairments; QoL, quality of life.
*Statistically significant difference (P,.05).
Effects of EXCAP on Mental Fatigue
From preintervention to postintervention, all participants experienced significantly worsened mental fatigue (EXCAP: 0.6 [0.2]; P=.01; usual care: 1.3 [0.2]; P<.01) (Table 2). However, EXCAP participants reported significantly less mental fatigue than usual care participants at postintervention (−0.7 [0.3]; P=.02). Among participants receiving 2-week chemotherapy cycles, those in the EXCAP group maintained the same level of mental fatigue (0.1 [0.4]; P=.72), whereas those in the usual care group reported a significant worsening of mental fatigue from preintervention to postintervention (1.7 [0.4]; P<.01). EXCAP participants receiving 2-week chemotherapy cycles also demonstrated significantly less mental fatigue than usual care participants at postintervention (−1.6 [0.5]; P<.01). Among participants receiving 3-week chemotherapy cycles, all experienced a significant worsening of their mental fatigue (EXCAP: 0.8 [0.3]; P=.01; usual care: 1.1 [0.3]; P<.01) from preintervention to postintervention. No significant differences in mental fatigue were observed between EXCAP and usual care participants receiving 3- or 4-week chemotherapy cycles.
Relationships Among Exercise, CRCI, and Inflammatory Response
The intervention effects on individual inflammatory cytokines were previously reported by this team, and all findings are detailed in the prior publication.22 Therefore, these data are not presented in the current article. Herein, we present the results of our SEM using a latent variable, “inflammatory response” (its construction from individual cytokine data and relevance are detailed in the “Statistical Analyses” section and in Appendix 1). SEM demonstrated a significant positive relationship between exercise and CRCI score (0.1 [0.1]; P=.03), indicating that greater exercise is associated with higher CRCI scores, reflecting less cognitive impairment, and vice versa. SEM also revealed a significant positive relationship between “inflammatory response” and CRCI score (0.2 [0.1]; P<.01). These findings suggest that a healthy “inflammatory response,” indicated by increases in both proinflammatory and anti-inflammatory cytokines during chemotherapy, is associated with a higher CRCI score, indicating less cognitive impairment (Figure 3).
Figure 3.
Relationships among exercise, cognitive impairment, and inflammation.
Abbreviation: EXCAP, Exercise for Cancer Patients intervention.
*Statistically significant difference (P#.05).
Participant Feedback
Most EXCAP participants (92%) reported a more positive view of exercise after participating in the study. Additionally, 97% indicated they would recommend EXCAP to other patients receiving chemotherapy to help reduce CRCI.
Discussion
Results from this nationwide, multicenter, phase III RCT suggest that EXCAP is an effective intervention for treating CRCI and mental fatigue in patients receiving 2-week cycles of chemotherapy. These benefits were not observed in patients receiving 3- and 4-week chemotherapy cycles. The reasons for this difference remain unclear. Our data show no significant differences in adherence to EXCAP or in CRCI severity across chemotherapy cycle durations. Possible explanations include that patients with longer chemotherapy cycles may (1) be sicker and have confounding symptomatic toxicities that make it more difficult to influence CRCI, (2) require a higher or longer dose of exercise to impact CRCI, or (3) have a genetic predisposition that makes them less responsive to exercise.
Our data indicate that the EXCAP intervention helps patients maintain daily walking during chemotherapy, whereas patients who do not receive a formal exercise prescription reduce their daily walking by 53%. Patients who did not receive a formal exercise prescription reduced their daily walking to an average of 1,905 steps (<1 mile) during chemotherapy. Walking <2,000 steps per day has been significantly associated with higher all-cause mortality.56 Our data also show that EXCAP effectively helped patients begin moderate-intensity resistance exercise during chemotherapy, performing an average of 25 minutes per session, 3 times per week, whereas patients without a formal exercise prescription did not engage in resistance exercise. In summary, these findings suggest that individualized exercise prescriptions for walking and resistance band exercises at the beginning of chemotherapy may help patients avoid significant reductions in their walking to levels that are associated with higher all-cause mortality, while also improving CRCI and mental fatigue.
Results of this study confirm previous findings that exercise is an effective intervention for CRCI and extend these findings by showing that exercise during chemotherapy can also reduce mental fatigue.31,36,37 These results further suggest that immunosuppression contributes to CRCI experienced by patients receiving chemotherapy.
Although it is recommended that all patients with cancer have access to trained exercise oncology professionals, this is often challenging and not always possible in community-based oncology practices across the United States. Notably, this nationwide, multicenter, phase III RCT demonstrated that EXCAP individualized exercise prescriptions are practical and can be successfully implemented in busy community-based oncology practices across the United States. Existing community-based oncology practice staff (eg, clinical research coordinators, research assistants, nurses) trained by ACSM-certified clinical exercise physiologists with a specialization in exercise oncology can successfully deliver standardized EXCAP prescriptions for patients beginning chemotherapy and, ultimately, reduce the CRCI and mental fatigue experienced by these patients. Results also demonstrate that patients receiving chemotherapy at community-based oncology clinics across the United States can safely and effectively adhere to the EXCAP home-based individualized exercise prescription.
Despite positive results, this study has several limitations. The study design did not include a behavioral placebo, and there were no objective measures of CRCI or mental fatigue. The results may not be generalizable to all types and doses of exercise (ie, mode, frequency, duration, intensity). Additionally, the study population was largely female (94%), diagnosed with breast cancer (83%), and non-Hispanic White (85%), which may limit generalizability. Future phase III RCTs with CRCI as a primary outcome are needed to confirm and replicate these findings. Future clinical trials should compare EXCAP to an appropriate behavioral exercise placebo, evaluate a variety of exercise types and doses to identify the most effective prescriptions, explore what patients receiving 3- and 4-week chemotherapy cycles need to achieve benefit from exercise, determine the duration of benefits longer term, enhance generalizability to more diverse populations, and investigate moderating and mediating biologic targets (ie, inflammatory/inflammasome signatures) for CRCI and mental fatigue. Future research should also examine the specific effects of exercise prescriptions on these newly identified biologic targets to improve the magnitude of exercise benefits on CRCI and mental fatigue.
Conclusions
Our data suggest that patients receiving chemotherapy can adhere to home-based, individually tailored, progressive EXCAP prescriptions. EXCAP may reduce CRCI and mental fatigue, specifically, in patients receiving 2-week chemotherapy cycles. A healthy inflammatory response, characterized by increases in both proinflammatory and anti-inflammatory cytokines, is associated with less cognitive impairment during chemotherapy. Oncologists should consider training staff in their clinics or referring patients to qualified exercise professionals in their communities to provide individually tailored exercise prescriptions that combine walking and resistance band exercises to reduce CRCI and mental fatigue in patients receiving chemotherapy.
Supplementary Material
Supplementary material is published online at https://doi.org/10.6004/jnccn.2025.7118
Acknowledgments
We acknowledge and thank all patients who participated in this study, the participating NCORP community oncology practices and staff, and the URCC NCORP Research Base study staff. The work described in this publication also benefited from the support of the Human Biophysiology Shared Resource at the Wilmot Cancer Institute, supported in part by the University of Rochester Wilmot Cancer Institute Support Grant #P30CA272302.
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