Exercise Program in Cancer and Cognition (EPICC)

Influence of Exercise on Neurocognitive Function in Breast Cancer

This randomized control trial will examine whether a well-controlled and monitored exercise intervention improves cognitive function in postmenopausal women with early-stage breast cancer and will explore whether neuroimaging metrics of brain health, pro-inflammatory biomarkers and symptoms (fatigue, sleep problems, depression, anxiety) mediate the effects of exercise on cognitive function. Furthermore, the study will explore whether the magnitude of the improvements in cognitive function are modified by estradiol levels.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Behavioral: Moderate-Intensity Aerobic Exercise Intervention

Detailed Description

The specific aims include:

1. Compared to usual care, examine whether the 6-month exercise intervention improves cognitive function in postmenopausal women with early stage breast cancer.

   Hypothesis 1. Exercise will improve cognitive function in women in a domain specific fashion such that attention, executive and memory functions will be influenced more than other domains.

2. Compared to usual care, examine the direct effects of exercise on neuroimaging metrics of brain health including regional gray matter volume, white matter architecture and functional dynamics of the brain and the pro-inflammatory biomarkers (IL-6 as primary outcomes; TNF-α as secondary), and explore the direct effects of exercise on symptoms (fatigue, sleep problems, depression, anxiety).

   Hypothesis 2. Exercise will improve neuroimaging metrics of brain health and pro-inflammatory biomarkers.

3. Compared to usual care, explore whether the effects of exercise on cognitive function are mediated by a) neuroimaging metrics of cognitive function, b) IL-6 and TNF-α levels and c) symptoms (fatigue, sleep problems, depression, anxiety), and moderated by E2 levels.

• Study Type: Interventional
• Enrollment (Actual): 153
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Postmenopausal female
2. Maximum age 80 years
3. Able to speak and read English
4. Minimum completion of 8 years of education
5. Diagnosed with Stage 0, 1, 2 or 3a Breast Cancer
6. Within 2 years post-completion of primary treatment
7. At least two weeks post-breast conserving surgery or three weeks post-breast conserving surgery with sentinel lymph node biopsy or four weeks post-mastectomy

Exclusion Criteria:

1. Prior treatment with cancer chemotherapy, central nervous system radiation, or intrathecal therapy 2. Clinical evidence of distant metastases 3. Self-report of hospitalization for psychiatric illness within the last two years 4. History of neurologic illness 5. Any of the following breast cancer surgery complications unless approved by the participant's health care provider: persistent seroma requiring aspiration, wound dehiscence, infection, prolonged drain output, lymphedema 6. Reconstructive surgery unless approved by the participant's health care provider 7. Any significant medical condition that would preclude them from exercising (e.g., uncontrolled diabetes, congestive heart failure, angina, uncontrolled arrhythmia or other symptoms that indicate increased risk for an acute cardiovascular or respiratory event) If necessary, we will verify this information with a participant's health care provider 8. Eating disorders or a history of substance abuse 10. Any use of an assisted walking device 11. Recent history of falls or balance problems

Additional Exclusion Criteria for Neuroimaging subgroup:

1. Presence of metal implants (i.e., pacemaker, some stents)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Moderate-intensity aerobic exercise; Participants engage in a supervised 6-month moderate-intensity aerobic exercise intervention.	Behavioral: Moderate-Intensity Aerobic Exercise Intervention; The intervention is moderate-intensity aerobic exercise. Walking on a motorized treadmill will be the encouraged mode of exercise; however participants may use other equipment or home exercise. Participants will begin by exercising 10-15 minutes for 3 days/week during the first 2 weeks and gradually increase the duration for the following 4 weeks until they reach 40-50 minutes per session/3 days per week. This level is then maintained for the remainder of the 6 months. The rate of increase will be tailored based on baseline cardiorespiratory fitness and response to exercise. All sessions start and end with a vital sign check (in-person) and 5-10 minutes warm-up/cool-down. Trained exercise physiologists will supervise all exercise sessions and closely monitor adherence, intensity, and safety when sessions are completed in-person, or through regular communication when home-based exercise is warranted (due to COVID-19).
No Intervention: Usual Care; Physical activity neither limited nor withheld. Participants engage in activity in the same manner as if they were not part of an active intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cognitive Function	Cognitive function was assessed with a battery of 14 measures. A data reduction technique, exploratory factor analysis with principal component extraction and varimax (orthogonal) rotation, was used to create summary factors. The cognitive factors identified included processing speed, attention, mental flexibility, working memory, learning and memory, verbal memory, and executive function were derived via this factor analysis. Individual measures with the highest loadings were included in each factor. All measures had factor loadings >0.400. Scores from the individual measures for each factor were normed based on healthy controls of similar age and education to yield a z-score and these were summed to yield an average z-score for each factor. Z-scores range from -4 to +4, where higher z-scores indicate better performance for each factor.	Baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Brain Size	High-resolution anatomical MPRAGE (1mm3 voxels, 256 slices) images will be used for volumetric analyses. The FreeSurfer pipeline using its longitudinal option will be employed to compute cortical volumes.	Baseline and 6 months
Pro-inflammatory Cytokines	Cytokine levels for interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined using high-sensitivity, quantitative sandwich enzyme immunoassay run according to manufacturer's directions. Greater pgs/ML indicate higher levels of both IL-6 and TNF-aplha.	Baseline to 6 months
Peak VO2	Fitness will be measured by submaximal VO2 test. The submaximal test is similar to the full test, but stops at 85% of the age-predicted heart rate. The protocol involves walking at a self-selected pace between 2.0-4.0 mph with increasing grade increments of 2% every two minutes. The test is terminated when the subject reaches 85% of their age-predicted heart rate or at volitional exhaustion. Higher levels (ml/kg/minute) indicate better peak VO2.	Baseline and 6 months
Estradiol (E2) Levels	E2 was determined by a competitive binding immunoassay, according to manufacturer's directions. Greater pgs/ML indicate higher levels of estradiol.	Baseline to 6 months
Fatigue	The Fatigue 8a Patient Reported Outcomes Measurement Information System (PROMIS) short form was used to measure fatigue. It consists of 8 items on which participants respond using a 5-point Likert scale. The scores range from 0 to 24 with higher scores indicating greater fatigue.	Baseline and 6 months
Anxiety	The eight-item Anxiety 8a PROMIS short form was used to measure anxiety. Participants rate each item on a scale from 1 to 5. The score is the total of the responses with higher scores indicating greater anxiety. The range of scores is 5 to 40.	Baseline to 6 months
Sleep Problems	Sleep problems were measured using global score of the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a self-report measure that consists of 19 items. Each item is weighted on a 0-3 interval scale. The PSQI global score ranges from 0 to 21, where lower scores indicate better sleep quality, and higher scores indicate poorer sleep quality.	Baseline to 6 months
Depressive Symptoms	Depressive symptoms will be measured using the Beck Depression Inventory II (BDI II). The 21-item BDI II is a self-report measure on which participants rate depressive symptoms on a four-point scale. The BDI II score ranges from 0 to 63 with higher scores indicating greater depressive symptomatology.	Baseline to 6 months

Other Outcome Measures

Outcome Measure	Time Frame
Change in White Matter Microstructure	Baseline and 6 months
Changes in Prefrontal Cortex	Baseline and 6 months
Changes in Task-evoked Functional MRI Outcomes	Baseline and 6 months
Changes in Resting State Network	Baseline and 6 months

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Kirk I Erickson, PhD, University of Pittsburgh; Principal Investigator: Catherine M Bender, PhD, University of Pittsburgh

Publications and helpful links

General Publications

• Bender CM, Sereika SM, Gentry AL, Duquette JE, Casillo FE, Marsland A, Brufsky AM, Evans S, Gorantla VC, Grahovac TL, McAuliffe PF, Steiman JG, Zhu Y, Erickson KI. Physical activity, cardiorespiratory fitness, and cognitive function in postmenopausal women with breast cancer. Support Care Cancer. 2021 Jul;29(7):3743-3752. doi: 10.1007/s00520-020-05865-4. Epub 2020 Nov 19.
• Gentry AL, Erickson KI, Sereika SM, Casillo FE, Crisafio ME, Donahue PT, Grove GA, Marsland AL, Watt JC, Bender CM. Protocol for Exercise Program in Cancer and Cognition (EPICC): A randomized controlled trial of the effects of aerobic exercise on cognitive function in postmenopausal women with breast cancer receiving aromatase inhibitor therapy. Contemp Clin Trials. 2018 Apr;67:109-115. doi: 10.1016/j.cct.2018.02.012. Epub 2018 Mar 6.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): January 10, 2023
• Study Completion (Actual): January 10, 2023

Study Registration Dates

• First Submitted: May 20, 2016
• First Submitted That Met QC Criteria: June 7, 2016
• First Posted (Estimated): June 8, 2016

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Exercise; Cognitive Function; Alteration
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: STUDY19080223; 1R01CA196762-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: At the completion of the intervention, after investigators have been un-blinded to group status, and after the testing and publication of the primary aims and hypotheses, the investigators will provide de-identified data to interested investigators provided that they closely consult with Drs. Bender and Erickson with respect to study design, analytical procedures, and to avoid overlapping research in analyses or manuscript preparation. The primary investigative team will be given priority in addressing scientific questions of interest with the collected data, but will work closely with any interested investigators in maximizing the data to address other questions of interest that could be answered by these data.