Exercise to ReGain Stamina and Energy (The EXERGISE Study)

Study Overview
=================
Brief Summary
-----------------
About 20%-70% of breast cancer survivors experience fatigue after cancer therapy. Because epidemiologic evidence shows that old age is a risk factor for fatigue in adults with cancer history, older breast cancer survivors suffer from even more fatigue than younger survivors. The purpose of this study is to test types of walking exercise interventions and their ability to reduce fatigue in older breast cancer survivors.

Detailed Description
-----------------
Women with breast cancer often experience severe fatigue (asthenia) after cancer therapy, seen in approximately 40% of breast cancer survivors. Because older age is a risk factor for fatigue, older breast cancer survivors are at an increased risk versus those in younger age groups. Prior evidence suggests that aerobic exercise reduces inflammation and bioenergenesis disturbance, which are key factors that drive the pathogenesis of fatigue. Although interventional studies suggest that aerobic exercise can improve fatigue in younger breast cancer survivors, anti-fatigue effects of aerobic exercise tended to decrease with increasing age. The investigators postulate that novel interventions combined with aerobic exercise can enhance its effectiveness and alleviate severe fatigue further in older breast cancer survivors. In this pilot randomized clinical trial, the investigators will enroll 24 female cancer survivors aged ≥ 60 years who were diagnosed with invasive breast cancer but have completed adjuvant therapy for at least 3 months but no more than 1 year. Participants will be randomly assigned to either a center-based walking exercise intervention or a home-based walking exercise intervention for an 8 week period. By completing this pilot study, the investigators will be able to collect preliminary data; refine the recruitment, measurement, randomization, and retention strategy; and adjust the statistical strategy and timeline for the potential full-scale randomized clinical trial.

Official Title
-----------------
Center-Based and Home-Based Walking Exercise Intervention to Reduce Fatigue in Older Breast Cancer Survivors

Conditions
-----------------
Fatigue, Breast Cancer, Cancer, Therapy-Related

Intervention / Treatment
-----------------
* Behavioral: Center-Based Walking Exercise
* Behavioral: Home-Based Walking Exercise


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Consent to participate in the study Age ≥ 60 years old Had stage I-III invasive breast cancer The cancer is diagnosed in 2021 or 2022 Completed adjuvant therapy for at least 3 months but no more than 1 year Willingness to participate in all study procedures Had at least moderate-level fatigue (defined as raw score ≥ 8 on the PROMIS Measure) Exclusion Criteria: Failure to provide informed consent Current involvement in rehabilitation program Absolute contraindications to exercise training Significant cognitive impairment Progressive, degenerative neurologic disease Hip fracture, hip or knee replacement, or spinal surgery within past 4 months Other significant comorbidities that may impair ability to participate in the exercise intervention Pregnant Regular consumption of nicotinamide riboside supplement Simultaneous participation in other interventional studies Had no or very mild fatigue (defined as raw score ≤7 in PROMIS) Diagnosis of any of the following medical conditions in past three years (coronary heart disease, angina, heart attack, heart failure, stroke, high blood pressure, chronic obstructive pulmonary disease, chronic bronchitis, arthritis, diabetes mellitus, and chronic kidney disease), as measured by Behavioral Risk Factor Surveillance System Receipt of any oral or intravenous antibiotic 4 weeks prior to screening Receipt of any probiotics within 4 weeks of screening History of active treatment for HIV, hepatitis B, or hepatitis C infection Positive stool cultures for enteric pathogens, including Clostridium difficile Excessive alcohol use (i.e., > 14 drinks/week) or alcohol abuse (i.e., > 5 drinks/day for males or > 4 drinks/day for females) Other substance abuse within the past 3 years Smoking history in past 3 years

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 105 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Center-Based Walking Exercise<br>Subjects will be randomly assigned to receive a center-based walking exercise intervention 3 days per week for the duration of the study. | Behavioral: Center-Based Walking Exercise<br>* Each exercise session will begin with a short warm-up followed by 30 min of walking. Participants will initially be instructed to walk at a moderate intensity, equivalent to a 5-6 on Borg category-ratio (CR) scale. Participants will be encouraged to, if possible, incorporate brief periods of vigorous walking (7-8 on CR10 scale) with a goal of achieving at least 10 min of vigorous walking per session.<br>|
| Experimental: Home-Based Walking Exercise<br>Subjects will be randomly assigned to walk for exercise in their community five days/week. | Behavioral: Home-Based Walking Exercise<br>* Participants will be asked to walk for exercise in their community five days/week. Participants will be instructed to begin with 10-15 minutes of walking exercise/session in the first month of the intervention and to increase exercise duration by five minutes/session each week, facilitating reasonable but steady progress toward the goal of 30 minutes per session.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self-Reported Fatigue | Patient Reported Outcomes Measurement Information System (PROMIS) is a set of person-centered measures that evaluate and monitor physical, psychological, and social health based on experts' review of items reflecting general health, functional status, and quality of life. All items are measured based on a 5-point scale (1=never; 2=rarely; 3=sometimes; 4=often; and 5=always) and PROMIS reverse scores item 7. Scores of all items are summed, with higher scores indicating greater fatigue. Raw total scores will range from 7 to 35. | Baseline up to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mental Distress (Depression and Anxiety) | Mental distress (depression and anxiety) in past 7 days will be measured by PROMIS. Participants will answer 8 and 7 questions to reflect severity of depression and anxiety, respectively; for each question, a 5-point scale and normalized T-scores will be employed as measure of fatigue. | Baseline up to Week 8 | 
| Self-Reported Pain | Self-reported pain in past 7 days will be measured by 6 questions in PROMIS Pain Interference Short Form; the questions measure severity of pain and use a 5-point scale (1=not at all; 2=a little bit; 3=somewhat; 4=quite a bit; 5=very much) whose sum can be transformed to a normalized T-score. | Baseline up to Week 8 | 
| Self-Reported Sleep Disturbance | Self-reported sleep short form (8a) that assesses the pure domain of sleep disturbance in individuals aged 18 and older. Each item on the measure is rated on a 5-point scale (1=very good; 2=good; 3=fair; 4=poor; and 5=very poor) with a range in score from 8 to 40 with higher scores indicating greater severity of sleep disturbance whose sum can be transformed to a normalized T-score. | Baseline up to Week 8 | 
| Gait Speed | Gait speed will be assessed in by the 6 Minute Walk test, which measures the amount of distance the participant can complete on a standard walking course in six minutes without running or overexerting themselves. Gait speed will be measured by approach used in the National Health and Nutrition Examination Survey; participants will be asked to finish a 20-foot walking test and gait speed will be calculated as (20×0.3048 meter)/(time (seconds) to finish test). | Baseline up to Week 8 | 
| Physical Function | Physical function will be assessed by the the Short Physical Performance Battery (SPPB). This battery assess functional performance on different tasks including timed short distance walk, repeated chair stands, and a balance test. Additionally, isometric grip strength, a commonly used measure of upper body skeletal function, will be assess with a hand held dynamometer. | Baseline up to Week 8 | 
| Treatment-Induced Peripheral Neuropathy (TIPN) | The 10-item Treatment-induced Neuropathy Assessment Scale (TNAS) will be used to evaluate the severity and impact of peripheral neuropathy on daily functioning at baseline and following or during after chemotherapy treatment. All items are measured based on a 10-point scale. Scores of all items are summed, with higher scores indicating greater neuropathy. Two subscale scores will be calculated to evaluate symptoms related to sensory or interference dimensions. Sensory subscale score will be the mean of 6 sensory items: numbness, tingling, pain, hot or burning, feelings of coldness and disturbed sleep. The interference subscale score - the mean of 3 interference items: trouble walking, trouble with balance and difficulty using hands. | Baseline up to Week 8 | 
| Habitual Physical Activity | Self-administered questionnaire to assess habitual physical activity through three components: work activity, sport activity, and leisure activity. The Modified Baecke Questionnaire measures habitual activity in older adults, which includes questions on household activities, sports and leisure time activities. Free-living physical activity at baseline and follow-up will be measured using an Apple Watch. Adherence to walking exercise intervention will be measured based on four criteria: total walking minutes, total walking minutes within assigned target heart rate zone, percentage of prescribed walking minutes completed per week, and percentage of prescribed walking minutes within the target heart rate zone per week. | Baseline up to Week 8 | 
| Functional Assessment of Cancer Therapy - Breast (FACT-B) | The FACT-B is a 37-item instrument designed to measure five domains of HRQOL in breast cancer survivors: Physical, social, emotional, functional well-being as well as a breast-cancer subscale (BCS). Each item on the measure is rated on a 5 point Likert-type scale (Not at all; A little bit; Somewhat; Quite a bit; and very much). | Baseline up to Week 8 | 
| Perceived Stress | The Perceived Stress Scale (PSS-10) covers feelings and current life situation, both of which are measured on a 5-point Likert scale (0 = never, 1 = almost never, 2 = sometimes, 3 = fairly often, 4 = very often); higher scores indicate higher perceived stress. | Baseline up to Week 8 | 
| Dispositional Gratitude | The Gratitude Questionnaire-6 (GQ-6) is designed to measure four facets of dispositional gratitude: (a) intensity, (b) frequency, (c) span and (d) density. Each item is rated on a 7-point Likert-type scale ranging from 1 (strongly disagree) to 7 (strongly agree). Scores range from 6 to 42, with higher scores implying a greater level of dispositional gratitude and lower scores indicating a decreased disposition in gratitude. | Baseline up to Week 8 |