Tailored Exercise Interventions to Reduce Fatigue in Cancer Survivors

Study Overview
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Brief Summary
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Cancer-related fatigue (CRF) is a common and distressing symptom of cancer and/or cancer treatment that can persist for months or years in cancer survivors. Exercise is beneficial for the management of CRF, and general exercise guidelines for cancer survivors are available. However, exercise interventions have not been tailored to alleviate CRF in fatigued cancer survivors, and thus the potential to alleviate CRF may not have been realized. The primary aim of this research is to investigate the effect of a traditional vs. tailored 12-week exercise intervention on self-reported CRF severity.

Detailed Description
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Background and Rationale Approximately one-third of cancer survivors experience severe and persistent fatigue for a number of years post-treatment, but this distressing symptom is often under-treated by healthcare professionals due to a lack of mechanism-targeted interventions. The assessment of cancer-related fatigue (CRF) is reliant on subjective fatigue measurements such as self-report questionnaires. Less attention has been given to objective physiological measurements. However, there are well-established techniques which allow the assessment of neuromuscular fatigue and its peripheral and central origins which could be utilized in the study of CRF. Very few studies have considered these objective measures alongside self-report scales in the study of CRF and only two have used such techniques in cancer survivors. To date, no studies have investigated neuromuscular fatigue in whole body, dynamic activity as relevant to daily tasks (and involving the lower limb due to its functional relevance to locomotion). Novel testing developed in our laboratory could be used as part of a wider screening to develop individualized interventions to alleviate CRF. It is well accepted in the field that CRF is multidimensional and in addition to a potential neuromuscular component, the role of sleep disturbance may also be implicated. Interventions targeted at improving sleep quality are therefore warranted, and there is sound evidence for the efficacy of exercise interventions in particular for improving CRF in cancer survivors. As a non-pharmacological intervention, physical activity has the strongest evidence base for treating CRF. However, the mechanisms explaining the reduction of CRF with exercise are not understood. Due to the complex and multi-factorial nature of CRF, it would be of benefit to tailor exercise interventions to the specific deficits (in regards to neuromuscular mechanisms) or difficulties (for example sleep disturbance) experienced by the individual. Ultimately, mechanism-targeted exercise interventions could be translated to clinical rehabilitation programs and lead to an improved quality of for cancer survivors. Research Question & Objectives The primary aim of this research is to investigate the effect of a traditional vs. tailored 12-week exercise intervention on self-reported CRF severity. Methods Fatigued cancer survivors who have completed primary treatment ≥ 3 months and ≤ 5 years from enrollment will be randomly allocated to one of two treatment arms: traditional (active control) and tailored exercise. Participants in the traditional exercise group will engage in aerobic and resistance exercise that is consistent with published recommendations. The tailored exercise group will be prescribed an intervention designed to address individual deficits (identified at baseline) that may be related to CRF. Participants will be assessed before and after the intervention for patient-reported outcomes, neuromuscular function and fatigue in response to whole-body exercise, sleep quantity and quality, physical activity levels, cardiorespiratory fitness and blood biomarkers.

Official Title
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Tailored Exercise Interventions to Reduce Fatigue in Cancer Survivors

Conditions
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Cancer-related Fatigue

Intervention / Treatment
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* Other: Traditional Exercise
* Other: Tailored Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 18 and 75 years; Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score ≤ 34; Completion of treatment in ≥ 3 months and ≤ 5 years preceding enrollment; Approval received from personal physician and/or a Canadian Society for Exercise Physiology-Clinical Exercise Physiologist (CSEP-CEP); Command of the English language. Exclusion Criteria: Contraindication to experimental procedures including transcranial magnetic stimulation (TMS); Diagnosed as having obstructive sleep apnea or anemia; Currently participating in a structured exercise intervention; Participant is pregnant.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are assigned to one of two groups in parallel for the duration of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Traditional Exercise<br>A classical exercise intervention based on current guidelines for cancer survivors. | Other: Traditional Exercise<br>* The traditional exercise group will undertake a supervised exercise intervention involving aerobic exercise and light resistance training, in line with published guidelines for exercise in cancer survivors.<br>|
| Experimental: Tailored Exercise<br>A tailored and individualized exercise intervention based on the results of pre-intervention testing. | Other: Tailored Exercise<br>* The tailored training group will be prescribed an individualized exercise intervention designed specifically to counteract deficits (e.g. neuromuscular) of difficulties (e.g. sleep disturbance) identified during pre-intervention testing.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of change in the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) Scale | Self-report questionnaire for the assessment of cancer-related fatigue. | Baseline to after the 12-week intervention, at 6 month and 12 month follow up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of change in The Functional Assessment of Cancer Therapy - General (FACT-G) | General quality of life instrument intended for use with a variety of chronic illness conditions. | Baseline and after the 12-week intervention. | 
| Assessment of change in Edmonton Symptom Assessment System-revised tiredness scale | Self-report questionnaire for the assessment of of nine common symptoms experienced by cancer patients. | Baseline and after the 12-week intervention, and during follow up (6 and 12 months). | 
| Maximal Isometric Force in the Knee Extensors | A reduction in maximal isometric force in the knee extensors measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Cortical Voluntary Activation | A reduction voluntary activation (using transcranial magnetic stimulation) measured measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Voluntary Activation | A reduction voluntary activation (using femoral nerve stimulation) measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Potentiated Doublet Twitch Force | A reduction in potentiated quadriceps twitch force (from a high frequency doublet at 100 Hz) measured before, before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Muscle Compound Action Potential (M-Wave) Peak-to Peak Amplitude | Evoked from supra-maximal stimulation of the femoral nerve and measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Muscle Compound Action Potential (M-Wave) Peak-to Peak Duration | Evoked from supra-maximal stimulation of the femoral nerve and measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Muscle Compound Action Potential (M-Wave) Area | Evoked from supra-maximal stimulation of the femoral nerve and measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Motor Evoked Potential (MEP) Peak-to Peak Amplitude | Normalized to the maximal M-wave and measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Motor Evoked Potential (MEP) Peak-to Peak Duration | Normalized to the maximal M-wave and measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Motor Evoked Potential (MEP) Area | Normalized to the maximal M-wave and measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Cortical Silent Period | Evoked from TMS and measured (from stimulation artifact to the continuous resumption of EMG) before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Voluntary Electromyography (EMG) | Root mean square of the EMG signal during an MVC, measured before, during and after an intermittent cycling test. | Baseline and after the 12-week intervention. | 
| Amplitude of the Sleep-Wake Cycle | The mean difference between lowest and highest activity period, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| Peak Time of the sleep-wake Cycle | Time of day of the highest estimated level of wake, recorded by actigraphy. | Baseline and after the 12-week intervention. | 
| Mesor of the Sleep-Wake Cycle | Mean level of activity over 24 hours, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| inter-daily stability | the degree of regularity of the rest-activity patterns on individual days in the 24 h environment, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| intra-daily variability | the fragmentation of periods of rest and activity, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| L5 | The mean activity counts in the least active 5 h period in the average 24 h pattern) recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| L5 mid | The central time of the L5 period, usually referring to the through of the activity period), recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| Wake actigraphy | Amount of activity during wake, recorded with actigraphy | Baseline and after the 12-week intervention. | 
| Sleep Activity | Amount of activity during sleep periods, recorded with actigraphy | Baseline and after the 12-week intervention. | 
| Activity Index | Percentage of activity per epoch for wake and sleep, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| Time in bed | Time spent between the moment subject turn off the light to sleep and the moment he gets up, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| Actual Sleep Time | Time spent asleep during the night, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| Actual Wake Time | Time spent awaken during the night, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| Sleep Onset Latency | Time to fall asleep, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| Sleep Efficiency | Ratio between the time spent asleep and the total duration of sleep period, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| Fragmentation index | Indication of the sleep quality based on movement during night, recorded with actigraphy. | Baseline and after the 12-week intervention. | 
| Blood Biomarkers | Blood count, catecholamines, serotonin, cortisol, inflammatory markers and markers of oxidative stress. | Baseline and after the 12-week intervention. | 
| Assessment of change in the Centre for Epidemiological Studies Depression Scale (CES-D) questionnaire. | Self-report questionnaire for the assessment of health-related quality of life, specific to cancer type. | Baseline and after the 12-week intervention. | 
| Assessment of change in The Social Prevision Scale (SPS) | Self-report questionnaire for the assessment of social support. | Baseline and after the 12-week intervention. | 
| Assessment of change in The Functional Assessment of Cancer Therapy (FACT) Cancer Specific | Self-report questionnaire for the assessment | Baseline and after the 12-week intervention. | 
| Assessment of change in The Modified-Godin Leisure Time Exercise Questionnaire (GLTEQ) | Self-report questionnaire for the assessment of leisure time physical activity. | Baseline, after the 12-week intervention, and during follow up (6 and 12 months). | 
| Assessment of change in The Insomnia Severity Index (ISI) | Self-report questionnaire for the assessment of insomnia severity. | Baseline and after the 12-week intervention. | 
| Assessment of change in The Brief Pain Inventory Short Form (BPI-sf) | Self-report questionnaire for the assessment of pain. | Baseline and after the 12-week intervention. | 
| Assessment of change in Maximal Oxygen Uptake | The highest 30 second average oxygen uptake measured during an an incremental cycling test. | Baseline and after the 12-week intervention. | 
| Assessment of change in Muscle Cross-Sectional Area | Ultrasound measurement of the vastus lateralis and rectus femoris. | Baseline and after the 12-week intervention. | 
| Heart Rate Variability | Variation in the time interval between heartbeats. | Baseline and after the 12-week intervention. | 
| Assessment of change in Fat Mass | Measured using dual energy X-ray absorptiometry (DXA). | Baseline and after the 12-week intervention. | 
| Assessment of change in Fat Free Mass | Measured using dual energy X-ray absorptiometry (DXA). | Baseline and after the 12-week intervention. | 
| Assessment of change in Bone Mineral Density | Measured using dual energy X-ray absorptiometry (DXA). | Baseline and after the 12-week intervention. |