Postoperative Exercise Training and Colorectal Cancer Liver Metastasis

Study Overview
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Brief Summary
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Up to 25% of colorectal cancer (CRC) patients are diagnosed with liver metastases, which is the most common site of metastasis, already during the primary tumor diagnosis. Another 30% of the patients will develop liver metastases at a later stage. Even though patient can be treated by surgical resection of the metastatic tumor, 50-75% of the patients experience a relapse in less than two years. Due to the high probability of relapse, mCRC patients undergo multiple rounds of surgery and adjuvant treatment (chemotherapy/radiotherapy) which results in substantial physical de-conditioning. Physical activity has been shown to increase the progression-free survival rates in mCRC patients, when applied post-diagnosis. Increased cardiorespiratory fitness (VO2peak) at the time of diagnosis among CRC individuals has been associated with lower risk of all-cause mortality. Although data on the effect of chronic exercise on VO2peak have emerged, thus far, there is no randomized clinical trial that has investigated the effects of exercise training in mCRC patients early after surgical treatment with curative intent. Therefore, this project aims to address the beneficial effect of structured exercise training primarily on VO2peak and tumor recurrence in mCRC patients immediately after surgical treatment and while they are undergoing adjuvant chemotherapy/radiotherapy. A total of 66 participants will be recruited from the Department of Surgery and Transplantation, Rigshospitalet and randomly allocated to a standard care control group (n=22), standard care plus 150 min/week exercise training (n=22) or standard care plus 300 min/week exercise training (n=22). Participants will undergo exercise training for 6 months, starting immediately after surgery, and they will be followed for additional 6 months. Tumor recurrence will be evaluated up to 3 years after training initiation.

Official Title
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Post-Operative Exercise Training in Patients With Metastatic Colorectal Cancer

Conditions
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Cancer Metastatic to Liver, Cancer Colorectal

Intervention / Treatment
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* Other: Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Colorectal cancer patients diagnosed with liver metastasis and scheduled for liver metastasis surgical resection Exclusion Criteria: Age <18 Pregnancy Physical or mental disabilities that prohibit execution of test or training procedures Inability to understand the Danish language.

Ages Eligible for Study
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Minimum Age: 18 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Usual care<br> | |
| Experimental: Ex1<br>Low exercise volume (150 min/week) | Other: Exercise<br>* 6 months of combined aerobic and resistance exercise<br>|
| Experimental: Ex2<br>High exercise volume (300 min/week) | Other: Exercise<br>* 6 months of combined aerobic and resistance exercise<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in peak oxygen consumption (VO2peak) | Changes in VO2peak assessed during an incremental exercise test to volitional exhaustion on a bicycle ergometer | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-years recurrence-free survival | Proportion of patients who survive without relapse (formation of new tumors) for the 3-year period | Randomization to 3 years after randomization | 
| 3-years overall survival | Proportion of patients who are alive 3 years after randomization | Randomization to 3 years after randomization | 
| Changes in Aerobic Capacity: Ventilatory threshold | Changes in ventilatory threshold assessed during an incremental exercise test to volitional exhaustion on a bicycle ergometer | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Aerobic Capacity: Peak power output | Changes in peak power output assessed during an incremental exercise test to volitional exhaustion on a bicycle ergometer | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Muscle strength: Hand grip strength | Changes in hand grip strength, assessed using a dynamometer | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Muscle strength: Leg press maximal muscle strength | Changes in leg press one repetition maximum (1RM) | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Functional performance: Habitual gait speed | Changes in habitual gait speed | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Functional performance: Maximal gait speed | Changes in maximal gait speed | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Functional performance: Stair climbing performance | Changes in time required to climb a specific staircase | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Functional performance: 30 seconds Sit-to-stand | Changes in the number of stands from sitting position that can be performed during 30 seconds | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Body composition and anthropometrics: Body mass | Changes in body mass | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Body composition and anthropometrics: Total lean mass | Changes in total lean mass assessed by dual energy x-ray absorptiometry (DXA) | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Body composition and anthropometrics: Total fat mass | Changes in total fat mass assessed by DXA | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Body composition and anthropometrics: Bone mineral density | Changes in bone mineral density assessed by DXA | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Body composition and anthropometrics: Waist circumference | Changes in waist circumference | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Body composition and anthropometrics: Hip circumference | Changes in Hip circumference | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Systolic Blood pressure | Changes in resting systolic blood pressure | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Diastolic Blood pressure | Changes in resting diastolic blood pressure | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Heart rate | Changes in resting heart rate | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Blood biochemistry: leukocyte differential counts | Changes in resting leukocyte differential counts (total and per type [eosinophils, basophils, lymphocytes, monocytes, neutrophils]) | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Blood biochemistry: C-reactive protein | Changes in resting C-reactive protein levels in blood | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Blood biochemistry: Insulin | Changes in resting insulin blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Blood biochemistry: Glucose | Changes in resting glucose blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Blood biochemistry: Triglycerides | Changes in resting triglycerides blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Blood biochemistry: LDL-Cholesterol | Changes in resting LDL-cholesterol blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Blood biochemistry: HDL-Cholesterol | Changes in resting HDL-cholesterol blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Cytokine levels in blood: Interleukin-6 | Changes in resting Interleukin-6 blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Cytokine levels in blood: Interleukin-1 | Changes in resting Interleukin-1 blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Cytokine levels in blood: Interleukin-7 | Changes in resting Interleukin-7 blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Cytokine levels in blood: Interleukin-8 | Changes in resting Interleukin-8 blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Cytokine levels in blood: Interleukin-15 | Changes in resting Interleukin-15 blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Cytokine levels in blood: Interleukin-1β | Changes in resting Interleukin-1β blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Cytokine levels in blood: Interleukin-10 | Changes in resting Interleukin-10 blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Cytokine levels in blood: Tumor-necrosis-factor alpha (TNFalpha) | Changes in resting TNFalpha blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Cytokine levels in blood: Interferon gamma (IFN-gamma) | Changes in resting IFN-gamma blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Immune cells in blood: Natural killer (NK) cells | Changes in resting NK cells | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Immune cells in blood: CD4 T cells | Changes in resting CD4 T cells | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Immune cells in blood: CD8 T cells | Changes in resting CD8 T cells | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Immune cells in blood: B cells | Changes in resting B cells | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Osteonectin | Changes in resting osteonectin blood levels | Baseline, 3-, 6-, 9- and 12 months after exercise training initiation | 
| Changes in Patient-reported symptomatic adverse events | Patient-reported symptomatic adverse events, assessed using the using the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Health-related quality of life: Physical well-being | Changes in patient-reported physical well-being assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) (scale scoring 0-28, the higher the score the better quality of life) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Health-related quality of life: Social well-being | Changes in patient-reported social well-being assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) (scale scoring 0-28, the higher the score the better quality of life) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Health-related quality of life: Emotional well-being | Changes in patient-reported emotional well-being assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) (scale scoring 0-24, the higher the score the better quality of life) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Health-related quality of life: Functional well-being | Changes in patient-reported functional well-being assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) (scale scoring 0-28, the higher the score the better quality of life) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Health-related quality of life: General | Changes in patient-reported general health-related qualify of life assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) (scale scoring 0-108, the higher the score the better quality of life) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Health-related quality of life: Colorectal cancer specific | Changes in patient-reported colorectal-cancer specific health-related quality of life assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) (scale scoring 0-28, the higher the score the better quality of life) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Health-related quality of life: total score | Changes in patient-reported in health-related quality of life (total score) assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) (scale scoring 0-136, the higher the score the better quality of life) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Health-related quality of life: Trial outcome index | Changes in patient-reported trial outcome index assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) (scale scoring 0-84, the higher the score the better quality of life) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Health-related quality of life: Fatigue | Changes in patient-reported fatigue assessed using the Functional Assessment of Cancer Therapy - Fatigue scale (FACIT-Fatigue) (scale score: 0-52, the higher the score the less fatigue) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Depression | Changes in patient-reported depression, assessed using the Hospital Anxiety and Depression Scale (HADS) (scale scoring: 0-21, the higher the score the worse the condition) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Anxiety | Changes in patient-reported anxiety, assessed using the Hospital Anxiety and Depression Scale (HADS) (scale scoring: 0-21, the higher the score the worse the condition) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Physical activity: Walking | Changes in patient-reported weekly duration of walking, assessed using the International Physical Activity Questionnaire (IPAQ) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Physical activity: Moderate intensity physical activity | Changes in patient-reported weekly duration of moderate intensity physical activity, assessed using the International Physical Activity Questionnaire (IPAQ) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Physical activity: Vigorous intensity physical activity | Changes in patient-reported weekly duration of vigorous intensity physical activity, assessed using the International Physical Activity Questionnaire (IPAQ) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Physical activity: Total intensity physical activity | Changes in patient-reported weekly duration of total intensity physical activity, assessed using the International Physical Activity Questionnaire (IPAQ) (Expressed as metabolic equivalent (MET)-min per week: MET level x minutes of activity x events per week) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Physical activity: sitting time | Changes in patient-reported weekly sitting time, assessed using the International Physical Activity Questionnaire (IPAQ) | Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation | 
| Changes in Circulating tumor DNA (ctDNA) | Changes in ctDNA in blood | Baseline, 6-, and 12 months after exercise training initiation | 
| Changes in DNA methylation | Changes in DNA methylation derived from blood | Baseline, 6-, and 12 months after exercise training initiation | 
| Changes in treatment tolerance: Relative dose intensity (RDI) of adjuvant chemotherapy | RDI (%) of adjuvant chemotherapy, calculated as the actual dose intensity / standard dose intensity x 100% | From date of planned initiation to end of adjuvant chemotherapy | 
| Postoperative hospital admissions | Incidence of postoperative hospital re-admissions, defined as any non-scheduled ≥ 24 h hospitalization | From discharge to 12 months after exercise training initiation | 
| Postoperative complications | Incidence of postoperative complications up to 30 days after surgery (total and by grade and type), assessed using the Clavien-Dindo classification | From discharge to 30 days after discharge |