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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
66
6 months of combined aerobic and resistance exercise
Rigshospitalet (CFAS)
Copenhagen, Denmark
Change in peak oxygen consumption (VO2peak)
Changes in VO2peak assessed during an incremental exercise test to volitional exhaustion on a bicycle ergometer
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
3-years recurrence-free survival
Proportion of patients who survive without relapse (formation of new tumors) for the 3-year period
Time frame: Randomization to 3 years after randomization
3-years overall survival
Proportion of patients who are alive 3 years after randomization
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Functional performance: Habitual gait speed
Changes in habitual gait speed
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Functional performance: Maximal gait speed
Changes in maximal gait speed
Time frame: 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
Time frame: 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
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Body composition and anthropometrics: Body mass
Changes in body mass
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Body composition and anthropometrics: Waist circumference
Changes in waist circumference
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Body composition and anthropometrics: Hip circumference
Changes in Hip circumference
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Systolic Blood pressure
Changes in resting systolic blood pressure
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Diastolic Blood pressure
Changes in resting diastolic blood pressure
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Heart rate
Changes in resting heart rate
Time frame: 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 \[eosinophils, basophils, lymphocytes, monocytes, neutrophils\])
Time frame: 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
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Blood biochemistry: Insulin
Changes in resting insulin blood levels
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Blood biochemistry: Glucose
Changes in resting glucose blood levels
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Blood biochemistry: Triglycerides
Changes in resting triglycerides blood levels
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Blood biochemistry: LDL-Cholesterol
Changes in resting LDL-cholesterol blood levels
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Blood biochemistry: HDL-Cholesterol
Changes in resting HDL-cholesterol blood levels
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Immune cells in blood: B cells
Changes in resting B cells
Time frame: Baseline, 3-, 6-, 9- and 12 months after exercise training initiation
Changes in Osteonectin
Changes in resting osteonectin blood levels
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: Baseline, 3-, 6-, 9-, 12-, 24- and 36 months after exercise training initiation
Changes in Circulating tumor DNA (ctDNA)
Changes in ctDNA in blood
Time frame: Baseline, 6-, and 12 months after exercise training initiation
Changes in DNA methylation
Changes in DNA methylation derived from blood
Time frame: 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%
Time frame: 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
Time frame: 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
Time frame: From discharge to 30 days after discharge
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