Clinical trial NCT04751773: Postoperative Exercise Training in Patients With Colorectal Liver Metastases Undergoing Surgery (ELMA)
Official title: Postoperative Exercise Training in Patients With Colorectal Liver Metastases Undergoing Surgery (ELMA)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Colorectal Liver Metastasis
Keywords: Aerobic exercise
Resistance exercise
Perioperative medicine
Prehabilitation
Rehabilitation
Cancer
Surgical oncology
Surgery
Exercise oncology
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2021-02-12
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Surgery is a primary treatment modality in the intended curative treatment of colorectal liver metastases (CRLM). However, surgery elicits a cascade of potentially detrimental stress responses that may drive the onset of long-term disease progression. Exercise training is emerging as an adjunct treatment in surgical oncology and holds potential to modify the surgical stress response. Against this background, we designed the present randomized controlled trial to evaluate the therapeutic role of pre- and postoperative exercise training in patients with CRLM undergoing open liver resection.

Detailed description: BACKGROUND:

Colorectal cancer is the third most frequent type of cancer in Denmark, with more than 5000 new cases annually. Colorectal liver metastases (CRLM) develop in nearly one fourth of all patients with colorectal cancer, and poses a poor prognostic outlook, with low survival rates and short time to disease progression. Surgical resection, either upfront or following downstaging with perioperative treatments, confers substantial survival benefit in patients with CRLM, and may even comprise a curative treatment modality. However, surgery elicits a cascade of biological responses characterized by increased dissemination of tumor cells and modulation of neuroendocrine, inflammatory, and immunological factors. These local and systemic perturbations typically persist for days to weeks following surgery and may independently or in concert drive the onset of long-term disease progression. Under normal physiological conditions, exercise training is a potent modulator of immune function, systemic inflammation, and the neuroendocrine system, raising the possibility that perioperative exercise training may ameliorate the surgical stress response during and after surgery. However, in a recent systematic review and meta-analysis (submitted), we found that the effects and safety of preoperative and early postoperative exercise are unknown in patients with gastrointestinal cancers (including CRLM) due to lack of studies, widespread methodological issues, and poor ascertainment and reporting of adverse events. Safety is arguably the single most important consideration for the application perioperative exercise, and methodological robust trials evaluating the safety and tolerability of perioperative exercise training along with preliminary information on treatment efficacy are needed to inform the application of exercise in surgical oncology.

Against this background, we designed the present randomized controlled trial to evaluate the therapeutic role of postoperative exercise training in patients with CRLM undergoing open liver resection. The primary trial objective and hypothesis are:

1. To compare the number of serious adverse events (SAE) in standard care plus postoperative exercise (EX) vs. standard care alone (CON) in patients with colorectal liver metastases scheduled to undergo open liver resection. The primary research hypothesis is that the number of SAEs is non-inferior in EX vs. CON

   The key secondary study objectives and hypotheses are:
2. To compare the effect of EX vs. CON on incidence of postoperative hospital admissions in patients with CRLM undergoing surgery. We hypothesize that the incidence of postoperative hospital admissions are non-inferior in EX vs. CON
3. To compare the effect of EX vs. CON on relative dose intensity of adjuvant chemotherapy and time from surgery to initiation of adjuvant chemotherapy in patients with CRLM undergoing surgery. We hypothesize that the relative dose intensity of adjuvant chemotherapy and time from surgery to initiation of adjuvant chemotherapy are non-inferior in EX vs. CON.
4. To compare the effect of EX vs. CON on selected patient-reported symptomatic adverse events in patients with CRLM undergoing surgery
5. To compare the effect of EX vs. CON on surgical stress responses (neuroendocrine, inflammatory, and immune factors) in patients with CRLM undergoing surgery.

   The secondary study objectives are:
6. To evaluate the feasibility of EX.
7. To compare the effect of EX vs. CON on functional capacity, muscle strength, aerobic capacity, and body composition in patients with CRLM undergoing surgery.
8. To compare the effect of EX vs. CON on clinical outcomes in patients with CRLM undergoing surgery.
9. To compare the effect of EX vs. CON on patient-reported outcomes in patients with CRLM undergoing surgery.
10. To compare the effect of EX vs. CON on circulating tumor DNA and DNA methylation in patients with CRLM undergoing surgery
11. To evaluate the effects of acute pre- and postoperative exercise on neuroendocrine, immunological, and inflammatory factors in patients with CRLM undergoing surgery.
12. To conduct explorative preclinical sub-studies.

TRIAL DESIGN:

This trial is a single-center, randomized, controlled, parallel-group trial performed at Centre for physical Activity (CFAS), Rigshospitalet, Copenhagen, Denmark, and Department of Surgical Gastroenterology, Rigshospitalet, Copenhagen, Denmark.

A total of 60 participants with CRLM will be included and randomly allocated 2:1 to standard care and postoperative exercise training (EX) or standard care alone (CON). The participants will undergo two trial visits at CFAS during the study period: One preoperative trial visit (1-3 days after inclusion and 2-7 days before surgery) and one post-surgery trial visit (8 weeks after discharge). For each visit, the participants will be assessed for body composition and anthropometrics, resting cardiovascular factors, standard blood biochemistry, aerobic capacity (VO2peak, ventilatory threshold), maximal muscle strength, and functional performance. In addition, blood samples will be taken before, during, and immediately after surgery, and on post-operative day 1, 3, and 15 and neuroendocrine, inflammatory, and immune factor will be analyzed. Patient-reported outcomes will be collected at all trial visits and 1, 2, and 3 years after randomization. Data from medical records regarding mortality and disease recurrence will be collected up to 3 years after randomization. As an optional procedure, we will collect blood samples before, during, and after a pre- and a postoperative supervised exercise training session.

Eligibility criteria: Inclusion Criteria: Participants diagnosed with colorectal liver metastasis planned for open surgery of liver metastases

Exclusion Criteria:

* Age \<18
* Pregnancy
* Other known malignancy requiring active cancer treatment that prohibits execution of test or training procedures
* Conditions that prohibit execution of trial procedures
* Inability to understand the Danish language.

Primary outcomes:
measure: Serious adverse events
timeFrame: From discharge to 8 weeks after discharge
Secondary outcomes:
measure: Postoperative hospital admissions
timeFrame: From discharge to 8 weeks after discharge
measure: Relative dose intensity (RDI) of adjuvant chemotherapy
timeFrame: From date of planned initiation of adjuvant chemotherapy until 8 weeks after discharge
measure: Time to initiation of adjuvant chemotherapy
timeFrame: From surgery until 8 weeks after discharge
measure: Patient-reported symptomatic adverse events
timeFrame: Baseline, 7 days after discharge, 7 days after each administration of adjuvant chemotherapy, 8 weeks after discharge.
measure: Surgical stress: IL-1β
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: IL-6
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: IL-8
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: IL-10
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: interferon- γ
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: C-reactive protein
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: Leukocyte differential counts
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: Natural killer (NK) cells
timeFrame: Baseline, after resection, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: T cells
timeFrame: Baseline, after resection, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: Adrenocorticotropic hormone (ACTH)
timeFrame: After last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 2, postoperative day 3, postoperative day 15
measure: Surgical stress: Cortisol
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: Adrenaline
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Surgical stress: Noradrenaline
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Other outcomes:
measure: 3-years cancer-specific survival
timeFrame: Randomization to 3 years after randomization
measure: 3-years overall survival
timeFrame: Randomization to 3 years after randomization
measure: Carcinoembryonic antigen (CEA)
timeFrame: Baseline, postoperative day 15, 8 weeks after discharge
measure: Circulating tumor DNA (ctDNA)
timeFrame: Baseline, postoperative day 15, 8 weeks after discharge
measure: DNA methylation
timeFrame: Baseline, 3 days before surgery, 1 h before anesthesia, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 2, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Exercise feasibility: Exercise sessions attendance rate
timeFrame: From baseline to 8 weeks after discharge
measure: Exercise feasibility: Relative dose intensity (RDI) of exercise
timeFrame: From baseline to 8 weeks after discharge
measure: Exercise feasibility: Early termination of exercise sessions
timeFrame: From baseline to 8 weeks after discharge
measure: Exercise feasibility: Exercise intervention interruptions
timeFrame: From baseline to 8 weeks after discharge
measure: Exercise feasibility: Exercise sessions requiring dose modifications
timeFrame: From baseline to 8 weeks after discharge
measure: Exercise feasibility: Permanent discontinuation of the exercise intervention
timeFrame: From baseline to 8 weeks after discharge
measure: Exercise feasibility: Time from discharge to initiation of postoperative exercise
timeFrame: From surgery to 8 weeks after discharge
measure: Exercise feasibility: Patient-reported symptomatic adverse events (paint, dizziness, nausea, fatigue, other)
timeFrame: Immediately before and immediately after each exercise session performed from baseline to 8 weeks after discharge
measure: Intraoperative factors: Blood loss during surgery
timeFrame: During surgery
measure: Intraoperative factors: Duration of surgery
timeFrame: During surgery
measure: Intraoperative factors: Blood transfusions
timeFrame: During surgery
measure: Resting cardiovascular factors: Resting systolic blood pressure
timeFrame: Baseline, 8 weeks after discharge
measure: Resting cardiovascular factors: Resting diastolic blood pressure
timeFrame: Baseline, 8 weeks after discharge
measure: Resting cardiovascular factors: Resting heart rate
timeFrame: Baseline, 8 weeks after discharge
measure: Resting cardiovascular factors: Hemoglobin concentration
timeFrame: Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 2, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: Aerobic capacity: Peak oxygen consumption
timeFrame: Baseline, 8 weeks after discharge
measure: Aerobic capacity: Ventilatory threshold
timeFrame: Baseline, 8 weeks after discharge
measure: Aerobic capacity: Peak power output
timeFrame: Baseline, 8 weeks after discharge
measure: Muscle strength: Leg press maximal muscle strength
timeFrame: Baseline, 8 weeks after discharge
measure: Muscle strength: Chest press muscle strength
timeFrame: Baseline, 8 weeks after discharge
measure: Muscle strength: Hand grip strength
timeFrame: Baseline, 8 weeks after discharge
measure: Functional performance: Habitual gait speed
timeFrame: Baseline, 8 weeks after discharge
measure: Functional performance: Maximal gait speed
timeFrame: Baseline, 8 weeks after discharge
measure: Functional performance: Stair climbing power
timeFrame: Baseline, 8 weeks after discharge
measure: Body composition and anthropometrics: Body mass
timeFrame: Baseline, 8 weeks after discharge
measure: Body composition and anthropometrics: Body mass index
timeFrame: Baseline, 8 weeks after discharge
measure: Body composition and anthropometrics: Total lean mass
timeFrame: Baseline, 8 weeks after discharge
measure: Body composition and anthropometrics: Appendicular lean mass
timeFrame: Baseline, 8 weeks after discharge
measure: Body composition and anthropometrics: Abdominal fat mass
timeFrame: Baseline, 8 weeks after discharge
measure: Body composition and anthropometrics: Total fat mass
timeFrame: Baseline, 8 weeks after discharge
measure: Body composition and anthropometrics: Fat percentage
timeFrame: Baseline, 8 weeks after discharge
measure: Body composition and anthropometrics: Hip circumference
timeFrame: Baseline, 8 weeks after discharge
measure: Body composition and anthropometrics: Waist circumference
timeFrame: Baseline, 8 weeks after discharge
measure: Standard blood biochemistry: Total cholesterol
timeFrame: Baseline, 8 weeks after discharge
measure: Standard blood biochemistry: Low-density lipoprotein cholesterol
timeFrame: Baseline, 8 weeks after discharge
measure: Standard blood biochemistry: High-density lipoprotein cholesterol
timeFrame: Baseline, 8 weeks after discharge
measure: Standard blood biochemistry: Triglyceride
timeFrame: Baseline, 8 weeks after discharge
measure: Standard blood biochemistry: Glycated hemoglobin A1c
timeFrame: Baseline, 8 weeks after discharge
measure: Standard blood biochemistry: Insulin
timeFrame: Baseline, 8 weeks after discharge
measure: Standard blood biochemistry: Glucose
timeFrame: Baseline, 8 weeks after discharge
measure: Health-related quality of life: Physical well-being
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Health-related quality of life: Social well-being
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Health-related quality of life: Emotional well-being
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Health-related quality of life: Functional well-being
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Health-related quality of life: Colorectal-cancer specific
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Health-related quality of life: General
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Health-related quality of life: Trial outcome index
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Health-related quality of life: Total score (Functional Assessment of Cancer Therapy - Colorectal)
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Depression
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Anxiety
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Self-reported physical activity: Walking
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Self-reported physical activity: Moderate intensity physical activity (PA)
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Self-reported physical activity: Vigorous intensity physical activity (PA)
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Self-reported physical activity: Total physical activity (PA)
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Self-reported physical activity: Sitting time
timeFrame: Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
measure: Effect of acute perioperative exercise: IL-1β
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: IL-6
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: IL-8
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: IL-10
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: Interferon- γ
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: C-reactive protein
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: Leukocyte differential counts
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: Natural killer cells
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: T cells
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: Adrenocorticotropic hormone (ACTH)
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: Cortisol
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: Adrenaline
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: Effect of acute perioperative exercise: Noradrenaline
timeFrame: 10 min before exercise, immediately after aerobic exercise
measure: LPS-induced IL-6 production of whole blood
timeFrame: Baseline, after resection, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
measure: LPS-induced TNF-a production of whole blood
timeFrame: Baseline, after resection, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
Study officials:
affiliation: Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Denmark
name: Jesper F Christensen, PhD
role: PRINCIPAL_INVESTIGATOR
References: