Postoperative Exercise Training in Patients With Colorectal Liver Metastases Undergoing Surgery (ELMA)

Colorectal Liver Metastasis Clinical Trial

— ELMA  

Official title:

Postoperative Exercise Training in Patients With Colorectal Liver Metastases Undergoing Surgery (ELMA)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04751773
• Other study ID #: ELMA
• Status: Active, not recruiting
• Phase: N/A
• Start date: March 12, 2021
• Est. completion date: March 2026

Study information

• Verified date: November 2023
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 60
• Est. completion date: March 2026
• Est. primary completion date: September 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Liver Metastasis
• Liver Neoplasms
• Neoplasm Metastasis

Intervention

Behavioral:
• Exercise training
Perioperative exercise training

Locations

Country	Name	City	State
Denmark	Rigshospitalet	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	3-years cancer-specific survival	Proportion of patients who have not died from colorectal cancer 3 years after randomization	Randomization to 3 years after randomization
Other	3-years overall survival	Proportion of patients who are alive 3 years after randomization	Randomization to 3 years after randomization
Other	Carcinoembryonic antigen (CEA)	Changes in blood CEA	Baseline, postoperative day 15, 8 weeks after discharge
Other	Circulating tumor DNA (ctDNA)	Changes in blood ctDNA	Baseline, postoperative day 15, 8 weeks after discharge
Other	DNA methylation	Changes in DNA methylation	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
Other	Exercise feasibility: Exercise sessions attendance rate	Exercise sessions attendance rate (%), defined as number of attended exercise sessions / number of prescribed exercise sessions x 100	From baseline to 8 weeks after discharge
Other	Exercise feasibility: Relative dose intensity (RDI) of exercise	RDI (%) of exercise, defined as prescribed exercise dose / performed exercise dose x 100	From baseline to 8 weeks after discharge
Other	Exercise feasibility: Early termination of exercise sessions	Incidence of early termination of attended exercise sessions, defined as termination of an exercise session before the prescribed exercises have been performed	From baseline to 8 weeks after discharge
Other	Exercise feasibility: Exercise intervention interruptions	Incidence of exercise intervention disruptions, defined as a period of = 7 days without an attended exercise session	From baseline to 8 weeks after discharge
Other	Exercise feasibility: Exercise sessions requiring dose modifications	Incidence of exercise sessions requiring dose modifications, defined as any deviation from the prescribed exercise	From baseline to 8 weeks after discharge
Other	Exercise feasibility: Permanent discontinuation of the exercise intervention	Incidence of permanent discontinuations of the exercise intervention, defined as participants that withdraw entirely from the exercise intervention, regardless of whether they remain in the trial	From baseline to 8 weeks after discharge
Other	Exercise feasibility: Time from discharge to initiation of postoperative exercise	Time from discharge to first attended postoperative exercise session	From surgery to 8 weeks after discharge
Other	Exercise feasibility: Patient-reported symptomatic adverse events (paint, dizziness, nausea, fatigue, other)	Changes in patient-reported symptomatic adverse events (paint, dizziness, nausea, fatigue, other)	Immediately before and immediately after each exercise session performed from baseline to 8 weeks after discharge
Other	Intraoperative factors: Blood loss during surgery	Blood loss during surgery	During surgery
Other	Intraoperative factors: Duration of surgery	Duration of surgery	During surgery
Other	Intraoperative factors: Blood transfusions	Incidence of blood transfusions	During surgery
Other	Resting cardiovascular factors: Resting systolic blood pressure	Changes in resting systolic blood pressure	Baseline, 8 weeks after discharge
Other	Resting cardiovascular factors: Resting diastolic blood pressure	Changes in resting diastolic blood pressure	Baseline, 8 weeks after discharge
Other	Resting cardiovascular factors: Resting heart rate	Changes in resting heart rate	Baseline, 8 weeks after discharge
Other	Resting cardiovascular factors: Hemoglobin concentration	Changes in hemoglobin concentration	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
Other	Aerobic capacity: Peak oxygen consumption	Changes in peak oxygen consumption assessed during an incremental exercise test (ergometer bicycling) to volitional exhaustion	Baseline, 8 weeks after discharge
Other	Aerobic capacity: Ventilatory threshold	Changes in ventilatory threshold assessed during an incremental exercise test (ergometer bicycling) to volitional exhaustion	Baseline, 8 weeks after discharge
Other	Aerobic capacity: Peak power output	Changes in peak power output assessed during an incremental exercise test (ergometer bicycling) to volitional exhaustion	Baseline, 8 weeks after discharge
Other	Muscle strength: Leg press maximal muscle strength	Changes in leg press one repetition maximum (1RM)	Baseline, 8 weeks after discharge
Other	Muscle strength: Chest press muscle strength	Changes in chest press 1RM	Baseline, 8 weeks after discharge
Other	Muscle strength: Hand grip strength	Changes in hand grip strength, assessed using a dynamometer	Baseline, 8 weeks after discharge
Other	Functional performance: Habitual gait speed	Changes in habitual gait speed	Baseline, 8 weeks after discharge
Other	Functional performance: Maximal gait speed	Changes in maximal gait speed	Baseline, 8 weeks after discharge
Other	Functional performance: Stair climbing power	Changes in stair climbing power	Baseline, 8 weeks after discharge
Other	Body composition and anthropometrics: Body mass	Changes in body mass	Baseline, 8 weeks after discharge
Other	Body composition and anthropometrics: Body mass index	Changes in body mass index	Baseline, 8 weeks after discharge
Other	Body composition and anthropometrics: Total lean mass	Changes in total lean mass, assessed by dual energy x-ray absorptiometry (DXA)	Baseline, 8 weeks after discharge
Other	Body composition and anthropometrics: Appendicular lean mass	Changes in appendicular lean mass, assessed by DXA	Baseline, 8 weeks after discharge
Other	Body composition and anthropometrics: Abdominal fat mass	Changes in abdominal fat mass, assessed by DXA	Baseline, 8 weeks after discharge
Other	Body composition and anthropometrics: Total fat mass	Changes in total fat mass, assessed by DXA	Baseline, 8 weeks after discharge
Other	Body composition and anthropometrics: Fat percentage	Changes in fat percentage, assessed by DXA	Baseline, 8 weeks after discharge
Other	Body composition and anthropometrics: Hip circumference	Changes in hip circumference	Baseline, 8 weeks after discharge
Other	Body composition and anthropometrics: Waist circumference	Changes in waist circumference	Baseline, 8 weeks after discharge
Other	Standard blood biochemistry: Total cholesterol	Changes in total cholesterol concentration	Baseline, 8 weeks after discharge
Other	Standard blood biochemistry: Low-density lipoprotein cholesterol	Changes in low-density lipoprotein cholesterol concentration	Baseline, 8 weeks after discharge
Other	Standard blood biochemistry: High-density lipoprotein cholesterol	Changes in high-density lipoprotein cholesterol concentration	Baseline, 8 weeks after discharge
Other	Standard blood biochemistry: Triglyceride	Changes in triglyceride concentration	Baseline, 8 weeks after discharge
Other	Standard blood biochemistry: Glycated hemoglobin A1c	Change in glycated hemoglobin A1c concentration	Baseline, 8 weeks after discharge
Other	Standard blood biochemistry: Insulin	Changes in insulin concentration	Baseline, 8 weeks after discharge
Other	Standard blood biochemistry: Glucose	Changes in blood glucose concentration	Baseline, 8 weeks after discharge
Other	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)	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	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)	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	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).	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	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).	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	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).	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	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).	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	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).	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	Health-related quality of life: Total score (Functional Assessment of Cancer Therapy - Colorectal)	Changes in patient-reported in health-related quality of life (total score) assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C).	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	Depression	Changes in patient-reported depression, assessed using the Hospital Anxiety and Depression Scale (HADS).	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	Anxiety	Changes in patient-reported anxiety, assessed using the Hospital Anxiety and Depression Scale (HADS).	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	Self-reported physical activity: Walking	Changes in patient-reported weekly duration of walking, assessed using the International Physical Activity Questionnaire (IPAQ)	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	Self-reported physical activity: Moderate intensity physical activity (PA)	Changes in patient-reported weekly duration of moderate intensity PA, assessed using the International Physical Activity Questionnaire (IPAQ)	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	Self-reported physical activity: Vigorous intensity physical activity (PA)	Changes in patient-reported weekly duration of vigorous intensity PA, assessed using the International Physical Activity Questionnaire (IPAQ)	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	Self-reported physical activity: Total physical activity (PA)	Changes in patient-reported weekly duration of total PA, assessed using the International Physical Activity Questionnaire (IPAQ)	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	Self-reported physical activity: Sitting time	Changes in patient-reported weekly sitting time, assessed using the International Physical Activity Questionnaire (IPAQ)	Baseline, 8 weeks after discharge, 1 year after randomization, 2 years after randomization, 3 years after randomization
Other	Effect of acute perioperative exercise: IL-1ß	Changes in blood IL-1ß concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: IL-6	Changes in blood IL-6 concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: IL-8	Changes in blood IL-8 concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: IL-10	Changes in blood IL-10 concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: Interferon- ?	Changes in blood interferon- ? concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: C-reactive protein	Changes in blood C-reactive protein concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: Leukocyte differential counts	Changes in blood leukocyte cell counts (total and per type [eosinophils, basophils, lymphocytes, monocytes, neutrophils]) during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: Natural killer cells	Changes in blood natural killer cell count during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: T cells	Changes in blood T cell count during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: Adrenocorticotropic hormone (ACTH)	Changes in blood ACTH concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: Cortisol	Changes in blood cortisol concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: Adrenaline	Changes in blood adrenaline concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	Effect of acute perioperative exercise: Noradrenaline	Changes in blood noradrenaline concentration during acute perioperative exercise	10 min before exercise, immediately after aerobic exercise
Other	LPS-induced IL-6 production of whole blood	Changes in concentation of IL-6 in LPS-stumulated whole blood	Baseline, after resection, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Other	LPS-induced TNF-a production of whole blood	Changes in concentation of TNF-a in LPS-stumulated whole blood	Baseline, after resection, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Primary	Serious adverse events		From discharge to 8 weeks after discharge
Secondary	Postoperative hospital admissions	Incidence of postoperative hospital re-admissions, defined as any non-scheduled = 24 h hospitalization	From discharge to 8 weeks after discharge
Secondary	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 of adjuvant chemotherapy until 8 weeks after discharge
Secondary	Time to initiation of adjuvant chemotherapy	Time from surgery to initiation of adjuvant chemotherapy	From surgery until 8 weeks after discharge
Secondary	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, 7 days after discharge, 7 days after each administration of adjuvant chemotherapy, 8 weeks after discharge.
Secondary	Surgical stress: IL-1ß	Changes in blood IL-1ß concentration	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: IL-6	Changes in blood IL-6 concentration	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: IL-8	Changes in blood IL-8 concentration	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: IL-10	Changes in blood IL-10 concentration	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: interferon- ?	Changes in blood interferon- ? concentration	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: C-reactive protein	Changes in blood C-reactive protein	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: Leukocyte differential counts	Changes in blood leukocyte cell counts (total and per type [eosinophils, basophils, lymphocytes, monocytes, neutrophils])	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: Natural killer (NK) cells	Changes in blood NK cell count	Baseline, after resection, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: T cells	Changes in blood T cell count	Baseline, after resection, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: Adrenocorticotropic hormone (ACTH)	Changes in blood ACTH concentration	After last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 2, postoperative day 3, postoperative day 15
Secondary	Surgical stress: Cortisol	Changes in blood cortisol concentration	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: Adrenaline	Changes in blood adrenaline concentration	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge
Secondary	Surgical stress: Noradrenaline	Changes in blood noradrenaline concentration	Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge