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

Study Overview
=================
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: 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: 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 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. To compare the effect of EX vs. CON on selected patient-reported symptomatic adverse events in patients with CRLM undergoing surgery 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: To evaluate the feasibility of EX. To compare the effect of EX vs. CON on functional capacity, muscle strength, aerobic capacity, and body composition in patients with CRLM undergoing surgery. To compare the effect of EX vs. CON on clinical outcomes in patients with CRLM undergoing surgery. To compare the effect of EX vs. CON on patient-reported outcomes in patients with CRLM undergoing surgery. To compare the effect of EX vs. CON on circulating tumor DNA and DNA methylation in patients with CRLM undergoing surgery To evaluate the effects of acute pre- and postoperative exercise on neuroendocrine, immunological, and inflammatory factors in patients with CRLM undergoing surgery. 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.

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

Conditions
-----------------
Colorectal Liver Metastasis

Intervention / Treatment
-----------------
* Behavioral: Exercise training


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard care alone (CON)<br>Participants allocated to CON receive the standard patient care program, as provided by Rigshospitalet, Copenhagen, Denmark. Participants allocated to CON are allowed to exercise on their own initiative or participate in any standard care hospital- or municipality-based exercise training program. | |
| Experimental: Postoperative exercise training and standard care (EX)<br>Participants allocated to EX receive the standard patient care program, as provided by Rigshospitalet, Copenhagen, Denmark, and postoperative exercise training. The postoperative exercise training program consists of 8 weeks of supervised and home-based exercise 5 times/week. The intensity and duration are progressively increased during the postoperative period | Behavioral: Exercise training<br>* Perioperative exercise training<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious adverse events |  | From discharge to 8 weeks after discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative hospital admissions | Incidence of postoperative hospital re-admissions, defined as any non-scheduled ≥ 24 h hospitalization | From discharge to 8 weeks after discharge | 
| 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 | 
| Time to initiation of adjuvant chemotherapy | Time from surgery to initiation of adjuvant chemotherapy | From surgery until 8 weeks after discharge | 
| 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. | 
| Surgical stress: IL-1β | Changes in blood IL-1β concentration | Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge | 
| 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 | 
| 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 | 
| 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 | 
| Surgical stress: interferon- γ | Changes in blood interferon- γ concentration | Baseline, after last incision, after resection, 3 hour post-surgery, postoperative day 1, postoperative day 3, postoperative day 15, 8 weeks after discharge | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Aerobic exercise, Resistance exercise, Perioperative medicine, Prehabilitation, Rehabilitation, Cancer, Surgical oncology, Surgery, Exercise oncology