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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.

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

Exercise training

Jesper F Christensen, PhD

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.

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.

The participants and the exercise intervention instructors cannot be blinded, given the nature of the intervention. The outcome assessors of the primary and key secondary outcomes (adverse events and markers of surgical stress, respectively) will be blinded. For practical reasons, the outcome assessors of the following secondary outcomes will be not be blinded: resting cardiovascular factors, aerobic capacity, muscle strength, functional performance, and body composition and anthropometrics.

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

Proportion of patients who have not died from colorectal cancer 3 years after randomization

Proportion of patients who are alive 3 years after randomization

Exercise sessions attendance rate (%), defined as number of attended exercise sessions / number of prescribed exercise sessions x 100

RDI (%) of exercise, defined as prescribed exercise dose / performed exercise dose x 100

Incidence of early termination of attended exercise sessions, defined as termination of an exercise session before the prescribed exercises have been performed

Incidence of exercise intervention disruptions, defined as a period of ≥ 7 days without an attended exercise session

Incidence of exercise sessions requiring dose modifications, defined as any deviation from the prescribed exercise

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

Time from discharge to first attended postoperative exercise session

Changes in patient-reported symptomatic adverse events (paint, dizziness, nausea, fatigue, other)

Changes in resting systolic blood pressure

Changes in resting diastolic blood pressure

Changes in peak oxygen consumption assessed during an incremental exercise test (ergometer bicycling) to volitional exhaustion

Changes in ventilatory threshold assessed during an incremental exercise test (ergometer bicycling) to volitional exhaustion

Changes in peak power output assessed during an incremental exercise test (ergometer bicycling) to volitional exhaustion

Changes in leg press one repetition maximum (1RM)

Changes in hand grip strength, assessed using a dynamometer

Changes in total lean mass, assessed by dual energy x-ray absorptiometry (DXA)

Changes in appendicular lean mass, assessed by DXA

Changes in abdominal fat mass, assessed by DXA

Changes in total fat mass, assessed by DXA

Changes in fat percentage, assessed by DXA

Changes in total cholesterol concentration

Changes in low-density lipoprotein cholesterol concentration

Changes in high-density lipoprotein cholesterol concentration

Change in glycated hemoglobin A1c concentration

Changes in patient-reported physical well-being assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C)

Changes in patient-reported social well-being assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C)

Changes in patient-reported emotional well-being assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C).

Changes in patient-reported functional well-being assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C).

Changes in patient-reported colorectal-cancer specific health-related quality of life assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C).

Changes in patient-reported general health-related qualify of life assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C).

Changes in patient-reported trial outcome index assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C).

Changes in patient-reported in health-related quality of life (total score) assessed using the Functional Assessment of Cancer Therapy - Colorectal (FACT-C).

Changes in patient-reported depression, assessed using the Hospital Anxiety and Depression Scale (HADS).

Changes in patient-reported anxiety, assessed using the Hospital Anxiety and Depression Scale (HADS).

Changes in patient-reported weekly duration of walking, assessed using the International Physical Activity Questionnaire (IPAQ)

Changes in patient-reported weekly duration of moderate intensity PA, assessed using the International Physical Activity Questionnaire (IPAQ)

Changes in patient-reported weekly duration of vigorous intensity PA, assessed using the International Physical Activity Questionnaire (IPAQ)

Changes in patient-reported weekly duration of total PA, assessed using the International Physical Activity Questionnaire (IPAQ)

Changes in patient-reported weekly sitting time, assessed using the International Physical Activity Questionnaire (IPAQ)

Changes in blood IL-1β concentration during acute perioperative exercise

Changes in blood IL-6 concentration during acute perioperative exercise

Changes in blood IL-8 concentration during acute perioperative exercise

Changes in blood IL-10 concentration during acute perioperative exercise

Changes in blood interferon- γ concentration during acute perioperative exercise

Changes in blood C-reactive protein concentration during acute perioperative exercise

Changes in blood leukocyte cell counts (total and per type \[eosinophils, basophils, lymphocytes, monocytes, neutrophils\]) during acute perioperative exercise

Changes in blood natural killer cell count during acute perioperative exercise

Changes in blood T cell count during acute perioperative exercise

Changes in blood ACTH concentration during acute perioperative exercise

Changes in blood cortisol concentration during acute perioperative exercise

Changes in blood adrenaline concentration during acute perioperative exercise

Changes in blood noradrenaline concentration during acute perioperative exercise

Changes in concentation of IL-6 in LPS-stumulated whole blood

Changes in concentation of TNF-a in LPS-stumulated whole blood

Incidence of postoperative hospital re-admissions, defined as any non-scheduled ≥ 24 h hospitalization

RDI (%) of adjuvant chemotherapy, calculated as the actual dose intensity / standard dose intensity x 100%

Time from surgery to initiation of adjuvant chemotherapy

Patient-reported symptomatic adverse events, assessed using the using the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

Changes in blood interferon- γ concentration

Changes in blood leukocyte cell counts (total and per type \[eosinophils, basophils, lymphocytes, monocytes, neutrophils\])

Changes in blood adrenaline concentration

Changes in blood noradrenaline concentration

Rigshospitalet, Denmark

Principal investigator

Nervous System Diseases

Behaviors and Mental Disorders

Parasomnias

Sleep Initiation and Maintenance Disorders

Sleep Wake Disorders

Sleep Disorders, Intrinsic

Dyssomnias

Mental Disorders

Psychotic Disorders

Neurologic Manifestations

Jin sanqing, MD

Zhou Yan, MD

SanQing Jin, MD

Although patients with cancers are prone to insomnia, especially waiting for surgery during hospitalization, and insomnia promotes acute respiratory infections (ARI) and is not conducive to the postoperative quality of recovery (QoR), evidence that preoperative insomnia delays postoperative recovery is still lacking. In this prospective observational study, we enroll 175 non-elderly subjects with abdominal cancer who will undergo non-emergency cancer resection surgery. Insomnia Severity Index scale (ISI) is used to assess the insomnia severity during hospitalization while awaiting surgery. The Quality of Recovery-15 (QoR-15) is used to evaluate the overall recovery after surgery. Meanwhile, wrist watch and sleep diary are used to record sleep. The aim of the study is to investigate the association between preoperative insomnia and postoperative QoR, the association between preoperative insomnia and postoperative ARI,and to describe preoperative sleep traits.

In the single-center, prospective observational study, ISI is used to investigate the perceptive sleep during hospitalization waiting for surgery,and QoR-15 is used to investigate the overall quality of functional recovery at postoperative 1, 3, 7, 14, and 30 days (POD1/3/7/14/30). At the same time, both of ARI within POD30 and neutrophil to lymphocyte ratio(NLR) in peripheral blood perioperation are recorded. The study is divided into four phases: (1) Screening: on the first day of admission, the subjects are screened according to the inclusion and exclusion criteria, and the basic data are collected, including ISI, QoR-15 and depression/anxiety questionnaires, et al. (2) Enrollment (sleep survey during hospitalization waiting for surgery) : ISI is performed in the day of surgery to perceive the severity of insomnia during the whole period of hospitalization waiting for surgery, and objective and subjective sleep are investigated by wrist watch and sleep diary. (3) Surgical and anesthesia period: the key medical data related to surgery, anesthesia and nursing occurred during the operation are recorded. (4) Follow-up: QoR-15 is investigated POD1/3/7/14/30. Meanwhile, both of ARI and NLR are investigated.

The planned enrollment is 175 subjects. No randomized or any protocol-driven treatment is administered to the subjects during the study. The effect size f2 of the independent variable (ISI scores of hospitalization waiting for surgery) on the dependent variable (QoR-15 on POD1) is expected to be 0.1. The number of covariates is predicted to be 46, α is set as two-sided 0.05, and the power is 0.9. The sample size calculated by PASS software is 157 cases. Considering 10% dropout, a sample size of 175 will be required. Data will be presented as mean±standard deviation, median and number (%). Logistic multivariate, or multivariable models will be both performed by statisticians.

Association Between Preoperative Insomnia and Postoperative Quality of Recovery : A Prospective Observational Study

Association Between Preoperative Insomnia and Postoperative Quality of Recovery in Non-elderly Patients Undergoing Non-emergency Cancer Resection Surgery: A Prospective Observational Study

ISI is used to assess insomnia during the time when waiting for surgery in hospital from the day of admission to the day of surgery.

ISI is used to assess how satisfied with sleep patterns and psychological distress or impairments in daytime functioning associated with sleep difficulties.

ISI is filled in by subjects on the day before surgery or the day of surgery. ISI contents 7 items, which item is measured by an 0-4 point rating scale (0="very satisfaction"; 4="very dissatisfaction").

ISI total scores range from 0 to 28, with higher scores indicating higher severity of insomnia.

QoR-15 is a patient-reported measure, and is used to assess global recovery quality after surgery physiologically and psychologically.

QoR-15 is filled on postoperative day 1. QoR-15 contents 15 items, which item is constructed by an 11-point numerical rating scale (for positive items, 0= "none of the time" to 10="all of the time"; for negative items the scoring was reversed). The total scores are ranging from 0(extremely poor QoR) to 150 (excellent QoR).

A Consensus Sleep Diary (CSD) is used to asses subjective sleep quantity everyday when waiting for surgery in hospital from the day of admission to the day of surgery.

The CSD items assess sleep-onset latency (time taken to fall asleep), the number of awakenings, and the total duration of sleep. Subjects also allow to record factors that could influence sleep, including use of sleep medication.

A Consensus Sleep Diary (CSD) is used to asses subjective sleep quantity everyday waiting for surgery in hospital from the day of admission to the day of surgery.

The CSD items assess sleep-onset latency (time taken to fall asleep), the number of awakenings, and the total duration of sleep. Subjects also allow to record factors that could influence sleep, including use of sleep medication.

QoR-15 is a patient-reported measure, and is used to assess global recovery quality after surgery physiologically and psychologically.

QoR-15 is filled on postoperative day 1. QoR-15 contents 15 items, which item is constructed by an 11-point numerical rating scale (for positive items, 0="none of the time" to 10="all of the time"; for negative items the scoring was reversed). The total scores are ranging from 0(extremely poor QoR) to 150 (excellent QoR).

Acute Respiratory Tract Infection (ARTI): including acute upper respiratory infection and acute lower respiratory infection, according to patients self-reporting.

Peripheral blood neutrophil/lymphocyte ratio on postoperative day 1 resulting from blood routine examination

Peripheral blood neutrophil/lymphocyte ratio on postoperative day 3 from blood routine examination

Peripheral blood neutrophil/lymphocyte ratio on postoperative day 7 from blood routine examination

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Postoperative Exercise Training in Patients With Colorectal Liver Metastases Undergoing Surgery (ELMA)	NCT04751773	Colorectal Live...	Exercise traini...	18 Years - 100 Years	Rigshospitalet, Denmark
Association Between Preoperative Insomnia and Postoperative Quality of Recovery : A Prospective Observational Study	NCT06008873	Sleep Disorder		18 Years - 64 Years	Sixth Affiliated Hospital, Sun Yat-sen University

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