Multimodal Prehabilitation During Chemotherapy in Patients With Colorectal Liver Metastases

Study Overview
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Brief Summary
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Liver resection is the only curative treatment for patients with colorectal liver metastases (CRLM). Most patients undergo chemotherapy (CT) before liver surgery. CT objectively decreases patient functional capacity. It has already been demonstrated that a structured training program carried out during the 4 weeks following CT, while the patient is waiting for liver resection, is able to return the functional capacity to baseline levels. Despite this, multimodal prehabilitation programs (MPP) during preoperative CT have not been evaluated or implemented. The aim of this study is to investigate whether a 16-week MPP applied during and following CT in CRLM patients will result in a significant increase in physical fitness when compared to those that undergo MPP only during the 4-weeks, between the end of CT and liver resection.

Detailed Description
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The primary aim of the study is to evaluate the effectiveness of a multimodal prehabilitation program (MPP) in CRLM patients, which will be implemented right through the period of preoperative CT and during the 4-weeks of recovery before liver resection. MPP will consist of in-hospital high-moderate intensive exercise training, nutritional assessment and high-protein supplementation, smoking cessation, psychological support and Comprehensive Geriatric Assessment. Expected improvement in physical fitness will be measured by the difference in meters achieved in the six-minute walk test (6MWT) and will be compared with patients that will follow the MPP only during the 4-weeks before surgery, when preoperative CT has been finished. Secondary aims include patient reported outcomes measures such as quality of life, postoperative complications, length of hospital stay, 30-day mortality and re-admissions. Protocol feasibility will be evaluated by monitoring all interventions.

Official Title
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Multimodal Prehabilitation During Neoadjuvant Chemotherapy in Patients With Colorectal Liver Metastases: a Randomized Controlled Trial

Conditions
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Prehabilitation, Neoadjuvant Therapy, Liver Metastases

Intervention / Treatment
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* Behavioral: Physical Prehabilitation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Written informed consent obtained from subject to participate in the study. Exclusion Criteria: Age <18 years ASA health class status IV-V Mental conditions or disabling orthopedic and neuromuscular disease that prevent physical exercise or may compromise adherence to the program Medical contraindication to perform exercise Inability to obtain informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The participant will be randomized (1:1) using seed, a Stata's random-number generated function. The subjects will be allocated into one of the two groups of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 16W group<br>Multimodal prehabilitation program (MPP) will be implemented during 16 weeks, 12 weeks during chemotherapy (CT) and 4 weeks while waiting for surgery. | Behavioral: Physical Prehabilitation<br>* The prehabilitation program consists of the following interventions: in-hospital high-moderate intensive exercise training, nutritional assessment and high-protein supplementation, smoking cessation, psychological support and Comprehensive Geriatric Assessment.<br>* Other names: Comprehensive Geriatric Assessment (CGA) and co-morbidity assessment;|
| Active Comparator: 4W group<br>Multimodal prehabilitation program (MPP) will start at the end of preoperative chemotherapy (CT) until surgery (4 weeks in total). | Behavioral: Physical Prehabilitation<br>* The prehabilitation program consists of the following interventions: in-hospital high-moderate intensive exercise training, nutritional assessment and high-protein supplementation, smoking cessation, psychological support and Comprehensive Geriatric Assessment.<br>* Other names: Comprehensive Geriatric Assessment (CGA) and co-morbidity assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical Fitness- 6MWT | Change in physical fitness will be measured by the six-minute walk test (6MWT). This test measures the distance an individual can walk, in metres, in a 6-minute period. Greater distance walked during the 6MWT indicates greater functional capacity. | Baseline (before chemotherapy), week 12 (end of chemotherapy), week 16 (before surgery), 4 weeks postoperative, 8 weeks postoperative, 1 year postoperative | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative complications- Clavien-Dindo classification | The Clavien-Dindo classification consists of 7 grades. Grade I: any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological interventions; Grade II: Requiring pharmacological treatment with drugs other than such allowed for grade I complications; Grade III (IIIa, IIIb): Requiring surgical, endoscopic or radiological intervention; Grade IV (Iva, IVb): Life-threatening complication requiring IC/ICU management; Grade V: death of the patient. | Through study completion, up to one year postoperative | 
| Postoperative complications- CCI | The Comprehensive Complication Index (CCI) integrates in a single formula all complications by severity, ranging from 0 (uneventful course) to 100 (death). | Through study completion, up to one year postoperative | 
| Postoperative hospital length of stay | The patient's postoperative length of stay will be recorded from the medical records. It will be calculated from the date of surgery until to the date of discharge from the hospital. It will be reported in days. | Postoperative period: assessed up to the first year postoperative | 
| Readmissions rate | Rate of un-planned hospital readmissions within 30 days of discharge after hospitalization. | Postoperative period: Up to 30 postoperative days | 
| Functional capacity- 30CST | The 30-second sit to stand test (30CST) measures lower body strength by recording the maximum number of times an individual can go from a seated position to a standing position, without using their arms, in a 30-second period. | Baseline (before chemotherapy), week 12 (end of chemotherapy), week 16 (before surgery), 4 weeks postoperative, 8 weeks postoperative, 1 year postoperative | 
| Health-related quality of life- SF-36 | Quality of life will be evaluated by using the SF-36 mental health score. This survey measures eight scales of health: physical function, role physical, role emotional, social functioning, bodily pain, general health, vitality, and mental health. Each items are scored on a 0 to 100 range. A high score defines a more favorable health state. | Baseline (before chemotherapy), week 16 (before surgery), 8 weeks postoperative, 1 year postoperative | 
| Psychological health- HADS | Emotional health will be measured using the Hospital Anxiety and Depression Scale (HADS). The HADS contains seven items, each scored from 0 to 3 points for anxiety and depression. It provides summary measures on a scale of 0-21, with scores exceeding 8 suggesting the presence of a mood disorder | Baseline (before chemotherapy), week 16 (before surgery), 8 weeks postoperative, 1 year postoperative | 
| Functional capacity- Handgrip strength | It will be measured using an hydraulic hand dynamometer. Three measures from each hand will be taken, with patient seated and arm bent at a 90-degree angle. The average of the three measures for each hand will be recorded. | Baseline (before chemotherapy), week 12 (end of chemotherapy), week 16 (before surgery), 4 weeks postoperative, 8 weeks postoperative, 1 year postoperative | 
| Nutritional status- PG-SGA | The Patient-Generated Subjective Global Assessment (PG-SGA) is a validated questionnaire used to assess the nutritional and functional status of cancer patients. The scoring system allows patients at risk for malnutrition to be identified and triaged for nutritional intervention. A score ≥9 indicates a critical need for nutritional intervention. | Baseline (before chemotherapy), week 12 (end of chemotherapy), week 16 (before surgery), 4 weeks postoperative, 8 weeks postoperative, 1 year postoperative | 
| Nutritional status- BMI | Body Mass Index (BMI) is weight in kilograms divided by height in meters squared. | Baseline (before chemotherapy), week 12 (end of chemotherapy), week 16 (before surgery), 4 weeks postoperative, 8 weeks postoperative, 1 year postoperative | 
| Nutritional status- BIA | The Bio-electrical Impedance Analysis (BIA) is a method to determine body composition. The measurement of body fat in relation to lean body mass. | Baseline (before chemotherapy), week 12 (end of chemotherapy), week 16 (before surgery), 4 weeks postoperative, 8 weeks postoperative, 1 year postoperative | 
| Nutritional status- UMA | Upper-arm muscle area (UMA) is the circumference of the left upper arm, measured at the mid-point between the tip of the shoulder and the tip of the elbow. | Baseline (before chemotherapy), week 12 (end of chemotherapy), week 16 (before surgery), 4 weeks postoperative, 8 weeks postoperative, 1 year postoperative |