Multimodal Prehabilitation for Lung Cancer Surgery

Study Overview
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Brief Summary
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The main objective of this randomized controlled trial (RCT) is to investigate whether a multimodal prehabilitation intervention combining a mixed-nutrient supplement with structured exercise training (MM) or the supplement alone (NUT), against a placebo (CTRL), leads to improvement in functional capacity and postoperative outcomes in surgical patients with lung cancer, at nutritional risk. This will be tested in a single centre RCT of 3 parallel arms, double-blinded for the supplement. Female and male participants (n=168, >=45 y) will be randomized to a 10-week intervention spanning 4 weeks pre-surgery and 6 weeks post-hospital discharge. The primary outcome is functional capacity as measured by the 6-minute walk test. Secondary outcomes include muscle mass, quality and strength, quality of life, length of hospital stay, and postoperative complications.

Detailed Description
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RATIONALE: The preoperative period is an opportune time to actively engage and empower patients in improving their functional, nutritional and mental status in anticipation of the surgical stress. Considering that lung cancer patients often present with poor nutritional status and physical function prior to surgery, providing a nutritional supplement to increase protein, leucine, vitamin D and omega-3 fatty acid FA intake with a structured exercise program and relaxation techniques should improve muscle mass, strength and physical performance. MAIN OBJECTIVE: to test the effect of a multimodal RCT prehabilitation intervention (MM) combining a mixed-nutrient supplement with structured exercise training or the supplement alone (NUT) against a placebo (CTRL), on functional pre- and postoperative outcomes in surgical patients with lung cancer at nutritional risk. STUDY DESIGN: 10-week randomized controlled trial of 3 parallel arms, double-blinded for supplement: control (CTRL), multi-nutrient supplement (NUT) and multimodal intervention (MM). After baseline assessment, patients will be randomized to either group in a 1:1:1 CTRL:NUT:MM ratio using a computer-generated randomization scheme by permuted block sizes, with stratification by sex and functional capacity (< or > 450 m on the 6-minute walk test (6MWT). Consecutive adult patients = or > 45 years scheduled for elective video-assisted thoracic surgery or open thoracotomy surgery of non-small cell lung cancer (NSCLC) stages I, II or IIIa and a Patient-Generated Subjective Global Assessment (PG-SGA) score = or > 3, will be approached following their first appointment with their surgeon at the McGill University Health Centre (MUHC)-Montreal General Hospital. INTERVENTION: The NUT arm will ingest a multi-nutrient supplement consisting of whey protein + leucine + viatmin D, and fish oil. The CTRL participants will receive placebo supplements with the same physical aspect, flavor and packaging as the active supplement.The MM arm will receive the NUT intervention in addition to performing structured exercise and relaxation techniques for 4 weeks prior to surgery and 6 weeks after hospital discharge. OUTCOMES: Primary: physical capacity measured by the 6MWT; Secondary: physical function, muscle strength, total skeletal muscle mass, leg muscle volume and density, body composition, quality of life, length of stay and post-operative complications; Other: dietary intake, physical activity, exercise tolerance, pulmonary function, clinical markers. STATISTICAL ANALYSIS: Intention-to-treat analysis will be performed in the primary analyses. For preoperative data, analysis of covariance (ANCOVA) will compare between-group differences at 4-week preoperative time, conditioned for baseline data, including predefined covariates in the model (age, sex, BMI). The hypothesis of full recovery from the intervention at 6 weeks postoperative (i.e. 6MWT returning back to or exceeding baseline) will be tested by logistic regression (yes/no). Between-group changes in other outcomes will be evaluated as differences in mean or proportions, as appropriate, with 95% CIs.

Official Title
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A Novel Multimodal Intervention for Surgical Prehabilitation of Patients With Lung Cancer: the MMP-LUNG Trial

Conditions
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Lung Cancer, Surgery

Intervention / Treatment
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* Dietary Supplement: Mixed-nutriend supplement (NUT)
* Other: Multimodal Prehabilitation (MM)
* Dietary Supplement: Placebo Control (CTRL)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged 45 years and over Diagnosed with NSCLC stages I, II or IIIa and scheduled for video-assisted thoracic surgery (VATS) or open thoracotomy surgery for cancer resection At nutritional risk (defined as Patient Generated-Subjective Global Assessment score = or >3) Exclusion Criteria: Prior recent (<2 months) adjuvant therapy (chemo- or radio-therapy) Inability to perform, or comorbidities contraindicating, exercise (defined as CPET <10 mL O2/kg/min) Unable to walk (uses a wheelchair) Allergy to milk or seafood Hypercalcemia (total serum Ca >2.60 mmol/L or ionized Ca >1.30 mmol/L) Hypervitaminosis D (serum 25(OH)D >375 nmol/L) Glomerular filtration rate (<30 mL/min/1.73m2) Insufficient understanding of English or French to provide informed consent Patients taking omega-3 FA supplements will be asked to withhold them during the study; those taking vitamin D will continue unless baseline serum 25(OH)D >80 nmol/L.

Ages Eligible for Study
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Minimum Age: 45 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: Randomized controlled trial, 3 parallel arms (multimodal intervention, MM; nutritional supplement, NUT; control, CTRL), double-blind and placebo-controlled for supplement, single centre.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control (CTRL)<br>Participants will be treated following Enhanced Recovery After Surgery (ERAS) protocols + placebo supplements containing maltodextrin and sunflower oil | Dietary Supplement: Placebo Control (CTRL)<br>* Participants will follow ERAS protocol and will receive dietary counselling and anxiety management counselling as needed. They will receive a placebo dietary supplement made of maltodextrin and sunflower oil.<br>|
| Active Comparator: Mixed-nutriend supplement (NUT)<br>Mixed nutrient supplement containing whey protein, leucine, vitamin D and omega 3 fatty acids | Dietary Supplement: Mixed-nutriend supplement (NUT)<br>* Participants will follow ERAS protocol and will receive dietary counselling and anxiety management counselling as needed. They will receive the active multi-nutrient supplement made of whey protein + leucine + vitamin D doses pre-mixed in unlabeled packets prepared by Gruppo Nutrition to dilute in a cup (250 mL) of water. In addition, participants will ingest 15 mL of fruit-flavored fish oil, provided as a liquid oil. They will receive a dosing cup, pre-marked to 15 mL, for a total dose providing 2120 mg eicosapentaenoic acid (EPA) and 1320 mg docosahexaenoic acid (DHA).<br>|
| Active Comparator: Multi-modal intervention (MM)<br>Multimodal prehabilitation including structured exercise (1 supervised exercise session per week + home-based exercise program), nutritional optimization with dietician, NUT intervention, and relaxation strategies. | Dietary Supplement: Mixed-nutriend supplement (NUT)<br>* Participants will follow ERAS protocol and will receive dietary counselling and anxiety management counselling as needed. They will receive the active multi-nutrient supplement made of whey protein + leucine + vitamin D doses pre-mixed in unlabeled packets prepared by Gruppo Nutrition to dilute in a cup (250 mL) of water. In addition, participants will ingest 15 mL of fruit-flavored fish oil, provided as a liquid oil. They will receive a dosing cup, pre-marked to 15 mL, for a total dose providing 2120 mg eicosapentaenoic acid (EPA) and 1320 mg docosahexaenoic acid (DHA).<br>Other: Multimodal Prehabilitation (MM)<br>* Participants will follow ERAS protocol and will receive dietary counselling and anxiety management counselling as needed. They will receive the NUT intervention + structured exercise training prescribed by a kinesiologist (1. 30 min of aerobic exercise per day of their preferred type (ex. walking) and 2. 30 min of resistance exercise targeting major muscle groups, every second day for 2 sets of 8-12 reps). Training will be performed for 4 weeks prior to surgery (1x/week supervised by kinesiologist at hospital, 2x/week at alone at home)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in preoperative functional walking capacity | 6-Minute walking test (6MWT): measured as the distance walked during 6 minutes, along a 20-m corridor, expressed in meters | From baseline (4 weeks pre-surgery) to surgery | 
| Postoperative functional walking capacity | 6-Minute walking test (6MWT): measured as the distance walked during 6 minutes, along a 20-m corridor, expressed in meters | 6 weeks after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in handgrip strength | Handgrip strength using hand-held Jamar dynamometer, measured in kg | From baseline (4 weeks pre-surgery) to 6 weeks after surgery | 
| Change in total skeletal muscle mass | Estimated using deuterium-labeled creatine (D3-creatine), measured in kg | From baseline (4 weeks pre-surgery) to 6 weeks after surgery | 
| Change in foreleg muscle surface area | Skeletal muscle surface area will be measured in the dominant foreleg, using peripheral quantitative computerized tomography (pQCT, Stratec XCT2000), measured in cm2. | From baseline (4 weeks pre-surgery) to 6 weeks after surgery | 
| Change in foreleg myosteatosis (radiodensity) | Skeletal muscle radiodensity will be measured in the dominant foreleg, using peripheral quantitative computerized tomography (pQCT, Stratec XCT2000), measured in mg/cm3. | From baseline (4 weeks pre-surgery) to 6 weeks after surgery | 
| Change in body weight and composition | Soft lean and fat mass measured by bioelectrical impedance (seca mBCA 515) | From baseline (4 weeks pre-surgery) to 6 weeks after surgery | 
| Change in self-reported quality of life | Measured by the 36-item Short Form Survey (SF36, score 0-100; higher means better quality of life) | From baseline (4 weeks pre-surgery) to 6 weeks after surgery | 
| Change in self-reported functional assessment | Measured by the Functional Assessment of Cancer Therapy - Lung questionnaire (FACT-L score 0-136, higher means better quality of life) | From baseline (4 weeks pre-surgery) to 6 weeks after surgery | 
| Length of hospital stay | Recorded from medical charts, expressed in days | 6 weeks after surgery | 
| Number and severity of postoperative complications | Recorded from medical charts and graded by severity following the Clavien-Dindo classification | 6 weeks after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prehabilitation, Nutritional Supplement