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.

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.

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.

The blinding of exercise is not possible therefore participants will be aware if they are in the MM group. However, research personnel performing outcome assessments will be blinded to group allocation. Groups CTRL and NUT will be double-blinded. Supplements will be packaged by the supplier in coded-labeled sachets (for powder) and bottles (for oil). The supplier will disclose the code to a research person not associated with the trial. Research staff will prepare boxes of supplements (or placebo) according to coded group allocation. All participants will be instructed to not self-supplement with commercially available products, to minimize the risk of group contamination. All data and biological samples will be coded such that participant's identification will not be disclosed to research personnel conducting analyses.