Preoperative Calorie Restriction and Exercise in Patients With Obesity Undergoing Colorectal Cancer Resection

Colorectal cancer is one of the most prevalent malignancies worldwide, positioned as the fifth most common type of cancer. Surgery remains the primary treatment for most patients, yet it triggers an important stress response often followed by postoperative complications. More than 40% of patients with colorectal cancer undergoing surgery experience such complications, an issue that importantly affect long-term prognosis and quality of life. In this context, patients with obesity are at a higher risk compared to their normal-weight counterparts. Thus, combating obesity in the preoperative period could be of great importance for enhancing post-surgical outcomes.

Prehabilitation - defined as the process of physiologically and metabolically preparing patients for surgery - has gained relevance during the last decade. It has been reported that prehabilitation can reduce postoperative complications in colorectal cancer patients undergoing surgery. However, the presence of obesity may diminish these benefits. In a previous work, we demonstrated that a multidisciplinary prehabilitation positively modulates pro-tumoral gene signatures in both tumor and non-tumor colonic tissues. Nevertheless, these effects were significantly attenuated in patients with obesity, suggesting a reduced benefit in this population. This highlights the clinical and social relevance of exploring whether a preoperative weight-loss intervention could further enhance surgical outcomes in this high-risk group.

Evidence from bariatric surgery suggests that preoperative weight loss significantly improves prognosis in individuals with obesity. Similar strategies may also benefit patients with colorectal cancer undergoing surgery, but current evidence is limited and derived from studies with low sample sizes and poor methodological quality. Caloric restriction is a well-known method that can effectively induce short-term weight loss. However, it is not exempt from certain adverse events as often results in 20-30% loss of lean muscle mass. Considering that \>60% of patients with colorectal cancer are affected by malnutrition, and that this nutritional status is strongly associated with increased postoperative morbidity, combining caloric restriction with nutritional education appears to be essential. Exercise is a well-established approach that can prevent lean mass loss and improve post- surgical prognosis, thus being considered a key component of preoperative care.

To maximize the effectiveness and safety of these interventions, they should be delivered by interdisciplinary teams including surgeons, nutritionist and exercise physiologist. This is critical not only to reduce excess body weight, but also preserve muscle mass, optimize metabolic health and improve surgical resilience.

Usual care group will follow the usual institutional preoperative care

Other: Usual Care

Preoperative calorie restriction and supervised exercise

Other: PRECAREX intervention

Participants allocated to PRECAREX will complete a structured preoperative weight loss intervention combining individualized controlled caloric restriction and supervised combined exercise training. The intervention will last approximately 4 weeks, depending on the interval between inclusion and surgery. Its objective is to induce a controlled preoperative weight loss of approximately 5%, while preserving skeletal muscle function and improving functional reserve, with the primary clinical aim of reducing postoperative morbidity. The program is conceived as a supervised metabolic intervention targeting the biological profile of patients with obesity, characterized by excess adiposity, metabolic dysfunction, systemic inflammation, and reduced physiological adaptability.

Participants allocated to usual care will follow the 2025 standard ERAS-based perioperative pathway, including routine preoperative assessment, perioperative management, and postoperative follow-up. This may include standard nutritional screening and nutritional optimization according to hospital protocols and ERAS recommendations, including oral nutritional supplementation or immunonutrition when clinically indicated as part of routine care and independently of study allocation. No structured weight loss program, supervised exercise, or research-prescribed individualized hypocaloric dietary intervention will be provided. Physical activity and dietary intake will be monitored to account for potential behavioral changes and to document any usual-care nutritional or lifestyle advice received outside the intervention.

Plazo: From enrollment to surgery.

Feasibility will be assessed through recruitment and retention rates, attendance at supervised exercise sessions, and adherence to the prescribed calorie restriction.

Plazo: From intervention initiation to surgery.

Safety will be assessed by recording adverse events occurring during the intervention, including their severity.

Plazo: Within 30 and 90 days after surgery.

Overall postoperative complication burden assessed using the Comprehensive Complication Index, which integrates all postoperative complications into a score ranging from 0 (no complications) to 100 (death).

Plazo: Within 30 and 90 days after surgery.

Proportion of participants experiencing at least one postoperative complication, expressed as a percentage.

Plazo: Within 30 and 90 days after surgery.

Proportion of participants experiencing major postoperative complication (CCI \> 20), expressed as a percentage.

Plazo: Within 30 and 90 days after surgery.

Proportion of participants experiencing at least one medical complication, expressed as a percentage.

Plazo: Within 30 and 90 days after surgery.

Proportion of participants experiencing at least one surgical complication, expressed as a percentage.

Plazo: Within 90 days after surgery.

Number of days from surgery to discharge from the hospital.

Plazo: Within 30 and 90 days after surgery.

Proportion of participants attending emergency department after discharge, expressed as a percentage.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Blood samples will be drawn from patient' antecubital vein in a supine position during the morning after an overnight fasting to assess the glycemic profile. We will obtain plasma glucose (mg/dL) and insulin (mg/dL) levels.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Blood samples will be drawn from patient' antecubital vein in a supine position during the morning after an overnight fasting to assess the lipid profile. We will obtain total cholesterol (mg/dL), Light-Density Lipoprotein Cholesterol (mg/dL), High-Density Lipoprotein Cholesterol (mg/dL), and Triglycerides (mg/dL) levels.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Blood samples will be drawn from patient' antecubital vein in a supine position during the morning after an overnight fasting to assess the hepatic transaminases levels. Serum alanine aminotransferase (ALT), aspartate aminotransferase (GOT), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) will be measured and expressed in units per litre (U/L).

Plazo: Baseline, preoperatively, and 1 month after surgery.

Blood samples will be drawn from patient' antecubital vein in a supine position during the morning after an overnight fasting to assess the immunological blood profiles. The following parameters will be obtained: Leukocytes (10\*3 uL), Neutrophils (10\*3 uL), Lymphocytes (10\*3 uL), Monocytes (10\*3 uL), Eosinophils (10\*3 uL), Basophils (10\*3 uL) and LUC cells (10\*3 uL).

Plazo: Baseline, preoperatively, and 1 month after surgery.

Blood samples will be drawn from patient' antecubital vein in a supine position during the morning after an overnight fasting to assess the red cells levels, including red blood cell count (×10\^12/L), haemoglobin (g/dL), haematocrit (%), mean corpuscular volume (fL), mean corpuscular haemoglobin (pg), mean corpuscular haemoglobin concentration (g/dL), and red cell distribution width (%).

Plazo: Baseline, preoperatively, and 1 month after surgery.

Blood samples will be drawn from patient' antecubital vein in a supine position during the morning after an overnight fasting to assess the tumour markers levels (CA 19-9, CEA, CA 125, TPA and CA 15.3; all will be expressed as pg/mL))

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in systolic blood pressure will be assessed by blood pressure monitor.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in diastolic blood pressure will be assessed by blood pressure monitor.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in cardiorespiratory fitness assessed using the six-minute walk test.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in upper body muscular strength assessed through handgrip test.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in lower body muscular strength will be assessed using the 30 seconds sit-to-stand test.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in lower body muscular strength will be assessed using the 5 sit-to-stand test

Plazo: Baseline, preoperatively, and 1 month after surgery.

Body weight (kilograms) will be measured by a digital scale

Plazo: Baseline, preoperatively, and 1 month after surgery.

Body height (meters and centimeters) will be measured by a stadiometer

Plazo: Baseline, preoperatively, and 1 month after surgery.

Fat mass will be assessed by assessed by bioelectrical impedance analysis (BIA).

Plazo: Baseline, preoperatively, and 1 month after surgery.

Fat-free Mass will be assessed by assessed by bioelectrical impedance analysis (BIA).

Plazo: Baseline, preoperatively, and 1 month after surgery.

Neck circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry

Plazo: Baseline, preoperatively, and 1 month after surgery.

Waist circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry

Plazo: Baseline, preoperatively, and 1 month after surgery.

Hip circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in health-related quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). This 30-item questionnaire comprises five functional scales (physical, role, emotional, cognitive, and social functioning), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and six single-item measures (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). All scale and single-item scores are transformed to a range of 0-100. Higher functional and global health status/quality of life scores indicate better functioning and quality of life, whereas higher symptom and financial difficulties scores indicate greater problems.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in fatigue assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Cancer Related Fatigue Module (EORT-QLQ-FA12). This is a 12-item validated multi-dimensional questionnaire evaluating physical fatigue (5 items), emotional fatigue (3 items), cognitive fatigue (2 items), and interference/social impact (2 single items) over the past week. Items are scored on a 4-point Likert scale (1 = Not at all, 4 = Very much). Raw scores for each subscale are linearly transformed into a standardized 0 to 100 metric. Higher scores indicate a higher level of fatigue severity and greater functional impairment.

Plazo: Baseline, preoperatively, and 1 month after surgery.

General health will be assessed by the EuroQol 5 dimensions 5 levels (EQ-5D-5L). Values ranged from 0 to 100. Higher values mean better outcome.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in anxiety and depressive symptoms assessed using the Hospital Anxiety and Depression Scale (HADS). Minimum value: 0 // Maximum value: 21. Higher scores mean a better outcome.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in sleep quality assessed using the Pittsburgh Sleep Quality Index (PSQI). PSQI global score ranges from 0 to 21, with a score higher than 5 indicating poor sleep quality

Plazo: Baseline, preoperatively, and 1 month after surgery.

Changes in dietary pattern assessed using the Food Frequency Questionnaire (FFQ).

Plazo: Day of surgery

Colon tumor tissue samples will be collected during surgical resection and analyzed using molecular techniques (e.g., gene expression profiling) to assess markers associated with tumor progression.

Plazo: Baseline, preoperatively, and 1 month after surgery.

Shotgun metagenomic sequencing of DNA extracted from stool samples to determine microbial functional capacity through the analysis of metabolic pathways.

PREoperative CAlorie Restriction and EXercise in Patients With Obesity Undergoing Colorectal Cancer Resection: the PRECAREX Pilot Randomized Controlled Trial