Preoperative Physical Exercise, Nutritional Support, and Psychological Intervention (Multimodal Prehabilitation) to Strengthen Patients' Overall Health and Reduce Postoperative Complications

Postoperative complications leading to death represent the third leading cause of mortality worldwide, equating to roughly one in 13 deaths and forming what has been termed a hidden pandemic. Analysis of the ACS NSQIP database further illustrates this impact, revealing that 19% of surgical patients had not returned home within 30 days. The severity of these complications is strongly associated with long-term survival outcomes. However, for individuals with advanced or recurrent gastrointestinal cancers-including pelvic, peritoneal, oesophageal, hepatic, gastric, and pancreatic disease-complete surgical resection remains the sole potentially curative treatment. In Germany alone, approximately 85,000 patients undergo major gastrointestinal cancer surgery annually, making complication reduction a key clinical goal. This multicenter German trial is the first to comprehensively integrate exercise, nutrition, psychological support, and patient education into a modern multimodal prehabilitation strategy.

The main outcome measure of this trial is the incidence of severe postoperative complications defined as Clavien-Dindo grade III-V. The central hypothesis is that prehabilitation decreases postoperative complications and thus improves prognosis and survival. The intended study population includes patients with substantial comorbidities who face a high risk of complications, elevated healthcare costs, and poor cancer outcomes, often due to impaired physiological fitness and failure to complete intended oncological therapy.

Inclusion criteria are:

• age ≥18/ ≤80 years
• elective major abdominal cancer surgery (pelvic exenteration, cytoreductive surgery, oesophagectomy, transhiatal gastrectomy, hepatectomy, pancreatectomy, rectum resection)
• Duke Activity Status Index (DASI) score <40
• high risk for surgical complications: => presence of comorbid disease as one or more of the following:
• known or documented history of coronary artery disease
• known or documented history of heart failure or brain-derived natriuretic peptide (BNP) >400pg/mL
• high risk of pulmonary complications as documented by Ariscat score >4434
• diabetes currently treated with an oral hypoglycemic agent and/or insulin
• preoperative serum creatinine >200 μmol/l
• morbid obesity with body mass index (BMI) ≥35 kg/m2
• preoperative deconditioning as confirmed by six-minute walk test (6-MWT) <400 meters or by cardiopulmonary exercise testing (CPET) derived parameters (either anaerobic threshold (if done) <12 ml/kg/min, peak oxygen consumption (VO2) <16 mL/kg/min, peak VO2<710 mL/m2, or Ve/VCO2 [ventilator equivalents for carbon dioxide] >35)
• schedule allowing for at least 4 weeks for intervention with multimodal prehabilitation prior to surgery and patient's willingness to exercise

Exclusion criteria are:

• non-elective surgery
• unstable cardiac or respiratory disease
• locomotor limitations precluding exercise training, including severe deconditioning and frailty as reflected by inability to complete CPET test or peak VO2 <10 ml/kg/min
• cognitive deterioration impeding adherence to the programme

The prehabilitation programme includes a preoperative exercise intervention complemented by nutritional and psychological support. Patients will be randomized to either an individualized, progressive preoperative exercise and education programme or to usual care. Those in the control group will receive written recommendations on exercise and nutrition. General physical activity and dietary behaviour will be assessed in both groups throughout the study period, and programme adherence will be documented for per-protocol analysis. In the preparatory phase of the trial (months 1-6), standardized exercise materials and an exercise SOP will be developed and provided to all participating centers. Consistent implementation will be ensured through uniform delivery of the exercise programme and weekly video conferences to monitor fidelity and Borg scale application.

The overall aim of this prehabilitation programme is to maximize the physical capacity (in regards of strength and endurance) within the given time frame. The supervised progressive exercise programme will be conducted and supervised by a professional sport therapist, consisting of three 50-min sessions per week. Each session will be divided in (i) a resistance exercise part, aiming to increase patients' strength and (ii) an endurance part aiming to improve patients' cardio-respiratory fitness. A home-based walking programme (as per usual care) will be conducted in the intervention group on the days, when they are not attending the prehabilitation programme.

Outcome measures will be evaluated by a blinded endpoint committee consisting of two independent researchers, with inter-observer variability assessed and reported. The primary endpoint is the incidence of major postoperative complications (Clavien-Dindo grade III-V), a validated and widely used outcome strongly associated with surgical risk and five-year survival in cancer patients. This endpoint will be analyzed within a clinically relevant time frame of 30 days after surgery or until discharge, as preliminary data indicate that most grade III-V complications occur during this period. Previous prehabilitation studies have demonstrated feasibility and improvements in functional capacity, and recent randomized trials suggest a reduction in complications. However, these studies largely focus on colorectal cancer, whereas patients with upper gastrointestinal malignancies-who face complication rates of 30-40%-are the focus of the present trial. Secondary endpoints include the Comprehensive Complication Index, specific medical complications, ICU and hospital length of stay, days at home after surgery, initiation of adjuvant therapy, cost-effectiveness, functional capacity, quality of life, and perioperative anxiety and depression.

In addition to all endpoints mentioned above, serum / peripheral blood mononuclear cells (PBMCs) and tumour material will be stored for mechanistic analysis (e.g. inflammation, wound healing, immune function) in secondary step. Putative biological mechanisms attributed to the effectiveness of prehabilitation include the pleiotropic effects of exercise, which through numerous physiological systems may impact surgical outcome. Exercise as part of prehabilitation stimulates bone-marrow derived cells improving vascular function and wound healing. An episode of maximal exercise mobilized progenitor populations into the peripheral circulation in some patients and this was associated with fewer postoperative complications. Exercise also generates erythropoietin, increasing red cell counts and stimulates natural killer cell production, which may modulate the tumor defense response. Recent evidence suggests that preoperative exercise may down-stage tumor grade. These beneficial effects may be driven by exercise-induced anti-inflammatory pathways as well as by a mobilization and activation of tumor-competitive lymphocytes. The above mechanisms will be investigated in consecutive analyses with regard to the research topics: 1. endothelial regeneration, 2. inflammation 3. tumor defense and 4. cognitive function. An additional research proposal will be submitted in order to clarify on the specific translational mechanisms (i.e. exercise-stimulation of natural killer cells for clinical tumor defense).