The PROPOSE RCT is a two-arm randomized controlled trial that will be conducted to test the efficacy of a personalized, multidisciplinary pre-operative prehabilitation program (preventive prehabilitation) to reduce serious complications and facilitate recovery after surgery in high-risk patients.

The multimodal prehabilitation program is a preoperative intervention that includes exercise training, nutritional therapy and anxiety reduction techniques, with the aim of preventing or mitigating the functional decline brought about by surgery. 400 patients scheduled for elective major abdominal (including urological), thoracic (including breast) or gynecological cancer surgery will be enrolled. They will be randomized (1:1 ratio) and assigned either to the intervention group (Prehabilitation) or to the control group, which will only be treated according to the usual standard of care within the Enhanced Recovery After Surgery (ERAS) pathways.

The standard treatment for most solid cancer includes surgery and concurrent medical therapies, both of which have been shown to significantly improve prognosis. However, cancer treatments impose impactful physiological stress and have detrimental effects on acute and long-term health outcomes.

Physical, nutritional, and mental status can influence surgical outcomes, functional recovery and quality of life throughout the course of the disease.

The importance of postoperative rehabilitation on physical performance and recovery is well-recognized. However, the preoperative period provides a unique opportunity to address comorbidities and modifiable risk factors. In addition, the metabolic stress induced by neoadjuvant therapy has been documented to frequently result in muscle atrophy and diminished functional capacity. The recognition that selected risk factors of poor postoperative outcome can be modified has prompted clinicians to identify proactive interventions to facilitate the recovery process. In this context, prehabilitation, aimed at enhancing the patients' functional capacity to enable them to withstand the physiological stress of surgery, has emerged as a promising approach. Although the term prehabilitation is not novel, the concept of optimizing patients before acute stressor or treatment has gained attention over the last decade. Nonetheless, quantifiable evidence of its effectiveness has yet to be fully demonstrated.

This study is a multicenter randomized controlled trial to assess the efficacy of personalized procedure-specific prehabilitation programs on patient-centered surgical outcomes. A total of 400 patients will be recruited by systematic screening of patients scheduled for elective surgical procedures. All patients undergoing elective major abdominal (including urological), thoracic (including breast) or gynecological cancer surgery undergoing major cancer surgery will be screened for eligibility and those who meet the inclusion/exclusion criteria will be approached for consent. Research personnel will use a web-based randomization system to assign patients (1:1 ratio) to either the prehabilitation or control arm. Study personnel will also collect data on recruitment rates, with reasons for non-enrolment.

Eligible patients will be randomly assigned to 1 of 2 treatments:

1. multimodal prehabilitation program for at least three weeks started as soon as possible before surgery;
2. standard care.

The multimodal prehabilitation program will be individualized by carefully integrating and adapting various components to meet individual needs. The program will last at least three weeks (plus maintenance in case of delayed surgery), and will incorporate exercise training, nutritional therapy, and anxiety reduction techniques. After enrollment, patients will receive initial contact from trained personnel through telemedicine. To ensure personalized care, a comprehensive assessment will be conducted to identify specific physical, nutritional, or psychological challenges. Based on this assessment, a customized intervention plan will be prescribed to achieve tailored exercise training, optimized nutrition, and effective distress-coping strategies. All patients will be reassessed the day before surgery and 30 days after surgery. Based on the data obtained during the multimodal assessment, different domains and levels of care will be prescribed, focusing on exercise training, nutrition optimization, or distress-coping techniques-or a combination of these

Inclusion Criteria:

• Adult patient (age > 18 years);
• Scheduled for elective major abdominal (including urological), thoracic (including breast) or gynecological cancer surgery;
• Signed informed consent.

Exclusion Criteria:

A) Co-morbid medical, physical, and mental conditions interfering with the ability to complete study procedures, such as:

• Acute or unstable cardio-respiratory conditions (e.g., unstable angina or symptomatic severe aortic stenosis);
• Severe/end-stage organ diseases (e.g., cardiac failure NYHA functional classes III-IV, COPD FEV1 <50% pred, end-stage kidney or liver disease);
• American Society of Anesthesiologists (ASA) physical status classes 4-5;
• Disabling orthopedic and neuromuscular disease;
• Psychosis, dementia;
• Symptomatic anemia with a hemoglobin value < 7 gr/dl.

B) Patients with both optimal functional capacity (a Duke activity status index [DASI] score > 45) and optimal nutritional status (NRS-nutrition screening tool-score < 2).