INPACT: Implementation of Nutritional Support and Physical Activity During Cancer Treatment

INPACT (Implementation of Nutritional Support and Physical Activity during Cancer Treatment) is a prospective randomized controlled trial investigating the role of multimodal prehabilitation in patients undergoing oncological liver resection for primary liver cancer or liver metastases.

Patients undergoing liver surgery frequently present with impaired physical fitness, nutritional deficits, reduced physiological reserve, and the consequences of previous cancer treatments. These factors may negatively affect their ability to tolerate major surgery and recover adequately afterwards. Functional capacity has been identified as an important indicator of physiological reserve and has been associated with postoperative outcomes in surgical oncology populations.

Prehabilitation aims to optimize patients before surgery by improving their physical condition and nutritional status during the period between diagnosis and surgery. This interval represents a potential window of opportunity to enhance a patient's resilience to surgical stress. Previous studies have shown that multimodal prehabilitation programs combining exercise training, nutritional support, and psychological or respiratory interventions may improve preoperative functional capacity and patient wellbeing. However, evidence remains limited in patients undergoing oncological liver resection, particularly in highly optimized healthcare settings where enhanced recovery pathways and minimally invasive surgical techniques are already routinely implemented.

The INPACT study evaluates a multimodal program consisting of structured exercise training, nutritional support, and breathing exercises initiated before surgery and continued during postoperative rehabilitation. The study aims to determine whether this approach can improve patients' functional capacity before surgery and contribute to improved recovery following liver resection.

In addition to evaluating the direct effects of prehabilitation on functional capacity, the study will provide further insight into nutritional status, patient-reported outcomes, postoperative recovery, healthcare utilization, biological markers of inflammation and recovery, and long-term oncological outcomes. The results may contribute to the development and implementation of evidence-based prehabilitation programs for patients undergoing major oncological surgery.

Participants in the intervention group will follow a structured multimodal prehabilitation and rehabilitation program consisting of physical exercise, nutritional support with protein supplementation, and daily breathing exercises. The prehabilitation program starts approximately four weeks before surgery. After surgery, the program is gradually resumed during the rehabilitation phase according to the patient's recovery and individual capacity.

Behavioral: Multimodal Prehabilitation and Rehabilitation Program

Participants in the control group will receive usual care. Patients are encouraged to remain physically active and receive general advice regarding physical activity and healthy nutrition, but no individualized structured exercise and nutritional program is prescribed or monitored.

Other: Usual Care

The multimodal program combines physical exercise, nutritional support, and breathing exercises. During the approximately four-week preoperative period, participants perform two supervised in-hospital exercise sessions per week and three home-based cycling sessions per week. Participants also receive nutritional support including daily protein supplementation and perform daily breathing exercises using a Moonbird device. After surgery, the program is gradually resumed during the rehabilitation phase according to the patient's postoperative recovery and individual capacity.

Participants receive usual care for patients undergoing oncologic liver surgery. As part of usual care, patients are encouraged to remain physically active and receive general advice regarding physical activity and healthy nutrition. No individualized structured prehabilitation and rehabilitation program is prescribed or monitored.

Plazo: 4 weeks after baseline, prior to surgery

Functional capacity will be assessed using the 6-Minute Walk Test (6MWT). The distance walked during 6 minutes will be recorded in meters. The 6MWT distance at the preoperative assessment will be compared between the multimodal prehabilitation group and the usual care group.

Plazo: From baseline to 4 weeks after baseline and 6 weeks after surgery

Change in distance walked during the 6-Minute Walk Test (6MWT), expressed in meters, will be assessed and compared between the intervention and usual care groups.

Plazo: Baseline, 4 weeks after baseline, and 6 weeks after surgery

Cardiorespiratory fitness will be assessed using cardiopulmonary exercise testing (CPET). Maximum oxygen uptake (VO2max) will be compared between the intervention and usual care groups.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Upper-body muscle strength will be assessed using a handgrip strength test and expressed in kilograms. Results will be compared between groups over time.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Lower-extremity muscle strength will be assessed using Biodex dynamometry and compared between the intervention and usual care groups over time.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Lower-extremity muscle performance will be assessed using the single-leg calf raise test and compared between groups over time.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Functional lower-extremity performance will be assessed using the Sit-to-Stand Test. Participants are instructed to stand up and sit down 10 times as quickly as possible from a chair without using their hands. The outcome measure is the time required to complete 10 repetitions, expressed in seconds. Scores range from 0 seconds to no predefined maximum value. Lower completion times indicate better lower-extremity functional performance, whereas higher completion times indicate worse functional performance.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Health-related quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Scores are linearly transformed to a 0-100 scale according to the EORTC scoring manual. For the Global Health Status/Quality of Life scale and functional scales, higher scores indicate better quality of life and functioning. For symptom scales and single-item symptom measures, higher scores indicate greater symptom burden and worse quality of life.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Health-related quality of life and general health status will be assessed using the EuroQol 5-Dimension Questionnaire (EQ-5D). The EQ-5D descriptive system generates an index score ranging from less than 0 (health states considered worse than death) to 1.0 (perfect health), with higher scores indicating better health-related quality of life. The EQ-5D also includes a Visual Analogue Scale (EQ VAS), ranging from 0 to 100, where higher scores indicate better perceived health status.

Plazo: within 90 days after surgery

Postoperative morbidity will be assessed using the Comprehensive Complication Index (CCI), which summarizes all postoperative complications weighted according to their severity. The CCI score ranges from 0 to 100, where 0 indicates no postoperative complications and 100 indicates death. Higher scores indicate a greater overall burden of postoperative complications and therefore a worse postoperative outcome.

Plazo: From the date of surgery until hospital discharge, assessed up to 90 days after surgery

Length of postoperative hospital stay will be recorded as the number of days from the date of surgery until discharge from the hospital and compared between the intervention and usual care groups.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Nutritional status will be assessed using the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF). The total PG-SGA SF score ranges from 0 to 36, with higher scores indicating a greater risk of malnutrition and a worse nutritional status. Lower scores indicate a better nutritional status.

Plazo: From baseline until 6 weeks after surgery

Compliance with the prescribed nutritional supplementation will be assessed using the patient diary in participants allocated to the intervention group.

Plazo: From baseline until 6 weeks after surgery

Safety will be assessed by recording the total number of adverse events (AEs) and serious adverse events (SAEs), as well as the proportion of participants experiencing an AE or SAE.

Plazo: Throughout the prehabilitation and rehabilitation program, up to 6 weeks after surgery

Adherence to the exercise program will be assessed using the patient exercise diary and expressed as the percentage of prescribed exercise sessions completed. Perceived exertion during training will be assessed using the Borg Rating of Perceived Exertion Scale. The Borg Rating of Perceived Exertion Scale ranges from 6 to 20, with higher scores indicating greater perceived exercise intensity and exertion.

Plazo: 3 years after surgery

Disease-free survival is defined as the time from surgery to the first occurrence of disease recurrence. Participants without recurrence will be censored at the time of last follow-up.

Plazo: 3 years after surgery

Overall survival is defined as the time from surgery to death. Participants who are alive will be censored at the time of last follow-up.

Plazo: Through study completion, up to 6 weeks after surgery

An exploratory health-economic analysis will be performed using EQ-5D utility scores to estimate Quality-Adjusted Life Years (QALYs). The health-economic impact of the multimodal prehabilitation and rehabilitation program will be evaluated by comparing QALYs and healthcare resource utilization between the intervention and usual care groups.

Plazo: At or after 6 weeks after surgery

Participants' perceptions and experiences regarding the breathing exercises using the Moonbird device will be explored through semi-structured interviews. Responses will undergo qualitative thematic analysis. This is a qualitative outcome measure and no numerical score will be calculated.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Serum C-reactive protein (CRP) concentration (mg/L) will be measured and compared between groups. Higher values indicate a greater systemic inflammatory response.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

White blood cell count (WBC) (×10\^9/L) be measured and compared between groups. Higher values indicate a greater inflammatory response.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Plasma interleukin-6 (IL-6) (pg/mL) will be measured and compared between groups. Higher values indicate a greater inflammatory response.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Plasma interleukin-8 (IL-8) concentration (pg/mL) will be measured and compared between groups.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Plasma interleukin-10 (IL-10) concentration (pg/mL) will be measured and compared between groups.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Tumor Necrosis Factor Alpha (TNF-α) concentration (pg/mL) will be measured and compared between groups.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Serum troponin concentration (ng/L) will be measured and compared between groups.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Serum ferritin concentration (µg/L) will be measured and compared between groups.

Plazo: Baseline, 4 weeks after baseline, 2 weeks after surgery, and 6 weeks after surgery

Serum albumin concentration (g/L) will be measured and compared between groups. Lower values may indicate impaired nutritional status.

INPACT: Implementation of Nutritional Support and Physical Activity During Cancer Treatment