Rationale: The complication rate after pancreatic resection is high, especially in elderly and physically unfit patients. Aerobic capacity, as indicated by the ventilatory anaerobic threshold (VAT) assessed by a cardiopulmonary exercise test (CPET), can be used to identify high-risk patients. Previous studies have demonstrated that exercise prehabilitation can increase aerobic capacity in patients scheduled for intra-abdominal surgery, subsequently leading to better treatment outcomes. There is limited evidence on the feasibility of a (partly) supervised home-based prehabilitation program in patients scheduled for pancreatic resection.

Objective: The primary objective of this study is to assess the feasibility of a four-week supervised home-based prehabilitation program in patients scheduled for elective pancreatic resection. Secondary objectives are to evaluate individual responses to prehabilitation on a number of secondary endpoints (no cause-effect relationship to be established).

Study design: This study is a pragmatic multicenter study with a pretest-posttest design. It will take place at the Maastricht University Medical Center+ and University Medical Center Groningen in the Netherlands, and at the 'Città della Salute e della Scienza' in Torino, Italy.

Study population: Patients planned for elective resection of a pancreatic tumor will be screened for potential eligibility. High-risk patients, identified by an oxygen uptake (VO2) at VAT ≤13 ml/kg/min and/or VO2peak ≤18 ml/kg/min, will be asked to participate.

Intervention: A total of 45 patients will participate in a four-week (partly) supervised home-based personalized exercise training program before surgery (12 sessions in total). An advanced cycle ergometer (Lode Corival, Lode BV, Groningen, the Netherlands) will be delivered at the patient's home. Three weekly sessions of high-intensity interval training on the cycle will be combined with functional task exercise training. A trained physical therapist will visit the patient at least weekly to monitor progress.

Main study parameters: The main study parameter is feasibility of the (partly) supervised home-based prehabilitation program. Hereto participation rate and reasons for non-participation will be evaluated. In participating patients, adherence/compliance, dropout rate, reasons for dropout, adverse events, patient motivation, and patient and therapist appreciation will be assessed throughout the program.

Secondary endpoints: Secondary endpoints before and after prehabilitation include aerobic capacity, muscle function, body composition, functional mobility, immune system function, perceived fatigue, quality of life, and sarcopenia. Data on patient characteristics, neoadjuvant therapy, surgical procedure, and postoperative outcomes will also be collected for explorative purposes.

As the aging population grows, the incidence of malignancies of the pancreas will also rise. Surgery is an important treatment modality; at the same time, it is a challenge (allostatic load) for the patient's homeostasis. Age- and disease-related psychophysiological changes and comorbidities affect tolerance to surgery (adaptive capacity). Prehabilitation may increase a patient's ability to cope with surgical-induced allostatic load by improving the capacity and functioning of the respiratory, cardiovascular, and/or musculoskeletal systems, and therefore lower the risk of postoperative morbidity and mortality.

About 28% of patients undergoing pancreatic resection developed a major complication (Clavien-Dindo grade III or higher), and 3.2% deceased in-hospital in the Netherlands between 2014 and 2017. Older patients, especially physically unfit patients, are more prone to complications.

Preoperative aerobic capacity has been found to have a consistent relationship with postoperative outcome in major elective intra-abdominal surgery, such as pancreatic resection. Previous studies consistently indicated that an oxygen uptake (VO2) at the ventilatory anaerobic threshold (VAT) <11mL/kg/min and/or a VO2 at peak exercise (VO2peak) <18mL/kg/min, as determined during a cardiopulmonary exercise test (CPET), are cut-off points to identify patients that have a higher risk for postoperative morbidity and mortality. Exercise prehabilitation has been reported to be able to preoperatively increase the physical fitness of patients scheduled for elective intra-abdominal surgery, of which high-risk patients will benefit the most. Most prehabilitation programs were carried out under supervision in an outpatient clinic. Often however, patients are not able or willing to participate, for example because of travelling issues or because it is becoming 'too much'. Home-based programs are often unsupervised and lack the ability to monitor adherence of the patient, and therefore might lack effectiveness.

A personalized exercise program in a home-based setting might enhance the participation rate, motivation, and adherence of patients. This has proven to be the preferred method for previous prehabilitation programs. Although several studies investigated the effects of exercise prehabilitation before pancreatic resection and reported positive effects on preoperative physical fitness and postoperative morbidity, there is limited evidence addressing the feasibility and effectiveness of (partly) supervised home-based prehabilitation in these populations. Moreover, effectiveness has not been evaluated using sophisticated outcome measures.

In a recent study in patients planned for liver or pancreatic surgery the adherence rate of a semi-supervised home-based training program was 83%. Furthermore, it led to an increase in VO2 at the VAT of 17.8% and VO2peak of 17.2%. This leads to the hypothesis that a partly supervised home-based prehabilitation program is feasible in a high risk-group. To test this hypothesis further the study will investigate the feasibility of a (partly) supervised prehabilitation program and will focus on patients undergoing pancreatic resection.

Objectives:

The primary objective of the study is to assess feasibility of a four-week (partly) supervised home-based prehabilitation program in patients scheduled for elective pancreatic resection. This will be measured using participation rate, reasons for non-participation, adherence/compliance, dropout rate, reasons for dropout, adverse events, patient motivation, and patient and therapist appreciation.

Secondary objectives are to evaluate individual responses to prehabilitation on the secondary study parameters. Data on patient characteristics, neoadjuvant therapy, surgical procedure, and postoperative outcomes will also be collected for explorative purposes.

Study design:

This study is a pragmatic multicenter study with a pretest-posttest design. It will take place at the Maastricht University Medical Center+ and University Medical Center Groningen in the Netherlands, as well as at the 'Città della Salute e della Scienza' in Torino, Italy.

Patients planned for elective pancreatic resection will be screened for CPET by a trained oncology nurse specialist. A trained medical physiologist will perform the CPET. Patients are eligible for the study if they have an oxygen uptake (VO2) at the VAT of ≤13 ml/kg/min and/or VO2peak ≤18 ml/kg/min. Potential candidates will be given full details of the study and invited to participate. If patients give permission, they will be contacted by an investigator who provides extensive information about the study.

If patients sign informed consent, they will fill out the baseline questionnaires (perceived fatigue, quality of life, and sarcopenia), and undergo baseline testing. Baseline tests include body composition, functional mobility, questionnaires, and immune system function.

After baseline assessment an advanced cycle ergometer (Lode Corival Home+, Lode BV, Groningen, the Netherlands) will be delivered to the patient's home. A trained community physical therapist will visit the patient at home to explain correct use of the ergometer and to (partly) supervise training program. A steep ramp test will be carried out by the physical therapist. The high-intensity interval exercise training program on the cycle ergometer will be personalized based on a weekly supervised steep ramp test. Every training session on the ergometer will take 30 minutes. Next to training at the cycle ergometer, patients will complete 15 minutes of functional exercises (e.g., sit-to-stand exercises, stair-climbing, cycling, walking). The patient will be asked to perform different types of exercises, a total of 15 exercises of about 30 seconds, with 30 seconds of rest in between. The physical therapist will explain the functional exercises and supervise the patient in the first week. Based on the patient's progress in muscle function and functional mobility, which will be tested weekly using the 30-second chair stand test at the patient's home, the physical therapist will adjust the exercises weekly. Patients will be asked to train three times a week for four weeks. In the first week, the physical therapist visits three times, whereas the patient will be visited once a week in week 2, 3, and 4.

After the prehabilitation program, patient and therapist will fill out an appreciation questionnaire. The other questionnaires will be filled in again. Also, tests on aerobic capacity, body composition, functional mobility, and immune system function will be repeated.

Aerobic capacity A maximal CPET will be performed using a calibrated electronically braked cycle. Patients with contraindications for CPET due to cardiorespiratory comorbidities will not be able to participate in the study. The patient will be fitted with an electrocardiogram, as well as a calibrated respiratory gas analysis system, that will calculate breath-by-breath VO2, carbon dioxide production (VCO2), and minute ventilation. Blood pressure and peripheral oxygen saturation will be monitored. After two minutes of rest measurements, the patient starts cycling unloaded for 2 minutes. Thereafter, depending on the patient's physical fitness, the work rate will be linearly incremented with a 5, 10, 15, or 20W/min ramp protocol to ensure a test duration between eight and twelve minutes. Patients will be instructed to maintain a pedaling frequency of 80/min. Test effort will be considered maximal when the patient shows objective (heart rate at peak exercise >95% of predicted and/or a respiratory exchange ratio at peak exercise >1.10) and subjective (unsteady biking, sweating, facial flushing, inability to continue despite encouragement) signs of maximal effort. Perceived exertion before and directly after CPET, using a ten-point visual analog scale, will be asked. CPET interpretation will be performed by a trained and experienced medical physiologist. The ventilatory anaerobic threshold is defined as the point at which the ventilatory equivalent for oxygen and the partial end-tidal oxygen tension reached a minimum and thereafter began to rise in a consistent manner, coinciding with an unchanged ventilatory equivalent for carbon dioxide and partial end-tidal carbon dioxide tension. If this method appeared to provide uncertain results, the V-slope method will be used.

A steep ramp test will be performed on a weekly base at the patient's home under supervision of a physical therapist to assess and monitor aerobic fitness. The advanced cycle ergometer will be used for the steep ramp test. The patient will be fitted a heart rate belt around the chest (Polar Elektro Oy, Kempele, Finland) during the test. After three minutes of rest the test will start and the work rate will be increased by a constant increment of 10 W every 10 seconds in a ramp like manner. Test duration will be four to seven minutes. The pedaling frequency should be kept constant between 60 and 80 revolutions per minute. Peak exercise is the point at which there is a sustained drop in pedaling frequency from 60 revolutions per minute, despite verbal encouragement. Data will be stored for further use. A ten-point VAS will be used to ask the level of perceived exertion. The attained peak work rate (WRpeak) will be used to adjust the training protocol for the upcoming week.

Muscle function Muscle function measurement will be measured for patients in Città della Salute e della Scienza. Knee extensors torque will be recorded using an isokinetic device under isometric sub-maximal and maximal voluntary contractions. The rate of torque development will be calculated for each contraction at different submaximal amplitudes (from 20% to 80% of maximal voluntary torque). Lastly, to measure muscle fatigability, participants will perform a submaximal isometric contraction at 70% of maximal voluntary torque until task failure (the time failure typically occurs within 60 s). High-density surface electromyographic (HDEMG) signals will be recorded from the vastus lateralis and medialis muscle during all muscle contractions to record muscle fiber conduction velocity. Muscle fiber conduction velocity is an important physiological variable associated to the qualities of skeletal muscles. Furthermore, HDEMG signals will be decomposed to identify and assess the activity of a large number of motor units over a wide range of torques, providing direct evidence on the strategies used by the central nervous system to control muscle torque.

Body composition The patient's body mass and body height will be measured pre-, and post-intervention. Body mass will be measured weekly at the patient's home. To assess skeletal muscle mass and quality a single slice of the patient's abdominal CT-scan will be selected at the level of the third lumbar vertebra (L3). Scans will be analyzed using an automated segmentation system developed and validated at Maastricht University. Skeletal muscle, visceral adipose tissue, and subcutaneous adipose tissue areas will be normalized for the patient's body height to calculate the L3 index in cm2/m2. Skeletal muscle radiation attenuation will be assessed by calculating the average Hounsfield Units value of skeletal muscle mass.

Functional mobility Functional mobility will be assessed in all patients using the 30-second chair-stand test pre- and post-intervention at the hospital, and weekly at the patient's home. Additionally, a 2-minute walk test will be performed pre- and post-intervention. The 30-second chair-stand test evaluates a combination of functional mobility, balance, and lower leg muscle strength. The primary outcome is the repetitions of standing up from a sitting position and sitting back down with crossed arms within 30 seconds. The 2-minute walk test records the distance in meters that is walked within two minutes, with a walking aid if necessary.

Immunological phenotyping Given the evidence that exercise leads to changes in the innate and adaptive immune system, blood samples will be drawn pre- and post-intervention. Levels of interleukin 6, interleukin 8, and interleukin 10, as well as C-reactive protein, and tumor necrosis factor-α will be measured by multiplex analysis. Blood samples will be centrifuged, and plasma will be stored in aliquots at -80 °C until assayed for future analysis. Blood samples will be stored, for a maximum of ten years, in the biobank of the participating hospital. Future analysis must be in line with the aims of our current research; if not, informed consent must be obtained.

Questionnaires Patients will fill out the multidimensional fatigue index, a self-reporting questionnaire with 20 propositions about different dimensions and consequences of fatigue. A higher score means a higher level of perceived fatigue. Patients will also fill out the European Organisation for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30), a questionnaire with 30 items in four domains developed to assess the quality of life in cancer patients. A difference to baseline of 10 points can be considered clinically relevant. The SARC-F, a five-item questionnaire on the consequences of sarcopenia will also be filled out by the patients.

Preoperative patient characteristics:

Relevant demographic data (e.g., age and sex of participants), diagnosis, American Society of Anesthesiologists score, and Charlson comorbidity index will be collected preoperatively.

Postoperative care Details on type of surgery and intraoperative outcomes will also be collected. According to standard of care, all patients will receive postoperative physical therapy after surgery in all three participating centers. Postoperative complications will be recorded for 30 days and scored according to the Clavien-Dindo classification. The 30-day readmission rate will also be recorded. Surgical outcomes will be obtained from the electronic patient record system and from patient's physical examination on the ward.

Inclusion Criteria:

• An oxygen uptake (VO2) at the ventilatory anaerobic threshold (VAT) ≤13 ml/kg/min and/or an VO2peak ≤18 ml/kg/min assessed using cardiopulmonary exercise testing
• Age ≥18 years
• Scheduled for elective pancreatic resection at Maastricht UMC+, at the University Medical Center Groningen, or the Citta della Salute e della Scienza Hospital in Torino
• Willing to participate in the home-based prehabilitation program
• Providing informed consent to participate

Exclusion Criteria:

• Patients requiring acute (emergency) surgery;
• Patients undergoing surgery in another hospital;
• Patients not living within the catchment area of the hospital (<30 minutes);
• Patients not capable of cycling on a cycle ergometer;
• Patients with contraindications for physical exercise training;
• Unable to cooperate with the testing procedures (e.g., insufficient understanding of the Dutch or Italian language at the Maastricht University Medical Center+, at the University Medical Center Groningen, or at the 'Città della Salute e della Scienza' Hospital in Torino, respectively);
• No physical therapist with the right education (functional task training/home based prehabilitation) available in the living area of the patient.