Patient Reported Outcomes Measures to Predict Pancreatic Surgery Outcomes

Patients undergoing pancreatic surgery, even treated in high-volume centers, still experience significant postoperative morbidity and full recovery after surgery takes longer than expected, delaying access to adjuvant oncologic treatment and influencing disease prognosis and patient quality of life. Patient health status at the time of surgery represents a major determinant of postoperative recovery. However, it is often evaluated with traditional measures such as performance status and comorbidity indices, which are frequently inaccurate and fail to capture the multiple dimensions of health and the patients' perspective.

Recent literature promotes the adoption of patient reported outcome measures (PROMs) to assess health across different domains (e.g. symptoms, functional status, well-being). These measures generally take the form of questionnaires and allow a more holistic understanding of patient's health and how surgery can affect different aspects of it. Thus, PROMs could be used as tools to identify patients at higher risk for postoperative adverse events or prolonged recovery.

Once higher risk profile patients have been identified, they could be referred to a for a personalized optimization program before surgery (i.e. prehabilitation). In fact, a few studies have recently enrolled high-risk patients candidate for major elective abdominal surgery in preoperative programs including multimodal interventions (e.g. physical activity, nutrition, mental exercise) resulting in decreased postoperative complications and earlier return of function. Optimizing preoperative status may reduce postoperative complications, enhance postoperative functional recovery and lead to shorter hospital stay, fewer readmissions, less time off work and improve patient perceived health-related quality of life.

Since high-risk patients benefit more from preoperative optimization strategies, and the implementation of a prehabilitation program is costly and resource-intensive, identifying patients at higher risk for postoperative poor outcomes is a key aspect. Unfortunately, there is no consensus on the best method to define these patients in the context of pancreatic surgery.

The main objective of this project is to identify specific subgroups of patients planned for pancreatic resection, at high risk for postoperative morbidity and impaired recovery through preoperative screening of physical, functional, nutritional and psychological risk factors using patient reported questionnaires and performance tests. The findings of the present study will enable researchers to identify specific risk categories to plan personalized prehabilitation programs and modulate oncologic treatment strategies in cancer patients planned for pancreatic surgery.

PRO-PANC1 is a prospective single-center observational study including consecutive patients planned for pancreatic resection to screen for physical, functional, nutritional and psychological risk factors.

Patients will be enrolled for 18 months and evaluated at the pre-admission visit (usually 1-2 weeks before surgery), at time of admission (i.e. the day before surgery), during hospital stay and trough a telephone follow-up at 30 and 90 days after surgery. Both preoperative evaluation and early postoperative assessments will be carried out by study investigators while the patients is already in the hospital. Thirty- and ninety- day follow-up will be telephone-based. Patients will be given the choice to complete the postoperative questionnaires via email, or during a phone call. A nurse who is already involved in patient follow-up after surgery will prompt patients to complete the questionnaires. There will be no additional visits or costs for patients and healthcare personnel in this activity.

PROMS (PATIENT REPORTED OUTCOMES MEASURES)

At their pre-admission visit, within 4 weeks before surgery, enrolled patients after signing the informed consent, will be asked to fill the following self-reported questionnaires:

- "Patient Reported Outcomes Measurement Information System (PROMIS) 29+2 Profile v2.1 (PROPr)", which is a flexible set of tools designed to measure self-reported physical, mental and social health and wellbeing which has been constructed and validated rigorously. It contains items from the following domains: depression, anxiety, physical function, pain interference, fatigue, sleep disturbance and ability to participate in social roles and activities.

- Duke Activity Status Index (DASI) to evaluate patient physical status.

- Risk Analysis Index (RAI-C) to evaluate frailty, comorbidities and performance status.

- Patient Health Engagement scale (PHE-s) to assess patient engagement in their process of care based on their emotional and cognitive status.

- World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) - 12 items, a generic instrument to measure health and disability covering 6 domains of functioning.

PHYSICAL EVALUATION Physical performance testing will only be performed for a subgroup of patients in accordance with the availability of the physiotherapist. Baseline physical status will be evaluated through physical performance tests assessed by a trained physiotherapist at the time of hospital admission (i.e. the day before surgery). The patient, already admitted to the surgical ward, will undergo testing with the physiotherapist in a dedicated area within the hospital (i.e. rehabilitation gym).

Performance tests will include: six-minute walk test, time up and go test, strength tests (target muscles will be the quadriceps and the handgrip muscles: in both cases a specific dynamometer will be utilized) and the Modified Iowa Level of Assistance Scale (MILAS) evaluation.

NUTRITIONAL EVALUATION A baseline nutritional assessment will be performed at the pre-admission office visit or at the time of hospital admission (i.e. the day before surgery) by a study investigator. If the patient is already hospitalized, the evaluation will be performed at the patient bedside. The evaluation will include a nutrition history (e.g. weight loss, daily intake), measurement of anthropometric parameters including body weight (kg), height (cm), and body mass index (kg/m2). The Mini Nutritional Assessment (MNA) tool will be used to screen patients for nutrition risk. Standard biochemical markers of malnutrition and inflammation, including albumin, total proteins, total lymphocyte count, and C-reactive protein will be measured in all patients as part of the routine preoperative testing.

In a subgroup of patients, in accordance with the availability of the nutritionist, multi-frequency bioelectrical impedance vector analysis (BIVA) will be used to estimate total body water (TBW), extra-cellular water (ECW), fat free mass (FFM), fat mass (FM) and phase angle (PhA). This analysis will be performed at the time of the patient pre-admission visit or when the patient is admitted to the ward.

RADIOLOGIC EVALUATION Preoperative imaging (i.e. CT scan, MRI) performed within 30 days before surgery will be reviewed by a radiologist to evaluate pancreatic parenchyma morphological parameters with a potential impact on postoperative outcomes such as pancreatic duct size, pancreatic gland diameter, and fatty infiltration.

RISK SCORE ASSESSMENT Using a digital ecosystem platform, all information will be automatically captured and stored in the pancreatic disease institutional registry, in addition to other clinical information including laboratory tests, diagnostic imaging, pathology, and clinical history. After evaluating the performance of each screening test, a practical risk scoring system for postoperative outcomes will then be developed based on regression models.

An internal validation of the predictive score will be performed using bootstrapping methods.

The newly developed score will then be released on a web page and app to allow researchers and clinicians to individually compute the score preoperatively to both inform patients of risks and to modify perioperative treatment strategies.

SAMPLE SIZE AND ANALYSIS The number of pancreatic resections at the San Raffaele Hospital Division of Pancreatic Surgery is around 330 per year. The rate of patients at high risk to develop postoperative complication is assumed to be about 30%. Considering an overall rate of patients' refusal/not satisfying inclusion criteria of 10%, 445 patients are expected to be enrolled in 18 months, to have a hypothetical overall number of high risk patients of 148.

A score will be calculated for each test and questionnaire. After evaluating the performance of each screening test, a practical risk scoring system for postoperative outcomes will then be developed based on regression models.