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Prehabilitation in Pancreatic Surgery (PIPS)

Primary Purpose

Pancreatic Cancer, Periampullary Cancer, Frailty Syndrome

Status
Recruiting
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
Multimodal Prehabilitation
Sponsored by
IRCCS San Raffaele
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Pancreatic Cancer focused on measuring Prehabilitation, Physical function, Nutritional status

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Age ≥ 18 years Indication for curative resection for pancreatic or periampullary cancer Signed Informed consent Exclusion Criteria: Metastatic or unresectable disease found preoperatively Comorbidities contraindicating prehabilitation regimen (exercise and nutritional intervention) such as orthopedic, cognitive disabilities, chronic renal failure (dialysis or creatinine >250 mmol) ASA score 4-5 Pregnancy Illiteracy (inability to read and understand Italian language)

Sites / Locations

  • San Raffaele HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Multimodal Prehabilitation

Usual care

Arm Description

A 4-week long preoperative intervention including exercise training, nutritional therapy and anxiety reduction techniques

Usual preoperative care

Outcomes

Primary Outcome Measures

Comprehensive Complication Index (CCI)
Postoperative complications occurring during the index admission or in a subsequent readmission, when related to surgery, will be recorded up to 90 days after surgery and graded by severity using the Dindo-Clavien classification and the Comprehensive Complication index (CCI). The Dindo-Clavien system grades complications according to the therapy needed for treatment: Grade I, are complications that require bedside management; Grade II, are complications that require pharmacologic treatment; Grade III, are complications that require surgical or radiologic intervention and; Grade IV, are complications that require intensive care treatment. Dindo-Clavien Grade III or above are considered severe postoperative complications. The CCI, derived from the Dindo-Clavien system, is a validated metric summarizing the complete spectrum of complications that occurred and their severity in a single score ranging from 0 to 100.
Functional capacity
Functional capacity will be measured by the 6-minute walking test and compared between groups on the day before surgery, at 30-60-90 days after surgery.
Pro-inflammatory cytokines
Circulating levels of tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), interferon gamma (IFN-γ), and macrophage inflammatory protein α (MIP-1α) will be assessed by luminex immunoassays and compared between groups at baseline and one day before surgery.
Cancer cachexia related factors
Enzyme-linked immunosorbent assay (ELISA) will be used to measure the serum levels of the following cachexia-related factors: Activin A, carnosine dipeptidase-1 and zinc-α2-glycoprotein. The circulating levels will be compared between groups at baseline and one day before surgery.

Secondary Outcome Measures

Time to patient functional recovery (TFR)
TFR will be measured by subtracting the date of surgery from the date when participants achieve standardized criteria (tolerance of oral intake, recovery of lower gastrointestinal function, adequate pain control on oral analgesia, ability to mobilize and self-care and no evidence of untreated medical problems)
Lenght of stay (LOS)
LOS will be measured by subtracting the date of surgery from the date of discharge
Bioimpedance analysis (BIA) derived body composition
Extracellular and intracellular water as % of total body water, fat mass (FM) as % of body weight, skeletal muscle mass (SK) as % of fat-free mass (FFM), phase angle (PA°) and intramuscular fat mass (IMAT) will be assessed using bioimpedance analysis and compared between groups at baseline, on the day before surgery, at 30, 60, 90 days after surgery.
Computed tomography derived body composition
Skeletal muscle area (cm2), visceral fat area (cm2) and intra-muscular fat infiltration will be measured at the level of the third lumbar vertebra using preoperative CT scan imaging and compared between groups at baseline and on the day before surgery.
Generic health-related quality of life
Generic health-related quality of life will be measured using the Patient Reported Outcome Measure Information System (PROMIS)-29+2 Profile v2.1 (PROPr), a questionnaire designed to measure self-reported physical, mental and social health and wellbeing. Questions are ranked on a 5-point Likert Scale. Each domain (Depression, Anxiety, Physical Function, Pain Interference, Fatigue, Sleep Disturbance, and Ability to Participate in Social Roles and Activities) is scored from 4 to 20. For negative domains (i.e. Depression), lower scores represent better outcomes, higher scores represent worse outcomes. For positive domains (i.e. Physical function), lower scores represent worse outcomes, higher scores represent better outcomes.
Disease-specific health-related quality of life
Disease-specific health-related quality of life will be measured using the EORTC QLQ C30 and PAN-26 questionnaires, which have been validated to assess quality of life in cancer patients. EORTC QLQ C30 is a generic core questionnaire that measures health-related quality of life in patients with any cancer. It comprises a total of 30 items on 15 quality of life scales. EORTC QLQ PAN-26, is the pancreatic cancer module that supplements the EORTC QLQ-C30. The module comprises 26 questions that share the 4-level ordinal response options with QLQ-C30.

Full Information

First Posted
August 25, 2023
Last Updated
September 29, 2023
Sponsor
IRCCS San Raffaele
Collaborators
Ministry of Health, Italy
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1. Study Identification

Unique Protocol Identification Number
NCT06069297
Brief Title
Prehabilitation in Pancreatic Surgery
Acronym
PIPS
Official Title
Multimodal Prehabilitation in Localized Pancreatic Cancer Patients Undergoing Surgery: a Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 14, 2023 (Actual)
Primary Completion Date
July 13, 2025 (Anticipated)
Study Completion Date
July 13, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
IRCCS San Raffaele
Collaborators
Ministry of Health, Italy

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
In patients with pancreatic cancer, older age, multiple comorbidities, frailty, malnutrition and poor functional status are common, especially in individuals receiving neoadjuvant chemotherapy. These characteristics represent potentially modifiable risk factors for poor postoperative outcomes. The goal of this clinical randomized controlled trial is to evaluate the extent to which a four-week multimodal prehabilitation program impacts on postoperative morbidity, functional and nutritional status and health-related quality of life in patients with localized pancreatic or periampullary cancer scheduled for curative surgery. In addition, the impact of prehabilitation on circulating sarcopenia and cancer cachexia biomarkers in PDAC patients will be explored. Included patients will be randomized (ratio 1:1) and allocated either to the intervention group (Multimodal Prehabilitation), which will receive prehabilitation, or to the control group, which will receive no prehabilitation.
Detailed Description
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with 5-year survival around 10%. The combination of surgical resection and chemotherapy represents the most efficacious therapy to improve prognosis for localized PDAC. Patients with pancreatic cancer are generally older adults in whom frailty, sarcopenia and/or malnutrition are common. These features have all been associated with poor postoperative complications and reduced survival. Therefore, the preoperative period and the time window after the end of chemotherapy constitute a unique opportunity to condition modifiable risk factors, improve functional capacity and address deficiencies in physiologic reserves, which might otherwise preclude surgery or significantly impede recovery. Prehabilitation is defined as the process of enhancing patients' functional capacity to enable them to withstand a stressful event. Multimodal prehabilitation, which defines a program including physical, nutritional, and psychological interventions, has shown the most promising results in gastrointestinal cancer surgery. However, no high-quality evidence is currently available for PDAC patients. STUDY OBJECTIVES: Primary Aim: to evaluate if a 4-week multimodal structured prehabilitation program including physical exercise, nutritional and psychological interventions will result in a clinically significant increase in functional capacity, nutritional status and patient-reported health-related quality of life before surgery when compared to a usual care control group, and evaluate the extent to which multimodal prehabilitation impacts on postoperative morbidity and patient recovery compared to usual care. Secondary Aim: to analyze whether multimodal prehabilitation may impact on the concentration and activity of a panel of specific circulating molecules involved in cancer cachexia and skeletal muscle wasting, chronic inflammation. STUDY DESIGN: A randomized controlled trial will be performed in PDAC and periampullary cancer patients with indication to upfront pancreatic resection or pancreatic resection after completion of neoadjuvant chemotherapy. Included patients will be randomized (ratio 1:1) and allocated either to the intervention group (Multimodal Prehabilitation), which will receive prehabilitation, or to the control group, which will receive no prehabilitation. All patients will receive the same intraoperative and postoperative care based on an established enhanced recovery pathway. Inclusion and exclusion criteria as stated in the eligibility section will be assessed and patients consented to participate in the study if they fulfill inclusion criteria. RANDOMIZATION AND BLINDING: The trial is designed as a randomized, controlled, assessor-blind trial. Participants will be randomly assigned to either multimodal prehabilitation or no prehabilitation group with a 1:1 allocation using permuted blocks of random sizes. Randomization will be stratified by neoadjuvant chemotherapy and tumor location (periampullary or pancreatic head-neck cancer versus pancreatic body-tail cancer). Allocation concealment will be ensured as the randomization code will not be released until the patient has been recruited into the trial, which takes place after all baseline measurements have been completed and informed consent has been signed. PREOPERATIVE ASSESSMENT: All patients will be evaluated at baseline (T0) by: Patient medical history including comorbidities, presence of signs or symptoms, and frailty assessment using Fried's criteria. Physical performance tests including functional walking capacity (six-minute walk test), timed up and go test, gait speed assessment and handgrip strength test. Assessment of nutritional status by nutrition history, measurement of anthropometric parameters, completion of nutritional screening questionnaires (MNA, PG-SGA), and standard biochemical markers of malnutrition and inflammation including albumin, prealbumin, total lymphocyte count, and C-reactive protein. Body composition measurements assessed using two methods: multi-frequency bioelectrical impedance analysis (BIA) providing data on extracellular and intracellular water as % of total body water, fat mass (FM) as % of body weight, skeletal muscle mass (SK) as % of fat-free mass (FFM) and phase angle (PA°), intramuscular fat mass (IMAT), basal metabolic rate (BMR) energy expenditure and hypotalamic- pituitary- adrenal axis index (HPA); CT scan image analysis (using preoperative cancer staging and restaging chest and abdomen CT scans) performing automated imaging segmentation using Data Analysis Facilitation Suite (DAFS) by Voronoi Health Analytics, Inc. (https://www.voronoihealthanalytics.com/). Overall activity of the autonomic nervous system and heart rate variability through photoplethysmography (PPG) stress flow test. This exam allows the study and direct monitoring of all functions of the autonomic nervous system and the related process of biofeedback. Patient reported outcome questionnaires to measure health related quality of life and patient engagement. The following questionnaires will be administered Patient reported outcome measurement information system (PROMIS)29+2, a validated questionnaire designed to measure self-reported physical, mental and social health and wellbeing. Duke activity status index (DASI), a brief questionnaire designed to assess physical function by answering whether they are able to perform 12 listed activities of various intensity (i.e., ambulation, household tasks and leisure activities). EORTC QLQ C30, a generic core questionnaire that measures health-related quality of life in patients with any cancer. EORTC QLQ PAN-26, the pancreatic cancer module that supplements the EORTC QLQ-C30. - Medically unexplained symptoms (MUS) questionnaire investigates the presence of vague symptoms to describe a cluster of manifestations such us chronic fatigue, sleep or appetite disorders, irritable bowel or constipation, tone or mood disorders, non-specific pain syndromes which are sometimes underestimated. Patient activation measures (PAM)-13, a 13-item questionnaire measuring patients' self-reported knowledge, motivation, and skills for self-management. Hospital Anxiety and Depression Scale (HADS) questionnaire to measure anxiety and depression. Blood sample analysis of circulating cytokines, chemokines, interferons, colony stimulating factors, main hormones involved in metabolic homeostasis and cancer cachexia. Four weeks after baseline assessment, on the day before surgery (T1), all patients will repeat all evaluations previously performed at T0. STUDY INTERVENTION Included patients will be randomized (ratio 1:1) and allocated either to the intervention group (Multimodal Prehabilitation), which will receive prehabilitation, or to the control group, which will receive no prehabilitation. Patients in the control group will be treated according to usual standard of care and will be given informative material regarding healthy lifestyle and how to best prepare for surgery. The intervention will consist of a multimodal prehabilitation, a 4-week long preoperative intervention including exercise training, nutritional therapy and anxiety reducing techniques, aimed at preventing or attenuating surgery-driven functional decline as described in the arms and intervention section. VISITS AND FOLLOW-UP: Throughout patient hospital stay, postoperative outcomes including complications, will be recorded. After discharge, patients will be followed-up as routine care by phone calls from a nurse navigator. At 30 days (T2), 60 (T3) and 90 days (T4) after surgery, patient recovery will be re-evaluated during scheduled outpatient visits. Patients will be assessed for: Functional capacity by the 6MWT and other physical performance tests including TUG, gait speed assessment and handgrip strength test. Nutritional status by measurement of anthropometric parameters including body weight (kg), height (cm), and body mass index (kg/m2) Body composition by multi-frequency bioelectrical impedance vector analysis (BIVA) Health related quality of life through patient reported outcome questionnaires STATISTICAL METHODS: The analysis will be conducted on intention to treat basis. Continuous data will be presented as medians (interquartile range) or means (standard deviation); categorical data as absolute values and percentages. Dichotomous data will be compared by two tailed chi-square test or Fisher's exact test. Continuous measurements will be compared between groups using the Mann-Whitney U test or T-Student test for normally distributed data. Baseline characteristics of the two groups will be reported in order to confirm the adequacy of the randomization process. CCI will be described as the mean plus the standard deviation (SD) or median plus interquartile range (IQR), depending on its distribution. To analyze the difference in terms of CCI between groups t-student Test will be adopted in case of normal distribution, otherwise Mann-Whitney U test will be used. 6MWT as a functional capacity measure is a continuous variable. This data will be described as means, plus SD, at each time point. To accommodate the repeat measurements for individuals, a generalized linear mixed model will be used to compare results from both arms. Pre-planned subgroup analysis in patients with higher risk features at enrollment (e.g., malnourished, sarcopenic obese, low physical function, frail) will also be performed to evaluate the effectiveness of prehabilitation in this population. Statistical analysis will be performed using STATA® version 16 software. SAMPLE SIZE: The size of the sample was calculated on the basis of the primary aim of the study: the reduction of postoperative complications as determined with the CCI score at 90 days after surgery. In our preliminary data on PDAC surgical population, the mean (SD) CCI is 21.0 (SD 16), and the target reduction is 30%. An alpha of 0.05 and power of 0.80 (two-sided test) was used. Expecting a dropout rate of 10%, 113 patients are needed in each arm for an overall sample of 226 patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pancreatic Cancer, Periampullary Cancer, Frailty Syndrome, Malnutrition, Perioperative/Postoperative Complications
Keywords
Prehabilitation, Physical function, Nutritional status

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Enrolled patients will be randomized (ratio 1:1) and allocated either to the intervention group (Multimodal Prehabilitation) or to the usual care group
Masking
Outcomes Assessor
Masking Description
The trial is designed as a randomized, controlled, assessor-blind trial
Allocation
Randomized
Enrollment
226 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Multimodal Prehabilitation
Arm Type
Experimental
Arm Description
A 4-week long preoperative intervention including exercise training, nutritional therapy and anxiety reduction techniques
Arm Title
Usual care
Arm Type
No Intervention
Arm Description
Usual preoperative care
Intervention Type
Other
Intervention Name(s)
Multimodal Prehabilitation
Intervention Description
Preoperative multimodal intervention including exercise training, nutritional therapy and anxiety reducing techniques, aimed at preventing or attenuating surgery-driven functional decline. A personalized intervention program will be prescribed based on specific physical, nutritional and psychological conditions recognized during the multimodal assessment. Patients will follow a two to three-day per week training for 4 weeks. Exercise modalities will be adapted to personal preference and patient conditions. Based on dietary habits, medical conditions and nutritional status, a certified nutritionist will provide a comprehensive diet management program. A food-based intervention with a balanced macronutrient composition coupled with oral nutritional supplements will be prescribed to achieve the estimated daily energy and protein requirements. Participants will be instructed by psychology-trained personnel on how to reduce anxiety.
Primary Outcome Measure Information:
Title
Comprehensive Complication Index (CCI)
Description
Postoperative complications occurring during the index admission or in a subsequent readmission, when related to surgery, will be recorded up to 90 days after surgery and graded by severity using the Dindo-Clavien classification and the Comprehensive Complication index (CCI). The Dindo-Clavien system grades complications according to the therapy needed for treatment: Grade I, are complications that require bedside management; Grade II, are complications that require pharmacologic treatment; Grade III, are complications that require surgical or radiologic intervention and; Grade IV, are complications that require intensive care treatment. Dindo-Clavien Grade III or above are considered severe postoperative complications. The CCI, derived from the Dindo-Clavien system, is a validated metric summarizing the complete spectrum of complications that occurred and their severity in a single score ranging from 0 to 100.
Time Frame
90 days after surgery
Title
Functional capacity
Description
Functional capacity will be measured by the 6-minute walking test and compared between groups on the day before surgery, at 30-60-90 days after surgery.
Time Frame
One day before surgery; 30 days after surgery; 60 days after surgery; 90 days after surgery
Title
Pro-inflammatory cytokines
Description
Circulating levels of tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), interferon gamma (IFN-γ), and macrophage inflammatory protein α (MIP-1α) will be assessed by luminex immunoassays and compared between groups at baseline and one day before surgery.
Time Frame
One day before surgery
Title
Cancer cachexia related factors
Description
Enzyme-linked immunosorbent assay (ELISA) will be used to measure the serum levels of the following cachexia-related factors: Activin A, carnosine dipeptidase-1 and zinc-α2-glycoprotein. The circulating levels will be compared between groups at baseline and one day before surgery.
Time Frame
One day before surgery
Secondary Outcome Measure Information:
Title
Time to patient functional recovery (TFR)
Description
TFR will be measured by subtracting the date of surgery from the date when participants achieve standardized criteria (tolerance of oral intake, recovery of lower gastrointestinal function, adequate pain control on oral analgesia, ability to mobilize and self-care and no evidence of untreated medical problems)
Time Frame
90 days after surgery
Title
Lenght of stay (LOS)
Description
LOS will be measured by subtracting the date of surgery from the date of discharge
Time Frame
90 days after surgery
Title
Bioimpedance analysis (BIA) derived body composition
Description
Extracellular and intracellular water as % of total body water, fat mass (FM) as % of body weight, skeletal muscle mass (SK) as % of fat-free mass (FFM), phase angle (PA°) and intramuscular fat mass (IMAT) will be assessed using bioimpedance analysis and compared between groups at baseline, on the day before surgery, at 30, 60, 90 days after surgery.
Time Frame
One day before surgery; 30 days after surgery; 60 days after surgery; 90 days after surgery
Title
Computed tomography derived body composition
Description
Skeletal muscle area (cm2), visceral fat area (cm2) and intra-muscular fat infiltration will be measured at the level of the third lumbar vertebra using preoperative CT scan imaging and compared between groups at baseline and on the day before surgery.
Time Frame
One day before surgery.
Title
Generic health-related quality of life
Description
Generic health-related quality of life will be measured using the Patient Reported Outcome Measure Information System (PROMIS)-29+2 Profile v2.1 (PROPr), a questionnaire designed to measure self-reported physical, mental and social health and wellbeing. Questions are ranked on a 5-point Likert Scale. Each domain (Depression, Anxiety, Physical Function, Pain Interference, Fatigue, Sleep Disturbance, and Ability to Participate in Social Roles and Activities) is scored from 4 to 20. For negative domains (i.e. Depression), lower scores represent better outcomes, higher scores represent worse outcomes. For positive domains (i.e. Physical function), lower scores represent worse outcomes, higher scores represent better outcomes.
Time Frame
One day before surgery; 30 days after surgery; 60 days after surgery; 90 days after surgery
Title
Disease-specific health-related quality of life
Description
Disease-specific health-related quality of life will be measured using the EORTC QLQ C30 and PAN-26 questionnaires, which have been validated to assess quality of life in cancer patients. EORTC QLQ C30 is a generic core questionnaire that measures health-related quality of life in patients with any cancer. It comprises a total of 30 items on 15 quality of life scales. EORTC QLQ PAN-26, is the pancreatic cancer module that supplements the EORTC QLQ-C30. The module comprises 26 questions that share the 4-level ordinal response options with QLQ-C30.
Time Frame
One day before surgery; 30 days after surgery; 60 days after surgery; 90 days after surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 18 years Indication for curative resection for pancreatic or periampullary cancer Signed Informed consent Exclusion Criteria: Metastatic or unresectable disease found preoperatively Comorbidities contraindicating prehabilitation regimen (exercise and nutritional intervention) such as orthopedic, cognitive disabilities, chronic renal failure (dialysis or creatinine >250 mmol) ASA score 4-5 Pregnancy Illiteracy (inability to read and understand Italian language)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Nicolò Pecorelli, MD
Phone
+390226432111
Email
pecorelli.nicolo@hsr.it
First Name & Middle Initial & Last Name or Official Title & Degree
Francesca Di Salvo, PhD
Phone
+390226436046
Email
disalvo.francesca@hsr.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Massimo Falconi, MD
Organizational Affiliation
San Raffaele Hospital
Official's Role
Study Chair
Facility Information:
Facility Name
San Raffaele Hospital
City
Milan
State/Province
Lombardia
ZIP/Postal Code
20132
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicolò Pecorelli, MD
Phone
+390226432111
Email
pecorelli.nicolo@hsr.it

12. IPD Sharing Statement

Citations:
PubMed Identifier
32593337
Citation
Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet. 2020 Jun 27;395(10242):2008-2020. doi: 10.1016/S0140-6736(20)30974-0.
Results Reference
background
PubMed Identifier
33201129
Citation
Lambert JE, Hayes LD, Keegan TJ, Subar DA, Gaffney CJ. The Impact of Prehabilitation on Patient Outcomes in Hepatobiliary, Colorectal, and Upper Gastrointestinal Cancer Surgery: A PRISMA-Accordant Meta-analysis. Ann Surg. 2021 Jul 1;274(1):70-77. doi: 10.1097/SLA.0000000000004527.
Results Reference
background
PubMed Identifier
37465965
Citation
Pecorelli N, Guarneri G, Vallorani A, Limongi C, Licinio AW, Di Salvo F, Tamburrino D, Partelli S, Crippa S, Falconi M. Validation of the PROMIS-29 Questionnaire as a Measure of Recovery after Pancreatic Surgery. Ann Surg. 2023 Jul 19. doi: 10.1097/SLA.0000000000006020. Online ahead of print.
Results Reference
background

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Prehabilitation in Pancreatic Surgery

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