Pancreatic Cancer Malnutrition and Pancreatic Exocrine Insufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer (PAC-MAIN)

Malnutrition and cachexia are common in patients with advanced pancreatic ductal adenocarcinoma (PDAC) and have a significant influence on the tolerance and response to treatments. If timely identified, malnourished PDAC patients could be treated to increase their capacity to complete the planned treatments and therefore, possibly, improve their efficacy.

The aim of the study is to assess the impact of nutritional status, pancreatic exocrine insufficiency (PEI), and other clinical factors on patient outcomes in patients with advanced PDAC.

The nutritional status will be determined by means of Mini-Nutritional Assessment score and laboratory blood tests. PEI will be defined as the presence of typical symptoms and/or reduced fecal elastase. Analysis: chemotherapy dosing over the first 12 weeks of therapy (i.e. percent of chemotherapy received in the first 12 weeks, as defined above) PAC-MAIN will provide insights on the role of malnutrition and PEI in outcomes of PDAC.

Study Overview

• Status: Unknown
• Conditions: Pancreatic Cancer; Malnutrition; Chemotherapy; Exocrine Pancreatic Insufficiency; Metastatic Pancreatic Cancer; Locally Advanced Malignant Neoplasm

Detailed Description

Investigators hypothesize that malnutrition has an adverse impact on the clinical course of patients with advanced PDAC treated with chemotherapy.

Aims:

To investigate the association between the nutritional status and pancreatic exocrine function and the clinical outcomes of patients with advanced PDAC.

Study design:

The PAncreatic Cancer MAlnutrition and exocrine pancreatic INsufficiency in the course of chemotherapy in unresectable pancreatic cancer (PAC-MAIN) study is a non-profit, international, multicentre, prospective, observational, cohort study evaluating the effect of the nutritional status and pancreatic exocrine function on the main outcomes of patients with advanced PDAC. The study will be carried out in Russia, Turkey, Serbia, Romania, Italy, and Spain as a part of the Pancreas 2000 Educational Program. Pancreas 2000 is a post-graduate educational program that prepares young gastroenterologists, surgeons, radiologists, and other physicians for specialization in Pancreatology.

Patient-related:

• sex, race, age at diagnosis
• Mini-Nutritional Assessment (MNA) score
• sarcopenia (measured with computed tomography (CT) fat free mass is reduced; i.e. appendicular\L2 skeletal muscle mass index <7.2 kg/m2 (men) or <5.5 kg/m2 (women));
• cachexia (weight loss (WL)>5% in last 6 months, or WL>2% if body mass index (BMI) <20 kg/m² or sarcopenia);
• 12-item functional assessment of anorexia/cachexia therapy anorexia/cachexia subscale (FAACT-A/CS-12)
• a biliary stent
• a duodenal stent
• total and direct bilirubin
• ECOG status
• European Organization for Research and Treatment of Cancer (EORTC) QLQ-PAN26 scale
• Date of diagnosis, visit 1, visit 2 (3 months), and death/loss from follow up
• Check up on survival at 6m

Tumor-related:

• Tumor site documented by endoscopic ultrasound, CT, or magnetic resonance imaging (head, body, or tail)
• Stage according to the TNM classification
• Vessels involved
• Presence and site of metastatic disease
• Ascites
• CA-19-9
• Response evaluation criteria in solid tumors (RECIST) (for visit 2)

Nutritional parameters:

• Leucocytes (lymphocytes, neutrophils), neutrophil to lymphocytes ratio, erythrocytes, hemoglobin, hematocrit, platelets
• C-reactive protein, total protein, albumin, cholesterol, iron, transferrin, ferritin, magnesium, zinc
• International normalized ratio, activated partial thromboplastin time
• Blood fasting glucose, glycated hemoglobin

Pancreatic function and treatment:

• PEI, fecal elastase-1, pancreatic enzyme replacement therapy (PERT), date of starting PERT, the dosage of daily taken PERT
• Diabetes mellitus (DM), date of DM diagnosis, DM type, DM treatment

Treatment-related:

• Planned chemotherapy protocol Dosages of chemotherapy planned (mg/m2)
• Percent of standard chemotherapy dose delivered
• Percent of planned chemotherapy delivered
• Changes to the predefined schedule (dose reduction, schedule modifications, stop before planned)
• Date of treatment start and end
• Adverse events (National Cancer Institute toxicity scale for visit 2)

Description of the intervention (schedule of visits):

Visit 1 (screening, within 1 month from initial diagnosis). Patients will be informed about the study. Once patients agree with the inclusion in the study the investigators will evaluate the inclusion and exclusion criteria. Those patients who meet all the inclusion criteria and none of the exclusion criteria will be finally included in the study. In this visit, patients, tumor-related variables, and general patients' features will be recorded, and quality of life questionnaire will be administered. The researcher will record weight, height, body mass index (BMI), unplanned WL % for the last 6 months.

Each patient's baseline nutrition status will be evaluated using the MNA scores prior to starting chemotherapy. Patients will be classified as in the group with no nutritional risk, at risk of malnutrition, or malnourished.

Nutritional parameters and pancreatic function will be evaluated through blood tests and a fecal test.

Visit 2 (3 months after the first dose of planned chemotherapy). The researcher will record in the case report form (CRF) the planned chemotherapy, schedule, doses, dose reduction, and any adverse event. The same variables recorded at Visit 1 will be checked again.

Check up 3 (end of the study, 6 months). The researcher will record in the CRF the overall survival and time until progression.

Medication of the study:

The study is of observational nature, so a pre-planned treatment is not considered. However, the use of pancreatic enzyme replacement treatment will be recorded as well as data regarding the employed chemotherapy regimen.

Power size calculation:

The expected percent of chemotherapy delivered in well-nourished patients was based on a study that assessed the chemotherapy dose intensity in gastrointestinal malignancies included pancreaticobiliary disease during the firsts 8 weeks after the start of the chemotherapy23. Based on an expected percentage of chemotherapy delivered of 70% in well-nourished patients, with a type I error of 0.05 and a type II error of 0.20, a sample size of 93 patients per group will be required in case of a percentage difference of chemotherapy delivered of 20% between well-nourished and malnourished, 163 patients per group in case of a difference of 15% between both groups and 356 patients per group in case of 10% of difference.

Discussion:

Given the sparse overall scientific data on the subject, the investigators have designed a study that addresses the impact of patient's nutritional status and dietary intervention on the clinical course of patients with advanced PDAC treated with chemotherapy and is aimed at establishing whether it affects both tolerance and tumor response to medical therapy. PAC-MAIN will be the first study specifically investigating whether the nutritional status influences the possibility to complete planned chemotherapy in patients with advanced PDAC.

• Study Type: Observational
• Enrollment (Anticipated): 186

Contacts and Locations

• Study Contact: Name: Gabriele Capurso, MD, PhD; Phone Number: +39 02 26436548; Email: capurso.gabriele@hsr.it
• Study Contact Backup: Name: Enrique de Madaria, MD, PhD; Email: madaria@hotmail.com

Study Locations

• Italy
  • Milan, Italy
    • Recruiting
    • IRCCS San Raffaele Scientific Institute
    • Contact: Gabriele Capurso, MD, PhD; Phone Number: +39 02 26436548; Email: gabriele.capurso@gmail.com
• Romania
  • Bucharest, Romania
    • Recruiting
    • Clinical Emergency Hospital Bucharest
    • Contact: Vasile Sandru, MD; Phone Number: +0040728813095; Email: drsandruvasile@gmail.com
• Russian Federation
  • Moscow, Russian Federation
    • Recruiting
    • A.S. Loginov Moscow Clinical Scientific Center
    • Contact: Mariia Kiriukova, MD; Phone Number: +7 495 303 15 57; Email: kiryukovam@yandex.ru
• Serbia
  • Belgrade, Serbia
    • Not yet recruiting
    • University Clinic "Dr. Dragisa Misovic-Dedinje"
    • Contact: Nikola Panic, MD; Phone Number: +381 11 3630600; Email: nikola.panicmail@gmail.com
  • Belgrade, Serbia
    • Not yet recruiting
    • University of Belgrade
    • Contact: Nikola Panic, MD; Phone Number: +381 11 3630600; Email: nikola.panicmail@gmail.com
• Spain
  • Alicante, Spain
    • Not yet recruiting
    • Alicante University General Hospital
    • Contact: Enrique de Madaria, MD, PhD; Phone Number: +34 965 933 468; Email: madaria@hotmail.com
    • Contact: Maryana Bozhychko, MD; Phone Number: +34 965 933 468; Email: maryanabozhychko@gmail.com
  • Santiago De Compostela, Spain
    • Not yet recruiting
    • University Hospital of Santiago de Compostela
    • Contact: Daniel de la Iglesia Garcia, MD; Phone Number: +34981951364; Email: danieldelaiglesiagarcia@hotmail.com
• Turkey
  • Istanbul, Turkey
    • Recruiting
    • Istanbul University
    • Contact: Bartu Avci; Phone Number: +90 212 414 2000; Email: bartuavci@ogr.iu.edu.tr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

patients with unresectable locally advanced or metastatic PDAC

Description

Inclusion Criteria:

• age ≥ 18 years;
• histological diagnosis of PDAC within one month from recruitment to the study;
• radiological diagnosis of the advanced stage not suitable for upfront surgical resection (either locally advanced or metastatic) within 5 weeks from recruitment to the study;
• data on the variables and the outcomes of interest are available;
• a written consent to participate in the study;
• being planned for chemotherapy;
• no past history of anticancer treatment.

Exclusion Criteria:

• poor performance status (Eastern Cooperative Oncology Group scale (ECOG) ≥ 3);
• pregnancy;
• surgery for PDAC in the past and developed progression.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Normal nutritional status; Patients, fulfilled inclusion criteria with Mini-Nutritional Assessment score of 24-30 points.
Malnourished; Patients, fulfilled inclusion criteria with Mini-Nutritional Assessment score of fewer than 17 points.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of standard chemotherapy dose delivered	Drug doses will be expressed in weight-based, body surface area (BSA)-based, Area Under the Curve (AUC) units or flat dose, according to standard dosing practice for a given drug or combination. For each drug in a regimen, the sum of the doses delivered during the first 12 weeks of therapy will be divided by the sum of the expected doses based on published standard schedule and dosing. The mean percent dose delivered of all drugs in a regimen will be reported as 'percent of standard chemotherapy dose delivered.' The investigators will use percent of standard chemotherapy dose delivered to estimate the overall relative dose delivered.	12 weeks after the diagnosis
Percent of planned chemotherapy delivered	Similarly, the sum of the doses delivered during the first 12 weeks of therapy will be divided by the sum of the expected doses based on each patient's starting chemotherapy dose, and the mean percent dose delivered for all drugs in a regimen will be reported as 'percent of planned chemotherapy delivered.' The investigators will use percent of planned chemotherapy dose delivered to quantify further dose reductions from starting dose and as an indicator of overall toxicity.	12 weeks after the diagnosis

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival		6 months
Percent of patients with chemotherapy-related toxicity in each group		12 weeks after the diagnosis
Survival at 6 months		12 weeks after the diagnosis, 6 months
Quality of Life (EORTC) QLQ-PAN26 scale	The pancreatic cancer module is designed for patients at all disease stages undergoing surgical resection, palliative surgical intervention, endoscopic palliation or palliative chemotherapy (Fitzsimmons et al., 1999a,b). The module comprises 26 questions assessing pain, dietary changes, jaundice, altered bowel habit, emotional problems related to pancreatic cancer, and other symptoms (cachexia, indigestion, flatulence, dry mouth, taste changes). The answers range is the following: not at all - 1 point, a little - 2 points, quite a bit - 3 points, very much - 4 points. Minimum score is 26, maximum is 106. The higher total score represents the worse quality of life.	12 weeks after the diagnosis
Number of hospitalizations		12 weeks after the diagnosis
Factors associated with the percent of chemotherapy received		12 weeks after the diagnosis

Collaborators and Investigators

• Sponsor: Moscow Clinical Scientific Center
• Collaborators: IRCCS San Raffaele; Istanbul University; University of Belgrade; University of Santiago de Compostela; European Institute of Oncology; Hospital General Universitario de Alicante; Bucharest Emergency Hospital; University Clinic Dr Dragisa Misovic-Dedinje
• Investigators: Study Chair: Mariia Kiriukova, MD, Moscow Clinical Scientific Center

Publications and helpful links

General Publications

• Kiriukova M, de la Iglesia Garcia D, Panic N, Bozhychko M, Avci B, Maisonneuve P, de-Madaria E, Capurso G, Sandru V. Pancreatic Cancer Malnutrition and Pancreatic Exocrine Insufficiency in the Course of Chemotherapy in Unresectable Pancreatic Cancer. Front Med (Lausanne). 2020 Sep 3;7:495. doi: 10.3389/fmed.2020.00495. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2019
• Primary Completion (Anticipated): June 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: September 30, 2019
• First Submitted That Met QC Criteria: September 30, 2019
• First Posted (Actual): October 2, 2019

Study Record Updates

• Last Update Posted (Actual): October 16, 2019
• Last Update Submitted That Met QC Criteria: October 14, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: chemotherapy; nutritional status; pancreatic cancer; metastatic; locally advanced; exocrine pancreatic insufficiency; dose-intensity
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Nutrition Disorders; Pancreatic Diseases; Neoplasms; Pancreatic Neoplasms; Malnutrition; Exocrine Pancreatic Insufficiency
• Other Study ID Numbers: 2/2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No