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Pancrelipase

Pancreatin

Bilirubin

Biliary stent by ERCP is indicated both in palliative treatment, because of biliary duct decompression improves patient comfort by decreasing itching and jaundice, as in the treatment of the disease itself, because of it lets reach non-toxic levels of bilirubin which is necessary for chemotherapeutic treatment.

During ERCP, the cannulation of the main pancreatic duct may be performed for the placement of a pancreatic duct stent, which is performed routinely as a prophylaxis of post-ERCP acute pancreatitis in patients at risk. In patients with pancreatic cancer, the placement of a pancreatic stent could improve pancreatic secretion by clearing the main pancreatic duct and thus it could improve fat digestion and nutritional status of patients, avoiding the need for PERT

Insertion of a pancreatic stent during ERCP to improve pancreatic secretion

Pancreatic stent

Daniel de la Iglesia Garcia, MD

Paula Otero

Enrique Dominguez Munoz, MD

Background: exocrine pancreatic insufficiency (IPE), frequent in patients with pancreatic cancer, plays a major role in malnutrition and cachexia with a significant impact on survival, quality of life and tumor progression. IPE due to obstruction of the main pancreatic duct and atrophy of pancreatic parenchyma proximal to the tumor could be corrected by insertion of a pancreatic stent for improving nutritional status and consequently survival.

Aim: The aim of this study is to assess the impact of transpapilar drainage of the main pancreatic duct on exocrine pancreatic function, nutritional status, and life survival in patients with unresectable pancreatic adenocarcinoma.

Methods: Impact of pancreatic endoscopic drainage on exocrine pancreatic function in patients with unresectable pancreatic adenocarcinoma (DEPARA) is a double-blind, prospective, multicentre, international clinical trial. Unresectable locally advanced or metastatic pancreatic cancer (PDAC) will be diagnosed according to the National Comprehensive Cancer Network (NCCN) criteria and the indication of endoscopic retrograde cholangiopancreatography (ERCP) due to obstructive jaundice (\>3mg/dl). PEI will be defined by reduced fecal elastase levels. The nutritional status will be determined by means of Mini-Nutritional Assessment score, sarcopenia score (SARC-F) and laboratory blood tests. Primary aim: Evaluation of the improvement and difference of pancreatic secretion as measured by fecal elastase at 2 weeks post-stenting (biliopancreatic versus biliary). Secondary aims: evaluation of the prevalence of PEI post-stenting (biliopancreatic versus biliary) and proportion of patients normalizing pancreatic function. The difference in terms of weight loss, maldigestion symptoms, GI-Qol, nutricional status and performance status. Survival at 2 weeks, 3 and 6 months, overall survival. Analyzes: fecal elastase value at 2 weeks post-stenting (absolute value of fecal elastase) compared between biliopancreatic stent group and biliary stent group.

Discussion: DEPARA will provide insight into the role of pancreatic stents for PEI, malnutrition and progression-free survival in the outcomes of PDAC unresectable.

In a recent study by our group, 13 patients with unresectable pancreatic head cancer and PEI were randomized into 2 groups (biliopancreatic stent versus biliary stent), showing a statistically significant improvement in exocrine pancreatic function in favor of biliopancreatic drainage (absolute increase 13C-CRR 23.75% (CI 9.62, 31.74%) vs -1.92% (CI -4.17, 13.92%) p=0.015). All patients who underwent pancreatic drainage showed normalization of pancreatic function and nutritional parameters.

A randomized clinical trial is being conducted in patients with unresecable pancreatic cancer to evaluate the effectiveness of pancreatic stent placement in improving pancreatic secretion by desobstructing the main pancreatic duct and thus improving digestion, nutritional status and consequently patient survival.

HYPOTHESIS:

Transpapillary pancreatic drainage with a pancreatic stent is associated with a significant improvement in pancreatic function, nutritional status, maldigestion symptoms and quality of life in patients with unresectable pancreatic adenocarcinoma who require endoscopic bile duct drainage.

AIM:

To investigate the impact of transpapillary drainage of the pancreatic duct on exocrine pancreatic function, nutritional status, maldigestion symptoms and quality of life in patients with unresectable pancreatic adenocarcinoma.

METHODS:

Patients diagnosed with unresectable pancreatic adenocarcinoma according to the NCCN criteria that have an indication of performing an endoscopic retrograde cholangiopancreatography (ERCP) due to the presence of obstructive jaundice (\>3mg/dL).

VARIABLES:

The following variables will be recorded in a dedicated Case Report Form (CRF). All these measures are part of a standard workup of advanced PDAC patients and considered good clinical practice.

• Patient-related: Sex, race, age at diagnosis Significant comorbilities: chronic kidney failure, chronic heart failure, or respiratory insufficiency requiring oxygen treatment

Mini-Nutritional Assessment (MNA) score. Primarily developed for elderly patients, MNA score was successfully used in the PreMiO study (Prevalence of malnutrition in patients at first medical oncology visit) to identify the risk of malnutrition or malnutrition among cancer patients at their first medical oncology visit:

1. 0-7 points: Malnourished
2. 8-11 points: At risk of malnutrition
3. 12-14 points: Normal nutritional status Sarcopenia score (SARC-F score) Cachexia \[weightloss \>5% in the las 6 months or weightloss \>2% if IMC\<20kg/m2\] 12-item functional assessment of anorexia/cachexia therapy anorexia/cachexia subscale (FAACT-A/CS-12) Performance Status-ECOG European Organization for Research and Treatment of Cancer (EORTC) QLQ-PAN26 scale (22) A biliary, duodenal or pancreatic stent Date of diagnosis, visit 1, visit 2 (2 weeks), visit 3(3 months), visit 4 (6 months) and death/loss from follow-up .

   Check up on survival at third month and sixth month Chemotherapy regimen

   • Tumor-related: Tumor site documented by endoscopic ultrasound, CT, or magnetic resonance imaging (head, body, or tail) Stage according to National Comprehensive Cancer Network (NCCN) criteria

   • Nutritional parameters: C-reactive protein, total protein, albumin, cholesterol, iron, transferrin, ferritin, magnesium, zinc Blood fasting glucose, glycated hemoglobin

   • Pancreatic function and treatment: PEI will be defined by levels of fecal elastase-1 \<200 mcg/g; 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

   • Therapy-related (endoscopic procedure): ERCP will be performed under deep sedation by expert endoscopists. Endoscopic biliary sphincterotomy will be performed in all cases before biliary drainage. Partially or fully covered self-expandable metal biliary stents of 10mm in diameter (Wallstent RX biliary Stent System, Boston Scientific, Marlborough, Massachusetts, USA) will be used. Stent length will be selected to cover the length of the biliary stenosis. In patients allocated to pancreatic drainage, plastic pancreatic 7 to 10Fr straight stents (AdvanixTMand NaviFlexTM RX Pancreatic Delivery System, Boston Scientific, Marlborough, Massachusetts, USA) will be used. Stent length will be selected to cover the length of the pancreatic stenosis. Pancreatic sphincterotomy will be performed before pancreatic drainage if required.

   STUDY PERIOD Depending on approval of the Local Ethics Committees, enrollment is planned to start from Februrary 2023 and last until November 2023 or until the planned power calculation has been met.

   DESCRIPTION OF THE INTERVENTION (SCHEDULE OF VISITS) Patients with pancreatic head adenocarcinoma will be randomized to biliary stent placement versus bilio-pancreatic stent placement using the computer-generated total randomization method. The randomization process will be carried out by one of the collaborating researchers who will not participate in the follow-up of patients Screening visit (Hospitalization Unit) After diagnosis of locally advanced or metastatic pancreatic head adenocarcinoma, the investigator in charge of the study will evaluate the inclusion and exclusion criteria and will give the explanation of the study to the patients and delivery of informed consent.

   Visit 1 (inclusion and exclusion criteria evaluation, IC signature, baseline data collection)

   After the signature of the consent and the collection of the baseline data, all patients will do a complete analysis with nutritional parameters and FE-1 test. Nutritional scores and quality of life scores will be evaluated. Then, they will be randomized into the bilio-pancreatic stent group or biliary stent group. Patients randomized to the first group in which pancreatic cannulation is not achieved will be included in the biliary stent group in the protocol analysis. Patients in whom biliary cannulation is failed will be excluded because they need other techniques for biliary drainage.

   Visit 2 (2 weeks after ERCP) A new determination of FE-1 will be made. In patients with a fecal concentration of elastase\<100 µg/g, substitutive enzymatic treatment will be administered according to clinical guidelines and standard clinical practice (70,000 U.Ph. with main meals and 35,000 U.Ph. with minor meals).

   Visit 3 (3 months after ERCP) A new analysis will be made with nutritional parameters. Nutritional scores and quality of life scales will be analyzed.

   Visit 4 (6 months after ERCP) A new analysis will be made with nutritional parameters. Again, nutritional and quality of life scales will be evaluated MEDICATION OF THE STUDY The use of pancreatic enzyme replacement treatment will be recorded as well as data regarding the employed chemotherapy regimen.

   STATISTICAL ANALYSIS The data will be represented in absolute number or percentage, with their respective mean and standard deviation, median and interquartile range as a function of their distribution.

   Qualitative variables will be compared between both groups by chisquare test or Fisher's exact test as appropriate.

   Continuous variables will be compared using a Mann Whitney U test for independent samples.

   A logistic regression model will be created to know which factors are independently associated with the development of IPE (tumor size, tumor stage, main pancreatic duct dilation, pancreatic parenchymal atrophy).

   A proportional risk analysis of Cox will be performed to compare survival in both treatment groups.

   A value of \<0.05 will be considered statistically significant All data will be anonymous once data collection is completed, respecting the confidentiality of the subjects participating, in accordance with data protection laws. All analyses will be performed in STATA 16 (Statacorp LLC, Texas).

   POWER SIZE CALCULATION Based on data from our pilot study that included 20 patients with unresectable pancreatic head adenocarcinoma in which a difference in the FE-1 test of 96mcg/g (SD=151) between the two treatment groups was showed. Assuming an alpha error=0.05 and 80% potency, it would be necessary to include 39 patients in each treatment group. Given the nature of the pathology there is the possibility of a 5% loss, so the total estimated sample size would be 82 patients.

   DISCUSSION Given the sparse overall scientific data on the subject, the investigators have designed a clinical trial that addresses the impact of pancreatic stent on pancreatic secretion, nutritional status and survival of patients with advanced PDAC unresectable. DEPARA will be the first targeted study for investigating whether pancreatic stents positively influence nutritional status and survival of these patients.

Patients with pancreatic head adenocarcinoma will be randomized to biliary stent placement versus bilio-pancreatic stent placement using the computer-generated total randomization method. The randomization process will be carried out by one of the collaborating researchers who will not participate in the follow-up of patients

One of the collaborator of the study will define which treatment group is assigned each patient (Group A and Group B). Only that investigator and the person who perform the ERCP (care provider) will know to which group is assigned the patient. Patients, investigators and outcome assessor are blinded.

Impact of Pancreatic Endoscopic Drainage on Exocrine Pancreatic Function in Unresectable Pancreatic Cancer

Impact of Pancreatic Endoscopic Drainage on Exocrine Pancreatic Function in Patients With Unresectable Pancreatic Adenocarcinoma

Evaluation of the efficacy of the endoscopic insertion of biliopancreatic stent compared to biliary stent in the improvement of pancreatic secretion measured by FE-1 test in patients with unresectable pancreatic cancer

Quality of life and differences between both groups. It will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-PAN26 scale. Minimun of the scale 25 points, maximum 100. Higher puntuations are related to worse outcome.

Nutritional status in each treatment group using the Patient-Generated-Subjective Global Assessment (PS-GHS). Minimum of the scale 0 points. Maximum \>9 points. Higher puntuations are related to worse outcome

Difference in body weight between each of the treatment groups

Survival of patients with unresectable pancreatic adenocarcinoma in the group with biliopancreatic stent vs biliary stent.

Prevalence of PEI post-stenting measured by fecal elastase.

Hospital Clinico Universitario de Santiago

Director of Gastroenterology

Secretin

Hormones

Hormone Antagonists

Twelve patients will undergo S-MRCP, at a dose of 0.2 ucg/kg per exam. Secretin, provided by the Repligen Corporation, will be administered by IV bolus injection over 30 seconds followed by a 30 second saline flush. The maximum dose of secretin will be 18.5 ucg.

Synthetic Human Secretin

Harold Frucht, MD

The aim of our study is to evaluate S-MRCP, in comparison to direct pancreatic function, to measure pancreatic exocrine function in patients who have symptoms suspicious for insufficiency. We hypothesize that S-MRCP imaging parameters will correlate well with the direct pancreatic exocrine functioning.

Surgical resection offers the only hope of cure for pancreatic adenocarcinoma. While perioperative mortality rates have declined in recent years, pancreatic resection is still associated with significant postoperative malnutrition, maldigestion, and glucose intolerance, mostly as a result of pancreatic insufficiency. Quantifying individual pancreatic function remains a challenge, but is essential in improving the survival and quality of life of pancreatic cancer patients. Secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP) has recently emerged as a widely-accepted noninvasive technique to assess morphological changes in pancreatic ducts, as well as functional secretory capacity of the gland. The aim of our study is to evaluate S-MRCP as a means to evaluate for pancreatic exocrine insufficiency. This will be a prospective study of twelve patients who have undergone pancreatic resection and who have symptoms of abdominal pain, steatorrhea or weight loss. We will be comparing quantitative parameters of S-MRCP (maximal change in pancreatic duct diameter and volume before and after secretin administration) with endoscopic pancreatic function testing (maximal bicarbonate concentration in duodenal aspirate after secretin administration).

Comparison of Secretin-enhanced Magnetic Resonance Cholangiopancreatography (S-MRCP) to Endoscopic Pancreatic Function Test (ePFT) in Diagnosing Pancreatic Exocrine Insufficiency

Comparison of Secretin Enhanced MRCP to Endoscopic Pancreatic Function Testing in Diagnosing Exocrine Insufficiency in Patients Who Have Undergone Pancreas Cancer Resection

The primary outcome that we will be measuring will be correlation between duodenal filling on S-MRCP (expressed as percent of duct volume change from baseline and maximal values following secretin administration) with maximal bicarbonate concentration from ePFT.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Impact of Pancreatic Endoscopic Drainage on Exocrine Pancreatic Function in Unresectable Pancreatic Cancer	NCT05244174	Pancreatic Neop... Pancreatic Exoc...	Pancreatic sten...	18 Years -	Hospital Clinico Universitario de Santiago
Comparison of Secretin-enhanced Magnetic Resonance Cholangiopancreatography (S-MRCP) to Endoscopic Pancreatic Function Test (ePFT) in Diagnosing Pancreatic Exocrine Insufficiency	NCT01094600	Pancreatic Canc...	Synthetic Human...	18 Years - 75 Years	Columbia University

Spots Global Cancer Trial Database for pancreatic exocrine insufficiency