The Role of Muscle Cachexia in Pancreatic Cancer

The relationship between myopenia, nutritional status, and long-term oncologic outcomes remains poorly characterized in patients with anatomically resectable pancreatic cancer (PC). The investigators want to look at muscle properties in pancreatic cancer patients to determine possible therapeutic options toward better nutritional status. Patients with benign right upper quadrant pathology will be utilized as controls for the study.

The researchers hypothesize that improving cancer cachexia in PC will improve the quality of life and ultimately increase overall survival. The long term goal of is to identify areas of intervention to prevent and/or improve cachectic events in PC in order to significantly improve clinical outcomes. The first step in this long term goal is to fully characterize cachexia in the condition of PC. This research is to understand and modify the local response within skeletal muscle leading to a clinically relevant persistent wasting and to understand and interrupt the systemic stimulus produced by the tumor local environment resulting in these muscle specific mechanisms.

Study Overview

• Status: Withdrawn
• Conditions: Pancreas Cancer
• Intervention / Treatment: Procedure: Muscle Tissue Biopsy Sample

Detailed Description

Cancer cachexia (CC) is a devastating condition affecting up to 80% of cancer patients, diminishing quality of life and contributing to increased mortality. Cancer cachexia is a complex metabolic syndrome characterized by the loss of skeletal muscle mass and weakness. The muscle pathology of cancer cachexia is not only related to muscle atrophy but also to disruptions to the contractile apparatus of the muscle. While physiologic disruptions in muscle sarcomere and myofiber membrane integrity have been observed despite the lack of injury, the totality of the muscle specific mechanisms contributing to these phenotypes have not been described, nor investigated in the context of pancreatic cancer (PC) where cachexia is a significant clinical problem. Therefore, delineating specific mechanisms of muscle catabolism in PC is critical to developing clinical therapies to control wasting and improve patient quality of life, clinical outcomes and long-term survival.

A variety of tumor promoting and inflammatory cell signaling pathways have been implicated in cancer cachexia, whereby pro-inflammatory cytokines have been implicated as a driving force. Remarkably, approximately half of all patients with PC demonstrate a measurable acute phase response, which is associated with poor clinical outcomes. Importantly, systemic elevations of these inflammatory mediators are due to a complex local interplay between the developing tumor and the immune system which subsequently leads to a systemic chronic inflammatory state. PC appears to manipulate the immune system to promote its survival at the expense of nutritional stores which results in cachexia. Therefore, understanding of the local and systemic inflammatory response in PC and its relation to muscle specific mechanisms is crucial to developing effective therapies for cancer cachexia.

PC associated cachexia results in a significant therapeutic dilemma. Local approaches such as surgery for curative intent encounter a high recurrence rate which is indicative of the systemic nature of even very early-stage disease. Therefore, systemic therapies are necessary for long-term survival. Unfortunately, effective chemotherapies are only offered to patients with good clinical parameters such as nutritional status. In other words, if the patient is too weak, they are not offered effective therapies for the risk of causing more harm than good.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32611
      • UF Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pancreatic Cancer Patients who are potentially surgically resectable.

Exclusion Criteria:

• Patients who do not meet the criteria for surgical resection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pancreatic Cancer Patients; During the surgical resection for the pancreatic cancer a muscle tissue biopsy sample will be performed.	Procedure: Muscle Tissue Biopsy Sample; During surgical resection, to enter the abdominal cavity, anterior muscle groups such as the rectus abdominous muscle. This group of muscle is divided. During division, muscle fibers are released from fascial group and discarded off the operative field. This will be the target for specimen collection.
Active Comparator: Surgical Patients with benign pathology; During surgical resection for patients with benign right upper quadrant pathology, a muscle tissue biopsy sample will be performed.	Procedure: Muscle Tissue Biopsy Sample; During surgical resection, to enter the abdominal cavity, anterior muscle groups such as the rectus abdominous muscle. This group of muscle is divided. During division, muscle fibers are released from fascial group and discarded off the operative field. This will be the target for specimen collection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ultrastructural abnormalities in muscle tissue samples between the groups	To look at the extent of ultrastructural abnormalities in the skeletal muscle by histologic examination of muscle biopsies	day 1
Myofiber atrophy in muscle tissue samples between the groups	2) identify the growth and atrophy-related transcription factors associated with the muscle pathology and 3) identify the genome-wide gene networks and biological process associated with skeletal muscle pathology in surgically resected PC patients and healthy control patients by RT-PCR and histologic staining of tissues for transcriptional factors associated with cachexia.	day 1
Identify gene networks within the skeletal muscle between the groups	RT-PCR of RNA from biopsied muscle tissues	day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
History of weight lost	Clinical assessment at treatment follow-up	Baseline
Nutritional status	Clinical assessment at treatment follow-up	Approximately 2 years
Blood Chemistry composite	Clinical assessment at treatment follow-up	Approximately 2 years
Preoperative sarcopenia using a muscular index	Clinical assessment at treatment follow-up and radiographic measurements of muscle groups on routine surveillance for cancer recurrence or advancement	Approximately 2 years
Measurement of lymphatic metastasis	Pathologic specimen at time of resection to determine extent of pathologic stage which is routine	Approximately 2 years
Tumor grade	Noted at pathologic assessment and part of routine examination	Approximately 2 years
Survival data	Noted on routine follow-up	Approximately 2 years

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); The V Foundation for Cancer Research
• Investigators: Principal Investigator: Andrew Judge, PhD, University of Florida

Publications and helpful links

General Publications

• Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009 Apr;89(2):381-410. doi: 10.1152/physrev.00016.2008.
• Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, Marks D, Mitch WE, Muscaritoli M, Najand A, Ponikowski P, Rossi Fanelli F, Schambelan M, Schols A, Schuster M, Thomas D, Wolfe R, Anker SD. Cachexia: a new definition. Clin Nutr. 2008 Dec;27(6):793-9. doi: 10.1016/j.clnu.2008.06.013. Epub 2008 Aug 21.

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Actual): June 23, 2023
• Study Completion (Actual): June 23, 2023

Study Registration Dates

• First Submitted: June 3, 2015
• First Submitted That Met QC Criteria: August 3, 2015
• First Posted (Estimated): August 4, 2015

Study Record Updates

• Last Update Posted (Actual): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 26, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Pancreas; Cachexia; Pancreas Cancer; Muscle Biopsy; Muscle Cachexia
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Nutrition Disorders; Body Weight; Body Weight Changes; Pancreatic Diseases; Weight Loss; Thinness; Pancreatic Neoplasms; Wasting Syndrome; Cachexia
• Other Study ID Numbers: IRB201500239 - N; 2R01AR060209-06A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

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