Chemotherapy in the Context of Esophageal and Gastroesophageal Junction Cancer Cachexia

Study Overview
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Brief Summary
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Cachexia is a syndrome frequently associated with digestive cancers and more particularly with esophageal and gastroesophageal adenocarcinoma. Its pathophysiology remains poorly understood, multi-factorial, but strongly correlated to the prognosis of patients. It's a consequence of the imbalance of energy balance linked to tumoral process, to dysphagia and to anorexia, frequently present in these cancers. At the center of this imbalance, adipose tissue plays a major role. Recent studies showing that the mobilization of lipid substrates and the hypermetabolism of adipocytes are involving in its development, even before loss of muscle. As part of the management, neoadjuvant chemotherapy is usually administered with the main objective to reduce tumor extension and dissemination through actions on DNA and mitosis. These treatments will also alter the mitochondrial function of cells in other tissues, probably including that of adipocytes. A paradoxical effect on the cachectic process could thus be envisaged, as a decrease in mitochondrial activity and associated hypermetabolism, and therefore a preservation of fat mass, and by extension of muscle mass. Primary endpoint: identify the adipocyte factors involved in the energy imbalance associated with the cachectic process in patients managed for esophageal or gastroesophageal adenocarcinoma. Secondary endpoint: compare the results obtained before and after chemotherapy treatment according to the cachectic state and the anatomical location of the adipose sample (subcutaneous versus visceral) to evaluate the resting energy expenditure.

Detailed Description
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Two operative steps, separated by neoadjuvant chemotherapy, are classically planned in the management of esophageal and gastroesophageal adenocarcinoma: an exploratory laparoscopy as part of the disease extension assessment and the tumor resection surgery (esophagectomy). During these operations, the surgeon will perform a subcutaneous fat biopsy at the surgical approach and a visceral fat biopsy at the epiploic level. A portion of the samples will be immediately analyzed by high-resolution oxygraphy to evaluate the mitochondrial metabolism of the adipocytes. The rest of biopsies will be frozen for further biological analysis (enzymology, Western-blot, RT-qPCR) or embedded in paraffin for histological analysis (morphometry, inflammation, metabolism). Serum will also be recovered with the biopsies for specific biological analysis (inflammatory and lipid status). In days preceding the interventions, in addition to the usual management, will be performed: an evaluation of the energy expenditure by indirect calorimetry, an evaluation of the body composition by Dual Energy X-ray Absorptiometry (DEXA), physical tests to evaluate sarcopenia and cachexia, nutritional and quality of life questionnaires, and a medical examination with a dietetic consultation.

Official Title
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Effect of Chemotherapy on Metabolic Flexibility in the Context of Cachexia in Cancers of the Esophagus and Gastroesophageal Junction

Conditions
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Esophageal Adenocarcinoma

Intervention / Treatment
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* Procedure: Adipose tissue biopsies


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male Patients Patients aged over 18 Patients eligible for neoadjuvant FLOT chemotherapy (5-fluorouracil, oxaliplatin, docetaxel); Patients with a resealable adenocarcinoma of esophageal or gastroesophageal Patients able to give informed consent. Patients affiliated to a Health Care insurance Exclusion Criteria: Unresectable or metastatic esophageal or gastroesophageal adenocarcinoma; Another tumor histology than adenocarcinoma. Patients not eligible for neoadjuvant FLOT chemotherapy and/or for surgery Patients under guardianship, curators or deprived of liberty; Refusal to participate; Patients already participating in another interventional study of pharmacological, nutritional and/or rehabilitation study; Patients in a period of exclusion from another research protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Intervention Model: Single Group Assignment
Interventional Model Description: patient undergoing surgery for esophageal adenocarcinoma or for gastroesophageal adenocarcinoma
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interventional<br>patients with esophageal or gastroesophageal adenocarcinoma included to evaluate the energy expenditure before and after chemotherapy and evaluate parameters of cachexia | Procedure: Adipose tissue biopsies<br>* During the 2 surgical time, when patient is under general anesthesia, two adipose tissue biopsies of 20cc each (one from abdominal subcutaneous adipose tissue and one from omental adipose tissue) are taken and characterize by oxygraphy (respirometry). Before the 2 surgical times (before and after chemotherapy) patients will have evaluation of the muscle strength, cachexia (by scan analysis), energy expenditure, anthropometric criteria and biochemical inflammatory.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of mitochondrial respiration on adipose tissue by oxygraphy | Evaluation of mitochondrial respiration on adipose tissue before and after chemotherapy Mitochondrial respiration measurements in oxydo-phosphorylated conditions. For each patient measurements using ADP and carbohydrate or lipid substrates of the respiratory chain complexes for both the subcutaneous and the visceral tissue. | 6 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of sarcopenia (SARC-F : sarcopenia scoring) | level of sarcopenia between 0 to 12 including 5 questions | 1 week | 
| anthropometric data | BMI will be measured | 1 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mitochondria, Oxygraphy, Adipose Tissue, Gastroesophageal adenocarcinoma, Energy expenditure