Evaluation for the Individualization of Therapy in Adenocarcinomas of the Gastroesophageal Junction

Study Overview
=================
Brief Summary
-----------------
Metabolic and Molecular Response evaluation for the individualization of therapy in adenocarcinomas of the gastroesophageal junction by evaluation of the R0 resection rate for patients with metabolically (ie, according to PET criteria) chemotherapy-resistant locally advanced AEG, who receive an intensified neoadjuvant chemoradiotherapy (INRCT). Additonal efforts will be done by investigation of molecular and metabolic biomarkers in relation to their predictive and prognostic value by correlating them with histopathologic responses and clinical outcome in an exploratory approach.

Detailed Description
-----------------
Adenocarcinomas of the esophagus and the esophagogastric junction (AEG) are clinically-topographically divided into subtypes I-III according to the Siewert classification and show an increased incidence. Neoadjuvant and/or perioperative chemotherapy or preoperative radiochemotherapy is well established in the management of AEG. However, a significant number of patients do not respond to preoperative chemotherapy, suffering from toxicity and facing a worse outcome due to lower R0 resection rates. Previous results from the MUNICON-1 and MUNICON-2 trials have shown that PET-based therapy individualization can be successfully integrated in neoadjuvant treatment algorithms. Tumor-free resection edges (R0) constitute the greatest prognostic advantage in terms of overall survival. However, the R0 resection rates for patients who, according to early metabolic response evaluation, have not responded to the chemotherapy, have not been satisfactory, even after conversion to an - albeit moderate - radiochemotherapy in the MUNICON-2 trial. Thus, this patient population (so-called non responders) so far lack a beneficial neoadjuvant therapy modality. Based on these results, the primary goal of MEMORI study is to evaluate the R0 resection rate for patients with metabolically (ie, according to PET criteria) chemotherapy-resistant locally advanced AEG, who receive an intensified neoadjuvant chemoradiotherapy (INRCT). Secondary it is planned to investigate molecular and metabolic biomarkers in relation to their predictive and prognostic value by correlating them with histopathologic responses and clinical outcome in an exploratory approach.

Official Title
-----------------
Metabolic and Molecular Response Evaluation for the Individualization of Therapy in Adenocarcinomas of the Gastroesophageal Junction

Conditions
-----------------
Adenocarcinoma of the Esophagogastric Junction

Intervention / Treatment
-----------------
* Drug: Oxaliplatin
* Drug: Epirubicin
* Drug: Capecitabine
* Drug: 5-FU
* Drug: Carboplatin
* Drug: Paclitaxel
* Radiation: radiation
* Procedure: Biopsy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed AEG I-III Potentially R0 - resectable AEG and primary tumor category UT2 -4 Functional operability : Exclusion of OP - limiting comorbidities Intense FDG tracer uptake of the tumor during Baseline PET/CT examination and thus suitability for monitoring and early response prediction by FDG - PET ( [ 18F ] - FDG uptake in the tumor at baseline > 1.35 x liver SUV + 2 x standard deviation of the liver SUV) Performance status (ECOG ) 0 or 1 Age : ≥ 18 creatinine clearance > 60ml/min measured in a 24 h urine or calculated with the Cockgroft -Gault formula bilirubin ≤ 1.5 times upper limit of normal , serum transaminases (GOT / GPT ) ≤ 3 times ULN leukocytes ≥ 3.5 g / l, platelet ≥ 100 g / l Negative pregnancy test (determination of beta- HCG in urine or serum) in women of childbearing potential A signed consent form after implementation of medical education Exclusion Criteria: Existing distant metastases (M1b) Tumor infiltration into the tracheobronchial system Previous radiotherapy targeted at the thorax Lack of ability of the patient to adhere to the protocol rules Manifest heart failure despite optimal medication> NYHA I existing angina pectoris at rest or undergoing stress without clarification via interventional cardiology and / or myocardial infarction within the last 6 months Existing pregnancy or lactation childbearing or fertility without using recognized safe methods of contraception Coexisting other malignant diseases with the exception of a non-melanomatuous, localized skin tumor or carcinoma in situ of the cervix absence of a signed consent form

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-Responder<br>Oxaliplatin Epirubicin Capecitabine 5-FU Carboplatin Paclitaxel Radiation Biopsy | Drug: Oxaliplatin<br>* 130 mg/m2<br>* Other names: Oxaliplan;Drug: Epirubicin<br>* 50 mg/m2<br>* Other names: Epi Teva;Drug: Capecitabine<br>* 625 mg/m2<br>* Other names: Xeloda;Drug: 5-FU<br>* 200 mg/m2<br>* Other names: 5-FU medac;Drug: Carboplatin<br>* 2 mg/ml min<br>* Other names: Carboplatin SUN;Drug: Paclitaxel<br>* 50 mg/m2<br>* Other names: Taxomedac;Radiation: radiation<br>* total dosage 41,4 Gy<br>* Other names: intensitive neoadjuvant radiochemotherapy (INRCT);Procedure: Biopsy<br>* translational analysis<br>* Other names: esophagogastroduodenoscopy;|
| Active Comparator: Responder<br>Oxaliplatin Epirubicin Capecitabine 5-FU Biopsy | Drug: Oxaliplatin<br>* 130 mg/m2<br>* Other names: Oxaliplan;Drug: Epirubicin<br>* 50 mg/m2<br>* Other names: Epi Teva;Drug: Capecitabine<br>* 625 mg/m2<br>* Other names: Xeloda;Drug: 5-FU<br>* 200 mg/m2<br>* Other names: 5-FU medac;Procedure: Biopsy<br>* translational analysis<br>* Other names: esophagogastroduodenoscopy;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0 resection rate | R0 resection rate of patients suffering from metabolically (following PET criteria) chemotherapy-resistant, locally advanced AEG, who receive a more intensive neoadjuvant radio-chemotherapy (INRCT) | 1 day of surgery (in between day 28 to day 43 after radio-chemotherapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regression | Histological regression defined by Becker Criteria | 1 day of surgery (in between day 28 to day 43 after radio-chemotherapy) | 
| Overall survival | Overall survival defined as period from start of study to death (if necessary censored by end of follow-up period) | from day 0 to follow up visit 6 (24 months after surgery) | 
| Disease-free survival | Disease-free survival, defined as period from start of study to earlier occurring event: death or relapse until end of follow-up; Relapse will be separated into events of local failure, distant failure and local and distant failure | from day 0 to follow up visit 6 (24 months after surgery) | 
| QLQ-C30 | Quality of life, analyzed via EORTC QLQ-C30 questionnaires | from day 0 to follow up visit 6 (24 months after surgery) | 
| Metabilic response rate | Metabolic response rate under neoadjuvant chemotherapy | from day 0 to one time point of time period day 14 to 28 after chemotherapy | 
| Translational analysis | Translational analysis for identification of tumor determinants relevant for prognosis and therapy | 1 day of surgery (in between day 28 to day 43 after radio-chemotherapy) | 
| Adverse Events | Occurence of AEs | from day 0 to follow up visit 6 (24 months after surgery) | 
| QLQ-OG25 | Quality of life, analyzed via EORTC QLQ-OG25 questionnaires | from day 0 to follow up visit 6 (24 months after surgery) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Potentially R0 - resectable AEG and primary tumor category, Histologically confirmed AEG I-III, Functional operability, Intense FDG tracer uptake of the tumor