A Biomarker-driven Therapeutic Strategy for Esophageal Cancer Chemoradiotherapy in Patients With Resectable Adenocarcinoma of the ESophagus and Esophagogastric Junction

Study Overview
=================
Brief Summary
-----------------
Preoperative chemoradiotherapy followed by surgery has been accepted as the standard of care for resectable adenocarcinoma of the esophagus and esophagogastric junction (EGJ). However, in a large part of the cases the tumor is extremely resistant to chemoradiotherapy, and those patients do not benefit from this treatment but are exposed to its negative consequences such as toxicity and delayed surgical therapy. The hypothesis is that a biomarker-driven therapeutic strategy in which patients will receive preoperative chemoradiotherapy or upfront surgery based on the basal tumor expression of BIRC3 could improve the R0 resection rate if compared with a standard strategy in unselected patients.

Detailed Description
-----------------
BoRgES trial is a multicenter, randomized phase II study of BIRC3-expression directed preoperative chemoradiotherapy in patients with resectable adenocarcinoma of the esophagus and EGJ. The main objective of this proposal is to provide evidence for a novel therapeutic strategy with enormous significance for patients affected by this disease. Only a part of the patients with esophageal adenocarcinoma benefit from neoadjuvant therapy, and the clinical efficacy of chemoradiotherapy is reduced by the pre-existence of cellular drug resistance. Thus, there is an urgent need to identify patients who could not benefit from preoperative treatment. The study will define an innovative therapeutic strategy directed by the expression of BIRC3 as a predictive marker for discriminating patients who will most likely be resistant to preoperative chemoradiotherapy.

Official Title
-----------------
A Biomarker-driven Therapeutic Strategy for Esophageal Cancer, the BoRgES Trial: a Multicenter Randomized Phase II Study of BIRC3-expression Directed Preoperative Chemoradiotherapy in Patients With Resectable Adenocarcinoma of the ESophagus and Esophagogastric Junction

Conditions
-----------------
Esophageal Cancer

Intervention / Treatment
-----------------
* Other: BIRC3


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven adenocarcinoma of the esophagus and EGJ (Siewert I/II) surgical resectable (cT2-4a, N0-1, M0), as determined by Endoscopic Ultra Sound (EUS) and or PET-TC scan. cT1N1 tumors are eligible, T1N0 tumors and in situ carcinoma are not eligible. If tumor extends below the EGJ junction into the proximal stomach, the bulk of the tumor must involve the esophagus or GE junction. The tumor must not extend more than 2 cm into the stomach (Siewert III). Gastric cancers with minor involvement of the GE junction or esophagus are not eligible. Age >18, no age upper limit unless patient would be unable to tolerate chemoradiotherapy. Have given written informed consent prior to any study-specific procedures. ECOG performance status 0-2. No prior thoracic radiotherapy allowed. Adequate hematological, renal, cardiac, hepatic and pulmonary functions. Exclusion Criteria: -

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: open-label, multicenter, randomized phase II study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: experimental arm<br>fresh specimens from the tumour and normal mucosa will be collected endoscopically at diagnosis and placed immediately into RNALater to isolate RNA. The mRNA expression of BIRC3 will be quantified using a SYBR green-based real-time PCR analysis; the BIRC3 median expression in normal mucosa samples will be used as calibrator. Patients with a tumor expression level of BIRC3 lower than the established cutoff will receive a standard carboplatin/paclitaxel regimen with concurrent radiotherapy followed by surgery. Patients with an expression of BIRC3 higher or equal than the cutoff (chemoradiation resistant patients) will undergo upfront surgery. | Other: BIRC3<br>* BIRC3-expression directed preoperative chemoradiotherapy in patients with resectable adenocarcinoma of the esophagus and EGJ<br>|
| Active Comparator: control arm<br>fresh specimens from the tumour and normal mucosa will be collected endoscopically at diagnosis and placed immediately into RNALater to isolate RNA. The mRNA expression of BIRC3 will be quantified using a SYBR green-based real-time PCR analysis; the BIRC3 median expression in normal mucosa samples will be used as calibrator. Patients with a tumor expression level of BIRC3 lower than the established cutoff will receive a standard carboplatin/paclitaxel regimen with concurrent radiotherapy followed by surgery. Patients with an expression of BIRC3 higher or equal than the cutoff (chemoradiation resistant patients) will undergo upfront surgery. | Other: BIRC3<br>* BIRC3-expression directed preoperative chemoradiotherapy in patients with resectable adenocarcinoma of the esophagus and EGJ<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0, number of patients achieving R0 resection. | number of patients achieving R0 resection. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | overall survival | 3 years | 
| DFS | disease free survival | 3 years | 
| tumour response | tumour response evaluated either by Mandard's tumour regression grade | 3 years | 
| safety profile | safety profile (incidence of ≥ grade 3 adverse events using Common Terminology Criteria for Adverse Events - CTCAE - version 4.0). | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
esophageal-gastric junction cancer, preoperative chemoradiotherapy, BIRC3