Perioperative Chemotherapy Compared To Neoadjuvant Chemoradiation in Patients With Adenocarcinoma of the Esophagus

Study Overview
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Brief Summary
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The trial is designed to investigate differences in outcome of patients with esophageal adenocarcinoma and junctional adenocarcinoma treated with perioperative (neoadjuvant + adjuvant) chemotherapy (FLOT) plus surgical resection versus neoadjuvant chemoradiation (CROSS) plus surgical resection.

Detailed Description
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According to the given evidence a survival benefit of perioperative chemotherapy (periCTX) over Neoadjuvant chemoradiation (neoCRT) for patients with Esophageal adenocarcinomas (EAC) has not been proven in any randomized controlled trials (RCT). Data supporting the value of periCTX have all been obtained in studies including mixed patient cohorts with EAC and gastric adenocarcinoma (GAC). Due to relevant differences of histologic subtype distribution, response to periCTX and survival rates between EAC and GAC there is a clear need to obtain evidence concerning the value of periCTX for EAC. As nowadays periCTX is extensively and successfully applied in clinical practice in patients with EAC there is an obvious need to obtain evidence from a multicentre RCT. Moreover a confirmation of the superior survival rates of the recent RCT on neoCRT should be obtained in a RCT conducted exclusively on EAC. Therefore, this prospective RCT with the primary objective of longterm patient survival comparing periCTX and neoCRT was designed. Translational Projects: Project 1+2: Circulating Tumor Cells as Biomarker in EAC CTC laboratories at University of Hamburg and University of Freiburg Project 3: Prognostic and predictive biomarkers in EAC University of Leipzig, UCCL

Official Title
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Perioperative Chemotherapy (FLOT Protocol) Compared To Neoadjuvant Chemoradiation (CROSS Protocol) in Patients With Adenocarcinoma of the Esophagus

Conditions
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Esophageal Adenocarcinoma (UICC TNM7), Adenocarcinoma of the Esophagogastric Junction

Intervention / Treatment
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* Drug: 5-Fluorouracil
* Drug: Leucovorin
* Drug: Oxaliplatin
* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Paclitaxel
* Radiation: Neoadjuvant radiation


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically verified adenocarcinoma of the esophagus according to the UICC definition (TNM7) Pre-treatment stage cT1N+, M0 or cT2-4a, N0/+, M0 Age ≥18 years No prior abdominal or thoracic radiotherapy ECOG Performance status 0-2 Adequate cardiac function ( Patients with a cardiac history (e.g. myocardial infarction, heart failure, coronary artery disease) should have a cardiology review) Adequate bone marrow function (WBC>3x10^9/l; Hb>9g/dl; platelets >100x10^9/l) Adequate respiratory function. Symptomatic Patients should have pulmonary function tests with FEV1 >65% of predicted) Adequate renal function (GFR >60ml/min) Adequate liver function (serum bilirubin <1.5x Upper level of Normal (ULN); AST <2.5x ULN and ALT <3x ULN (ULN as per institutional standard) written informed consent Exclusion Criteria: Tumors of squamous or other non-adenocarcinoma histology Patients with advanced inoperable or metastatic esophageal adenocarcinoma Stage cT1N0 and cT4b Gastric carcinoma Prior chemotherapy for cancer, Clinically significant (i.e. active) cardiac disease (e.g. symptomatic coronary artery disease or myocardial infarction within last 12 months) Clinical significant lung disease (FEV1 <65% of predicted) Peripheral neuropathy Grade >1

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Perioperative Chemotherapy (FLOT):<br>The FLOT Arm consists of the FLOT protocol, which consists of 5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel. Repetition every 2 weeks (d15, q2w). Four neoadjuvant cycles (8 weeks) prior to surgery and four adjuvant cycles (8 weeks) postoperatively are given. Surgery is carried out by transthoracic subtotal esophagectomy or by transabdominal distal esophageal resection plus gastrectomy depending on tumor localization. | Drug: 5-Fluorouracil<br>* 2600 mg/m² (24 hours), d1 every two weeks;<br>Drug: Leucovorin<br>* 200 mg/m² in 250 ml NaCl 0.9%, d1 every two weeks;<br>Drug: Oxaliplatin<br>* 85 mg/m² in 500 ml G5% over 2h, d1 every two weeks;<br>Drug: Docetaxel<br>* 50mg/m2 in 250 ml NaCl 0.9% over 1h, d1 every two weeks;<br>|
| Active Comparator: Neoadjuvant Chemoradiation (CROSS):<br>The CROSS Arm consists of the CROSS protocol, which consists of neoadjuvant radiation therapy (41.4Gy / 23fractions) and concurrent chemotherapy with Carboplatin and Paclitaxel (5 weeks) prior to surgery. Surgery is carried out by transthoracic subtotal esophagectomy or by transabdominal distal esophageal resection plus gastrectomy depending on tumor localization. | Drug: Carboplatin<br>* Dose-dependant: 2mg/ml/min AUC in 500ml Glucose 5%, day 1, 8, 15, 22 and day 29.<br>Drug: Paclitaxel<br>* 50mg/m2 in 500ml NaCl 0.9% over 1 h, day 1, 8, 15, 22 and day 29;<br>Radiation: Neoadjuvant radiation<br>* 41.4Gy given in 23 fractions of 1.8Gy on days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival will be calculated as time from start of study treatment to death due to any cause. | At end of trial- up to 3 years in follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival time (PFS) | PFS will be calculated as the time interval from randomisation to the first event of locoregional failure, metastatic progression or death. | From randomisation up to 3 years in follow up | 
| Site of failure: local, regional or distant Failure |  | From time of surgery up to 3 years in follow up | 
| Recurrence free survival time | RFS will be calculated in resected patients who achieved an R0 or R1 resection as the time interval from surgery to the date of first recurrence (local, regional or distant) or death, whatever comes first. | From time of surgery up to 3 years in follow up | 
| Postsurgical Quality of Life |  | From randomization up to 3 years in follow up | 
| Postoperative complications |  | From time of surgery up to 90 days postoperatively | 
| Non-surgical site complications |  | From time of surgery up to 90 days postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esophageal neoplasms, gastro-esophageal junction neoplasms, adenocarcinoma, esophagectomy, surgery, radiotherapy, chemotherapy