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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Adenocarcinoma of the Esophagogastric Junction; Esophageal Adenocarcinoma (UICC TNM7)
• Intervention / Treatment: Drug: 5-Fluorouracil; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Docetaxel; Drug: Carboplatin; Drug: Paclitaxel; Radiation: Neoadjuvant radiation

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 438
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany
    • Uniklinik RWTH Aachen
  • Berlin, Germany, 12203
    • Charité Berlin - Campus Benjamin Franklin (CBF)
  • Berlin, Germany, 13353
    • Charité Berlin Campus Virchow-Klinikum (CVK)
  • Dortmund, Germany, 44137
    • Klinikum Dortmund gGmbH
  • Dresden, Germany, 03107
    • Universitatsklinikum Carl Gustav Carus An Der Technischen Universitat Dresden
  • Düsseldorf, Germany
    • Universitatsklinikum Dusseldorf
  • Erlangen, Germany, 91054
    • Universitatsklinikum Erlangen
  • Frankfurt am Main, Germany, 60590
    • Universitatsklinikum Frankfurt
  • Freiburg, Germany
    • Universitatsklinikum Freiburg
  • Göttingen, Germany, 37099
    • Universitatsmedizin Gottingen
  • Hamburg, Germany
    • Universitatsklinikum Hamburg-Eppendorf
  • Homburg, Germany, 66421
    • Universitätsklinikum des Saarlandes
  • Kiel, Germany
    • Universitatsklinikum Schleswig-Holstein, Campus Kiel
  • Köln, Germany, 50937
    • Uniklinik Koln
  • Leipzig, Germany
    • Universitätsklinikum Leipzig
  • Lübeck, Germany
    • Universitätsklinikum Schleswig-Holstein, Campus Lübeck
  • Magdeburg, Germany
    • Universitätsklinikum Magdeburg
  • Mainz, Germany
    • Universitätsmedizin Mainz
  • Mannheim, Germany, 68167
    • Universitätsklinikum Mannheim GmbH
  • Minden, Germany, 32429
    • Johannes Wesling Klinikum Minden
  • München, Germany
    • Klinikum der Universität München (LMU)
  • Münster, Germany
    • Universitatsklinikum Munster
  • Neuruppin, Germany, 16816
    • Ruppiner Kliniken GmbH
  • Offenbach, Germany, 63069
    • Sana Klinikum Offenbach GmbH
  • Regensburg, Germany, 93053
    • Universitätsklinikum Regensburg
  • Rostock, Germany, 18059
    • Universitätsmedizin Rostock
  • Stuttgart, Germany, 70174
    • Klinikum Stuttgart
  • Stuttgart, Germany, 70376
    • Robert-Bosch-Krankenhaus Stuttgart
  • Trier, Germany, 54290
    • Klinikum Mutterhaus
  • Würzburg, Germany
    • Universitatsklinikum Wurzburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Perioperative Chemotherapy (FLOT): 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; 2600 mg/m² (24 hours), d1 every two weeks; Drug: Leucovorin; 200 mg/m² in 250 ml NaCl 0.9%, d1 every two weeks; Drug: Oxaliplatin; 85 mg/m² in 500 ml G5% over 2h, d1 every two weeks; Drug: Docetaxel; 50mg/m2 in 250 ml NaCl 0.9% over 1h, d1 every two weeks;
Active Comparator: Neoadjuvant Chemoradiation (CROSS): 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; Dose-dependant: 2mg/ml/min AUC in 500ml Glucose 5%, day 1, 8, 15, 22 and day 29.; Drug: Paclitaxel; 50mg/m2 in 500ml NaCl 0.9% over 1 h, day 1, 8, 15, 22 and day 29; Radiation: Neoadjuvant radiation; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Schleswig-Holstein
• Collaborators: University of Leipzig; University of Luebeck; University of Hamburg-Eppendorf; University of Freiburg; Clinical Trials Unit Freiburg
• Investigators: Principal Investigator: Jens Hoeppner, Professor, University Medical Center Schleswig-Holstein, Campus Lübeck

Publications and helpful links

General Publications

• Hoeppner J, Lordick F, Brunner T, Glatz T, Bronsert P, Rothling N, Schmoor C, Lorenz D, Ell C, Hopt UT, Siewert JR. ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286). BMC Cancer. 2016 Jul 19;16:503. doi: 10.1186/s12885-016-2564-y.

Helpful Links

• ESOPEC Homepage

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Estimated): May 1, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: July 22, 2015
• First Submitted That Met QC Criteria: July 23, 2015
• First Posted (Estimated): July 28, 2015

Study Record Updates

• Last Update Posted (Actual): May 8, 2024
• Last Update Submitted That Met QC Criteria: May 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: chemotherapy; radiotherapy; surgery; adenocarcinoma; esophagectomy; Esophageal neoplasms; gastro-esophageal junction neoplasms
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Phytogenic; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Docetaxel; Carboplatin; Paclitaxel; Fluorouracil; Oxaliplatin; Leucovorin
• Other Study ID Numbers: P000760; 2015-001683-20 (EudraCT Number); DRKS00008008 (Registry Identifier: DRKS)