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

Sponsor

University Hospital Freiburg (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02509286

Collaborator

Clinical Trials Unit Freiburg (Other), CTC laboratories at University of Hamburg and University of Freiburg (Other), ESOPEC reference pathology at the University of Freiburg (Other), Universitätsklinikum Leipzig, Universitäres Krebszentrum (UCCL) (Other)

438

Enrollment

Locations

Arms

101

Duration (Months)

14.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Adenocarcinoma (UICC TNM7) Adenocarcinoma of the Esophagogastric Junction	Drug: 5-Fluorouracil Drug: Leucovorin Drug: Oxaliplatin Drug: Docetaxel Drug: Carboplatin Drug: Paclitaxel Radiation: Neoadjuvant radiation	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

438 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 1, 2016

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Overall survival [At end of trial- up to 3 years in follow up]
Overall survival will be calculated as time from start of study treatment to death due to any cause.

Secondary Outcome Measures

Progression free survival time (PFS) [From randomisation up to 3 years in follow up]
PFS will be calculated as the time interval from randomisation to the first event of locoregional failure, metastatic progression or death.
Site of failure: local, regional or distant Failure [From time of surgery up to 3 years in follow up]
Recurrence free survival time [From time of surgery up to 3 years in follow up]
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.
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Uniklinik RWTH Aachen	Aachen	Germany
2	Charité Berlin - Campus Benjamin Franklin (CBF)	Berlin	Germany	12203
3	Charité Berlin Campus Virchow-Klinikum (CVK)	Berlin	Germany	13353
4	Klinikum Darmstadt GmbH	Darmstadt	Germany	64283
5	Klinikum Dortmund gGmbH	Dortmund	Germany	44137
6	Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden	Dresden	Germany	03107
7	Universitätsklinikum Düsseldorf	Düsseldorf	Germany
8	Universitätsklinikum Erlangen	Erlangen	Germany	91054
9	Universitätsklinikum Frankfurt	Frankfurt am Main	Germany	60590
10	Universitätsklinikum Freiburg	Freiburg	Germany
11	Universitätsmedizin Göttingen	Göttingen	Germany	37099
12	Universitätsklinikum Hamburg-Eppendorf	Hamburg	Germany
13	Universitätsklinikum des Saarlandes	Homburg	Germany	66421
14	Universitätsklinikum Schleswig-Holstein, Campus Kiel	Kiel	Germany
15	Uniklinik Köln	Köln	Germany	50937
16	Universitätsklinikum Leipzig	Leipzig	Germany
17	Universitätsklinikum Schleswig-Holstein, Campus Lübeck	Lübeck	Germany
18	Universitätsklinikum Magdeburg	Magdeburg	Germany
19	Universitätsmedizin Mainz	Mainz	Germany
20	Universitätsklinikum Mannheim GmbH	Mannheim	Germany	68167
21	Johannes Wesling Klinikum Minden	Minden	Germany	32429
22	Klinikum der Universität München (LMU)	München	Germany
23	Universitätsklinikum Münster	Münster	Germany
24	Ruppiner Kliniken GmbH	Neuruppin	Germany	16816
25	Sana Klinikum Offenbach GmbH	Offenbach	Germany	63069
26	Universitätsklinikum Regensburg	Regensburg	Germany	93053
27	Universitätsmedizin Rostock	Rostock	Germany	18059
28	Klinikum Stuttgart	Stuttgart	Germany	70174
29	Robert-Bosch-Krankenhaus Stuttgart	Stuttgart	Germany	70376
30	Klinikum Mutterhaus	Trier	Germany	54290
31	Universitätsklinikum Würzburg	Würzburg	Germany