5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) Versus Epirubicin, Cisplatin and 5-FU (ECF) in Patients With Locally Advanced, Resectable Gastric Cancer

A Randomized Multicenter Phase II/III Study Comparing 5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) Versus Epirubicin, Cisplatin and 5-FU (ECF) in Patients With Locally Advanced Resectable Adenocarcinoma of the Esophagogastreal Junction or the Stomach

Patients with locally advanced resectable adenocarcinoma of the stomach or the esophagogastreal junction without previous therapy will be treated with one of two chemotherapy combinations before and after surgery. One half of the patients gets 5-Fluorouracil (5-FU), Leucovorin, Oxaliplatin and Docetaxel (FLOT), the others Epirubicin, Cisplatin and 5-FU (ECF). Main objective of the study is median overall survival.

Study Overview

• Status: Completed
• Conditions: Gastric Cancer
• Intervention / Treatment: Drug: Leucovorin; Drug: Oxaliplatin; Drug: 5-Fluorouracil; Drug: Docetaxel; Drug: Epirubicin; Drug: Cisplatin; Drug: 5-fluorouracil

Detailed Description

714 Patients with locally advanced resectable (T2-4 and/or N+, M0) adenocarcinoma of the stomach or the esophagogastreal junction without previous therapy will be included in this study. After randomization patients receive perioperatively 4 cycles FLOT or 3 cycles ECF, followed by a restaging of the tumour status and surgery. Subsequently another 4 cycles of FLOT or 3 cycles ECF are applicated. Then a central validation of the pathological remission rate is scheduled. Primary endpoint is overall survival, secondary endpoints are disease free survival, perioperative morbidity and mortality, histopathologic regression rate and R0-resection rate.

• Study Type: Interventional
• Enrollment (Actual): 716
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Frankfurt, Germany, 60488
    • Krankenhaus Nordwest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. locally advanced (>T1) and/or nodal positive (N+) histologically proven adenocarcinoma of the esophagogastreal junction (AEG I-III) or the stomach without distant metastases (M0) and without infiltration of adjacent structures and organs
2. no previous surgical resection
3. no previous cytostatic chemotherapy
4. Age > 18 years (female and male)
5. ECOG ≤ 2
6. surgical resectability
7. Exclusion of peritoneal carcinomatosis (if clinically suspected) via laparoscopy
8. Leucocytes > 3.000/µl
9. Platelets > 100.000/µl
10. Serum creatinin ≤ 1.5x of normal value, or Creatinin-Clearance > 50 ml/min
11. written informed consent.
12. Ejection fraction > 50% in echocardiography before start of therapy

Exclusion Criteria:

1. distant metastases or infiltration of adjacent structures or organs and all primarily not resectable stages
2. relapse
3. Hypersensitivity against 5- Fluorouracil, Leucovorin, Oxaliplatin, Cisplatin. Epirubicin and Docetaxel
4. Existence of contraindications against 5- Fluorouracil, Leucovorin, Oxaliplatin, Cisplatin, Epirubicin or Docetaxel
5. Active CHD, Cardiomyopathy or cardiac insufficiency stage III-IV according to NYHA
6. malignant secondary disease, dated back < 5 years (exception: In-situ-carcinoma of the cervix uteri, adequately treated skin basal cell carcinoma)
7. severe non-surgical accompanying disease or acute infection
8. peripheral polyneuropathy > NCI Grad II
9. severe liver dysfunction (AST/ALT>3,5xULN, AP>6xULN, Bilirubin>1,5xULN)
10. chronic inflammable gastro-intestinal disease
11. inclusion in another clinical trial
12. pregnancy or lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: FLOT; Docetaxel 50mg/m2, d1 5-FU 2600 mg/m², d1 Leucovorin 200 mg/m², d1 Oxaliplatin 85 mg/m², d1 every two weeks (q2w) 4 cycles (8 weeks) pre-OP and 4 cycles (8 weeks) post-OP	Drug: Leucovorin; 200 mg/m², d1, i.v., every 2 weeks; Drug: Oxaliplatin; 85 mg/m², d1, i.v., every 2 weeks; Drug: 5-Fluorouracil; 2600 mg/m²d1 i.v. every 2 weeks; Drug: Docetaxel; 50mg/m2, d1, i.v., every 2 weeks
ACTIVE_COMPARATOR: ECF; Epirubicin 50 mg/m2, d1 Cisplatin 60 mg/m², d1 5-FU 200 mg/m², d1-d21 every 3 weeks (q3w) 3 cycles (9 weeks) pre-OP and 3 cycles (9 weeks) post-OP	Drug: Epirubicin; 50 mg/m2, d1, i.v., every 3 weeks; Drug: Cisplatin; 60 mg/m², d1, i.v., every 3 weeks; Drug: 5-fluorouracil; 200 mg/m², d1-d21, i.v., every 3 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
median overall survival	2 years follow-up

Secondary Outcome Measures

Outcome Measure	Time Frame
histopathological regression rate	6 weeks after surgery
disease free survival (DFS)	2 years follow-up
correlation of pCR and DFS with survival	2 years follow-up
Perioperative Morbidity and Mortality	up to 2 months after surgery
R0-Resection rate	2 months after surgery

Collaborators and Investigators

• Sponsor: Krankenhaus Nordwest

Publications and helpful links

General Publications

• Zeng H, Wang C, Song LY, Jia SJ, Zeng X, Liu Q. Economic evaluation of FLOT and ECF/ECX perioperative chemotherapy in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma. BMJ Open. 2022 Nov 14;12(11):e060983. doi: 10.1136/bmjopen-2022-060983.
• Koch C, Reitz C, Schreckenbach T, Eichler K, Filmann N, Al-Batran SE, Gotze T, Zeuzem S, Bechstein WO, Kraus T, Bojunga J, Dux M, Trojan J, Blumenstein I. Sarcopenia as a prognostic factor for survival in patients with locally advanced gastroesophageal adenocarcinoma. PLoS One. 2019 Oct 22;14(10):e0223613. doi: 10.1371/journal.pone.0223613. eCollection 2019.
• Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Lohr C, Bernhard H, Schuch G, Rethwisch V, von Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Weniger J, Belle S, Gaiser T, Oduncu FS, Guntner M, Hozaeel W, Reichart A, Jager E, Kraus T, Monig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019 May 11;393(10184):1948-1957. doi: 10.1016/S0140-6736(18)32557-1. Epub 2019 Apr 11.
• Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Konigsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jager E, Monig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. doi: 10.1016/S1470-2045(16)30531-9. Epub 2016 Oct 22.
• Lorenzen S, Thuss-Patience P, Al-Batran SE, Lordick F, Haller B, Schuster T, Pauligk C, Luley K, Bichev D, Schumacher G, Homann N. Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy. Ann Oncol. 2013 Aug;24(8):2068-73. doi: 10.1093/annonc/mdt141. Epub 2013 Apr 16.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2010
• Primary Completion (ACTUAL): March 1, 2017
• Study Completion (ACTUAL): May 1, 2019

Study Registration Dates

• First Submitted: June 30, 2010
• First Submitted That Met QC Criteria: October 6, 2010
• First Posted (ESTIMATE): October 7, 2010

Study Record Updates

• Last Update Posted (ACTUAL): June 19, 2019
• Last Update Submitted That Met QC Criteria: June 18, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: FLOT; gastric cancer; perioperative; ECF; pathological complete remission; locally advanced resectable adenocarcinoma of the esophagogastric juction or the stomach
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Micronutrients; Antibiotics, Antineoplastic; Vitamins; Antidotes; Vitamin B Complex; Docetaxel; Cisplatin; Fluorouracil; Epirubicin; Oxaliplatin; Leucovorin
• Other Study ID Numbers: FLOT4