Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer

Jens Hoeppner; Thomas Brunner; Claudia Schmoor; Peter Bronsert; Birte Kulemann; Rainer Claus; Stefan Utzolino; Jakob Robert Izbicki; Ines Gockel; Berthold Gerdes; Michael Ghadimi; Benedikt Reichert; Johan F Lock; Christiane Bruns; Ernst Reitsamer; Maximillian Schmeding; Frank Benedix; Tobias Keck; Gunnar Folprecht; Peter Thuss-Patience; Ulf Peter Neumann; Andreas Pascher; Detlef Imhof; Severin Daum; Tanja Strieder; Christian Krautz; Simone Zimmermann; Jens Werner; Rolf Mahlberg; Gerald Illerhaus; Peter Grimminger; Florian Lordick

doi:10.1056/NEJMoa2409408

Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer

N Engl J Med. 2025 Jan 23;392(4):323-335. doi: 10.1056/NEJMoa2409408.

Authors

Jens Hoeppner¹, Thomas Brunner¹, Claudia Schmoor¹, Peter Bronsert¹, Birte Kulemann¹, Rainer Claus¹, Stefan Utzolino¹, Jakob Robert Izbicki¹, Ines Gockel¹, Berthold Gerdes¹, Michael Ghadimi¹, Benedikt Reichert¹, Johan F Lock¹, Christiane Bruns¹, Ernst Reitsamer¹, Maximillian Schmeding¹, Frank Benedix¹, Tobias Keck¹, Gunnar Folprecht¹, Peter Thuss-Patience¹, Ulf Peter Neumann¹, Andreas Pascher¹, Detlef Imhof¹, Severin Daum¹, Tanja Strieder¹, Christian Krautz¹, Simone Zimmermann¹, Jens Werner¹, Rolf Mahlberg¹, Gerald Illerhaus¹, Peter Grimminger¹, Florian Lordick¹

Affiliation

¹ From Bielefeld University, Medical School and University Medical Center Ostwestfalen-Lippe, Campus Hospital Lippe, Detmold, Germany (J.H.); the Department of Radiation Oncology, Medical University of Graz, Graz, Austria (T.B.); the Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany (C.S.); the Institute of Surgical Pathology, University Medical Center Freiburg, Germany (P.B.); the Department of Surgery, University Medical Center Schleswig-Holstein-Campus Lübeck, Lübeck, Germany (B.K., T.K.); Comprehensive Cancer Center Augsburg, Faculty of Medicine, University of Augsburg, Augsburg, Germany (R.C.); the Department of General and Visceral Surgery, University Medical Center Freiburg, Freiburg, Germany (S.U.); the Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.R.I.); the Department of Gastrointestinal Surgery, IRCCS San Raffaele Scientific Institute and San Raffaele Vita-Salute University, Milan (I.G.); the Department of General, Visceral, Thoracic, and Endocrine Surgery, Johannes Wesling University Hospital Minden, Ruhr University Bochum, Minden, Germany (B.G.); the Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany (M.G.); the Department of General, Visceral, Thoracic, Transplantation, and Pediatric Surgery, University Medical Center Schleswig-Holstein-Campus Kiel, Kiel, Germany (B.R.); the Department of General, Visceral, Transplantation, Vascular, and Pediatric Surgery, University Hospital, University of Würzburg, Würzburg, Germany (J.F.L.); the Department of General, Visceral, Cancer, and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany (C.B.); the Department of Hematology and Oncology, Sana Klinikum Offenbach, Offenbach am Main, Germany (E.R.); the Department of Surgery, Klinikum Dortmund, Klinikum der Universität Witten-Herdecke, Dortmund, Germany (M.S.); the Department of Surgery, University Hospital Magdeburg, Magdeburg, Germany (F.B.); the Department of Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany (G.F.); the Department of Hematology, Oncology, and Cancer Immunology, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin (P.T.-P.); the Department of General, Visceral, Cancer, and Transplantation Surgery, University Hospital Essen, Essen, Germany (U.P.N.); the Department of General, Visceral, and Transplantation Surgery, University Hospital Muenster, Muenster, Germany (A.P.); the Department of Radiotherapy and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany (D.I.); the Division of Gastroenterology, Rheumatology, and Infectology, Department of Medicine, Charité-Universitätsmedizin Berlin, Berlin (S.D.); the Department of Surgery, Robert Bosch Hospital, Stuttgart, Germany (T.S.); the Department of Surgery, University Medical Center Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany (C.K.); the Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany (S.Z.); the Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University Hospital, Munich, Germany (J.W.); the Department of Internal Medicine I, Klinikum Mutterhaus der Borromaerinnen, Trier, Germany (R.M.); the Departments of Hematology, Oncology, and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany (G.I.); the Department of General, Visceral, and Transplant Surgery, University Medical Center Mainz, Mainz, Germany (P.G.); and the Department of Medicine II, University Cancer Center Leipzig, Cancer Center Central Germany, University Medical Center Leipzig, Leipzig, Germany (F.L.).

PMID: 39842010
DOI: 10.1056/NEJMoa2409408

Abstract

Background: The best multimodal approach for resectable locally advanced esophageal adenocarcinoma is unclear. An important question is whether perioperative chemotherapy is preferable to preoperative chemoradiotherapy.

Methods: In this phase 3, multicenter, randomized trial, we assigned in a 1:1 ratio patients with resectable esophageal adenocarcinoma to receive perioperative chemotherapy with FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus surgery or preoperative chemoradiotherapy (radiotherapy at a dose of 41.4 Gy and carboplatin and paclitaxel) plus surgery. Eligibility criteria included a primary tumor with a clinical stage of cT1 cN+, cT2-4a cN+, or cT2-4a cN0 disease, in which T indicates the size and extent of the tumor (higher numbers indicate a more advanced tumor), and N indicates the presence (N+) or absence (N0) of cancer spread to the lymph nodes, without evidence of metastatic spread. The primary end point was overall survival.

Results: From February 2016 through April 2020, we assigned 221 patients to the FLOT group and 217 patients to the preoperative-chemoradiotherapy group. With a median follow-up of 55 months, overall survival at 3 years was 57.4% (95% confidence interval [CI], 50.1 to 64.0) in the FLOT group and 50.7% (95% CI, 43.5 to 57.5) in the preoperative-chemoradiotherapy group (hazard ratio for death, 0.70; 95% CI, 0.53 to 0.92; P = 0.01). Progression-free survival at 3 years was 51.6% (95% CI, 44.3 to 58.4) in the FLOT group and 35.0% (95% CI, 28.4 to 41.7) in the preoperative-chemoradiotherapy group (hazard ratio for disease progression or death, 0.66; 95% CI, 0.51 to 0.85). Among the patients who started the assigned treatment, grade 3 or higher adverse events were observed in 120 of 207 patients (58.0%) in the FLOT group and in 98 of 196 patients (50.0%) in the preoperative-chemoradiotherapy group. Serious adverse events were observed in 98 of 207 patients (47.3%) in the FLOT group and in 82 of 196 patients (41.8%) in the preoperative-chemoradiotherapy group. Mortality at 90 days after surgery was 3.1% in the FLOT group and 5.6% in the preoperative-chemoradiotherapy group.

Conclusions: Perioperative chemotherapy with FLOT led to improved survival among patients with resectable esophageal adenocarcinoma as compared with preoperative chemoradiotherapy. (Funded by the German Research Foundation; ESOPEC ClinicalTrials.gov number, NCT02509286.).

Publication types

Randomized Controlled Trial
Clinical Trial, Phase III
Multicenter Study
Comparative Study

MeSH terms

Adenocarcinoma* / mortality
Adenocarcinoma* / pathology
Adenocarcinoma* / surgery
Adenocarcinoma* / therapy
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols* / administration & dosage
Antineoplastic Combined Chemotherapy Protocols* / adverse effects
Carboplatin / administration & dosage
Carboplatin / adverse effects
Chemoradiotherapy* / adverse effects
Chemotherapy, Adjuvant / adverse effects
Chemotherapy, Adjuvant / methods
Docetaxel / administration & dosage
Docetaxel / adverse effects
Esophageal Neoplasms* / diagnosis
Esophageal Neoplasms* / mortality
Esophageal Neoplasms* / pathology
Esophageal Neoplasms* / therapy
Esophagectomy
Female
Fluorouracil / administration & dosage
Fluorouracil / adverse effects
Follow-Up Studies
Humans
Kaplan-Meier Estimate
Leucovorin / administration & dosage
Leucovorin / adverse effects
Male
Middle Aged
Neoadjuvant Therapy* / adverse effects
Neoadjuvant Therapy* / methods
Neoplasm Staging
Oxaliplatin / administration & dosage
Oxaliplatin / adverse effects
Paclitaxel / administration & dosage
Paclitaxel / adverse effects
Perioperative Care* / adverse effects
Perioperative Care* / methods
Radiotherapy Dosage
Treatment Outcome

Substances

Carboplatin
Docetaxel
Fluorouracil
Leucovorin
Oxaliplatin
Paclitaxel

Supplementary concepts

Adenocarcinoma Of Esophagus

Associated data

ClinicalTrials.gov/NCT02509286

Grants and funding

264590883/Deutsche Forschungsgemeinschaft