Intensive pre-surgery treatment for lymph node–positive esophageal and esophagogastric junction adenocarcinoma

Total Neoadjuvant Therapy for Lymph Node-positive Adenocarcinoma of the OESophagus and Oesophagogastric Junction: a Phase II Study

This study tests whether giving both FLOT chemotherapy and CROSS chemoradiation before surgery, in different orders, helps people with node-positive esophageal or esophagogastric junction adenocarcinoma live longer without the cancer coming back.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 216 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Erasmus Medical Center (Academic / other)
• Drugs / interventions: chemotherapy
• Locations: 10 sites (Eindhoven, North Brabant and 9 other locations)
• Trial ID: NCT06161818 on ClinicalTrials.gov

What this trial studies

This Phase 2 trial enrolls adults with resectable, clinically node-positive (cN+) adenocarcinoma of the esophagus or esophagogastric junction and randomizes them to two total neoadjuvant therapy sequences: FLOT followed by CROSS versus CROSS followed by FLOT, with planned surgery thereafter. The primary goal is to improve progression-free survival by at least 10% compared with an appropriate historical CROSS cohort, building on the feasibility signal from the prior TNT-OES-1 trial. Clinical staging requires EUS or PET/CT for nodal status and PET/CT to confirm no distant metastasis, and treatment combines systemic chemotherapy cycles and localized chemoradiation before surgery. Patients are treated and followed at participating Dutch centers with multidisciplinary oversight to confirm resectability and fitness for intensive therapy.

Who should consider this trial

Good fit: Adults (≥18 years) with resectable cT2-4a, clinically node-positive (cN+) M0 adenocarcinoma of the esophagus or esophagogastric junction (Siewert I–II) who are fit for intensive neoadjuvant therapy and planned for curative surgery.

Not a fit: Patients without clinical lymph node involvement (cN0), with distant metastases (M1), with unresectable tumors, or who are too frail for combined chemoradiotherapy and surgery are unlikely to benefit from this intensified pre-surgery approach.

Why it matters

Potential benefit: If successful, combining both systemic chemotherapy and localized chemoradiation before surgery could improve disease control and increase progression-free (and potentially overall) survival for node-positive patients.

How similar studies have performed: Previous randomized approaches (CROSS and FLOT) improved survival compared with surgery alone and TNT-OES-1 showed that total neoadjuvant therapy is feasible, but the optimal sequence of FLOT and CROSS remains unproven.

Eligibility criteria

Inclusion Criteria:

• Patients with cT2-4aN+M0 resectable adenocarcinoma of the oesophagus or EGJ (Siewert type I-II) according to the 8th edition of the Union for International Cancer Control (UICC) TNM classification for Esophageal Cancer who are planned to undergo nCRT or FLOT (43). In case of stage cT4a, curative resectability has to be explicitly verified by the multidisciplinary tumor board.

Clinical N+ status should be determined by EUS or 18F-FDG PET/CT. Clinical M0 status must be determined by 18F-FDG PET/CT.

* Maximum of 4 cm ingrowth in the cardia, measured by upper endoscopy.
* In case of tumor and/or lymph node involvement below the diaphragm, the most proximal involved lymph node station cannot be higher than N7 (Appendix C).
* In case of no tumor or lymph node involvement below the diaphragm, the most proximal involved lymph node station cannot be higher than N4 (Appendix C).
* Age ≥ 18 years. For patients aged 70 years or older, a geriatric screening tool (G8) should be used to assess functioning across the domains. If a patient has a score of 14 or lower on the G8, a comprehensive geriatric assessment (CGA) should be done prior to inclusion (Appendix D).
* No prior abdominal, thoracic or cervical radiotherapy overlapping with the CROSS irradiation fields.
* No prior cytotoxic chemotherapy for oesophageal cancer.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 (44).
* Weight loss \<10%.
* Adequate cardiac and respiratory function (cardiac or pulmonary function tests such only necessary in symptomatic patients).
* Adequate bone marrow function (White Blood Cells \>3x109/L; Haemoglobin \>5.5 mmol/L; platelets \>100x109/L). In the event of transfusions, the last red blood cell transfusion should be more than 2 weeks before inclusion.
* Adequate renal function (Glomerular Filtration Rate \>50 ml/min) or serum creatinine ≤1.5 x upper limit of normal (ULN) and adequate liver function (total bilirubin \<1.5x Upper Level of Normal (ULN); Aspartate transaminase (AST) \<2.5x ULN and Alanine transaminase (ALT) \<3x ULN.
* A negative serum pregnancy test in women of child-bearing potential during screening period.
* Use of adequate contraception during the study up to 3 months after the end of the study.
* Written informed consent and ability to understand the nature of the study and the study-related procedures and to comply with them.

Exclusion Criteria:

* Patients with tumours of squamous, adenosquamous or other non-adenocarcinoma histology.
* Patients who are eligible for and want to participate in the TRAP-2 trial (NCT05188313)
* Patients with overt hematogenous (organ) metastasis, distant lymphatic metastases (cervical/retroperitoneal), peritoneal or pleural dissemination, as detected on 18F-FDG PET/CT or regular CT-scan. In patients in whom a diagnostic laparoscopy is indicated (to assess resectability or to exclude peritoneal disease), tumor-positive cytology peritoneal fluid is also an exclusion criteria.
* Clinically significant (active) cardiac disease (e.g. symptomatic coronary artery disease of myocardial infarction within the last 12 months) or lung disease (forced expiratory volume in one second (FEV1) \<1.5L).
* Peripheral neuropathy grade \>1, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (37).
* Homozygous DPYD genotype (tested for \*2A, \*13, 2846A\>T, and 1236G\>A)
* Pregnant and lactating women, or patients of reproductive potential who are not using effective contraception. If barrier contraceptives are used, they must be continued by both sexes throughout the study.
* Other active malignancies with a prognosis interfering with that of oesophageal cancer.
* Expected lack of compliance with the protocol.
* Limitations such as language barriers, dementia, or altered mental status that make it impossible for the participant to understand the study, provide informed consent, and complete quality of life questionnaires. Participants who do not speak the primary study language may still be included if the study information is adequately translated or explained (e.g., read aloud in their native language) and they demonstrably understand the study procedures.

Where this trial is running

Eindhoven, North Brabant and 9 other locations

• Catharina Ziekenhuis — Eindhoven, North Brabant, Netherlands (Not_yet_recruiting)
• Frisius medisch centrum — Leeuwarden, North Brabant, Netherlands (Not_yet_recruiting)
• Elisabeth Tweesteden Ziekenhuis — Tilburg, North Brabant, Netherlands (Not_yet_recruiting)
• Amsterdam UMC — Amsterdam, North Holland, Netherlands (Not_yet_recruiting)
• Erasmus Medical Centre — Rotterdam, South Holland, Netherlands (Recruiting)
• Ziekenhuisgroep Twente — Almelo, Netherlands (Not_yet_recruiting)
• Antoni van Leeuwenhoek/Nederlands Kanker Instituut — Amsterdam, Netherlands (Not_yet_recruiting)
• Gelre ziekenhuis — Apeldoorn, Netherlands (Not_yet_recruiting)
• Leids Universitair Medisch Centrum — Leiden, Netherlands (Not_yet_recruiting)
• Radboud Universitair Medisch Centrum — Nijmegen, Netherlands (Not_yet_recruiting)

Study contacts

• Principal investigator: Bianca Mostert, MD, PhD — Erasmus Medical Centre
• Study coordinator: Bianca Mostert, MD, PhD

Conditions Esophageal Cancer; Adenocarcinoma of the Esophagus; Total Neoadjuvant Therapy; Chemotherapy; Chemoradiotherapy