A Phase 2 interventional study of FLOT-CROSS or CROSS-FLOT in Esophageal Cancer and Adenocarcinoma of the Esophagus, sponsored by Erasmus Medical Center. Recruiting at 10 sites in Netherlands. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-12-22.
Sponsored by Erasmus Medical Center · Phase 2, Interventional, and Treatment
Both neoadjuvant chemoradiotherapy (CROSS) and neoadjuvant chemotherapy (FLOT) have demonstrated overall survival benefit over surgery alone in esophageal and esophagogastric junction (EGJ) cancer. Despite these survival gains, the prognosis remains poor, especially in patients with nodal-positive adenocarcinoma (cN+ AC) (5-year survival 36%, compared to 55% for cN0). This highlights the need for more effective treatment options, and justifies treatment intensification in these patients.
The aim of this study is to determine the efficacy and feasibility of TNT FLOT-CROSS and TNT CROSS-FLOT in patients with resectable, cN+ AC of the esophagus or EGJ.
This study hypothesizes that the benefits of the locoregional control of CROSS combined with the systemic effect of FLOT leads to better disease control and survival in cN+ AC patients. This Total Neoadjuvant Treatment (TNT) strategy was found to be feasible in the previous TNT-OES-1 trial. The optimal sequence of CROSS and FLOT is yet unknown. Therefore, the hypothesis of this study is that the progression-free survival (PFS) of patients treated with TNT FLOT-CROSS and TNT CROSS-FLOT will be ≥10% compared to the PFS after CROSS in an appropriate historical cohort.
1,593 studies on the registry are indexed under Esophageal Neoplasms; 461 are open to participants now.
This study's planned enrollment of 216 is above the median of 58 across 1,171 interventional studies indexed under Esophageal Neoplasms.
Browse Esophageal Neoplasms studies →Erasmus Medical Center is the lead sponsor of 466 studies on the registry; 179 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Clinical N+ status should be determined by EUS or 18F-FDG PET/CT. Clinical M0 status must be determined by 18F-FDG PET/CT.
Exclusion Criteria:
Patients allocated to the TNT FLOT-CROSS arm will be treated with 4 cycles of FLOT chemotherapy followed by a response evaluation consisting of a CT-scan and upper endoscopy with bite-on-bite biopsies of the primary tumor site and of any other suspected lesions in the esophagus. Patients with distant metastases will go off-study. All other patients will proceed to CROSS chemoradiotherapy.
Drug: FLOT-CROSS or CROSS-FLOT
Patients allocated to the TNT CROSS-FLOT arm will be treated with CROSS chemoradiotherapy followed by a response evaluation consisting of a CT-scan and upper endoscopy with bite-on-bite biopsies of the primary tumor site and of any other suspected lesions in the esophagus. Patients with distant metastases will go off-study. All other patients will proceed to FLOT chemotherapy.
Drug: FLOT-CROSS or CROSS-FLOT
Randomization between TNT FLOT-CROSS and TNT CROSS-FLOT
Progression-free survival
To determine the progression-free survival (PFS) after TNT (both FLOT-CROSS and CROSS-FLOT), the PFS is defined as the time interval from randomization to the first event of locoregional failure after surgery, or locoregional progression leading to irresectability prior to surgery , progression to metastatic disease or death
Time frame: 24 months
Feasibility, completion of treatment
To assess the feasibility of TNT FLOT-CROSS and TNT CROSS-FLOT. Feasibility is defined as the proportion of patients that complete all 4 cycles of FLOT and all 5 chemotherapy cycles of CROSS, permitting dose reductions and delays.
Time frame: 30 months
Overall survival
To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on overall survival. OS is calculated from the date of randomization to the date of death due to any cause or, for patients alive at trial closure, date of last follow-up
Time frame: 24 months
Therapy-related toxicity
The number of patients with any major systemic therapy related toxicity, defined as grade ≥ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE ) version 5.0), up to one month after the last administration of TNT
Time frame: 30 months
Dose reductions of TNT
The number of patients requiring dose reductions or treatment delays during CROSS and FLOT
Time frame: 30 months
Need of G-CSF
The number of patients requiring G-CSF as primary or secondary prophylaxis
Time frame: 60 months
Postoperative morbidity and mortality
To assess the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on postoperative morbidity (Clavien-Dindo ≥3) and 30- and 90-day mortality.
Time frame: 42 months
Surgical-related outcomes
To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on surgery-related outcomes (i.e. proportion that proceed to esophagectomy as planned, radical (R0) resection rate).
Time frame: 42 months
Non-surgical related outcomes
To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on non-surgical outcomes: the proportion of patients who choose for active surveillance instead of surgery after CRE-2
Time frame: 30 months
Clinical response rate
To assess the clinical response rates after TNT FLOT-CROSS and TNT CROSS-FLOT. Clinical complete response (cCR) rate is defined as the percentage of patients without residual locoregional disease or distant metastases at CRE-2, measured by PET-scan and bite-on-bite biopsies with endoscopy and EUS.
Time frame: 42 months
Pathological response rate
To assess the pathological response rate after TNT FLOT-CROSS and TNT CROSS-FLOT. Pathological complete response (pCR) rate in those who underwent an oesophagectomy is defined as ypT0N0. Major pathological response in those who underwent oesophagectomy, defined as Mandard 1-2.
Time frame: 42 months
Distant metastases
To assess the proportion of distant metastases after TNT FLOT-CROSS and TNT CROSS-FLOT at 6 weeks after completion of treatment
Time frame: 30 months
Quality of life assessed by EORTC-C30
The quality of life will be assessed with the EORTC-C30 questionnaire
Time frame: 42 months
Quality of life assessed by EORTC QLQ-OG25
To determine the effect of TNT FLOT-CROSS and TNT CROSS-FLOT on quality of life, assessed by the QoL questionnaires: EORTC QLQ-OG25
Time frame: 42 months
The PD-L1 combined positive score (CPS)
The PD-L1 combined positive score (CPS) of TNT FLOT-CROSS and TNT CROSS-FLOT before treatment and in metastases. The PD-L1 CPS will be measured as a continuous variable. This will be measured using the 28-8 monoclonal antibody.
Time frame: 42 months
Predictive biomarkers
To collect blood at baseline, first clinical response evaluation (CRE-1), CRE-2 and postoperatively to enable future ctDNA based translational studies looking for biomarkers predictive of disease recurrence and early response.
Time frame: 63 months
Future ctDNA analysis
To collect tissue at baseline, CRE-1, CRE-2 and resection to enable future ctDNA based translational studies looking for biomarkers predictive of disease recurrence and early response.
Time frame: 63 months
Plan to share: No
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