Evaluation of Total Neoadjuvant Therapy with Folinic Acid, Fluorouracil, and Docetaxel in Lymph Node-Positive Oesophagogastric Junction Adenocarcinoma

The primary objective of the study is to determine the **progression-free survival** at 2 years following Total Neoadjuvant Therapy (TNT) using either the TNT FLOT-CROSS or TNT CROSS-FLOT combination in patients with lymph node-positive adenocarcinoma of the oesophagus and oesophagogastric junction. This is clinically relevant as it aims to evaluate the effectiveness of these therapeutic regimens in delaying disease progression, which is crucial for improving patient outcomes in this aggressive cancer type.

Secondary objectives include:

• Assessing the feasibility of TNT FLOT-CROSS and TNT CROSS-FLOT.
• Determining the effect of these therapies on **overall survival**.
• Evaluating therapy-related **toxicity**.
• Assessing the impact on postoperative morbidity and mortality.
• Determining the effect on surgical and non-surgical outcomes.
• Evaluating clinical and pathological response rates.
• Assessing the proportion of distant **metastases**.
• Determining the effect on **quality of life**.

These secondary objectives are essential for understanding the broader implications of the treatment regimens, including their safety, efficacy, and impact on patient quality of life, which are critical factors in the management of oesophagogastric junction cancer and oesophageal cancer.

The clinical trial involves participants diagnosed with **oesophagogastric junction cancer** or **oesophageal cancer**. The study population includes both male and female subjects, with an age range starting from 18 years and extending to older adults, as indicated by the inclusion of age categories 3 and 4. The trial does not involve a vulnerable population. Participants were selected based on specific criteria, including the presence of resectable adenocarcinoma of the oesophagus or EGJ, adequate organ function, and an ECOG Performance Status of 0-1. Lifestyle considerations such as weight loss of less than 10% are noted. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of total neoadjuvant therapy for patients with lymph node-positive adenocarcinoma of the **oesophagus** and oesophagogastric junction. This phase II trial is structured as a randomized, double-blind, controlled study, aiming to determine the progression-free survival at two years post-treatment. The trial will involve a combination of chemotherapy regimens, specifically TNT FLOT-CROSS and TNT CROSS-FLOT, with the primary endpoint being the time interval from randomization to the first event of local failure, regional failure, progression to metastatic disease, or death. Secondary endpoints include overall survival, feasibility of completing all chemotherapy cycles, and the incidence of major systemic therapy-related toxicities.

The trial is expected to commence recruitment on July 1, 2025, and conclude by July 1, 2028. Participants will be involved in the study for a maximum treatment period of eight weeks, with the possibility of early termination if they experience significant adverse events or fail to comply with the study protocol. The study will include an initial screening visit to confirm eligibility based on criteria such as adequate organ function, absence of prior overlapping radiotherapy, and an ECOG performance status of 0-1. Following randomization, participants will undergo a series of study visits to monitor treatment response and manage any adverse effects. These visits will include regular assessments of tumor progression, blood tests to evaluate organ function, and imaging studies to detect metastases.

The end-of-study visit will occur approximately one month after the last administration of the total neoadjuvant therapy, during which final assessments of treatment efficacy and safety will be conducted. Participants will be monitored for any late-onset adverse events, and their health-related quality of life will be evaluated using standardized questionnaires. Conditions that may lead to early termination from the study include significant clinical deterioration, inability to undergo planned surgical procedures, or the participant's decision to withdraw consent. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and are fully aware of the study's nature and potential risks.

The clinical trial involves the administration of several **experimental medications**. The first medication is **Folinic Acid**, marketed as Folinezuur Kalceks 10 mg/ml, which is provided as a solution for injection or infusion. The pharmaceutical form is a solution for injection/infusion, and it is administered intravenously. The dosage is calculated based on body surface area, with a maximum daily dose of 200 mg/m² and a total maximum dose of 800 mg/m² over a treatment period of up to 8 weeks.

Another medication used in the trial is **Fluorouracil**, available as Fluorouracil Accord 50 mg/ml. This medication is also provided as a solution for injection or infusion and is administered intravenously. The dosing schedule is similar to Folinic Acid, with a maximum daily dose of 200 mg/m² and a total maximum dose of 800 mg/m² over 8 weeks.

**Docetaxel**, marketed as Docetaxel Eugia 20 mg/ml, is provided as a concentrate for solution for intravenous infusion. It is administered intravenously with a maximum daily dose of 50 mg/m² and a total maximum dose of 200 mg/m² over a treatment period of up to 8 weeks.

**Oxaliplatin**, available as Oxaliplatine Fresenius Kabi 5 mg/ml, is also a concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 85 mg/m² and a total maximum dose of 340 mg/m² over 8 weeks.

**Paclitaxel**, marketed as Paclitaxel Fresenius Kabi 6 mg/ml, is provided as a concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 50 mg/m² and a total maximum dose of 250 mg/m² over a treatment period of up to 5 weeks.

Lastly, **Carboplatin**, available as Carboplatin Accord 10 mg/ml, is a concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 2 mg/ml and a total maximum dose of 10 mg/ml over a treatment period of up to 5 weeks.

All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy and safety of these experimental medications in the treatment of lymph node-positive adenocarcinoma of the esophagus and esophagogastric junction.

The efficacy of the clinical trial titled "Total Neoadjuvant Therapy for lymph node-positive adenocarcinoma of the OESophagus and oesophagogastric junction: TNT-OES-2 trial" will be assessed using several primary and secondary endpoints. The primary endpoint is the **progression-free survival**, defined as the time interval from randomization to the first event of local failure, regional failure, progression to metastatic disease, or death. This will be measured at 2 years post-treatment.

Secondary endpoints include the feasibility of treatment, overall survival, and the incidence of major systemic therapy-related toxicity. Feasibility is determined by the proportion of patients completing all cycles of FLOT and CROSS chemotherapy, allowing for dose reductions and delays. Overall survival is calculated from the date of randomization to the date of death from any cause or the last follow-up for patients alive at trial closure. Toxicity is assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, focusing on grade ≥3 toxicities up to one month after the last administration of treatment.

Additional secondary endpoints involve the rate of mucositis, the need for dose reductions or treatment delays, the use of G-CSF prophylaxis, and the occurrence of serious adverse events. Surgical outcomes, such as morbidity and mortality, are monitored through the Dutch upper gastrointestinal cancer audit. The trial also evaluates the proportion of radical resections, clinical and pathological complete response rates, and distant dissemination rates. Health-related quality of life is assessed using EORTC QLQ-OG25 and EORTC-C30 questionnaires.