NEoadjuvant chemoradiotherapy for Esophageal squamous cell carcinoma versus Definitive chemoradiotherapy with salvage Surgery as needed (The NEEDS Trial)

The primary objective of the study is to demonstrate that **definitive chemoradiotherapy** (dCRT) with salvage esophagectomy as needed is non-inferior to neoadjuvant chemoradiotherapy (nCRT) followed by surgery in terms of overall survival for patients with operable, locally advanced esophageal squamous cell carcinoma. This is clinically relevant as it may offer a less invasive treatment option with comparable survival outcomes, potentially reducing surgical risks and improving patient quality of life.

Secondary objectives include: - To study prespecified health-related quality of life (HRQOL) endpoints relevant to esophageal cancer and the effects of treatment during treatment and survivorship. - To determine event-free survival, loco-regional and distal relapse rates, and histological chemoradiotherapy response in the surgical specimen in the control arm. - To investigate the overall health economic impact of each intervention. - To investigate the impact on nutritional status of each intervention during follow-up. - To investigate whether any of the endpoints are affected by the type of radiological follow-up, CT or PET-CT, in the dCRT with salvage esophagectomy as needed trial arm. - To investigate if there are any gender differences in any of the endpoints. - To exploratively analyze putative tissue and liquid biomarkers for response to the different treatment strategies and long-term benefit.

The clinical trial involves a total of **900 participants** diagnosed with **resectable locally advanced squamous cell carcinoma of the esophagus**. The study population includes both male and female subjects, aged between 18 and 80 years, with a performance status of ECOG 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on histopathologically confirmed squamous cell carcinoma in locally advanced stages, with technically resectable disease as determined by a local multidisciplinary team conference or tumor board. The trial includes individuals with adequate organ function and excludes those who are pregnant or breastfeeding, with women of childbearing potential required to have a negative pregnancy test prior to randomization. Participants are expected to use highly effective birth control methods during the study and for at least six months after the last treatment. The trial population is characterized by a diverse range of lifestyle considerations, although specific details on diet, physical activity, or habits are not provided. The study does include a vulnerable population, ensuring comprehensive ethical considerations are in place.

The clinical trial is designed to evaluate the efficacy of two treatment strategies for **esophageal squamous cell carcinoma**. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. Participants will be randomly assigned to receive either neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy with salvage surgery as needed. The primary objective is to assess overall survival, with a minimum follow-up period of three years. Secondary endpoints include event-free survival, loco-regional and distant relapse rates, and health-related quality of life.

The trial is expected to run until December 31, 2030, with recruitment having commenced on May 28, 2022. Participants will be involved in the study for a maximum treatment period of five weeks, with the possibility of early termination if adverse events occur or if the disease progresses. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and adverse events, and an end-of-study visit to assess final outcomes and collect data on long-term effects.

Inclusion criteria require participants to have histopathologically confirmed locally advanced squamous cell carcinoma of the esophagus, be between 18 and 80 years of age, and have adequate organ function. Exclusion criteria are not specified in the provided data. The trial will utilize intravenous administration of chemotherapeutic agents, including **fluorouracil**, **cisplatin**, **carboplatin**, **paclitaxel**, **oxaliplatin**, and **folinic acid**. The study aims to provide comprehensive data on the comparative effectiveness of the treatment strategies, contributing to improved therapeutic approaches for this condition.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is **Fluorouracil Accord**, a solution for injection/infusion with a concentration of 50 mg/ml. It is administered intravenously with a maximum daily dose of 1000 mg/m². The treatment period is limited to a maximum of 5 days. Participant compliance is monitored through regular assessments of dosing schedules and adherence to the intravenous administration protocol.

Another experimental medication used in the trial is **Cisplatin Accord**, provided as a 1 mg/ml solution for infusion. This medication is also administered intravenously, with a maximum daily dose of 75 mg/m² over a treatment period of up to 5 days. Compliance is ensured by monitoring the infusion process and adherence to the prescribed dosing regimen.

**Carboplatin Accord** is included as a comparator treatment in the trial. It is available as a 10 mg/ml solution for infusion and is administered intravenously. The maximum daily dose is set at 1 mg/m², with a treatment duration of up to 5 days. Compliance monitoring involves verifying the correct administration of the infusion and adherence to the dosing schedule.

**Paclitaxel Accord** is another comparator treatment, provided as a 6 mg/ml solution for infusion. It is administered intravenously with a maximum daily dose of 50 mg/m², over a treatment period of up to 5 days. Participant compliance is monitored through regular checks of the infusion process and adherence to the dosing protocol.

**Oxaliplatin Accord** is used as an additional experimental medication. It is a 5 mg/ml solution for infusion, administered intravenously. The maximum daily dose is 85 mg/m², with a treatment period of up to 5 days. Compliance is monitored by ensuring the correct administration of the infusion and adherence to the prescribed dosing schedule.

Lastly, **Calcium folinate Sandoz** is used as a comparator treatment. It is a 10 mg/ml solution for injection/infusion, administered intravenously. The maximum daily dose is 200 mg/m², with a treatment period of up to 5 days. Compliance monitoring involves verifying the correct administration of the injection/infusion and adherence to the dosing regimen.

Efficacy in the clinical trial titled "NEoadjuvant chemoradiotherapy for Esophageal squamous cell carcinoma versus Definitive chemoradiotherapy with salvage Surgery as needed (The NEEDS Trial)" will be assessed using several primary and secondary endpoints. The primary endpoints include overall survival (OS) with a minimum follow-up of 3 years and health-related quality of life (HRQOL) one year after randomization. Secondary endpoints encompass event-free survival (EFS), loco-regional and distant relapse rates, histopathological response according to Mandard, health economy assessments, surgical complications, treatment-related adverse events, nutritional outcomes, gender-stratified analyses, and exploratory analyses for biomarkers.

Overall survival will be measured by tracking patient status over a period of at least three years. Health-related quality of life will be evaluated using patient-reported outcomes at baseline and at 6, 12, 24, 36, and 60 months post-randomization. Event-free survival will be determined by the time to relapse, initiation of any anti-tumor therapy beyond the study treatments, or death. Histopathological response will be assessed in operated patients using the Mandard classification and other pathological data. Quality-adjusted life years (QALYs) will be calculated using the EQ-5D instrument, with data collected at specified intervals. Surgical complications will be classified according to the Esophagectomy Complications Consensus Group and Clavien-Dindo classification. Treatment-related adverse events will be coded by NCI.CTCAE criteria version 5.0. Nutritional outcomes will include assessments of weight development, dysphagia, and appetite. The trial will also explore potential tissue and liquid biomarkers for response to treatment strategies.