Esophageal cancer is a major health burden in India, with squamous cell carcinoma (ESCC) accounting for nearly 80% of cases. Current multimodality treatments such as neoadjuvant chemotherapy (NACT), neoadjuvant chemoradiation (NACRT), perioperative chemotherapy, and adjuvant immunotherapy,show variable benefits and lack global consensus on the optimal approach for resectable locally advanced ESCC. High recurrence rates (40–50%) persist despite available treatments. Evidence shows promising activity of immunotherapy, especially nivolumab, in advanced and adjuvant settings, and early studies suggest improved pathological complete responses when used neoadjuvantly. However, these studies are limited and lack large randomized trials. There is also interest in evaluating low-dose immunotherapy, which may provide clinical benefit at significantly lower cost, particularly relevant for low-HDI settings. To address the uncertainty around the best treatment strategy, this study uses a Multi-Arm Multi-Stage (MAMS) randomized design to simultaneously compare multiple regimens and allow addition or dropping of arms over time.

The trial compares the current standard (NACRT plus surgery) with two experimental approaches that incorporate low-dose nivolumab:

1. Arm A: NACRT (CROSS regimen) followed by Surgery

2. Arm B: Neoadjuvant FLOT plus low-dose nivolumab followed by Surgery

3. Arm C: NACRT (CROSS) plus low-dose nivolumab followed by Surgery

The study will begin with a pilot/run-in phase in up to 5 centres to test feasibility. After successful completion, full recruitment will continue across participating sites.

Pre-Screening: All patients with potentially resectable ESCC at participating centres wil undergo review of available clinical and diagnostic information, including history, comorbidities, performance status, basic labs, imaging (CT/PET-CT), endoscopy, and other standard evaluations. Consent will be obtained for using biopsy samples in optional biomarker analyses.

Screening: Eligible patients (histologically proven ESCC, no prior treatment, appropriate stage, adequate organ function) will be counselled and undergo informed consent. Missing investigations will completed as per standard care. Patients with poor nutrition or uncontrolled diabetes will undergo 2–3 weeks of optimization before re-evaluation. The screening window is up to 21 days from consent.

Randomization: Patients meeting all eligibility criteria will receive a study ID and will be randomized centrally (1:1:1) to Arms A, B, or C using minimization, stratified by centre and nodal status. Additional endocrine labs will be performed for patients assigned to nivolumab-containing arms.

Treatment: Each arm has a defined neoadjuvant regimen, Arm A has weekly carboplatin plus paclitaxel with concurrent radiation (CROSS) for 5 weeks followed by Surgery within 8 weeks, Arm B has FLOT chemotherapy plus low-dose nivolumab every 14 days for 4 cycles followed by Surgery within 8 weeks and in Arm C patients will receive low-dose nivolumab 2 weeks prior to CROSS followed by CROSS regimen plus nivolumab (weeks 1, 3, 5) followed by Surgery within 8 weeks.

Before each treatment cycle, clinical assessment, toxicity review, and lab tests will be performed. Quality-of-life questionnaires (EORTC QLQ-C30, OES-18) will be collected at predefined time points. Pharmacokinetic samples for nivolumab will also be taken from consenting patients.

Surgery: Standardized esophagectomy procedures will be performed across centres. Postoperative complications will be monitored for 30 days and classified using ECCG/Clavien-Dindo criteria.

Follow up: Follow-up will start 3 months post-surgery and will continue every 3 months for 3 years, then 6 monthly till progression or death. Assessments include symptoms, clinical exam, toxicity evaluation, endocrine labs for immunotherapy arms, QoL questionnaires, and imaging (CT/PET-CT every 6 months for 3 years, then annually). After progression, only survival status and subsequent therapy will be recorded.