The goal of this clinical trial is to learn if adding high-dose-rate (HDR) brachytherapy can improve outcomes in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who have already received external beam radiotherapy (EBRT), chemotherapy, and the immune therapy drug nivolumab.

The main questions it aims to answer are:

• Does HDR brachytherapy reduce the chance of the cancer coming back in the esophagus or nearby areas within 12 months?
• What side effects or safety issues occur when HDR brachytherapy is given after EBRT, chemotherapy, and nivolumab?

Participants will:

• Receive 1-2 sessions of HDR brachytherapy delivered through a thin tube placed inside the esophagus, within three weeks after starting nivolumab.
• Continue nivolumab and be monitored with regular follow-up visits, imaging tests, and blood samples to check treatment response and safety.

This is a single-arm, phase II clinical trial designed to evaluate the efficacy and safety of high-dose-rate (HDR) esophageal brachytherapy in combination with external beam radiotherapy (EBRT), chemotherapy, and immune checkpoint inhibition with nivolumab in patients with locally advanced esophageal squamous cell carcinoma (ESCC).

Eligible patients include those with stage III-IVB ESCC who have previously received EBRT with concurrent platinum-fluoropyrimidine chemotherapy and who have initiated nivolumab therapy. HDR brachytherapy (5-12 Gy in 1-2 fractions) will be administered within three weeks following the start of nivolumab.

The primary endpoint is the 12-month cumulative incidence of locoregional failure. Secondary endpoints include overall survival, progression-free survival, overall response rate, disease control rate, safety and tolerability, tube-dependence-free survival, tumor-infiltrating lymphocyte density, and circulating tumor DNA dynamics.

The rationale for this trial is that HDR brachytherapy offers precise dose escalation directly to the esophageal tumor, which may improve locoregional control beyond EBRT alone. In addition, the combination of localized high-dose irradiation with systemic immune checkpoint inhibition has the potential to enhance antitumor immunity, thereby improving clinical outcomes in this high-risk population.

Inclusion Criteria:

• Age of 18-85 years, with ECOG performance 0-2.
• Locally-advanced esophageal squamous cell carcinoma with clinical stage III, IVA with biopsy proven.
• Prior treatment with EBRT (40-50.4 Gy in 20-28 fractions) and platinum + fluoropyrimidine chemotherapy, with residual or progressive disease, and deemed inoperable or unable to undergo surgery.
• No prior exposure to ICIs and had received first cycle of nivolumab after CCRT.
• Biopsy proven with PD-L1 [tumor cell (TC) ≥ 1%]
• Required at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
• Patients with limited stage IVB disease (e.g., non-visceral lymph node metastasis) may be enrolled if the primary tumor is locally dominant and suitable for brachytherapy, based on investigator's discretion.

Exclusion Criteria:

• Current or past history of severe hypersensitivity to any other antibody products.
• Patients with any metastasis in the brain or meninx that is symptomatic or requires treatment.
• Patients with active, known or suspected autoimmune disease
• Stenosis of esophageal lumen that cannot performed brachytherapy
• Involvement of tracheal mucosa or bronchial mucosa.
• The distribution of the lesions of interest exceeds 10 cm range.
• The patient is participating in other interventional clinical trials associated with immunotherapy.
• The patient is scheduled to undergo esophagostomy.