This is a prospective, randomized, phase II clinical study in patients with unresectable stage III-IVA esophageal squamous cell carcinoma (ESCC). Eligible patients will be randomly assigned in a 1:1 ratio to two treatment groups. The experimental group will receive 3 cycles of induction therapy with PD-1 antibody plus chemotherapy, followed by radiotherapy, and then maintenance therapy with PD-1 antibody monotherapy. The control group will receive concurrent chemoradiotherapy, followed by maintenance therapy with PD-1 antibody monotherapy. The primary endpoints are the complete response (CR) rate at 3 months after radiotherapy (assessed by investigators) and the 1-year progression-free survival (PFS) rate. Secondary endpoints include overall survival (OS), progression-free survival (PFS), duration of response, objective response rate (ORR), local-regional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), quality of life, and safety profile.

This is a prospective, randomized, two-arm, phase II clinical trial investigating induction chemo-immunotherapy followed by sequential radiotherapy versus concurrent chemo-immunotherapy plus radiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC).

Current standard of care for unresectable locally advanced ESCC is definitive concurrent chemoradiotherapy. However, outcomes remain suboptimal, with high rates of local recurrence and distant metastasis. The addition of PD-1 inhibitors to concurrent chemoradiotherapy has shown promising activity in recent studies, but optimal sequencing and integration of immunotherapy with radiotherapy are still under investigation.

This trial is designed to evaluate whether an induction strategy with chemo-immunotherapy followed by radiotherapy can improve response rates and long-term survival compared to the standard concurrent approach. Patients will be randomized to receive either:

• Experimental arm: Three cycles of induction chemo-immunotherapy, followed by definitive thoracic radiotherapy, then maintenance immunotherapy for up to one year.
• Control arm: Concurrent chemo-immunotherapy plus definitive thoracic radiotherapy, followed by maintenance immunotherapy for up to one year.

The primary objective is to compare the efficacy of the two regimens in terms of complete response and progression-free survival. Safety, tolerability, and quality of life will also be assessed to support the risk-benefit profile of each strategy.

Inclusion Criteria:

• Histologically or cytologically confirmed unresectable stage III-IVA esophageal squamous cell carcinoma (ESCC)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Adequate organ function (bone marrow, liver, renal, cardiac) within 2 weeks prior to randomization
• Measurable or evaluable disease per RECIST 1.1
• Willing to provide written informed consent

Exclusion Criteria:

• Previous radiotherapy to the chest or previous systemic chemotherapy for ESCC
• History of other malignancies within the last 5 years (except cured basal cell carcinoma or cervical carcinoma in situ)
• Severe comorbidities (uncontrolled hypertension, NYHA class III-IV heart failure, active infection, etc.)
• Known hypersensitivity to any study drugs (paclitaxel, cisplatin/carboplatin, PD-1 antibody)
• Pregnant or lactating women
• Participation in another clinical trial within 30 days prior to randomization