Early Response-guided Sequential Radiotherapy After Chemoimmunotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (Keystone006)

Inclusion Criteria:

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Participants must meet all of the following criteria:

Provide written informed consent before enrollment.

Age >18 years, male or female.

Histologically confirmed thoracic esophageal squamous cell carcinoma (ESCC).

Locally advanced, resectable disease according to AJCC/UICC 8th edition TNM staging system, defined as:

cT3-4aN0-2M0 or cT1-2N1-2M0;

No evidence of distant metastasis;

Considered initially resectable by a multidisciplinary surgical team.

Patients who have received neoadjuvant chemoimmunotherapy and have measurable disease response assessment according to RECIST v1.1, including complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).

At least one measurable lesion according to RECIST version 1.1.

Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Expected survival time >6 months.

Adequate organ function meeting the following criteria:

Bone marrow function:

Absolute neutrophil count ≥1,500/mm³;

Platelet count ≥100,000/mm³;

Hemoglobin ≥9 g/dL.

Renal function:

Serum creatinine ≤1.5 mg/dL and/or creatinine clearance ≥60 mL/min.

Hepatic function:

Total bilirubin ≤1.5 × upper limit of normal (ULN);

AST and ALT ≤1.5 × ULN.

Participants of childbearing potential must agree to use medically approved contraception during study treatment and for 3 months after completion of treatment. Female participants of childbearing potential must have a negative serum or urine pregnancy test within 7 days before enrollment and must not be breastfeeding.

Willingness and ability to comply with study procedures, safety assessments, and survival follow-up.

Exclusion Criteria:

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Participants will be excluded if any of the following criteria apply:

Evidence of distant metastasis.

Previous or concurrent malignancy, except adequately treated basal cell carcinoma of skin or cervical carcinoma in situ.

Previous thoracic radiotherapy.

Previous treatment with PD-1, PD-L1, or CTLA-4 inhibitors, or known hypersensitivity to PD-1 inhibitors or macromolecular protein products.

Active autoimmune disease or history of clinically significant autoimmune disease requiring systemic treatment.

Current use of immunosuppressive therapy or systemic corticosteroids exceeding the equivalent of prednisone 10 mg/day within 2 weeks before enrollment.

Clinically significant ascites or pleural effusion requiring therapeutic drainage.

Uncontrolled cardiovascular disease, including:

NYHA class II or higher heart failure;

Unstable angina;

Myocardial infarction within 1 year;

Clinically significant arrhythmias requiring treatment.

Significant coagulation abnormalities, bleeding tendency, or ongoing thrombolytic/anticoagulant therapy.

Active gastrointestinal disorders associated with bleeding or perforation risk, including esophageal varices, active gastric/duodenal ulcer, ulcerative colitis, portal hypertension, or active tumor bleeding.

History of severe bleeding, clinically significant hemoptysis, or thromboembolic events within specified periods.

Active infection or unexplained fever >38.5°C before treatment initiation.

Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks before study treatment.

History or evidence of interstitial lung disease, pulmonary fibrosis, radiation pneumonitis, drug-induced pneumonitis, pneumoconiosis, or severe pulmonary impairment.

Known immunodeficiency, including HIV infection, or active hepatitis infection requiring exclusion according to protocol criteria.

Participation in another clinical trial within 1 month before enrollment or concurrent systemic anticancer therapy.

Receipt of live vaccines within 4 weeks before treatment or planned live vaccination during study treatment.

Known history of substance abuse, alcoholism, or drug abuse.

Inability or unwillingness to comply with study-related procedures, examinations, or required costs.

Any other medical, psychological, social, or safety-related condition judged by the investigator to make the participant unsuitable for study participation.