Patients diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC) that is deemed unresectable face a bleak prognosis. Recent phase 1/2 studies have demonstrated the efficacy and safety of augmenting neoadjuvant concurrent chemoradiotherapy with immunotherapy in treating resectable ESCC. The present study is a prospective, 3-arm, randomized trial that seeks to evaluate the efficacy of diverse conversion therapy modalities in patients with unresectable ESCC. The study objectives include R0 resection rate, treatment-related adverse events, morbidity and mortality, 1-year progression-free survival (PFS), and 1-year overall survival (OS) rates.

Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity/specificity for programmed cell death protein 1 (PD-1). Tislelizumab was specifically engineered to minimize binding to FcɤR on macrophages, thereby abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy.

This trial will provide valuable insights into the effectiveness of the three conversion therapy modalities and help to inform clinical decision-making for patients with unresectable locally advanced ESCC.

Inclusion Criteria:

1. Histologically confirmed sorely ESCC without other histology subtypes.
2. Thoracic esophageal cancer.
3. No prior anti-cancer treatment, including but not limited to surgery, radiotherapy, chemotherapy, targeted therapy, or immunotherapy.
4. Borderline unresectable locally advanced ESCC deemed by investigators as suspicious of but not confirmed T4b according to the American Joint Committee on Cancer (AJCC) 8th edition staging classification or extracapsular lymph node involvement (ELNI).
5. The Karnofsky Performance Scale (KPS) ≥70.
6. Normal primary organ functions, including but not limited to hemoglobin (Hb) ≥ 100g/L; white blood cell (WBC) ≥ 3.5×10*9/L; neutrophil count (NEUT) ≥ 1.5×10*9/L; platelets (PLT) ≥ 100×10*9/L; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5×UNL; total bilirubin (TBIL) ≤ 1.5×UNL; creatinine ≤ 1.5UNL; blood urea nitrogen (BUN) ≤ 1.0×UNL.

Exclusion Criteria:

1. Synchronous and metachronous primary malignancies in but not limited to the upper aerodigestive tract, except for cured basal cell carcinoma of the skin and carcinoma in situ of the cervix.
2. Patients have undergone any type of anti-cancer treatment.
3. Baseline clinical stage M1 per AJCC 8th edition of staging classification, including supraclavicular lymph node metastases.
4. Investigators assessed major vessel involvement with high-risk hemorrhage.
5. A higher probability of esophageal perforation during conversion therapy.
6. Active infectious diseases, including but not limited to tuberculosis, hepatitis B virus, or hepatitis C virus.
7. Allergic to anti-cancer agents, including but not limited to anti-PD-1 or chemotherapy agents.
8. Given cardiopulmonary dysfunction, patients can not tolerate conversion therapy or surgery.
9. Pregnant or lactating women and women of childbearing potential who lacked effective contraception.
10. Non-compliance with the inclusion criteria judged by investigators.