Neoadjuvant Short-Course Radiotherapy Plus Tislelizumab and Chemotherapy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma

Study Protocol Full Document Official Title Neoadjuvant Short-Course Radiotherapy Followed by Tislelizumab Combined With Chemotherapy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma: A Prospective, Multicenter, Exploratory Study Acronym SCR-TILES-ESCC Brief Summary This is a prospective, randomized, two-arm, parallel-group, multicenter, exploratory Phase II clinical trial. It aims to evaluate the efficacy and safety of neoadjuvant short-course radiotherapy followed by tislelizumab plus chemotherapy in participants with locally advanced resectable esophageal squamous cell carcinoma (ESCC). Eligible participants will be randomized 1:1 to receive low-dose or high-dose short-course radiotherapy, followed by 3 cycles of tislelizumab, nab-paclitaxel, and carboplatin. Surgery will be performed 4-6 weeks after the last neoadjuvant treatment. The primary endpoint is pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR) rate, objective response rate (ORR), R0 resection rate, downstaging rate, 3-year event-free survival (EFS), 3-year overall survival (OS), safety, and quality of life. A total of 50 participants will be enrolled. Randomization will be stratified by tumor location, clinical T stage, and clinical N stage via an EDC/IWRS system using a stratified block design.

Detailed Description This is a prospective, randomized, two-arm, parallel-group, multicenter, exploratory Phase II clinical trial designed to evaluate the efficacy and safety of neoadjuvant short-course radiotherapy followed by tislelizumab combined with chemotherapy in participants with locally advanced resectable esophageal squamous cell carcinoma (ESCC).

• Study Rationale Neoadjuvant chemoradiotherapy followed by surgery is the standard of care for locally advanced esophageal cancer. However, recurrence remains high, and treatment-related toxicities may limit clinical application. Immunotherapy combined with chemotherapy has demonstrated promising pathological response rates in the neoadjuvant setting for ESCC. Radiotherapy can induce immunogenic cell death and enhance the anti-tumor effect of immune checkpoint inhibitors. This trial investigates a novel sequential strategy: short-course radiotherapy followed by tislelizumab plus chemotherapy, to optimize efficacy while minimizing perioperative complications.
• Study Design

This is a randomized, controlled, parallel-group Phase II study. Eligible participants will be randomized in a 1:1 ratio to two treatment groups via an electronic data capture (EDC) / interactive web randomization system (IWRS) using stratified block randomization. Stratification factors are:

Tumor location (upper thoracic esophagus / middle thoracic esophagus / lower thoracic esophagus) Clinical T stage (cT1-2 vs. cT3-4a) Clinical N stage (cN0 vs. cN+) Block size will be randomly set to 4 or 6 to ensure allocation concealment. Total planned enrollment: 50 participants.

• Study Population Inclusion Criteria Voluntarily signed written informed consent. Age 18-75 years, inclusive. Expected survival ≥ 3 months. Clinically judged to be resectable with expected R0 resection. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Histologically confirmed, treatment-naive, locally advanced resectable non-cervical esophageal squamous cell carcinoma: T1N1-3M0 or T2-4aN0-3M0 (T2 ≥3 cm or poorly differentiated).

No suspicious metastatic cervical lymph nodes on neck ultrasound or enhanced CT; no distant metastasis on imaging.

Presence of measurable tumor lesions. Adequate organ function confirmed by screening laboratory tests. Fertile males and females of childbearing potential agree to use effective contraception during study treatment and for 6 months after the last dose.

Good compliance with study follow-up. Exclusion Criteria Previous treatment with PD-1/PD-L1 inhibitors or other T-cell targeted agents. Active or suspected autoimmune disease. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage.

History of ≥ Grade 2 interstitial lung disease. Systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressants within 14 days before first study treatment.

Immunodeficiency disease, organ transplantation, or allogeneic hematopoietic stem cell transplantation.

Live vaccine within 4 weeks before first study treatment. Severe cardiovascular or cerebrovascular disease. Uncontrolled severe comorbidities or active infection requiring systemic antibiotics.

HIV positive; active hepatitis B or hepatitis C infection. Active tuberculosis. Other active malignancy within the past 2 years. History of drug abuse or psychiatric disorder. Pregnant or lactating female. Any other condition that may increase study risk or interfere with result interpretation (investigator's judgment).

• Treatment Interventions Group A: Low-dose radiotherapy group Radiotherapy: 10 Gy in 5 fractions (2.0 Gy per fraction)

Two days after radiotherapy:

Tislelizumab 200 mg IV Day 1 Q3W Nab-paclitaxel 125 mg/m² IV Day 1, Day 8 Q3W Carboplatin AUC=5 IV Day 1 Q3W 3 cycles total Group B: High-dose radiotherapy group Radiotherapy: 15 Gy in 5 fractions (3.0 Gy per fraction)

Two days after radiotherapy:

Tislelizumab, nab-paclitaxel, carboplatin same as Group A 3 cycles total Surgery Surgery will be performed 4-6 weeks after completion of the third neoadjuvant cycle. Surgical approaches include McKeown esophagectomy, Ivor-Lewis esophagectomy, open, thoracoscopic, or robotic-assisted surgery. All procedures will aim for R0 resection.

• Randomization This study will use a 1:1 randomized, stratified, block randomization design implemented via the EDC/IWRS system. Randomization will be stratified by tumor location, clinical T stage, and clinical N stage. A random block size (4 or 6) will be applied within each stratum to ensure balanced group allocation and effective allocation concealment. The randomization sequence will be generated by an independent statistician and securely stored in the EDC/IWRS system. Investigators, patients, and outcome assessors will be unaware of the block size and randomization list to avoid selection bias.
• Study Assessments Tumor Evaluation Baseline, pre-Cycle 3, pre-surgery: enhanced chest CT/MRI Response evaluated by RECIST v1.1 Postoperative pathology: tumor regression, residual disease, lymph nodes, margin status, pTNM stage Safety Assessments Adverse events (AEs) graded by CTCAE v5.0 Monitoring of AEs, SAEs, and immune-related AEs (irAEs) Laboratory tests, ECG, echocardiography, physical exams at each visit Quality of Life Assessed by SF-36 questionnaire
• Study Endpoints Primary Endpoint Pathological Complete Response (pCR) rate: no residual viable tumor cells in primary tumor bed and all sampled lymph nodes.

Secondary Endpoints Major Pathological Response (MPR) rate: residual viable tumor ≤10% Objective Response Rate (ORR): CR + PR per RECIST v1.1 R0 resection rate Downstaging rate 3-year Event-Free Survival (EFS) 3-year Overall Survival (OS) Safety profile Quality of life

• Follow-up Plan Safety follow-up: 30 (±7) days after last study treatment Survival follow-up: every 3 months for 2 years, every 6 months up to 5 years, then annually Assessments: physical exam, chest CT, tumor markers, blood biochemistry, survival status
• Statistical Methods pCR, MPR, ORR, R0 resection rate, downstaging rate: descriptive statistics (n, %, 95%CI) EFS, OS: Kaplan-Meier method, log-rank test Safety: frequency and severity summary QoL: t-test/ANCOVA (between groups); paired t-test (within groups)
• Study Timeline First patient enrollment: Q3 2026 Last patient enrollment: Q1 2028 Study completion: Q2 2029

Inclusion criteria

• Voluntarily provided written informed consent prior to any study-related procedures
• Aged 18 to 75 years, male or female
• Life expectancy of at least 3 months
• Predicted to achieve R0 surgical resection
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Histologically confirmed, treatment-naive, resectable locally advanced thoracic esophageal squamous cell carcinoma (ESCC) meeting the staging criteria: T1 N1-3 M0 or T2-4a N0-3 M0 (T2 ≥3 cm or poorly differentiated). No suspected metastatic cervical lymph nodes (except for upper thoracic esophageal cancer regional lymph nodes) on neck ultrasound or contrast-enhanced CT, and no distant metastasis on imaging
• Presence of measurable tumor lesions.
• Adequate organ function defined by laboratory parameters: Absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelet count ≥100×10⁹/L; hemoglobin ≥90 g/L. Total bilirubin ≤1.5×ULN; AST and ALT ≤2.5×ULN. Serum creatinine ≤1.5×ULN or calculated creatinine clearance ≥60 mL/min. INR ≤1.5, PT and APTT ≤1.5×ULN
• Men and women of childbearing potential must use effective contraception during treatment and for 6 months after the last dose of study treatment
• Good compliance and ability to complete scheduled follow-up.

Exclusion criteria

• Prior treatment with PD-1/PD-L1 inhibitors or other immunomodulatory agents targeting T-cell receptors (e.g., CTLA-4, OX40)
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage
• Active or suspected autoimmune disease, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, except type 1 diabetes controlled by replacement therapy, hypothyroidism, or skin disorders not requiring systemic therapy
• History of grade ≥2 interstitial lung disease
• Systemic corticosteroids (>10 mg prednisone daily or equivalent) or other immunosuppressive agents within 14 days before first study treatment
• Primary or acquired immunodeficiency, organ transplantation, allogeneic hematopoietic stem cell transplantation
• Live vaccine within 4 weeks before first study treatment
• Severe uncontrolled cardiovascular or cerebrovascular disease: Uncontrolled hypertension or pulmonary hypertension. Unstable angina, myocardial infarction, coronary artery bypass grafting, or stent implantation within 6 months. NYHA class ≥2 chronic heart failure. Left ventricular ejection fraction (LVEF) <50%.

Clinically significant arrhythmia requiring treatment. Cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 6 months. Uncontrolled active infection requiring systemic antibiotics. Positive HIV test, active hepatitis B or hepatitis C infection (exceptions: HBV DNA <500 IU/mL; HCV RNA undetectable).

Active pulmonary tuberculosis (TB). Other active malignancy within the previous 2 years, except adequately treated thyroid cancer, carcinoma in situ of the cervix, basal/squamous cell skin cancer, or ductal carcinoma in situ of the breast

• History of drug abuse or psychiatric disorder
• Pregnant or lactating women
• Any other severe medical, psychiatric, or laboratory abnormality that, in the investigator's opinion, would increase study-related risk or interfere with result interpretation.