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

Neoadjuvant Short-Course Radiotherapy Followed by Tislelizumab Combined With Chemotherapy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma: A Prospective, Multicenter, Exploratory Study

Neoadjuvant Short-Course Radiotherapy Followed by Tislelizumab Plus Chemotherapy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma 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 combined with chemotherapy in participants with locally advanced resectable esophageal squamous cell carcinoma (ESCC).

Eligible participants will be randomized in a 1:1 ratio to receive either low-dose or high-dose short-course radiotherapy, followed by tislelizumab, nab-paclitaxel, and carboplatin for 3 cycles. Surgery will be performed 4-6 weeks after the last neoadjuvant treatment.

Primary endpoint: Pathological Complete Response (pCR) rate. Secondary endpoints: 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 profile, and quality of life.

Approximately 50 participants will be enrolled. Randomization will be stratified by tumor location, clinical T stage, and clinical N stage using a stratified block design via an EDC/IWRS system.

Study Overview

• Status: Not yet recruiting
• Conditions: Esophageal Squamous Cell Carcinoma (ESCC)
• Intervention / Treatment: Drug: Albumin-bound paclitaxel; Radiation: Low-dose Short-course Radiotherapy; Drug: Tislelizumab Combined With Chemotherapy for 3 cycles; Drug: Carboplatin (AUC 5); Radiation: High-dose Short-course Radiotherapy

Detailed Description

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).

1. 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.

2. 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.

3. 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).

4. 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.

5. 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.
6. 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

7. 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

8. 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
9. 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)
10. Study Timeline First patient enrollment: Q3 2026 Last patient enrollment: Q1 2028 Study completion: Q2 2029

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Xiaolong Yan, Doctor; Phone Number: 029-84717551; Email: 18710959981@163.com

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710038
      • Tangdu Hospital, Fourth Military Medical University
      • Contact: Xiaolong Yan, Doctor; Phone Number: 029-84717551; Email: 18710959981@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-Dose Radiotherapy + Tislelizumab + Chemotherapy; Neoadjuvant low-dose short-course radiotherapy (10 Gy in 5 fractions) followed by tislelizumab combined with nab-paclitaxel and carboplatin for 3 cycles, then surgical resection.	Drug: Albumin-bound paclitaxel; Albumin-bound paclitaxel at a dose of 125 mg/m² is administrated intravenously on day 1 and day 8 of each 3-week cycle, for a total of 3 cycles.; Radiation: Low-dose Short-course Radiotherapy; Neoadjuvant short-course radiotherapy with a total dose of 10 Gy, delivered in 5 daily fractions of 2.0 Gy per fraction, administered consecutively before systemic combination therapy.; Drug: Tislelizumab Combined With Chemotherapy for 3 cycles; Anti-PD-1 monoclonal antibody tislelizumab 200 mg is given by intravenous infusion on day 1 of each 3-week cycle, for up to 3 cycles in the neoadjuvant treatment phase.; Drug: Carboplatin (AUC 5); Carboplatin is given intravenously on day 1 of each cycle at a targeted AUC of 5, repeated every 3 weeks for 3 cycles as part of neoadjuvant combination regimen.
Experimental: High-Dose Radiotherapy + Tislelizumab + Chemotherapy; Neoadjuvant high-dose short-course radiotherapy (15 Gy in 5 fractions) followed by tislelizumab combined with nab-paclitaxel and carboplatin for 3 cycles, then surgical resection.	Drug: Albumin-bound paclitaxel; Albumin-bound paclitaxel at a dose of 125 mg/m² is administrated intravenously on day 1 and day 8 of each 3-week cycle, for a total of 3 cycles.; Drug: Tislelizumab Combined With Chemotherapy for 3 cycles; Anti-PD-1 monoclonal antibody tislelizumab 200 mg is given by intravenous infusion on day 1 of each 3-week cycle, for up to 3 cycles in the neoadjuvant treatment phase.; Drug: Carboplatin (AUC 5); Carboplatin is given intravenously on day 1 of each cycle at a targeted AUC of 5, repeated every 3 weeks for 3 cycles as part of neoadjuvant combination regimen.; Radiation: High-dose Short-course Radiotherapy; Neoadjuvant short-course radiotherapy with a total dose of 15 Gy, delivered in 5 daily fractions of 3.0 Gy per fraction, administered consecutively before systemic combination therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR) Rate	The primary outcome measure is the rate of pathological complete response (pCR) after completion of neoadjuvant treatment. Pathological complete response is defined as the absence of residual invasive cancer cells in the primary esophageal tumor bed and all sampled regional lymph nodes, confirmed by postoperative pathological examination by a qualified pathologist.	Within 1 week after surgical resection.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response(MPR) Rate	Major pathological response is defined as the residual tumor burden being ≤10% of the primary tumor bed. This outcome measures the proportion of participants who achieve major pathological response after receiving the study intervention, reflecting the effectiveness of the treatment regimen in reducing tumor burden.	Within 1 week after surgical resection
R0 Resection Rate	R0 resection rate refers to the proportion of participants who achieve complete surgical resection with negative surgical margins (no residual tumor tissue at the resection edges), which is an important indicator of surgical efficacy and long-term prognosis.	At the time of surgical resection
Incidence of Treatment-Related Adverse Events (CTCAE v5.0)	To evaluate the incidence, type and severity of treatment-related adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 in all enrolled participants.	From start of neoadjuvant treatment through 30 days after last study treatment
Objective Response Rate (ORR)	The proportion of participants achieving complete response (CR) or partial response (PR) evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to surgical resection
3-Year Event-Free Survival (EFS) Rate	Event-free survival defined as the time from randomization to first occurrence of local recurrence, distant metastasis, tumor progression, or death from any cause, whichever comes first.	Followed up for up to 3 years from the date of randomization.
3-Year Overall Survival (OS) Rate	Overall survival defined as the time from randomization to death from any cause; the proportion of participants alive at 3 years after randomization will be reported.	Up to 3 years from randomization
Change in SF-36 Quality of Life Scale Score	The 36-Item Short Form Health Survey (SF-36). The total score ranges from 0 to 100; higher scores indicate better health-related quality of life. Changes in health-related quality of life measured by the SF-36 questionnaire across physical, mental and social function domains.	Baseline prior to neoadjuvant therapy, Perioperative (after all neoadjuvant cycles before surgery), 3 months post-surgery, 6 months post-surgery, 12 months post-surgery

Collaborators and Investigators

• Sponsor: Tang-Du Hospital

Publications and helpful links

General Publications

• Li C, Han Y, Zhao S, Kang X, Zheng Y, Cao Y, Yan Y, Shi L, Wang X, Lu T, Zou G, Li H, Che J, Xiang J, Zhu L, Hang J, Zhang Y, Jin R, Han D, Chen X, Jing H, Guo W, Cheng Z, Zhao L, Chen X, Yu B, Li J, Li B, Li Y, Li H. Preoperative pembrolizumab (anti-PD-1 antibody) combined with chemoradiotherapy for esophageal squamous cell carcinoma: a phase 1/2 trial (PALACE-2). Signal Transduct Target Ther. 2025 Nov 28;10(1):386. doi: 10.1038/s41392-025-02477-4.
• Ghalehtaki R, Amini A, Abyaneh R. Optimizing neoadjuvant radiotherapy for locally advanced esophageal squamous cell carcinoma: a comprehensive review on the role of concomitant or sequential immune checkpoint inhibitors. Esophagus. 2025 Jan;22(1):5-18. doi: 10.1007/s10388-024-01097-1. Epub 2024 Nov 19.
• He W, Bai H, Lv J, Tang P, Hu T, Zhou H, Xiao W, Peng L, Liu G, Wang K, Fang Q, Qi Y, Liang L, Zheng X, Qing H, Chen Y, Zhou Y, Xie W, Han Y, Leng X. Neoadjuvant chemotherapy or chemoradiotherapy plus sintilimab versus neoadjuvant chemoradiotherapy for locally advanced oesophageal squamous cell carcinoma: a study protocol of a multicentre, randomised, controlled, phase III trial (SCIENCE study). BMJ Open. 2025 Jun 4;15(6):e095828. doi: 10.1136/bmjopen-2024-095828.

Study record dates

Study Major Dates

• Study Start (Estimated): July 10, 2026
• Primary Completion (Estimated): January 31, 2028
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: May 24, 2026
• First Submitted That Met QC Criteria: June 28, 2026
• First Posted (Actual): July 1, 2026

Study Record Updates

• Last Update Posted (Actual): July 1, 2026
• Last Update Submitted That Met QC Criteria: June 28, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Neoadjuvant Therapy; Esophageal Squamous Cell Carcinoma; PD-1 Inhibitor; Short-Course Radiotherapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Esophageal Diseases; Carcinoma; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Therapeutics; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Coordination Complexes; Taxoids; Cyclodecanes; Diterpenes; Albumins; Paclitaxel; Albumin-Bound Paclitaxel; Carboplatin; Drug Therapy
• Other Study ID Numbers: IIT202601-03-KYB-03-XW

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: De-identified individual participant data (IPD) will not be made available to other researchers. This is an investigator-initiated exploratory trial with no formal data sharing platform or repository established.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No