PD-1 Inhibitors Combined With Local Therapy at Different Timings in Oligometastatic ESCC (ESO-shanghai31)

A Phase III Randomized Controlled Study Investigating the Combination of PD-1 Inhibitors With Local Therapy Administered at Distinct Treatment Timings Among Patients With Oligometastatic Esophageal Squamous Cell Carcinoma

Although immunotherapy combined with chemotherapy has become the first-line standard regimen for advanced esophageal squamous cell carcinoma (ESCC) and improved clinical outcomes in advanced patients, the prognosis of patients with esophageal cancer remains unsatisfactory, with a 5-year overall survival rate below 20%. As an effective modality for local disease control, local radiotherapy has no established optimal sequencing schedule when combined with systemic therapy. The timing of radiotherapy intervention may directly affect treatment efficacy, treatment tolerance and quality of life of patients.

Several studies have explored the impact of radiotherapy timing in oligometastatic ESCC, yet substantial limitations persist in current evidence, resulting in a lack of unified guideline recommendations and wide heterogeneity in clinical practice. Most existing investigations are retrospective or small-sample prospective studies with high heterogeneity in study design, patient population selection and treatment regimens, yielding inconsistent conclusions that cannot support consistent clinical consensus.

To clarify the impact of radiotherapy timing on clinical efficacy in oligometastatic esophageal cancer, the investigator designed the present clinical trial. This study aims to compare the efficacy and safety of concurrent radiotherapy versus sequential radiotherapy on the basis of immunochemotherapy among patients with oligometastatic ESCC, so as to fill the evidence gap in existing research.

Study Overview

• Status: Recruiting
• Conditions: Esophageal Squamous Cell Carcinoma (ESCC)
• Intervention / Treatment: Other: Two arms adopt local intervention administered at distinct timings.

• Study Type: Observational
• Enrollment (Estimated): 354

Contacts and Locations

• Study Contact: Name: Guangmin Mao; Phone Number: 86-13732284526; Email: melly01@256.com
• Study Contact Backup: Name: Kuaile Zhao; Phone Number: 86-18017312534; Email: kuaile_z@fudan.edu.cn

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Guangmin Mao; Phone Number: 86-13732284526; Email: melly01@126.com
      • Principal Investigator: Kuaile Zhao, MD

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Oligometastatic ESCC

Description

Inclusion Criteria:

1. An eastern cooperative oncology group (ECOG) score of 0-1.
2. Histologically or cytologically confirmed diagnosis of esophageal squamous cell carcinoma.
3. Genuine oligometastasis (without a history of polyme-tastatic disease).
4. A total of four or fewer distant metastases, a maximum of three metastases in a single organ, and a maximum diameter of each metastatic lesion not exceeding 5 cm.
5. Biopsy of a metastatic lesion, PET/CT scan, and PD-L1 CPS (IHC 22C3) are not required but preferred.
6. No history of anti-PD-1/PD-L1 therapy. However, the following conditions are also eligible for inclusion: the use of anti-PD1/PD-L1 during induction/neoadjuvant/ concurrent therapy, or the use of anti-PD1/PD-L1 for maintenance therapy but not due to toxicity or disease progression interrupting anti-PD1/PD-L1 treatment, and the interruption has lasted for more than 3 months.
7. Adequate hematological, hepatic, renal, and coagula-tion function. Baseline laboratory tests required to assess eligibility, including ANC ≥ 1.5 × 10^9/L, PLT ≥ 80 × 10^9/L, Hb ≥85 g/L, ALB ≥28 g/L, TBIL ≤ 1.5 × ULN, ALT and AST ≤ 3 × ULN, Cr ≤ 1.5 × ULN or CrCl ≥40 mL/min, FEV1 ≥ 1 L. (liver metastases ALT and AST ≤ 5 × ULN, liver or bone metastases AKP ≤ 5 × ULN).(9) Enrolled voluntarily and signed informed consent by the patient himself or his legal representative.

Exclusion Criteria:

1. Pregnant or lactating women.
2. Lung V20 remains over 25%.
3. Confirmed diagnosis or clinical suspicion of esophageal fistula.
4. Recurrence in the irradiated field.
5. Active infection requiring systemic therapy.
6. Active autoimmune disease requiring systemic treat-ment in the past 2 years.
7. Immunodeficiency diagnosis, systemic steroid therapy, or any immunosuppressive treatment within 7 days before the first study treatment dose.
8. Patients with a known history of grade 3 or higher adverse events, which are unsuitable for Anti-PD-1 therapy or adverse events that have not recovered to ≤CTCAE grade 1 (except alopecia).
9. Uncontrolled pleural effusion, pericardial effusion, or pelvic ascites requiring repeated drainage.

10. Unable or rejection to receive Anti-PD-1 therapy or unable to comply with study requirements or follow-up schedule.(11) Inability to provide informed consent.

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Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Early Local Therapy Arm; Patients assigned to this study arm will initiate local therapy prior to the administration of the first two cycles of systemic treatment (immunotherapy or chemoimmunotherapy).	Other: Two arms adopt local intervention administered at distinct timings.; Both study arms receive chemoimmunotherapy combined with local intervention modalities, which encompass radiotherapy, surgery and ablation. In the early local therapy arm, local intervention is initiated within 2 cycles of chemoimmunotherapy, whereas patients in the delayed local therapy arm start local intervention after completing 4 cycles of chemoimmunotherapy.
Delayed Local Therapy Arm; Patients assigned to this study arm will initiate local therapy after completion of the first four cycles of systemic treatment (immunotherapy or chemoimmunotherapy).	Other: Two arms adopt local intervention administered at distinct timings.; Both study arms receive chemoimmunotherapy combined with local intervention modalities, which encompass radiotherapy, surgery and ablation. In the early local therapy arm, local intervention is initiated within 2 cycles of chemoimmunotherapy, whereas patients in the delayed local therapy arm start local intervention after completing 4 cycles of chemoimmunotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression free survival (PFS）	PFS is defined as the time interval between the date of the first treatment and the date of first confirmed disease progression or death from any cause. If the patient does not have tumor progression or death at the time of data analysis, the time of the last tumor evaluation will be used as the endpoint for PFS.	3-years
overall survival (OS)	the interval between the date of first systemic treatment and the date of death from any cause, and for patients who are still alive at the time point of the final analysis, the time of their last contact will be used as the survival time.	3-years

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Study Director: Kuaile Zhao, MD, Fudan University

Study record dates

Study Major Dates

• Study Start (Estimated): July 15, 2026
• Primary Completion (Estimated): July 15, 2029
• Study Completion (Estimated): July 15, 2031

Study Registration Dates

• First Submitted: July 2, 2026
• First Submitted That Met QC Criteria: July 9, 2026
• First Posted (Actual): July 13, 2026

Study Record Updates

• Last Update Posted (Actual): July 13, 2026
• Last Update Submitted That Met QC Criteria: July 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Anti-PD-1; Radiotherapy; Esophageal Squamous Cell Carcinoma; Oligometastatis
• 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
• Other Study ID Numbers: ESO-shanghai 31

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No