Radiotherapy Combined With Immunochemotherapy in Metastatic Esophageal Squamous Cell Carcinoma

First-line Anti-PD-1 Therapy Plus Chemotherapy With or Without Radiotherapy in Metastatic Esophageal Squamous Cell Carcinoma: A Phase II Multi-center Trial (SCR-ESCC-01)

SCR-ESCC-01 is a multicenter, randomized, phase II study aiming to investigate the benefit of early involvement of low-dose radiotherapy(LDRT) and conventionally fractionated radiotherapy(CFRT) in the first-line anti-PD-1 based treatment of metastatic ESCC. It begins with a safety run-in phase, followed by a randomized controlled comparison against standard immunochemotherapy.

In metastatic esophageal squamous cell carcinoma (ESCC), radiotherapy is often administered for palliative purposes to alleviate dysphagia. Recent studies suggest that combining radiotherapy with immunotherapy may have a synergistic effect on treatment outcomes. This study aims to investigate the efficacy and safety of adding Low-Dose Radiotherapy (LDRT) combined with Conventionally Fractionated Radiotherapy (CFRT) to first-line immunochemotherapy.

Study Design:The protocol follows a sequential two-phase design:

1. Phase IIa (Safety Run-in / Pilot Phase):An initial cohort of approximately 20-25 patients will receive the experimental regimen (LDRT + CFRT + Immunochemotherapy) in a single-arm setting. The primary objective of this phase is to evaluate safety and feasibility.

   Safety Stopping Rule: A strict stopping rule is defined for the transition to the randomized phase. If 2 or more patients in the run-in cohort experience treatment-related death (Grade 5 Treatment-Related Adverse Events), the study will be terminated and will not proceed to Phase IIb.

2. Phase IIb (Randomized Controlled Phase):Upon confirmation that the safety criteria are met (i.e., < 2 treatment-related deaths and acceptable toxicity profile), subsequent patients will be randomly assigned (1:1) to:

Arm A (Experimental): PD-1 inhibitor plus chemotherapy (paclitaxel and platinum regimen) combined with LDRT and CFRT.

Arm B (Control): PD-1 inhibitor plus chemotherapy alone. Primary Endpoint:The primary endpoint for the randomized phase is median progression-free survival (PFS).

Inclusion Criteria:

1. Age ≥18;
2. Metastatic esophageal squamous cell carcinoma (stage IVB, M1) confirmed by pathology;
3. ECOG performance status: 0-1 point;
4. No prior anti-tumor treatment;
5. Adequate hematologic, renal, hepatic, and cardiac functions that meet the requirements for chemotherapy and immunotherapy assessed by investigators.

Exclusion Criteria:

1. Non-squamous cell esophageal carcinoma or ESCC mixed with other pathological types of esophageal cancer;
2. Patients who are potentially curable with surgery as assessed by investigators;
3. Pleural metastasis or malignant pleural effusion, pericardial effusion;
4. Any prior anti-tumor therapy for esophageal cancer, i.e., surgery, radiotherapy, chemotherapy, or immunotherapy;
5. High risk of gastrointestinal bleeding, esophageal fistula, or perforation;
6. Patients with Patient-Generated Subjective Globe Assessment (PG-SGA) score≥9;
7. Unstable cardiac diseases or symptoms;
8. History of interstitial pulmonary disease, non-infectious pneumonitis; pulmonary fibrosis, or other uncontrolled acute pulmonary disease;
9. Active autoimmune disease or history of autoimmune disease;
10. Conditions of immunodeficiency or active infection requiring systemic therapy;
11. Pregnant or breastfeeding;
12. Patients with synchronous second primary cancer and a history of malignancy within the past 5 years (excluding completely cured cervical carcinoma in situ or basal cell or squamous cell skin carcinoma).