Esophageal cancer (EC) ranks among the leading malignant gastrointestinal tumors globally in terms of both incidence and mortality. Cases of EC in China account for over 50% of the global total, with squamous cell carcinoma being the primary pathological type. Locally advanced EC (LAEC), particularly cases where radical surgical resection is not feasible, exhibits high recurrence rates and low 5-year survival rates. However, studies have shown that patients with LAEC who undergo comprehensive treatment followed by surgery experience significantly prolonged survival and improved quality of life compared to those who do not receive surgical intervention.
Current conversion treatment regimens under investigation include: chemotherapy alone, chemoradiotherapy, immunotherapy combined with chemotherapy, and immunotherapy combined with chemoradiotherapy-each of these approaches has distinct advantages and limitations. Immunochemotherapy has emerged as a current research focus: it not only demonstrates significantly superior efficacy compared to chemotherapy alone but also exhibits lower cumulative toxicity than radiotherapy-combined conversion regimens, resulting in a more favorable overall benefit-risk ratio. As such, it represents the most promising conversion treatment strategy.
Retrospective and prospective clinical studies have shown that low-dose radiotherapy targeting the small intestine can enhance the anti-tumor response of immune checkpoint inhibitors (ICIs) in patients with advanced solid tumor, prolong their overall survival, and increase the incidence of the abscopal effect. Further mechanistic investigations have revealed that intestinal low-dose radiotherapy (ILDR) may augment the immune cancerous lethality by modulating the gut microbiota and their metabolic profiles.
Based on the findings from these preliminary studies, the current research plans to conduct a prospective phase II single-arm clinical trial to investigate the efficacy and safety of ILDR combined with immunochemotherapy as conversion therapy in patients with borderline resectable or unresectable esophageal squamous cell carcinoma (BR/UR ESCC). This research plans to enroll at least 39 evaluable cases or a total of 43 cases in two seperated stages, focusing on patients with thoracic BR/UR ESCC. Patients will receive a single fraction of ILDR with a mean dose of 1 Gy, concurrently with 3 cycles of albumin-bound paclitaxel (260 mg/m² on day 1), cisplatin (75 mg/m² on day 1), and tislelizumab (200 mg on day 1). The efficacy and safety of the treatment will be evaluated throughout the study.
Patients voluntarily enroll in this study, sign an informed consent form, and demonstrate good compliance.
Age ≥18 years and ≤75 years; both sexes are eligible.
ECOG performance status score of 0-1.
Pathologically confirmed esophageal squamous cell carcinoma (ESCC) prior to surgery.
Patients with distant metastases other than supraclavicular lymph node metastases.
Presence or high risk of esophageal perforation.
Patients with contraindications to radiotherapy or immune checkpoint inhibitor (ICI) therapy.
Patients who previously experienced unacceptable toxicity after receiving ICI therapy.
Single group
Intestinal Low Dose Radiotherapy-1Gy
Radiation1Gy ILDR will be administered to patients in a single fraction. The radiation treatment volume composes both the jejunum and ileum.
PD-1/PD-L1 inhibitors
Drug3 cycles of tislelizumab（200 mg D1 q3w）
Chemotherapy
Drug3 cycles of albumin-bound paclitaxel（260 mg/m2 D1 q3w）+ cisplatin（75 mg/m2 D1 q3w）
Surgery
Procedure/SurgeryMcKeown esophagectomy or laparoscopic-assisted McKeown esophagectomy is recommended, with either two-and-a-half-field lymphadenectomy or three-field lymph node dissection.
Pathological Complete Response (pCR) Rate
The proportion of patients who, following conversion therapy, exhibit no residual invasive cancer cells in either the primary tumor site or regional lymph nodes upon pathological evaluation of surgical resection specimens, expressed as a percentage of the total treated population.
Major Pathological Response (MPR) Rate
MPR is defined as the proportion of patients with ≤10% residual viable tumor cells in surgical specimens following treatment. Pathological evaluation requires standardized sampling and separate assessment of lymph node metastases.
Objective Response Rate (ORR)
Proportion of patients achieving complete response (CR) or partial response (PR) (sustained ≥4 weeks) per RECIST v1.1 and iRECIST criteria.
Disease Control Rate (DCR)
DCR is defined as the proportion of patients achieving complete response (CR), partial response (PR), or stable disease (SD) post-treatment, as measured by RECIST 1.1 and iRECIST criteria.
Adverse Event Incidence Rate
The proportion of patients experiencing adverse events of any grade (graded according to CTCAE 6.0, Common Terminology Criteria for Adverse Events, grades 1-5) during treatment.
Peripheral Blood Immune Landscape
Flow cytometry analysis is performed on peripheral blood samples.
Peripheral Blood Transcriptomics
RNA sequencing is performed on peripheral blood samples.
Peripheral Blood Immune Receptor Repertoire
TCR sequencing is performed on peripheral blood samples.
Serum Metabolomics
The wide arrays of metabolites in peripheral blood samples are analyzed qualitatively and quantitatively.
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Chuangzhen Chen
Lead sponsor
Shantou University Medical College
Sponsor institution
BeOne Medicines
Collaborator