Intestinal Low-Dose Radiotherapy Combined With Immune Checkpoint Inhibitors in Solid Tumors With Liver Metastases

Brief summary public domain (ClinicalTrials.gov)

This study aims to evaluate the effectiveness and safety of combining low-dose radiotherapy to the intestines with immune checkpoint inhibitors (ICIs) in patients with liver metastases from solid tumors. Liver metastases often create an "immune desert" that makes immunotherapy less effective. Recent research has shown that low-dose irradiation of the gut (1 Gy) can reshape the gut microbiome and activate the immune system, potentially reversing resistance to immunotherapy. This is a prospective, single-arm, single-center cohort study. We plan to enroll 120 patients with liver metastases from non-small cell lung cancer (NSCLC), colorectal cancer, or pancreatic cancer. All participants will receive a single low dose of radiotherapy to the intestine (1 Gy), followed by standard immune checkpoint inhibitors and chemotherapy. The main goal of this study is to see how well the liver metastases respond to this combined treatment. We will also monitor survival, side effects, and changes in the gut bacteria and blood immune markers to understand how this treatment works. This strategy may provide a low-cost, low-toxicity new option for patients whose liver metastases have stopped responding to standard immunotherapy.

Detailed description public domain (ClinicalTrials.gov)

Background: Liver metastasis is a common cause of death in advanced solid tumors and is associated with systemic immune suppression, leading to primary resistance to immune checkpoint inhibitors (ICIs). Preclinical and clinical evidence suggests that low-dose irradiation of the gut (ILDR, 1-3 Gy) can induce the migration of regulatory dendritic cells (mregDCs) from mesenteric lymph nodes to tumor-draining lymph nodes, cross-activate CD8+ T cells, and reprogram metabolism, thereby synergizing with ICIs. The Chen et al. (Cancer Cell 2025) study demonstrated that ILDR (1-3 Gy) significantly improved overall survival in patients receiving SABR plus anti-PD-L1, with an inverted U-shaped dose-response relationship. This study aims to prospectively evaluate the efficacy and safety of ILDR combined with ICIs in patients with liver metastases from solid tumors. Study Design: This is a prospective, single-arm, single-center, exploratory cohort study. A one-sided exact binomial test will be used to compare the liver metastasis ORR with historical controls. The study plans to enroll 120 patients in three cohorts: Cohort A (NSCLC, driver gene negative, after first-line platinum-based chemotherapy plus PD-1/PD-L1 inhibitor progression, expected ORR 30% vs 10%), Cohort B (NSCLC, driver gene positive, after first-line targeted therapy progression, expected ORR 55% vs 35%), and Cohort C (colorectal/pancreatic cancer, after up to two lines of therapy progression, expected ORR 35% vs 15%). A two-stage execution rule with futility analysis will be applied. Intervention: Patients will receive ILDR (1 Gy/1 fraction, IMRT/VMAT) targeting the jejunum, ileum, and mesentery (Dmean = 1 Gy) on Day 1. ICIs (PD-1/PD-L1 inhibitors) will be administered 24-72 hours after ILDR, every 3 weeks, for up to 2 years. Combined chemotherapy regimens include docetaxel for Cohort A, platinum-based doublet for Cohort B, and XELOX/FOLFOX/FOLFIRI/AG for Cohort C. Endpoints: The primary endpoint is liver metastasis objective response rate (ORR) per RECIST v1.1. Secondary endpoints include overall ORR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety (CTCAE 5.0), and multi-omics analysis (gut microbiome, metabolomics, immune profiling) of peripheral blood and stool samples. Statistical Analysis: The primary endpoint will be analyzed using the Clopper-Pearson exact method for 95% CI. PFS and OS will be estimated using the Kaplan-Meier method. Multi-omics data will be analyzed using Wilcoxon signed-rank test, Mann-Whitney U test, LEfSe, PLS-DA, and Spearman correlation analysis.