{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T06:15:09Z","timestamp":1778566509924,"version":"3.51.4"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Metastatic colorectal cancer (mCRC) has limited treatment options beyond the second-line. Accumulating evidence has reported that liver metastases harbor a greater abundance of immunosuppressive cells relative to primary tumors. However, about 70% of mCRC patients have liver metastases, which worsen prognosis and reduce immunotherapy benefits. Local therapies, such as liver-directed radiotherapy, have shown promise in reducing tumor burden and improving survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This phase II trial aims to evaluate the efficacy and safety of sintilimab combined with fruquintinib, with or without liver-directed radiotherapy, versus fruquintinib alone in the third-line treatment of colorectal cancer with liver metastases (CRCLM). Patients aged 18\u201375 years with microsatellite stable CRCLM who have received first- and second-line therapies will be randomized 3:3:2 into intervention, control, and standardized treatment groups. Patients in the intervention group will be given sintilimab plus fruquintinib in combination with liver-directed radiotherapy. For liver oligometastases, stereotactic body radiation therapy (SBRT) will be performed with a dose of 40\u201350 Gy\/5\u00a0F, 60\u201370 Gy\/10\u00a0F, or 65 Gy\/13\u00a0F. For multiple liver metastases, SBRT plus low-dose radiation therapy (LDRT) will be performed. The appropriate lesions will be selected to receive SBRT with a dose of 40\u201350 Gy\/5\u00a0F, 60\u201370 Gy\/10\u00a0F, or 65 Gy\/13\u00a0F, and the remaining liver lesions will undergo LDRT at a total dose of 1\u201310 Gy with 0.5-2.0 Gy\/F. Patients in the control group will be treated with sintilimab plus fruquintinib, and patients in the standardized treatment group will be treated with fruquintinib only. The primary endpoint is PFS and secondary endpoints are objective response rate, disease control rate, OS, and safety.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>We hypothesize that combining sintilimab with liver-directed radiation therapy on the basis of fruquintinib will enhance disease control and prolong survival compared to treatment with fruquintinib plus sintilimab alone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>clinicalTrials.gov<\/jats:ext-link>\n                      , identifier (NCT06356584).\n                    <\/jats:p>\n                  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