Most colorectal cancers are microsatellite stable (MSS) or mismatch repair-proficient (pMMR) subtypes, which show limited efficacy to PD-1 inhibitors. Radiotherapy can enhance the release of tumor-associated antigens, thereby improving the responsiveness of pMMR/MSS colorectal cancers to PD-1 blockade. Tumor-draining lymph nodes (TDLNs) are critical sites where PD-1 inhibitors exert their antitumor effects; however, previous studies have reported that direct radiation-induced damage and fibrosis may impair lymphatic drainage and antitumor immunity. Early reports have demonstrated a remarkable pathological complete response (pCR) rate of 77.8% with lymph node-sparing short-course radiotherapy (25 Gy in 5 fractions) in locally advanced rectal cancer. In metastatic colorectal cancer, single-fraction high-dose irradiation (6-8 Gy) has been shown to induce robust abscopal effects. Based on these findings, our study aims to evaluate whether lymph node-sparing hypofractionated radiotherapy (25 Gy/5F or 24 Gy/4F) followed sequentially by chemotherapy and PD-1 blockade can increase the pCR rate, improve tolerability, and ultimately enhance outcomes in patients with pMMR/MSS high-risk locally advanced colon cancer.
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Age ≥ 18 and ≤ 75 years at enrollment.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Life expectancy > 2 years.
Suspicious metastatic lesions or the presence of unresectable locally advanced disease, regardless of stage.
Malignancy other than colorectal cancer within 5 years prior to enrollment. Subjects cured by local therapy for other malignancies (e.g., basal or squamous cell skin cancer, superficial bladder cancer, ductal carcinoma in situ) are not excluded.
Receipt of any investigational drug or device within 4 weeks prior to the first dose of study drug.
Intestinal obstruction, perforation, gastrointestinal bleeding, or other conditions requiring emergency surgery.
Parallel
Node-Sparing Radiotherapy(25Gy/5F) plus Chemotherapy and PD-1 inhibitor
Combination productPatients will receive node-sparing modified short-course radiotherapy(25Gy/5F), followed by 4 cycles of CAPOX chemotherapy combined with a PD-1 inhibitor. After neoadjuvant treatment, patients will undergo surgery.
Node-Sparing Radiotherapy(24Gy/4F) plus Chemotherapy and PD-1 inhibitor
Combination productPatients will receive node-sparing modified short-course radiotherapy(24Gy/4F), followed by 4 cycles of CAPOX chemotherapy combined with a PD-1 inhibitor. After neoadjuvant treatment, patients will undergo surgery.
Pathological Complete Response(pCR) Rate
Evaluate 25Gy/5F or 24Gy/4F node-sparing modified short-course radiotherapy followed by sequential chemotherapy and PD-1 inhibitor as total neoadjuvant therapy can better improve the pathological complete response(pCR) rate in colon cancer.
Tumor regression grade (TRG)
Tumor downstaging rate
R0 resection rate
3-year overall survival (OS) rate
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