Most rectal cancers are microsatellite stable (MSS) or mismatch repair-proficient (pMMR) and respond poorly to PD-1 inhibitors. Radiotherapy can enhance tumor antigen release and improve responsiveness to PD-1 blockade in MSS/pMMR rectal cancer. Tumor-draining lymph nodes (TDLNs) are critical sites for anti-tumor immune activation, but radiation-induced damage and fibrosis may impair lymphatic drainage and immune responses. Previous studies have reported a remarkable pathologic complete response (pCR) rate of 77.8% using node-sparing radiotherapy in locally advanced rectal cancer. This study aims to evaluate whether node-sparing short-course radiotherapy followed by sequential chemotherapy and PD-1 blockade can improve complete response rate in the phase II part and event-free survival in phase III part, together with sphincter preservation, treatment tolerance, and prognosis in patients with mid-low pMMR/MSS rectal cancer.
• Voluntarily signs a written informed consent form.
Aged between 18 and 75 years at the time of enrollment.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Expected survival of more than 2 years.
• Presence of suspected metastatic lesions or unresectable locally advanced disease, regardless of clinical stage.
History of any other malignancy within 5 years prior to enrollment, excluding those considered cured by local therapy (e.g., basal cell carcinoma, squamous cell carcinoma of the skin, superficial bladder cancer, or ductal carcinoma in situ of the breast).
Lesions initially staged as T1N0 eligible for local excision, or T2N0 suitable for sphincter-preserving surgery after multidisciplinary discussion.
Evidence of acute conditions requiring emergency surgery, such as bowel obstruction, perforation, or gastrointestinal bleeding.
Parallel
Node-Sparing Radiotherapy plus Chemotherapy and PD-1 inhibitor
Combination productPatients will receive node-sparing modified short-course radiotherapy, followed by six cycles of CAPOX chemotherapy combined with a PD-1 inhibitor. After neoadjuvant treatment, patients will either undergo total mesorectal excision (TME) surgery or enter a watch-and-wait strategy based on clinical assessment.
Conventional Radiotherapy plus Chemotherapy
Combination productPatients will receive conventional-target short-course radiotherapy, followed by six cycles of CAPOX chemotherapy. After neoadjuvant treatment, patients will either undergo TME surgery or enter a watch-and-wait strategy based on clinical assessment.
Complete response (CR) rate
Phase II: Evaluate whether node-sparing modified short-course radiotherapy followed by sequential chemotherapy and PD-1 inhibitor as total neoadjuvant therapy can improve the complete response (CR) rate in mid/low MSS rectal cancer.
Event-Free Survival (EFS)
Phase III: To evaluate whether node-sparing modified short-course radiotherapy combined with chemotherapy and a PD-1 inhibitor can improve Event-Free Survival (EFS) in patients with pMMR/MSS rectal cancer.
Sphincter preservation rate
Tumor regression grade (TRG)
R0 resection rate
Incidence of treatment-related adverse events (toxicity)
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