Node-Sparing Low-Dose Radiotherapy Concurrent With Chemotherapy and PD-1 Inhibitor in pMMR/MSS High-Risk Locally Advanced Colon Cancer: A Prospective, Single-Arm, Phase II Trial
Most colorectal cancers belong to the microsatellite stable (MSS) or proficient mismatch repair (pMMR) subtypes, with limited response to PD-1 inhibitors. Radiotherapy can increase the release of tumor-associated antigens, thereby improve responsiveness to PD-1 blockade in MSS/pMMR rectal cancer. Tumor-draining lymph nodes are important sites for PD-1 inhibitors to exert antitumor effects, and studies have reported that direct radiation-induced damage and fibrosis can inhibit lymph node drainage and anti-tumor function. Accumulating evidence indicates that low-dose radiotherapy reprograms the tumor microenvironment (TME), transforming immunosuppressive 'cold' tumors into immunostimulatory 'hot' tumors. This transition is mediated by modulating the gut microbiota, eliciting innate and adaptive immune responses, inhibiting immunosuppressive cells, and promoting the infiltration of T and B lymphocytes.Therefore, this study aims to evaluate whether node-sparing low-dose radiotherapy (1Gy/8f) concurrent with chemotherapy and PD-1 inhibitor can improve the pathological complete response (pCR) rate, enhance tolerability, and improve prognosis in patients with pMMR/MSS high-risk locally advanced colon cancer.
• Voluntarily signed written informed consent.
• Age ≥ 18 years and ≤ 75 years at the time of enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
• Life expectancy \> 2 years.
• Histologically confirmed adenocarcinoma of the colon (without squamous or sarcomatoid components).
• Tumor biopsy immunohistochemistry (IHC) indicates pMMR (proficient Mismatch Repair), defined as positive expression of all four proteins: MSH1, MSH2, MSH6, and PMS2; or genetic testing indicates MSS (Microsatellite Stable).
• Staged as T4 and/or N+ (Stage IIB-III) according to the AJCC 8th edition, as evaluated by imaging (contrast-enhanced CT or MRI).
• Prior to enrollment, the subject must be evaluated by a surgeon responsible for the operation based on medical history to confirm eligibility for R0 resection with curative intent.
• No prior systemic or local anti-tumor therapy for colon cancer before study treatment, including radiotherapy, chemotherapy, immunotherapy, biologics, small molecule targeted therapy, etc.
⁃ Subjects agree to the collection of tumor tissue and peripheral blood samples required during the screening period and the study process for use in related research.
⁃ Adequate organ function:
⁃ a) Hematology (no use of blood components or cell growth factors within 7 days prior to the start of study treatment): i. Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L (1,500/mm³). ii. Platelet count ≥ 100 × 10⁹/L (100,000/mm³). iii. Hemoglobin ≥ 90 g/L. b) Renal: i. Calculated Creatinine Clearance (CrCl) ≥ 50 mL/min (calculated using the Cockcroft-Gault formula: CrCl (mL/min) = {(140 - Age) × Weight (kg) × 0.85 \[if female\]} / (Serum Creatinine (mg/dL) × 72)).
⁃ ii. Urine protein \< 2+ or 24-hour urine protein quantification \< 1.0 g. c) Hepatic: i. Serum Total Bilirubin (TBil) ≤ 1.5 × ULN (Upper Limit of Normal). ii. AST and ALT ≤ 2.5 × ULN. iii. Serum Albumin (ALB) ≥ 28 g/L. d) Coagulation: i. International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN.
⁃ e) Cardiac Function: i. Left Ventricular Ejection Fraction (LVEF) ≥ 50%.
⁃ Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 3 days prior to study treatment (if the urine test result cannot confirm negativity, a serum pregnancy test is required, and the serum result prevails). If a female subject of childbearing potential engages in sexual activity with a non-sterilized male partner, she must use an acceptable method of contraception starting from screening and agree to continue using it for 120 days after the last dose of the study drug; cessation of contraception after this point should be discussed with the investigator. Periodic abstinence and rhythm methods are not acceptable forms of contraception.
∙ Women of childbearing potential are defined as women who have not undergone surgical sterilization (i.e., bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or are not postmenopausal (menopause is defined as at least 12 consecutive months of amenorrhea without an alternative medical cause, with serum Follicle-Stimulating Hormone \[FSH\] levels within the laboratory reference range for postmenopausal women).
‣ Highly effective contraception refers to methods with a low failure rate (e.g., less than 1% per year) when used consistently and correctly. Not all contraceptive methods are highly effective. In addition to barrier methods, female subjects of childbearing potential must independently use a hormonal contraceptive method (e.g., birth control pills) to ensure pregnancy does not occur.
⁃ Subjects are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study requirements.