PD-1 + FOLFOXIRI vs CAPOX as Total Neoadjuvant Therapy for pMMR Low Rectal Cancer

Inclusion criteria

• Histologically confirmed rectal adenocarcinoma.
• pMMR status documented by immunohistochemistry (MSH1, MSH2, MSH6 and PMS2 all positive) or by MSI testing showing MSS or MSI-L.
• Primary tumor located within 5 cm from the anal verge on pelvic MRI.
• Clinical stage cT3-4bN0M0 or cTxN+M0, with or without positive mesorectal fascia (MRF) and/or extramural vascular invasion (EMVI), and assessed by the multidisciplinary team as resectable with the potential for R0 resection.
• No clinical or radiologic evidence of bowel obstruction.
• No prior colorectal surgery.
• No prior chemotherapy or radiotherapy.
• No prior treatment with biologic agents (e.g., monoclonal antibodies), immune checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4), or other investigational drugs.
• Age 18 to 75 years (inclusive).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Estimated life expectancy > 2 years.
• Adequate bone marrow function: WBC > 3.5 × 10^9/L; platelets > 100 × 10^9/L; hemoglobin > 80 g/L.
• Adequate liver function: ALT and AST ≤ 1.5 × upper limit of normal (ULN); total bilirubin < 23.0 μmol/L.
• Adequate renal function: eGFR ≥ 60 mL/min/1.73 m² (CKD-EPI) or creatinine clearance (Ccr) ≥ 60 mL/min.
• Ability to understand and willingness to sign a written informed consent form.

Exclusion criteria

• Evidence of inguinal or lateral pelvic lymph node metastasis (lymph node short-axis diameter ≥ 7 mm or MRI features typical for metastatic lymph nodes).
• Clinically significant cardiac disease, including arrhythmias requiring anti-arrhythmic treatment (except β-blockers or digoxin), symptomatic coronary artery disease or myocardial ischemia (myocardial infarction within the last 6 months), or congestive heart failure > NYHA class II.
• Uncontrolled severe hypertension.
• History of HIV infection or active chronic hepatitis B (HBV DNA > 2 × 10^3 IU/mL) or hepatitis C (HCV RNA > 1 × 10^3 IU/mL).
• Active pulmonary tuberculosis under treatment or having received anti-tuberculosis therapy within 1 year before screening.
• Other active severe infections (as defined by NCI-CTCAE v5.0).
• Evidence of distant metastasis outside the pelvis before treatment.
• Cachexia or decompensated organ dysfunction.
• Prior pelvic or abdominal radiotherapy.
• Multiple primary colorectal cancers.
• History of seizures requiring ongoing treatment (e.g., corticosteroids or anti-epileptic drugs).
• History of another malignancy within the past 5 years, except adequately treated cervical carcinoma in situ or basal cell carcinoma of the skin.
• Drug or alcohol abuse, or any medical, psychological, or social condition that, in the investigator's judgment, could interfere with study participation or the evaluation of study results.
• Any active autoimmune disease or history of autoimmune disease (including but not limited to interstitial pneumonia, uveitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, or hypothyroidism).
• Receipt of any prophylactic vaccine against infectious diseases (e.g., influenza, varicella) within 4 weeks before enrollment.
• Requirement for long-term immunosuppressive therapy or systemic/local corticosteroids at immunosuppressive doses (equivalent to > 10 mg/day of prednisone or other corticosteroids).
• Known or suspected allergy or hypersensitivity to any study drug or to any component of the study treatments.
• Any unstable condition or other circumstance that may, in the opinion of the investigator, compromise patient safety or study compliance.
• Pregnant or breastfeeding women, or women of childbearing potential who are unwilling or unable to use adequate contraception during the study.
• Refusal or inability to provide written informed consent.