Overview

In a single-center, prospective, phase II study (ClinicalTrials registration number: \[to be filled in\]) initiated by our center to evaluate the safety and preliminary efficacy of short-course radiotherapy followed by sequential CAPOX chemotherapy combined with serplulimab and bevacizumab as total neoadjuvant therapy for MSS-type mid-low locally advanced rectal cancer, patients with mid-low MSS-type locally advanced rectal adenocarcinoma were enrolled. They received short-course radiotherapy combined with CAPEOX, serplulimab, and bevacizumab as preoperative total neoadjuvant therapy. It is anticipated that 30 subjects with locally advanced rectal cancer will be enrolled between September 2025 and September 2027.

This phase II exploratory study targets patients with locally advanced mid-low MSS/pMMR rectal cancer. It employs short-course radiotherapy combined with CAPEOX, serplulimab, and bevacizumab as preoperative total neoadjuvant therapy, aiming to clarify the efficacy and safety of this new combined radiotherapy, chemotherapy, targeted therapy, and immunotherapy approach, while also assessing the rectal/anal preservation rate and quality of life of patients. After neoadjuvant therapy, patients will undergo imaging and endoscopic evaluations to determine subsequent treatment strategies. Radical surgical resection will be performed on patients after neoadjuvant immunotherapy, followed by further analysis of the pathological complete response (pCR) rate. The primary study endpoint is the pCR rate, and secondary study endpoints include the objective response rate, organ preservation rate, 3-year disease-free survival (DFS), 3-year overall survival (OS), incidence of adverse events, and quality of life scores (EORTC QLQ-C30, EORTC QLQ-CR29, Wexner).

Eligibility

Inclusion Criteria:

• Patients who have a desire to preserve the anus and are willing to receive the entire course of neoadjuvant therapy.
  • Aged between 18 and 75 years, with no gender restrictions.
    • Diagnosed via pelvic MRI and rectoscopy with a tumor located ≤10 cm from the anal verge, with a clinical stage of cT3-4N0/+M0, and lymph nodes confined within the mesorectum.
      • Histologically diagnosed with rectal adenocarcinoma; genetic testing indicates MSS or MSI-L, or immunohistochemistry of tumor biopsy indicates pMMR (positive for MSH1, MSH2, MSH6, and PMS2 proteins).
        • ECOG performance status score of 0-1.

          ⑥ No prior antitumor therapy, immunotherapy, anti-angiogenic therapy, or pelvic radiotherapy before inclusion.

          ⑦ Laboratory tests must meet the following criteria: i. White blood cell count ≥3.5×10⁹/L, absolute neutrophil count ≥1.8×10⁹/L, platelet count ≥100×10⁹/L, and hemoglobin ≥100 g/L; ii. INR ≤1.5, and APTT ≤1.5 times the upper limit of normal, or partial thromboplastin time (PTT) ≤1.5 times the upper limit of normal; iii. Total bilirubin ≤1.25 times the upper limit of normal; ALT and AST ≤3 times the upper limit of normal; serum albumin ≥28 g/L; iv. 24-hour creatinine clearance rate ≥50 mL/min or serum creatinine ≤1.5 times the upper limit of normal.

          ⑧ Willing to participate in this study voluntarily, sign the informed consent form, and comply with the scheduled outpatient visits and related procedural requirements to complete follow-up.

Exclusion Criteria:

• In addition to a confirmed diagnosis of rectal cancer, there is a current or past history of active malignant tumors.
  • Patients with metastases to other sites indicated by preoperative staging.
    • Patients with suspicious positive lymph nodes in non-draining areas of the rectum, such as the internal and external iliac lymph nodes, as assessed by preoperative MRI or CT.
      • Patients requiring emergency surgery due to complications such as intestinal obstruction, intestinal perforation, or intestinal hemorrhage.
        • Patients with severe comorbid conditions and an estimated life expectancy of ≤5 years.
          • Patients with known allergies to any components in the study.

            ⑦ Patients who have received immunosuppressive or systemic corticosteroid therapy for immunosuppressive purposes within 30 days prior to the initiation of study treatment.

            ⑧ Patients who have received any other investigational drug treatment (including immunotherapy) or participated in another interventional clinical trial within 30 days prior to screening.

            ⑨ Patients with other factors that may affect the study results or lead to premature termination of the study, such as alcoholism, drug abuse, other severe diseases requiring combined treatment (including psychiatric disorders), and severe laboratory abnormalities.

            ⑩ Patients with congenital or acquired immunodeficiency (such as HIV infection).

            ⑪ Vulnerable populations, including individuals with psychiatric disorders, cognitive impairments, critically ill patients, minors, pregnant women, illiterate individuals, etc.

            ⑫ Other circumstances where, in the investigator's judgment, the patient is deemed unsuitable to participate in the clinical trial.