mFOLFOXIRI Plus Bevacizumab for Organ Preservation in Locally Advanced Rectal Cancer

Wait and watch following neoadjuvant chemoradiotherapy is a effective organ preservation strategy in locally advanced rectal cancer. However, radiotherapy is associated with significant pelvic organ toxicity and does not reduce the risk of distant metastasis. Neoadjuvant mFOLFOXIRI plus bevacizumab can achieve effective tumor shrinkage and might simultaneously reduce micrometastatic disease. On this basis, we here propose an active organ-preservation strategy using neoadjuvant mFOLFOXIRI plus bevacizumab in locally advanced rectal cancer. This multicenter, single-arm, phase II trial will enroll patients with stage II-III rectal cancer to receive six cycles of neoadjuvant mFOLFOXIRI plus bevacizumab. Based on clinical response after treatment, patients will undergo watch-and-wait, local excision, or total mesorectal excision. Post-treatment surveillance will combine imaging with tumor-informed circulating tumor DNA (ctDNA) monitoring. The primary endpoint is the 3-year disease-free survival rate. This study is expected to provide clinical evidence on the safety and efficacy of a radiotherapy-free active watch-and-wait strategy for rectal cancer.

Inclusion criteria

• Sign the informed consent form and comply with the planned visits, study treatment, laboratory tests, and other trial procedures;
• Age 18-75 years;
• Histologically confirmed rectal adenocarcinoma;
• The lower edge of the rectal tumor is <10 cm from the anal verge (as assessed by pelvic MRI);
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
• Willing to choose the "organ preservation" strategy according to the study protocol;
• Locally staged as cTNM stage II-III (T3-4 with any N, or any T with N1-2) by contrast-enhanced pelvic MRI;
• No prior antitumor therapy for colorectal cancer, including cytotoxic drugs, radiotherapy, molecular targeted therapy, immune checkpoint inhibitors, etc.;
• Adequate organ function as indicated by the following laboratory values obtained during the screening period: white blood cell count ≥3×10⁹/L, neutrophil count ≥1.5×10⁹/L, platelet count ≥75×10⁹/L, serum total bilirubin ≤1.5× upper limit of normal (ULN), aspartate aminotransferase or alanine aminotransferase ≤2.5× ULN, serum creatinine ≤1.5× ULN.

Exclusion criteria

• Distant metastasis (M1) confirmed by chest/abdominal/pelvic CT, pelvic MRI, or PET-CT;
• Bowel obstruction, active gastrointestinal bleeding, or perforation caused by the tumor;
• Tumor complicated by intestinal fistula or pelvic abscess;
• Concurrent malignant tumors of other organ systems (except malignancies that have been curatively treated with no recurrence for more than 5 years, or carcinoma in situ that can be cured by adequate treatment);
• Thrombotic or embolic events within 12 months prior to enrollment, such as cerebrovascular accident (including transient ischemic attack), pulmonary embolism, or deep vein thrombosis;
• Within 12 months prior to enrollment, any of the following: myocardial infarction, severe/unstable angina, New York Heart Association (NYHA) class ≥ II cardiac dysfunction, clinically significant supraventricular or ventricular arrhythmia, and symptomatic congestive heart failure;
• Tumors diagnosed as mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) by immunohistochemistry or PCR;
• Uncontrolled systemic infection or unexplained fever (>38.5°C) within 2 weeks prior to enrollment;
• Concurrent presence of any of the following other diseases: human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness; poorly controlled diseases including but not limited to non-infectious pneumonitis, diabetes mellitus, hypertension, pulmonary fibrosis, acute pneumonia, aneurysm, and coagulation disorders; or any other disease that, in the investigator's opinion, may affect the assessment of study endpoints;
• Known or suspected allergy to the study drugs;
• Pregnant or lactating women;
• Patients with other serious physical or mental illnesses or laboratory abnormalities that may increase the risk of study participation, interfere with study results, or who are considered unsuitable for participation by the investigator.