MRD-guided Deferred Adjuvant Therapy in Resectable Early-stage Colon Cancer

Inclusion criteria

Participants must fit all of the following inclusion criteria to be enrolled in this study:

• Over 18 years old (including 18 years old) and under 70 years old (including 70 years old) when signing the informed consent form;
• The Eastern Cooperative Oncology Group (ECOG) physical status scores are 0-1 and do not deteriorate within 2 weeks before enrollment. The expected survival time is no less than 12 weeks;
• Histological or cytological confirmed stage II high-risk and stage III low-risk none high microsatellite instability (MSI-H) colon adenocarcinoma according to the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) primary tumor, regional nodes, metastasis (TNM) stage (8th edition). High-risk factors for stage II patients include: T4, poorly differentiated histology (high-grade, excluding MSI-H status), vascular invasion, neural invasion, intestinal obstruction or tumor site perforation pre-operation, positive or unknown margins, insufficient margin distance and examined lymph nodes less than 12; Stage III low-risk patients include patients with T1-3 N1 (excluding T4 or N2).
• No evidence of distant metastasis (distant organ and/or distant lymph node metastasis) confirmed by comprehensive examination;
• The distal end of the tumor is ≥12cm from the anal edge evaluated by pre-operative endoscopy. If the endoscopy is absent before surgery, the distance could be evaluated by radiology or during the surgery;
• Patients who have not received neoadjuvant therapy and can achieve R0 radical resection;
• Sufficient surgical fresh tissue samples for customized personalized MRD testing panels detected by whole exome sequencing (WES); available for preoperative blood, post-operative day (POD) 3-7 blood, and POD 21-30 blood samples for MRD testing;
• Females of the childbearing period should take appropriate contraceptive measures and should not breastfeed from the screening stage to 3 months post-treatment. Before starting treatment, a negative pregnancy test, or one of the following criteria should be confirmed for no risk of pregnancy:

• Post-menopause, defined as age greater than 50 years and amenorrhea for at least 12 months after cessation of all exogenous hormone replacement therapy.
• Women younger than 50 years who have been amenorrhea for 12 months or more after cessation of all exogenous hormone therapy and whose luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are within laboratory postmenopausal reference values can also be considered as post-menopausal.
• Have undergone irreversible sterilization surgery, including hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, except bilateral tubal ligation.
• Male participants should use barrier contraception (i.e., condoms) from the screening stage to 3 months post-treatment;
• The participants volunteer to join in the study and signed the informed consent in writing;
• Patients who are suitable for CAPEOX and mFOLFOXIRI adjuvant therapy.

Exclusion criteria

Participants who meet any of the following criteria are not eligible for this study:

• Received any of the following treatments:

• Received neoadjuvant therapy in the past;
• Previously received any systemic chemotherapy or immunotherapy for colon cancer;
• Previously received any radiotherapy for colon cancer;
• Undergone colon cancer surgery in the past;
• Previously or concomitantly diagnosed of other malignant tumors (except for adequately treated cervical carcinoma in situ, basal or squamous cell skin cancer);
• Patients with other histological types rather than adenocarcinoma (such as neuroendocrine carcinoma, sarcoma, lymphoma, squamous cell carcinoma, etc.);
• MSI-H/deficient mismatch repair (dMMR) patients;
• Pathological, clinical, or radiologic evidence of metastatic lesions, including isolated, distant, or discontinuous intra-abdominal metastases;
• Patients with multiple primary colorectal cancer;
• Received other parts of open surgery rather than the colon within 14 days prior to the patient's enrollment;
• Cannot provide surgical tissues for customized personalized MRD testing or fail to customize personalized MRD testing panels.
• Cannot provide pre-operative blood, POD 3-7 blood, and POD 21-30 for MRD testing.
• Suffer from other serious diseases that may affect the follow-up and short-term survival according to the judgment of the investigators;
• Any other medical conditions and social/psychological problems, which make the patient unfit to participate in this study;
• History of blood transfusion within 2 weeks before surgery or during surgery;
• Those who cannot afford contrast-enhanced magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) for clinical follow-up;
• Previously used Chinese patent medicine (CPM) with anti-tumor effect. Those who have used CPM with anti-tumor effect for less than 7 days, and have stopped for over 2 weeks can be enrolled in the study;
• Have serious or uncontrolled systemic diseases (such as severe mental disease, neurological disease, epilepsy or dementia, unstable or uncompensated respiratory, cardiovascular, hepatic or renal diseases, left ventricular ejection fraction (LVEF) < 50%, evidence of uncontrolled hypertension [greater than or equal to CTCAE grade 3 hypertension despite drug therapy]); patients with dysphagia, active gastrointestinal disease, or other diseases that significantly affect drug absorption, distribution, metabolism, and excretion. Those who have ever undergone major gastrectomy;
• Fever and body temperature above 38°C within the past 1 week, or active infection with clinical significance. Active tuberculosis. Active fungal, bacterial, and/or viral infections requiring systemic treatment;
• Those with active bleeding or new thrombotic disease who are taking therapeutic anticoagulant drugs or have bleeding tendency;
• Those with severe clinical abnormalities in rhythm, conduction, or morphology on the resting electrocardiogram, such as complete left bundle branch block, second-degree cardiac block, clinically significant ventricular arrhythmia, or atrial fibrillation, unstable angina, congestive heart failure, chronic heart failure with New York Heart Association (NYHA) class ≥ 2;
• Myocardial infarction, coronary/peripheral artery bypass, or cerebrovascular accident occurred within 3 months;
• QT interval (QTc) ≥450ms for males and ≥470ms for females in 12-lead electrocardiogram;
• Presence of risk factors leading to prolongation of the QTc or arrhythmia, such as heart failure, ≥CTCAE (version 4.03) 2nd-degree hypokalemia (2nd-degree hypokalemia is defined as serum potassium < the lower limit -3.0mmol/L, with symptoms need treatment), congenital long QT syndrome, family history of long QT syndrome;
• Intake of any drug known to prolong the QT interval within 2 weeks before enrollment;
• Insufficiency of bone marrow reserve or organ function, reaching any of the following laboratory limits (without corrective treatment within 1 week before blood draw for laboratory examination):

• Absolute neutrophil count <1.5×109/L;
• Platelet count <90×109/L;
• Hemoglobin <90 g/L (<9 g/dL);
• Alanine aminotransferase >3 times the upper limit of normal (ULN);
• Aspartate aminotransferase>3×ULN
• Total bilirubin > 1.5×ULN;
• Creatinine > 1.5×ULN or creatinine clearance rate < 45 mL/min (calculated by Cockcroft-Gault formula);
• Serum albumin (ALB) <28 g/L;
• Female subjects who are pregnant, lactating, or planning pregnancy during the study;
• Other circumstances in which the researchers assess that participants are not fit for this study.