The goal of this randomized controlled trial is to investigate whether ctDNA methylation is a more precise indicator to guide postoperative adjuvant chemotherapy in stage Ill colorectal cancer. The main questions it aims to answer are:

1. Whether ctDNA methylation-guided escalation strategy is superior to standard treatment for stage III high-risk CRC patients.
2. Whether ctDNA methylation-guided de-escalation strategy is non-inferior to standard treatment for stage III low-risk CRC patients.

325 cases were included in the high-risk cohort (T4 and/or N2) and 665 cases were included in the low-risk cohort (T1-T3, N1). Then patients in each cohort were randomly assigned to ctDNA-guided treatment (ctDNA-guided group) and standard treatment (standard treatment group) in a ratio of 2:1. The standard treatment group and ctDNA-negative group in the high-risk cohort were treated with XELOX regimen for 6 months, and the ctDNA-positive group in the high-risk cohort was treated with cmFOLFOXIRI regimen for 6 months. The standard treatment group and the ctDNA-positive group in the low-risk cohort were treated with XELOX regimen for 3 months, while the ctDNA-negative group in the low-risk cohort did not receive adjuvant chemotherapy.

Inclusion Criteria:

1. 18 years old ≤ age < 75 years old.
2. Stage III (T1-4, N1-2, M0) colorectal cancer patients.
3. Patients who can undergo R0 resection.
4. ECOG score 0 ~ 2.
5. Expected survival ≥ 6 months.
6. No history of other malignant tumors.
7. Voluntarily participate in this study and sign the informed consent. If the subject does not have the ability to read the informed consent (e.g., illiterate subjects), a witness must witness the informed process and sign the informed consent.

Exclusion Criteria:

1. Patients who have received neoadjuvant chemotherapy.
2. Known high clinical risk of adjuvant chemotherapy.
3. Patients with clear contraindications to adjuvant chemotherapy (i.e. due to physical condition, comorbidities, active second cancer, or age).
4. Patients who are unable to undergo subsequent chemotherapy due to other reasons (travel distance, compliance).
5. Vulnerable groups, including people with mental illness, people with cognitive impairment, critically ill patients, minors, pregnant women, etc.
6. There are any other circumstances that the researcher deems unsuitable for inclusion.