TPS3645 Background: Adjuvant chemotherapy is often deemed unnecessary in pathological stage II colorectal cancer (CRC) following initial surgery without high-risk factors for recurrence. However, the efficacy of adjuvant chemotherapy for pT1-3N0M0 CRC following preoperative chemotherapy or chemoradiotherapy remains uncertain. Some cases of clinical locally advanced CRC (cTxN1-2M0), which are down-staged to pT0-3N0M0 after preoperative chemotherapy or chemoradiotherapy, may not truly require adjuvant chemotherapy due to the down-staging effects of preoperative treatments or false-positive imaging diagnosis of lymph nodes. Methods: CANWATCH is a multicenter, open-label, randomized, phase III study with a parallel design conducted in China. Patients were randomly assigned (1:1) to the wait-and-watch group or the adjuvant chemotherapy group. Enrollment and random assignment were performed using a computerized randomization management system. Patients in the wait-and-watch group did not receive adjuvant chemotherapy but were followed up periodically, while patients in the adjuvant chemotherapy group continued to receive adjuvant chemotherapy based on 5-FU or 5-FU analogues (mFOLFOX6 or Capeox). This study is the first prospective randomized controlled study to assess the necessity of adjuvant chemotherapy for patients with locally advanced CRC who received neoadjuvant therapy and achieved a down-staging to pT0-3N0M0. The study aims to provide precise clinical evidence for individualized precision treatment in locally advanced CRC patients. Key inclusion criteria included preoperative clinical tumor stage III (cTxN1-2M0) CRC, pathologically confirmed CRC adenocarcinoma by endoscopic biopsy, postoperative pathological stage T0-3N0M0 without high-risk factors for recurrence, and patient ability to understand and sign written informed consent. Main exclusion criteria were a history of other malignant tumors, complications requiring emergency surgery (occlusion, sub-occlusion, massive hemorrhage, and abscesses), colorectal tumor extension toward the abdominal wall and/or adjacent organs preventing immediate R0 resection of liver metastases, non-resectable lymph node metastasis, American Society of Anesthesiologists (ASA) grading ≥ IV, and/or Eastern Cooperative Oncology Group (ECOG) score ≥ 2. A total of 650 patients are planned to be enrolled in this study, and 301 patients have been enrolled as of February 6, 2024. The study is registered with ClinicalTrials.gov (NCT03748485) and is ongoing. Clinical trial information: NCT03748485 .