At present, the combined modality treatment of preoperative neoadjuvant chemoradiotherapy (NCRT) followed by radical surgery has become the standard of care for the locally advanced mid/low rectal cancer, having been proved to substantially improve the local control of the disease, whereas not being able to improve the long-term survival. According to present clinical practice guidelines, all patients with cT3-4N0M0 or cTanyN1-2M0 mid/low rectal cancer are recommended to undergo the preoperative long-term radiotherapy with concurrent 5FU based chemotherapy, followed by the radical resection of the tumor. After surgery, adjuvant chemotherapy (ACT) is recommended for all these patients without considering the postoperative pathological results. Recently, however, some authors proposed that different strategy of combined modality therapy should be applied in different patients according to their risk of relapse, instead of using the uniform NCRT strategy. In this research, on the basis of investigator's previous clinical practice and researches, investigators plan to stratify the patients with cT3-4N0M0 or cTanyN1-2M0 mid/low rectal cancer into several subgroups according to tumor stages and the risk of relapse. Different therapeutic strategy will be applied in different groups, at the aim of improving the overall therapeutic effects, as well as reducing the treatment adverse effects.

This research consists of four trials.

Trial A: A multicenter, prospective, randomized trial to compare neoadjuvant chemoradiotherapy (NCRT) followed by radical surgery with surgery alone for cT3a-bN0-1aM0 mid rectal cancer.

Research objects: Patients with locally advanced rectal cancer, being clinically staged T3a-bN0-1aM0 by rectal MRI and/or endorectal ultrasonography (ERUS), the tumor being located 6-12 cm above the anal verge.

After giving fully informed consent, the prospective participants will be randomly divided into two groups, receiving the following two treatment modalities.

Group A1: radical surgery + adjuvant chemotherapy (ACT) Group A2: NCRT + radical surgery + ACT

Trial B: A multicenter, prospective, randomized trial to compare combined versus single-agent chemotherapy with concurrent radiotherapy for cT4NanyM0 or cTanyN2M0 rectal cancer.

Research objects: Patients with locally advanced rectal cancer, being clinically staged cT4NanyM0 or cTanyN2M0 by rectal MRI and/or ERUS, or patients with any other risk factors for tumor relapse.

After giving fully informed consent, the prospective participants will be randomly divided into two groups, receiving the following two treatment modalities.

Group A1: NCRT with combined chemotherapy (Capox regimen) + radical surgery + ACT Group A2: NCRT with single-agent chemotherapy (Capecitabine) + radical surgery + ACT

Trial C: A multicenter, prospective, randomized trial to compare transanal ndoscopic microsurgery (TEM) excision versus radical resection of rectal cancer being staged clinical complete response (cCR) after NCRT.

Research objects: Patients with locally advanced rectal cancer, being clinically staged cCR after NCRT.

After giving fully informed consent, the prospective participants will be randomly divided into two groups, receiving the following two treatment modalities.

Group A1: TEM excision + ACT Group A2: radical surgery + ACT

Trial D: A prospective, observational study to determine the value of circulating tumor DNA (ctDNA) for predicting the therapeutic effects of NCRT for locally advanced rectal cancer and the patients' long-term prognosis.

Research objects: Patients with locally advanced mid/low rectal cancer (cT3-4N0M0 or cTanyN+M0) who undergo NCRT.

After giving fully informed consent, the prospective participants will undergo the classical 'NCRT + radical surgery + ACT' comprehensive treatment. Serial analysis of ctDNA will be performed at specific time points including pre-NCRT, post-NCRT, postoperative week 1, post-ACT, postoperative year 1, 2, and 3. The next-generation sequencing of surgical specimens will be performed as well. Participants will be observed and examined during the entire course of treatment and the follow-up period. The pathological results of the surgical specimen and the 3 year disease free survival (3y-DFS) will be the main end-points.

Inclusion Criteria:

Patients aged 18 to 75 years old. Patients with cT3-4N0M0 or cTanyN+M0 mid/low rectal cancer. Patients with ASA physical status scroe of I to III. Patients who can fully understand the content of the informed consent form and sign it upon their own opinions.

Patients who can coordinate with the researchers to undergo the long-term post-treatment rechecks and follow-ups.

Exclusion Criteria:

Patient has any underlying or current medical condition, which, in the opinion of the Investigator, would interfere with the evaluation of the patient (e.g., end-stage liver disease, pulmonary hypertension, systemic lupus erythematosis etc.).

Patient is pregnant or lactating. Patient has a history of malignancy within 5 years except curatively treated basal cell carcinoma, squamous cell carcinoma in a non-mucosal, ultraviolet exposed area, or cervical carcinoma.

Patient is participating in any other clinical trials within 30 days prior to screening.

Patient has severe mental illness. Patient has any other conditions, which, in the opinion of the Investigator, would interfere with the evaluation of the subject.