This is a prospectively randomized controlled trial to compare RAMIE and MIE in the treatment for locally advanced ESCC after neoadjuvant therapy. According to previous studies, long-term survival after RAMIE seemed to be at least comparable to MIE or open esophagectomy. Therefore, the RAMIE-2 study was designed as a non-inferiority trial, which was based on the hypothesis that the 5-year overall survival of patients who received RAMIE is uncompromised to MIE. To achieve the primary endpoint, 260 cases will be recruited in our hospital. Based on the volume of esophagectomy (1000 cases/year) and the proportion of patients with neoadjuvant therapy (50%) in our institution, approximately 10 patients will be enrolled for each group per month for this trial. The study will be performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent will be obtained from each participant. The flow chart of this trial is also presented.

Neoadjuvant therapy followed by radical resection is the recommended treatment for locally advanced esophageal cancer, which could achieve a better R0 resection and overall survival. With the development of multidisciplinary treatment of esophageal cancer, especially the emerging concept of "watch and wait", surgery may only be a new era of salvage treatment for patients with poor response to neoadjuvant or recurrence after definitive treatment in the future. At that time, the technical advantage of RAMIE should be even more valuable. Early results of the RAMIE trial (conducted by our group)15, has demonstrated that RAMIE can achieve shorter operative time as well as better lymph node dissection in patients who received neoadjuvant therapy, compared to conventional MIE. In addition, this benefit was more obviously observed in lymph nodes along the bilateral recurrent laryngeal nerves, which were considered as the most challenging steps.

Therefore, we put forward a hypothesis: whether the robot's superior human-surgical interface is beneficial to achieve better surgical and oncological results in patients with locally advanced ESCC after neoadjuvant therapy. Based on the results of RAMIE trial, the present RAMIE-2 study is trying to answer such a question.

Inclusion Criteria:

1. Age ranges from 18 to 75 years;
2. European Clinical Oncology Group Performance Status (ECOG PS) 0-2;
3. Histological subtype of esophageal squamous cell carcinoma;
4. Primary tumors are located at the intrathoracic esophagus;
5. Pre-treatment stage as cT1b-4aN1-3M0, cT3N0M0 (AJCC/UICC 8th Edition);
6. With neoadjuvant chemoradiotherapy, chemotherapy and immunotherapy;
7. Without any anticancer therapy for other malignant diseases;
8. Written informed consent.

Exclusion Criteria:

1. Cervical esophageal cancer and carcinoma of gastro-esophageal junction;
2. Patients with unresectable or metastatic esophageal cancer;
3. Histological subtype of esophageal non-squamous cell carcinoma;
4. History of previous thoracic surgery;
5. Patients with other malignant tumor (previous or current);
6. Participation in another clinical trial during this study.