Comparison Between NCRT and NCT Followed by MIE for Treatment of Locally Advanced Resectable ESCC

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the outcomes of neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by minimally invasive esophagectomy on patients with locally advanced resectable esophageal squamous cell carcinoma(cT3-4aN0-1M0).

Detailed Description
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It is a prospective randomized phase III clinical trial sponsored by Shanghai Zhongshan Hospital with other eight hospitals in China participating in. 264 patients with locally advanced resectable esophageal squamous cell carcinoma(cT3-4aN0-1M0) are recruited and randomly assigned into the neoadjuvant chemoradiotherapy group (NCRT group) and the neoadjuvant chemotherapy group (NCT group) according to the proportion of 1:1.The safety,efficacy of protocols and prognosis of patients are compared between the two regimens.

Official Title
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Neoadjuvant Chemoradiotherapy VS. Neoadjuvant Chemotherapy Followed by Minimally Invasive Esophagectomy for Locally Advanced Resectable Esophageal Squamous Cell Carcinoma（cT3-4aN0-1M0):A Multi-center Prospective Randomized Clinical Trial

Conditions
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Esophageal Squamous Cell Carcinoma Stage cT3-4aN0-1M0

Intervention / Treatment
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* Procedure: Neoadjuvant Chemoradiotherapy
* Procedure: Neoadjuvant Chemotherapy
* Procedure: Minimally Invasive Esophagectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed squamous cell carcinoma of the esophagus; Tumors of the esophagus are located in the thoracic cavity; Pre-treatment stage as cT3-4aN0-1M0 (AJCC/UICC 7th Edition) (In case of stage cT4a, curative resectability has to be explicitly verified by the local surgical investigator prior to randomization). Age is between 18 years and 75 years, Eastern Cooperative Oncology Group (ECOG) performance status 0-1; Adequate cardiac function. All patients should perform ECG, and those with a cardiac history or ECG abnormality should perform echocardiography with the left ventricular ejection fraction > 50 %. Adequate respiratory function with FEV1≥1.2L, FEV1%≥50% and DLCO≥50% shown in pulmonary function tests. Adequate bone marrow function (White Blood Cells >4x10^9 /L; Neutrophil >2.0×10^9 /L; Hemoglobin > 90 g/L; platelets>100x10^9 /L); Adequate liver function (Total bilirubin <1.5x Upper Level of Normal (ULN); Aspartate transaminase(AST) and Alanine transaminase (ALT) <1.5x ULN); Adequate renal function (Glomerular filtration rate (CCr) >60 ml/min; serum creatinine (SCr) ≤120 µmol/L)； The patient has provided written informed consent and is able to understand and comply with the study; Exclusion Criteria: Patients with non-squamous cell carcinoma histology; Patients with advanced inoperable or metastatic esophageal cancer; Pre-treatment stage as cT1-2N0-1M0 (AJCC/UICC 7th Edition); Pre-treatment stage as cN2-3 or cT4b(non-curatively-resectable verified by the local surgical investigator, AJCC/UICC 7th Edition); Patients with another previous or current malignant disease which is likely to interfere with treatment or the assessment of response in the judgement of the local surgical investigator. Any patient with a significant medical condition which is thought unlikely to tolerate the therapies. Such as cardiac disease (e.g. symptomatic coronary artery disease or myocardial infarction within last 12 months), clinically-significant lung disease, clinically-significant bone marrow, liver, renal function disorder; Pregnant or lactating women and fertile women who will not be using contraception during the trial; Allergy to any drugs; Participation in another intervention clinical trial with interference to the chemotherapeutic or chemoradiotherapeutic intervention during this study or during the last 30 days prior to informed consent; Expected lack of compliance with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant chemoradiotherapy<br>Neoadjuvant chemoradiotherapy (NCRT) is performed followed by minimally invasive esophagectomy in enrolled patients. | Procedure: Neoadjuvant Chemoradiotherapy<br>* Before surgery, patients in this group receive neoadjuvant chemoradiotherapy. A total dose of 40 Gy is delivered in 20 fractions (5 fractions per week) for 4 weeks. Chemotherapy is delivered concomitantly and composed of four cycles of paclitaxel 50mg per square meter of body-surface area and cisplatin 25mg per square meter of body-surface area weekly at the intervals of radiotherapy. After neoadjuvant therapy of 4-8 weeks, minimally invasive esophagectomy is performed.<br>* Other names: Preoperative Chemoradiotherapy;Procedure: Minimally Invasive Esophagectomy<br>* After neoadjuvant therapy, patients in groups receive minimally invasive esophagectomy<br>* Other names: MIE;|
| Active Comparator: Neoadjuvant chemotherapy<br>Neoadjuvant chemotherapy (NCT) is performed followed by minimally invasive esophagectomy in enrolled patients. | Procedure: Neoadjuvant Chemotherapy<br>* Before surgery, patients in this group receive neoadjuvant chemotherapy. Chemotherapy is delivered and composed of two cycles of paclitaxel 135mg per square meter of body-surface area and cisplatin 75mg per square meter of body-surface area every 4 weeks. After neoadjuvant therapy of 4-8 weeks, minimally invasive esophagectomy is performed.<br>* Other names: Preoperative Chemotherapy;Procedure: Minimally Invasive Esophagectomy<br>* After neoadjuvant therapy, patients in groups receive minimally invasive esophagectomy<br>* Other names: MIE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival(OS) |  | Up to the date of death of any causes since the date of randomization, up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival(PFS) | Disease recurrence is defined as locoregional (esophageal bed or anastomotic or regional lymph nodes) or metastatic (supraclavicular lymph nodes or distant organs). | Up to the date of disease recurrence since the date of randomization, up to 36 months | 
| Pathological response rate(pCR) | The resected specimen following neo-adjuvant treatment are assessed by using standardised work up of the resection specimen in the pathology department and standardised histological criteria for tumour regression grading. The degree of histomorphologic regression is clarified into four categories as follows: grade 1, no evidence of vital residual tumor cells (pathological complete response); grade 2, less than 10% vital residual tumor cells; grade 3, 10 to 50%; and grade 4, more than 50%. | Up to the date of pathological reports obtained since the date of randomization, up to 12 months | 
| R0 resection rate | No vital tumor is presented at the proximal, distal, or circumferential resection margin, it is considered to be R0 resection. If a vital tumor is shown at 1 mm or less from the proximal, distal, or circumferential resection margin, it is considered to be microscopically positive (R1). | Up to the date of pathological reports obtained since the date of randomization, up to 12 months | 
| Positive lymph nodes' number | According to pathological reports, record the number of positive lymph nodes | Up to the date of pathological reports obtained since the date of randomization, up to 12 months | 
| Treatment related complications | Number and severity of adverse events that are related to treatment of each patients, and hospital readmission. | Up to 1 month after surgery since the data of randomization, up to 13 months | 
| Quality of life(QOL) | QOL is respectively evaluated at randomization and 1 month, 3 month, 6 month and yearly after surgery among patients by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ-C30) and EORTC QLQ-OES18 | Up to the end of follow-up since the data of surgery, up to 36 months | 
| Recurrence-free survival (RFS) | RFS is defined in resected patients who achieved an R0 or R1 resection as the time interval from surgery to the date of first recurrence (local, regional or distant) or death, whichever comes first. | Up to the date of disease recurrence since the date of surgery, up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant Chemoradiotherapy, Neoadjuvant Chemotherapy, Minimally Invasive Esophagectomy, Esophageal Squamous Cell Carcinoma（cT3-4aN0-1M0）