The Long-term Effect of D4 Lymphadenectomy for Gastric Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the effect of extensive lymphadenectomy procedure in treatment of gastric cancer. This study is designed as a open-label, multi-centers, randomized controlled trial. The overall survival and free disease survival are primary outcomes, with postoperative complication, hospital charges, and life quality as secondary outcomes.

Detailed Description
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Background: Gastric cancer is the second leading cause of cancer-associated death worldwide, with high incidence in China. The prognosis of advanced gastric cancer is quite poor. Although perioperative chemotherapy may help to prolong survival in cases of advanced disease, radical tumor resection remains the most effective treatment for curable gastric cancer. Nowadays, radical gastrectomy with extended (D2) lymphadenectomy has become the standard for treatment of advanced gastric cancer. However, this surgical procedure cannot achieve a radical tumor resection for most cases with advanced disease. Hence, a more extensive (D2 plus para-aortic nodal dissection, D4) lymphadenectomy along with gastrectomy has been performed in Japan and other Asian countries. A recent study by Sasako et al. indicated that a prophylactic D4 lymphadenectomy did not improve the prognosis of curable gastric cancer, but increased the blood loss and operation time compared with single D2 procedure. We reviewed our database, which had collected almost 2,000 gastric cancer cases since its establishment in 1994, and found that the D4 surgical procedure actually improved the prognosis of T4 tumor and tumor with lymph node metastasis at the second stations. To further confirm the results from our retrospective analysis, we performed a prospective study with multicenter, open-label, and randomized design in the affiliated hospitals of Sun Yat-sen University. This study would be helpful to improve the prognosis of patients with advanced gastric cancer, and find more efficient management for curable gastric cancer. Method: This study, which started from January, 2011 and planned to close after ten years, has been approved by the ethic committee of Sun Yat-sen University, with written inform consent obtained from all enrolled subjects. Patients who had histologically proven gastric adenocarcinoma and confirmed lymph node metastasis to para-aortic nodes (<3 enlarged lymph nodes) were prospectively enrolled in this trial. A standard D2 lymphadenectomy or D4 procedure was randomly decided by a formal randomization program. The primary end point of this study was overall survival, defined as the time from randomization to death. The secondary end points were recurrence-free survival, postoperative complications, length of stay, and hospital charges. Recurrence-free survival was defined as the time from randomization to the first recurrence of cancer or death from any cause. The follow-up period would last for at least five years after the definitive operation. Significance: This study would further confirm the efficacy of D2 plus para-aortic nodal dissection(PAND) procedure for management of advanced gastric cancer as compared with the classic D2 lymphadenectomy operation. Moreover, the therapeutic measures employed in current study may guide the future treatment of advanced gastric cancer in China.

Official Title
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The Long-term Effect of D4 Lymphadenectomy for Gastric Cancer: a Multicenter, Open-label, Randomized Trial

Conditions
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Gastric Cancer, Surgery, Effects of Chemotherapy

Intervention / Treatment
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* Procedure: Radical Gastrectomy Plus D2 Lymphadenectomy
* Procedure: Radical Gastrectomy Plus D4 Lymphadenectomy
* Drug: S-1+Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The informed consent has been obtained from the patient. With confirmed pathological diagnosis of gastric cancer and visible para-aortic lymph nodes metastasis. Endurable D2/D4 gastrectomy and neoadjuvant chemotherapy. With moderate/good ECOG health rating (PS): 0-1 score. Exclusion Criteria: Pregnant woman or lactating woman. With confirmed distant metastasis in liver, lung, bones, or other organs. Intolerable operation or neoadjuvant chemotherapy. With severe comorbidities, such as cardiovascular disease, chronic obstructive pulmonary disease, diabetes mellitus, and chronic renal dysfunction. With bad compliance or contraindication to enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: D4 Lymphadenectomy<br>This is the interventional group in which additional para-aortic lymph nodes are dissected meanwhile. Under this arm, main therapeutic measures are listed as follows: three-cycle SOX chemo regimen (S-1+Oxaliplatin) as neoadjuvant chemotherapy radical gastrectomy plus D4 lymphadenectomy five-cycle SOX chemo as adjuvant chemotherapy five-year follow-up program to evaluate the prognosis. | Procedure: Radical Gastrectomy Plus D4 Lymphadenectomy<br>* This surgical procedure is also performed by the same high-experienced surgical team as the control arm. Lymph nodes around stomach (station 1&2 LNs) and para-aortic lymph nodes must be removed during the operation.<br>* Other names: D4 Lymphadenectomy;Drug: S-1+Oxaliplatin<br>* A perioperative chemotherapy, known as SOX regimen, should be performed in each enrolled patient with three-cycle treatments followed after a pathological carcinoma diagnosis. After a radical operation (arm groups), additional five-cycle treatments of adjuvant chemotherapy (SOX regimen) would be performed, followed by follow-up program. The treatment bundles are listed as follows: S-1: 40 60mg bid，po, Day1 14 （S-1：BSA <1.25m2, 40mg bid, 1.25m2≤BSA≤1.5m2,50mg bid, BSA>1.5m2, 60mg bid） Oxaliplatin: 130mg/m2，iv drip for 2h，Day1<br>* Other names: SOX chemo Regimen;|
| Experimental: D2 Lymphadenectomy<br>This is the control group in which a classic surgical procedure for gastric cancer is performed. Under this arm, main therapeutic measures are included as follows: three-cycle SOX chemo regimen (S-1+Oxaliplatin) as neoadjuvant chemotherapy radical gastrectomy plus D2 lymphadenectomy (Without para-aortic lymph nodes dissection) five-cycle SOX chemo as adjuvant chemotherapy five-year follow-up program to evaluate the prognosis. | Procedure: Radical Gastrectomy Plus D2 Lymphadenectomy<br>* This surgical procedure is performed by the same high-experienced surgical team as the control arm. All lymph nodes around stomach (station 1&2 LNs) must be removed to achieve a radical lymphadenectomy. Para-aortic lymph nodes should not be dissected even if a suspected lymph node metastasis is diagnosed from radiographic exams.<br>* Other names: D2 Lymphadenectomy;Drug: S-1+Oxaliplatin<br>* A perioperative chemotherapy, known as SOX regimen, should be performed in each enrolled patient with three-cycle treatments followed after a pathological carcinoma diagnosis. After a radical operation (arm groups), additional five-cycle treatments of adjuvant chemotherapy (SOX regimen) would be performed, followed by follow-up program. The treatment bundles are listed as follows: S-1: 40 60mg bid，po, Day1 14 （S-1：BSA <1.25m2, 40mg bid, 1.25m2≤BSA≤1.5m2,50mg bid, BSA>1.5m2, 60mg bid） Oxaliplatin: 130mg/m2，iv drip for 2h，Day1<br>* Other names: SOX chemo Regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | five years after surgery | 
| Relapse-free Survival |  | five years after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early complications | Rate of early postoperative events, such as anastomotic leak, intra-abdominal hemorrhage, adhesive intestinal obstruction and surgical site infection, in each arm. | within the first 30 days after surgery | 
| Perioperative mortality |  | within the first 30 days after surgery | 
| Life quality measured by HRQOL score | a questionnaire form would be sent to each enrolled patients after surgery. | five years after surgery | 
| Length of Hospital stay | The duration between admission and final discharge from hospital. An average of 4 weeks is expected. | an expected average of 4 weeks after admission | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gastrectomy, lymphadenectomy, gastric cancer, adjuvant chemotherapy, overall survival