Efficacy of HIPEC in the Treatment of Locally Advanced Gastric Cancer After radIcal Gastrectomy With D2

Study Overview
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Brief Summary
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HIPEC-01 is a prospective, open, randomized multicenter phase III clinical study conducted in China. To determine the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of locally advanced gastric cancer, patients are randomized into HIPEC group and control group. In HIPEC group, the patients undergo radical gastrectomy with D2 lymphadenectomy and HIPEC with paclitaxel and postoperative chemotherapy. Patients in the control group just undergo radical gastrectomy with D2 lymphadenectomy followed by postoperative chemotherapy. Patients in both groups receive 6-8 cycles of postoperative systemic chemotherapy (XELOX or SOX regimens) and are followed up for 5 years or until death.

Detailed Description
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Gastric cancer (GC) is the fourth most common cancer, and the second leading cause of cancer-related death worldwide. Advances in diagnostic and therapeutic approaches have achieved long-term survival for early GC. However, receiving perioperative/postoperative systemic chemotherapy and gastrectomy with D1-D2 lymph node dissection, 5-year survival rates of advanced gastric cancer remain under 30%. 40-60% of recurrences are peritoneal and/or locoregional. hyperthermic intraperitoneal chemotherapy (HIPEC) technique is increasingly used in the curative treatment of primary and digestive peritoneal carcinomatosis, in association with cytoreductive surgery. Theoretically, HIPEC eliminates free cancer cells that can be released into peritoneal cavity during the gastrectomy and prevents peritoneal carcinomatosis recurrences. The benefit of using HIPEC as an adjuvant treatment for advanced gastric cancer has been reported in several randomized studies and a meta-analysis. Surgical resection combined with HIPEC significantly reduces the peritoneal recurrences and improves the overall survival of GC patients. But there is not a prospective and randomized phase III clinical study of HIPEC in the treatment of locally advanced gastric cancer after radical surgery in China so far. In order to evaluate the survival benefit and safety of radical surgery and HIPEC followed by postoperative chemotherapy in local advanced gastric cancer, patients who fulfill the inclusion and exclusion criteria will be recruited in this study and randomized to two treatment groups (HIPEC group and control group). In HIPEC group, the patients undergo radical gastrectomy with D2 lymphadenectomy and HIPEC with paclitaxel and postoperative chemotherapy. Patients in the control group just undergo radical gastrectomy with D2 lymphadenectomy followed by postoperative chemotherapy. Patients in both groups receive 6-8 cycles of postoperative systemic chemotherapy (XELOX or SOX regimens) . Patients are followed up for 5 years and the survival outcome will be analyzed.

Official Title
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A Phase III Study of Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Locally Advanced Gastric Cancer After radIcal Gastrectomy With D2

Conditions
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Gastric Cancer

Intervention / Treatment
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* Procedure: D2 lymphadenectomy
* Procedure: Hyperthermic Intraperitoneal Chemotherapy
* Drug: Systemic chemotherapy (XELOX or SOX regimens)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 < age ≤ 70 years old Male or Non pregnant female The Eastern Cooperative Oncology Group (ECOG) status 0-1 T3 or T4 gastric adenocarcinoma (visual determination according to AJCC 2010 7th edition) No distance metastasis, eligible for D2 lymphadenectomy Have not received cytotoxic chemotherapy, radiotherapy or immunotherapy White blood cells > 4,000/mm3 neutrophils ≥ 1,500/mm3 platelets ≥ 100,000/mm3 hemoglobin>9g/l Alanine transaminase (ALT) and aspartate aminotransferase (AST) < or = 2.5 times upper limit of nominal (ULN) total bilirubin (TBIL) < 1.5 times ULN serum creatinine < 1 times ULN Having given written informed consent prior to any procedure related to the study Exclusion Criteria: Have other cancer within 5 years Existence of distance metastasis during surgey (M1) Prior malignant tumors with detectable signs of recurrence or distant metastasis Poorly controlled disease e.g. atrial fibrillation, stenocardia, cardiac insufficiency, persistent hypertension despite medicinal treatment, ejection fraction<50% Epileptic seizures patients need medicine control Uncontroled mental disease or mental disorder Drug abuse or psychological or social factors affect the judgment of results Contraindication to any therapy contained in this regimen specific to the study Receiving other chemotherapy, radiotherapy or immunotherapy Without given written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: HIPEC group<br>Postoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is performed after radical surgery, followed by 6-8 cycles of systemic chemotherapy. The first HIPEC is conducted within 48 h after surgery: Paclitaxel 75 mg/m^2, 43°C, 60min. The second HIPEC is performed after 24 hours of the first HIPEC. The regimens are Paclitaxel 100 mg/m^2, 43°C, 60min. Systemic chemotherapy (XELOX or SOX regimens): XELOX regimen: Oxaliplatin: 130 mg/m^2, IV, d1; Capecitabine: 1 g/m^2 bid, days 1-14, every 3 weeks for a total of 6-8 cycles. If XELOX regimen is not conducted in some collaborators, SOX regimen is also permitted. The regimen is Oxaliplatin: 130 mg/m^2, IV, d1; S-1, 40-60 mg/m^2 bid, po, day 1-14, every 3 weeks for a total of 6-8 cycles. | Procedure: D2 lymphadenectomy<br> <br> * Other names: surgical resection or radical surgery;Procedure: Hyperthermic Intraperitoneal Chemotherapy<br>* The first HIPEC is conducted within 48 h after surgery: Normal saline 3000 -4000ml, Paclitaxel 75mg/m^2, 43°C, 60min. The second HIPEC is performed after 24 hours of the first HIPEC. The regimens are Paclitaxel 100 mg/m^2, 43°C, 60min.<br>* Other names: HIPEC;Drug: Systemic chemotherapy (XELOX or SOX regimens)<br>* XELOX regimen: Oxaliplatin: 130 mg/m^2, IV, d1; Capecitabine: 1 g/m^2 bid, days 1-14, every 3 weeks for a total of 6-8 cycles. SOX regimen: Oxaliplatin: 130 mg/m^2, IV, d1; S-1, 40 mg/m^2 bid, po, day 1-14 (S-1: BSA <1.25m^2, 40mg bid, 1.25m^2≤ BSA ≤1.5m^2, 50mg bid, BSA>1.5m^2, 60 mg bid) bid, d1-14, po, every 3 weeks for a total of 6-8 cycles.<br>* Other names: XELOX or SOX regimens;|
| Placebo Comparator: Control group<br>6-8 cycles of systemic chemotherapy (XELOX or SOX regimens) were performed after radical gastrectomy with D2 lymphadenectomy. XELOX regimen is Oxaliplatin: 130 mg/m^2, IV, d1; Capecitabine: 1 g/m^2 bid, days 1-14, every 3 weeks for a total of 6-8 cycles. If XELOX regimen is not conducted in some collaborators, SOX regimen as comment systemic chemotherapy in Asia is also permitted to treat the patients. The treatment bundles are listed as follows: Oxaliplatin: 130 mg/m^2, IV, d1; S-1, 40-60 mg/m^2 bid (S-1: BSA <1.25m^2, 40mg bid, 1.25m^2≤ BSA ≤1.5m^2, 50mg bid, BSA>1.5m^2, 60 mg bid), po, day 1-14, every 3 weeks for a total of 6-8 cycles. | Procedure: D2 lymphadenectomy<br> <br> * Other names: surgical resection or radical surgery;Drug: Systemic chemotherapy (XELOX or SOX regimens)<br>* XELOX regimen: Oxaliplatin: 130 mg/m^2, IV, d1; Capecitabine: 1 g/m^2 bid, days 1-14, every 3 weeks for a total of 6-8 cycles. SOX regimen: Oxaliplatin: 130 mg/m^2, IV, d1; S-1, 40 mg/m^2 bid, po, day 1-14 (S-1: BSA <1.25m^2, 40mg bid, 1.25m^2≤ BSA ≤1.5m^2, 50mg bid, BSA>1.5m^2, 60 mg bid) bid, d1-14, po, every 3 weeks for a total of 6-8 cycles.<br>* Other names: XELOX or SOX regimens;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year overall survival | assess overall survival during 5 years in both study arms | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year progression-free survival | assess progression-free survival rate during 5 years in both study arms | 5 years | 
| liver metastatic rate | calculate the percent of liver metastatic in both two arms during 5 years | 5 years | 
| local recurrence rate | calculate the percent of local recurrence in both two arms during 5 years | 5 years | 
| side effects | determine percent of adverse events or side effects according to NCI criteria, Common Terminology Criteria for AE (CTCAE 4.0). | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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locally advanced gastric cancer, Hyperthermic Intraperitoneal Chemotherapy, radical gastrectomy with D2 lymphadenectomy