Neoplasms

Digestive System Diseases

All Conditions

Rare Diseases

Stomach Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Stomach Cancer

Antineoplastic Agents

All Drugs and Chemicals

Docetaxel

Oxaliplatin

Patients will receive hyperthermic intraperitoneal chemotherapy (HIPEC) during laparoscopic staging. Then 3 cycles of preoperative chemotherapy and clinical evaluation of chemotherapy will be performed. If the patient's disease is evaluated as progressed, the patient will receive systemic therapy. If it's stable or remission, a second time laparoscopic staging and peritoneal cytology examination will be performed. If peritoneal implant is observed, the patients will receive systemic therapy. If the peritoneal cytology is still positive, the treatment will be decided according to the suggestion of MDT discussion. If the peritoneal cytology is converted negative, standard gastrectomy with D2 lymphadenectomy and extensive intraperitoneal lavage (EIPL) will be performed. Postoperative chemotherapy will be determined according to the pathological evaluation of preoperative chemotherapy response.

Patients in this arm will receive standard gastrectomy with D2 lymphadenectomy after randomization. Hyperthermic intraperitoneal chemotherapy (HIPEC) and extensive intraperitoneal lavage (EIPL) will be applied before abdominal closure. After surgery, 8 cycles of postoperative chemotherapy will be performed.

standard distal or total gastrectomy and accorded D2 lymphadenectomy

standard gastrectomy with D2 lymphadenectomy

Intraperitoneal docetaxel of 100mg/m2 at 42℃ for 30 minutes

hyperthermic intraperitoneal chemotherapy

Lavage of peritoneal cavity with 1000ml saline for 10 times

Extensive intraperitoneal lavage

Oxaliplatin 130mg/m2 D1 S-1 40-60mg Bid D1-14 Repeated every 3 weeks.

Preoperative chemotherapy

SOX regimen postoperative chemotherapy (Oxaliplatin 130mg/m2 D1, S-1 40-60mg Bid D1-14, Repeated every 3 weeks) for surgery-first arm. Regimen for chemotherapy-first arm is determined according to the postoperative pathologic evaluation of response.

Postoperative chemotherapy

Rulin Miao, M.D.

Jiafu Ji, M.D.

Ziyu Li, M.D.

Gastric cancer with positive is defined as stage IV disease in 7th AJCC/UICC TNM staging system. Controversy exists on the treatment of this part of patients. This trial aimed to explore the optimal treatment strategy for stage IV gastric cancer with positive peritoneal cytology as the only non-curable factor.

In the 7th AJCC/UICC TNM staging system, gastric cancer with positive peritoneal cytology (CY+) is defined as stage IV disease. In NCCN clinical practice guidelines, it is suggested that positive peritoneal cytology in the absence of visible peritoneal implants should be considered as M1 disease and surgery as initial treatment is not recommended for patients with positive peritoneal cytology. However, in the Japanese gastric cancer treatment guidelines 2014, it is suggested that standard gastrectomy can be proposed for patients with no other non-curative factors and if the CY+ status was revealed after surgery, postoperative treatment with S-1 can be recommended as the tentative standard. Previous studies have also proved that extensive intraperitoneal lavage(EIPL) and Hyperthermic Intraperitoneal Chemotherapy(HIPEC) are effective methods for the treatment of peritoneal metastasis.

In order to optimize the treatment strategy of this part of patients, this trial is designed to compare the effectiveness of 2 treatment strategies.

Treatment Strategy for Stage IV Gastric Cancer With Positive Peritoneal Cytology as the Only Non-curable Factor

Treatment Strategy for Stage IV Gastric Cancer With Positive Peritoneal Cytology as the Only Non-curable Factor (Cy-plus): a Phase 2, Randomized Controlled Trial

Peking University

President of Peking University Cancer Hospital

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pharmaceutical Solutions

EIPL is performed after completing resection and lymphadenectomy: the abdominal cavity has to be washed ten times with one liter Ringer's solution. Each liter has to be well dispersed manually in the abdominal cavity, and removed and disposed completely. 100 ml of the last liter of lavage fluid will be harvested and sent for analysis.

Contrary to the Japanese trial, Ringer's solution will be used instead of normal saline solution because of a presumed higher likelihood of peritoneal adhesions when employing the latter (7). Ringer's solution is the standard used for all intraperitoneal lavage procedures at the study centre. To avoid hypothermia, the lavage fluid will be warmed to body temperature (37° Celsius).

Extensive Intraperitoneal Lavage (EIPL)

Ulrich Ronellenfitsch, MD

A Japanese study showed that the additional use of an "Extensive Intraperitoneal Lavage" (EIPL), i.e. an extensive washing of the abdominal cavity with water, during surgery for gastric cancer can lead to a significant increase in survival. However, the study was confined to patients in whom upon commencing surgery, free peritoneal tumor cells were detected, which is only a small fraction of patients.

The primary objective of our study is to assess in all patients undergoing removal of the stomach and adjacent lymph nodes for stomach cancer, if EIPL can eliminate free peritoneal tumor cells which have been present at the beginning of the surgery or after the stomach and lymph node removal. Secondary objectives are to assess how often free peritoneal tumor cells occur in patients with stomach cancer, how often surgical resection itself leads to a release of tumor cells, the safety of the EIPL procedure, and disease-free and overall survival of patients undergoing EIPL. Based on the outcome of this japanese study we want to test with special laboratory methods why this lavage leads to a better outcome.

Specifically, the trial will test the hypotheses that a) lymph node dissection causes a release of tumor cells in the abdominal cavity, and b) EIPL eliminates free peritoneal tumor cells.

In spite of the existence of multimodal therapy, the long-term survival of patients with gastric cancer remains poor. In advanced tumor stages, five-year survival rates rarely exceed 30%. One of the factors limiting overall survival is peritoneal carcinomatosis, which frequently occurs after surgical treatment with curative intention.

Peritoneal carcinomatosis is supposed to develop from peritoneal implantation of tumor cells already present in the abdominal cavity during primary surgery. It is assumed that both serosal tumor infiltration and intraoperative lymphadenectomy, which per se leads to a survival improvement (1) and is therefore considered standard in Europe and Japan ((2), http://www.jpca.jp/PDFfiles/ Guidelines2004_eng.pdf), can release tumor cells into the peritoneal cavity. Of note, a Japanese study found that tumor cells were released into the peritoneal cavity during lymphadenectomy in 14-46% of patients, depending on preoperative tumor stage (3).

A randomized clinical trial from Japan (4) demonstrated that an "extensive intraperitoneal lavage" (EIPL), i.e. an irrigation of the abdominal cavity with ten times one liter of physiological saline solution, in combination with intraperitoneal chemotherapy (IPC) carried out after gastrectomy and lymphadenectomy, led to a significant improvement in overall survival compared to patients who received only surgery and IPC without EIPL, and those who received surgery alone without EIPL and IPC. These results suggest that the largest survival benefit is attributable to the addition of EIPL to IPC (5-year survival rate: 43.8% vs. 4.6%) and not to the addition of IPC to surgery alone (5-year survival rate: 4.6% vs. 0%).

However, it is important to consider that the study included only patients in whom peritoneal tumor cells were detected before resection of the stomach and lymph nodes. Thus, only 90 of 1522 (5.9%) patients operated in the participating centers throughout the study period fulfilled the inclusion criteria. Furthermore, the study design was not appropriate to assess if EIPL really leads to a reduction of free tumor cells as assumed. Regarding this hypothesis, the only available results stem from single patients out of smaller studies (4;5). To date, there is no higher level evidence from larger populations.

The present trial, for the first time, uses EIPL as additional treatment in patients with any tumor stage and regardless of the detection of intraperitoneal tumor cells at the beginning of the operation.

Intraperitoneal lavage fluid will be harvested and assessed for tumor cells at three different points of time:

(i) before gastrectomy and lymphadenectomy (ii) after gastrectomy and lymphadenectomy, directly before EIPL (iii) after EIPL

The trial will test the hypotheses that a) lymph node dissection causes a release of tumor cells in the abdominal cavity, and b) EIPL eliminates free peritoneal tumor cells.

Elimination of Peritoneal Tumor Cells With Extensive Peritoneal Lavage During Surgery in Patients With Gastric Cancer

Elimination of Peritoneal Tumor Cells With "Extensive Intraperitoneal Lavage (EIPL)" During Surgical Treatment of Gastric Adenocarcinoma

The Peritoneal Conversion Rate (PCR) is defined as the proportion of patients in whom no free peritoneal tumor cells are detected after EIPL among all patients in whom free peritoneal tumor cells were detected before EIPL. In other words, the PCR measures in what proportion of patients EIPL leads to an elimination of intraperitoneal tumor cells.

The Peritoneal Release Rate (PRR) is defined as the proportion of patients in whom free peritoneal tumor cells are detected after gastrectomy and lymphadenectomy among all patients in whom no free peritoneal tumor cells were detected before gastrectomy and lymphadnectomy. In other words, this denotes the proportion of patients in whom tumor cells are released into the peritoneal cavity due to the surgical measures performed.

This denotes the proportion of patients in whom free intraperitoneal tumor cells can be detected upon laparotomy among all operated patients.

Overall survival is defined as the time between surgery and death, independent of the cause of death.

Recurrence-free survival is defined as the time between surgery and the appearance of a local recurrence, peritoneal carcinomatosis, or distant metastases.

All complications occuring throughout the hospital stay of the patient are assessed according to the Clavien-Dindo classification for surgical complications (6).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Treatment Strategy for Stage IV Gastric Cancer With Positive Peritoneal Cytology as the Only Non-curable Factor	NCT02969122	Stomach Neoplas...	standard gastre... hyperthermic in... Extensive intra... Preoperative ch... Postoperative c...	-	Peking University
Treatment Strategy for Stage IV Gastric Cancer With Positive Peritoneal Cytology as the Only Non-curable Factor	NCT02969122	Stomach Neoplas...	standard gastre... hyperthermic in... Extensive intra... Preoperative ch... Postoperative c...	-	Peking University
Elimination of Peritoneal Tumor Cells With Extensive Peritoneal Lavage During Surgery in Patients With Gastric Cancer	NCT01476553	Adenocarcinoma Stomach Neoplas...	Extensive Intra...	18 Years -	Universitätsmedizin Mannheim

Spots Global Cancer Trial Database for extensive intraperitoneal lavage