Cytoreductive Surgery (CRS) With/Without HIPEC in Gastric Cancer With Peritoneal Carcinomatosis

Study Overview
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Brief Summary
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Patients with histological proven gastric cancer (including cancer of the esophagogastric junction (AEG)) and synchronous peritoneal carcinomatosis, who fulfill the inclusion and exclusion criteria, can be recruited in this study. There are two treatment groups (A and B). The chemotherapy applied intravenously is the same in both groups and is approved for the treatment of gastric cancer. Patients with negative or unknown HER-2 status will be administered Epirubicin, Oxaliplatin and Capecitabine (EOX). Patients with positive HER-2 status will be treated with Cisplatin, Capecitabine and Trastuzumab (CCT). The chemotherapy is followed by surgical cytoreduction in both groups. Patients randomized into group B will be treated with an intraperitoneal (in the abdominal cavity) chemoperfusion with Mitomycin C and Cisplatin . Patients in both groups receive 3 cycles of postoperative chemotherapy within 4-12 weeks after the surgical procedure and are followed up for 30 months. If progress of the tumor is detected the patient will no longer be treated according to the study therapy. Patients of group B may get a HIPEC intervention without surgical cytoreduction if contraindication to the drugs applied can be excluded.

Detailed Description
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The objective of the trial is to compare the treatment of patients with peritoneal metastasized gastric cancer including carcinoma of the AEG (Adenocarcinoma of the oesophago-gastric-junction) without evidence of other distant metastases treated with neoadjuvant chemotherapy followed by cytoreduction with intraperitoneal chemoperfusion (HIPEC) and postoperative chemotherapy (Group B) and patients treated with cytoreduction alone after neoadjuvant chemotherapy and postoperative chemotherapy (Group A). Hypothesis of the trial is that surgical cytoreduction with intraperitoneal chemoperfusion (Group B) is superior to cytoreduction alone (Group A) in terms of overall survival. The trial is designed as a prospective, randomized, open, multicenter and parallel group study.

Official Title
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Prospective Multicenter Phase III Trial Using CRS With / Without HIPEC After Preoperative Chemotherapy in Patients With Peritoneal Carcinomatosis of Gastric Cancer Incl. Adenocarcinoma of the Esophagogastric Junction

Conditions
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Malignant Neoplasm of Stomach, Secondary Malignant Neoplasm of Peritoneum, Secondary Malignant Neoplasm of Other and Unspecified Sites

Intervention / Treatment
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* Procedure: HIPEC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological proved diagnosis of peritoneal metastasized gastric cancer including carcinoma of the AEG No evidence of other distant metastases than peritoneal carcinomatosis with exception of Krukenberg Tumors Peritoneal Staging with laparoscopy (or explorative laparotomy) and estimation of Peritoneal Cancer Index (PCI) with the possibility of 80% tumor reduction at cytoreductive surgery Karnofsky Index 70% or better Written informed consent is obtained prior to commencement of trial treatment Exclusion Criteria: Other than peritoneal metastasis of the gastric cancer incl. AEG and Krukenberg tumors Previous or concurrent malignancies, with the exception of adequately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix Any previous chemotherapy or radiotherapy, and any investigational treatment for gastric cancer Active systemic infections Patients with known interstitial lung disease with New York Heart Association classification > 2 Serious cardiac dysrhythmia or condition, New York Heart Association classification of III or IV, congestive cardiac failure cardiac arrhythmia Uncontrolled hypertension (diastolic blood pressure constantly >100 mm Hg, systolic blood pressure constantly > 180 mm Hg). Inadequate bone marrow function at the beginning of the trial, defined as platelet count less than <150 GPT/L or neutrophil granulocyte count less than <1.5 GPT/L cardiac function EF < 55% Inadequate renal function at the beginning of the trial, defined as GFR less than <60 ml/min Inadequate liver function at the beginning of the trial, defined as Bilirubin >1.5 times ULN Active vaccination within 6 weeks prior to randomisation Active hepatitis B or C infection Female patients who are pregnant or breast feeding Fertile female patients (defined as women with less than a 12-month elapse after the last menstruation) not using an acceptable form of contraception during the trial Missing of capacity to contract contraindication to the drugs which are used in the trial Participation in another therapeutic clinical trial Persons institutionalised due to regulatory actions ore by court order.

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
Interventional Model Description: intraperitoneal (in the abdominal cavity) chemoperfusion with Mitomycin C and Cisplatin
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: without HIPEC<br>Preoperative chemotherapy 3 cycles, each cycle 21 days. Patients with negative or unknown HER-2 status receive Epirubicin 50 mg/m² infusion (maximum 100mg/d). Oxaliplatin 130 mg/m² infusion (maximum 260 mg/d) and capecitabine oral 625 mg/m² two times a day (maximum 2500 mg/d). Patients with positive HER-2 status receive: Cisplatin : 80 mg/m² infusion (maximum of 160 mg/d). Capecitabine: oral 1000 mg/m2 (two times a day maximum of 4000 mg/d), on day 1-14. Trastuzumab: 8 mg/kg infusion (on cycle 1 and 6 mg/kg on cycle 2 and 3). CRS is performed and 4-12 weeks after CRS 3 cycles of postoperative chemotherapy have to be applied. In case of therapy failure patients will be continued to be treated by the responsible investigator according to his medical status. | |
| Experimental: With HIPEC<br>Patients will be treated with a preoperative chemotherapy as described for the control group. EOX or CCT depending on the HER-2 status. CRS will be performed 2 to 3 weeks after end of last chemotherapy cycle. HIPEC with mitomycin C and cisplatin either at the time of CRS or a delayed HIPEC within 5-7 days. HIPEC: Mitomycin C: 15 mg/m2 (max. 30 mg/ m2, max. 5 L Perfusion). Cisplatin: 75 mg/m2/L (max. 150 mg/m2, max. 5 L Perfusion). 4-12 weeks after cytoreductive surgery 3 cycles postoperative chemotherapy will be applied. Patients may get a HIPEC intervention without surgical cytoreduction if contraindication to the drugs can be excluded. In case of therapy failure patients will be continued to be treated by the responsible investigator according to his medical status. | Procedure: HIPEC<br>* HIPEC: Mitomycin C: 15 mg/m2 (max. 30 mg/ m2, max. 5 L Perfusion). Cisplatin: 75 mg/m2/L (max. 150 mg/m2, max. 5 L Perfusion). 4-12 weeks after cytoreductive surgery 3 cycles postoperative chemotherapy will be applied.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome measure is overall survival | Overall survival from randomisation up to end of study, follow up every 3 months till 2.5 years | Death or 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30 days complication-rate | 30 days complication-rate. Complications are ranked from grade 0-5 according to CTCAE V4.0 | 30 days postoperative | 
| time to progress | time to progress of tumor, follow up every 3 months till 2.5 years | follow up every 3 months till 2.5 years end of study, 2.5 years | 
| time to other distant metastases | time to other distant metastases follow up every 3 months till 2.5 years | end of study follow up every 3 months till 2.5 years | 
| quality of life | quality of life (EORTC QLQ-30, STO 22). Every 6 months to 2,5 years | Every 6 months to 2,5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric cancer, cancer of the esophagogastric junction, peritoneal carcinomatosis, hyperthermic intraperitoneal chemotherapy, HIPEC