Extensive Intraoperative Peritoneal Lavage After Curative Gastrectomy for Locally Advanced Gastric Cancer (SEIPLUS) (SEIPLUS)

• ClinicalTrials.gov Identifier: NCT02745509
• Recruitment Status: Completed
• First Posted: April 20, 2016
• Last Update Posted: February 21, 2019
• Sponsor: Sun Yat-sen University
• Collaborators: Anhui Provincial Hospital; The First Affiliated Hospital of Anhui Medical University; Anqing Municipal Hospital; Yuebei People's Hospital; The First Affiliated Hospital of Guangdong Pharmaceutical University; Guangdong Provincial Hospital of Traditional Chinese Medicine; Jiangsu Cancer Institute & Hospital; Jiangxi Provincial Cancer Hospital; Tianjin Medical University Cancer Institute and Hospital; First Affiliated Hospital of Wannan Medical College; Lishui hospital of Zhejiang University; Second Affiliated Hospital, School of Medicine, Zhejiang University
• Information provided by (Responsible Party): Dazhi Xu, Sun Yat-sen University

Tracking Information

• First Submitted Date: March 28, 2016
• First Posted Date: April 20, 2016
• Last Update Posted Date: February 21, 2019
• Study Start Date: March 2016
• Actual Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 16, 2016)

Overall survival [ Time Frame: 3-year ]

The survival rate between the surgery to the 3rd year due to all-cause death or last follow-up.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 19, 2016)

• Disease-free survival [ Time Frame: 3-year ]
  The progression-free or all-cause death rate between the surgery and the 3rd year.
• Peritoneal recurrence [ Time Frame: 3-year ]
  The Peritoneal recurrence rate between the surgery and the 3rd year
• Postoperative complications [ Time Frame: an average of 10 days ]
  complications such bleeding, infection, obstruction and leakage
• Post-operative quality of life [ Time Frame: an average of 10 days ]
  The postoperative quality of life will be assessed by factors such as Swallowing，Pain and discomfort，Dietary restrictions, Upper gastrointestinal symptoms, mental status and others.

Original Secondary Outcome Measures (submitted: April 16, 2016)

• Disease-free survival [ Time Frame: 3-year ]
  The progression-free or all-cause death rate between the surgery and the 3rd year.
• Peritoneal recurrence [ Time Frame: 3-year ]
  The Peritoneal recurrence rate between the surgery and the 3rd year
• Postoperative complications [ Time Frame: an average of 10 days ]
  complications such bleeding, infection, obstruction and leakage
• Quality of life [ Time Frame: an average of 10 days ]
  factors such Swallowing，Pain and discomfort，Dietary restrictions, Upper gastrointestinal symptoms, mental status and others.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Extensive Intraoperative Peritoneal Lavage After Curative Gastrectomy for Locally Advanced Gastric Cancer (SEIPLUS)
• Official Title: A Prospective, Multicentral, Open-label, Randomized, Controlled Clinical Trial to Investigation the Value of Extensive Intraoperative Peritoneal Lavage After Curative Gastrectomy for Locally Advanced Gastric Cancer

Brief Summary

The investigators study aims to explore the potential function of extensive intraoperative peritoneal lavage in improving the overall survival and progression-free survival for locally advanced gastric cancer after curative resection.

Hypothesis: Overall survival and progression-free survival of locally advanced gastric cancer are improved by extensive intraoperative peritoneal lavage.

Detailed Description

Gastric cancer has been one of the most frequently common cancers and remains the third leading cause of death among malignant tumors all over the world. Surgery has always been considered as the most effective treatment. While significant surgical technique and perioperative management have dramatically improved the survival of patients with advanced gastric cancer, patients with T4 stage or serosal-positive gastric cancer often suffer from recurrence as peritoneal dissemination, and the prognosis of those patients is extremely poor. Despite curatively resected, Peritoneal metastasis is completed by the implantation of peritoneal free cancer cells exfoliated from serosa-invasive tumors. Therefore, things need to be done to eliminate the free exfoliated cancer cells on the peritoneal lining in order to reduce the risk of peritoneal recurrence.

A multi-institutional prospective, randomized trial has been launched by Kuramoto recently. The trail was intended to demonstrate the superiority in overall survival of addition of Extensive Intraoperative peritoneal Lavage (EIPL) to standard treatment in patients with≥T3 carcinoma of stomach. Based on the'limiting dilution theory', after total or distal gastrectomy with D2 lymphadenectomy, the peritoneal cavity is extensively rinsed 10 times with 1 L physiological saline at a time, followed by complete aspiration of the fluid. In total, 10 L saline is to be used. In this study, the EIPL-IPC group had a significantly lower incidence of peritoneal recurrence. Furthermore, the 5-year overall survival rate of the patients in the EIPL-IPC group (43.8%) was significantly better than that of the intraperitoneal chemotherapy (IPC) group (4.6%) and the surgery-alone group (0%). All in all, EIPL is easy to carry out, safe and inexpensive. Therefore, gastrectomy with EIPL will be a new standard treatment of gastric cancer.

To ensure the quality of the study, two interim analyses will be planned at the half and the completion of the study respectively. The Data and Safety Monitoring Committee will independently review the interim analysis and stop the study ahead of schedule if necessary. Furthermore, to improve the study progress and quality, the in-house interim monitoring will be performed.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: Gastric Cancer

Intervention

Other: Extensive Intraoperative Peritoneal Lavage

Extensive Intraoperative Peritoneal Lavage

Other Name: EIPL

Study Arms

• Experimental: Extensive Intraoperative Peritoneal Lavage
  Gastrectomy with D2 lymphadenectomy is performed. The peritoneal cavity of subject will be washed with 10 liters of warmed normal saline (1 liter per cycle for 10 cycles), followed by complete aspiration of the fluid . The abdomen will be closed as per standard.
  Intervention: Other: Extensive Intraoperative Peritoneal Lavage
• No Intervention: Standard Treatment
  Gastrectomy with D2 lymphadenectomy is performed. The peritoneal lavage will be done < 3 cycles with 3 liters or less of warmed normal saline. The abdomen will be closed as per standard.

Publications *

• Mezhir JJ, Posner MC, Roggin KK. Prospective clinical trial of diagnostic peritoneal lavage to detect positive peritoneal cytology in patients with gastric cancer. J Surg Oncol. 2013 Jun;107(8):794-8. doi: 10.1002/jso.23328. Epub 2013 Mar 26.
• Tang B, Peng ZH, Yu PW, Yu G, Qian F, Zeng DZ, Zhao YL, Shi Y, Hao YX, Luo HX. Aberrant expression of Cx43 is associated with the peritoneal metastasis of gastric cancer and Cx43-mediated gap junction enhances gastric cancer cell diapedesis from peritoneal mesothelium. PLoS One. 2013 Sep 11;8(9):e74527. doi: 10.1371/journal.pone.0074527. eCollection 2013.
• Hamazoe R, Maeta M, Kaibara N. Intraperitoneal thermochemotherapy for prevention of peritoneal recurrence of gastric cancer. Final results of a randomized controlled study. Cancer. 1994 Apr 15;73(8):2048-52. doi: 10.1002/1097-0142(19940415)73:83.0.co;2-q.
• Xu DZ, Zhan YQ, Sun XW, Cao SM, Geng QR. Meta-analysis of intraperitoneal chemotherapy for gastric cancer. World J Gastroenterol. 2004 Sep 15;10(18):2727-30. doi: 10.3748/wjg.v10.i18.2727.
• Sautner T, Hofbauer F, Depisch D, Schiessel R, Jakesz R. Adjuvant intraperitoneal cisplatin chemotherapy does not improve long-term survival after surgery for advanced gastric cancer. J Clin Oncol. 1994 May;12(5):970-4. doi: 10.1200/JCO.1994.12.5.970.
• Rosen HR, Jatzko G, Repse S, Potrc S, Neudorfer H, Sandbichler P, Zacherl J, Rabl H, Holzberger P, Lisborg P, Czeijka M. Adjuvant intraperitoneal chemotherapy with carbon-adsorbed mitomycin in patients with gastric cancer: results of a randomized multicenter trial of the Austrian Working Group for Surgical Oncology. J Clin Oncol. 1998 Aug;16(8):2733-8. doi: 10.1200/JCO.1998.16.8.2733.
• Coccolini F, Cotte E, Glehen O, Lotti M, Poiasina E, Catena F, Yonemura Y, Ansaloni L. Intraperitoneal chemotherapy in advanced gastric cancer. Meta-analysis of randomized trials. Eur J Surg Oncol. 2014 Jan;40(1):12-26. doi: 10.1016/j.ejso.2013.10.019. Epub 2013 Nov 5.
• Kuramoto M, Shimada S, Ikeshima S, Matsuo A, Yagi Y, Matsuda M, Yonemura Y, Baba H. Extensive intraoperative peritoneal lavage as a standard prophylactic strategy for peritoneal recurrence in patients with gastric carcinoma. Ann Surg. 2009 Aug;250(2):242-6. doi: 10.1097/SLA.0b013e3181b0c80e.
• Misawa K, Mochizuki Y, Ohashi N, Matsui T, Nakayama H, Tsuboi K, Sakai M, Ito S, Morita S, Kodera Y. A randomized phase III trial exploring the prognostic value of extensive intraoperative peritoneal lavage in addition to standard treatment for resectable advanced gastric cancer: CCOG 1102 study. Jpn J Clin Oncol. 2014 Jan;44(1):101-3. doi: 10.1093/jjco/hyt157. Epub 2013 Nov 27.
• Guo J, Xu A, Sun X, Zhao X, Xia Y, Rao H, Zhang Y, Zhang R, Chen L, Zhang T, Li G, Xu H, Xu D. Three-year outcomes of the randomized phase III SEIPLUS trial of extensive intraoperative peritoneal lavage for locally advanced gastric cancer. Nat Commun. 2021 Nov 15;12(1):6598. doi: 10.1038/s41467-021-26778-8.
• Guo J, Xu A, Sun X, Zhao X, Xia Y, Rao H, Zhang Y, Zhang R, Chen L, Zhang T, Li G, Xu H, Xu D. Combined Surgery and Extensive Intraoperative Peritoneal Lavage vs Surgery Alone for Treatment of Locally Advanced Gastric Cancer: The SEIPLUS Randomized Clinical Trial. JAMA Surg. 2019 Jul 1;154(7):610-616. doi: 10.1001/jamasurg.2019.0153.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 5, 2018): 508
• Original Estimated Enrollment (submitted: April 16, 2016): 530
• Actual Study Completion Date: November 2017
• Actual Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Lower age limit of research subjects 18 years old and upper age limit of 80 years old.
2. ECOG score standard (ECOG）performance status of 0 or 1 and expected to survive more than 6 months.
3. Without any other malignancies.
4. Written informed consent from the patient.
5. Histologically proven primary gastric adenocarcinoma.
6. Patients planned for open gastrectomy.
7. Patients who have T3 (subserosal) or T4 (serosal) disease based on Ultrasound gastroscopy and intra-operative inspection with any N staging and M0 gastric cancer.
8. No preoperative neoadjuvant chemotherapy.
9. Length of esophageal invasion≤3cm and no need of thoracotomy for resection.

10. Intraoperative inclusion criteria:

    1. Clinically T3, T4a or T4b.
    2. Clinically H0 and M0. No peritoneal dissemination or Distant metastases.
    3. Possible for R0 surgery.

Exclusion Criteria:

1. Female in pregnancy or lactation.
2. Supraclavicular lymph nodes metastases，pelvis or ovarian implantation，peritoneal dissemination，liver，lung and bone metastases.
3. Massive ascites or cachexia.
4. Patients participating in any other clinical trails currently，or participated in other trails within 1 months.
5. Without a history of stomach or esophageal cancers, including stromal tumor，sarcoma，lymphoma and carcinoid.
6. Suffering from other serious diseases, including cardiovascular, respiratory, kidney, or liver disease, complicated by poorly controlled hypertension, diabetes, mental disorders or diseases.
7. Patients with poor compliance or considered to be poor compliance.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT02745509
• Other Study ID Numbers: SEIPLUS
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Dazhi Xu, Sun Yat-sen University
• Original Responsible Party: Same as current
• Current Study Sponsor: Sun Yat-sen University
• Original Study Sponsor: Same as current

Collaborators

• Anhui Provincial Hospital
• The First Affiliated Hospital of Anhui Medical University
• Anqing Municipal Hospital
• Yuebei People's Hospital
• The First Affiliated Hospital of Guangdong Pharmaceutical University
• Guangdong Provincial Hospital of Traditional Chinese Medicine
• Jiangsu Cancer Institute & Hospital
• Jiangxi Provincial Cancer Hospital
• Tianjin Medical University Cancer Institute and Hospital
• First Affiliated Hospital of Wannan Medical College
• Lishui hospital of Zhejiang University
• Second Affiliated Hospital, School of Medicine, Zhejiang University

• Investigators: Not Provided
• PRS Account: Sun Yat-sen University
• Verification Date: February 2019