Standard Versus Super-extended Lymphadenectomy After Neo-adjuvant Chemotherapy for Gastric Cancer (Neo-D2plus)

In this study the patients with histological evidence of adenocarcinoma of the stomach will be screened and, if eligible, submitted to neo-adjuvant chemotherapy (NAC). After conclusions of NAC and obtaining informed consent, they will be registered and randomized to receive surgical D2 vs. D2plus lymphadenectomy.

Study Overview

• Status: Recruiting
• Conditions: Locally Advanced Gastric Cancer
• Intervention / Treatment: Procedure: Gastrectomy with D2 lymphadenectomy; Procedure: Gastrectomy with D2plus lymphadenectomy

Detailed Description

This is a prospective multi-centre phase III, two-group, randomized and controlled trial designed to prove superiority of the experimental treatment arm (neo-adjuvant chemotherapy and super-extended lymphadenectomy).

The trial population consists of patients who have histologically confirmed adenocarcinoma of the stomach with locally advanced primary tumour and no evidence of distant metastases (stage IIA-IIIC gastric cancer). The lymph node clinical metastases, before neo-adjuvant chemotherapy, must be limited to the first and second compartments (stations 1-12).

STANDARD GROUP: Neoadjuvant chemotherapy + surgical gastrectomy with D2 lymphadenectomy.

Patients who are assigned to neoadjuvant chemotherapy+ surgical D2 treatment group will undergo either subtotal or total gastrectomy, depending on the location of the primary tumour. Standardized D2-lymph node dissection is required with specific information about lymph node stations.

EXPERIMENTAL GROUP: Neoadjuvant chemotherapy + surgical gastrectomy with D2plus lymphadenectomy.

Patients who are assigned to neoadjuvant chemotherapy + surgical D2plus extended lymphadenectomy treatment group will undergo either subtotal or total gastrectomy, depending on the location of the primary tumour. Standardized D2 lymph node dissection plus resection of stations 8p, 12b/p, 13, 14v, 16a2/b1 is required with specific information about lymph node stations.

In both groups, surgical treatment should be performed within 4-6 weeks after the end of the last cycle of NAC.

The primary objective of this study is to compare overall and cancer-related survival between D2 and D2+ lymphadenectomy following neo-adjuvant chemotherapy for resectable gastric cancer.

In addition, response to chemotherapy, resection rate, quality of life, complications attributable to surgical intervention / side effects of chemotherapy and the duration of hospitalization will be evaluated.

Sample size estimation was performed, to detect the minimum number of patients to be recruited in each arm. A two-sided log rank test with an overall sample size of 539 subjects, of which 270 are in group 1 and 269 are in group 2.

Data will be analyzed using SPSS software. Level of significance will be defined as 5%.

The trial will be open for recruitment from October 2018 to September 2023.

• Study Type: Interventional
• Enrollment (Anticipated): 539
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Daniele Marrelli; Phone Number: +39577585157; Email: daniele.marrelli@unisi.it

Study Locations

• Italy
  • Siena, Italy, 53100
    • Recruiting
    • General and Surgical Oncology Department, University of Siena
    • Contact: Daniele Marrelli; Phone Number: +39577585157; Email: daniele.marrelli@unisi.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age equal or greater than 18 years
• IIA-IIIC histologically proven primary gastric adenocarcinoma, before the treatment with NAC. Not including gastro-oesophageal junction/cardia carcinoma but only Siewert 3, without any previous treatment (surgery and / or chemotherapy) for this diagnosis

• Lack in CT scan of following:

  1. Mediastinal lymph nodes
  2. Lung metastases
  3. Peritoneal metastases
  4. Liver metastases
  5. Pleural effusion, ascites
  6. Metastases to para-aortic lymph nodes No 16a2/b1
  7. Metastases to lymph nodes located in the "posterior" area (8p, 12 b/p, 13)
  8. Extra-regional lymph node metastases
• ECOG performance status ≤ 2
• No prior radio- or chemotherapy conflicting with the treatment of gastric cancer
• No oesophageal invasion, or invasion <=3cm
• Negative peritoneal washing cytology findings and no peritoneal metastases in staging laparoscopy
• No gastric stump cancer
• No signs of cervical and subclavear lymph nodes or distal metastases
• Patient's consent form obtained, signed and dated before beginning specific protocol procedures
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Exclusion Criteria:

• Contraindications for any sort of appropriate chemotherapy according to local standards
• Linitis plastica
• Second uncontrolled malignant tumour (synchronous or metachronous (last 5 years) other than Cis or mucosal cancer
• Neoplasms involving the esophago-gastric junction (Siewert types I and II)
• Expected unresectability after neo-adjuvant treatment or progression in metastases
• Emergency surgery due to bleeding or perforation
• Uncontrolled infections
• Other serious underlying medical conditions that could impair the ability of the patient to participate in the study
• Pregnant or lactating women
• Significant neurologic or psychiatric disorders
• Severe cardiac illness (NYHA class IV)
• Under treatment of systemic steroids
• Participation in any other clinical trial that might interfere with the results of this trial
• Lack of compliance
• Inability to fill in questionnaires (insufficient command of language, dementia, lack of time)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Group; Neoadjuvant chemotherapy + surgical gastrectomy with D2 lymphadenectomy	Procedure: Gastrectomy with D2 lymphadenectomy; Patients who are assigned to the neoadjuvant chemotherapy+ surgical D2 treatment group will undergo either subtotal or total gastrectomy, depending on the location of the primary tumour. Standardized D2-lymph node dissection is required with specific information about lymph node stations.
Experimental: Experimental Group; Neoadjuvant chemotherapy + surgical gastrectomy with D2plus lymphadenectomy	Procedure: Gastrectomy with D2plus lymphadenectomy; Patients who are assigned to the neoadjuvant chemotherapy + surgical D2+ extended lymphadenectomy treatment group will undergo either subtotal or total gastrectomy, depending on the location of the primary tumour. Standardized D2+ lymph node dissection plus resection of stations 8p, 12p, 13, 14v, 16a2/b1 is required with specific information about lymph node stations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival analysis	Overall survival analysis will be analysed during follow up visits	This outcome measure will be estimated from the time of randomization to the date of death or last follow up visit, assessed approximately 5 years after the disease diagnosis.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence free-survival	That part will also be analysed during follow up visits. The recurrence has to be documented in radiological, endoscopic or pathological examination, when possible.	This outcome measure will be estimated from the time of randomization to the date of recurrence, assessed approximately 5 years after the disease diagnosis.
Post-operative morbidity	Severity of post-operative complications will be analysed using Clavien-Dindo classification	This outcome measure will be assessed approximately 3 month after the operation date.
Post-operative mortality	Deaths after surgery	Within 30 days from operation or during the hospital stay
R0 resection	Absence of microscopic (R1) or macroscopic (R2) residual tumor after surgery	This outcome measure will be assessed approximately 3 month after the operation date.
Percentage of completion of protocol treatment	Percentage of patients who will complete the protocol treatment, including adjuvant chemotherapy	This outcome measure will be assessed approximately 12 month after the date of enrollment.

Collaborators and Investigators

• Sponsor: University of Siena
• Investigators: Principal Investigator: Franco Roviello, University of Siena

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2018
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): November 1, 2028

Study Registration Dates

• First Submitted: March 12, 2019
• First Submitted That Met QC Criteria: May 21, 2019
• First Posted (Actual): May 23, 2019

Study Record Updates

• Last Update Posted (Actual): May 23, 2019
• Last Update Submitted That Met QC Criteria: May 21, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms
• Other Study ID Numbers: Neo-D2plus trial

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No