Niguarda 1 - OPEN vs MIS

Title:

OPEN VERSUS MINIMALLY INVASIVE GASTRECTOMY FOR ADVANCED GASTRIC CANCER: A PROPENSITY SCORE MATCHING ANALYSIS OF SURVIVAL IN A WESTERN POPULATION

Sponsor:

Gruppo Italiano Ricerca Cancro Gastrico (GIRCG)

Coordinator

Pietro Maria Lombardi (pietro.lombardi@ospedaleniguarda.it)

Proposing Institution

Chirurgia Generale Oncologica e Mini-Invasiva (Primario Dott. Giovanni Ferrari), Ospedale Niguarda

Rationale

Surgery is the standard treatment for patients affected by localized gastric cancer. Complete R0 resection with adequate lymphadenectomy represent the imperative goal of surgery.

Although surgical intervention was traditionally performed via a laparotomy, minimally invasive approach has gained attention during the past years. Its application seems to be associated with potential advantages when compared to open surgery, such as less blood loss, reduced postoperative pain, accelerated recovery, and reduced hospital stay.  

Since Kitano in 1994 first reported the use of mini-invasive approach in the treatment of gastric cancer, several efforts were made in order to clarify the technical feasibility and oncological radicality of the laparoscopic approach for distal and total gastrectomy.

Regarding distal gastrectomy, short-term outcomes in Early and Advanced Gastric Cancer were investigated by the JCOG0912 study and the KLASS 02 Trial. Both studies reported that laparoscopic distal gastrectomy with D2 lymphadenectomy shows benefits in terms of lower complication rate, faster recovery, and less pain compared with open surgery, with no differences in 90-day mortality observed. Subsequently, KLASS 01 and CLASS 01 Trials reported similar overall and cancer-specific survival rates between patients receiving laparoscopic and open distal gastrectomy for Early and Advanced Gastric Cancer, showing the non-inferiority of laparoscopic distal gastrectomy regarding 3-years disease-free survival in Advanced Gastric Cancer. Focusing on total gastrectomy, the CLASS 02 and the KLASS 03 Trial investigated short-term outcomes in Early Gastric Cancer, showing the safety, in terms of morbidity and mortality, of the laparoscopic approach for stage I gastric cancer.

At present, in contrast to the encouraging experience from Eastern countries, data regarding the survival outcomes after minimally invasive gastrectomy are lacking in the West, with few experiences reported in literature about long-term outcomes. In addition, there is a need to clarify whether long-term outcomes are not being compromised with the use of minimally invasive gastrectomy, especially when considering advanced-stage tumors.

Aims of the study

To compare 3-year overall survival between patients undergoing curative-intent distal or total gastrectomy for advanced gastric cancer by either minimally invasive or open approaches performed in several national institutions.

Clinical Phase:

Observational, retrospective, multicentric

List of partecipating Centres

TBD

Study design:

Data of patients affected by advanced gastric adenocarcinoma who underwent curative-intent open or minimally-invasive gastrectomy with or without neoadjuvant chemotherapy will be retrospectively retrieved.

The period of the study will be Jan 2015- Jun 2018.

Follow-up data will be collected, along with patient-related, tumor-related and treatment-related variables.

The last follow-up date is established in June 2021.

Data will be collected in a designated database.

 Inclusion Criteria

• Age from over 18 years old;
• ASA (American Society of Anesthesiology) score < 4
• Patients with primary, histologically confirmed gastric carcinoma of the upper, middle, lower stomach
• Staging cT2-4a, N0-3, M0 at preoperative evaluation according to AJCC 8th edition Cancer Staging Manual, performed with thoraco-abdominal computed tomography (CT) scan
• Curative resection can be accomplished through distal or total gastrectomy with D2 lymphadenectomy
• Absence of distant metastases (haematogenous, extra-regional lymph nodes, negative peritoneal cytology on intraoperative peritoneal washing)

Exclusion Criteria

• Tumor involving the gastro-esophageal junction
• tumor invading the duodenum at surgical intervention
• Patients intraoperatively/post-operatively staged as M1, with preoperative staging M0. Distant metastases include, among others: liver, peritoneum, pelvic metastasis, extra-regional lymph nodes, positive peritoneal lavage cytological examination
• Multivisceral resection
• History of previous gastrectomy, endoscopic mucosal resection or endoscopic submucosal dissection
• History of other malignant disease within the past three years
• History of previous chemotherapy (except neoadjuvant chemotherapy administered prior gastrectomy) and/or radiotherapy within the past three years
• Patients lost to follow-up within 3 years from operation

Treatment Plan:

• Patients submitted to intent-curative distal or total gastrectomy, with or without neoadjuvant chemotherapy
• Additional treatments after surgery when indicated (ie, adjuvant chemotherapy)
• Follow-up schedule

Variables under study:

Tumor-related:

• Clinical stage at diagnosis (cTNM according to AJCC 8th edition)
• Tumor location (Upper, middle, lower)
• Tumor size at pathologic report (maximum diameter) (mm)
• Lauren histotype
• WHO histotype
• Grading
• Presence of lymphovascular (LVI) invasion
• Number of retrieved lymph nodes
• Lymph node ratio (LNR), defined as the ratio between positive lymph nodes and the total number of retrieved lymph nodes
• Pathological stage (pTNM/ypTNM according to AJCC 8th edition)
• Margin status

Patient-related:

• Sex
• Age
• ASA Score
• BMI (Body Mass Index) (pre-treatment)
• aCCI (age-adjusted Charlson comorbidity index

Treatment-related:

• Neoadjuvant chemotherapy regimen adopted (if performed)
• Accomplishment of neoadjuvant chemotherapy (if the patients completed all the scheduled cycles)
• Extent of gastrectomy (distal gastrectomy, total gastrectomy)
• Nature of post-operative complications (as defined by Baiocchi et al in “International consensus on a complications list after gastrectomy for cancer”, Gastric Cancer, 2019)
• Severity of post-operative complications (Clavien-Dindo > 2)
• Post-operative length of stay (LOS), defined as the number of days between the day of operation (day 0) and discharge date
• Adjuvant chemotherapy regimen adopted (if performed)
• Accomplishment of adjuvant chemotherapy (if the patients completed all the scheduled cycles)

Survival-related variables

• Three-Year Overall Survival (OS)
• Three-Year disease-free Survival (DFS)
• Recurrence
• Pattern of recurrence
• Date of recurrence
• Patient’s status at last follow-up
• Date of last follow-up/date of death

Study Endpoints

Primary:

• Three-Year overall survival (OS), defined as the percentage of patients who are alive three years after surgical intervention

Secondary:

• Three-Year disease-free survival (DFS), defined as the percentage of patients who are alive disease-free three years after surgical intervention
• Morbidity and mortality

• Intraoperative complications
• Postoperative complications
• Postoperative Severe complications
• 30-day readmission

• Number of harvested lymph nodes
• Radicality of resection

Follow-up

At least 3 years for OS/DFS

Statistical methods, Propensity Score Matching, Sample size

Data will be expressed as median and interquartile range (IQR) and number and relative percentage. Normal distribution of continuous variables will be assess with the Kolmogorov-Smirnov test.

Continuous variables will be analyzed using the student t-test or Mann-Whitney test and categorical variables using Fisher exact test or Chi-Square test as appropriate.

In order to reduce the bias arising from patient’s selection and lack of randomization, and thus achieving balanced exposure groups at baseline, a Propensity Score Matching will be performed, with a 1:1 nearest-neighbour matching and a caliper of 0.1.

Significant variables (p<0.05) at univariate and well-known variables affecting outcomes will be used to run the matching.:

OS and DFS will be estimated using the Kaplan-Meier method and analyzed by the log-rank test. Patients who died within 90 days were excluded from survival analysis, either for OS and DFS. When DFS will be considered, patients with positive surgical margin at the histological specimen will be excluded.

Factors associated with survival will be analyzed by univariate and multivariate Cox regression. Variables with p<0.1 will be included in the risk-adjusted Cox regression analysis, together with other well-known factors related to mortality. These data will be reported as hazard ratio (HR) and 95% confidential interval.

All statistics will be 2-tailed and statistical significance will be accepted when p<0.05. All statistical analyses will be performed using R (R Core Team)

Sample size

It was calculated that a sample size of 520 patients (260 per group) will be adequate in order to detect a difference of survival between the two groups, with a significance level (alpha) of 5% and a power (1-beta) of 80%.

Duration of the

Study

9 months (Apr 2021 – Jan 2022)

Months 1 - 3: Centers recruiting and validation, ethical committee

Months 4 - 5: Data collection

Months 6: Data analysis

Months 7 - 9: Discussion of results, manuscript writing and reviewing

Ethical Committee

NA

Dataset and Datadictionary

Dataset and Datadictionary will be provided to all partecipant centres.

Data management

The Data Centre ASST Grande Ospedale Metropolitano Niguarda will be responsible for collecting case report forms, controlling the quality of the reported data and generating reports and analyses, in cooperation with the Study Coordinator and the Data Manager

Insurance

NA