Study settings
All hospitals belonging to the Italian Research Group for Gastric Cancer are eligible to participate in the ADiGe Trial, irrespective of their hospital volume. A total of 9 Centers applied to participate, and the study has already been approved by the local Ethics Committee of four centers (Verona University Hospital, the leading Center, Orbassano Hospital of Turin, San Raffaele Hospital of Milan, Morgagni Hospital of Forlì).
Eligibility criteria
All consecutive patients that undergo total (TG) or subtotal gastrectomy (STG) with curative intent, for histologically proven gastric cancer or esophago-gastric junction cancer (Siewert type II or III), in participating centers from the beginning of the study until reaching the accrual number.
Inclusion criteria:
- Esophageal involvement <= 2 cm
- Patients planned for upfront surgery or treated with a neoadjuvant/perioperative chemotherapy or chemo-radiotherapy
- Open, hybrid, laparoscopic or robotic approach
- All types of anastomoses (circular stapled, linear stapled, hand sewn)
Exclusion criteria:
- Refuse to sign informed consent
- Age <18
- severe heart disease (Heart failure New York Heart Association - NYHA Class IV)
- severe liver disease (Child >= B7)
- Pregnancy
- Metastatic disease
- Emergency surgery
- Palliative surgery
- Operation different from total or subtotal oncological gastrectomies (e.g. pylorus preserving, proximal gastrectomy)
- <D1 lymph nodal dissection
- Reconstruction different from Roux-en-Y or Billroth II
- Multiple organ resection (except for cholecystectomy)
- Gastric cancer with duodenal involvement
- Intraoperative Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
Compared to three RCTs already published on this topic [10,11,12], we include also patients that undergo neoadjuvant/perioperative therapies, as these treatments are currently the standard of care for locally advanced gastric tumours. Moreover, considering that minimally invasive and open surgery outcomes are nowadays comparable, we decided to include both type of approaches.
Who will take informed consent
Patients eligible for participation are informed about the trial by one of the surgeons during the preoperative visit at the outpatient clinic. Patients can agree to participate until the day before the operation by signing the informed consent.
Interventions
Intervention description
Operation and Intraoperative drop out
Randomized patients included in the control group (Group A) receive one abdominal drain (any type of drainage is allowed) placed below the liver, passing by the duodenal stump with the apex posterior to the esophago-jejunal or gastro-jejunal anastomosis. No drainage is placed in patients assigned to the experimental group (Group B). Towards the end of the operation the leading surgeon can classify a patient as an intraoperative drop out before knowing the randomisation arm, if one or more of the following criteria are met:
- Intraoperative finding of non-radically resectable disease (R2 resection)
- Need for unplanned multiple organ resection (except for cholecystectomy)
- High risk anastomosis defined as: intraoperative test (e.g. methylene blue or pneumatic test) positive for leak or intraoperative evidence of a positive resection margin.
- Other intraoperative complication that has to be specified on the case report form (unintended intraoperative damage to major vessels and/or organs requiring reconstruction or resection, intraoperative bleeding requiring urgent transfusion, unexpected medical conditions interrupting or changing the planned procedure [13]).
Postoperative procedure
All patients follow the usual postoperative pathway of each participating center except for abdominal drain management. Prophylactic drain in group A patients is daily evaluated checking for suspicious debt. In patients with a normal debt, a methylene blue test (200 ml of water/tea with 5 ml of methylene blue) is performed on postoperative day (POD) 4 and the test is considered negative if no blue staining of drain output is apparent within 60 minutes. After the blue test is confirmed as negative, the drain can be removed. Each Center is allowed to remove drain on whatever POD after a negative test. Drain management in patients with a suspicious debt or positive blue test is left to Center preference. Postoperative complications are recorded until POD 30 or in hospital if hospital stay is longer than 30 days.
Reoperation under general anaesthesia and/or percutaneous abdominal/thoracic drain placement during the first 30 PODs for any cause related to the previous gastrectomy are considered as an event in both groups. After discharge, patients are evaluated in the outpatient clinic on POD 30 or in the subsequent week. Follow up calls are conducted by authorised medical or nursing staff at POD 60 and 90 in order to assess patient’s clinical status.
Outcomes
The primary composite endpoint is the cumulative incidence of reoperation and/or percutaneous drainage placement by the 30th postoperative day.
Secondary endpoints are:
- Incidence, severity and time to diagnosis of anastomotic and duodenal leak;
- Length of hospital stays;
- Overall 30 days morbidity or in hospital if longer than 30 days;
- Overall 90 days mortality;
- 30 days readmission rate.
Length of hospital stay is considered from the day of operation until discharge at home or at other facilities, or death. Postoperative complications, including anastomotic and duodenal leak, are classified according to the International Consensus on a Complications List After Gastrectomy for Cancer [13] and stratified by severity using the Clavien-Dindo classification [14].
Prophylactic drain related complications observed in drain group, such bleeding from drain site, will be considered both apart from and together with overall complications.
Participant timeline
The timeline of study events is displayed in Fig.1 and Fig.2. After patient’s inclusion, a medical authorized staff member randomizes the participant using an online secure module on the International Gastrectomy Complications Database website (www.gastrodata.org), the day before the operation. Upon filling out the randomization form, an immediate reply is obtained, containing the study group. “Group A” includes patients with prophylactic drain placed at the end of the operation, “Group B” includes patients without any abdominal drain at the end of the operation. The ratio 1:1 is obtained using a computer-generated randomization scheme, equally stratified (1:1 ratio) for type of surgery (STG or TG). Enrolment type is competitive.
Sample size
According to a systematic review conducted by our Center in January 2019 the cumulative incidence of reoperation was 11.9% (95% CI 8.8-15.6%) in the drain group and 5.6% (95% CI 2.9-9.6%) in the no drain group. Cumulative incidence of additional drain was 3.7% (95% CI 2.8-4.8%) in the drainage group and 10.7% (95% CI 8.5-13.1%) in the no drain group. Assuming a 70-75% of overlap between the two procedures in the drain group, the estimated proportion of the composite outcome is 14.5%, while assuming a 30-35% overlap in the no drain group, the estimated proportion of the composite outcome is 9%.
Hence, we assumed a reference group proportion of 14.5%, and a treated group proportion of 19% under the null hypothesis of inferiority and 9% under the alternative hypothesis of non-inferiority. Sample sizes of 128 in group one and 128 in group two (256 patients) achieve 80% power to detect a non-inferiority margin difference between the group proportions of 4.5% (= 19-14.5 %), with a one-sided significance level of 5%. Considering a 15.5% drop-out rate, 304 patients (152 in each group) are needed. In order to have a balanced percentage between total and subtotal gastrectomies, recruitment will end at 152 patients for each type of gastrectomy.
Assignment of interventions
Sequence generation and concealment mechanism
Randomization plan has been generated using www.randomization.com program and no one of the investigator has access to the list. Participants are randomized in a 1:1 ratio, using a secure web based randomization system to receive either intervention or routine care, stratified by type of gastrectomy.
Blinding
The leading surgeon and the patient are blinded to the arm assigned until gastrointestinal reconstruction is completed (and anastomosis integrity test is done, if applicable). Before discovering the arm assigned, the surgeon will decide whether the patient meet or not the dropout criteria. There is no blinding for the patient, care providers, or coordinating researcher after the operation.
Data Collection and management
Data is collected via a secured Internet module and each participating center has in custody the informed consents on paper. A secured and anonymized online module has been especially designed for the ADiGe trial, in collaboration with the Gastrectomy Complications Consensus Group on www.gastrodata.org. Every patient will be identified by a numeric unique code. Data are collected until POD 91. Before recruitment process starts, investigators from each participating Center will practice with the Leading Center data manager in order to increase proficiency in data entry. The Leading Center will monitor the quality of data collection of all included patients and regular audit will be held with all participating Centers.
Statistical methods
Analysis population
The primary analysis will be performed on a modified Intention To Treat (mITT) population, including all randomized patients who have undergone gastrectomy. Patients will be analyzed according to the treatment assigned at pre-operative randomization.
A sensitivity analysis will be performed on the As Treated Population, including the same patients enclosed in the mITT population, classified according to whether they actually underwent the prophylactic drain placement or not.
A secondary analysis will be carried out on the Per Protocol (PP) population, including only patients undergoing surgery according to the arm assigned at randomization, and followed-up for at least 30 days.
Statistical analysis
Categorical variables will be presented as absolute and percent frequencies, continuous variables as mean and standard deviation when normally distributed and as median and interquartile range otherwise.
The proportion of patients undergoing re-intervention or percutaneous drain placement (primary endpoint) will be computed for each group with the corresponding 95% confidence interval. The difference between the primary end-point proportion in the treated group and in the control group will be computed with the corresponding confidence interval. If the upper limit of the 90% confidence interval of this proportion does not exceed the non-inferiority margin difference of 4.5%, the null hypothesis of inferiority will be rejected.
Further statistical analysis on the primary endpoint will follow a hierarchical approach: if the non-inferiority null hypothesis will be rejected, significance of differences in the primary endpoint between control and experimental arms will be further investigated with a Fisher’s exact test. The relation between the primary endpoint and treatment (drain placement or avoidance) will be further investigated using a multivariable logistic model, adjusting for center, sex, age, tumor site and histology, tumor stage, type of gastrectomy (total/subtotal).
To evaluate significance of differences between control and experimental arms, Fisher’s exact test or chi-square test will be used for nominal variables (reoperation, placement of additional percutaneous drain, anastomotic or duodenal stump fistula, postoperative mortality, hospital readmission), Wilcoxon-Mann-Whitney test for ordinal variables (fistula or complication severity), and t test (or the corresponding non-parametric test) for continuous variables (length of hospital stay, time from surgery to fistula detection). Statistical significance will be set at p<0.05. Statistical analyses will be performed using Stata®/IC 16.0 for windows (StataCorp LLC, College Station, Texas, USA).
Oversight and monitoring
A data monitoring Committee has not been established nor interim analysis have been planned due to the short expected duration and minimal calculated risks of the Trial.
As all the participating Centers are part of GIRCG quality of surgery and postoperative care were considerate adequate for this Trial according to our previous studies [15,16].
As both arms include treatment commonly applied in daily clinical practice (drain placement and drain avoidance), the standard hospital insurance was considered acceptable. Nonetheless, adverse events related to drain placement/avoidance from the day of operation until the end of the follow up period (91 POD) will be recorded. Investigators will determine the correlation of an adverse event to the study variable based on timing, type of complication and probability of cause-effect relationship between the event and drain placement/avoidance. Moreover, any adverse event that meets the following criteria will be recorded as “serious adverse event” and reported to the local institutional review board: life threatening condition; severe or permanent disability, prolonged hospitalisation.
Ethical Committee approval
The design of ADiGe Trial was approved by the scientific committee of GIRCG. The Ethical Committee for Clinical Trial (CESC) of Verona has approved the present protocol with the following code: 2245CESC. Prior to implementation, any protocol amendment will be approved by GIRCG scientific committee and CESC of each participating Center. Study information in ClinicalTrials.gov will be updated accordingly.
Dissemination policy
Results of this trial will be published in a peer-reviewed journal. The abstract will be submitted for presentations at different congresses. Within 6 months of completion of the trial, the ClinicalTrials.gov site will be updated to include summary results.
Authorship is granted to authors who make important contributions to the creation of the final publication in accordance with recommendations from the International Committee of Medical Journal Editors and GIRCG group internal policy. Authors can contribute via written or physical help in this clinical trial.
The datasets used during the current study will be available from the corresponding author on reasonable request within 1 year after completion of the Trial.