Patients diagnosed with middle and lower gastric adenocarcinoma who underwent laparoscopic-assisted radical resection of distal gastric cancer will be recruited from the 13 hospitals listed in Table 1. To achieve adequate enrolment, all surgeons in the gastrointestinal departments of the cooperating hospitals have been informed of this trial. Patients will be recruited for the study from the gastrointestinal surgery or gastrointestinal surgery outpatient clinic or by referral from the local affiliated hospital. The enrolment period is expected to be completed within 10 months from the beginning of recruitment. A total of 400 eligible patients will be selected and randomly (1:1) enrolled in the ERAS group and the traditional treatment group. Figure 1 shows the test group selection flow chart.
Table 1. The Thirteen Participating Surgical Centres
Number
|
Centre
|
Department and investigator
|
01
|
Affiliated Hospital of Qingdao University
|
Gastrointestinal Surgery, Yanbing Zhou
|
02
|
Shandong Provincial Hospital
|
Gastrointestinal Surgery, Leping Li
|
03
|
Qilu Hospital of Shandong University
|
Gastrointestinal Surgery, Qingsi He
|
04
|
Qianfoshan Hospital of Shandong Province
|
Gastrointestinal Surgery, Lijian Xia
|
05
|
Second Hospital of Shandong University
|
Gastrointestinal Surgery, Yinlu Ding
|
06
|
Yantai Yuhuangding Hospital
|
Gastrointestinal Surgery, Lixin Jiang
|
07
|
Weihai Municipal Hospital
|
Gastrointestinal Surgery, Huanhu Zhang
|
08
|
Weifang People's Hospital
|
Oncological Surgery, Yiran Shi
|
09
|
Dongying People's Hospital
|
General Surgery, Hao Wang
|
10
|
Rizhao People's Hospital
|
General Surgery, Xizeng Hui
|
11
|
Qingdao Municipal Hospital
|
Gastrointestinal Surgery, Weizheng Mao
|
12
|
Jining People's Hospital
|
Gastrointestinal Surgery, Xianqun Chu
|
13
|
Weihai Central Hospital
|
Gastrointestinal Surgery, Xinjian Wang
|
For randomization, a central dynamic, stratified strategy is adopted. The randomization sequence is generated using the Pocock-Simon minimization method in SAS version 9.3 (SAS Institute Inc) and stratified by participating site (13 hospitals) and surgical procedure (laparoscopic or robotic). Participating centres will submit the above information to the data centre at the Department of Gastrointestinal Surgery, Affiliated Hospital of Qingdao University, Qingdao, China, where central randomization will be performed. Information on treatment allocation is subsequently sent to each participating centre.
The inclusion criteria are as follows: 1) newly treated patients with no chemotherapy, radiotherapy or other antitumour treatment performed before the beginning of the clinical trial; 2) patients aged between 18 and 75 years old; 3) patients at a clinical stage of advanced T (1-4a), N (0-3), or M0 scheduled to undergo radical resection of distal gastric cancer; 4) male or non-pregnant and lactating females; 5) patients pathologically diagnosed with gastric adenocarcinoma; 6) patients with Eastern Cooperative Oncology Group (ECOG) score 0-1; and 7) patients who voluntarily sign the informed consent.
The exclusion criteria were as follows: 1) other malignant tumours within 5 years; 2) M1 disease found during the operation; 3) severe or uncontrolled medical diseases and infections found at the same time; 4) use of opioid analgesics or hormones within 7 days before the operation; 5) severe or uncontrollable mental illness; 6) any unstable condition or condition that may endanger the safety and compliance of the patient; and 7) participation and treatment with anticancer drugs in other clinical trials.
Perioperative management
Before surgery, chest computed tomography (CT), total abdominal enhanced CT, and pelvic CT will be performed to confirm the size and location of the tumour, and distant organ metastasis will be excluded according to evaluations by two experienced radiologists. Upper abdominal computed tomography angiography (CTA) will be used to evaluate variation in the gastric blood supply of the patients, reduce the risk of intraoperative bleeding and guide lymph node dissection [18]. Echocardiography and pulmonary function tests will be used to evaluate the tolerance of cardiopulmonary function to laparoscopic surgery.
Laparoscopic-assisted radical resection of distal gastric cancer will be performed under general anaesthesia. During the operation, we will follow the basic principles of tumour treatment, master the appropriate scope of gastrectomy, perform fine lymph node dissection and gastrointestinal reconstruction, and record the amount of intraoperative infusion, blood loss, operation time, and use of any opioids or muscle relaxants.
After the operation, if adverse reactions occur, they will be closely observed and actively treated. All drugs used will be recorded and described on the case report form (CRF). Laboratory examinations will be performed before the operation and 2 days, 4 days and 7 days after the operation. The measurements will include routine blood, liver and kidney function, electrolytes, procalcitonin, CPR, IL-6, and TNF-α. For patients with pathological stage II or above, 6-8 cycles of S-1 capsule combined with oxaliplatin adjuvant chemotherapy will be performed. Finally, oncology experts will choose the scheme and duration of treatment according to the actual situation of the patients.
Intervention protocols
Laparoscopic-assisted radical resection of distal gastric cancer will be performed by an experienced surgical team from the 13 centres listed in Table 1. Each of these centres performs at least 100 gastric cancer operations each year. Lymph node resection will be performed under laparoscopy, the main anastomosis will be performed with the assistance of a small incision, and the abdominal incision will be < 8 cm. According to the research programme, the experimental group will actively carry out pre-rehabilitation before the operation, including lifestyle intervention, exercise advice, diet guidance, and health education (outpatient and hospitalization individualized condition consultation and answer). The specific interventions are shown in Table 2. However, target-oriented liquid management and early enteral nutrition (EN) after surgery require special attention. The goals of goal-directed therapy (GDT) are to maintain central euvolemia while avoiding excess salt and water and a 24-hour postoperative fluid balance on +1 to 1.5 L. Intraoperative detection indicators are as follows: blood pressure, cardiac output, estimated blood loss, end tidal carbon dioxide and heart rate. The maintenance fluid flow rate is 1~4 ml kg-1h-1 (predicted body weight), and large deviations from "zero balance" should be avoided [19]. The well-defined principles for oral intake in the ERAS groups are as follows: drinking a small amount of water and chewing xylitol on the day of operation; drinking 500~1000 ml water and chewing xylitol on postoperative day 1 (POD1); oral EN (mainly polypeptide) and chewing xylitol on POD2; oral EN (mainly integrin type) and chewing xylitol on POD3; oral EN, a small amount of semifluid and chewing xylitol on POD4; oral EN, semifluid (mainly) and chewing xylitol on POD5, but the patients in the traditional treatment group began sequential EN support treatment according to the dietary pattern of the ERAS group after anal exhaust.
Study endpoints
The main endpoint is the comparison of 3-year overall survival (OS) and disease-free survival (DFS) between the ERAS pathway group and the traditional treatment group.
The secondary endpoints are the total incidence of postoperative complications, incidence of major complications, 30-day rehospitalization rate, 30-day mortality rate, hospitalization days and hospitalization costs, as well as other short-term clinical outcomes.
The exploratory results are changes in inflammatory indexes (i.e., leukocytes, neutrophil percentage, CPR, procalcitonin, TNF-α, and IL-6).
Table 2. Perioperative Pathway Management for Gastric Cancer
Programme components
|
ERAS group
|
Traditional treatment group
|
Preoperative
|
*Health education, exercise advice, dietary guidance
|
Yes
|
Yes
|
|
*Organ function evaluation
|
Yes
|
Yes
|
|
*Pre-rehabilitation treatment
|
Yes
|
No
|
|
*MDT, Clinical Decision Making
|
Yes
|
Yes
|
|
*Preoperative nutritional assessment and intervention
|
Yes
|
Yes
|
|
Intestinal preparation
|
Enteral nutrition
No mechanical bowel preparation
|
No
Traditional mechanical intestinal preparation
|
|
*Preoperative fasting and abstinence from drinking
|
Fasting 6 hours before the operation
2-hour oral glucose infusion 200 ml
|
Fasting and drinking
for 6 hours before the operation
|
Intraoperative
|
*Intraoperative safety check (Checklist)
|
Yes
|
Yes
|
|
Local anaesthesia in the deep layers of the incision at the end of surgery
|
Local anaesthesia (30 ml 0.25% bupivacaine)
|
No
|
|
Prevention of antibiotic use
|
30 minutes before operation, operation time >3 hours, or more than one bleeding event ≥1000 ml
|
Application for 1-2 days
|
|
*Surgical incision
|
Small midline (<8 cm) incision at the upper abdomen
|
Small midline (<8 cm) incision
at the upper abdomen
|
|
*Precision Surgery
|
Laparoscopic or robotic surgery
|
Laparoscopic or robotic surgery
|
|
*Anaesthesia mode
|
General anaesthesia combined with epidural anaesthesiaa (T7-T9)
|
General anaesthesia
|
|
Intraoperative heatb preservation
|
Yes
|
Yes
|
Postoperative
|
Urinary catheter
|
Removal within 24 hours
|
Routine indwelling catheter for 1-3 days after operation (until the patient is ambulatory and can urinate on his own)
|
|
Abdominal drainage tube
|
Avoid placement or removal early
after the operation as much as possible
|
Removal before dischargec
|
|
Gastric tube
|
No use or removal ≤ 24 h
|
Retention for 1-3 daysd
|
|
*Early bedside activity
|
Start cautiously and plan your activities
|
2-3 days after operation
|
|
*Postoperative analgesia
|
Multimodal analgesiae
|
Opioidsf
|
|
*Target-oriented liquid management
|
Yes
|
No
|
|
Prevention of deep venous thrombosis
|
Basic prevention + Physical prevention + Drug prevention
|
Drug prevention
|
|
*Early EN after operation
|
Sequential EN treatment after
awakening from anaesthesia
|
Gradually start EN after anal exhaust
|
Notes: * Core provisions of perioperative ERAS pathway management.
Abbreviations: NSAIDs, Non-steroidal anti-inflammatory drugs; EN, Enteral nutrition.
a Dose/drug: 500 mg of ropivacaine + 400 mg of lidocaine and liquid intake rate of 2 ml/h
b Heat preservation measures: Pre-heated fluid replenishment, thermal blanket, heater
c Extubation indication: The drainage fluid is light red or clear, with a volume of less than 20 ml, and pancreatic amylase is negative for 24 hours
d Criteria for the removal of nasogastric tube: Recovery of intestinal peristalsis, anal exhaust and oral intake of clear fluids
e Multimodal analgesia: POD1~2 patient controlled epidural analgesia (Lidocaine + Ropivacaine); POD3~5, 0.65 g of regular oral paracetamol q8h; when the visual analogue scale≥4, 50 mg of flurbiprofen is injected intravenously.
f Opioids: POD1~2, 50 mg of tramadol q8h; when the visual analogue scale≥4, 50 mg of tramadol is injected intravenously (dose ≤ 400 mg/d).
|
Data collection and management
Once informed consent is signed, the clinical researchers will collect baseline data such as age, sex, body mass index and complications. The laboratory indexes—routine blood, liver and kidney function, electrolyte, carcinoembryonic antigen, carbohydrate antigen 199 (CA199), CA724, CA242, alpha fetoprotein (AFP), hepatitis, human immunodeficiency virus, syphilis, blood coagulation routine, and blood type—will also be assessed and recorded before and during hospitalization. The designated surgeon will record the details of the procedure, such as the surgical approach, the location of the tumour, lymph node metastasis, and pathological stage.
Starting on day 1 after the operation, the clinical observation data (e.g., extubation time, food intake, activity, anastomotic leakage, first exhaust and defecation time, postoperative hospital stay, complications) will be recorded by nurses daily to evaluate postoperative recovery. Clinicians will be responsible for patient management and will not be involved in data collection.
All relevant information for each patient should be recorded in the CRF in a timely and accurate manner by trained and independent research staff. If there are any errors in the CRF, the investigator will correct them immediately. When revising raw data, the investigator must sign their name and the date. All data will be acquired only by study investigators who have signed a confidential disclosure agreement. Any information collected in this clinical study that could be used to disclose an individual’s personal identity will not be released or disclosed at will without consent, except in special circumstances as required by law. No research publications using these data, including journal literature, papers or research briefs, will use any identifying patient information. The Ethics Committee of the Affiliated Hospital of Qingdao University will be responsible for ensuring that the rights and well-being of patients are protected and for maintaining compliance with the currently approved protocol, data collection, statistical analysis, and anonymity in publications.
Discharge criteria
The criteria for discharge are as follows: 1) postoperative pain score with oral analgesics controlled well (visual analogue scale below 4); 2) oral semifluid food without intravenous rehydration; 3) satisfactory exercise regimen (6 hours a day or up to preoperative level); 4) adequate out-of-hospital care; 5) voluntary discharge of the patient; and 6) no surgical complications, such as fever, abdominal pain, or infection. In addition, the contact information and address of each patient will be confirmed before discharge. Follow-up will be conducted by telephone within 24 hours after discharge, with a focus on dietary tolerance, pain, defecation and any discomfort.
Follow-up
After the operation, a special follow-up team will be responsible for performing patient follow-up, and the first outpatient review will begin at 3 weeks after the end of treatment.
From 0~2 years after the operation, follow-up every 3 months will include a routine blood examination, an analysis of biochemical markers and digestive tract tumour indicators, and imaging examinations. In addition, endoscopic examinations will be performed once a year. At each follow-up, the adjuvant treatment, postoperative recovery and short-term and long-term side effects will be assessed, as shown in Figure 2.
From 2~3 years after the operation, follow-up will occur every 6 months, as outlined above.
Statistical analyses
Classification variables will be analysed by the chi-square test or Fisher’s exact test, and continuous variables will be analysed by the independent t-test. DFS will be defined as the time from surgery to death or recurrence of gastric cancer, whichever occurs first. The Kaplan-Meier method will be used to generate survival curves, and the log-rank will be applied to compare the differences between survival curves. The hazard ratio and 95% confidence interval will be calculated with the Cox regression model. Variables will be selected for inclusion in the final multivariable model using a stepwise method, and significance levels of 0.25 and 0.15 will be employed as the criteria for inclusion and retention. P<0.05 will be considered to indicate statistical significance. Data analysis will be performed using SPSS® software package version 22.0 (SPSS Inc., Chicago, IL, USA).
Sample size estimate
This study adopts the design of a noninferiority test, and the calculation of sample size is based on the following historical data and assumptions. Previous studies have shown that the overall 3-year survival rate for gastric cancer patients is approximately 50%[20]. The centre followed patients who underwent radical resection of gastric cancer under the management of ERAS from 2011 to 2014, and the 3-year survival rate was approximately 65% [21]. Assuming that patient selection will require 10 months, the median follow-up time should be approximately 3 years, and the noninferiority threshold is therefore set to 1.33, according to a 1:1 random ratio. Assuming a significance level of α= 0.05 (bilateral) and test efficiency of 1-β= 80%, the withdrawal rate of either branch group should be 10%, and the total sample thus requires at least 400 patients (200 in the test group and 200 in the control group).
Interim analyses and trial termination
This clinical trial project plans to recruit 400 patients and conduct an interim data analysis, faithfully reflecting changes in their condition during and after the operation, at the point in which approximately 200 patients have been enrolled. To improve the trial further, we have established a data monitoring committee that consists of surgical experts, statistics experts and ethics experts, independent of the clinical research team of the project, to weigh the effectiveness and safety comprehensively at the midpoint of the clinical trial according to the data accumulated to date and then make important decisions regarding whether to "continue the trial", "continue the trial after adjusting the protocol" or "terminate the trial". The results of the interim analysis will be released to all investigators.
Strengths and limitations of this study
The feasibility of ERAS pathway management in improving long-term prognosis has not yet been determined in a prospective randomized controlled trial. This trial will be the first multicentre randomized controlled clinical trial to evaluate the impact of perioperative ERAS pathway management on the short-term clinical outcomes and long-term prognoses of patients undergoing laparoscopic-assisted radical resection for distal gastric cancer. Jieshou Li, academician affiliated with the Chinese Academy of Sciences, first introduced this concept in 2007. Our centre began to explore ERAS pathway management for gastric cancer patients during the same year and published RCT research findings on perioperative ERAS management for gastric cancer in 2010 [11]. Our team has accumulated rich experience in perioperative management for gastric cancer to ensure the safety of patients and enhance their recovery. At the same time, our cooperating centres are all members of the gastric cancer ERAS group, each with an annual operation volume of more than 100 cases, have undertaken national clinical projects, and have performed strong clinical research. The primary outcome of this study is the comparison of 3-year OS and DFS between the two groups. The ERAS team will be required to record the data in a timely and accurate manner and to enhance postoperative follow-up in order to avoid loss to follow-up. To this end, we specifically established a data inspection committee and a special follow-up team to ensure the timeliness, validity and authenticity of the clinical data.
In this study, it is expected that the ERAS team will experience some difficulty in completely implementing all interventions in the protocol due to individual differences, patient compliance, medical factors and other reasons. We will integrate the elements involved in the clinical pathway. To ensure recovery and reduce hospitalization in the days after gastric surgery, we will pay particular attention to the ‘key components’ of the ERAS programme, namely, six basic elements: preoperative patient information and education, preoperative pre-rehabilitation, thoracic epidural anaesthesia combined with multimodal analgesia, target-oriented liquid management, no nasogastric tube, early oral feeding and mobilization.