Aim of the trial
The aim of trial is to find out the possible advantages of CP combined with end-to-end anastomosis reconstruction in robotic surgery. We hypothesize that the new method has lower pancreatic fistula rate and could reduce the occurrence of postoperative complications.
Primary and secondary endpoints
Primary endpoint is postoperative pancreatic fistula which is the essential indicator for pancreatic surgery. The definition and grading of postoperative pancreatic fistula are based on the 2016 update of the International Study Group13. We will examine the amylase level in abdominal drainage fluid and blood in the first, third, fifth and seventh day after operation.
Secondary endpoints care about the postoperative morbidity rate and mortality rate, including the rates of lymphatic fistula, postoperative hemorrhage, DGE (delayed gastric emptying), infection and reoperation. Lymphatic fistula is based on the definition of the International Study Group of Pancreatic Surgery (ISGPS) 201715 and Postoperative hemorrhage is based on the definition of ISGPS 200716. Reoperation will be performed when severe complication happens, and it could not be solved by normal treatments. DGE is based on the definition of ISGPS 200717, Clavien–Dindo Grade will be used to estimate the severity of complications18. Moreover, readmission rates, days of hospital stay and days of stay in intensive care unit will also be assessed in our study. The definition of the endpoints is shown in Table 1.
The trial is designed as Chinese single center randomized clinical trial. The feature of this trial design is a randomized study. Randomization will reduce confounding factors, and PLA General Hospital is a big center with enough number of participants and advanced surgery technique. Single center research guarantees all the patients received equal level treatments during their hospitalization. The primary and secondary outcomes are objective indicators, so our results could hardly affect by subjective factors. The schedule of the trial is showed in Fig.1.
The randomized clinical trial will be conducted in Second Department of Hepatopancreatobiliary Surgery, PLA General Hospital. One hundred and seventy patients with benign and low malignant potential lesions in the neck and body of pancreas will be included. The exclusion criteria can be limited to tumors do not invade the main pancreatic duct and suitable for enucleation, distant pancreatic stump shorter than 5cm and suspected high malignant lesions. All the candidates should fully aware of the trial and could give informed consents before the randomization. The inclusion and exclusion criteria are showed in Table 2.
The follow-up for each patient will be 3 months, and all the data will be documented properly. We will give suggestion and suggestion to the patients to guarantee follow-up rates. The patient data is documented in Table 3. The schedule of enrolment, interventions and assessment is planned in standard form14.
We will compare the outcome of two different types of CP in selected patients. All the operations will be performed by an experienced team. Operation initiates by establishing pneumoperitoneum and putting trocars. The placement of ports is shown in Fig.2. Then open lesser sac and expose pancreas. Neoplasms and the relationship with blood-vessel are identified with the use of intraoperative ultrasonography. The superior mesenteric, portal, and splenic veins are separated smoothly from the pancreas and the middle pancreas is dissected by ultrasonic scalpel. After the resection is the reconstruction. The procedures of two kinds of CP is different from now on. For conventional CP, the cephalic portion ligates with suture and single layer pancreatojejunostomy anastomosis is performed at distant part of pancreas. A pancreatic stent should be placed into the main pancreatic duct and two drainage tubes are left close to the anastomosis and cephalic stump respectively. As for CP combined with end-to-end anastomosis reconstruction, the main pancreatic duct of two parts is identified and a temporary pancreatic stun is placed in it. The superior and inferior margins of two stumps are oversewn and the sections of pancreas suture in U-shaped way. Then the cephalic and distant parts are pulled together, and the anastomosis is completed by continuous suture of posterior and anterior parts respectively. Two drainage tubes are placed close to the posterior and anterior parts of anastomosis. The operation is accomplished without other reconstruction of digest tract.
All the patients will be randomized after they are diagnosed as pancreatic neck and body benign and low malignant lesions compared. The randomization with variable block length will be performed with a 1:1 ratio before the CP. All the patients will be randomized to either the new CP group or the conventional CP group basing on computer-generated random list. The randomization and assignment will be performed by scientific secretary of Second Department of Hepatopancreatobiliary Surgery, PLA general hospital, and the allocation results will be informed to surgeon before the CP. If the operation method changes due to the patient’s condition, the patient will be excluded from this research. Study design flow chart is shown in Fig.3.
Patients do not know the anastomosis method after operation, for it is difficult for patients to know the operation method without the help of CT or MRI. The surgeons will not know the anastomosis method and remain blinded before the CP. The treatments after operation will be decided and carried out by doctors blinded to the anastomosis procedure. If patients are in serious conditions and blinding could affect the treatment, the doctors will be unblinded. The data of patients will be documented and analyzed by doctors and secretaries blinded to allocation group.
A systematic review which contained 94 studies involving 963 patients indicated that the POPF rates of traditional CP were 30.8%25. A retrospective study of PLA general hospital showed that the POPF rates of CP combined with end-to-end anastomosis reconstruction were 65.6%9. The required sample size (Z-Pooled normal approximation; power 80%; alpha 0.05) will be seventy-eight per group. We will recruit eighty-five patients per group to reduce influence of loss of follow-up.
A data collection group will develop the plan of statistical analysis and carry out it. The continuous variables will be showed as mean ± SD, and it will be compared by using Student’s t test or the Wilcoxon rank-sum test. The categorical data will be analyzed with x2 test or Fisher’s exact test. Ranked data, including age, POPF, Clavien-Dindo grade, will be compared in Wilcoxon signed-rank test. P<0.05 is statistically significant and we will use two-sided statistical tests to calculate P value. A midterm test will be planned during the research. The data of enrolled patients, including blood loss, POPF rate, complication rate, will be analyzed by investigators in midterm test.
All the data will be collected and recorded in case report forms (CRFs) by investigators. The patients’ demographic, baseline clinical and outcome data will include in CRFs. Only authorized people have access to the data. To protect patients’ privacy, each person will have a unique number in CRFs. All the data will be documented in an electronic database by two responsible researchers to ensure the accuracy of data, and the data will be analyzed by investigators who do not know the allocated groups.
Monitoring will be performed in the entire study by our research secretaries. The duty of them is to ensure that all the procedures of the study are following the protocol. Furthermore, they will supervise the data and solve problems developed during the trail. To evaluate the safety of the trial, a midterm analysis will be performed when half of the participants enrolled in the study.
All the complications will be uploaded to the database immediately, and serious adverse events will be evaluated by safety monitor group. The study will be stopped if patients have high risks of complication caused by intervention. A midterm analysis will be made, and the trial will be adjusted or canceled if the results indicate the high risk of CP combined with end-to-end anastomosis reconstruction. Patients could withdraw from the study at any time and they will be excluded from the trail.
The study will be conducted in accordance with the Declaration of Helsinki. The trial has been approved by the Ethics Committee of PLA General Hospital (S2016–098–02). All the patients will be informed the purpose, method, risk of the study and their rights to withdrew. They will sign their names with fully aware of the trial voluntarily.