Design
STRAP-PD is a single center, randomized, controlled trial aiming is to demonstrate the superiority of surgical stapler for transection of the pancreatic parenchyma during PD compared with conventional methods using a scalpel, ultrasonic coagulation cutting device or vessel sealing system. Patients with soft pancreatic parenchyma are randomized into control arm A (conventional method) or study treatment arm B (surgical stapler method) depending on what is used for transection of the pancreatic parenchyma during PD. We seek to demonstrate the superiority of the surgical stapler method by comparing the rates of grade B/C postoperative pancreatic fistula (POPF).
The STRAP-PD trial is being conducted at Wakayama Medical University, which has been board-certified as a training institution by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. To ensure the high quality of the study, all operations are performed by instructors and expert surgeons certified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery.
Randomization
A flow diagram of the STRAP-PD trial is shown in Fig. 1. Randomization will be performed using the randomization schedule retained in the enrollment office and will be completed by the start of surgery. After confirmation of eligibility, including written informed consent, patients will be randomized in a 1:1 allocation ratio to either arm A (conventional method) or arm B (surgical stapler) with a random block size. Random allocation is performed using an allocation table stored by the enrollment office, and assignments are made randomly before the start of the surgery. The allocation table is generated using a permutation block method with a block size of 6, based on the following allocation adjustment factors. The enrollment office securely stores the allocation table in a lockable cabinet to prevent external leakage. The allocation adjustment factors are surgical approach (open surgery/minimally-invasive surgery) and preoperative chemotherapy (yes/no). All patients are blinded to the surgical method they will receive, and they are required to sign an informed consent form before enrollment in the study. Blinding of the surgeons is not possible because of the different method used during the operation. Assessment of the result will be made by an independent researcher who will be blinded to the surgical method.
Interventions
Study treatment arm (surgical stapler method)
Surgical stapler (Endo GIA™ or Signia™ Stapling System, Medtronic, Minneapolis, MN) is used for transection of the pancreatic parenchyma during PD. The surgeon should select the optimal cartridge for the automatic suture. The stapler is not released immediately after firing; the jaws of the stapler are held shut for 1 min [17].
After the main pancreatic duct is identified by intraoperative echo, the staples at the main pancreatic duct are manually removed on that site alone and a 5 Fr pancreatic duct tube is placed to secure the main pancreatic duct. The main pancreatic duct should be visually confirmed before pancreatojejunostomy.
If bleeding from the end of the remnant pancreas is observed, additional hemostasis is performed with a surgical clip, or suture hemostasis is performed using a 5-0 proline thread. If a crush, for example, of the remnant pancreas is observed and the surgeon judges that repair is necessary, it is acceptable to perform suture repair using 5-0 proline threads. Additional resection is acceptable if the crush of the remnant pancreas is significant and it clearly affects the postoperative course.
Control arm (conventional transecting method)
In conventional transecting methods, the pancreatic parenchyma is transected using a scalpel, ultrasonic coagulation cutting device or vessel sealing system. In this procedure, a surgical loop is used to gently tie on the remnant pancreas side to prevent bleeding from the remnant pancreatic stump. For arterial bleeding from the remnant pancreatic stump, a 5-0 proline thread is used for suture hemostasis. The main pancreatic duct is visually confirmed and secured by placement of a 5 Fr pancreatic duct tube.
Study endpoints
The primary endpoint is the incidence of grade B/C POPF within 90 days from the date of surgery. POPF is defined according to the 2017 International Study Group of Pancreatic Surgery (ISGPS) criteria [14]. Secondary endpoints are the incidence of other postoperative complications, which are graded by Clavien-Dindo classification within 90 days from the date of surgery [15]. Furthermore, we evaluate the frequency of residual pancreatitis, pancreatic endocrine function, and pancreatic exocrine function.
Statistical analysis
Sample size
In our previous study, the rate of grade B/C POPF rates after PD was 20% for patients with soft pancreas [3]. The rate of grade B/C POPF in arm A using a scalpel, ultrasonic coagulation cutting device or vessel sealing system was therefore estimated to be 20% (PA = 0.20). The rate of grade B/C POPF using surgical stapler in the study treatment (arm B) group was estimated to be 5% (PB=0.05) because it occurred in one of the 20 patients treated in a pilot study by the surgical stapler at our institution [16]. The difference in rates of grade B/C POPF is therefore calculated as PA- PB=0.15. When assessing the unilateral alternative hypothesis H1 “the rates of grade B/C POPF in the arm A and arm B differs” against the null hypothesis H0 “the rates of grade B/C POPF in the arm A and arm B is the same” using the test of population proportion at the α=0.05 level of significance, the minimum sample size required for the power 100 (1-β) of more than 80% is a total sample size of 146 cases (with 73 cases in each group) in two groups. Furthermore, approximately 10% of the patients are expected to be ineligible for surgery, so the cumulative target sample size is set at 160 cases, with 80 cases in each group. These parameters will be documented for comprehensive reporting and clarity in study design and statistical analysis.
Statistical analysis plan
The primary objective of this study is to evaluate whether the use of surgical stapler to resect pancreatic parenchyma reduces grade B/C POPF compared with the conventional method. In the assessment of the primary endpoint, if the p-value falls below the significance level of 0.05, and the occurrence frequency of POPF in the experimental treatment group is lower than that in the conventional method group, it will be a demonstration of the superiority of the stapler method in resection of pancreatic parenchyma. In such a case, we could conclude that pancreatic transection with the surgical stapler is a more beneficial method. If no statistically significant difference is observed between the two groups, the conventional procedure would continue to be considered the standard method for pancreatic transection. The primary analysis will employ the Mantel-Haenszel test, with adjustment factors being allocation adjustment and treatment as a covariate, using the full analysis set. Construction of 95% confidence intervals for the incidence rates of POPF in each group will utilize the Clopper & Pearson exact method. These details will be documented to ensure a comprehensive presentation of the study design, statistical analysis, and interpretation of results.
Study population
Eligible patients are those scheduled for PD in our department without a dilated main pancreatic duct (MPD), parenchymal atrophy or pancreatitis according to the preoperative enhanced computed tomography. Both open surgery and minimally invasive procedures (including robot-assisted approaches) are acceptable.
Inclusion criteria
- Patients judged to have soft pancreas among those scheduled for pancreaticoduodenectomy.
- The thickness of the pancreatic parenchyma can be cut with surgical stapler.
- ECOG Performance Status (PS) is 0-1.
- Age 20 years or older.
- The functions of major organs (bone marrow, heart, liver, kidneys, lungs, etc.) are maintained.
- Sufficient judgment to understand the content of the research and providing written informed consent.
Exclusion criteria
- Serious ischemic heart disease.
- Complication of liver cirrhosis or active hepatitis.
- Dyspnea requiring oxygen administration due to interstitial pneumonia or pulmonary fibrosis.
- Undergoing dialysis for chronic renal failure.
- Requiring combined resection of surrounding organs.
- Considered to require arterial reconstruction of the superior mesenteric artery, common hepatic artery, celiac artery, etc.
- Active double cancers that may affect adverse events or overall survival.
- Long-term oral steroid use that may cause adverse events.
- Psychosis or psychiatric symptoms judged to potentially cause difficulty in participation in the study.
- History of abdominal operation including gastrectomy, colectomy, rectal resection, hepatectomy, but excluding cholecystectomy.
- Inability to use both iodine-based drugs and gadolinium-based drugs due to serious drug allergies.
Common to both groups (allowable procedures)
Operative Procedure
In our standard procedure, the stomach is divided just proximal to the pylorus, so that more than 95% of the stomach is preserved. In patients with malignant disease, the lymph nodes are dissected at the hepatoduodenal ligament, around the common hepatic artery, around the superior mesenteric artery, and around the pancreatic head. Reconstruction is Billroth II reconstruction. The retained jejunum is brought through the transverse mesocolon, and end-to-side pancreatojejunostomy is performed, followed by end-to-side hepaticojejunostomy and then antecolic end-to-side gastrojejunostomy [3, 18].
Pancreatojejunostomy procedure
Anastomosis is performed in a duct-to-mucosa fashion using a single layer of interrupted 5–0 PDS-II® (double-armed, polydioxanone suture; Johnson and Johnson Co., Tokyo, Japan) with eight or more sutures. A 5-Fr polyethylene pancreatic stent tube (Akita Sumitomo Bake, Akita, Japan) is cut to a length of 5 cm and placed at the pancreaticojejunal anastomotic site as an internal stent. If the main pancreatic duct is too large or too small for a 5-Fr stent tube, no stent is placed [3].
Suture of pancreatic parenchyma and jejunal seromuscular layer is performed by modified Blumgart mattress method. The trans-pancreatic suture started from anterior to posterior straight through the pancreas using 4–0 MONOFLEN® (double-armed, polyvinylidene fluoride monofilament; Alfresa Pharma Co., Osaka, Japan). A suture is placed through the seromuscular layer of the jejunal posterior wall from back to front in the direction of the short axis, followed by replacement of the mattress suture from the front to the back of the jejunal posterior wall, and then the trans-pancreatic suture is made in a posterior-to-anterior direction [3].
Postoperative Management
This study does not plan to provide medical procedures beyond the routine practice. All patients are to be treated according to the standardized postoperative management for PD [5, 19]. Drain management and measurement of the drainage fluid amylase levels are as follows: 1 BLAKE Silicone Drain 10 mm Flat type® (Ethicon, Inc., Somerville, NJ) is placed near the pancreatic anastomosis. The drain is removed on postoperative day 4 if the drainage fluid is clear, and if pancreatic fistula and bacterial contamination are absent. Amylase level in the serum and the drainage fluid will be routinely measured on postoperative days 1, 3, and 4 [5]. Combination therapies and supportive care including antibiotics and proton-pump inhibitors products that may be used in intraoperative and postoperative management are not specified. Octreotide prophylaxis should not be given.
Standardization and validation of interventions
To guarantee the quality of operative procedure, the surgeon or teaching assistant will be an advanced skill specialist certified by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. A photographic record after pancreatic transection is necessary for both groups for validation of intervention quality. Central judgment will be conducted for the both groups, and the photographs will be reviewed by more than two members at that time.
Recruitment
This clinical study will be conducted between September 2023 and December 2027 at a single institute: Wakayama Medical University Hospital. Prior to the start of the study, the treating physician shall provide patients with an easy-to-understand explanation and give them time to contemplate, and request the patients to participate in the study based on a thorough understanding of the content of the study. The informed consent form shall include the name of the physician who provides the explanation, the name of the patient who provides informed consent, and the date of obtaining informed consent, and it will be signed by both the physician and the patient. Then, one copy is generated to be handed over to the patient and the original copy of the informed consent form is stored in the specified storage site.
Criteria for discontinuation/completion of protocol treatment
The protocol treatment will be completed with the anastomosis of the pancreas and gastrointestinal tract (pancreaticojejunostomy) following PD. Follow-up will be performed up to 90 days after surgery.
If the protocol treatment cannot be continued for the following reasons, it should be discontinued for the following listed reasons:
- The patient requests withdrawal from the study.
- Peritoneal or liver metastasis is found after laparotomy and PD is not performed.
- Changes in surgical technique during surgery, such as combined resection of other organs, bypass surgery, and exploratory laparotomy.
- Forced closure without completing the protocol treatment due to an emergency that prevents continuation of the operative procedures (e.g., myocardial infarction, major bleeding, or cardiac arrest due to neural reflex).
- The surgeon judges the use of medical staplers to be difficult during surgery (e.g., due to thick pancreatic parenchyma).
Follow-up after completion of treatment (postoperative day 90)
The schedule of this trial is shown in Fig. 2. The day of surgery is set as Day 0, and testing may be performed between two weeks before and after postoperative day 90. The following items are examined, observed, and investigated 90 days after surgery:
- Postoperative complications: presence or absence and grades of pancreatic fistula, delayed gastric emptying, and intraabdominal bleeding (assessed according to the ISGPS criteria), and presence or absence and severity of all postoperative complications (assessed according to the Clavien-Dindo classification)
- Rate of postoperative remnant pancreatitis (post-pancreatectomy acute pancreatitis classification by ISGPS. [20]
- Adherence between the remnant pancreas and the reconstructed intestine as well as the extent of pancreatic duct dilatation on CT.
- Endocrine and exocrine pancreatic function.
- Operative mortality up to 30 days and 90 days after surgery.
- Degree of residual tumor (R0/R1).
- T, N, M stages according to the eighth edition of the UICC-TNM classification.
- Postoperative hospital stay (time from the day of surgery to the day of discharge when the day of surgery is indicated as Day 0).
Data and safety monitoring
During the study, an independent data monitoring committee (Clinical Study Support Center, Wakayama Medical University) will monitor the safety of the trial subjects by qualitative analyses of feasibility, accrual rate, and adverse events, as well as dropouts every 6 months. Data are collected via a paper-based case report form and stored and managed securely by the data monitoring committee. To improve the quality of data, after written consent is signed, all baseline assessments will be conducted before randomization. The principal investigator has the right to terminate the trial at any time in consultation with the biostatistician. The trial will be terminated if the incidence or severity of adverse events in the trial indicates a potential health hazard caused by the study treatment. In order to discontinue the entire study, the principal investigator must request a review by Wakayama Medical University.
Ethics Review Board
All investigators involved in this research will conduct this study in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies of the Ministry of Health, Labour and Welfare of Japan. The protocol has been approved by the Wakayama Medical University Hospital Institutional Review Board (approval number 3923). The trial protocol has also been registered in the protocol registration system at the University Hospital Medical Information Network Clinical Trials Registry (UMIN000052089). The registration date was 1st September 2023. All patients will be scheduled only after comprehensive information concerning the nature, scope, and possible consequences of the clinical trial has been provided to them in an understandable way by the investigator. Written informed consent for the study will be obtained from each patient before the operation. The procedure, benefits, risks, and data management of this study will be clarified in detail for the patients during the preoperative conversation.
Dissemination policy
The results of the STRAP-PD trial will be submitted to a peer-reviewed journal and will be presented at national and international conferences, regardless of the trial outcomes. Authorship will be agreed in accordance with the STRAP-PD trial publication policy and in line with international guidelines.