Total laparoscopic pancreaticoduodenectomy versus open pancreaticoduodenectomy (TJDBPS01): study protocol for a multicenter randomized controlled trial.
Hang Zhang1, Junfang Zhao1, Yechen Feng1, Rufu Chen2, Xuemin Chen3, Wei Cheng4, Dewei Li5,
Jingdong Li6, Xiaobing Huang7, Heguang Huang13, Deyu Li14, Jing Li7, Jianhua Liu8, Jun Liu9,
Yahui Liu10, Zhijian Tan11, Xinmin Yin4, Wenxing Zhao12, Yahong Yu1, Min Wang1✉, Renyi Qin1
✉.
Minimally Invasive Pancreas Treatment Group in the Pancreatic Disease Branch of China’s
International Exchange and Promotion Association for Medicine and Healthcare.
1 Department of Biliary–Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
2 Department of Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou
510120, China.
3 Department of Pancreaticobiliary Surgery, The Third Affiliated Hospital of Soochow University,
Jiangsu 213000, China.
4 Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, The First Affiliated
Hospital of Hunan Normal University, Changsha, Hunan 410000, China.
5 Department of Hepatobiliary Surgery, First Affiliated Hospital of Chongqing Medical University,
Chongqing 404100, China.
6 Department of Pancreatico-Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical
College, Sichuan 637000, China. 7 Department of Pancreatico-Hepatobiliary Surgery, The Second Affiliated Hospital, Army
Medical University, PLA, Chongqing 404100, China.
8 Department of Hepato–Pancreato–Biliary Surgery, The Second Hospital of Hebei Medical
University, Shijiazhuang, Hebei 050017, China.
9 Department of Hepato–Pancreato–Biliary Surgery, Shandong Provincial Hospital, Shandong
250000, China.
10 Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, 71
Xinmin Street, Changchun, Jilin 130021, China.
11 Department of Hepatobiliary and Pancreatic Surgery, Guangdong Province Hospital of Chinese
Medicine, Guangzhou, Guangdong 510120, China.
12 Department of General Surgery, The Affiliated Hospital of Xuzhou Medical College, Xuzhou,
221004, China.
13 Department of Hepato–Pancreato–Biliary Surgery, Fujian Medical University Union Hospital，
Fuzhou，Fujian，350000，China.
14 Department of Hepatobiliary Pancreatic Surgery, People’s Hospital of Zhengzhou University,
Henan Provincial People’s Hospital, No.7 Wei Wu Road, Zhengzhou, Henan, 450003, China.
Email address for authors: [email protected] for Hang Zhang, [email protected] for Junfang Zhao, [email protected] for Yechen Feng, [email protected] for Rufu Chen, [email protected] for Xuemin Chen, [email protected] for Wei Cheng, [email protected] for Menghua Dai, [email protected] for Dewei Li, [email protected] for Jingdong Li, [email protected] for Defei Hong, [email protected] for Xiaobing Huang, [email protected] for Heguang Huang, [email protected] for Deyu Li, [email protected] for Jing Li, [email protected] for
Jianhua Liu, [email protected] for Jun Liu, [email protected] for Yahui Liu, [email protected] for Zhijian Tan, [email protected] for Xinmin Yin, [email protected] for Wenxing Zhao, [email protected] for Yahong Yu.
✉Corresponding author
Renyi Qin, MD
Department of Biliary–Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030,
China.
Tel.: +27-8366-5294; Fax: +27-8366-5294
Email: [email protected]
Min Wang, MD
Department of Biliary–Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030,
China.
Tel.: +27-8366-5294; Fax: +27-8366-5294
Email: [email protected].
Abstract
Background: Pancreatoduodenectomy (PD) is one of the most complex abdominal operations, usually performed for tumors of the periampullary region and chronic pancreatitis. Minimally invasive surgery has been progressively developed, first with the advent of hybrid-laparoscopy and recently with the total laparoscopy surgeries, but a number of issues are currently being debated, including the superiority between total laparoscopic pancreaticoduodenectomy (TLPD) and the open pancreaticoduodenectomy (OPD). Studies comparing these two surgery techniques are merging and randomized controlled trials (RCT) are lacking but clearly required.
Methods/design: TJDBPS01 is a multicenter prospective, randomized controlled, parallel-group, superiority trial in centers with pancreatic surgery expertise who have performed ≥104 TLPDs and OPDs, respectively. A total of 630 patients underwent PD will be randomly allocated to the
TLPD group or OPD group with an enhanced recovery after surgery (ERAS) pattern. The trial hypothesis is that TLPD has superiority or equivalent in safety and advantages in postoperative recoveries compared with OPD. The primary outcome variable is the estimated blood loss in the surgical procedure. Discussion: Despite the fact there are several RCTs comparing TLPD and
OPD, this trial will be the first comparing TLPD and OPD in a large multicenter setting.
Trial registration: Clinical Trials Register, NCT03138213. Registered on 28 Apr 2017.
Keywords: pancreaticoduodenectomy, laparoscopic surgery, open surgery, whipple, randomized controlled trial.
Protocol version: TJDBPS01 1.0, date: 20 Mar, 2018
Funding:
This study was supported by grants from The National Natural Science Foundation of China
(81272659, 81772950, 81773160), HUBEI Natural Science Foundation (WJ2017Z010).
Background
Pancreatic cancer constitutes a major health problem and is dreadful affair worldwide. By some estimates, it is the ninth most common cancer in United States, yet also the fourth leading cause of cancer death [1]. Surgery is the primary treatment for patients with resectable disease.
Pancreaticoduodenectomy (PD) is one of the most complex abdominal operations, involving removal of the head of pancreas, duodenum and common bile duct, and is usually performed for treatment of pancreatic cancer and relieving pain in chronic pancreatitis [2]. Introduced by Gagner et al, who performed the first laparoscopic pancreaticoduodenectomy (LPD) in 1994, the use of laparoscopy in pancreas surgery has continued to grow and rapidly spread because of its potential technical advantages, such as the precision of movements achieved using laparoscopic instruments and a three-dimensional view provided by the special vision system [3]. To date, many studies confirmed the advantages of laparoscopic techniques in gastric, renal and cervical surgeries [4-6].
However, only few low-quality studies reported the application of total laparoscopy in pancreas surgery, let alone in PD surgery. In particular, recently performed meta-analyses have been poor due to the small number of studies with good quality [7-10]. However, several limitations must be highlighted among these studies including the different nature of these surgical approaches, the different baseline characteristics of each study’s patients, the relatively small sample sizes for individual study, the high heterogeneity of data, the lack of basic features regarding the procedures, such as the detailed type of surgical reconstruction, and the inadequate or non-accessibility of data regarding both the short-term outcomes and the oncological follow-up.
Similarly, all of the studies that reported results in this topic emphasize the need for large randomized trials. However, RCTs are difficult to perform and are very costly. There should be further consideration regarding the need for the detection of numerous surgical, clinical and oncological variables. Thus, it is imperative for such a study to have a large number of patients enrolled. A study recruiting sufficient patients is desirable.
Therefore, this project, namely TJDBPS01 trial, a large registry will be created by collecting data from the fourteen qualified centers in China to create a working basis for analyzing outcomes of interest and obtaining evidence in comparing TLPD and OPD.
Rationale for the trial
In recent years, TLPD is emerging and plays a rising role in compare with the OPD due to the improvement of both the surgeons’ technique and the surgical instruments. It is widely reported that the TLPD was associated with a reduction in estimated blood loss (EBL), a lower transfusion rate and a shorter length of hospital stay than OPD group. Meanwhile TLPDs have much longer operative time than OPD. Finally, there were no significant differences between the 2 procedures in major complications, mortality. Not only many retrospective studies and meta-analyses, but also several RCTs have been working on this specified topic. Palanivelu et al published the worldwide first RCT and concluded that LPD offered a shorter hospital stay comparing with OPD [11]. Poves came up with the same conclusion in the following year [12]. Both of their studies are in a single center setting and recruit only 60 and 66 patients in their trials, respectively. The researchers claimed a multicenter trial is of necessity. There it comes the LEOPARD-2, the first multicenter
RCT, recruiting 99 patients didn’t reveal the superiority of the TLPD, and ceased with an estimated mortality rate of 6%, where 5 patients died in laparoscopic group and 1 patient died in the open group [13]. This result limited the application of TLPD and hindered the development of the technique through the Netherland. Therefore, a multicenter setting RCT with expertise in laparoscopic guaranteeing a sufficient enrolment is necessary. The study TJDBPS01 plans to recruit 630 patients and all the surgeries are performed by adequate qualified surgeons who definitely overcome their learning curves in LPD. Also, it is possible for TJDBPS01 to acquire long-term outcomes of the PD patients which hadn’t been reported by any study.
Objectives
The objective of this trial is to evaluate the safety of TLPD and OPD procedures. The main hypothesis is that TLPD has superiority or equivalent in safety and advantages in postoperative recoveries compared with OPD. The primary outcome variable is the estimated blood loss in the surgical procedure. The secondary outcome variables including length of stay, operation time, complication rate, R0 resection and overall survival et al.
Trial Design
The TJDBPS01 trial is designed as a multicenter, randomized, controlled, superiority trial with two parallel groups and a primary endpoint of 2-year survival after surgery in fourteen pancreatic centers in China. Randomization will be performed in a third unity with a 1:1 allocation (Fig. 1).
Methods/Design
Study settings
The TJDBPS01 trial choose the participating sites in 14 provinces in China, providing a minimal
＞50PDs annually. All the participating fourteen centers with pancreatic surgery expertise had have performed ≥104 TLPDs and OPDs, respectively. Screening and identification of eligible patients will take place at the participating center’s pancreatic multidisciplinary team (MDT) meeting. All patients to be about to undergo PD would come through a standard evaluation:
Contrast enhanced multi-thin sliced CT scan (1mm) with or without endoluminal ultrasound
(EUS), which will be discussed at the MDT. Patients recommended for resection on the basis of a high likelihood of a malignant lesion will be contacted and provided with detailed consensus.
Consent (version date 2018-03-20, Ver 1.0) will be obtained by an investigator who should comply with applicable regulatory requirements and should adhere to the ethical principles that have their origin in the Declaration of Helsinki. It is not necessary for patients to have a histological diagnosis of malignancy before surgery provided that the MDT has confirmed that the lesion is of sufficient concern to require resection [14].
Eligibility
Inclusion criteria
1) Age between 18 years and 75 years
2) Histologically proven periampullary cancer, including pancreatic cancer, bile duct cancer,
duodenal cancer, et al
3) Indication for elective PD even benign or premalignant disease in the pancreatic or
periampullary region
4) Both TLPD and OPD feasible also the subject can undergo the surgery according to the MDT
team
5) The subject understands the nature of this trial and willing to comply
6) Ability to provide written informed consent 7) Patients treated with curative intent in accordance to international guidelines [15]
Exclusion criteria
1) Distant metastases: peritoneal carcinomatosis, liver metastases, distant lymph node metastases,
involvement of other organs
2) Subjects undergoing left, central or total pancreatectomy or other palliative surgery
3) Patients with high operative risk as defined by the American Society of Anesthesiologists
(ASA) score ≥ 4
4) Synchronous malignancy in other organs or second cancer requiring resection during the same
procedure
5) Pregnancy
6) Neo-adjuvant therapy including medication or radiotherapy
Interventions
TLPD techniques
The standard operative technique is described as following (Fig. 2). Any small variations according to the surgeon’s preference, such as a different order for surgical steps, a variation in approach or pancreatic anastomosis technique, are allowed, but must be recorded authentically in the case record form.
All procedures are performed by two regular trained pancreatic surgeons (see section on Study setting). Patients are under general anesthesia and is placed in a supine position; an anti-Trendelenburg position (10°-30°) has been used if necessary. The right arm is placed along the body and the left arm in 90° abduction for accessing arterial monitoring. A 12-mm trocar (VersaportTM, COVIDIENTM) has been placed slightly lower than the umbilicus, and pneumoperitoneum has been established. Two 12-mm trocars are then placed, both lateral to the first trocar on the right and left in midclavicular lines. Another two 5-mm trocars are placed at the right and left infracostal arch on both sides of the anterior axillary line (3-4 cm subcostal).
Diagnostic laparoscopy is performed to rule out any abnormalities and metastasis. The cystic duct and artery are transected, the gallbladder is moved and set aside. The round ligament is retracted to the anterior abdominal wall, with either a suture according to the surgeons’ experience. The lesser sac is opened and a Kocher maneuver is performed, and the duodenum then has been
mobilized. The gastro-epiploic artery and vein are transected. The distal stomach are transected on the left side of the pylorus with endostapler (COVIDIENTM, Endo GIATM, Auto SutureTM) after removal of the nasogastric tube. The common hepatic artery are identified on the inferior border of the pancreas and suspended with a rubber band. Lymph node station 8a is dissected. Subsequently, the right gastric artery and gastroduodenal artery are ligated and transected with at least 2
Hem-o-lok clips (WECK ) and 1 firm ligation (Ethicon ). The portal vein (PV) has been then ® ® identified at the superior border of the pancreatic neck, and the superior mesenteric vein (SMV) has been identified at the inferior border of the pancreas. A tunnel is created posterior to the pancreatic neck and anterior to the SMV and PV. The pancreas is slung with a vascular blocking band and then transected with ultrasonic shears (THUNDERBEAT, OLYMPUS), but the pancreatic duct is transected sharply with scissors and intubated to ensure that it is open. The jejunum is transected approximately 15 cm from the ligament of Treitz with endostapler
(COVIDIENTM, Endo GIATM, Auto SutureTM). After retracting the duodenum and jejunum to the right side of the mesenteric root, the duodenum is stretched and the uncinate process is mobilized. The branches of the SMA and SMV are carefully handled until the uncinate process is fully dissected. Retroportal lymph nodes are resected according to the International Study Group on
Pancreatic Surgery guidelines [16]. The common hepatic duct is tunneled and transected for anastomosis.
Preparation of the pancreatic stump and jejunal loop. The pancreatic stump remnant has been dissected to approximately 0.5 cm (no more than 1.0 cm) in length, and careful hemostasis is established with the ultrasonic shears or absorbable sutures. A 6 to 8Fr plastic catheter is then inserted as a stent into the pancreatic duct remnant to prevent pancreatic duct stenosis after suture placement. The jejunal limb is brought up to the right of the middle colic vessels in a retrocolic manner, and the blind end is placed near the pancreatic remnant. Negative resection margin status on the frozen section of the specimen will be confirmed before intracorporeal reconstruction if malignancy is suspected.
Pancreaticojejunal anastomosis An imbedding end-to-side PJ including four layers of mattress sutures is then performed [17]. The first layer of the anastomosis is created between the posterior wall of the pancreatic stump and the posterior seromuscular layer of the jejunum. Two completely transpancreatic 4-0 prolene (Premilene, BRAUN) mattress sutures are placed at a point approximately 0.2 cm from the superior and inferior edge of the main pancreatic duct, respectively.
The most critical surgical step in placement of the first and second mattress sutures is interlocking them in the posterior wall of the jejunum. Care should be taken to preset the sutures to avoid passing them through or injuring the main pancreatic duct. Both mattress sutures are preplaced approximately 0.5 cm from the cut edge of the pancreatic remnant. The number of these sutures varies depending on the size of pancreatic duct, but typically ranges between two and four. After a small full-thickness jejunotomy is created in line with the pancreatic duct, the second layer of the anastomosis is created between the posterior wall of the pancreatic stump and the posterior wall of the small jejunum hole. Two completely transpancreatic 4-0 prolene mattress sutures are placed following the first two sutures, but full-thickness mattress suture in the posterior wall of the small hole has been made in the jejunum approximately 0.2 cm from the edge. The third and fourth mattress sutures are interlocked in the posterior wall of the jejunal hole. The posterior wall of the jejunal loop is then tightly anastomosed with the posterior wall of the pancreatic stump without any remaining suture intervals. The third layer of the anastomosis is made between the anterior wall of the pancreatic stump and the anterior wall of the jejunum. Two incompletely transpancreatic interlocking 4-0 prolene mattress sutures are placed as described for the second layer of the anastomosis. However, the mattress sutures does not completely penetrate the pancreatic parenchyma, but only enters the tissue half-way. The fifth and sixth mattress sutures are supposed to interlock in the anterior wall of the jejunal hole. The fourth layer of the anastomosis has been made between the anterior wall of the pancreatic stump and the anterior wall of the jejunum. Four incompletely transpancreatic interrupting 4-0 prolene mattress sutures are placed to close the gaps in the superoinferior margin of the anastomosis and strengthen the sutures on its anterior wall, achieving pancreas–enteric anastomosis. Approximately 10cm distally, an end-to-side hepaticojejunostomy is performed with running (bile duct dilatation of >5 mm) or interrupted (bile duct dilatation of ≤5 mm) sutures (Novosyn, BRAUN). Approximately 40cm distal to the biliary anastomosis, an antecolic side-to-side gastroenterostomy has been performed with the staple technique, and 2 layers of running 3-0 sutures (Novosyn, BRAUN) are used to close the gastric stump. Two 27Fr surgical drains are placed through Winslow and the upper region in the PJ stoma. After hemostatic control, the trocars are removed. The specimen is extracted through an upper-middle incision, which is subsequently closed in layers together with the closure of the trocars.
OPD techniques
The open pancreaticoduodenectomy has been performed by the same group of surgeons. Right side rectus muscle abdominal incision is preferred for better exposure. The key steps taken are essentially similar to TLPD group. Since outcomes of open pancreatoduodenectomy in worldwide are fairly promising and convincing, the surgical technique in the OPD arm reflects their usual practice; also, the anastomoses will be performed according to each center’s protocol. Procedure variations according to the surgeon’s preference are allowed, but must be recorded in the case record form. Two surgical drains are placed the same as the TLPD procedure.
Conversion from TLPD to OPD
Conversion is defined as any TLPD group in which a skin incision is used for reasons other than trocar placement or specimen removal. Subjects allocated to TLPD who undergo intraoperative conversion to open pancreatoduodenectomy will be analyzed in the TLPD group according to intention-to-treat principles also will be calculated as per-protocol analysis. Reasons for conversion are registered and should be carefully recorded in the surgical record.
Postoperative management
Patients are given antibiotics twice during surgery, one in thirty minutes before skin incision and another would be two hours after the incision. Whether to moving the nasogastric tube after the anesthesia depends on each participating centers’ preference. Postoperative pain control consists of patient-controlled analgesia (PCA). Patients are encouraged to be out of bed and walking around the ward under the guidance of a nurse the day after surgery in accordance with the enhanced recovery after surgery principle. Patients will be discharged when they can pass stools, are able to drink, can walk, and are comfortable with orally administered analgesia. Drain management could be handled at home under guidance.
Follow-up
Adjuvant chemotherapy with Gemcitabine, for 1 year is included in protocol treatment for patients with pancreatic cancers. The different regimens are permitted base on the NCCN guideline [15].
All patients are followed up for 2 years or until death. When referring to the malignant, the follow-up will be extended to 5 years. Enhanced CT scans of the chest and abdomen are evaluated every 3-6 months (Fig. 3).
Withdrawal
All the patients are freely informed to participate in this study and can decide to withdraw from this trial at any time. If a patient withdraws, his/her information will not be recorded in this study.
However, the research team can still collect outcome data from the healthcare records.
Outcomes
Primary outcome measure The primary outcome variable is the estimated blood loss in the surgical procedure.
Secondary outcome measures
The secondary outcome variables including length of stay, operation time, complication rate, mortalities, R0 resection and overall survival.
Participant timeline
The trial time schedule of enrolment is estimated in a 2-year interval, following by a 2-year follow-up visit. Once the eligibility of the patients is confirmed, randomization will be applied.
When to apply the interventions is not strictly defined, every participating center could made their own adjustment to their preference. The assessments and visits for patients are mandatory in the first 1 month, 3 month, 6 month 12 month and 24 month.
Sample size
According to the latest systemic review [18], it is reported MIPD was also associated with less estimated blood loss (mean difference [MD] -300 mL). Accordingly, the sample size was determined based on primary objective of comparing the EBL between two surgery methods.
Based on expected mean EBL differences in two surgical group, it required 283 patients in the
TLPD group and 283 in the OPD group wash out or loss (α=0.05, β=0.2, power=0.8). Considering of follow-up, we enlarged the sample size by 10% to compensate for withdrawal/dropout. Then the final sample size was 630. Thus, there are 315 patients in each group.
Recruitment
Each center will screen eligible patients through out-patient department or advertising by the qualified surgeons. The duration of recruitment period is estimated as 24 months interval depending on each centers recruiting rate. No financial incentives are provided to trial investigators or patients for enrolment in the recruitment period.
Participating surgeons and centers criteria:
To prevent surgeon bias, participating surgeons satisfy the following criteria: (1) having experience of more than 104 TLPDs, (2) having experience of more than 104 OPDs, (3) complete the Tongji Hospital TLPD training program.
All the participating centers are the biggest representative pancreatic surgery centers in their region ensuring 50 PDs were performed annually. If willing to join the trial, each surgeon was mandated to offer two recently unedited surgery videos for evaluation. The video would be sent to the Board and saved appropriately. Only did the Board approve the surgical techniques could the surgeon and their center participated as a collaborator.
Allocation
Allocation was conducted by the data manager. In detail, when appropriate patient is enrolled, the researcher will inform the data manager and then the random number as well as exact treatment group will be returned simultaneously.
Blinding All the patients and surgeons are not blinded for the intervention. Meanwhile all the analysis and recording are blinded.
Randomization
The study applied the simple randomized design. The randomization was centralized through a computer-generated system and performed in a parallel fashion. A data manager, who was not involved in the data analysis or patient enrolment, generated the randomization schedule. A sequence of 630 random numbers were generated and the smaller 315 random numbers were defined as group 1 and the larger 315 random numbers were defined as group 2. Allocation was conducted by the data manager. In detail, when appropriate patient is enrolled, the researcher will inform the data manager and then the random number as well as exact treatment group will be returned simultaneously. The randomization schedule was not available to study recruiters or physicians until baseline assessment was completed.
Trial population
All adult patients with an indication for PD including but not limited to pancreatic cancer, bile duct cancer, duodenal cancer and the benign disease like mass-forming pancreatitis et al.
Data collection
Patient demographics: Year of birth, Sex, Body mass index, Surgical risk (ASA score),
Comorbidities, Previous surgery history, Main complaint, Preoperative biliary drainage, Preoperative blood samples: hemoglobin levels, white blood cell count, granulocyte: lymphocyte
(G:L) ratio, plasma levels of total bilirubin, carbohydrate antigen (CA) 19-9, CA125, Carcino
Embryonie Antigen (CEA), Alpha Fetal Protein (AFP), Date of admission, Income.
Surgery information: Operation date, Type of surgical approach (open, total laparoscopic), Type of digestive tract reconstruction, Anastomosis approach (intracorporeal, extracorporeal),
Anastomosis performance (linear stapler, circular stapler, hand-sewn or combinations), Placement of intra-abdominal drain, Placement of nasogastric tube, Total operative time, Each anastomosis time (pancreaticojejunostomy, cholangiohepaticojejunostomy, pancreatogastrostomy), Texture of pancreas, Diameter of the main pancreatic duct, Estimated blood loss (EBL), Intraoperative blood transfusion, Conversion to open surgery, Intraoperative complications, Intraoperative death, Extent of lymphadenectomy.
Histopathological information: Surgical margin status (R0 resection rates), Number of retrieved lymph nodes, Number of positive lymph nodes, Tumor location, Size of the tumor, Depth of invasion (T classification), Lymph node status (N classification), AJCC pathological stage (the eighth edition) [19], Histological type [20].
Postoperative clinical findings: Length of postoperative hospital stays, Postoperative blood transfusion, Patient mobilization (post-operative day (POD)), Liquid diet (POD), Soft solid diet
(POD), Drain removal (POD), Length of intravenous analgesic use, Cost for hospitalization, Cost for surgery, Drain production and amylase, Haemoglobin levels, White cell count, Tumor marker level after surgery, Type of complication, Reoperation, Clavien-Dindo grade [21].
Follow-up: Date of last follow-up visit, Adjuvant chemotherapy, Adjuvant radiotherapy, Patient status at last follow-up visit (alive, dead, lost to follow-up), Disease-free or not during follow-up. All the data will be placed into the local database via a data registry server managed by the data collection group. In this trial, the follow-up and statically staff are masked to the intervention arms.
Data management
In this study, the EDC data collection system was used for data collection. The roles of the staff involved in data collection include raw material photographers, clinical research coordinator
(CRC), clinical research associate (CRA), etc.
All staff involved in the data collection process are qualified in order to access to the research database. Data collection needs to be collected in accordance with standard specification processes.
Photographers should be in accordance with the visit process requirements and eCRF fill in the guide to the original data to the system, the system cannot automatically identify the data by the data entry person for manual input.
Statistical methods
All statistical analyses will be carried out with SAS 9.4, SPSS v22.0, PASS 11.0 and other required statistical software programs. All statistical tests were tested with two sides, and P＜0.05 was considered to have statistically significant differences, with a confidence interval of 95% confidence. Quantitative data statistics are described by number of cases, means, standard deviation, median, quartile, maximum and minimum values. Qualitative data statistics are described by frequency, constituent ratio, or percentage. The effect research and the analysis comparison will select the data set according to the specific research goal with the appropriate statistical analysis method. The inter-group comparison of qualitative data will use Chi-square test, and the independent sample T test is used to compare the quantitative data between the groups.
The inter-group comparison of control covariance can be compared by covariance analysis or generalized linear model.
All adverse events are standardized by MedDRA coding, and according to the System Organ
Classification (SOC) and the preferred language (PT) and CTCAE grading in the MedDRA encoding. The incidence of adverse events (reactions), those level 3 or above will be compared among the two groups.
The study will be analyzed and reported following the CONSORT guidelines [22, 23].
Data monitoring
Efficacy and safety the duration of data acquisition is 90 days after the patient signs the informed consent (ICF) and the visit. Security data will evaluate the severity of adverse events based on the
CTCAE 4.0 standard. All adverse events are recorded in the CRF, from the signing of ICF to the end of the study. Each patient will receive a planned visit and will record specific data at different points in time of the visit.
Harms
All the harms including adverse events or even severe adverse events will be record detailly according to the Common Terminology Criteria for Adverse Events (CTCAE ver 4.0). The data will also be collected to the Hospital Ethical Committee and the Chinese Chinical Trial Registry.
Auditing
Auditing is handled by an independent agency with an anticipated frequency of one month.
Protocol amendments
Any modifications of the protocol which may impact on the conduct of the study, potential benefit of the patients or may affect patient’s safety, including changes of study design, sample size, study procedures will require a formal amendment to the protocol. And also, would be submitted to the
Hospital Ethic Committee and notified to the health authorities in accordance with local regulations.
Confidentiality
All study-related information and participant information will be stored securely at the study site with locked cabinets in areas with limited access. All local database will be secured with password-protected access system.
DEFINITIONS
Intraoperative adverse events
Intraoperative bleeding: Any occurrence of relevant blood loss that caused an action by the surgeon, which was described in the surgical or anesthesiologic reports, or evidence undertaken urgent transfusion therapy during surgeries.
Injury of visceral organs or vessels: Any injuries to abdominal organs described on the surgical report, requiring additional surgical procedures which were unrelated to the predefined procedures.
Anesthesia complications: Any complications occurring during surgery related to anesthesia that induced the interruption of the surgery or changed the normal course of the procedures.
Conversion: Any reasons result in conversion surgery should be carefully reported.
Other complications: Other events leading to a deviation from the normal operation course, reported by the surgeons or anesthetists.
Post operation complications
The following postoperative events will be detected and analyzed.
Hemorrhage: Any evidence of postoperative hemorrhage, including intraluminal and intra-abdominal bleeding. Descriptions of clinical signs and symptoms, or the need for transfusion should be recorded. Report of radiological (digital subtraction angiography) or endoscopic examinations or any surgical procedures should be included (If needed).
Postoperative pancreatic fistula (POPF): Drain amylase was monitored after surgery, the detection and severity of pancreatic fistula was classified according to the system of the
International Study Group of Pancreatic Fistula (ISGPF) [24].
Delayed gastric emptying (DGE): Delayed gastric emptying was defined according to the definition provided by the International Study Group of Pancreatic Surgery (ISGPS) [25].
Bile leakage: The drain bilirubin was monitored after surgery, any elevation for the bilirubin level or the diagnostic puncture proved bile fluid in abdominal cavity.
Wound infection: Superficial or deep surgical-site infections are both considered and should be reported in medical records. Superficial infections are considered when skin or subcutaneous tissue is involved, whereas deep infection is considered when extending into the fascial layer.
Intra-abdominal fluid collection/abscess: Evidence of collection of fluid material, with or without the characteristics of an abscess, confirmed by ultrasound, CT or contrast-enhanced CT.
Intestinal obstruction and ileus: Reported diagnosis based on clinical examination and signs of intestinal dilatation on abdominal X-ray.
Wound hernia or Dehiscence: Hernia or separation that occurred through a surgical incision in the abdominal wall deriving either from laparotomy or trocar incisions. All available data will be considered from medical records.
Other complications: Complications include surgical-related complications, not classified by any of the above, and deriving from all available patient records.
Follow-up
The analysis will be made based on the following data:
Last follow-up visit: Date of the last record reporting the patient’s condition or the annotated date of death, or date of the last reported contact between the patient and the hospital.
Patient status: The patient’s condition (alive/dead) at last follow-up.
Lost to follow-up assessment: A patient who at one point has become lost or unreachable or has moved away from the trial.
Disease-free survival: The length of time after surgery that the patient survives without any signs or symptoms of cancer or recurrence. This will be calculated according to the date of surgery and the date of the first radiological reports, attesting the recurrence of the disease until the last follow-up visits if the patient has been disease free.
Other definitions
Estimated blood loss: The volume was recorded carefully by the anesthetist through a vacuum system, namely suction volume minus irrigation volume.
Operation time: The time was calculated from either skin incision or trocar placement to the entire skin closure.
Type of the digestive tract reconstruction procedure: Child anastomosis or roux-en-y anastomosis would be carefully recorded in surgeons’ report.
Staging tumor: The stage will be described according to the Seventh Edition of the American
Joint Committee on Cancer American Joint Committee/International Union against Cancer tumour node metastasis classification for cancer [19].
Cost: The hospitalization cost as well as the surgery cost will be recorded.
Publications
Each participating investigator, with equal right, will be able to access the data of the registry, perform statistical analysis, discuss the results and freely write scientific manuscripts. The manuscript would be approved by all the authors before publication.
Discussion
The TJDBPS01 trial is a multicenter randomized controlled trial. The trial hypothesis is that TLPD has advantages in postoperative recoveries and be equivalent in operation time, oncological results compared with open pancreaticoduodenectomy. The trial was conducted after the completion of a structured training program for TLPD in China. The length of the learning curve was analyzed, taking the argument on timing. Based on the results for a retrospective study for the LPD in China, a minimum of 40 total LPD was decided to be a cut-off point [26]. When the surgeon finished the
104th LPD, the surgical technique would be regard as mature and stable. Thus, a minimum of 104
TLPD was decided to be the threshold to participate in the TJDBPS01 trial.
As mentioned before, this wasn’t the only RCT on this topic. Palanivelu et al published their RCT trial results in year 2017 [11]. They conducted a trial comparing LPD and OPD in treating periampullary tumors in a single tertiary-care teaching institute in India and come up with the conclusion that laparoscopy offered a shorter hospital stay than open pancreatoduodenectomy in their randomized trial. The trial recruited 64 patients in a two-year interval setting. This study demonstrated a significant advantage for the laparoscopic group in terms of shortened median duration of postoperative hospital stay, which was decreased by half compared with that of open surgery. Also, the laparoscopic approach was better regarding blood loss and transfusion requirements in their study, but the difference was less pronounced when procedures with venous resection were excluded. Other outcomes including complication rate, lymph node retrieval, R0 resection were comparable in two groups. They also reported that their study has limitations, including a relatively small sample size, which resulting in some outcomes were not assessed, such as recurrence and survival (disease-free and overall), and long-term complications. The same conclusion was supported by the Poves study [12]. Unlike the promising conclusions of the previous two studies, the first multicenter trial LEOPARD-2 demonstrated a concern of the safety on TLPD [13]. Their trial came up with a higher mortality rate in laparoscopic group and the authors stated that a small volume center and an early learning curve might have influenced the outcomes, although all enrolled surgeons were required to have completed training programs for
TLPDs. With all these pros and cons, it’s necessary and important to carry out a RCT in a multicenter setting with the premise that both safety and quality are well guaranteed.
In conclusion, the TJDBPS01 trial is a multicenter randomized controlled trial investigating the safety and the effectiveness of TLPD and OPD performed by surgeons who have performed ＞
104 TLPDs and OPDs respectively. This trial aims to evaluating the TLPD and OPD in daily practice within the high-volume pancreatic centers. When this trial is completed with the hypothesis confirmed, it will popularize the application of TLPD and improve the patient’s outcomes.
Declarations
Abbreviations
AFP: Alpha fetal protein; ASA: American Society of Anesthesiologists; CA: Carbohydrate antigen;
CBD Common bile duct; CEA: Carcino embryonie antigen; CHA Common hepatic artery; DGE:
Delayed gastric emptying; DPH Department of Public Health, Tongji Medical College, Huazhong
University of Science and Technology; ERAS: Enhanced recovery after surgery; EUS:
Endoluminal ultrasound; GB: Gall bladder; GDA: Gastroduodenal artery; ISGPS: International
Study Group of Pancreatic Surgery; IVC: Inferior vena cava; LPD: Laparoscopic pancreaticoduodenectomy; LRV: Left renal vein; MD: mean difference; MDT: Multi-disciplinary team; MIPD: Minimally invasive pancreaticoduodenectomy; OPD: Open pancreaticoduodenectomy; OR: odds ratio; PCA: Patient-controlled analgesia; PD:
Pancreatoduodenectomy; PDAC: Pancreatic ductal adenocarcinoma; PHA: Proper hepatic artery;
POD: Post-operative day; POPF: Postoperative pancreatic fistula; PV: Portal vein; RCT:
Randomized controlled trial; SF-36 Short Form 36 Health Survey; SMA: Superior mesenteric artery; SMV: Superior mesenteric vein; TLPD: Total laparoscopic pancreaticoduodenectomy;
Acknowledgements
We thank Prof. Jingdong Ma and Dr. Tingting Qin from the Department of Epidemiology and
Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, for the data monitoring and statistical support.
Authors’ contributions
Rufu Chen, Xuemin Chen, Wei Cheng, Dewei Li, Jingdong Li, Defei Hong, Xiaobing Huang,
Heguang Huang, Deyu Li, Jing Li, Jianhua Liu, Jun Liu, Yahui Liu, Zhijian Tan, Xinmin Yin,
Wenxing Zhao and Renyi Qin performed the operations. Hang Zhang, Junfang Zhao and Yechen
Feng collected and analyzed the data. Min Wang and Renyi Qin designed the study. All authors contribute in writing the manuscript and have read and approved the final version.
Ethics approval and consent to participate
Approval from Tongji Hospital Ethics Committee (TJ-IRB20180512) was received in May 2018.
All patients signed an informed consent document before entering the study. Consent was taken by the consultant or designated team member and was preserved by the data collection group. This study has gained ethical approval at both central and local levels central ethical approval has been confirmed from Tongji Hospital Ethics Committee (ref approval no. TJ-IRB20180512) and we will not begin recruiting at other centres in the trial until local ethical approval has been obtained.
Competing interests Hang Zhang declares no conflict of interest. Junfang Zhao declares no conflict of interest. Yechen Feng declares no conflict of interest. Rufu Chen declares no conflict of interest. Xuemin Chen declares no conflict of interest. Wei Cheng declares no conflict of interest.
Dewei Li declares no conflict of interest. Jingdong Li declares no conflict of interest. Xiaobing
Huang declares no conflict of interest. Heguang Huang declares no conflict of interest. Deyu Li declares no conflict of interest. Jing Li declares no conflict of interest. Jianhua Liu declares no conflict of interest. Jun Liu declares no conflict of interest. Yahui Liu declares no conflict of interest. Zhijian Tan declares no conflict of interest. Xinmin Yin declares no conflict of interest.
Wenxing Zhao declares no conflict of interest. Min Wang declares no conflict of interest. Renyi
Qin declares no conflict of interest.
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