Three dimension laparoscopic pancreaticoduodenectomy versus open pancreaticoduodenectomy.
A trial protocol of a randomized, multicentre trial.
ABSTRACT
Introduction: Pancreatoduodenectomy 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 comparisons between three dimension laparoscopic pancreaticoduodenectomy and the open pancreaticoduodenectomy, the real advantages of three dimension vision systems, the reproducibility of a total intracorporeal technique and the oncological results achievable during long-term follow-up after pancreaticoduodenectomy.
Methods/design: This is a prospective, randomized, controlled multicenter trial with two treatment arms, three dimension laparoscopic pancreaticoduodenectomy versus open pancreaticoduodenectomy. The trial hypothesis is that three dimension laparoscopic pancreaticoduodenectomy has advantages in postoperative recoveries and be equivalent in operation time, oncological results and long-term follow-up compared with open pancreaticoduodenectomy. The duration of the entire trial is two years including prearrangement, follow-up and analyses.
Discussion: Despite the fact more and more studies comparing laparoscopic pancreaticoduodenectomy and open approach. This trial will be the first multi-center RCT comparing three dimension laparoscopic pancreaticoduodenectomy and open pancreaticoduodenectomy.
Trial registration: NCT03138213
Keywords: pancreaticoduodenectomy; three dimension laparoscopic; open surgery,
INTRODUCTION
Background Pancreatic cancer constitutes a major health problem and is dreadful in many parts of the world.
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 pain in chronic pancreatitis [2].
Minimally invasive surgery (MIS) is progressively emerging in the management of pancreatic cancer through the development of new surgical devices and the advancement of surgical techniques.
Introduced by Gagner et al [3], 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.
To data, many studies confirmed the advantages of three dimensional laparoscopic in gastric, renal and cervical surgeries [4-6]. However, only few low quality studies reported the application of three dimensional laparoscopy in pancreas surgery, let alone PD.
In particular, recently performed meta-analyses have been poor due to the small number of studies of good quality [7-9]. Most of the analyses confused 3D LPD and 2D LPD and robotic pancreaticoduodenectomy (RPD) with the hybrid of them. The literature regarded all of them as
MIS.
However, several limitations must be highlighted 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.
Thus, this trial aimed to create the most extensive multi-center database, to date, of patients receiving PD using a 3D laparoscopic or open approach, involving institutions with experience in pancreas surgeries.
Rationale
The research areas in the context of involved instituitions are particularly directed towards evaluating the possible advantages of 3D LPD versus OPD in perioperative outcomes, postoperative outcomes and quality of life while respecting oncological principles.
Although there is growing attention concerning the role of LPD, the current level of evidence on this topic is of low quality. Only few retrospective analyses had been reported [10-12]. There was no even one RCT comparing LPD versus OPD, and no RCTs have been performed for 3D LPD surgeries.
LPD is regarded as a technically feasible procedure as described in many reports that have demonstrated its safety; however, different studies have reported differences related to the surgeon’s laparoscopic skills and experience, the hospital’s volume and the surgeon’s number of performed PD procedures.
Over the past decade, MIS has shown underlined advantages as the following. The most advantage is the faster and better recovery compared with open procedures, and the other advantages including the possibility of performing an extended lymphadenectomy as long as facilitating the performance of an intracorporeal anatomy and anastomosis. Current studies in the literature are inconsistent for these aspects.
The main problems found in clinical studies on laparoscopic versus open surgery for PD that should be overcome by a new study are as following:
1) In some comparative or retrospective studies, there is selection bias in matching the comparative groups. Even in the same trial group, differences that also could have been subjected to different extensive surgeries.
2) In some centers, the decision whether to receive laparoscopic versus open treatment is made by the patient after informed discussion about the different approaches, as the patient often incurs the extra expense for laparoscopic surgery.
3) Most studies do not clearly indicate the method of anastomotic technique such as intracorporeal versus extracorporeal reconstruction. The data are often mixed with either intracorporeal or extracorporeal anastomosis or even a lack of information on the anastomotic methods.
4) There are significant discrepancies between studies concerning the length of hospital stay and post-operative management of patients.
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. Therefore, a multicenter study is desirable. At present, a multicenter registry may represent the best research method to assess the role of
3D-TLPD approaches in periampullary cancer by comparing the methods to traditional open surgery.
Therefore, this project, a large registry will be created by collecting data from the different participating centers in China to create a working basis for analyzing outcomes of interest and obtaining directions for further investigation.
METHODS/DESIGNS
General study settings
The overall purpose of this study is to develop and maintain an ongoing comprehensive multi-institutional data-base comprising of information regarding surgical, clinical and oncological features of patients undergoing surgery for periampullary cancer with laparoscopic or open approaches and subsequent follow-ups.
Screening and identification of eligible patients will take place at the participating center’s pancreatic multidisciplinary team (MDT) meeting; all such sites are supra-regional referral centres for suspected pancreatic malignancy. All patients with suspected periampullary malignancy would undergo 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 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) Histologically proven periampullary cancer, including pancreatic cancer, bile duct cancer,
duodenal cancer, et al.
2) Highly presumed malignancy with difficulties to obtain histological evidence.
3) Preoperative staging work up performed by upper abdomen enhanced CT scan.
4) The subject understands the nature of this trial and willing to comply.
5) Ability to provide written informed consent.
6) 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.
3) Patients with high operative risk as defined by the American Society of Anesthesiologists
(ASA) score >4.
4) Synchronous malignancy in other organs.
5) Previous pancreatic resections. 6) Palliative surgery.
Research center criteria:
All centers and participating surgeons have expertise in performing PD at high volume; have confirmed experience with both 3D-TLPD and OPD.
Data collection
Patient demographics
Year of birth
Sex
Body mass index
Surgical risk (ASA score)
Comorbidities
Previous surgery history
Main complaint
Preoperative biliary drainage
Neoadjuvant chemotherapy (If any)
Neoadjuvant radiotherapy (If any)
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
Surgery
Operation date
Type of surgical approach (open, 3D-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
Intraoperative blood transfusion
Conversion to open surgery
Intraoperative complications
Intraoperative death
Extent of lymphadenectomy
Surgical margin status (R0 resection rates)
Number of retrieved lymph nodes Number of positive lymph nodes
Tumor
Tumor location
Size of the tumor
Depth of invasion (T classification)
Lymph node status (N classification)
AJCC pathological stage [16]
Histological type [17]
Postoperative clinical findings
Length of postoperative hospital stays
Postoperative blood transfusion
Patient mobilisation (post-operative day (POD) number)
Liquid diet (POD number)
Soft solid diet (POD number)
Drain removal (POD number)
Length of intravenous antibiotic use
Length of intravenous analgesic use
Cost for hospitalization
Cost for surgery
Postoperative daily clinical findings (POD numbers 1, 3, 5, 7)
Drain production and amylase
Haemoglobin levels
White cell count
G:L ratio
In-hospital postoperative complications
Type of complication
Reoperation for complication
Clavien-Dindo grade [18]
Early and late surgery-related complications after discharge
Date of occurrence
Type of complication
Death related to the complication
Need of readmission
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
Outcome measures
Primary outcomes
Safety and feasibility of 3D-TLPD procedures: Operation time, estimated blood loss, conversion rate, intraoperative blood transfusion.
Oncological outcomes: R0 resection rate, number of lymph node retrieved, surgical specimen margin, histopathological results.
Survival: overall survival and disease free survival achieved at 1 and 2 years from surgery. Also if possible, this data will be calculated for 5 years.
Secondary outcome measures
Recovery of gastrointestinal functions and physical status allowing the discharge of the patient: time to first flatus, time to start oral intake, length of stay and length of ICU stay.
Postoperative outcomes: mortalities, morbidities, rate of specific surgical complications (POPF,
DGE, hemorrhage, reoperation and et al.)
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 anesthesiological 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.
Postoperation 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) [19].
Delayed gastric emptying (DGE): Delayed gastric emptying was defined according to the definition provided by the International Study Group of Pancreatic Surgery (ISGPS) [20].
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
Operation time: The time was calculated from either skin incision or troca placement to the entire skin closure.
Estimated blood loss: The volume was recorded carefully by the anesthetist through a vacuum system, namely suction volume minus irrigation volume.
Type of the anastomosis 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[16].
Cost: The hospitalization cost as well as the surgery cost will be recorded.
Overall survival (OS) was defined as the time interval between the date of surgery and the date of death and was censored at the last follow-up date for patients who were alive.
Recurrence-free survival (RFS) was defined as the time interval between the date of surgery and the date of recurrence or death, whichever came first, and was censored at last follow-up date for patients who were alive without recurrence.
Statistical analysis Based on the data of the registry, every investigator can perform all the statistical analysis needs for research purposes, while a basic analysis for monitoring the study will be performed as follows.
SPSS v 19.0 will be used to carry out this statistical analysis. The dichotomous variables will be expressed as numbers and percentages, while continuous variables will be expressed as mean and
SD, or median and IQR (also minimum and maximum values). Continuous variables will be compared using one-way analysis of variance with post hoc multiple comparison by Tukey’s procedure. Pearson’s χ2 test or Fisher’s exact test, as appropriate, will be used for analysis of categorical data. For each of these tests a value of <0.05 will be considered statistically significant.
The study will be analyzed and reported following the CONSORT guidelines [22, 23]
Timeline and recruitment
Centers with proven track records will recruit into this trial. All local investigators have confirmed their expertise in both 3D-TLPD and open techniques are willing to randomize with clinical equipoise. Recruitment will run over 2 years with at least 2 year follow up.
Sample size
According to the number and volume of the participating centers and to reach a sample of 200 participants treated with 3D-laparoscopic surgery, is estimated that data of at least 400 patients need to be collected.
Publications Each participating center, with equal right, will be able to access the data of the registry, perform statistical analysis, discuss the results and freely write scientific manuscripts. However, each study that is generated based on the registry must be disseminated to all the centers before final publication.
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