Clinical trial NCT00830778: Reduced Pancreatic Fistula Rate Following Pancreaticoduodenectomy: Trial on Pancreaticogastrostomy Versus Pancreaticojejunostomy
Official title: Reduced Postoperative Pancreatic Fistula Rate Following Pancreaticoduodenectomy; Multicentric Randomized Controlled Trial on Pancreaticogastrostomy vs. Pancreaticojejunostomy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tumors
Keywords: pancreas
surgery
cancer
pancreaticoduodenectomy (PD)
peri-ampullary tumours (ampulla, duodenum, distal bile duct, and miscellaneous tumours)
pancreatic tumors
peri-ampullary tumors
Lead sponsor: University Hospital, Gasthuisberg
Sponsor class: OTHER
Collaborators: name: Erasme ULB, Brussels
name: Jolimont, Brussels
name: St.Lucas, Brugge
name: General Hospital Groeninge
name: Université Catholique de Louvain
name: Clinique Saint Joseph, Liège
name: University Hospital, Antwerp
name: Jan Palfijn, Antwerp
name: AZ Sint-Lucas Brugge
name: Monica, Deurne
First posted: 2009-01-28
Enrollment: 336
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: The incidence of complications after pancreaticoduodenectomy (PD) is around 50 %. The postoperative course after PD is strongly dependent of the occurrence of pancreatic fistula (POPF), which determines postoperative mortality, length of hospital stay and costs. The incidence of POPF after PD is dependent of its definition, and is reported in up to 20% of patients.

There is disagreement on whether to perform a pancreaticojejunostomy (PJ) or a pancreaticogastrostomy (PG) after PD. The aim of the current randomized controlled trial is to study whether PG significantly reduces the rate of POPF following PD for pancreatic or peri-ampullary tumours. Secondary endpoints are the reduction of overall postoperative complication rate and their severity.

Detailed description: Therapeutic intervention

* Surgeons who have performed a minimum of five (5) PG and PJ procedures can include patients in this randomized trial.
* Any dissection device or technique is allowed.
* Pancreatic anastomosis (PG or PJ)

  * 1-layer or 2-layer anastomosis is allowed but has to be registered
  * mono-filament and/or poly-filament suture material is allowed but has to be registered
  * no pancreatic stent will be placed
* Drainage: one (1) or more closed drain(s) with or without suction is allowed in the vicinity of the pancreatic anastomosis
* Enteral tube feeding (tube positioned in the jejunum at the time of surgery, and distal to the pancreatic anastomosis) as well as total parenteral nutrition (TPN) is allowed
* Gastrostomy tube (percutaneous) is allowed
* Somatostatin: start intra-operatively and administered for seven (7) days after surgery at a dose of 6 mg/d
* Prophylactic use of antibiotics during 24h post-operatively
* Prophylactic use of Ranitidine as well as any PPI (proton pump inhibitor) is allowed to prevent peptic ulcer

Clinical evaluation and assessment criteria

* The number and type of POPF will be recorded according to the ISGPF guidelines and based on findings on day 3 (three) after surgery
* The number and type of postoperative complications will be recorded. The therapy-oriented severity grading system (TOSGS) of complications will be used and complications will be allocated to surgical (SSC) and non-surgical site (NSSC) complications
* The adequacy of the surgical resection margins (pR0) and the magnitude of the tumour-free resection margin (millimetres) will be monitored
* Postoperative length of hospital stay (LOS) will be registered

Patient randomization and registration procedure (randomization lists attached)

* This is a multicentric randomized controlled trial.
* Patient randomization will be done intra-operatively since a substantial number of patients could be dropped out intra-operatively because of the presence of unexpected intra-abdominal metastases at the time of surgery.
* Patient stratification will be performed for each centre and will be based on the diameter of the pancreatic duct. A pancreatic duct at the level of the surgical transsection margin measuring 3 millimetres or less in diameter is defined as being a "soft pancreas". A pancreatic duct measuring more than 3 millimetres is defined as a "hard pancreas".
* A prospective registration of following parameters will be performed: intra-operative diameter of the pancreatic duct at the surgical transection margin, diameter of the pancreas at the surgical transection margin, pancreatic tissue consistency assessed by the surgeon: soft vs. hard, post-operative pathology parameters.

Statistical analysis and sample size calculation based on a stratified design

* 40% of patients are expected to have a hard pancreas and 60% a soft pancreas.
* It is assumed that the magnitude of the effect of the intervention (PJ vs. PG) on the POPF rate, expressed as an odds ratio (OR), is similar in both strata.
* The needed sample size is calculated to have 80% power to detect a common odds ratio of 2.7. POPF rates of 12% and 20% are assumed after PJ within the hard and soft pancreas stratum respectively (yielding 4.8% and 8.4% after PG). Note that, given the unequal size strata, this leads to an expected POPF rate of 16.8% after PJ and 7% after PG (≈12% POPF overall).
* A 2-sided (with alpha=5%) Mantel-Haenszel test of OR=1 for stratified 2x2 tables is planned
* 168 patients are required per group (total patient population 336)
* Expected duration of recruitment: 3-4 years
* An interim analysis will be performed annually (i.e. after inclusion of 1/3 and 2/3 of the patients) to to allow early stop of the study (or accrual of patients in a specific treatment group) due to rejection of the null hypothesis. Using the O'Brien-Fleming method (O'Brien and Fleming 1979) results in respectively \|3.471\|, \|2.454\| and \|2.004\| as critical values for the Z-statistic at the three analysis moments. Otherwise stated, p-values are declared significant if \<.00052, \<0.0141 and \<0.0451 at respectively the first interim analysis, the second interim analysis and at the final analysis.
* Exact 95% confidence intervals will be calculated for the POPF and post-operative complication rates within each stratum. A stratified Mann-Whitney U test will be used for the TOSGS grading.

Translational research: optional Prognostic relevance of gene expression profiling in pancreatic cancer: analyses will be performed at UZ.Leuven/KU.Leuven (project coordinator B.Topal)

* Fresh tissue samples from pancreatic cancer and from non-tumoral pancreatic tissue will be stored in RNA-later (samples in 2 separate tubes; 5-10 volumes of RNA-later)
* Sample tubes will be transported (or picked up by the coördinator's research team), within 3 days from sampling, to be stored in -80°C for further analyses

Eligibility criteria: Inclusion Criteria:

* Patients, male or female, who undergo PD for a pancreatic or peri-ampullary tumor
* Age between 18 to 85 years
* Patients with and without pre-operative biliary drainage (for obstructive jaundice)
* Concomitant surgical procedures such as simultaneous colonic resection etc.
* Reconstruction of the portal vein or superior mesenteric vein

Exclusion Criteria:

* Age \< 18years
* Pregnancy
* Pre-operative radiotherapy
* PD for IPMT
* PD for chronic pancreatitis
* PD for pancreatic trauma
* PD for post-ERCP complications
* Any arterial reconstruction at the time of surgery

Primary outcomes:
measure: Reduction of clinical postoperative pancreatic fistula (POPF) rate
timeFrame: 3 years
Secondary outcomes:
measure: Reduction of overall postoperative pancreatic fistula rate
timeFrame: 3 years
measure: Reduction of the severity of postoperative complications
timeFrame: 3 years
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: University Hospital Gasthuisberg
Study officials:
affiliation: Universitaire Ziekenhuizen KU Leuven
name: Baki Topal, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hospital Jolimont, Brussels
name: Claude Bertrand, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Erasme (ULB), Brussels
name: Jean Closset, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: AZ. St.Lucas, Brugge
name: Henk Thieren, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: General Hospital Groeninge
name: Franky Vansteenkiste, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Université Catholique de Louvain
name: Jean-Francois Gigot, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: St.Joseph Hospital, Liège
name: Joseph Weerts, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Antwerp, Antwerp
name: Geert Roeyen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: J.Palfijn Hospital, Antwerp
name: Marc Janssens, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St.Jan Hospital, Brugge
name: Tom Feryn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Monica Hospital, Deurne
name: Steven Pauli, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Topal B, Fieuws S, Aerts R, Weerts J, Feryn T, Roeyen G, Bertrand C, Hubert C, Janssens M, Closset J; Belgian Section of Hepatobiliary and Pancreatic Surgery. Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy for pancreatic or periampullary tumours: a multicentre randomised trial. Lancet Oncol. 2013 Jun;14(7):655-62. doi: 10.1016/S1470-2045(13)70126-8. Epub 2013 May 2.
citation: Bertrand C, Squifflet JP, Gys T, Berrevoet F, Jehaes C, Lerut T, Malaise J, Topal B. The Society for Internet-based Scientific Studies: a new platform to promote multicentric studies in the Royal Belgian Society for Surgery. Acta Chir Belg. 2010 Jan-Feb;110(1):3-5. doi: 10.1080/00015458.2010.11680554. No abstract available.