Reduced Pancreatic Fistula Rate Following Pancreaticoduodenectomy: Trial on Pancreaticogastrostomy Versus Pancreaticojejunostomy
Condition: Tumors
MeSH terms: Pancreatic Fistula; Fistula
Study type: Interventional
Phase: Phase 3

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
    

Intervention name(s): Pancreaticojejunostomy; Pancreaticogastrostomy
Intervention type(s): Procedure; Procedure
Intervention description(s): Pancreaticojejunostomy (PJ) reconstruction/anastomosis; Pancreaticogastrostomy (PG) reconstruction/anastomosis
Allocation: Randomized
Primary purpose: Treatment
Keywords: pancreas; surgery; cancer; pancreaticoduodenectomy (PD); peri-ampullary tumours (ampulla, duodenum, distal bile duct, and miscellaneous tumours); pancreatic tumors; peri-ampullary tumors