Trial Information

Reduced Postoperative Pancreatic Fistula Rate Following Pancreaticoduodenectomy; Multicentric Randomized Controlled Trial on Pancreaticogastrostomy vs. Pancreaticojejunostomy

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