PANENCA: Preventing postoperative complications in patients undergoing high-risk pancreatoduodenectomy with a bundle approach including hydrocortisone, octreotide, and the teres ligament patch: an international randomized controlled multicentre trial

Despite advances in perioperative care, pancreatoduodenectomy (PD) remains associated with substantial morbidity and mortality. The primary cause of both is postoperative pancreatic fistula (POPF), particularly in high-risk patients with a small (≤3 mm) main pancreatic duct and soft pancreatic texture. In this subgroup, the pancreato-enteric anastomosis is inherently vulnerable, increasing the risk of leakage and subsequent complications such as postpancreatectomy hemorrhage (PPH), sepsis, and multi-organ failure.

Over the past decade, several interventions have individually demonstrated efficacy in reducing POPF or its sequelae. However, despite being pragmatic and low-cost, these strategies have not reached consensus and are not widely implemented in international guidelines or routine clinical practice.

The PANENCA trial was designed to address this gap by evaluating a pragmatic bundle approach combining three promising interventions: hydrocortisone, octreotide, and a ligamentum teres patch (the HOP bundle). These interventions have expected complementary mechanisms of action without interaction. Hydrocortisone reduces the inflammatory response involved in fistula formation and has been associated with a significant reduction in major complications in a randomized trial; octreotide reduces pancreatic exocrine secretion, thereby limiting enzymatic damage; and the ligamentum teres patch provides mechanical protection of the gastroduodenal artery stump against enzymatic erosion in the event of a leak.

To date, no multicentre randomized controlled trial has evaluated this combination strategy. PANENCA aims to determine whether bundling these interventions reduces major postoperative complications in high-risk patients undergoing PD.

PANENCA is an international, multicentre, randomized controlled superiority trial.

Adult patients undergoing PD with a main pancreatic duct diameter of ≤3 mm on preoperative CT imaging, representing a well-defined high-risk population for clinically relevant POPF.

The HOP bundle consists of:

Standard of care

The primary endpoint is the rate of major postoperative complications, defined as Clavien–Dindo grade ≥III and/or the need for postoperative abdominal drain placement.

Key secondary endpoints include:

This is a pragmatic trial embedded in routine clinical care, with no additional diagnostics beyond standard perioperative protocols. Patients are followed from surgery through standard postoperative follow-up until postoperative day 90.

The planned sample size is 400 patients, powered to detect an absolute risk reduction of 14% in the primary endpoint. Randomization is performed 1:1 with stratification by centre and BMI (<30 vs ≥30).

The PANENCA trial addresses several key clinical questions:

Ultimately, the trial aims to generate robust evidence to establish consensus on the use of hydrocortisone, octreotide, and the ligamentum teres patch, inform international guidelines, and define a new standard of care for this high-risk population.

PANENCA is actively recruiting centres across Europe and beyond, and is currently conducted in more than eight countries, including the Netherlands, Ukraine, Sweden, Norway, Finland, Denmark, Belgium, and Italy. Centres performing PD are encouraged to participate in this collaborative effort.