Robot-assisted versus open pancreatoduodenectomy for cancer in the pancreatic head (DIPLOMA-2x2): study protocol for an international multicentre patient- and assessor-blinded randomized controlled non-inferiority trial

Background: Robot-assisted pancreatoduodenectomy (RPD) is increasingly performed for cancer in the pancreatic head. Randomised evidence confirming its oncological safety and efficacy is lacking. The DIPLOMA-2x2 trial aims to compare the oncological safety of RPD versus OPD in terms of radicality (microscopically radical resection [R0] resection). We hypothesise that RPD is non-inferior to OPD in terms of radicality and superior regarding time to functional recovery. Methods: The DIPLOMA-2x2 trial is an investigator-initiated, international, multicentre, patient- and assessor-blinded randomised non-inferiority trial. The trial was conducted as a roll-over of the DIPLOMA-2 trial and includes 20 high-volume tertiary referral hospitals in 7 countries. Minimum surgeon's experience is 60 RPD and 60 OPD, with a minimum annual centre volume of 30 RPD prior to trial initiation. Eligible patients are adults (≥18 years) with suspected or proven upfront resectable pancreatic ductal adenocarcinoma (PDAC) and distal cholangiocarcinoma (DCC) without any vascular involvement. Participants are randomised in a 2:1 ratio to RPD or OPD, respectively, stratified by tumour indication (proven PDAC versus other) and preoperative pancreatic fistula risk (high versus low). In total, 413 patients will be included, of which 137 previously randomised in DIPLOMA-2 and 276 newly recruited in DIPLOMA-2x2. Patients are blinded up to postoperative day 5. Primary outcome is pathological R0-resection rate (pR0; >1 mm tumour clearance at surgical resection margins and anatomical surfaces, 0 mm clearance at anterior surface), tested for non-inferiority with a -7% margin. Pathological assessment is blinded, and a randomly selected 10% of specimen will undergo central review. The key secondary outcome, tested for superiority, is time to functional recovery. Other secondary outcomes include lymph node retrieval, initiation/completion of adjuvant therapy, time to start of adjuvant therapy, disease-free and overall survival, quality of life, and cost-effectiveness. Safety outcomes include major complications (Clavien-Dindo grade ≥ III), serious adverse events, and 90-day mortality. Primary analyses will be based on the modified intention-to-treat principle, including all patients who underwent resection. Postoperative follow-up is up to 90 days for short-term outcomes and up to 60 months for survival. Discussion: The DIPLOMA-2x2 trial evaluates whether RPD is oncologically safe compared to OPD in patients with upfront resectable PDAC and DCC in experienced high-volume centres. Trial registration: ISRCTN27483786. Registered: January 11, 2021 (updated: February 6, 2025). First enrolment: January 3, 2021. Expected completion of enrolment: May 2026.