Minimally invasive versus open distal pancreatectomy for pancreatic ductal adenocarcinoma (DIPLOMA): study protocol for a randomized controlled trial
Authors: van Hilst Jony , Korrel Maarten , Lof Sanne , de Rooij Thijs , Vissers Frederique , Al-Sarireh Bilal , Alseidi Adnan , Bateman Adrian C. , Björnsson Bergthor , Boggi Ugo , Bratlie Svein Olav , Busch Olivier , Butturini Giovanni , Casadei Riccardo , Dijk Frederike , Dokmak Safi , Edwin Bjorn , van Eijck Casper , Esposito Alessandro , Fabre Jean-Michel , Falconi Massimo , Ferrari Giovanni , Fuks David , Groot Koerkamp Bas , Hackert Thilo , Keck Tobias , Khatkov Igor , de Kleine Ruben , Kokkola Arto , Kooby David A. , Lips Daan , Luyer Misha , Marudanayagam Ravi , Menon Krishna , Molenaar Quintus , de Pastena Matteo , Pietrabissa Andrea , Rajak Rushda , Rosso Edoardo , Sanchez Velazquez Patricia , Saint Marc Olivier , Shah Mihir , Soonawalla Zahir , Tomazic Ales , Verbeke Caroline , Verheij Joanne , White Steven , Wilmink Hanneke W. , Zerbi Alessandro , Dijkgraaf Marcel G. , Besselink Marc G. , Abu Hilal Mohammad ,   for the European Consortium on Minimally Invasive Pancreatic Surgery (E-MIPS)
Published: September 2021

Abstract
Background
Recently, the first randomized trials comparing minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for non-malignant and malignant disease showed a 2-day reduction in time to functional recovery after MIDP. However, for pancreatic ductal adenocarcinoma (PDAC), concerns have been raised regarding the oncologic safety (i.e., radical resection, lymph node retrieval, and survival) of MIDP, as compared to ODP. Therefore, a randomized controlled trial comparing MIDP and ODP in PDAC regarding oncological safety is warranted. We hypothesize that the microscopically radical resection (R0) rate is non-inferior for MIDP, as compared to ODP.

Methods/design
DIPLOMA is an international randomized controlled, patient- and pathologist-blinded, non-inferiority trial performed in 38 pancreatic centers in Europe and the USA. A total of 258 patients with an indication for elective distal pancreatectomy with splenectomy because of proven or highly suspected PDAC of the pancreatic body or tail will be randomly allocated to MIDP (laparoscopic or robot-assisted) or ODP in a 1:1 ratio. The primary outcome is the microscopically radical resection margin (R0, distance tumor to pancreatic transection and posterior margin ≥ 1 mm), which is assessed using a standardized histopathology assessment protocol. The sample size is calculated with the following assumptions: 5% one-sided significance level (α), 80% power (1-β), expected R0 rate in the open group of 58%, expected R0 resection rate in the minimally invasive group of 67%, and a non-inferiority margin of 7%. Secondary outcomes include time to functional recovery, operative outcomes (e.g., blood loss, operative time, and conversion to open surgery), other histopathology findings (e.g., lymph node retrieval, perineural- and lymphovascular invasion), postoperative outcomes (e.g., clinically relevant complications, hospital stay, and administration of adjuvant treatment), time and site of disease recurrence, survival, quality of life, and costs. Follow-up will be performed at the outpatient clinic after 6, 12, 18, 24, and 36 months postoperatively.

Discussion
The DIPLOMA trial is designed to investigate the non-inferiority of MIDP versus ODP regarding the microscopically radical resection rate of PDAC in an international setting.

Trial registration
ISRCTN registry ISRCTN44897265. Prospectively registered on 16 April 2018.