Several systematic reviews and meta-analyses of single-center retrospective studies have demonstrated the benefits of minimally invasive distal pancreatic resection over open surgery [3, 13, 14]. These benefits include a shorter hospital stay and reduced blood loss. Currently, three randomized controlled trials have been published comparing MI-DP to ODP (Table 1).

The LEOPARD trial published in 2019 is a large multicentric RCT that supported the findings from non-randomized single-center experiences. In this multicenter patient-blinded randomized controlled trial, MI-DP was compared to ODP. In summary, 108 patients from 14 centers with all kinds of pancreatic tumors (benign, premalignant, malignant) were included. The authors demonstrated faster functional recovery by 2 days (4 days [interquartile range (IQR) 3–6] vs. 6 days [IQR 5–8]; p < 0.001), less operative blood loss (150 ml vs. 400 ml; p < 0.001), and less serious delayed gastric emptying (DGE; grade B/C 6% vs. 20%; p = 0.04), but longer operative times (217 min [IQR 135–277] vs. 179 min [IQR 129–231]; p = 0.005) in the MI-DP group. The quality of life (QoL) within the first 3–30 days was better in the MI-DP group. There was no evaluation of oncological parameters like overall survival (OS) and disease-free survival (DFS), or of pathological parameters like resection margin (R) und lymph node harvest [15].

In a randomized single-center study by Björnsson et al., the duration of hospital stay after MI-DP and ODP was evaluated. This trial confirmed the findings of the other studies, with a shorter hospital stay after MI-DP (5 days [IQR 4–5] vs. 6 days [IQR 2–6]; p = 0.002). Oncological parameters (OS and DFS) and pathological parameters (R and lymph nodes) were also not sufficiently investigated this trial [16]. In 2021, Korrel et al. published the long-term data from the LEOPARD trial again with a focus on QoL of the patients. Interestingly, the authors could demonstrate that there were no significant differences in QoL between the groups in the long run. On closer evaluation, it seemed that the effect of MI-DP on QoL dissolves at day 30. Only the cosmetic satisfaction was higher in the MI-DP group [17].

Sulpice et al. conducted a study using French healthcare databases in 2015 and found that only a small percentage (12.6%) of PDAC patients underwent minimally invasive surgery [18]. These findings were further supported by a propensity score-matched analysis of the German Pancreas Register by Wellner et al., who found that in Germany, only 13% of PDAC patients underwent MI-DP [19].

A large meta-analysis and review of five case–control studies by Ricci et al. comprising 261 patients compared MI-DP to ODP for PDAC and found no significant differences in terms of R0 resection rates, harvested lymph nodes, overall morbidity, and eligibility for adjuvant treatment. Furthermore, the study confirmed the previously reported benefits of MI-DP, such as shorter hospital stay and less blood loss [20]. To evaluate the effectiveness of MI-DP for PDAC treatment, a subsequent Cochrane Review was conducted. This review included 11 non-randomized studies with a total of 1506 patients, all of which were retrospective cohort-like or case–control studies. The Cochrane Group found no statistically significant differences in terms of short- and long-term mortality, serious adverse events, pancreatic fistula (POPF), recurrence at maximal follow-up, or positive resection margins. Mean length of hospital stay was reduced by 2.4 days in the laparoscopic group. However, the overall quality of evidence was very low because of the high number of observational studies in the collective and the consequently high risk of confounding bias [7].

The most current landmark study for evaluation of minimally invasive distal pancreatic resection in comparison to open resection is the DIPLOMA trial. This pan-European study compared MI-DP to ODP for PDAC using propensity score matching and involved 1212 patients from 34 centers in 11 countries. After matching, 340 patients underwent MI-DP, and 340 patients underwent ODP. The results of the study showed that both procedures had similar overall survival rates, but MI-DP had the advantage of less blood loss (200 ml vs. 300 ml; p = 0.001) and a shorter hospital stay (8 days vs. 9 days; p < 0.001). The pathological outcomes, however, showed higher R0 resection rates (67% vs. 58%; p = 0.019) for the MI-DP group. The authors also found that the MI-DP group had fewer harvested lymph nodes (14 vs. 22; p < 0.001) and less frequent resection of Gerota’s fascia compared to ODP [21]. Long-term results and survival data are pending.

Currently, two meta-analyses have been published comparing robotic distal pancreatic resection (RDP) with LDP for PDAC. The first metanalysis included six retrospective studies out of which five were single-center studies and one was a multicenter study. A total of 572 patients (152 RDP, 420 LDP) were analyzed. In summary, the results indicated that the RDP group exhibited higher R0 resection rates compared to the LDP group (OR: 2.96; 95% CI 1.78–4.93; I2 = 36%; p < 0.00001). However, there were no significant differences between the two groups in terms of operative time, tumor size, and harvested lymph nodes [22].

A recent international study conducted by members of the E‑MIPS compared 542 patients (103 RDP, 439 LDP) from 33 centers in 11 countries. They found that RDP and LDP had comparable R0 resection rates (75.7% vs. 69.3%; p = 0.404). However, RDP was associated with a longer operative time (290 vs. 240 min; p < 0.001) more vascular resections (7.6% vs. 2.7%; p = 0.030), a lower conversion rate (4.9% vs. 17.3%; p = 0.001), more major complications (26.2% vs. 16.3%; p = 0.019), improved lymph node yield (18 vs. 16; p = 0.021), and longer hospital stay (10 vs. 8 days; p = 0.001) than LDP [23].

Several studies have shown that expert surgeons can successfully and safely perform the technically demanding MI-PD procedure (feasibility) [24,25,26,27,28,29,30]. Currently, there are many ongoing randomized controlled studies comparing MI-PD with OPD (see Table 2). In a comprehensive meta-analysis of 19 comparative studies and two register studies with a total of 19,996 patients, the E‑MIPS consortium found that MI-PD resulted in shorter hospital stays, less blood loss, and delayed gastric emptying (DGE) compared to OPD. However, the quality of the included cohort studies was low, which introduces potential biases [6]. Currently, five randomized controlled trials evaluating laparoscopic pancreatoduodenectomy have been published on the topic (Table 1; [31,32,33,34,35]). The second study conducted by van Hilst, which investigated the inflammatory response after LPD and OPD, is a sidearm study of the LEOPARD-2 patient cohort and was therefore excluded from most subsequent meta-analysis [33].

The first randomized clinical trial from Palanivelu was published in 2017 (PLOT trial). The PLOT trial was a single-center study which compared LPD to OPD. In total, 64 patients were randomized, 32 to each group. Only patients with resectable periampullary (cholangiocarcinoma, duodenal, ampullary, and pancreatic head cancer) were included. All procedures were performed by only two very experienced surgeons with more than 25 minimally invasive procedures. The follow-up was 90 days. The trial showed a shorter hospital stay (7 days vs. 13 days; p = 0.001), less blood loss (250 ml vs. 401 ml; p < 0.001), and less blood transfusion (3 vs. 7; p = 0.034) for the LPD procedure. Postoperative complications were comparable for both procedures except for fewer surgical site infections in the LPD group (12.5% vs. 25%; p = 0.015). Histopathological analysis showed comparable results for resection margins, number of harvested lymph nodes, and tumor size, but the LPD group had a lower incidence of perineural invasion (19% versus 28%; p = 0.002) [31].

Poves et al. conducted the second RCT, which was published in 2018. This trial, the PADULAP study, was also a prospective single-center RCT that compared the perioperative outcomes of LPD to OPD for patients with various histologies, including benign, premalignant, and malignant disease. The LPD procedures were performed by only one single expert surgeon. The primary endpoint of this study was the length of hospital stay (LOS). A total of 66 patients were included in the study, with 34 in the LPD group and 32 in the OPD group. The study found no statistically significant differences between the two groups in terms of pathological findings such as resection margin, number of lymph nodes, tumor size, grade of differentiation, perineural invasion, and lymphovascular invasion. The majority of patients in both groups had a malignant diagnosis, with 75% in the LPD group and 86.2% in the OPD group, although this difference was not statistically significant (p = 0.88). Regarding the primary endpoint, LPD showed a shorter LOS compared to OPD (13.5 days vs. 17 days; p = 0.024). In addition, LPD demonstrated benefits in terms of fewer severe postoperative complications compared to OPD (Clavien-Dindo classification [CDC] grade 3–5: 15.6% vs. 37.9%; p = 0.048). Pancreas-specific complications, including pancreatic fistula (POPF), delayed gastric emptying (DGE), and postpancreatectomy hemorrhage (PPH) were not significantly different. Consistent with other studies, the LPD group had a significantly longer operative time compared to the OPD group (460 min vs. 365 min; p = 0.000) [32].

Van Hilst et al. in 2019 performed the first multicentric randomized controlled trial (LEOPARD-2) that was defined to evaluate levels of inflammatory cytokines after open or laparoscopic PD. The LEOPARD-2 trial was performed in four centers in the Netherlands that each performed a total 20 or more PDs annually. All participating surgeons had performed more than 50 advanced laparoscopic gastrointestinal procedures, including a dedicated training program for laparoscopic distal and pancreatic head resection (LAELAPS). Prior to inclusion, the surgeon had to have performed 20 or more LPDs. This trial was designed as a phase 2/3 study. For the phase 2 component the primary outcome was cytokine IL‑6 levels after surgery. The primary outcome of the phase 3 component was time to functional recovery, defined as a composite endpoint of adequate pain control (only oral analgetic), independent mobility, daily oral food intake greater than 50% of required daily calories, no fluid administration, and no signs of infection. The follow-up was 90 days. The trial enrolled a total of 105 patients, including 42 in phase 2 and 63 in phase 3, with 54 patients undergoing LPD and 51 undergoing OPD. 15% (3 of 20) of the patients in the LPD group died within 90 days in phase 2, while none of the patients in the OPD group died. Discussion of these discrepancies in the safety and monitoring board still led to a continuation of the study to phase 3. Due to a higher mortality rate within 90 days in the laparoscopic group (mortality LPD: 5/50; 10%) compared to the open group (mortality OPD: 1/49; 2%) and a risk ratio of 4.90 (95% CI 0.59–40.44; p = 0.20), the trial was recommended for premature termination by the data and safety monitoring board. The evaluation of the available data indicated no significant difference between the LPD and OPD groups in terms of histopathological results such as resection margin and number of lymph nodes. It is worth noting, however, that the proportion of resected PDAC was 28% in the LPD group and 31% in the OPD group.

In 2021, Wang et al. published the latest and second multicenter randomized controlled trial, which compared LPD and OPD across 14 Chinese pancreatic centers for periampullary tumor entities (including malignant, premalignant, and benign cases). This study involved highly experienced surgeons with a minimum of 104 LPDs performed. The primary outcome was LOS. A total of 656 patients were randomized, with 328 patients in each group. The LPD group had a significantly shorter LOS than the OPD group by one day (15 days vs. 16 days; p = 0.02). There were no significant differences between the two groups in terms of 90-day mortality, morbidity, and pancreas-specific complications.