Pancreaticoduodenectomy (PD) is the standard surgical treatment for pancreatic and periampullary tumors, which involves resection of the duodenum as well as with or without the distal stomach, the first portion of the jejunum, the pancreatic head, and common bile duct with the gallbladder (1). Owing to the complicated operation process and potentially lethal complications, PD should be performed by proficient surgeons in high-volume centers (2). Despite improved proficiency and technique, the perioperative mortality rate of PD remains up to 3% in highly specialized centers (3). PD remains the most difficult procedure of abdominal surgery and is associated with a high risk of morbidity and mortality (4).

The advantage of minimal invasiveness, reduced pain, and fast recovery from laparoscopic surgery has made it become the standard procedure in appendectomy and cholecystectomy (5, 6). With the accumulation of laparoscopic surgical experience and the development of surgical instruments, laparoscopic surgery has also been widely used in complex procedures such as gastrectomy, colectomy, and rectectomy, and it has been proven to be safe and feasible as compared with the open approach (7–9). During the past decades, there has been an increasing effort to perform more complex procedures like PD with a laparoscopic approach. However, a laparoscopic procedure in such complex conditions often arouses concerns with the difficult maneuvering of vascular structures, complicated digestive tract reconstruction, and prolonged operative time.

Laparoscopic pancreatoduodenectomy (LPD) was first reported in Canada in 1994 by Gagner et al., where it was performed with a pylorus-preserving procedure for a patient with chronic pancreatitis (10). In the initial stage, most surgeons choose to carry out LPD for patients with benign diseases. Due to improvements in surgical technique, LPD has been increasingly applied in the treatment of pancreatic and periampullary tumors, regardless of their benign or malignant nature (3). In recent years, a series of cohort studies have demonstrated the technical feasibility and safety of LPD for pancreatic and periampullary tumors (11, 12). However, the effects of LPD versus open pancreaticoduodenectomy (OPD) on morbidity, oncologic adequacy, and mortality are still controversial (13). Despite that there were several meta-analyses that assessed surgical and oncologic outcomes between LPD and OPD in the past 5 years (14–19), which included few articles and patients, and there had been conflicting pooled results. Some have included a few available randomized controlled trials (RCTs), which could not show any significant differences (14–16). Furthermore, some meta-analyses included studies that reported overlapped data from the same database during the crossed time period and therefore were prone to bias (17, 19–21). There is evidence that pooling of high-quality non-randomized comparative trials (NRCTs) is appropriate in a meta-analysis comparing surgical procedures, as existing RCTs are few, have a small sample size, and are underpowered (22).

This meta-analysis aims to assess the potential advantage of LPD compared with OPD for pancreatic and periampullary tumors using all the available high-quality published trials, RCTs and NRCTs, while focusing on perioperative outcomes such as mortality, morbidity, hospital stay, operative time, blood loss, transfusion, oncologic adequacy, reoperation, and readmission.

This meta-analysis followed the Cochrane Handbook for Systematic Reviews of Interventions, as well as Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (23, 24). This study was registered at PROSPERO (CRD42022338832).

This meta-analysis compared the perioperative outcomes of LPD to OPD based on both RCTs and NRCTs, which included 4,262 patients who have undergone LPD. To our knowledge, it is the largest meta-analysis to date comparing LPD and OPD for pancreatic and periampullary tumors. From the perspective of pooled analysis results, this study supports the ongoing trend of laparoscopic surgery to cure tumors of the pancreatic head and periampullary region. Our findings clearly demonstrate that LPD leads to lower overall postoperative complications, hospital stay, estimated blood loss, intraoperative blood transfusion, and DGE, and it improves R0 resection rate with similar retrieval of lymph nodes. Rates of postoperative mortality, serious postoperative complications, POPF, PPH, BL, reoperation, and unplanned readmission are comparable between LPD and OPD. However, the duration of surgery is longer for patients undergoing LPD.

Published meta-analyses that only included RCTs were incomplete, and data from a small volume of cases prevented a valid comparison between LPD and OPD. The recent meta-analyses included three RCTs that did not show any difference between LPD and OPD except for longer operative time and lower blood loss in LPD (14–16). However, these findings were limited due to the high risk of bias and low certainty of evidence. As the surgeons in three RCTs (35–37) might not have surmounted the learning curve for LPD, the non-significant results pooled from RCTs did not mean that the LPD had no advantage over OPD, and these results should be interpreted with caution. Moreover, no subgroup analysis was performed in any of these studies due to the small number of patients and events included. In our analysis, more cases from NRCTs were analyzed. Quality assessment of the included NRCTs was based on a validated tool developed for NRCT evaluation, as well as 24 of which had a high-quality score and constituted two-thirds of the included studies. In consistent with these RCT meta-analyses, our analysis also showed LPD reduced blood loss and prolonged operative time. Although there was high heterogeneity within included studies and among subgroup analyses, it suggested a consistent difference. In addition, lower intraoperative blood transfusion was found in this meta-analysis, which had significant differences in both the RCT and NRCT subgroups.

Recently, several meta-analyses have been conducted comparing LPD to OPD for pancreatic ductal adenocarcinoma (17–19). The studies of Sun et al. (17) and Feng et al. (19) showed a higher R0 rate in LPD, whereas Chen et al. (18) found no significant difference between the techniques. The meta-analysis of Sun et al. (17) showed lower intraoperative blood transfusion in LPD, whereas Feng et al. (19) showed no difference. The meta-analysis of Sun et al. (17) just showed shorter hospital stay in LPD, while Feng et al. (19) further demonstrated less overall morbidity, serious postoperative complications, and estimated blood loss in LPD. However, the meta-analysis of Sun et al. (17) included a study about robotic PD (RPD), whereas Chen et al. (18) did not include two eligible studies of Kantor et al. (32) and Delitto et al. (48) Furthermore, both meta-analyses of Sun et al. (17) and Feng et al. (19) included two studies of Kantor et al. (32) and Chapman et al. (30), which reported overlapped patient data from the NCDB. One recent network meta-analysis from Kamarajah et al. (20) compared open, laparoscopic, and robotic PD for periampullary cancers and showed similar mortality, serious complications, POPF, BL, and R0 resection between LPD and OPD, but shorter hospital stay and higher retrieval of lymph nodes in LPD. Another similar network meta-analysis from Aiolfi et al. (21) compared open, laparoscopic, and robotic PD in the setting of the malignant, borderline, or benign disease and also showed similar mortality, serious complications, POPF, lymph nodes retrieved, and R0 resection between LPD and OPD, but reduced hospital stay, estimated blood loss, overall postoperative complications, and readmission in LPD. However, the two network analyses included studies of Kantor et al. (32), Chapman et al. (30), and Sharpe et al. (31), which reported overlapped data from NCDB, as well as studies of Xourafas et al. (34) and Zimmerman et al. (33), which presented overlapped data from NSQIP. Overall, these previous meta-analyses showed inconstant results and suffered some degree of bias. Compared to these previous studies, our analyses excluded the possible overlapped patient data and conducted a comparison specifically for LPD and OPD. Furthermore, our study performed subgroup analysis in terms of all malignancies, benign and malignant, LPD cases of 50 or less, LPD cases of more than 50, baseline matching incomplete, and baseline matching complete, which might add precision to our comparison of LPD versus OPD.

Our meta-analyses support the notion that LPD is equally safe as the conventional open approach. There was no significant difference regarding the rate of postoperative mortality, serious postoperative complications, POPF, PPH, BL, reoperation, and unplanned readmission. Over the last decade, increasing improvements in equipment and surgical technique have extended indications of LPD (1, 2). Despite these advances, perioperative mortality remains up to 3% for LPD in high-volume centers (3, 4). The postoperative mortality rates of LPD and OPD for pancreatic and periampullary tumors in our meta-analysis were comparable (3.3% and 4.1%, respectively). With no significant difference, serious postoperative complication rates for LPD and OPD in our meta-analysis were 20.7% and 20.6%, respectively. Pancreas-specific complications such as POPF, PPH, and BL are common morbidity after pancreatic surgery, which accounted for the main cause of surgical mortality (72–74). Severe POPF, PPH, or BL is a dreaded adverse event that may cause metabolic disorders, peritonitis, intraperitoneal empyema or abscess, anemia, sepsis, shock, and sometimes reoperation, as well as leads to fasting accompanying intravenous nutrition and prolonged hospital stay (72–74). Almost all of the included studies defined these complications according to the International Study Group of Pancreatic Surgery (ISGPS) (72–74), most of which reported clinically relevant grades (grades B and C). Consistent with the results of most existing clinical studies (35–38), the analyses of these complications for LPD and OPD in our meta-analysis were comparable and had high homogeneity within included studies. Overall, LPD has been shown to be comparable to OPD in the safety related to the operation for the treatment of pancreatic and periampullary tumors.

One striking finding for our meta-analysis was decreased DGE in the LPD versus OPD. Although not imminently life-threatening, DGE remains the most common complication after PD, which causes significant discomfort and results in prolonged hospital stay (75). A review study assessed the average rate of clinically relevant DGE (grades B and C) after PD was 14.3% according to the ISGPS definition (76). Consistently, as most of the included studies reported clinically relevant DGE according to the ISGPS definition, DGE rates for LPD and OPD in our meta-analysis were 12.4% and 16.5%, respectively. The exact mechanisms of DGE are still unclear and are mostly multifactorial results involving vagal denervation. A recent retrospective study demonstrated that preservation of the hepatic branch of the vagus nerve could help reduce the incidence of DGE during LPD (77). These results are likely to be related to fine dissection and meticulous manipulation, as laparoscopic surgery offers a magnified view that facilitates precise identification of nerves and effective prevention of excessive nerve injury. A potential advantage of LPD is that reducing DGE incidence should be taken into account, and prospective studies are warranted to validate this effect in the future.

LPD is a more technically demanding and time-consuming procedure, which can be attributed to the challenging dissection of the pancreatic head and difficult reconstruction of the digestive tract by laparoscopic tools. Due to the complicated operation process, it is generally accepted that achieving a good level of surgical proficiency for LPD requires a long learning curve. Some studies have shown the number of cases required to surmount the learning curve ranged from 40 to 60 LPD cases (78). The included RCTs had reported their surgeons’ LPD experience when the trials started, which is all less than 40 LPD cases except for the RCT of Wang et al. (38) with at least 104 LPD cases. As is the case with all surgical studies, the surgeon’s technical proficiency plays an important role in the postoperative outcomes of LPD. Unfortunately, most included NRCTs did not explicitly describe their proficiency in LPD, which prevented subgroup analysis addressing relations between surgical proficiency and outcomes. Nevertheless, most of the included studies were carried out at large-volume hospitals, and therefore, LPD is likely not appropriate for low-volume hospitals (2, 4). We believe that LPD should only be implemented in high-volume centers by experienced specialists who have performed a sufficient amount of procedures and surmounted the learning curve for LPD.

With conducted analysis specifically for all malignancies, the comparable result of serious postoperative complications favored LPD. In addition, the pooled estimate showed a higher R0 rate for LPD. Given the higher surgical requirement for malignancy, surgeons’ selection bias could have influenced these results, and these results should be interpreted with caution. Surgeons might be more conservative and discreet to choose LPD for malignancy because lymphadenectomy and negative margin are indispensable for radical cure and can be more challenging during laparoscopic surgery; therefore, healthier patients with earlier tumor stage may have been chosen for LPD especially in the initial stage of performing LPD (34, 44, 48, 64, 79). The lower intraoperative blood transfusion rate became not significant in LPD when studies analyzed all malignancies, which could be attributed to the increased complexity of radical resection by the laparoscopic approach. As LPD for malignancy might attenuate the effect of lower blood loss and transfusion, surgical indication selection for LPD should be considered and explored in future studies.

The lower overall postoperative complications and intraoperative blood transfusion for LPD became not significant in the subgroup analysis of studies with no more than 50 LPD cases. Although the operative time was still longer for LPD than the open procedure, the subgroup analysis of studies with more than 50 LPD cases demonstrated a significant reduction of operative time in LPD compared to studies with no more than 50 LPD cases. Given the detection power of sample size, some studied outcomes such as postoperative morbidity, intraoperative blood transfusion, and operative time may also have been influenced by sample size issues (4, 14, 80). Although all RCTs explicitly described their calculation method for ascertaining sample size, the ascertained sample sizes had great discrepancy. The RCTs of Palanivelu et al. (35) and Poves et al. (36) calculated the sample size according to the primary outcome of hospital stay and indicated that only 32 patients were required in each group. However, Wang et al. (38) also calculated hospital stay and assessed that the minimum number of patients required in each group was 274. Furthermore, the RCT of van Hilst et al. (37) calculated a sample size of 68 patients for each group according to the time of postoperative functional recovery but was prematurely terminated with only 50 LPD cases. It was suggested that some of the current studies may be underpowered for comparing complex surgical procedures, and further trials with larger numbers of patients are indispensable to clarify surgical outcomes between LPD and OPD with adequate statistical power.

The improved overall postoperative complications and hospital stay were influenced by studies of baseline matching incomplete in subgroup analysis. We think outcomes such as hospital stay and overall complications are susceptible to bias, where comparable baseline characteristics and standard definitions are important for accurate comparison of surgical procedures. In addition, our analyses showed that serious postoperative complications were not reduced in the LPD group. Because the laparoscopic technique is less invasive, LPD might mainly decrease medical and minor surgical complications. This is not surprising because the reduced medical and minor surgical complications of the laparoscopic technique also could help to reduce hospital stay (27, 81). However, a more detailed analysis of postoperative complications was not performed due to lack of information. LPD could provide benefits in reducing medical and minor surgical complications and hospital stay; further studies designed to validate this phenomenon should match completely, unify perioperative management, and use standard outcome definition.

There were several limitations in this study. Significant heterogeneity was shown in some outcomes, which might be explained by differences in study design, sample size, surgeons’ proficiency, baseline characteristics, healthcare system, postoperative recovery protocol, and other factors. Variations in sample size among studies were large, and some studies enrolled patients during a wide study period, which may have introduced biases due to the advancement in mastering surgical skills and improvement in surgical instruments. Pilot studies that might be more prone to choose LPD for benign or low-grade malignant patients may also have introduced biases. All of the factors above might make the surgical results more susceptible to the methodological quality of clinical trials and lead to high heterogeneity among studies. The economical results and long-term oncologic outcomes are not evaluated in our study, as adequate data are missing at present. With the technological advances of computer vision and artificial intelligence playing a role in the improvement of LPD, whether these theoretical advantages could translate into improved patient outcomes, especially for a more complex condition such as malignancy, needs further studies (82, 83).

In conclusion, the results of our meta-analysis suggest that LPD is associated with non-inferior short-term surgical outcomes and oncologic adequacy compared to OPD when performed by experienced surgeons at high-volume centers. LPD may result in reduced overall postoperative morbidity, blood loss, intraoperative transfusion, and DGE, but prolonged operative time. In addition, recent studies have addressed the issue of surgical safety of LPD but may not have been sufficiently powered to evaluate the differences in postoperative complications between LPD and OPD. Further RCTs are required to investigate whether there are advantages of LPD for the management of pancreatic and periampullary tumors.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

Data acquisition: YY, YH, and YS. Manuscript drafting: YY, YH, and YS. Statistical analysis: YY, CC, and XZ. Manuscript revision: BW and YS. All authors contributed to the article and approved the submitted version.