Laparoscopic Pancreaticoduodenectomy Versus Conventional Open Approach for Patients With Pancreatic Duct Adenocarcinoma: An Up-to-Date Systematic Review and Meta-Analysis

Background To compare perioperative and oncological outcomes of pancreatic duct adenocarcinoma (PDAC) after laparoscopic versus open pancreaticoduodenectomy (LPD vs. OPD), we performed a meta-analysis of currently available propensity score matching studies and large-scale retrospective cohorts to compare the safety and overall effect of LPD to OPD for patients with PDAC. Methods A meta-analysis was registered at PROSPERO and the registration number is CRD42021250395. PubMed, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched based on a defined search strategy to identify eligible studies before March 2021. Data on operative times, blood loss, 30-day mortality, reoperation, length of hospital stay (LOS), overall morbidity, Clavien–Dindo ≥3 complications, postoperative pancreatic fistula (POPF), blood transfusion, delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), and oncologic outcomes (R0 resection, lymph node dissection, overall survival, and long-term survival) were subjected to meta-analysis. Results Overall, we identified 10 retrospective studies enrolling a total of 11,535 patients (1,514 and 10,021 patients underwent LPD and OPD, respectively). The present meta-analysis showed that there were no significant differences in overall survival time, 1-year survival, 2-year survival, 30-day mortality, Clavien-Dindo ≥3 complications, POPF, DGE, PPH, and lymph node dissection between the LPD and OPD groups. Nevertheless, compared with the OPD group, LPD resulted in significantly higher rate of R0 resection (OR: 1.22; 95% CI 1.06–1.40; p = 0.005), longer operative time (WMD: 60.01 min; 95% CI 23.23–96.79; p = 0.001), lower Clavien–Dindo grade ≥III rate (p = 0.02), less blood loss (WMD: −96.49 ml; 95% CI −165.14 to −27.83; p = 0.006), lower overall morbidity rate (OR: 0.65; 95% CI 0.50 to 0.85; p = 0.002), shorter LOS (MD = −2.73; 95% CI −4.44 to −1.03; p = 0.002), higher 4-year survival time (p = 0.04), 5-year survival time (p = 0.001), and earlier time to starting adjuvant chemotherapy after surgery (OR: −10.86; 95% CI −19.42 to −2.30; p = 0.01). Conclusions LPD is a safe and feasible alternative to OPD for patients with PDAC, and compared with OPD, LPD seemed to provide a similar OS. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/#recordDetails.


INTRODUCTION
The incidence of pancreatic cancer (PC) has risen, and PC is likely to become the second most frequent cause of cancer-related death by 2030 (1). Moreover, pancreatic duct adenocarcinoma (PDAC) is the most common type of PC and the 14th most common cancer all over the world (2). Despite significant progress in adjuvant and neoadjuvant treatment options, pancreaticoduodenectomy (PD) has been shown to be the only effective and potentially curative treatment which can provide cure or prolonged survival for patients diagnosed to have PDAC. Due to the complexity of PD, it is often performed by laparotomy. But since Gagner and Pomp reported laparoscopic pancreaticoduodenectomy (LPD) in 1994 (3), LPD is increasingly used worldwide. Previous literature has confirmed the safety and feasibility of LPD and emphasized that it is superior to open pancreaticoduodenectomy (OPD) in reducing blood loss and involves shorter hospital stay, earlier oral intake, less pain, and faster recovery (4)(5)(6). Despite that there have been several other published meta-analyses assessing surgical and oncological outcomes between LPD and OPD in the past 3 years (7-9), the results of these studies are controversial. For this reason, which one is the better approach for PDAC, LPD or OPD, is unclear. We carried out an up-to-date meta-analysis to specifically study the perioperative, oncological outcomes and long-term survival of LPD versus OPD for PDAC.

Search Strategy and Study Selection
This study followed the PRISMA guidelines (10). Published studies which investigated LPD versus OPD for PDCA were systematically searched in PubMed, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases before March 22, 2021, by two independent researchers (QF, WL). The combinations of the following key terms and their combinations were used: laparoscopic, open, conventional, whipple, and pancreaticoduodenectomy. In order to gain additional studies, the references of eligible studies were manually searched.

Inclusion and Exclusion Criteria
Two investigators (QF, WL) reviewed currently available literature and screened all titles and abstracts independently and identified eligible studies according to the following criteria.
The inclusion criteria were as follows: 1) participants: patients with PDAC; 2) types of interventions: LPD and OPD; 3) types of studies: randomized controlled trials (RCTs), retrospective studies, cohort studies, and case-control studies; and 4) primary articles published in English.
The exclusion criteria were as follows: 1) non-English or experimental studies; 2) studies without available data; and 3) the publication type was editorial, abstract, letter, case report, and expert opinion.

Data Extraction and Quality Assessment
The original data from all candidate articles were independently assessed and extracted by two reviewers (QF, WL) by using a unified datasheet, and any ambiguity was resolved by a third researcher (ZX) who was consulted to review the study to reach a consensus. Data extracted included the following items: study and patient characteristics and operative and postoperative outcomes. Study and patient characteristics include first author, country, publication year, research design, sample size, and mean age; the latter included operative time, blood loss, blood transfusion, overall morbidity and 30-day mortality, length of hospital stay (LOS), R0 resections, number of harvested lymph nodes, overall survival (OS), postoperative long-term survival, and the time to starting postsurgical adjuvant chemotherapy. The quality of the included studies was assessed by the Newcastle-Ottawa Scale (NOS) (11). Every included study was independently evaluated by two authors (QF, WL), and NOS score ≥6 is considered as being of high quality.

Statistical Analysis
Review Manager 5.3 software was used to analyze the data. The weighted mean difference (WMD) with the 95% confidence interval (CI) and odds ratio (OR) were used to compare continuous variables and dichotomous, respectively. For overall survival data, the method of Tierney et al. was adopted to estimate natural logarithm hazard ratios (HRs), standard errors (SE), and 95% CIs from survival curves (12). We adopted the method described by Hozo et al. to convert medians with ranges into means with standard deviations (13). Begg's funnel plot and Egger's test were used to assess potential publication bias. Statistical heterogeneity was quantified using Higgin's I 2 index. A fixed-effects model (FEM) was adopted when heterogeneity is low or moderate (I 2 < 50%), while when heterogeneity is high (I 2 ≥ 50%), a random-effects model (REM) will be used.

Search Results and Characteristics of the Included Studies
A total of 1,147 relevant English publications from various electronic databases were obtained. Finally, according to the inclusion criteria, 10 retrospective studies (14-23) comparing LPD and OPD in a total of 11,535 patients (1,154 and 10,021 underwent LPD and OPD, respectively) were included for further analysis. A flow diagram of our analysis protocol is shown in Figure 1. The general information and NOS scores of all the included studies are listed in Table 1, while all results of this meta-analysis are presented in Table 2.

Time to Starting Adjuvant Chemotherapy After Surgery
The data of time to starting adjuvant chemotherapy after surgery were available in six studies (14,18,19,(21)(22)(23). The result of the meta-analysis revealed time to starting adjuvant chemotherapy after surgery was earlier in the LPD group (OR: −10.86; 95% CI −19.42 to −2.30; p = 0.01). Heterogeneity was high (I 2 = 97%) and analyzed in REM (Figure 8).

Publication Bias
Begg's funnel plot was drawn for each outcome and adopted to investigate publication bias. All studies lie inside the 95% CIs in the funnel plot of R0 rate and overall survival, which indicated no obvious publication bias (Figure 9). instruments and the accumulation of surgical experience, LPD has been proven to be safe and feasible and has many advantages over OPD, but the operation is more difficult and time-consuming (24,25). Owing to the complicated operation process and high requirements for surgeons, LPD is considered as the "Everest" of abdominal minimally invasive surgery. Many institutions choose to include patients with benign diseases when they carry out LPD in the initial stage. In order to compare the real difference between LPD and OPD in the treatment of PDAC, we analyzed the data from the literature that cases were pathologically diagnosed as PDAC. Finally, the present meta-analysis included the latest studies from 2014 to 2021 to compare the safety and efficacy of LPD and OPD for PDAC. Although none of the studies was RCTs, most of included studies were relatively high quality according to NOS. Finally, our study included 10 publications with 11,535 (LPD 1,514 vs. OPD 10,021) patients and reflects the newest surgical results for the treatment of PDAC. Three previous meta-analyses comparing perioperative and oncologic outcomes of LPD to OPD were published in the last 3 years. However, two of them (7,9) included an article about RPD in the treatment of PDAC. The study of Chen et al. (7) is the only meta-analysis that focuses on LPD and OPD. Six articles were included in the study of Chen et al. and focused on oncologic outcomes and long-term survival. They found that LPD was associated with longer 3-year survival, 4-year survival, and 5-year   time, fewer blood loss, lower transfusion rate, and shorter length of hospital stay. There were no significant differences in morbidity, POPF, DGE, the number of harvested lymph nodes, and mortality. Compared with the results of other studies, our study included some recent studies and excluded the study comparing RPD and OPD. The results of our meta-analysis showed LPD has a shorter LOS and less blood loss but no difference in blood transfusion. Why do we have different results for blood loss and the same blood transfusion rate in the two groups? It is because five studies with a total of 1,195 patients (14,15,18,22,23) had reported blood loss. Another five studies (14,18,20,22,23) with 1,260 patients reported blood transfusion, and heterogeneity was very high (I 2 = 81%), indicating that there is obvious publication bias. The results of our meta-analysis showed LPD has a longer operative time than OPD, which was similar with the study of Yin et al. The main factors that lead to the longer operation time of LPD are longer pancreatectomy and digestive tract reconstruction under a laparoscope.

DISCUSSION
The current meta-analysis shows non-significant difference in the 30-day mortality, overall complication rates, POPF, and the incidence of severe complications (Clavien-Dindo 3/4 grade complications) between the two groups, indicating that the safety of the two groups was similar. PPH is one of the most severe complications after pancreatic surgery. The meta-analysis of Floortje van Oosten et al. (26) showed that the incidence of PPH was about 5% after pancreatectomy, and the overall mortality caused by PPH accounted for 21%. Our metaanalysis shows that the rate of PPH was 6% (60/952 patients; range 4.1%-10.7%), and pooling the data of five studies (14,16,18,20,23) with 952 patients revealed no difference in PPH between the LPD and OPD groups.
Negative margin and the number of lymph node dissection are two important malignancy prognosis factors in PD. Pooled data from this meta-analysis revealed that LPD has a higher rate of R0 resection than OPD. We think that this may be explained by the fact that patients with PDAC in early stage were selected to perform LPD. From the perspective of tumor radical effect, the results of this study show that the two surgical methods have the same effect in the number of lymph node dissection, suggesting that LPD and OPD have the same tumor radical effect, which is basically consistent with the results of most existing clinical studies.
When it comes to long-term survival, according to our search, there are still no RCTs comparing the long-term survival between LPD to OPD in patients with PDAC. At present, the largest overall survival outcomes data of LPD in the treatment of PDAC come from the National Cancer Database (NCDB). Kantor et al. reported that 8,213 patients with PDAC underwent PD (828 underwent LPD and 7,385 underwent OPD) and revealed a non-significant difference in survival time in the two groups (20.7 vs. 20.9 months) (19). However, Chapman et al. compared the survival data of 1,768 patients with PDAC (248 underwent LPD and 1,520 underwent OPD) also from NCDB and suggested that LPD and OPD can achieve a median overall survival of 19.8 and 15.6 months, respectively (p = 0.022) (21). Although our meta-analysis revealed that the LPD group has an earlier time to get starting adjuvant chemotherapy after surgery, there is no significant difference in OS (HRs: 1.30; 95% CI 0.80 to 2.13; p = 0.41). In some ways, the pooled data demonstrated that LPD is not oncologically inferior to OPD and even can achieve superior oncologic outcome compared with OPD.
To evaluate the safety and efficiency of LPD for PDAC, this meta-analysis included 10 studies and revealed that LPD was comparable to OPD. But some limitations in this study should be considered. First, no RCTs were included which may contribute selection bias. Furthermore, of the 10 included studies, TNM stage, tumor size, and differentiation degree of patients with PDAC have not been reported in some studies. What is more, only a few studies reported long-term survival outcomes such as overall survival and 5-year survival time of LPD. Therefore, further large-scale prospective comparative studies and RCTs are expected to provide more convincing results to further assess the effectiveness and safety of LPD for patients with PDAC.

CONCLUSION
In summary, the present meta-analysis revealed that LPD is a technically and oncologically safe and feasible approach for PDAC patients and provided similar long-term overall survival time with OPD.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

AUTHOR CONTRIBUTIONS
Study concept and design (QF, KY), acquisition of data (All authors), analysis and interpretation of data (QF, ZX, WL), drafting of the manuscript (QF, JD, WL), critical revision of the manuscript for important intellectual content (KY), administrative, technical, or material support, study supervision (YZ). All authors contributed to the article and approved the submitted version.