Safety and Efficacy for Robot-Assisted Versus Open Pancreaticoduodenectomy: A Meta-Analysis of Multiple Worldwide Centers


 Objectives: To compare the efficacy of robot-assisted pancreaticoduodenectomy with that of laparotomy.Methods: The PubMed, EMBASE, Cochrane Library, and other databases were searched for literature available from their respective inception dates up to May 2020 to find studies comparing robot-assisted pancreaticoduodenectomy (RPD) with open pancreaticoduodenectomy (OPD). The RevMan 5.3 statistical software was used for analysis to evaluate surgical outcome and oncology safety. The combination ratio (RR) and weighted mean difference (WMD) and their 95% confidence intervals (CIs) were calculated using fixed effect or random effect models.Results: 18 cohort studies from 16 medical centers were eligible with a total of 5795 patients including 1420 RPD group patients and 4375 OPD group patients. The RPD group fared better than the OPD group in terms of estimated blood loss (EBL) (WMD =-175.65, 95% CI (-251.85, -99.44), P<0.00001), wound infection rate (RR=0.60, 95%CI (0.44,0.81), P= 0.001), reoperation rate (RR=0.61, 95%CI (0.41,0.91), P=0.02), hospital day (WMD = -2.95, 95% CI (-5.33,-0.56), P = 0.02), intraoperative blood transfusion (RR = 0.56, 95% CI(0.42, 0.76), P=0.0001), overall complication (RR = 0.78, 95% CI(0.64,0.95), P = 0.01), and clinical pancreatic fistula (PF) (RR = 0.54, 95% CI(0.41,0.70), P < 0.0001). In terms of lymph node clearance (WMD = 0.48, 95% CI(-2.05,3.02), P = 0.71), R0 rate (RR = 1.05, 95% CI(1.00,1.11), P = 0.05), postoperative pancreatic fistula (POPF) (RR=1, 95% CI(0.85,1.19), P = 0.97), bile leakage (RR = 0.99, 95% CI(0.54,1.83), P = 0.98), delayed gastric emptying (DGE) (RR = 0.79, 95% CI(0.60,1.03), P = 0.08), mortality (RR = 0.82, 95% CI(0.62,1.10), P=0.19), and severe complication (RR = 0.98, 95% CI(0.71,1.36), P = 0.91), there were no significant differences between the two groups. Laparoscopic surgery was inferior to open surgery in terms of operational time (WMD = 80.85, 95% CI (16.09,145.61), P=0.01).Conclusions: RPD is not inferior to OPD, and it is even more advantageous for DGE, wound infection rate, reoperation rate, hospital stay, transfusion, overall complication and clinical PF. However, these findings need to be further verified by high-quality randomized controlled trials.


Introduction
Pancreaticoduodenectomy is a method used to treat pancreatic head tumors, periampullary tumors, chronic pancreatitis with biliary stricture, and other diseases. Pancreaticoduodenectomy is one of the most complicated operations in abdominal surgery and is characterized by marked trauma and a high incidence of complications. In 2003, Giulianotti et al. [1] rst reported Da Vinci-assisted robotic pancreaticoduodenectomy (RPD). The Da Vinci robot has the following advantages: (1) the operation eld of vision can be magni ed up to 10 ×, providing a naked-eye, 3D, high-resolution image for the operator; (2) the end of the device simulates the wrist: it is exible and controllable, the movement can be scaled reasonably, and it can accurately complete various operations and eliminate shaking. These advantages are incomparable to those of traditional laparotomy and robotic surgery. However, the feasibility, safety, and effectiveness of this robot method have not been fully determined. In the past 10 years, many retrospective studies have reported the e cacy of both approaches in PD. Therefore, we conducted this meta-analysis to evaluate the e cacy of robot-assisted PD and open PD in the treatment of pancreatic diseases. Data And Methods

Retrieval strategy
We searched the PubMed, MEDLINE, Cochrane Library, and other databases by computer, and limited the search deadline to May 2020. The search terms used were ((open) OR laparotomy) AND ((pancreaticoduodenectomy) OR pancreatectomy) AND ((robotic) OR robot-assisted). The semi-quantitative star system was adopted for evaluation of document quality by NOS, with a full score being 9 stars. The details were attached to the Appendix le 1.

Statistical Analyses
The Review Manager 5.3 software was used for meta-analysis. For binary data, relative risk (RR) was used, and for continuous data, the weighted mean difference (WMD) and its 95% con dence interval (CI) were used to represent the combined statistics. Heterogeneity among the included studies was qualitatively evaluated using a χ2-based Q test. P values less than 0.05 showed statistically signi cant heterogeneity across the studies. The level of heterogeneity among studies was evaluated using I 2 statistics. I 2 < 30% was considered to indicate low heterogeneity; for these studies, a xed-effects model was applied. Moreover, 30% ≤ I 2 ≤ 60% was considered to indicate moderate heterogeneity, and I 2 > 60% represented high heterogeneity. A random-effects model was applied when I 2 ≥ 30%. Sensitivity analysis was performed by removing 1 study at a time to assess whether the results could have been markedly affected by any single study. The results with less heterogeneity between the studies were selected if results were reversed after sensitivity analysis. Deleted literatures were described in the results section. Funnel plot was used to qualitatively evaluate publication bias. (Appendix le 2) Stata software (version SE15.0) was used to calculate Begg's test and Egger's test for quantitative evaluation of publication bias of the included studies, with the signi cant level limited to 0.05. The details were attached to the Appendix le 3.

Literature search results
A total of 25 articles  were retrieved, of which 18 articles [2, 4-8, 10, 12-15, 17-20, 22, 23, 25] were included in the analysis. The ow chart of the literature screening is shown in Fig. 1. There were 11 cohort studies from prospective databases and 7 cohort studies from retrospective databases. A total of 5795 patients were included in the 18 articles, comprising 1420 patients in the RPD group and 4375 cases in the OPD group. Table 3 shows the basic characteristics and quality evaluation of the included documents. In this study, 15 postoperative e cacy outcomes of RPD and OPD were analyzed, and sensitivity analysis was performed for each outcome. The outcomes as shown in Table 1. Subgroup analysis was conducted according to whether studies were prospective, retrospective, or propensity score matching (PSM) cohort, as shown in Table 2.
Using a random-effects model, the combined RR was 0.56, 95%CI (0.42, 0.76), P = 0.0001, and the rate of transfusion in the RPD group was signi cantly lower than that in the OPD group. After sensitivity analysis, the meta-results did not show any reversal changes. However, when Cai et al. [14] was eliminated, the heterogeneity was signi cantly reduced (I 2 = 0%, P = 0.43), the xed-effects model yielded an RR of 0.65, 95%CI (0.50, 0.86), P = 0.002, and the statistically signi cant difference remained. In both retrospective and prospective cohort studies, there was a statistically signi cant difference in the number of transfusion between the RPD group and the OPD group (RR = 0.69, 95% CI: 0.48, 0.99, P = 0.04; RR = 0.48, 95% CI: 0.31, 0.75, P = 0.001, respectively) (Figs. 2C).
After sensitivity analysis, the meta-analysis results show reversal changes. When studies by McMillan et al. [19] was sequentially eliminated, the heterogeneity was signi cantly reduced (I 2 = 33%, P = 0.14). The combined RR of the random effect model was 0.78, 95%CI (0.64,0.95), P = 0.01, and there was statistically signi cant difference. Subgroup analysis showed that, in the retrospective, prospective and PSM cohort study, there was no statistically signi cant difference between the RPD group and OPD group (Fig. 3C).

Bile leakage rate
Six studies [6,12,13,17,18,22] reported the bile leakage rate. There was a low degree of heterogeneity (I 2 = 0%, P = 0.6) among the studies. Using a xed-effects model, the combined RR was 0.99, 95%CI (0.54, 1.83), P = 0.98. There was no statistically signi cant difference between the RPD and OPD groups. Subgroup analysis showed that there was no signi cant difference in bile leakage rate between the RPD group and OPD group in the prospective and retrospective cohort studies. (Appendix le 4A)
Using the xed-effects model, the combined RR was 0.98, 95% CI: 0.60, 1.03, P = 0.08), and the difference was not statistically signi cant. Subgroup analysis showed that there was no signi cant difference in the incidence of DGE between the RPD group and OPD group for prospective or PSM studies (RR = 1.07, 95% CI: 0.49,2.37, P = 0.86; and RR = 0.72, 95% CI: 0.31, 1.65, P = 0.44, respectively). However, DGE in the RPD group was signi cantly lower than that in the OPD group among the eight prospective cohort studies. (Appendix le 4B)
Using the xed-effects model, the combined RR was 0.98, 95%CI (0.71,1.36), P = 0.91, with no statistically signi cant difference. After sensitivity analysis, the meta-analysis showed no reversal changes. Subgroup analysis showed that there was no signi cant difference between the RPD group and OPD group in either prospective, retrospective or PSM cohort studies. (Appendix le 4C)

Incidence of clinical PF
Eight studies [7, 10, 12-15, 18, 19, 22] reported the incidence of clinical PF. There was moderate heterogeneity (I 2 = 58%, P = 0.58) among the studies. Using a xed-effects model, the combined RR was 0.54, 95%CI (0.41, 0.70), P < 0.0001). Subgroup analysis showed that the incidence of PF in the RPD group was lower than that in the OPD group in prospective,

Incidence of POPF
Fifteen studies [2-7, 9-15, 17, 18] reported the incidence of POPF. There was moderate heterogeneity (I 2 = 0%, P = 0.75) among the studies. Using the xed-effect model, the combined RR was 1.00, 95%CI (0.85,1.19), P = 0.97, and there was no statistically signi cant difference. Subgroup analysis showed that there was no signi cant difference in POPF between the RPD group and the OPD group in the prospective, retrospective and PSM studies, respectively (Appendix le 5A).

Sensitivity analysis and bias risk assessment
Sensitivity analysis was carried out in each meta-analysis. The heterogeneity of operation time, estimated blood loss, intraoperative blood transfusion, lymph node dissection, and hospital day was large. After the relevant literature was removed, the heterogeneity was signi cantly reduced, but the results were not reversed. After the relevant literature was removed, the heterogeneity of overall complication is reduced, but the result reversed. The sensitivity analysis showed that other results were not reversed after sequential removal of each study. The funnel plots of the publications were found to be symmetrical, which suggested no publication bias. No publication bias was detected by Begg's test and Egger's test, except for the hospital day in the Egger's test (Appendix le 3).

Discussion
Pancreaticoduodenectomy was rst reported by Whipple et al. in 1935 [27] Traditional pancreaticoduodenectomy is considered to be the most The results of this meta-analysis showed that RPD was signi cantly better than open surgery in the estimated blood loss, wound infection rate, reoperation rate, postoperative hospital stay, transfusion, overall complication and clinical PF. Additionally, no signi cantly different were found in the lymph node dissection, R0 rate of cutting edge, bile leakage rate, delayed gastric emptying, postoperative mortality, FOPF, severe complication. In terms of operation time, open surgery was better than robot surgery.
Four previous meta-analyses [28][29][30][31] discussed the safety and effectiveness of robot technology in pancreaticoduodenal surgery and concluded that pancreaticoduodenectomy is a safe and feasible alternative to open surgery. However, these meta-analyses also have some limitations. One of the limitations is that their meta-analysis included all the published literature at that time, but the data of many literatures came from the same institution, and there may be overlap. This study provides a comprehensive and up-to-date meta-analysis, in which not only new institutions are included, but also the most recent studies with the largest sample size and highest quality from previous institutions are selected. Up to now, randomized controlled trials (RCTs) were still lack; however, it is di cult to conduct a prospective, randomized study because of ethical issues and patients' concerns for malignant tumors. It has been pointed out that the meta-analysis of carefully designed non-randomized comparative studies of surgery may be as accurate as that of RCTs. [32] And we used comparative meta-analysis, which will be better accepted as a supplementary tool for qualitative review in medical literature [33].
Postoperative complications of pancreaticoduodenectomy are some of the most di cult problems for surgeons. Postoperative complications after pancreaticoduodenectomy occur in 40-50% of patients [34]. POPF is widely considered the most common and most dangerous complication after pancreatectomy, which is the most important factor in death due to pancreaticoduodenectomy. Whether via a new material or new surgical technique, reducing pancreatic stula has become the focus of surgeons. The results of this meta-analysis showed that there was no signi cant difference between the RPD group and the OPD group in terms of POPF, while for clinical PF, the incidence in the RPD group decreased by 47% (95%CI: 29%~60%), which was statistically signi cant. Clinical pancreatic leakage, also known as BC grade pancreatic leakage, requires clinical intervention; hence, the reduction of RPD will undoubtedly reduce the occurrence and development of a series of other problems. As in this meta-analysis, overall complication is also reduced.
This meta-analysis concluded that the estimated blood loss, intraoperative transfusion, and the length of stay of the RPD patients were reduced compared to those of OPD patients, but the operation time was longer for RPD than for OPD. However, there was a high degree of heterogeneity between the studies in the terms. Although the random-effects model is used to combine the effect amount, the high degree of heterogeneity will greatly weaken the interpretation of the results. The most likely reason for the marked heterogeneity is that many studies are still in the initial stage of the learning curve. In the prospective database collection study, there was no signi cant difference in operative time and postoperative hospital stay between the RPD group and the OPD group, while in the retrospective cohort study, there was a signi cant difference; but EBL's situation was the opposite. Different types of database studies were included, which may have introduced a bias in these outcome indicators. Thus, there is a need to verify this further by better-designed, high-quality RCTs.
R0 resection and lymph node dissection are two important prognostic factors in patients with pancreaticoduodenectomy [35]. The survival rate can be improved by increasing the number of lymph node dissections, clarifying lymph node metastasis, and guiding postoperative treatment [36,37]. This meta-analysis showed that the R0 resection rate and lymph node dissection of robotic surgery were not signi cant different from that of open surgery, which was consistent with the previous meta-analyses by Podda et al. [29], but Zhao et al. [31] and Yan et al [30]. Nevertheless, they may have partially overlapping patients, which may lead to bias. Long-term survival and tumor recurrence rates were not evaluated due to incomplete data. Therefore, it is di cult to make a reliable conclusion regarding tumor safety.
With the development of neoadjuvant chemotherapy, the current treatment strategy for pancreaticoduodenal cancer is a multidisciplinary comprehensive treatment with surgery at the core. The brogenic response and cytotoxicity caused by neoadjuvant chemotherapy leads to the loss of a normal tissue plane, which brings great challenges to all surgeries. Whether robotic surgery can overcome the new problems caused by new adjuvant therapy due to its unique advantages remains unclear. Some of the studies included in this meta-analysis, such as those by Baimas-George et al. [2], Cai et al. [7], Ielpo et al. [12],Marino et al. [18], Mejia et al. [20], reported the number of people who had received neoadjuvant therapy in the RPD and OPD groups; however, without a separate subgroup analysis, it was impossible to obtain the RPD and OPD effect comparison after receiving neoadjuvant therapy. In future, the safety and effectiveness of using robots in pancreaticoduodenectomy after neoadjuvant chemotherapy, compared with open surgery, should be further explored.

Conclusions
This meta-analysis showed that RPD is superior to OPD in terms of the rate of R0 at the cutting edge, the rate of infection at the wound site, the rate of reoperation, the length of stay after operation, the number of blood transfusions required during operation, and the rate of clinical pancreatic leakage; however, the operation time is longer than that of open surgery. Robot-assisted surgery is a safe and feasible alternative to OPD with regard to short outcomes. This needs to be further veri ed by high-quality clinical trials.

Limitations
Most of the studies included in this meta-analysis were retrospective, and there was, consequently, a risk of selection bias. In addition, RPD is a complex process and is still in its infancy; therefore, the number of cases in each study is small, and some studies reported on data obtained during the learning curve stage of these processes.

Availability of Data and Materials
All the data comes from databases. The author has sorted out all the data and attached to the attachment at the end of the article.