Robotic pancreaticoduodenectomy provides better histopathological outcomes as compared to its open counterpart: a meta-analysis

The aim of this meta-analysis was to evaluate whether robotic pancreaticoduodenectomy (PD) may provide better clinical and pathologic outcomes compared to its open counterpart. The Pubmed, EMBASE, and Cochrane Library were systematically searched. Overall postoperative morbidity and resection margin involvement rate were the primary endpoints. Secondary endpoints included operating time, estimated blood loss (EBL), incisional surgical site infection (SSI) rate, length of hospital stay (LOS), and number of lymph nodes harvested. Twenty-four studies totaling 12,579 patients (2,175 robotic PD and 10,404 open PD were included. Overall postoperative mortality did not significantly differ [OR (95%CI) = 0.86 (0.74, 1.01); p = 0.06]. Resection margin involvement rate was significantly lower in robotic PD [15.6% vs. 19.9%; OR (95%CI) = 0.64 (0.41, 1.00); p = 0.05; NNT = 23]. Operating time was significantly longer in robotic PD [MD (95%CI) = 75.17 (48.05, 102.28); p < 0.00001]. EBL was significantly decreased in robotic PD [MD (95%CI) = − 191.35 (− 238.12, − 144.59); p < 0.00001]. Number of lymph nodes harvested was significantly higher in robotic PD [MD (95%CI) = 2.88 (1.12, 4.65); p = 0.001]. This meta-analysis found that robotic PD provides better histopathological outcomes as compared to open PD at the cost of longer operating time. Furthermore, robotic PD did not have any detrimental impact on clinical outcomes, with lower wound infection rates.

paring robotic to open PD for benign and/or malignant disease were eligible for inclusion. Non-comparative descriptive studies, studies comparing any of the interventions of interest to a non-relevant intervention such as laparoscopic pancreaticoduodenectomy or robotic tumor resection followed by mini-laparotomy for reconstruction, and review articles were excluded.
Postoperative complications were classified according to Clavien-Dindo classification 21 . Surgical site infections (SSI) were defined according to the Center for Disease Control National Nosocomial Infections Surveillance System 22 .
The primary endpoints of this systematic review were overall postoperative complication and resection margin involvement rates. Secondary endpoints included operating time, estimated blood loss, postoperative complication rate, postoperative pancreatic fistula rate, rate of delayed gastric emptying, surgical site infection rate, reoperation rate, length of hospital stay, and number of lymph nodes harvested.
Search strategy and study selection. The Pubmed, EMBASE, and Cochrane Library were systematically searched using the following MeSH terms: 'pancreatoduodenectomy' , 'pancreaticoduodenectomy' , 'whipple' , and 'robotic' combined with the Boolean operator ' AND' and all synonyms combined with the Boolean operator 'OR' . In addition, clinicaltrials.gov was searched for any ongoing studies. The details of Pubmed search strategy are presented in Supplement 1. Relevant articles were identified, and the results of the search were screened through the title, abstract and/or full text article. The sensitivity of the search strategy was tested by screening the references of included articles for additional publications.
Data extraction and quality assessment. The data from the included articles were collected to predefined Microsoft Excel tables and studies were assessed for validity by three researchers independently (MG, XDD, and DMF). Extracted data items included publication-specific variables (authors and affiliations, journal and year of publication), study-specific variables (study design, study span, sample size, definitions of interventions and endpoints, conclusions, potential biases), and patient-specific variables (baseline characteristics, intraand postoperative outcomes, pathologic outcomes). Quality assessment of each individual study was performed according to Cochrane Handbook for Systematic Reviews of Interventions on the following items: selection, performance, detection, attrition, selective reporting, and other bias risks 18 . In addition, Risk Of Bias In Nonrandomized Studies (ROBINS-I) tool was utilized to evaluate the quality of observational studies on the following biases: confounding, selection, classification of interventions, deviations of intended comparability, and outcomes 23 . Statistical analysis. Inverse variance method with mean difference (MD) and standard error as the measure of an effect estimate was used for continuous variables, whereas Mantel-Haenszel method with odds ratios and 95% confidence intervals (OR (95%CI)) was employed for dichotomous variables. In cases when continuous variables were reported in median and interquartile range in the included studies, mean and standard deviation were estimated using Hozo's formula 24 . Statistical heterogeneity among effect estimates was assessed using Cochran Chi 2 and I 2 , and between-study variance was assessed using Tau 2 statistic when the I 2 was 50% or greater 25 . Random-effects model was utilized for meta-analysis. The results of the meta-analysis were illustrated on forest plots. Ad-hoc meta-regression analysis with Omnibus test was performed to evaluate the impact of potential confounding factors on outcomes. To assess clinical significance of the statistical findings for dichotomous endpoints, relative risk reduction (RRR), absolute risk reduction (ARR) and number needed to treat/ harm (NNT) with 95%CI were calculated. Clinical significance of the MD was assessed for numeric endpoints. The variability of the effect of intervention over different settings was assessed using 95% prediction intervals 26 . Visual assessment of funnel plots and Egger's test were utilized to assess for publication bias. A leave-one-out

Results
Literature search and study selection. Details of the search strategy and study selection are presented in the PRISMA flowchart ( Fig. 1). Four databases were searched and revealed 237 records. Additionally, two articles were found at clinicaltrials.gov and through the references of eligible studies. Twenty-nine studies (including published abstracts of conference proceedings) were included in the qualitative synthesis after excluding duplicates, non-relevant articles, and articles not reporting the outcome of interest.
Quality assessment. The risk of bias summary and graph of the included studies are presented in Fig. 2A,B.
The risk of selection, performance and detection bias was high in all included studies given their observational nature. Attrition, reporting, and other bias risks were moderate or low in included studies. The results of quality assessment using the ROBINS-I tool are presented in Supplement 2. Overall risk of bias was assessed as serious in most studies.
Description of included studies. Figure 3 highlights the time span of included studies published from the same institutions, which may increase the risk of duplicate data synthesis. Due to an overlap of the studies by Napoli et al. 27 and Boogi et al. 28 from the University of Pisa, only the study by Boogi et al. 28 was included as it covers a longer time span. An abstract published by Walsh et al. 29 from Cleveland Clinic was excluded as there was an overlap with the study by Chalikonda et al. 30 There were five studies from the University of Pittsburgh that overlap to a certain extent. After excluding three (McMillan et al. 31 , Varley et al. 32 and Wilson et al. 33 ), studies by Boone et al. 34 and Cai et al. 35 with a maximal time span covered and minimal overlap were included. Twenty-four studies were included in the final quantitative data synthesis, totaling 12,579 patients (2,175 robotic PD and 10,404 open PD) 8,28,30, . Seven studies 30,34,36,38,41,50,52 were prospective cohort studies and 17 retrospective cohort studies 8,28,35,37,39,40,[42][43][44][45][46][47][48][49]51,53,54 . In four of these studies 34,40,43,50 , data were extracted from the abstracts of conference proceedings published in indexed journals. Five studies 8,36,38,41,52 had the Oxford CEBM   Table 2. The definitions of the interventions are summarized in Table 3. Robotic PD was a totally robotic procedure in 17 studies 8,28,[34][35][36]38,39,41,42,44,45,47,49,[51][52][53][54] . A hybrid procedure was performed in four studies 30,37,46,48 and three studies 40,43,50 did not specify the type of the procedure. Six studies reported DaVinci console type (both Si/Xi in three studies 38,44,52 ; Si 49,50 in two and S in one 41 ).
Intervention categories that were described for both open and robotic surgery included type of procedure (Whipple procedure, pylorus preserving PD, or multivisceral resection) and type of anastomosis (pancreaticojejunostomy, pancreaticogastrostomy and/or duct-to-mucosa). Vein resection was reported in 10 studies 8,28,30,35,36,38,41,42,46,47 and was up to 25% in the robotic and up to 38% in the open group. Further categories www.nature.com/scientificreports/ described in Table 3 were routine or selective placement of pancreaticojejunal anastomotic stent, antecolic or retrocolic location of the jejunal loop, and routine or selective use of abdominal drainage.

Meta-analysis.
All 24 studies, regardless of the evidence level and risk of bias, were included in this metaanalysis. Primary outcomes were overall postoperative morbidity and margin involvement rate. Secondary clinical outcomes were operating time, estimated blood loss, postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), surgical site infection (SSI), reoperation rate, and length of hospital stay. An additional secondary outcome was the number of lymph nodes harvested.  (Fig. 4A). The RRR was 22% and the NNT was 9 (7, 12) (    (Fig. 5F). RRR was 1%, NNT was 3,007, 95% prediction interval was 0.61, 1.04 with very low GRADE certainty of evidence (Table 4). with high among-study heterogeneity (I 2 = 97%; Tau 2 = 2.29) (Fig. 5G). Although the clinical importance of the MD was assessed to be moderate, 95% prediction interval was − 4.32, 2.32 and GRADE certainty of evidence was very low (Table 4).  (Fig. 5H). Although the clinical importance of the MD was be moderate, 95% prediction interval was − 3.97, 9.73 and GRADE certainty of evidence was low (Table 4).

Meta-regression analysis.
Ad-hoc meta-regression analysis was performed to assess the impact of potential covariates on the statistical findings. Covariates utilized for meta-regression analysis included the central tendency values for age and BMI, proportion of males, proportion patients with ASA > 2, and study design. A statistically significant correlation was found between overall postoperative mortality and average age in robotic PD (Omnibus p = 0.040) (Fig. 6A). However, only a statistical trend in correlation was found between overall postoperative mortality and open PD (Omnibus p = 0.075) (Fig. 6B). No statistically significant impact of the above-mentioned covariates on margin involvement rate and secondary endpoints was found.
Publication bias and sensitivity analysis. Publication bias was evaluated by visual assessment of symmetry on the funnel plot (Fig. 7) and using Egger's test (Overall postoperative morbidity: t = 0.534, p = 0.522; Margin involvement rate: t = 0.478, p = 0.641). No significant risk of publication bias was found. A sensitivity analysis of the included observational studies was performed using leave-one-out forest plots. Consecutive exclusion of studies did not significantly impact the findings (Fig. 8). The results of the evaluation of the certainty of evidence are summarized in Table 4.

Discussion
Currently, general surgery is the fastest growing specialty for the DaVinci robotic platform in the US. Specifically, robotic PD is experiencing widespread growth since its introduction 7 . Similar to laparoscopic distal pancreatectomy has seen its use expanded three-fold between 1998 and 2009, robotic PD is also subject to significant growth nationwide 56 . Pancreaticoduodenectomy remains a technically demanding operation with significant risks of morbidity 57 . Historically, minimally invasive surgery has often been compared to open approach in non-inferiority studies. With improved visualization through magnification of target anatomy and ergonomics allowing more precise excision along critical resection margins, robotic approach may allow superior dissection and skeletonization of critical borders. Margins near the uncinate process along the superior mesenteric artery requiring dissection down to the adventitia is facilitated with the robotic instruments. Although resection margins are important for overall survival and locoregional recurrence, the ability to achieve R0 resection can be as low as 60% in some open cases 14,58 . One of the important findings of this meta-analysis is the improvement in resection margin in robotic PD. Patients with non-involved resection margins have improved overall survival as well as decreased locoregional recurrence risk in comparison to R1 resection 14 . The benefits of R0 resection is especially pronounced in patients with N0 disease 14 .
Previously, the benefits of robotic surgery for pancreatic cancer in terms of margin status have been reported 12,45 . With the high rate of locoregional failure, assessment of the circumferential margin of the Whipple specimen was re-defined in 2006 58 . Verbeke et al. advocated a standardized protocol for margin assessment since circumferential margin positivity can be underestimated by as much as 60% 59 . Unfortunately, the method of margin quantification in the majority of these studies were not clearly defined based on the papers reviewed 58 . Furthermore, only two studies stated their adherence to the standardized Leeds Pathology Protocol (LEEPP) for margin assessment. Only two papers 45,49 specified that the LEEPP protocol were followed. Nonetheless, Peng et al. performed a meta-analysis previously and showed improved margin status favoring robotic surgery over open surgery 12,60 . Within their findings, only 8 studies were included which discussed oncologic outcomes 12 . Kauffman et al. performed a propensity score matched analysis of robotic versus open PD and found equivalent rates of R1 resection 45 . The authors did comment, as speculated by many robotic surgeons, that following the peri-adventitial dissection plane close to the right side of the SMA, following early ligation of the inferior pancreaticoduodenal artery makes the retroperitoneal dissection easier. The retroperitoneal dissection plan is particularly efficient using the minimally invasive robotic approach 45 . In this meta-analysis, we confirmed the significant difference in resection margin involvement rates favoring robotic approach.
Similar to margin status, an increase in the number of lymph nodes harvested is frequently associated with improved staging and optimal resection margins 17 . In this study, we also identified that robotic PD has an increased number of lymph node harvested as compared to open. Previously, studies have shown both that total number of lymph nodes evaluated and a higher positive lymph node ratio to be superior in terms of oncological outcome. This meta-analysis is one of the first to present superior nodal sampling with the use of robotic surgery.  www.nature.com/scientificreports/ As expected, clinical outcomes favoring robotic surgery included significantly lower estimated blood loss, decreased incisional SSI rate, and lower length of hospital stay at the cost of longer operating time. These findings confirmed the results of previous meta-analyses. No significant difference in POPF, DGE, and reoperation rates was found.
One of the strengths of this meta-analysis is the number of studies and thereby number of patients included. Other strengths were prospective development and registration of the protocol, and rigorous literature search. This meta-analysis has several limitations. Given the observational nature, all included studies were subject to high risk of selection, performance, and detection biases. Moreover, all studies reported only short-term outcomes. The differences in surgical approaches and perioperative management across the globe may have contributed further to the heterogeneity and variance across the included studies. The lack of other histopathological details including and not limited to lymphovascular and perineural invasion adds additional heterogeneity. Another limitation was a lack of standardization in the definitions of interventions, a fact that may have contributed to the risk of performance bias.

Conclusion
This meta-analysis found that robotic PD was associated with improved resection margins and number of lymph node harvested as compared to open PD. Moreover, robotic PD allowed surgery with less blood loss and was associated with decreased wound infection rates and shorter length of hospital stay, at the expense of increased operating time and surgical cost. The current application of robotic PD needs further experimental and observational prospective studies given the possible benefits over open PD.

Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.