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Does center or surgeon volume influence adoption of minimally invasive versus open pancreatoduodenectomy? A systematic review and meta-regression
Surgery xxx (2020) 1e9
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Does center or surgeon volume influence adoption of minimally invasive versus open pancreatoduodenectomy? A systematic review and meta-regression Sivesh K. Kamarajah, BMedSci, MBChBa,b,*, Mohammed Abu Hilal, MD, PhD, FRCS, FACSc, Steven A. White, MD, FRCPS, FRCSa,b a b c
Department of HPB and Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, United Kingdom Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom Department of Surgery, Southampton University Hospital NHS Foundation Trust, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 17 September 2020 Available online xxx
Background: There has been increasing uptake of minimally invasive pancreatoduodenectomy during the past decade, but it remains a highly specialized procedure as benefits over open pancreatoduodenectomy remain contentious. This study aimed to evaluate current evidence on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy in terms of impact of center volume on outcomes. Methods: A systematic review of articles on comparative cohort and registry studies on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy published until 31st December 2019 were identified, and meta-analyses were performed. Primary endpoints were International Study Group on Pancreatic Fistula grade B/C postoperative pancreatic fistula and 30-day mortality. Results: After screening 7,390 studies, 43 comparative cohort studies (8,755 patients) with moderate methodological quality and 3 original registry studies (43,735 patients) were included. For the cohort studies, the median annual hospital minimally invasive pancreatoduodenectomy volume was 10. No significant differences were found in grade B/C postoperative pancreatic fistula (odds ratio: 0.98, 95% confidence interval: 0.78e1.23) or 30-day mortality (odds ratio: 1.14, 95% confidence interval: 0.65e2.01) between minimally invasive pancreatoduodenectomy when compared with open. No publication biases were present and meta-regression identified no confounding for grade B/C postoperative pancreatic fistula, center volume or 30-day mortality. Minimally invasive pancreatoduodenectomy was only strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection, shorter length of stay, and significantly higher rates of R0 margin resections. Conclusion: Minimally invasive pancreatoduodenectomy remains noninferior to open pancreatoduodenectomy for grade B/C postoperative pancreatic fistula but is strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection. Minimally invasive pancreatoduodenectomy can be adopted safely with good outcomes irrespective of annual center resection volume. © 2020 Elsevier Inc. All rights reserved.
Introduction Pancreaticoduodenectomy (PD) remains the only potentially curative treatment for a variety of periampullary cancers. Despite recent advances in outcomes related to centralization of services, improved perioperative care and patient * Reprint requests: Dr Kathir Kamarajah, BMedSci, MBChB, Department of Hepatobiliary, Pancreatic and Transplant Surgery, Department of Surgery, Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, United Kingdom. E-mail address: [email protected] (S.K. Kamarajah). https://doi.org/10.1016/j.surg.2020.09.019 0039-6060/© 2020 Elsevier Inc. All rights reserved.
selection,1-3 PD is still associated with postoperative morbidity rates of 23% to 66% and mortality rates of 3% to 5%.2e4 Laparoscopic PD was first described in the early 1990s, whereas the first publications for robot-assisted PD appeared 10 years later.5 However, minimally invasive PD (MIPD) is a technically demanding operation and has not yet gained the same support in the surgical community, especially among hepatobiliary and pancreatic surgeons, as other minimally invasive gastrointestinal procedures.6 This is almost certainly owing to technical difficulty and the high-risk nature of minimally invasive pancreatic surgery.7,8
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Inclusion and exclusion criteria Inclusion criteria were (1) studies reporting the comparison of surgical techniques (by any method) in human subjects receiving PD for any indication and (2) studies published in the English language. Exclusion criteria were (1) conference abstracts, review articles, and case reports (<5 patients); (2) publications with mixed populations where the outcomes of patients undergoing either other types of pancreatic surgery (distal pancreatectomy) could not be separated from those of patients undergoing PD; and (3) hybrid procedures, where any MIPD procedure included a component of open surgery. Following exclusion duplicates, 2 researchers (S.K.K., J.R.B.) independently reviewed the titles and abstracts of studies identified by the literature search. Where a study was considered potentially relevant to the research question a full copy of the publication was obtained for further review. The reference lists of all included studies were hand searched in order to identify other potentially relevant studies. Any areas of disagreement between the 2 primary researchers were resolved through discussion with all authors. Study outcomes Fig 1. PRISMA diagram of included studies from the systematic literature review.
Postoperative pancreatic fistulas (POPFs) remain one of the most threatening complications after PD, with rates ranging from 4% to 33%.9 Cohort studies have suggested that MIPD, compared with open pancreatoduodenectomy (OPD), can safely improve postoperative morbidity rates and enhance postoperative recovery.10 Further, several studies have demonstrated equivalence in overall costs between MIPD and OPD, with MIPD associated with lower postoperative costs from reduced complications and length of stay.11e14 However, many studies were not comparative, and selection bias has likely influenced these findings. In 2016, a systematic review comparing MIPD versus OPD, comprising 19 observational studies, demonstrated higher 30-day mortality in high-volume centers compared with low-volume centers.15 During the past 4 years, many high-volume series have reported their outcomes, including both cohort16,17 and registry studies,18 which raised concerns regarding the safety of MIPD. An updated systematic review of the literature on MIPD could clarify the impact of these recent studies. The primary aim of this systematic review was to assess the evidence for MIPD versus OPD comparing postoperative and oncological outcomes. This review also aimed to assess impact of center volume on these outcomes.
Methods
The primary outcome measure was clinically relevant POPF (CRPOPF) and 30-day mortality. CR-POPF was defined according to the International Surgery Group for Pancreatic Surgery (ISGPS). Secondary outcome measures were postoperative complications (both overall and major), POPF, delayed gastric emptying, bile leak, 90day mortality, 30-day and 90-day readmission, reoperation, length of stay, and oncological (lymph node harvest and R0 resection) outcomes for malignant indications. Data extraction One researcher (S.K.K.) extracted data on study characteristics (author, year of publication, country of origin, study design, patient number), patient demographics (age, sex), method and details of surgical techniques, and reported clinical outcomes. Definitions MIPD was any technique such as totally laparoscopic (TL) and totally robotic (TR). TR was defined as the complete use of the robotic technique for PD, including resection and reconstruction, without laparoscopic or hand-assisted techniques. Nevertheless, this did include the use of laparoscopic ports by a surgical assistant as part of the robotic procedure, which is regarded as standard. TL was defined as the complete use of a laparoscopic technique for PD, including resection and reconstruction without robotic or handassisted techniques. Annual center volume was derived as a pro rata of the total operations performed over the study period.
Search strategy A systematic search of PubMed, EMBASE, and the Cochrane Library databases were conducted on the 1st of January 2020 by 2 independent investigators (S.K.K., J.R.B.). The search terms used were “robotic surgery” or “laparoscopy” or “robot-assisted,” “open,” and “Pancreaticoduodenectomy” or “Whipple procedure” or “pancreatectomy” or “pylorus-preserving pancreaticoduodenectomy” individually or in combination. Search terms used for this review are presented in Supplementary Table I. The “related articles” function was used to broaden the search, and all citations were considered for relevance. A manual search of reference lists in recent reviews and eligible studies was also undertaken. This paper is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Fig 1).19
Assessment of methodological quality Methodological quality and standard of outcome reporting within included studies were assessed by 2 independent researchers (S.K.K., J.R.B.). Methodological quality was formally assessed using the Newcastle-Ottawa score for cohort studies (S.K.K., R.G.) and the Cochrane Risk of Bias Tool for randomized controlled trial.20,21 Statistical analysis This systematic review and network meta-analysis was conducted in accordance with the recommendations of the Cochrane Library and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.22 Data analysis was undertaken using R Foundation Statistical software (R 3.2.1; R Foundation for Statistical
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Computing, Vienna, Austria), as previously described,23 to produce a random-effects meta-analysis for each outcome, providing pooled odds ratios (OR) with 95% confidence intervals (95% CIs). The choice of a random-effects analysis was based on the variability of minimally invasive techniques within each comparison group (eg, TR, TL) between the studies, which might influence the magnitude of the treatment effect.24 The I2 test was used to evaluate statistical heterogeneity of the included studies, with levels of heterogeneity defined as not important (I2: 0%e40%), moderate (I2: 30%e60%), substantial (I2: 50%e90%), or considerable (I2: 75%e100%).25 The c2 test was used for the same purpose, with a statistical significance level of P < .05 indicating presence of statistical heterogeneity. Publication bias and small-study effects were assessed using the Egger test for statistical asymmetry in the funnel plot, with a statistical significance level of P < .10 indicating publication bias or small-study effects. Random-effects meta-regression was used to adjust for potential confounding by the following variables: patient age (median), physical status according to the American Society of Anesthesiologists (ASA) class (I, II, III, and IV), surgery type, and use of chemo (radio)-therapy (neoadjuvant therapy used if present, otherwise adjuvant therapy; yes and no) upon the results of the outcomes. These adjusted estimates were presented as pooled OR with 95% confidence intervals, where applicable. Cutoffs for the annual MIPD and OPD volume were derived from the median of the included studies. Results Study inclusion Of the 7,390 studies identified, 77 studies were identified for full text analysis. Of these 77 studies, 31 studies were excluded as 18 studies26e43 were duplicates, 9 studies44e52 included a handassisted component, and 4 studies53e56 compared TR versus TL. Forty-six studies were included into this systematic review (Fig 1). One study by Song et al10 included 3 cohorts of patients, 1 for resections of benign conditions, 1 for resection of ampullary carcinoma, and another for resection of pancreatic ductal adenocarcinoma with outcomes reported separately. As such, these cohorts were treated separately within the analyses.
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the studies was moderate (I2 ¼ 39%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .9), arguing against small-study effects or publication bias. Meta-regression indicated confounding factors were ASA grade, body mass index, retrospective case series, and studies published in Europe (Supplementary Table IV). In subset analyses (Table I), studies published in Europe were associated with higher rates of CR-POPF, while prospective cohort studies were associated with significantly lower rates of CR-POPF. However, analyses by annual center volume by overall volume (Fig 2), OPD only volume or MIPD only volume did not demonstrate any association with CR-POPF by quintiles. 30-day mortality A total of 31 studies reported 30-day mortality (Supplementary Fig 2). The pooled analysis revealed similar rates of 30-day mortality after MIPD when compared with OPD (2% vs 2%, OR 1.14, 95% CI: 0.65e2.02; P ¼ .6). The statistical heterogeneity of these studies was substantial (I2 ¼ 73%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .3), arguing against small-study effects or publication bias. Meta-regression indicated confounding factors were ASA grade, body mass index, retrospective case series, and studies published in Europe (Supplementary Table V). In subset analyses (Table II), studies published in Europe were associated with higher rates of CR-POPF, while prospective cohort studies were associated with significantly lower rates of CR-POPF. However, analyses by annual center volume by overall volume (Fig 3), OPD only volume or MIPD only volume did not demonstrate any association with 30-day mortality by quintiles. Secondary outcomes Overall complications A total of 33 studies reported overall complications. The pooled analysis revealed similar rates of overall complications after MIPD when compared with OPD (41% vs 49%, OR 0.87, 95% CI: 0.71e1.05; P ¼ .1). The statistical heterogeneity of the studies was substantial (I2 ¼ 63%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .5), arguing against smallstudy effects or publication bias.
Study characteristics Of these studies, 46 were cohort studies, and 3 were randomized clinical trials, together including 52,490 patients. In this cohort, 7,592 (14.5%) patients underwent MIPD. Some characteristics of the included studies are presented in Supplementary Table II. From the total MIPD (n ¼ 46), 12 studies reported TR. The median patient age was reported in 44 studies for both MIPD (96%) and OPD (96%) studies. Physical status (ASA class) was reported for both comparison groups in 20 studies (43%). The quality scores of the cohort studies varied between 5 and 9, with a median value of 7 according to the Newcastle-Ottawa scale (Supplementary Table II). The 3 randomized clinical trials were evaluated to have low risks of bias, except for performance bias owing to the problem of masking surgical treatment, according to the Cochrane Collaborations Risk of Bias Tool.
Major complications A total of 29 studies reported major complications (Supplementary Fig 3). The pooled analysis revealed similar rates of major complications after MIPD compared with OPD (19% vs 33%, OR 0.99, 95% CI: 0.81e1.23; P ¼ .9). The statistical heterogeneity of the studies was moderate (I2 ¼ 42%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .06), arguing against small-study effects or publication bias.
Primary outcomes
Grade B/C delayed gastric emptying A total of 13 studies reported Grade B/C delayed gastric emptying. The pooled analysis revealed similar rates of Grade B/C delayed gastric emptying after MIPD compared with OPD (13% vs 8%, OR 0.83, 95% CI: 0.49e1.40; P ¼ .5). The statistical heterogeneity of the studies was substantial (I2 ¼ 71%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .7), arguing against small-study effects or publication bias.
Clinically relevant POPF A total of 29 studies reported CR-POPF (Supplementary Fig 1). The pooled analysis revealed similar rates of CR-POPF after MIPD when compared with OPD (12% vs 9%, OR 0.98, 95% CI 0.78e1.24; P ¼ .9) (Supplementary Table III). The statistical heterogeneity of
Bile leak A total of 15 studies reported bile leak. The pooled analysis revealed similar rates of bile leak after MIPD compared with OPD (5% vs 5%, OR 1.12, 95% CI: 0.69e1.82; P ¼ .7). The statistical heterogeneity of the studies was not important (I2 ¼ 0%). The funnel
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Table I Sensitivity analyses of studies for CR-POPF
Study year 2009e2014 2015e2019 Study region Asia Europe North America Study duration 3 y >3 y Study design PCS RCS RCT Study type Institutional Registry Case matching No Yes Total annual volume 30 >30 Open annual volume 20 >20 MI annual volume 10 >10 MI approach MI TL TR
Studies, n
OR (95% CI)
Z value
P value
I2
Egger's
4 25
0.93 (0.54e1.61) 0.99 (0.76e1.28)
e0.25 e0.1
.8 .9
0 47
0.3 1.0
11 6 12
0.74 (0.50e1.09) 1.54 (1.03e2.30) 0.92 (0.66e1.28)
e1.54 2.12 e0.48
.1 .034 .6
0 22 52
0.8 0.3 0.9
9 20
1.24 (0.92e1.66) 0.89 (0.66e1.19)
1.43 e0.79
.2 .4
0 52
0.9 0.9
2 24 3
0.46 (0.30e0.69) 1.15 (0.95e1.41) 0.73 (0.34e1.58)
e3.71 1.41 e0.81
<.001 .2 .4
0 12 16
0.4 0.4
28 1
0.97 (0.76e1.24)
e0.26 -
.8 -
41 -
0.9 -
17 12
1.13 (0.86e1.48) 0.72 (0.49e1.05)
0.9 e1.71
.4 .1
46 12
0.2 0.3
12 17
1.23 (0.82e1.84) 0.93 (0.71e1.22)
0.98 e0.53
.3 .6
8 50
0.6 0.9
15 14
0.92 (0.65e1.31) 1.02 (0.75e1.39)
e0.45 0.14
.7 .9
0 61
0.3 0.5
12 17
1.25 (0.83e1.88) 0.93 (0.71e1.21)
1.07 e0.56
.3 .6
7 50
0.4 0.9
2 19 8
1.29 (0.70e2.37) 0.94 (0.73e1.22) 1.03 (0.591.80)
0.82 e0.46 0.09
.4 .6 .9
12 15 69
0.4 0.7
Bolded values indicate significant findings. PCS, prospective cohort study; RCS, retrospective cohort study.
plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .6), arguing against small-study effects or publication bias. Surgical site infection A total of 26 studies reported surgical site infection (SSI) (Supplementary Fig 4). The pooled analysis revealed significantly lower rates of SSI after MIPD compared with OPD (13% vs 21%, OR 0.69, 95% CI: 0.55e0.86; P ¼ .001). The statistical heterogeneity of the studies was not important (I2 ¼ 13%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .07), arguing against small-study effects or publication bias. Postoperative pulmonary complications A total of 15 studies reported postoperative pulmonary complications (PPC) (Supplementary Fig 5). The pooled analysis revealed significantly lower rates of PPC after MIPD compared with OPD (10% vs 17%, OR 0.70, 95% CI: 0.59e0.83; P < .001). The statistical heterogeneity of the studies was not important (I2 ¼ 0%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .7), arguing against small-study effects or publication bias. 90-day mortality A total of 8 studies reported 90-day mortality. The pooled analysis revealed similar rates of 90-day mortality after MIPD compared with OPD (4% vs 5%, OR 1.09, 95% CI: 0.59e2.02; P ¼ .8). The statistical heterogeneity of the studies was moderate (I2 ¼ 53%). The funnel plot was symmetrical both according to visual and
statistical testing (Egger test, P ¼ .2), arguing against small-study effects or publication bias. 30-day and 90-day readmission A total of 18 studies reported 30-day readmission. The pooled analysis revealed similar rates of 30-day readmission after MIPD compared with OPD (10% vs 10%, OR 1.13, 95% CI: 0.90e1.41; P ¼ .3). The statistical heterogeneity of the studies was not important (I2 ¼ 31%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .4), arguing against small-study effects or publication bias. A total of 4 studies reported 90-day readmission. The pooled analysis revealed similar rates of 90-day readmission after MIPD compared with OPD (27% vs 26%, OR 0.90, 95% CI: 0.54e1.51; P ¼ .7). The statistical heterogeneity of the studies was substantial (I2 ¼ 75%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ 1.0), arguing against small-study effects or publication bias. Length of stay A total of 42 studies reported length of stay (Supplementary Fig 6). The pooled analysis revealed significantly shorter length of stay after MIPD compared with OPD (mean: 13.0 vs 14.8 days, SD: e1.29, 95% CI: e1.99 to e0.60; P < .001). The statistical heterogeneity of the studies was considerable (I2 ¼ 100%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .9), arguing against small-study effects or publication bias. R0 resection margin Of the studies on cancer resection (n ¼ 31 studies), a total of 19 studies reported R0 margins (Supplementary Fig 7). The pooled
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Fig 2. Impact of overall center annual resectional volume on CR-POPF: (A) Quintile 1, (B) Quintile 2, (C) Quintile 3, (D) Quintile 4, and (E) Quintile 5.
analysis revealed significantly higher R0 resections after MIPD compared with OPD (84% vs 80%, OR: 1.61, 95% CI: 1.02e2.54; P ¼ .041). The statistical heterogeneity of the studies was substantial
(I2 ¼ 74%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .2), arguing against smallstudy effects or publication bias.
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Table II Sensitivity analyses of studies for 30-d mortality
Study year 2009e2014 2015e2019 Study region Asia Europe North America Study duration 3 years >3 years Study design PCS RCS RCT Study type Institutional Registry Case matching No Yes Total annual volume 30 >30 Open annual volume 20 >20 MI annual volume 10 >10 MI approach MI TL TR
Studies, n
OR (95% CI)
Z value
P value
I2
Egger's
9 22
0.78 (0.35e1.73) 1.25 (0.64e2.47)
e0.61 0.65
.5 .5
0 80
0.9 0.5
10 6 15
1.04 (0.41e2.65) 0.79 (0.37e1.67) 1.34 (0.59e3.03)
0.08 e0.62 0.69
.9 .5 .5
0 0 85
0.8 0.6 0.8
9 22
1.07 (0.59e1.92) 1.08 (0.53e2.18)
0.22 0.2
.8 .8
0 80
0.5 0.3
3 25 3
0.84 (0.21e3.31) 1.16 (0.61e2.20) 1.22 (0.17e8.82)
e0.25 0.46 0.2
.8 .6 .8
0 77 40
0.3 0.4 0.3
28 3
0.98 (0.64e1.49)
e0.1 0.62
.9 .5
0 98
0.8 0.9
20 11
0.83 (0.63e1.10) 1.59 (0.56e4.55)
e1.31 0.87
.2 .4
0 55
0.6 0.001
16 15
0.96 (0.42e2.23) 1.20 (0.69e2.08)
e0.08 0.64
.9 .5
85 0
0.4 0.4
18 13
1.08 (0.48e2.44) 1.06 (0.63e1.80)
0.18 0.22
.9 .8
82 0
0.5 0.7
18 13
0.99 (0.45e2.15) 1.34 (0.71e2.50)
e0.03 0.91
1.0 .4
83 0
0.3 0.4
3 20 8
2.48 (0.39e15.88) 0.86 (0.63e1.17) 0.75 (0.33e1.69)
0.96 e0.97 e0.7
.3 .3 .5
93 0 0
0.8 0.5 0.9
Bolded value indicates significant findings. PCS, prospective cohort study; RCS, retrospective cohort study.
Lymph node harvest Of the studies on cancer resection (n ¼ 31), a total of 18 studies reported lymph node harvest (Supplementary Fig 8). The pooled analysis revealed no significant difference in number of lymph node harvest between MIPD compared with OPD (median: 18 vs 17 nodes, SD: 0.51, 95% CI: e0.35 to 1.36; P ¼ .2). The statistical heterogeneity of the studies was substantial (I2 ¼ 86%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .2), arguing against small-study effects or publication bias. Discussion This systematic review and meta-analysis of 52,490 patients from 46 studies demonstrates that MIPD is associated with a noninferior CR-POPF and 30-day mortality when compared with OPD. Meta-regression for CR-POPF and 30-day mortality demonstrated no confounders affecting these outcomes. Stratified analyses for total annual, open, or minimally invasive center volume demonstrated no significant difference in rates of CR-POPF or 30day mortality across these quintiles. Notably, MIPD were only strongly associated with significantly lower rates of PPC and SSI, shorter length of stay, and significantly higher rates of R0 margin resections. These findings are clinically important, because they may lead to quicker postoperative recovery, earlier receipt of adjuvant therapy for cancer patients, and hence may translate to improvement to long-term survival. Although several meta-analyses have compared outcomes for MIPD against the conventional open approach,57e61 none have explored the relationship between center volume and MIPD on postoperative outcomes. This review demonstrated no impact of
CR-POPF and 30-day mortality when stratified by center-volume quintiles. This is counterintuitive, because the relationship between center volume and surgical outcome is well established, with improved outcomes in higher-volume centers.62,63 A registry study from Adam et al64 on MIPD demonstrated hospital volume is significantly associated with improved outcomes from MIPD, with a threshold of 22 cases per year, despite the majority of resections being at low-volume centers. There are 2 reasons for the observed findings in this review. Firstly, centers adopting MIPD are likely to be existing high-volume centers, where outcomes are less likely to be affected, which is confirmed from our subgroup analyses. Secondly, it is also possible that high-volume surgeons, rather than a high-volume center, are the ones performing MIPD within these centers, which has been described previously.65 Current evidence for MIPD is limited to observational studies, and only 3 randomized controlled trials (RCTs) comparing laparoscopic versus open PD have been published.66e68 From these RCTs, only 2 demonstrated that laparoscopic PD was associated with a significantly shorter length of hospital stay66,67 and compares other variations to the conventional open PD. In the present study, MIPD was associated with significantly shorter length of hospital stay but was associated with a wide range for both MIPD (range: 6e27 days) and OPD (range: 8e61 days). This is likely related to institutional practices such as presence of Enhanced Recovery After Surgery services or surgeon preferences in patient discharge, although this remains unclear at present. In contrast, one RCT68 was stopped early owing to higher mortality, but this was likely owing to inclusion of low- and high-volume centers compared with the previously reported RCTs. In addition, there have been an increased adoption of robotic PD in some centers, but no RCT at present owing
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Fig 3. Impact of overall center annual resectional volume on 30-day mortality: (A) Quintile 1, (B) Quintile 2, (C) Quintile 3, (D) Quintile 4, and (E) Quintile 5.
to surgeons being at various stages in their learning curves. Moving forward, further RCTs are required to truly demonstrate the impact of MIPD, and data from this study will help plan study design and primary outcomes of interest.
The study has both strengths and weaknesses. A strength is the extensive literature search, covering randomized and nonrandomized clinical trials, which provided a large number of patients. The low presence of heterogeneity, small-study effects, and
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symmetrical funnel plots for all outcomes reflects higher internal validity of these studies and hence strengthens the validity of the results for these outcomes. Notably, a majority of papers included in this review were published from 2014 onwards, precluding any bias owing to improved treatment over time. The meta-regression was adjusted for important technical factors and showed no confounding by these factors. Yet, residual confounding cannot be excluded, especially for patient- (ie, age, ASA grade, previous history of pancreatitis) and tumor-related (ie, tumor size) factors, which was only reported in relatively few of the included papers. There is a possibility that patients with beneficial prognostic variables, for example, younger age and less comorbidity, were more readily selected for MIPD rather than OPD. Furthermore, only 3 studies were RCTs, and the remaining included studies were retrospective cohort studies. Therefore, these selection biases may also reflect higher R0 margins in MIPD compared with OPD. Another limitation to highlight is the variation in the stages of learning curve of surgeons performing these operations are not well captured or documented in the included studies. Therefore, it was not possible to limit analyses to studies where learning curves were achieved. In conclusion, over the past decade, MIPD remained noninferior to OPD for CR-POPF, but strongly associated with significantly lower rates of PPC and SSI. MIPD can be adopted safely with good outcomes irrespective of annual center resection volume provided the operative surgeon has the appropriate level of technical skill, appropriate training, and experience. Conflict of interest/Disclosure All authors have nothing to disclose. Funding/Support There is no funding to disclose. Supplementary materials Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.1016/j.surg.2020. 09.019. References 1. Gooiker GA, Lemmens VE, Besselink MG, et al. Impact of centralization of pancreatic cancer surgery on resection rates and survival. Br J Surg. 2014;101: 1000e1005. 2. de Wilde RF, Besselink MG, van der Tweel I, et al. and the Dutch Pancreatic Cancer Group. Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. Br J Surg. 2012;99:404e410. 3. Elberm H, Ravikumar R, Sabin C, et al. Outcome after pancreaticoduodenectomy for T3 adenocarcinoma: a multivariable analysis from the UK Vascular Resection for Pancreatic Cancer Study Group. Eur J Surg Oncol. 2015;41:1500e1507. 4. Abu Hilal M, Di Fabio F, Badran A, et al. Implementation of enhanced recovery programme after pancreatoduodenectomy: a single-centre UK pilot study. Pancreatology. 2013;13:58e62. 5. Gagner M, Pomp A. Laparoscopic pylorus-preserving pancreatoduodenectomy. Surg Endosc. 1994;8:408e410. 6. Kamarajah SK, Bundred JR, Marc OS, et al. A systematic review and network meta-analysis of different surgical approaches for pancreaticoduodenectomy. HPB (Oxford). 2020;22:329e339. 7. Mathur A, Ross SB, Luberice K, et al. Margin status impacts survival after pancreaticoduodenectomy but negative margins should not be pursued. Am Surg. 2014;80:353e360. 8. de la Fuente SG. Laparoscopic pancreaticoduodenectomies: a word of caution. J Am Coll Surg. 2013;216:1218. 9. Lyu Y, Li T, Cheng Y, Wang B, Chen L, Zhao S. Pancreaticojejunostomy versus pancreaticogastrostomy after pancreaticoduodenectomy: an up-to-date metaanalysis of RCTs applying the ISGPS (2016) criteria. Surg Laparosc Endosc Percutan Tech. 2018;28:139e146.
10. Song KB, Kim SC, Hwang DW, et al. Matched case-control analysis comparing laparoscopic and open pylorus-preserving pancreaticoduodenectomy in patients with periampullary tumors. Ann Surg. 2015;262:146e155. 11. Tan CL, Zhang H, Peng B, Li KZ. Outcome and costs of laparoscopic pancreaticoduodenectomy during the initial learning curve vs laparotomy. World J Gastroenterol. 2015;21:5311e5319. 12. Speicher PJ, Nussbaum DP, White RR, et al. Defining the learning curve for team-based laparoscopic pancreaticoduodenectomy. Ann Surg Oncol. 2014;21: 4014e4019. 13. Tran TB, Dua MM, Worhunsky DJ, Poultsides GA, Norton JA, Visser BC. The first decade of laparoscopic pancreaticoduodenectomy in the United States: costs and outcomes using the Nationwide Inpatient Sample. Surg Endosc. 2015;30: 1778e1783. 14. Boggi U, Signori S, De Lio N, et al. Feasibility of robotic pancreaticoduodenectomy. Br J Surg. 2013;100:917e925. 15. de Rooij T, Lu MZ, Steen MW, et al. and the Dutch Pancreatic Cancer Group. Minimally invasive versus open pancreatoduodenectomy: systematic review and meta-analysis of comparative cohort and registry studies. Ann Surg. 2016;264:257e267. 16. Dokmak S, Fteriche FS, Aussilhou B, et al. Laparoscopic pancreaticoduodenectomy should not be routine for resection of periampullary tumors. J Am Coll Surg. 2015;220:831e838. 17. El Nakeeb A, Askar W. Laparoscopic pancreaticoduodenectomy for resection of periampullary tumors should be routine? HPB. 2018;20(Supplement 2): S649eS650. 18. Torphy RJ, Friedman C, Halpern A, et al. Comparing short-term and oncologic outcomes of minimally invasive versus open pancreaticoduodenectomy across low and high volume centers. Ann Surg. 2019;270:1147e1155. 19. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. 20. Lo CK, Mertz D, Loeb M. Newcastle-Ottawa Scale: comparing reviewers' to authors' assessments. BMC Med Res Methodol. 2014;14:45. 21. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603e605. 22. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008e2012. 23. Kamarajah SK, Sutandi N, Robinson SR, French JJ, White SA. Robotic versus conventional laparoscopic distal pancreatic resection: a systematic review and meta-analysis. HPB (Oxford). 2019;21:1107e1118. 24. Riley RD, Higgins JP, Deeks JJ. Interpretation of random effects meta-analyses. BMJ. 2011;342:d549. 25. Gottlieb-Vedi E, Kauppila JH, Malietzis G, Nilsson M, Markar SR, Lagergren J. Long-term survival in esophageal cancer after minimally invasive compared to open esophagectomy: a systematic review and meta-analysis. Ann Surg. 2019;270:1005e1017. 26. Kowalsky SJ, Zenati MS, Steve J, et al. A combination of robotic approach and ERAS pathway optimizes outcomes and cost for pancreatoduodenectomy. Ann Surg. 2019;269:1138e1145. 27. Adam MA, Choudhury K, Dinan MA, et al. Minimally invasive versus open pancreaticoduodenectomy for cancer: practice patterns and short-term outcomes among 7061 patients. Ann Surg. 2015;262:372e377. 28. Croome KP, Farnell MB, Que FG, et al. Pancreaticoduodenectomy with major vascular resection: a comparison of laparoscopic versus open approaches. J Gastrointest Surg. 2014;19:189e194; discussion 194. 29. Sharpe SM, Talamonti MS, Wang CE, et al. Early national experience with laparoscopic pancreaticoduodenectomy for ductal adenocarcinoma: a comparison of laparoscopic pancreaticoduodenectomy and open pancreaticoduodenectomy from the National Cancer Data Base. J Am Coll Surg. 2015;221:175e184. 30. Kantor O, Talamonti MS, Sharpe S, et al. Laparoscopic pancreaticoduodenectomy for adenocarcinoma provides short-term oncologic outcomes and long-term overall survival rates similar to those for open pancreaticoduodenectomy. Am J Surg. 2017;213:512e515. 31. Chapman BC, Gajdos C, Hosokawa P, et al. Comparison of laparoscopic to open pancreaticoduodenectomy in elderly patients with pancreatic adenocarcinoma. Surg Endosc. 2017;32:2239e2248. 32. Kutlu OC, Lee JE, Katz MH, et al. Open pancreaticoduodenectomy case volume predicts outcome of laparoscopic approach: A population-based analysis. Ann Surg. 2018;267:552e560. 33. Varley PR, Zenati MS, Klobuka A, et al. Does robotic pancreaticoduodenectomy improve outcomes in patients with high risk morphometric features compared to the open approach. HPB (Oxford). 2019;21:695e701. 34. Mesleh MG, Stauffer JA, Bowers SP, Asbun HJ. Cost analysis of open and laparoscopic pancreaticoduodenectomy: a single institution comparison. Surg Endosc. 2013;27:4518e4523. 35. Boggi U, Napoli N, Costa F, et al. Robotic-assisted pancreatic resections. World J Surg. 2016;40:2497e2506. 36. Gerber MH, Delitto D, Crippen CJ, et al. Analysis of the cost effectiveness of laparoscopic pancreatoduodenectomy. J Gastrointest Surg. 2017;21:1404e1410. 37. Girgis M, Zenati M, Steve J, et al. Robotic approach mitigates risk of wound infection and perioperative morbidity in obese patients following pancreaticoduodenectomy. HPB (Oxford). 2017;19:93e98.
S.K. Kamarajah et al. / Surgery xxx (2020) 1e9 38. McMillan MT, Zureikat AH, Hogg ME, et al. a propensity score-matched analysis of robotic vs open pancreatoduodenectomy on incidence of pancreatic fistula. JAMA Surg. 2017;152:327e335. 39. Zimmerman AM, Roye DG, Charpentier KP. A comparison of outcomes between open, laparoscopic and robotic pancreaticoduodenectomy. HPB (Oxford). 2018;20:364e369. 40. Xourafas D, Pawlik TM, Cloyd JM. Independent predictors of increased operative time and hospital length of stay are consistent across different surgical approaches to pancreatoduodenectomy. J Gastrointest Surg. 2018;22: 1911e1919. 41. Kantor O, Pitt HA, Talamonti MS, et al. Minimally invasive pancreatoduodenectomy: is the incidence of clinically relevant postoperative pancreatic fistula comparable to that after open pancreatoduodenectomy? Surgery. 2018;163:587e593. 42. Nassour I, Wang SC, Christie A, et al. Minimally invasive versus open pancreaticoduodenectomy: a propensity-matched study from a national cohort of patients. Ann Surg. 2018;268:151e157. 43. Girgis MD, Zenati MS, et al. Oncologic outcomes after robotic pancreatic resections are not inferior to open surgery [e-pub ahead of print]. Ann Surg. 2019. https://doi.org/10.1097/SLA.0000000000003615. Accessed February 22, 2020. 44. Mendoza 3rd AS, Han H-S, Yoon Y-S, Cho JY, Choi Y. Laparoscopy-assisted pancreaticoduodenectomy as minimally invasive surgery for periampullary tumors: a comparison of short-term clinical outcomes of laparoscopy-assisted pancreaticoduodenectomy and open pancreaticoduodenectomy. J Hepatobiliary Pancreat Sci. 2015;22:819e824. 45. Tan JKH, Ng JJ, Yeo M, et al. Propensity score-matched analysis of early outcomes after laparoscopic-assisted versus open pancreaticoduodenectomy. ANZ J Surg. 2019;89:E190eE194. 46. Langan RC, Graham JA, Chin AB, et al. Laparoscopic-assisted versus open pancreaticoduodenectomy: early favorable physical quality-of-life measures. Surgery. 2014;156:379e384. 47. Wang Y, Bergman S, Piedimonte S, Vanounou T. Bridging the gap between open and minimally invasive pancreaticoduodenectomy: the hybrid approach. Can J Surg. 2014;57:263e270. 48. Wellner UF, Küsters S, Sick O, et al. Hybrid laparoscopic versus open pyloruspreserving pancreatoduodenectomy: retrospective matched case comparison in 80 patients. Langenbecks Arch Surg. 2014;399:849e856. 49. Piedimonte S, Wang Y, Bergman S, Vanounou T. Early experience with robotic pancreatic surgery in a Canadian institution. Can J Surg. 2015;58:394e401. 50. Kim HS, Han Y, Kang JS, et al. Comparison of surgical outcomes between open and robot-assisted minimally invasive pancreaticoduodenectomy. J Hepatobiliary Pancreat Sci. 2018;25:142e149. 51. Patel B, Leung U, Lee J, Bryant R, O'Rourke N, Cavallucci D. Laparoscopic pancreaticoduodenectomy in Brisbane, Australia: an initial experience. ANZ J Surg. 2017;88:E440eE444. 52. van Hilst J, de Rooij T, van den Boezem PB, et al, and the Dutch Pancreatic Cancer Group. Laparoscopic pancreatoduodenectomy with open or laparoscopic reconstruction during the learning curve: a multicenter propensity score matched study. HPB (Oxford). 2019;21:857e864.
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53. Liu R, Zhang T, Zhao ZM, et al. The surgical outcomes of robot-assisted laparoscopic pancreaticoduodenectomy versus laparoscopic pancreaticoduodenectomy for periampullary neoplasms: a comparative study of a single center. Surg Endosc. 2017;31:2380e2386. 54. Nassour I, Wang SC, Porembka MR, et al. Robotic versus laparoscopic pancreaticoduodenectomy: a NSQIP analysis. J Gastrointest Surg. 2017;21: 1784e1792. 55. Nassour I, Choti MA, Porembka MR, Yopp AC, Wang SC, Polanco PM. Roboticassisted versus laparoscopic pancreaticoduodenectomy: oncological outcomes. Surg Endosc. 2017;32:2907e2913. 56. Zhang Y, Hong D, Zhang C, Hu Z. Total laparoscopic versus robot-assisted laparoscopic pancreaticoduodenectomy. Biosci Trends. 2018;12:484e490. 57. Chen K, Liu XL, Pan Y, Maher H, Wang XF. Expanding laparoscopic pancreaticoduodenectomy to pancreatic-head and periampullary malignancy: major findings based on systematic review and meta-analysis. BMC Gastroenterol. 2018;18:102. 58. Correa-Gallego C, Dinkelspiel HE, Sulimanoff I, et al. Minimally-invasive vs open pancreaticoduodenectomy: systematic review and meta-analysis. J Am Coll Surg. 2014;218:129e139. 59. Peng L, Lin S, Li Y, Xiao W. Systematic review and meta-analysis of robotic versus open pancreaticoduodenectomy. Surg Endosc. 2017;31:3085e3097. 60. Zhang H, Wu X, Zhu F, et al. Systematic review and meta-analysis of minimally invasive versus open approach for pancreaticoduodenectomy. Surg Endosc. 2016;30:5173e5184. 61. Peng L, Zhou Z, Cao Z, Wu W, Xiao W, Cao J. Long-term oncological outcomes in laparoscopic versus open pancreaticoduodenectomy for pancreatic cancer: a systematic review and meta-analysis. J Laparoendosc Adv Surg Tech A. 2019;29: 759e769. 62. Ghaferi AA, Birkmeyer JD, Dimick JB. Hospital volume and failure to rescue with high-risk surgery. Med Care. 2011;49:1076e1081. 63. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med. 2002;346:1128e1137. 64. Adam MA, Thomas S, Youngwirth L, Pappas T, Roman SA, Sosa JA. Defining a hospital volume threshold for minimally invasive pancreaticoduodenectomy in the United States. JAMA Surg. 2017;152:336e342. 65. Birkmeyer JD, Stukel TA, Siewers AE, Goodney PP, Wennberg DE, Lucas FL. Surgeon volume and operative mortality in the United States. N Engl J Med. 2003;349:2117e2127. 66. Palanivelu C, Senthilnathan P, Sabnis SC, et al. Randomized clinical trial of laparoscopic versus open pancreatoduodenectomy for periampullary tumours. Br J Surg. 2017;104:1443e1450. 67. Poves I, Burdio F, Morato O, et al. Comparison of perioperative outcomes between laparoscopic and open approach for pancreatoduodenectomy: the PADULAP randomized controlled trial. Ann Surg. 2018;268:731e739. 68. van Hilst J, de Rooij T, Bosscha K, et al. and the Dutch Pancreatic Cancer Group. Laparoscopic versus open pancreatoduodenectomy for pancreatic or periampullary tumours (LEOPARD-2): a multicentre, patient-blinded, randomised controlled phase 2/3 trial. Lancet Gastroenterol Hepatol. 2019;4: 199e207.
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Does center or surgeon volume influence adoption of minimally invasive versus open pancreatoduodenectomy? A systematic review and meta-regression Sivesh K. Kamarajah, BMedSci, MBChBa,b,*, Mohammed Abu Hilal, MD, PhD, FRCS, FACSc, Steven A. White, MD, FRCPS, FRCSa,b a b c
Department of HPB and Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, United Kingdom Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom Department of Surgery, Southampton University Hospital NHS Foundation Trust, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 17 September 2020 Available online xxx
Background: There has been increasing uptake of minimally invasive pancreatoduodenectomy during the past decade, but it remains a highly specialized procedure as benefits over open pancreatoduodenectomy remain contentious. This study aimed to evaluate current evidence on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy in terms of impact of center volume on outcomes. Methods: A systematic review of articles on comparative cohort and registry studies on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy published until 31st December 2019 were identified, and meta-analyses were performed. Primary endpoints were International Study Group on Pancreatic Fistula grade B/C postoperative pancreatic fistula and 30-day mortality. Results: After screening 7,390 studies, 43 comparative cohort studies (8,755 patients) with moderate methodological quality and 3 original registry studies (43,735 patients) were included. For the cohort studies, the median annual hospital minimally invasive pancreatoduodenectomy volume was 10. No significant differences were found in grade B/C postoperative pancreatic fistula (odds ratio: 0.98, 95% confidence interval: 0.78e1.23) or 30-day mortality (odds ratio: 1.14, 95% confidence interval: 0.65e2.01) between minimally invasive pancreatoduodenectomy when compared with open. No publication biases were present and meta-regression identified no confounding for grade B/C postoperative pancreatic fistula, center volume or 30-day mortality. Minimally invasive pancreatoduodenectomy was only strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection, shorter length of stay, and significantly higher rates of R0 margin resections. Conclusion: Minimally invasive pancreatoduodenectomy remains noninferior to open pancreatoduodenectomy for grade B/C postoperative pancreatic fistula but is strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection. Minimally invasive pancreatoduodenectomy can be adopted safely with good outcomes irrespective of annual center resection volume. © 2020 Elsevier Inc. All rights reserved.
Introduction Pancreaticoduodenectomy (PD) remains the only potentially curative treatment for a variety of periampullary cancers. Despite recent advances in outcomes related to centralization of services, improved perioperative care and patient * Reprint requests: Dr Kathir Kamarajah, BMedSci, MBChB, Department of Hepatobiliary, Pancreatic and Transplant Surgery, Department of Surgery, Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, United Kingdom. E-mail address: [email protected] (S.K. Kamarajah). https://doi.org/10.1016/j.surg.2020.09.019 0039-6060/© 2020 Elsevier Inc. All rights reserved.
selection,1-3 PD is still associated with postoperative morbidity rates of 23% to 66% and mortality rates of 3% to 5%.2e4 Laparoscopic PD was first described in the early 1990s, whereas the first publications for robot-assisted PD appeared 10 years later.5 However, minimally invasive PD (MIPD) is a technically demanding operation and has not yet gained the same support in the surgical community, especially among hepatobiliary and pancreatic surgeons, as other minimally invasive gastrointestinal procedures.6 This is almost certainly owing to technical difficulty and the high-risk nature of minimally invasive pancreatic surgery.7,8
2
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Inclusion and exclusion criteria Inclusion criteria were (1) studies reporting the comparison of surgical techniques (by any method) in human subjects receiving PD for any indication and (2) studies published in the English language. Exclusion criteria were (1) conference abstracts, review articles, and case reports (<5 patients); (2) publications with mixed populations where the outcomes of patients undergoing either other types of pancreatic surgery (distal pancreatectomy) could not be separated from those of patients undergoing PD; and (3) hybrid procedures, where any MIPD procedure included a component of open surgery. Following exclusion duplicates, 2 researchers (S.K.K., J.R.B.) independently reviewed the titles and abstracts of studies identified by the literature search. Where a study was considered potentially relevant to the research question a full copy of the publication was obtained for further review. The reference lists of all included studies were hand searched in order to identify other potentially relevant studies. Any areas of disagreement between the 2 primary researchers were resolved through discussion with all authors. Study outcomes Fig 1. PRISMA diagram of included studies from the systematic literature review.
Postoperative pancreatic fistulas (POPFs) remain one of the most threatening complications after PD, with rates ranging from 4% to 33%.9 Cohort studies have suggested that MIPD, compared with open pancreatoduodenectomy (OPD), can safely improve postoperative morbidity rates and enhance postoperative recovery.10 Further, several studies have demonstrated equivalence in overall costs between MIPD and OPD, with MIPD associated with lower postoperative costs from reduced complications and length of stay.11e14 However, many studies were not comparative, and selection bias has likely influenced these findings. In 2016, a systematic review comparing MIPD versus OPD, comprising 19 observational studies, demonstrated higher 30-day mortality in high-volume centers compared with low-volume centers.15 During the past 4 years, many high-volume series have reported their outcomes, including both cohort16,17 and registry studies,18 which raised concerns regarding the safety of MIPD. An updated systematic review of the literature on MIPD could clarify the impact of these recent studies. The primary aim of this systematic review was to assess the evidence for MIPD versus OPD comparing postoperative and oncological outcomes. This review also aimed to assess impact of center volume on these outcomes.
Methods
The primary outcome measure was clinically relevant POPF (CRPOPF) and 30-day mortality. CR-POPF was defined according to the International Surgery Group for Pancreatic Surgery (ISGPS). Secondary outcome measures were postoperative complications (both overall and major), POPF, delayed gastric emptying, bile leak, 90day mortality, 30-day and 90-day readmission, reoperation, length of stay, and oncological (lymph node harvest and R0 resection) outcomes for malignant indications. Data extraction One researcher (S.K.K.) extracted data on study characteristics (author, year of publication, country of origin, study design, patient number), patient demographics (age, sex), method and details of surgical techniques, and reported clinical outcomes. Definitions MIPD was any technique such as totally laparoscopic (TL) and totally robotic (TR). TR was defined as the complete use of the robotic technique for PD, including resection and reconstruction, without laparoscopic or hand-assisted techniques. Nevertheless, this did include the use of laparoscopic ports by a surgical assistant as part of the robotic procedure, which is regarded as standard. TL was defined as the complete use of a laparoscopic technique for PD, including resection and reconstruction without robotic or handassisted techniques. Annual center volume was derived as a pro rata of the total operations performed over the study period.
Search strategy A systematic search of PubMed, EMBASE, and the Cochrane Library databases were conducted on the 1st of January 2020 by 2 independent investigators (S.K.K., J.R.B.). The search terms used were “robotic surgery” or “laparoscopy” or “robot-assisted,” “open,” and “Pancreaticoduodenectomy” or “Whipple procedure” or “pancreatectomy” or “pylorus-preserving pancreaticoduodenectomy” individually or in combination. Search terms used for this review are presented in Supplementary Table I. The “related articles” function was used to broaden the search, and all citations were considered for relevance. A manual search of reference lists in recent reviews and eligible studies was also undertaken. This paper is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Fig 1).19
Assessment of methodological quality Methodological quality and standard of outcome reporting within included studies were assessed by 2 independent researchers (S.K.K., J.R.B.). Methodological quality was formally assessed using the Newcastle-Ottawa score for cohort studies (S.K.K., R.G.) and the Cochrane Risk of Bias Tool for randomized controlled trial.20,21 Statistical analysis This systematic review and network meta-analysis was conducted in accordance with the recommendations of the Cochrane Library and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.22 Data analysis was undertaken using R Foundation Statistical software (R 3.2.1; R Foundation for Statistical
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Computing, Vienna, Austria), as previously described,23 to produce a random-effects meta-analysis for each outcome, providing pooled odds ratios (OR) with 95% confidence intervals (95% CIs). The choice of a random-effects analysis was based on the variability of minimally invasive techniques within each comparison group (eg, TR, TL) between the studies, which might influence the magnitude of the treatment effect.24 The I2 test was used to evaluate statistical heterogeneity of the included studies, with levels of heterogeneity defined as not important (I2: 0%e40%), moderate (I2: 30%e60%), substantial (I2: 50%e90%), or considerable (I2: 75%e100%).25 The c2 test was used for the same purpose, with a statistical significance level of P < .05 indicating presence of statistical heterogeneity. Publication bias and small-study effects were assessed using the Egger test for statistical asymmetry in the funnel plot, with a statistical significance level of P < .10 indicating publication bias or small-study effects. Random-effects meta-regression was used to adjust for potential confounding by the following variables: patient age (median), physical status according to the American Society of Anesthesiologists (ASA) class (I, II, III, and IV), surgery type, and use of chemo (radio)-therapy (neoadjuvant therapy used if present, otherwise adjuvant therapy; yes and no) upon the results of the outcomes. These adjusted estimates were presented as pooled OR with 95% confidence intervals, where applicable. Cutoffs for the annual MIPD and OPD volume were derived from the median of the included studies. Results Study inclusion Of the 7,390 studies identified, 77 studies were identified for full text analysis. Of these 77 studies, 31 studies were excluded as 18 studies26e43 were duplicates, 9 studies44e52 included a handassisted component, and 4 studies53e56 compared TR versus TL. Forty-six studies were included into this systematic review (Fig 1). One study by Song et al10 included 3 cohorts of patients, 1 for resections of benign conditions, 1 for resection of ampullary carcinoma, and another for resection of pancreatic ductal adenocarcinoma with outcomes reported separately. As such, these cohorts were treated separately within the analyses.
3
the studies was moderate (I2 ¼ 39%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .9), arguing against small-study effects or publication bias. Meta-regression indicated confounding factors were ASA grade, body mass index, retrospective case series, and studies published in Europe (Supplementary Table IV). In subset analyses (Table I), studies published in Europe were associated with higher rates of CR-POPF, while prospective cohort studies were associated with significantly lower rates of CR-POPF. However, analyses by annual center volume by overall volume (Fig 2), OPD only volume or MIPD only volume did not demonstrate any association with CR-POPF by quintiles. 30-day mortality A total of 31 studies reported 30-day mortality (Supplementary Fig 2). The pooled analysis revealed similar rates of 30-day mortality after MIPD when compared with OPD (2% vs 2%, OR 1.14, 95% CI: 0.65e2.02; P ¼ .6). The statistical heterogeneity of these studies was substantial (I2 ¼ 73%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .3), arguing against small-study effects or publication bias. Meta-regression indicated confounding factors were ASA grade, body mass index, retrospective case series, and studies published in Europe (Supplementary Table V). In subset analyses (Table II), studies published in Europe were associated with higher rates of CR-POPF, while prospective cohort studies were associated with significantly lower rates of CR-POPF. However, analyses by annual center volume by overall volume (Fig 3), OPD only volume or MIPD only volume did not demonstrate any association with 30-day mortality by quintiles. Secondary outcomes Overall complications A total of 33 studies reported overall complications. The pooled analysis revealed similar rates of overall complications after MIPD when compared with OPD (41% vs 49%, OR 0.87, 95% CI: 0.71e1.05; P ¼ .1). The statistical heterogeneity of the studies was substantial (I2 ¼ 63%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .5), arguing against smallstudy effects or publication bias.
Study characteristics Of these studies, 46 were cohort studies, and 3 were randomized clinical trials, together including 52,490 patients. In this cohort, 7,592 (14.5%) patients underwent MIPD. Some characteristics of the included studies are presented in Supplementary Table II. From the total MIPD (n ¼ 46), 12 studies reported TR. The median patient age was reported in 44 studies for both MIPD (96%) and OPD (96%) studies. Physical status (ASA class) was reported for both comparison groups in 20 studies (43%). The quality scores of the cohort studies varied between 5 and 9, with a median value of 7 according to the Newcastle-Ottawa scale (Supplementary Table II). The 3 randomized clinical trials were evaluated to have low risks of bias, except for performance bias owing to the problem of masking surgical treatment, according to the Cochrane Collaborations Risk of Bias Tool.
Major complications A total of 29 studies reported major complications (Supplementary Fig 3). The pooled analysis revealed similar rates of major complications after MIPD compared with OPD (19% vs 33%, OR 0.99, 95% CI: 0.81e1.23; P ¼ .9). The statistical heterogeneity of the studies was moderate (I2 ¼ 42%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .06), arguing against small-study effects or publication bias.
Primary outcomes
Grade B/C delayed gastric emptying A total of 13 studies reported Grade B/C delayed gastric emptying. The pooled analysis revealed similar rates of Grade B/C delayed gastric emptying after MIPD compared with OPD (13% vs 8%, OR 0.83, 95% CI: 0.49e1.40; P ¼ .5). The statistical heterogeneity of the studies was substantial (I2 ¼ 71%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .7), arguing against small-study effects or publication bias.
Clinically relevant POPF A total of 29 studies reported CR-POPF (Supplementary Fig 1). The pooled analysis revealed similar rates of CR-POPF after MIPD when compared with OPD (12% vs 9%, OR 0.98, 95% CI 0.78e1.24; P ¼ .9) (Supplementary Table III). The statistical heterogeneity of
Bile leak A total of 15 studies reported bile leak. The pooled analysis revealed similar rates of bile leak after MIPD compared with OPD (5% vs 5%, OR 1.12, 95% CI: 0.69e1.82; P ¼ .7). The statistical heterogeneity of the studies was not important (I2 ¼ 0%). The funnel
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Table I Sensitivity analyses of studies for CR-POPF
Study year 2009e2014 2015e2019 Study region Asia Europe North America Study duration 3 y >3 y Study design PCS RCS RCT Study type Institutional Registry Case matching No Yes Total annual volume 30 >30 Open annual volume 20 >20 MI annual volume 10 >10 MI approach MI TL TR
Studies, n
OR (95% CI)
Z value
P value
I2
Egger's
4 25
0.93 (0.54e1.61) 0.99 (0.76e1.28)
e0.25 e0.1
.8 .9
0 47
0.3 1.0
11 6 12
0.74 (0.50e1.09) 1.54 (1.03e2.30) 0.92 (0.66e1.28)
e1.54 2.12 e0.48
.1 .034 .6
0 22 52
0.8 0.3 0.9
9 20
1.24 (0.92e1.66) 0.89 (0.66e1.19)
1.43 e0.79
.2 .4
0 52
0.9 0.9
2 24 3
0.46 (0.30e0.69) 1.15 (0.95e1.41) 0.73 (0.34e1.58)
e3.71 1.41 e0.81
<.001 .2 .4
0 12 16
0.4 0.4
28 1
0.97 (0.76e1.24)
e0.26 -
.8 -
41 -
0.9 -
17 12
1.13 (0.86e1.48) 0.72 (0.49e1.05)
0.9 e1.71
.4 .1
46 12
0.2 0.3
12 17
1.23 (0.82e1.84) 0.93 (0.71e1.22)
0.98 e0.53
.3 .6
8 50
0.6 0.9
15 14
0.92 (0.65e1.31) 1.02 (0.75e1.39)
e0.45 0.14
.7 .9
0 61
0.3 0.5
12 17
1.25 (0.83e1.88) 0.93 (0.71e1.21)
1.07 e0.56
.3 .6
7 50
0.4 0.9
2 19 8
1.29 (0.70e2.37) 0.94 (0.73e1.22) 1.03 (0.591.80)
0.82 e0.46 0.09
.4 .6 .9
12 15 69
0.4 0.7
Bolded values indicate significant findings. PCS, prospective cohort study; RCS, retrospective cohort study.
plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .6), arguing against small-study effects or publication bias. Surgical site infection A total of 26 studies reported surgical site infection (SSI) (Supplementary Fig 4). The pooled analysis revealed significantly lower rates of SSI after MIPD compared with OPD (13% vs 21%, OR 0.69, 95% CI: 0.55e0.86; P ¼ .001). The statistical heterogeneity of the studies was not important (I2 ¼ 13%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .07), arguing against small-study effects or publication bias. Postoperative pulmonary complications A total of 15 studies reported postoperative pulmonary complications (PPC) (Supplementary Fig 5). The pooled analysis revealed significantly lower rates of PPC after MIPD compared with OPD (10% vs 17%, OR 0.70, 95% CI: 0.59e0.83; P < .001). The statistical heterogeneity of the studies was not important (I2 ¼ 0%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .7), arguing against small-study effects or publication bias. 90-day mortality A total of 8 studies reported 90-day mortality. The pooled analysis revealed similar rates of 90-day mortality after MIPD compared with OPD (4% vs 5%, OR 1.09, 95% CI: 0.59e2.02; P ¼ .8). The statistical heterogeneity of the studies was moderate (I2 ¼ 53%). The funnel plot was symmetrical both according to visual and
statistical testing (Egger test, P ¼ .2), arguing against small-study effects or publication bias. 30-day and 90-day readmission A total of 18 studies reported 30-day readmission. The pooled analysis revealed similar rates of 30-day readmission after MIPD compared with OPD (10% vs 10%, OR 1.13, 95% CI: 0.90e1.41; P ¼ .3). The statistical heterogeneity of the studies was not important (I2 ¼ 31%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .4), arguing against small-study effects or publication bias. A total of 4 studies reported 90-day readmission. The pooled analysis revealed similar rates of 90-day readmission after MIPD compared with OPD (27% vs 26%, OR 0.90, 95% CI: 0.54e1.51; P ¼ .7). The statistical heterogeneity of the studies was substantial (I2 ¼ 75%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ 1.0), arguing against small-study effects or publication bias. Length of stay A total of 42 studies reported length of stay (Supplementary Fig 6). The pooled analysis revealed significantly shorter length of stay after MIPD compared with OPD (mean: 13.0 vs 14.8 days, SD: e1.29, 95% CI: e1.99 to e0.60; P < .001). The statistical heterogeneity of the studies was considerable (I2 ¼ 100%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .9), arguing against small-study effects or publication bias. R0 resection margin Of the studies on cancer resection (n ¼ 31 studies), a total of 19 studies reported R0 margins (Supplementary Fig 7). The pooled
S.K. Kamarajah et al. / Surgery xxx (2020) 1e9
5
Fig 2. Impact of overall center annual resectional volume on CR-POPF: (A) Quintile 1, (B) Quintile 2, (C) Quintile 3, (D) Quintile 4, and (E) Quintile 5.
analysis revealed significantly higher R0 resections after MIPD compared with OPD (84% vs 80%, OR: 1.61, 95% CI: 1.02e2.54; P ¼ .041). The statistical heterogeneity of the studies was substantial
(I2 ¼ 74%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .2), arguing against smallstudy effects or publication bias.
6
S.K. Kamarajah et al. / Surgery xxx (2020) 1e9
Table II Sensitivity analyses of studies for 30-d mortality
Study year 2009e2014 2015e2019 Study region Asia Europe North America Study duration 3 years >3 years Study design PCS RCS RCT Study type Institutional Registry Case matching No Yes Total annual volume 30 >30 Open annual volume 20 >20 MI annual volume 10 >10 MI approach MI TL TR
Studies, n
OR (95% CI)
Z value
P value
I2
Egger's
9 22
0.78 (0.35e1.73) 1.25 (0.64e2.47)
e0.61 0.65
.5 .5
0 80
0.9 0.5
10 6 15
1.04 (0.41e2.65) 0.79 (0.37e1.67) 1.34 (0.59e3.03)
0.08 e0.62 0.69
.9 .5 .5
0 0 85
0.8 0.6 0.8
9 22
1.07 (0.59e1.92) 1.08 (0.53e2.18)
0.22 0.2
.8 .8
0 80
0.5 0.3
3 25 3
0.84 (0.21e3.31) 1.16 (0.61e2.20) 1.22 (0.17e8.82)
e0.25 0.46 0.2
.8 .6 .8
0 77 40
0.3 0.4 0.3
28 3
0.98 (0.64e1.49)
e0.1 0.62
.9 .5
0 98
0.8 0.9
20 11
0.83 (0.63e1.10) 1.59 (0.56e4.55)
e1.31 0.87
.2 .4
0 55
0.6 0.001
16 15
0.96 (0.42e2.23) 1.20 (0.69e2.08)
e0.08 0.64
.9 .5
85 0
0.4 0.4
18 13
1.08 (0.48e2.44) 1.06 (0.63e1.80)
0.18 0.22
.9 .8
82 0
0.5 0.7
18 13
0.99 (0.45e2.15) 1.34 (0.71e2.50)
e0.03 0.91
1.0 .4
83 0
0.3 0.4
3 20 8
2.48 (0.39e15.88) 0.86 (0.63e1.17) 0.75 (0.33e1.69)
0.96 e0.97 e0.7
.3 .3 .5
93 0 0
0.8 0.5 0.9
Bolded value indicates significant findings. PCS, prospective cohort study; RCS, retrospective cohort study.
Lymph node harvest Of the studies on cancer resection (n ¼ 31), a total of 18 studies reported lymph node harvest (Supplementary Fig 8). The pooled analysis revealed no significant difference in number of lymph node harvest between MIPD compared with OPD (median: 18 vs 17 nodes, SD: 0.51, 95% CI: e0.35 to 1.36; P ¼ .2). The statistical heterogeneity of the studies was substantial (I2 ¼ 86%). The funnel plot was symmetrical both according to visual and statistical testing (Egger test, P ¼ .2), arguing against small-study effects or publication bias. Discussion This systematic review and meta-analysis of 52,490 patients from 46 studies demonstrates that MIPD is associated with a noninferior CR-POPF and 30-day mortality when compared with OPD. Meta-regression for CR-POPF and 30-day mortality demonstrated no confounders affecting these outcomes. Stratified analyses for total annual, open, or minimally invasive center volume demonstrated no significant difference in rates of CR-POPF or 30day mortality across these quintiles. Notably, MIPD were only strongly associated with significantly lower rates of PPC and SSI, shorter length of stay, and significantly higher rates of R0 margin resections. These findings are clinically important, because they may lead to quicker postoperative recovery, earlier receipt of adjuvant therapy for cancer patients, and hence may translate to improvement to long-term survival. Although several meta-analyses have compared outcomes for MIPD against the conventional open approach,57e61 none have explored the relationship between center volume and MIPD on postoperative outcomes. This review demonstrated no impact of
CR-POPF and 30-day mortality when stratified by center-volume quintiles. This is counterintuitive, because the relationship between center volume and surgical outcome is well established, with improved outcomes in higher-volume centers.62,63 A registry study from Adam et al64 on MIPD demonstrated hospital volume is significantly associated with improved outcomes from MIPD, with a threshold of 22 cases per year, despite the majority of resections being at low-volume centers. There are 2 reasons for the observed findings in this review. Firstly, centers adopting MIPD are likely to be existing high-volume centers, where outcomes are less likely to be affected, which is confirmed from our subgroup analyses. Secondly, it is also possible that high-volume surgeons, rather than a high-volume center, are the ones performing MIPD within these centers, which has been described previously.65 Current evidence for MIPD is limited to observational studies, and only 3 randomized controlled trials (RCTs) comparing laparoscopic versus open PD have been published.66e68 From these RCTs, only 2 demonstrated that laparoscopic PD was associated with a significantly shorter length of hospital stay66,67 and compares other variations to the conventional open PD. In the present study, MIPD was associated with significantly shorter length of hospital stay but was associated with a wide range for both MIPD (range: 6e27 days) and OPD (range: 8e61 days). This is likely related to institutional practices such as presence of Enhanced Recovery After Surgery services or surgeon preferences in patient discharge, although this remains unclear at present. In contrast, one RCT68 was stopped early owing to higher mortality, but this was likely owing to inclusion of low- and high-volume centers compared with the previously reported RCTs. In addition, there have been an increased adoption of robotic PD in some centers, but no RCT at present owing
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7
Fig 3. Impact of overall center annual resectional volume on 30-day mortality: (A) Quintile 1, (B) Quintile 2, (C) Quintile 3, (D) Quintile 4, and (E) Quintile 5.
to surgeons being at various stages in their learning curves. Moving forward, further RCTs are required to truly demonstrate the impact of MIPD, and data from this study will help plan study design and primary outcomes of interest.
The study has both strengths and weaknesses. A strength is the extensive literature search, covering randomized and nonrandomized clinical trials, which provided a large number of patients. The low presence of heterogeneity, small-study effects, and
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symmetrical funnel plots for all outcomes reflects higher internal validity of these studies and hence strengthens the validity of the results for these outcomes. Notably, a majority of papers included in this review were published from 2014 onwards, precluding any bias owing to improved treatment over time. The meta-regression was adjusted for important technical factors and showed no confounding by these factors. Yet, residual confounding cannot be excluded, especially for patient- (ie, age, ASA grade, previous history of pancreatitis) and tumor-related (ie, tumor size) factors, which was only reported in relatively few of the included papers. There is a possibility that patients with beneficial prognostic variables, for example, younger age and less comorbidity, were more readily selected for MIPD rather than OPD. Furthermore, only 3 studies were RCTs, and the remaining included studies were retrospective cohort studies. Therefore, these selection biases may also reflect higher R0 margins in MIPD compared with OPD. Another limitation to highlight is the variation in the stages of learning curve of surgeons performing these operations are not well captured or documented in the included studies. Therefore, it was not possible to limit analyses to studies where learning curves were achieved. In conclusion, over the past decade, MIPD remained noninferior to OPD for CR-POPF, but strongly associated with significantly lower rates of PPC and SSI. MIPD can be adopted safely with good outcomes irrespective of annual center resection volume provided the operative surgeon has the appropriate level of technical skill, appropriate training, and experience. Conflict of interest/Disclosure All authors have nothing to disclose. Funding/Support There is no funding to disclose. Supplementary materials Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.1016/j.surg.2020. 09.019. References 1. Gooiker GA, Lemmens VE, Besselink MG, et al. Impact of centralization of pancreatic cancer surgery on resection rates and survival. Br J Surg. 2014;101: 1000e1005. 2. de Wilde RF, Besselink MG, van der Tweel I, et al. and the Dutch Pancreatic Cancer Group. Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. Br J Surg. 2012;99:404e410. 3. Elberm H, Ravikumar R, Sabin C, et al. Outcome after pancreaticoduodenectomy for T3 adenocarcinoma: a multivariable analysis from the UK Vascular Resection for Pancreatic Cancer Study Group. Eur J Surg Oncol. 2015;41:1500e1507. 4. Abu Hilal M, Di Fabio F, Badran A, et al. Implementation of enhanced recovery programme after pancreatoduodenectomy: a single-centre UK pilot study. Pancreatology. 2013;13:58e62. 5. Gagner M, Pomp A. Laparoscopic pylorus-preserving pancreatoduodenectomy. Surg Endosc. 1994;8:408e410. 6. Kamarajah SK, Bundred JR, Marc OS, et al. A systematic review and network meta-analysis of different surgical approaches for pancreaticoduodenectomy. HPB (Oxford). 2020;22:329e339. 7. Mathur A, Ross SB, Luberice K, et al. Margin status impacts survival after pancreaticoduodenectomy but negative margins should not be pursued. Am Surg. 2014;80:353e360. 8. de la Fuente SG. Laparoscopic pancreaticoduodenectomies: a word of caution. J Am Coll Surg. 2013;216:1218. 9. Lyu Y, Li T, Cheng Y, Wang B, Chen L, Zhao S. Pancreaticojejunostomy versus pancreaticogastrostomy after pancreaticoduodenectomy: an up-to-date metaanalysis of RCTs applying the ISGPS (2016) criteria. Surg Laparosc Endosc Percutan Tech. 2018;28:139e146.
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