Outcomes of Robotic versus Laparoscopic Partial Nephrectomy: an Updated Meta-Analysis of 4,919 Patients

Outcomes of Robotic versus Laparoscopic Partial Nephrectomy: an Updated Meta-Analysis of 4,919 Patients

Author's Accepted Manuscript Outcomes After Robotic Versus Laparoscopic Partial Nephrectomy: An Updated Meta-Analysis Of 4919 Patients Jeffrey J. Leow...

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Author's Accepted Manuscript Outcomes After Robotic Versus Laparoscopic Partial Nephrectomy: An Updated Meta-Analysis Of 4919 Patients Jeffrey J. Leow , Nathaniel H. Heah , Steven L. Chang , Yew Lam Chong , Keng Siang Png

PII: DOI: Reference:

S0022-5347(16)30583-3 10.1016/j.juro.2016.06.011 JURO 13792

To appear in: The Journal of Urology Accepted Date: 2 June 2016 Please cite this article as: Leow JJ, Heah NH, Chang SL, Chong YL, Png KS, Outcomes After Robotic Versus Laparoscopic Partial Nephrectomy: An Updated Meta-Analysis Of 4919 Patients, The Journal of Urology® (2016), doi: 10.1016/j.juro.2016.06.011. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.

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Outcomes After Robotic Versus Laparoscopic Partial Nephrectomy: An Updated Meta-Analysis Of 4919

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Patients

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Siang Png1

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Jeffrey J. Leow1,2*, Nathaniel H. Heah1, Steven L. Chang2, Yew Lam Chong1, Keng

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Department of Urology, Tan Tock Seng Hospital, Singapore

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Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard

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Corresponding Author:

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Medical School, Boston, MA, United States

Jeffrey J. Leow, MBBS, MPH

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Department of Urology, Tan Tock Seng Hospital 11 Jalan Tan Tock Seng, Singapore 308433

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Email: [email protected] Abstract word count: 249 (max 250) Manuscript word count: 2386 (max 2500) Tables: 3; Figures: 3; References: 30 (max 30) Key words: partial nephrectomy, kidney neoplasms, robot-assisted, robotic surgery, technology, outcomes Running title: Outcomes of laparoscopic vs. robotic partial nephrectomy

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ABSTRACT

Purpose: To evaluate current literature comparing outcomes of robotic partial

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nephrectomy (RPN) versus laparoscopic partial nephrectomy (LPN).

Materials and methods: We performed a literature search according to Cochrane

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guidelines up to December 2015 including studies comparing RPN and LPN. We

compared baseline patient and tumour characteristics. We performed a meta-analysis

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to evaluate safety, effectiveness and functional outcomes of RPN vs. LPON, using weighted mean difference (WMD) and inverse variance pooled risk ratios (RR) respectively.

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Results: A total of 4919 patients were included from 25 studies (2681 RPN, 2238 LPN). No significant differences exist between the 2 groups in terms of age, sex, laterality, and final malignant pathology. RPN patients had larger tumours (WMD= +0.17cm, p=0.001),

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higher mean RENAL nephrometry scores (WMD= +0.59, , p=0.002) and was associated with decreased likelihood of conversion to laparoscopic/open surgery compared to LPN

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(RR: 0.36, p<0.001), any (Clavien≥1) (RR: 0.84, p=0.007) and major (Clavien≥3) (RR: 0.71, p=0.023) complications, positive margins (RR: 0.53, p<0.001) and shorter WIT by 4.3 mins (p<0.001). Both approaches had similar operative time (WMD: -12.2 minutes, p=0.34), estimated blood loss (WMD: -24.6 mls, p=0.15) and postoperative change in eGFR.

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Conclusions: This updated meta-analysis of retrospective cohort studies found that RPN confers a superior morbidity profile compared to LPN in most of the examined perioperative outcomes. Despite being the strongest available evidence (Level 2b) for

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randomized trials to lend Level 1 support for either approach.

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outcomes of RPN vs. LPN thus far, there has been no completed or ongoing

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INTRODUCTION PN is the gold standard treatment option for clinical T1 renal masses, according to the latest guidelines. Technological advances, improvement in equipment, and

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operator skills have enabled surgeons to perform minimally invasive PN preferentially over open surgery for small renal masses, especially in light of equivalent oncologic outcomes, decreased peri-operative morbidity and convalescence.1-3 However, it is also

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well recognized that pure LPN is technically challenging with a relatively prolonged learning curve due to the necessity for precise tumour resection and time-dependent

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renal reconstruction. Some have suggested that the technical and ergonomic difficulties faced by surgeons during LPN have limited its dissemination.2,4,5

The rapid adoption of robot-assisted radical prostatectomies has increased

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urologists’ experience and familiarity with pelvic robotic surgery. Over the years, we have seen this familiarity translated to kidney surgery. A recent NIS study from 2008 to 2010 found that RPN has overtaken LPN as the predominant minimally invasive option

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for PN (23.9% vs. 9.2%).6 However, with regard to outcomes, there still exists controversy as to whether RPN or LPN is superior. Recent systematic reviews and

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meta-analysis have presented mixed results with overlapping studies from the same centres included, with the latest meta-analysis including only studies published up to December 2013.4 Given the recent publication of 8 new studies, including a large 5center study in 2015,2,3,5,7-11 the need for an updated and accurate meta-analysis is clear. This study aims to provide the latest evidence in the comparison of outcomes of RPN vs. LPN.

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MATERIALS AND METHODS

Search strategy

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A systematic literature search of PubMed and Embase was performed to identify observational cohort studies and randomized controlled trials performed prior to

December 2015 which examined outcomes of RPN vs. LPN. References were manually

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reviewed to identify additional studies of interest. The following search terms and

related variants were used: kidney or renal neoplasm/ cancer/ carcinoma, robotics,

Inclusion criteria and study eligibility

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computer-assisted surgery, telerobot, remote operation/surgery, da Vinci.

We evaluated all search results according to the Preferred Reporting Items

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Systematic Reviews and Meta-Analysis (PRISMA) statement. We defined study eligibility using the patient population, intervention, comparator, outcomes and setting approach. We included studies that focused on patients with kidney cancer or small

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renal masses, and those that compared outcomes between RPN and LPN. We excluded studies that (1) included patients with solitary kidneys and (2) included

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patients who underwent hand-assisted laparoscopic surgery instead of the conventional laparoscopic approach. Studies which did not have primary data (i.e. review papers, commentaries, meta-analyses) were excluded, however they were also examined to ensure all relevant studies were included in our updated meta-analysis.

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There were several studies which data from an overlapping study period from the same institution published by the same authors; we only included the latest study to ensure that we did not have duplicated data. Where there was missing or unavailable

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information, effort was made to contact the corresponding authors via email. The

corresponding authors of 2 studies replied with additional information as requested12,13

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and are acknowledged.

Several studies reported medians, inter-quartile ranges, or minimum and

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maximum values.9,14-18 Because only means and standard deviations are permitted for the computational portion of meta-analyses, we utilized a novel and validated mathematical method to convert medians, inter-quartile ranges, or minimum/maximum

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values into means and standard deviations.19

Data extraction and analysis

Guidelines for meta-analysis of observational studies were followed given that

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there were no randomized trials included. Retrieved abstracts were independently reviewed by two authors (JL and NH), with full articles retrieved for further review.

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Subsequently, information on all available variables were extracted; these include baseline characteristics (age, gender, body mass index, tumour characteristics (tumour laterality [left/right], final malignant pathology, size, location [upper/middle/lower], RENAL nephrometry score), peri-operative outcomes (operative time, WIT, EBL, LOS positive margins, conversion to open/laparocopic surgery or radical nephrectomy, postoperative complications [Clavien ≥1], postoperative major complications [Clavien

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≥3]) and functional outcomes (change in eGFR). Disagreement was resolved by consensus.

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Statistical analysis

For continuous and categorical outcomes, WMDs and RRs were calculated with 95% CI. Statistical heterogeneity between studies was defined as a Cochran-Q p-value

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<0·05 or I2 statistic>50%. A fixed effects model was used unless there was statistically significant heterogeneity (either by Cochrane-Q statistic or by I2). Because some series

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represented more than 1 center, we calculated annualized volume per center. We arbitarily dichotomized annualized volume into high (≥24) and low (<24) per year per center, which represents ≥2 and <2 per month. To evaluate publication bias, Egger linear regression and funnel plots were examined. All statistical analyses were

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performed using STATA/SE version 12.0 (Stata, College Station, TX). The study was deemed exempt by the Institutional Review Board at Tan Tock Seng Hospital,

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Singapore.

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RESULTS Baseline characteristics We identified 25 eligible studies (Figure 1),2,3,5,7-18,20-29 with a total of 4,919

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patients, of which 2,681 underwent RPN and 2,238 underwent LPN (Table 1). In terms of baseline characteristics (Table 2), we found no statistically significant differences between patients who underwent RPN vs. LPN in terms of age (p=0.25), gender

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(p=0.84), laterality (left vs. right) (p=0.09), final malignant pathology (p=0.73),

highlighting that these 2 groups were generally comparable (Online Supplement

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Figures 1a-d).

Tumour size was 0.17 cm larger (95% CI: 0.06 to 0.27) for RPN compared to LPN (p=0.001). RPN had higher mean nephrometry scores (WMD= +0.59, 95% CI: 0.21

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to 0.97, p=0.002) (Online Supplement Figures 1e and 1f).

Safety outcomes

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Table 3 summarizes the outcomes reported by included studies. Our intraoperative safety outcomes included conversion to laparoscopic/open surgery and

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radical nephrectomy (Figures 2a-b). RPN was associated with decreased likelihood of conversion to laparoscopic/open surgery compared to LPN (RR: 0.36, 95% CI: 0.22 to 0.61, p<0.001). RPN was less likely to conversion to radical nephrectomy (RR: 0.44, 95% CI: 0.18 to 1.09) however this was not statistically significant (p=0.08).

Our postoperative safety outcomes included complication rates as defined by the

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Clavien classification system (Figures 2c-d). RPN was associated with 16% decreased risk of any complications (Clavien≥1) (RR: 0.84, 95% CI: 0.73 to 0.95, p=0.007) and 29% decreased risk of major complications (Clavien≥3) (RR: 0.71, 95% CI: 0.52 to 0.95,

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p=0.023).

Effectiveness outcomes

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Intraoperative effectiveness outcomes include operative time, EBL and WIT (Figures 2e-g). There were no significant differences between RPN and LPN in terms

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of operative time (WMD: -12.2 minutes, 95% CI: -37.4 to +13.0 minutes, p=0.34) and EBL (WMD: -24.6 mls, 95% CI: -57.9 to +8.8 mls, p=0.15. We found that RPN was associated with shorter WIT by 4.3 mins (95% CI: -6.2 to -2.5 mins, p<0.001). The only postoperative effectiveness outcome was hospital LOS also did not differ significantly

Functional outcomes

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between both groups (WMD: -0.22, 95% CI: -0.47 to +0.04, p = 0.10) (Figure 2h).

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Compared to LPN, RPN patients did not have any statistically significant difference in terms of preoperative (p=0.63) and postoperative (=0.49) eGFR. In terms

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of the change in eGFR, it was similar as well (WMD: -2.1, 95% CI: -8.2 to +4.0, p=0.50) (Figures 2i-k).

Oncologic outcomes

For positive margins, 5 studies had zero positive margins in both RPN and LPN arms, so were excluded from the analysis. RPN had a 47% decreased risk of positive

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margins compared to LPN (RR: 0.53, 95% CI: 0.39 to 0.72, p<0.001) (Figure 2l).

Subgroup analysis of complex tumours (RENAL Nephrometry ≥7)

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There were 3 studies which included only patients who had complex renal tumours as defined by RENAL nephrometry scores ≥7.1,17,24 Other studies were

excluded as they did not report outcomes stratified by nephrometry scores. Across

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these 3 studies, there were a total of 724 patients (369 RPN; 355 LPN). Baseline

characteristics were comparable in terms of age (p=0.06), gender (p=0.42), tumour

nephrometry score (p=0.77).

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laterality (p=0.96), final malignant pathology (p=0.94), tumour size (p=0.51), and

As for operative time, RPN was found to be faster by 28 min (95% CI: 6 to 49

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mins, p=0.011), had shorter LOS (WMD: -0.27 days, 95% CI: -0.03 to -0.52, p=0.029) and shorter WIT (WMD: -1.48 min, 95% CI: -2.90 to -0.07, p=0.04). There was no difference in EBL (WMD: +2.104 mls, 95% CI: =81.396 to +85.604 mls, p=0.961),

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positive margins (RR: 0.64, 95% CI: 0.16 to 2.49, p=0.52), rates of any complications (RR: 0.94, 95% CI: 0.73 to 1.22, p=0.65), or major complications (RR: 0.97, 95% CI:

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0.48 to 1.96, p=0.93). Conversions to lap/open surgery was not assessed because there was only data from 1 study available (Online Supplement Figure 2a-l).

Subgroup analysis of high vs. low volume centers We also performed a subgroup analysis of high volume (≥24/year/center) vs. low volume (<24/year/center) series. Forrest plots for each outcome stratified by volume

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status are shown in Online Supplement Figures 3(a) to (i). Results are summarized in Table 3 as well.

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For operative time, EBL and postoperative change in eGFR, there were no

differences between RPN and LPN at high- or low-volume centers. For hospital LOS, there was no difference between RPN and LPN at high volume centers (WMD: -0.04

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days, 95% CI: -0.41 to +0.33, p=0.82); however LOS was shorter at low-volume centers for RPN compared to LPN (WMD: -0.40 days, 95% CI: -0.75 to -0.05, p=0.027). RPN

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had shorter WIT compared to LPN at both high-volume (WMD: -3.0 mins, 95% CI: -5.8 to -0.2, p=0.033) and low-volume centers (WMD: -5.5 mins, 95% CI: -8.1 to -2.9,

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p<0.001).

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DISCUSSION This is an updated meta-analysis taking into consideration more than double the number of patients (N=4919) compared to the previously published meta-analysis by

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Choi et al (N=2240) in 2015.4 This is also the first meta-analysis to take into account the complexity of the tumour by comparing the nephrometry score in both groups. Our meta-analysis found that despite having larger tumours with higher nephrometry scores,

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RPN continued to demonstrate shorter WIT, decreased rates of positive surgical

margins, fewer conversions, fewer major complications and complications overall when

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compared to LPN.

Previous meta-analyses conducted comparing the perioperative outcomes of RPN and LPN had shown no differences in terms of LOS, EBL, operative times and

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complication rates, however these studies had small numbers. Choi et al conducted the most recent meta-anlysis of RPN vs. LPN outcomes, and while numbers were reasonable (N=2240), the study included overlapping studies that diluted the pool of

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unique patients in the combined cohort.4 Our current meta-analysis has more than doubled the previous study in terms of numbers, with the inclusion of 8 new studies

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published in 2015;2,3,5,7-11 these represented outcomes from large centres with mature robotic programs which were performing RPN on larger, more complex tumours, compared to earlier studies.2,27,29

The main advantage of robot-assisted surgery for partial nephrectomy is instrument dexterity, allowing the surgeon to perform the complex tasks of excising

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renal tumours and reconstructing the collecting system and the cortex, while working within the constraints of warm ischemia.1,2,5,9 While laparoscopic surgery inherently shares the same advantages of shorter hospital stays, reduced pain, quicker return to

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daily activities and better cosmesis when compared to open surgery, the limited range of motion from laparoscopic instruments makes partial nephrectomies challenging. Our subgroup analysis from 3 studies that included results stratified for complex

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tumours1,17,24 showed that RPN operative time was found to be 28 mins faster than LPN. This highlights the unique ability of RPN in managing these complex tumours, and

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emphasizes the advantage that the robotic approach offers the surgeon due to the increased manoeuvrability of the instruments.

We attempted to study the benefit of robot-assistance in both high-volume

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(≥24/year/center) and low-volume centers. We found operative time and hospital LOS was shorter for RPN compared to LPN at low-volume centers, but no differences at high-volume centers. This supports our notion that RPN should be the technique of

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choice for nephron sparing surgery (over LPN) at low-volume centers (<24 cases/year), presumably because robot-assistance shortens the learning curve compared to

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conventional laparoscopy. This benefit may be mitigated in high volume centers with skilled laparoscopic surgeons. WIT is shorter for RPN regardless of whether the center was high or low volume, indicating the superiority of the robotic approach for preventing nephron ischemia. There was however no difference in postoperative change in eGFR between these 2 approaches. The oncologic equivalance of RPN to LPN is demonstrated with no difference in positive margin rates even at low-volume centers.

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Additionally, the safety of performing RPN at low-volume centers is demonstrated when similar rates of any complications (Clavien≥1) and major complications (Clavien≥3) are

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seen.

Current evidence for RPN continues to lack randomized controlled trials.

Furthermore, current practice dictates that the likelihood of randomized controlled trials

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being performed remains low, as most partial nephrectomies will continue to be performed via the robotic approach. Additionally, patients may not be willing to

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participate in randomised trials, which may subject them to a technique that they may consider to be less technologically advanced. Although lacking in RCTs, the strength of this meta-analysis is in its size (N=4941), representing the strongest available evidence

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(Level 2b) for outcomes of RPN vs. LPN.

Limitations

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Despite strengths, this study has several limitations. First, the studies evaluated contained no prospective RCTs due to the lack of the availability of these studies.

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Therefore although this study is the largest series of RPN vs. LPN, this is at best Level 2b evidence. Second, the study was not conducted with the raw individual patient data, which would be able to more accurately aggregate results. Additionally, we cannot compare variables which were not reported in individual studies, for example, costs, individual surgeon volume/experience, readmissions, or blood transfusions. During the study periods represented, several centers have switched their approach from pure

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laparoscopic to robotic, therefore the robotic experience is based on the learning curve being partly completed during the lap experience. Third, short follow-up duration imply that no oncologic outcomes (e.g. overall survival) could be evaluated. Fourth,

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complexity and location of a renal tumour make a substantial difference in both RPN and LPN. There is a distinct lack of analysis according to the nature of the tumour. The RENAL nephrometry score acts as a surrogate to characterise tumour location and

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complexity. This meta-analysis only contained 3 studies that clearly stratified results according to RENAL scoring. In the wake of this current meta-analysis, further efforts

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should focus on studies which perform stratified analyses based on tumour location and complexity. Fifth, we did not compare partial nephrectomy to other nephron-sparing treatment modalities (such as ablation) which may represent feasible clinical alternatives especially for T1 renal masses. Sixth, the differences in tumor size and

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nephrometry score between RPN and LPN were statistically, but not clinically significant (0.16cm and <1 score on nephrometry). Lastly, it should be noted that while our metaanalysis demonstrates superiority in outcomes for RPN over LPN, LPN remains a

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relevant and viable surgical option for the management of small renal masses,

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particularly when considering its advantages over open surgery.30

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CONCLUSIONS This meta-analysis showed that RPN demonstrates favourable results compared to LPN in the peri-operative outcomes of LOS, EBL, WIT, positive margin rate, and

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conversion to open surgery, while being associated with a decreased risk of any,

including major, complications when compared to LPN. In addition, RPN was found to have lower operating times for complex tumours when compared to LPN. The clinician

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should use discretion in applying this data to clinical practice due to the limitations of this meta-analysis. Further studies are needed to analyse the difference between RPN

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and LPN for complex renal tumours, as well as long term follow up to evaluate

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oncologic outcomes.

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ACKNOWLEDGEMENTS We would like to acknowledge Drs. Alexandra Masson-Lecomte, Morgan Roupret, and

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accurately represent their work included in this meta-analysis.

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Nora Lee for responding to our emails and providing us with further information to

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LEGENDS

Table 1. Details Of Studies Comparing Robotic (RPN) And Laparoscopic Partial

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Nephrectomy (LPN)

Table 2. Demographic and Tumour Characteristics of Studies Comparing Robotic

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(RPN) And Laparoscopic Partial Nephrectomy (LPN)

Table 3. Summary of Meta-Analysis Results, Including Subgroup Analysis of High vs.

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Low Volume Series (≥ and <24 cases/year/center)

Figure 1. PRISMA Flowchart

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Figure 2. Forrest plots of meta-analysis outcomes of robotic partial nephrectomy compared to laparoscopic partial nephrectomy for (a) operating room time (b) hospital

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length of stay (c) estimated blood loss (d) warm ischemia time (e) positive surgical margins (f) conversion to laparoscopic/open surgery (g) any complications (h) major complications (i) preoperative eGFR (j) postoperative eGFR (k) change in eGFR .

Figure 3. Operating Room Time, Subgroup Analysis of Complex Tumors

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Deane LA, Lee HJ, Box GN, et al: Robotic versus standard laparoscopic partial/wedge nephrectomy: a comparison of intraoperative and perioperative results from a single institution. Journal of endourology / Endourological Society 2008; 22: 947–952.

30.

Gill IS, Kavoussi LR, Lane BR, et al: Comparison of 1,800 Laparoscopic and Open Partial Nephrectomies for Single Renal Tumors. J. Urol. 2007; 178: 41–46.

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Table 1. Details Of Studies Comparing Robotic (RPN) And Laparoscopic Partial Nephrectomy (LPN) First Author

Year

Journal

Instituition

Study Period

Country

1

Wang 1

2015

BJU Int

Chinese People’s Liberation Army General Hospital

2008 to 2014

2015

World J Urol

2003 to 2011

2015

Arch Ital Urol Androl

(1) Seoul St. Mary's Hospital, (2) Chungbuk National University, (3) Korea University School of Medicine, (4) Seoul National University Bundang, (5) Seoul National University Hospital Chinese PLA General Hospital

2015

World J Urol

Institute Mutualiste Montsouris

2015

J Chin Med Assoc

Taipei Veterans General Hospital

2015

J Minim Access Surg

Muljibhai Patel Urological Hospital

Kim

3

Ricciardulli

4

Carneiro

5

Li 10

6

Ganpule

7

Webb

8

Wu 5

9

Faria

11

7

14

2

10

Zargar

11

Jang 17

12

3

Leow

20 13

2015

Urol Ann

Ain Shams University

2014

BJU Int

Second Military Medical University

2014

World J Urol

MD Anderson Cancer Center

2014

BJU Int

2014

Korean J Urol

(1) Washington University, (2) Henry Ford Detriot, (3) NYU Langone Medical Center, (4) Johns Hopkins Hospital, (5) Cleveland Clinic Samsung Medical Center

2014

BJU Int

Singapore General Hospital

2013

BJU Int

127

89

38

2002 to 2014

Singapore

103

52

51

2007 to 2011

France

265

220

45

2006 to 2010

USA

86

27

59

2008 to 2012

France

98

54

44

2007 to 2010

USA

216

108

108

2005 to 2011

USA

381

199

182

2004 to 2010

USA

42

27

15

2009 to 2011 (LPN) 2011 to 2012 (RPN) 2009 to 2010

USA

69

30

39

Korea

27

13

14

Queen Mary Hospital

Hong Kong

20

10

10

Mount Sinai Medical Center

2005 to 2009

USA

38

20

18

Lahey Clinic

2007 to 2010

USA

28

13

15

Cleveland Clinic

2012

JSLS

Indiana University

2012

Can J Urol

Boston University Medical Center

30

24

Kural

2009

J Endourol

25

Jeong 27

2009

J Endourol

26

Deane

29

2008

J Endourol

EP

Wongkwang University School of Medicine

AC C

Can J Urol

TE D

University of Michigan

Eur Urol

JSLS

15

Korea

J Urol

2010

58

2007 to 2013

2012

2011

73

646

2012

DeLong 26

India

1185

Long 24

Lavery

2010 to 2013

1831

Ellison

23

55

USA

17

22

47

146

16

18

102

137

23

Korean J Urol

Taiwan

283

Hôpital Pontchaillou

Hong Kong Med J

2004 to 2012

USA

World J Urol

2011

152

2002 to 2008 (LPN) 2008 to 2012 (RPN) 2004 to 2013

Prog Urol

2011

258

44

31

2013

16

58

196

91

2013

Cho

316

France

14

22

21

China

2000 to 2014

146

Chaste

Seo 25

195

45

15

20

195

237

Williams 21

Lee 12

390

Egypt

14

Lucas

Korea

China

(1) Pitié Salpétrière, Assistance Publique – Hôpitaux de Paris, (2) Henri Mondor, Assistance Publique – Hôpitaux de Paris, (3) CHU de Reims, Reims, (4) CHU Rangueil, Toulouse, (5) CHU Bretonneau, Tours, (6) CHU Caremeau, Nimes Beth Israel Deaconess Medical Center

19

No. Of LPN 135

2005 to 2011

Masson-Lecomte

18

No. Of RPN 81

2009 to 2013

13

15

China

Total No. 216

2012 to 2014

SC

2

M AN U

8

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S/No

2008 to 2009

Istanbul Bilim University

2003 to 2009

Turkey

31

11

20

Yonsei University College of Medicine

2006 to 2008

Korea

57

31

26

University of Illinois

2003 to 2007

USA

23

11

12

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Table 2. Demographic and Tumour Characteristics of Studies Comparing Robotic (RPN) And Laparoscopic Partial Nephrectomy (LPN)

LPN 63.5 (14.8) 54.7 (12.7) 49.4 (12.7) 60.2 (11) 58.7 (14) . . 50.9 (11.6) 64.5 (7.2) 57.4 (12.4) 54.7 (11.8) 57.1 (11.9) 63 (9.2) 54.6 (11.7) . 59.4 (12.1) 59.5 (13) 49.4 (20.3) 57 (11) 53.9 (11.6) 56 (12) 53.6 (11.1) 53.6 58.9 (15.1) 58.7 (8.4) 54

RPN 33 71 14 14 24 .

LPN 46 65 89 56 17 .

28 71 476 30 16 78 10

51 54 258 9 13 23 18

42 80 8 13 3 2 9 5 3 16 1

42 70 10 10 6 5 4 7 6 13 4

RPN 25.2 (5.1) . 23.9 (3) 25.1 (3.7) . . . 24.8 (3.3) 32.5 (6.9) 30 (6.4) 24.3 (3.3) 25.8 (3.7) 26.4 (4.2) 27.2 (3.7) . 30.9 (6.5) 30.7 (7.2) 29.6 (4.3) 30 (7) 23.8 (2.3) . 30.1 (5.8) 28.9 26.7 (3.8) 24.1 .

LPN 24.3 (4.2) . 25.1 (3.8) 25.6 (4.5) . . . 24 (3.1) 31.4 (5.7) 29.6 (7.1) 25.3 (2.9) 26.2 (5) 26.3 (5.3) 28.9 (3.9) . 29.3 (6.1) 29.2 (5.3) 27.8 (11.2) 29 (5) 24.6 (2.7) . 29.3 (5.1) 26.6 27.8 (2.9) 24.8 .

No. On Leftside RPN LPN . . 82 103 22 123 25 74 . . . . . . 48 65 64 70 . . 40 21 30 25 76 . 14 31

Malignant Pathology RPN LPN 72 115 . . 51 215 . . . . 55 9 . 78 98 118 113 955 492 82 38 . . 183 33 22 58

56 110 . 16 9 7 9 6 8 . 7

92 161 17 27 11 9 15 13 11 22 11

RI PT

RPN 61.2 (12.6) 54.4 (13) 51.9 (10.6) 59 (13) 55.2 (13.2) . . 51.6 (10.7) 58.8 (10.5) 59.3 (11.2) 49.1 (12.6) 54.5 (12.7) 59 (11.6) 55.7 (11.2) . 55.9 (10.6) 58.5 (11.5) 62.1 (12) 59 (11) 54.2 (12.4) 63 (10.5) 55.4 (11.1) 59.7 50.8 (13.2) 53.4 (14) 53.2

Mean BMI (S.D.)

SC

BJU Int World J Urol Arch Ital Urol Androl World J Urol J Chin Med Assoc J Minim Access Surg Urol Ann BJU Int World J Urol BJU Int Korean J Urol BJU Int BJU Int World J Urol Prog Urol J Urol Eur Urol JSLS Can J Urol Korean J Urol Hong Kong Med J JSLS Can J Urol J Endourol J Endourol J Endourol

No. Female

M AN U

2015 2015 2015 2015 2015 2015 2015 2014 2014 2014 2014 2014 2013 2013 2013 2012 2012 2012 2012 2011 2011 2011 2010 2009 2009 2008

Mean Age (S.D.)

TE D

Journal

EP

1

Wang Kim 8 Ricciardulli Carneiro 3 10 Li Ganpule 11 Webb 7 Wu 5 Faria 14 2 Zargar Jang17 Leow 20 Masson-Lecomte 13 21 Williams Chaste 22 Ellison 23 Long 24 Lucas 15 12 Lee Seo 25 Cho 16 Lavery 18 26 DeLong Kural 30 Jeong 27 Deane 29

Year

AC C

First Author

51 96 . 24 4 5 6 7 12 . 7

84 145 11 36 9 8 14 9 16 18 10

Mean Tumour Size (S.D.) RPN LPN 3.8 (2.2) 3.6 (1.7) 2.35 (1.16) 2.29 (1.06) 3.08 (1.48) 3.23 (1.34) 3.48 (1.15) 3.15 (1.8) 3.85 (1.98) 3.59 (1.72) . . . . 3.6 (1.28) 3.3 (1.63) 3.35 (1.15) 3.43 (1.31) 2.3 (0.96) 2 (0.99) 3 (1.3) 2.5 (1) 2.68 (1.05) 2.59 (1.13) 3.05 (1.27) 3.04 (1.22) 2.47 (1.18) 3.08 (2.17) . . 2.9 (1.6) 2.7 (1.4) 3.8 (1.8) 4 (1.7) 2.4 (0.47) 2.2 (1.55) 3.2 (1.2) 3.1 (1.2) 2.7 (1.2) 2 (1.2) 2.7 (0.65) 2.8 (0.5) 2.47 (0.83) 2.26 (1.18) 2.6 2.8 3.22 (0.87) 3.15 (1.35) 3.4 (4.2) 2.4 (1.7) 3.1 (0.47) 2.3 (1.41)

Tumour Location (Upper/ Middle/Lower Pole) RPN LPN . . . . . . 13 / 14 / 18 50 / 42 / 60 . . . . . . . . . . . . . . 14 / 19 / 19 16 / 17 / 18 . . . . . . . . . . . . 6 / 15 / 9 13 / 20 / 6 1/8/4 2/7/5 3/4/3 5/5/0 8/5/6 4/5/7 . . 3/2/6 3/8/9 . . . .

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Table 3. Summary Of Results For Meta-Analysis of Studies Comparing Robotic (RPN) And Laparoscopic Partial Nephrectomy (LPN)

High Volume Series (>24/year/center)

WMD or RR (95% CI)*

p-value

Favours

WMD or RR (95% CI)*

Conversion to lap/open surgery

0.36 (0.22 to 0.61)

<0.001

RPN

0.19 (0.1 to 0.34)

Conversion to radical nephrectomy

0.44 (0.18 to 1.09)

0.08

RPN

0.38 (0.14 to 1.04)

Outcomes

p-value

WMD or RR (95% CI)*

p-value

<0.001

0.53 (0.26 to 1.07)

0.075

0.061

0.82 (0.1 to 6.69)

0.85

SC

Perioperative Safety

Low Volume Series (<24/year/center)

RI PT

Main Analysis

0.84 (0.73 to 0.95)

0.007

RPN

0.88 (0.77 to 1.01)

0.07

0.8 (0.59 to 1.08)

0.15

Major complications (Clavien≥3)

0.71 (0.52 to 0.95)

0.023

RPN

0.73 (0.53 to 1.02)

0.06

0.76 (0.41 to 1.4)

0.38

Perioperative Effectiveness Operative time

-12.19 (-37.37 to 12.98)

0.34

Similar

Estimated blood loss

-24.55 (-57.89 to 8.78)

0.15

Similar

Hospital length of stay

-0.22 (-0.47 to 0.04)

0.1

Similar

Warm ischaemia time

-4.34 (-6.17 to -2.51)

<0.001

RPN

-2.1 (-8.17 to 3.96)

0.5

Similar

0.53 (0.39 to 0.72)

<0.001

Change in eGFR

AC C

Positive margins

EP

Oncologic

4.46 (-10.79 to 19.7)

0.567

-25.16 (-49.97 to -0.36)

0.047

-19.711 (-71.72 to 32.3)

0.46

-41.16 (-94.59 to 12.27)

0.13

-0.02 (-0.37 to 0.32)

0.902

-0.47 (-0.77 to -0.17)

0.002

-2.91 (-5.74 to -0.07)

0.044

-6.19 (-8.64 to -3.74)

<0.001

-6.58 (-21.24 to 8.08)

0.38

0.79 (0.1 to 1.49)

0.025

0.53 (0.39 to 0.72)

<0.001

1.17 (0.57 to 2.4)

0.67

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Perioperative Functional

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Complications (Clavien≥1)

RPN

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Figure 1. PRISMA Flowchart

RI PT

Studies iden*fied through ini*al searches of electronic databases, N=663

Poten*al ar*cles for screening, N=548

SC

Duplicates removed (n=115)

M AN U

Records excluded aRer screening *tles and abstracts, n=504

Excluded studies (n=18) - Hand assisted n=2 - Solitary kidney n=1 - Review paper n=4 - Commentaries n=4 - Duplicate report n=7

EP

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Full texts assessed for eligibility, n=44

AC C

Studies included in quan*ta*ve analysis, n=26

1

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Figure 2. Forrest plots of meta-analysis outcomes of robotic partial nephrectomy compared to laparoscopic partial nephrectomy for (a) operating room time (b) hospital length of stay (c) estimated blood loss (d) warm ischemia time (e) positive surgical margins (f) conversion to laparoscopic/open surgery (g) conversion to radical nephrectomy (h) any complications (i) major complications (j) preoperative eGFR (k) postoperative eGFR (l) change in eGFR

2

SC

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ACCEPTED MANUSCRIPT Figure 2(a) – Conversion to Laparoscopic or Open Surgery

p < 0.001

Favors LPN

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Favors RPN

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Excluded due to same no. of events in both groups

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Figure 2(b) – Conversion to Radical Nephrectomy

p = 0.08 3 Favors RPN

Favors LPN

Favors RPN

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Figure 2(c) – Any Complications (Clavien≥1) ACCEPTED MANUSCRIPT

p = 0.007

Favors LPN

AC C

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Figure 2(d) – Major Complications (Clavien≥3)

p = 0.023 Favors RPN

Favors LPN

4

Favors RPN

p = 0.34

Favors LPN

AC C

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Figure 2(f) – Estimated Blood Loss

M AN U

SC

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Figure 2(e) – Operating Room Time MANUSCRIPT ACCEPTED

p = 0.15 5 Favors RPN

Favors LPN

Favors RPN

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SC

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Figure 2(g) – Warm Ischemia Time ACCEPTED MANUSCRIPT

p < 0.001

Favors LPN

AC C

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Figure 2(h) – Hospital Length of Stay

p = 0.10 6 Favors RPN

Favors LPN

ACCEPTED MANUSCRIPT

p = 0.63

Favors LPN

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Favors RPN

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Figure 2(i) – Pre-operative Estimated Glomerular Filtration Rate

AC C

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Figure 2(j) – Post-operative Change in Estimated Glomerular Filtration Rate

p = 0.49 Favors RPN

Favors LPN

7

ACCEPTED MANUSCRIPT

p = 0.50

Favors LPN

AC C

EP

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Favors RPN

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Figure 2(k) – Postoperative Change in Estimated Glomerular Filtration Rate

8

RI PT

ACCEPTED MANUSCRIPT

Excluded due to same no. of events in both groups

AC C

EP

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Figure 2(l) – Positive Surgical Margins

Favors RPN

p < 0.001 Favors LPN

9

ACCEPTED MANUSCRIPT

Online Supplement

RI PT

Figure 1. Forrest plots of meta-analysis of baseline characteristics of robotic partial nephrectomy compared to laparoscopic partial nephrectomy for (a) age (b) gender (c) laterality (left/right) (d) final malignant pathology (e) tumor size (f) RENAL nephrometry score

AC C

EP

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Online Supplement Figure 1(a). Age

Favors LPN

p = 0.25

Favors RPN

10

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

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Online Supplement Figure 1(b). Gender

Favors LPN

p = 0.84

Favors RPN

11

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

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Online Supplement Figure 1(c). Tumor Laterality (Left vs. Right)

Favors LPN

p = 0.09 Favors RPN

12

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

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Online Supplement Figure 1(d). Final malignant pathology

Favors LPN

p = 0.73

Favors RPN

13

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ACCEPTED MANUSCRIPT

AC C

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Online Supplement Figure 1(e). Tumor Size

Favors LPN

p = 0.001 Favors RPN

14

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ACCEPTED MANUSCRIPT

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Online Supplement Figure 1(f). RENAL Nephrometry Scores

Favors LPN

p = 0.002

Favors RPN

15

ACCEPTED MANUSCRIPT

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Online Supplement Figure 2. Forrest plots of metaanalysis outcomes of robotic partial nephrectomy compared to laparoscopic partial nephrectomy for patients with complex tumours only (RENAL nephrometry score ≥7)

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(a) operating room time (b) hospital length of stay (c) estimated blood loss (d) warm ischemia time (e) positive surgical margins (f) conversion to laparoscopic/ open surgery (g) conversion to radical nephrectomy (h) any complications (i) major complications (j) preoperative eGFR (k) postoperative eGFR (l) change in eGFR

AC C

EP

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Online Supplement Figure 2(a) – Operating Room Time

Favors RPN

p = 0.011

Favors LPN

16

SC

RI PT

MANUSCRIPT Online Supplement Figure ACCEPTED 2(b) – Length of Stay

M AN U

p = 0.029

Favors LPN

Favors RPN

AC C

EP

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Online Supplement Figure 2(c) – Estimated Blood Loss

p = 0.96

Favors RPN

Favors LPN 17

ACCEPTED MANUSCRIPT

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SC

RI PT

Online Supplement Figure 2(d) – Warm Ischemia Time

p = 0.04

Favors LPN

TE D

Favors RPN

AC C

EP

Online Supplement Figure 2(e) – Positive Surgical Margins

p = 0.52

Favors RPN

Favors LPN

18

SC

Excluded due to same no. of events in both groups

RI PT

ACCEPTED MANUSCRIPT Online Supplement Figure 2(f) – Conversion to Laparoscopic or Open Surgery

Favors LPN

TE D

Favors RPN

M AN U

p = 0.001

AC C

EP

Online Supplement Figure 2(g) – Conversion to Radical Nephrectomy

p = 0.63

Favors RPN

Favors LPN

19

SC

RI PT

Online Supplement Figure ACCEPTED 2(h) – Any Complications MANUSCRIPT(Clavien≥1)

Favors RPN

M AN U

p = 0.65

Favors LPN

AC C

EP

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Online Supplement Figure 2(i) – Major Complications (Clavien≥3)

p = 0.93

Favors RPN

Favors LPN 20

SC

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ACCEPTED MANUSCRIPT Online Supplement Figure 2(j) – Pre-operative Estimated Glomerular Filtration Rate

M AN U

p = 0.64

Favors LPN

Favors RPN

AC C

EP

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Online Supplement Figure 2(k) – Post-operative Change in Estimated Glomerular Filtration Rate

p = 0.46

Favors RPN

Favors LPN 21

SC

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ACCEPTED MANUSCRIPT Online Supplement Figure 2(l) – Postoperative Change in Estimated Glomerular Filtration Rate

M AN U

p = 0.13

Favors LPN

AC C

EP

TE D

Favors RPN

22

ACCEPTED MANUSCRIPT

Online Supplement Figure 3. Forrest plots of meta-analysis outcomes of robotic partial nephrectomy (RPN) compared to laparoscopic partial nephrectomy (LPN), stratified by volume status

M AN U

Online Supplement Figure 3(a). Operative Time

TE D

Low Volume (<24/year/center)

p = 0.047

AC C

EP

High Volume (≥24/year/center)

SC

RI PT

(a) operating room time (b) hospital length of stay (c) estimated blood loss (d) warm ischemia time (e) positive surgical margins (f) conversion to laparoscopic/open surgery (g) any complications (h) major complications (i) postoperatiev change in eGFR

Favors RPN

p = 0.567

Favors LPN

23

RI PT

ACCEPTED MANUSCRIPT

Online Supplement Figure 3(b). Length of Stay

M AN U

SC

Low Volume (<24/year/center)

TE D

High Volume (≥24/year/center)

p = 0.902

EP AC C

Favors RPN

p = 0.002

Favors LPN

24

Online Supplement Figure 3(c). Estimated Blood Loss

M AN U

SC

Low Volume (<24/year/center)

RI PT

ACCEPTED MANUSCRIPT

EP

TE D

High Volume (≥24/year/center)

p = 0.46

Favors LPN

AC C

Favors RPN

p = 0.13

25

Online Supplement Figure 3(d). Warm Ischemia Time

M AN U

SC

Low Volume (<24/year/center)

RI PT

ACCEPTED MANUSCRIPT

p < 0.001

TE D

High Volume (≥24/year/center)

AC C

EP

p = 0.044

Favors RPN

Favors LPN

26

RI PT

ACCEPTED MANUSCRIPT

Online Supplement Figure 3(e). Positive Margins

M AN U

SC

Low Volume (<24/year/center)

Excluded due to same no. of events in both groups

AC C

Favors RPN

p = 0.67

Excluded due to same no. of events in both groups

p < 0.001

EP

TE D

High Volume (≥24/year/center)

Favors LPN

27

ACCEPTED MANUSCRIPT

RI PT

Online Supplement Figure 3(f). Conversion to Laparoscopic/Open Surgery

M AN U

SC

Low Volume (<24/year/center)

Excluded due to same no. of events in both groups

EP

TE D

High Volume (≥24/year/center)

AC C

Favors RPN

p = 0.075

Excluded due to same no. of events in both groups

p < 0.001

Favors LPN

28

ACCEPTED MANUSCRIPT

RI PT

Online Supplement Figure 3(g). Any Complications (Clavien≥1)

M AN U

SC

Low Volume (<24/year/center)

TE D

High Volume (≥24/year/center)

p = 0.15

AC C

EP

p = 0.07

Favors RPN

Favors LPN

29

ACCEPTED MANUSCRIPT

RI PT

Online Supplement Figure 3(h). Major Complications (Clavien≥3)

M AN U

SC

Low Volume (<24/year/center)

TE D

High Volume (≥24/year/center)

p = 0.38

AC C

EP

p = 0.06

Favors RPN

Favors LPN

30

RI PT

ACCEPTED MANUSCRIPT

SC

Online Supplement Figure 3(i). Postoperative Change in eGFR

M AN U

Low Volume (<24/year/center)

EP

TE D

High Volume (≥24/year/center)

p = 0.38

Favors LPN

AC C

Favors RPN

p = 0.025

31

ACCEPTED MANUSCRIPT

Abbreviations And Acronyms

AC C

EP

TE D

M AN U

SC

RI PT

PN = Partial Nephrectomy RPN = Robotic PN LPN = Laparoscopic PN WMD = Weighted Mean Difference RR = Risk Ratio WIT = Warm Ischemia Time EBL = Estimated Blood Loss LOS = Length of Stay eGFR = estimated Glomerular Filtration Rate