EUROPEAN UROLOGY 62 (2012)

Transcription

1 EUROPEAN UROLOGY () available at journal homepage: Platinum Priority Review Kidney Cancer Editorial by Jihad H. Kaouk and Riccardo Autorino on pp. 5 of this issue Laparoendoscopic Single-Site Nephrectomy Compared with Conventional Laparoscopic Nephrectomy: A Systematic Review and Meta-analysis of Comparative Studies Xinxiang Fan a,y, Tianxin Lin a,y, Kewei Xu a, Zi Yin b, Hai Huang a, Wen Dong a, Jian Huang a,y, * a Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, China; b Department of General Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China Article info Article history: Accepted May 8, Published online ahead of print on June 5, Keywords: Laparoendoscopic single-site surgery LESS Conventional laparoscopy Nephrectomy Systematic review Meta-analysis Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Context: Laparoendoscopic single-site (LESS) surgery has increasingly been used to perform radical, partial, simple, or donor nephrectomy to reduce the morbidity and scarring associated with surgical intervention. Studies comparing LESS nephrectomy (LESS-N) and conventional laparoscopic nephrectomy (CL-N) have reported conflicting results. Objective: To assess the current evidence regarding the efficiency, safety, and potential advantages of LESS-N compared with CL-N. Evidence acquisition: We comprehensively searched PubMed, Embase, and the Cochrane Library and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) and retrospective comparative studies assessing the two techniques. Evidence synthesis: Two RCTs and retrospective studies including a total of 94 cases were identified. Although LESS-N was associated with a longer operative time (weighted mean difference [WMD]: 9.87 min; 95% confidence interval [CI],.7.8; p =.) and a higher conversion rate (% compared with.%; odds ratio: 4.8; 95% CI,.87.45; p =.), patients in this group might benefit from less postoperative pain (WMD:.48; 95% CI,.95 to.; p =.4), lower analgesic requirement (WMD: 4.78 mg; 95% CI, 8.59 to.97; p =.), shorter hospital stay (WMD:. d; 95% CI,.55 to.9; p =.7), shorter recovery time (WMD: 5.8 d; 95% CI, 8.49 to.8; p =.), and better cosmetic outcome (WMD:.7; 95% CI,.7.48; p <.). Perioperative complications, estimated blood loss, warm ischemia time, and postoperative serum creatinine levels of graft recipients did not differ significantly between techniques. Conclusions: LESS-N offers a safe and efficient alternative to CL-N with less pain, shorter recovery time, and better cosmetic outcome. Given the inherent limitations of the included studies, future well-designed RCTs are awaited to confirm and update the findings of this analysis. # European Association of Urology. Published by Elsevier B.V. All rights reserved. y These authors contributed equally to this study. * Corresponding author. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 7 W Yanjiang Road, Guangzhou 5, China. Tel. +8 8; Fax: address: yehjn@yahoo.com.cn (J. Huang). -88/$ see back matter # European Association of Urology. Published by Elsevier B.V. All rights reserved.

2 EUROPEAN UROLOGY (). Introduction Since the first report of laparoscopic nephrectomy by Clayman et al. in 99 [], this technique has gained worldwide acceptance. Laparoscopic surgery has been established as the gold standard technique for nephrectomy []. Natural orifice transluminal endoscopic surgery (NOTES) and laparoendoscopic single-site (LESS) surgery have been developed in an attempt to further reduce the morbidity and scarring associated with surgical intervention [,4]. NOTES is more technically challenging, and its transition to clinical use in urology has been slow []. Clinical interest is therefore mainly focused on LESS. This innovative technique accesses the abdominal cavity using a single small-length incision through which different laparoscopic tools pass simultaneously to perform a complete surgical procedure. The most widespread approach is transumbilical; the navel is used as a natural embryonic orifice to hide the access scar to the peritoneal cavity [5]. Even though several studies comparing LESS nephrectomy (LESS-N) and conventional laparoscopic nephrectomy (CL-N) have been reported, most are small series with conflicting results [ ]. It is still uncertain whether the benefits of LESS are restricted to improved cosmesis. We therefore systemically searched and analyzed the available literature to evaluate the efficiency, safety, and potential advantages of LESS-N compared with CL-N.. Evidence acquisition A prospective protocol of objectives, literature-search strategies, inclusion and exclusion criteria, outcome measurements, and methods of statistical analysis was prepared a priori according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis and Meta-analysis of Observational Studies in Epidemiology recommendations for study reporting [,]... Literature-search strategy A literature search was performed in February without restriction to regions, publication types, or languages. The primary sources were the electronic databases of PubMed, Embase, and the Cochrane Library. The following MeSH terms and their combinations were searched in [Title/Abstract]: single port/site/incision, natural orifice transluminal, natural orifice transumbilical, and laparoendoscopic/laparoscopic nephrectomy. The Related Articles function was also used to broaden the search, and the computer search was supplemented with manual searches of the reference lists of all retrieved studies, review articles, and conference abstracts. When multiple reports describing the same population were published, the most recent or complete report was used... Inclusion and exclusion criteria All available randomized controlled trials (RCTs) and retrospective comparative studies (cohort or case control studies) that compared LESS-N with CL-N in all age groups, and that had at least one of the quantitative outcomes mentioned in the next section of this paper, were included. Editorials, letters to the editor, review articles, case reports, and animal experimental studies were excluded... Data extraction and outcomes of interest Data from the included studies were extracted and summarized independently by two of the authors (Xu and Lin). Any disagreement was resolved by the adjudicating senior authors (J. Huang and Fan). The primary outcomes were perioperative complication rates, conversion rates, postoperative pain, and cosmetic satisfaction. If sufficient data were available, perioperative complications were subdivided into intraoperative complications and postoperative complications within d of surgery. Postoperative complications were classified according to the Clavien-Dindo grading system [4]. Postoperative pain was measured using a visual analog scale (VAS) and analgesic requirement. The use of an additional -mm trocar was still considered as LESS [4,5]. Conversions in the LESS-N group were defined as follows: () to reduced port laparoscopy (addition of one 5- or -mm trocar), () to conventional laparoscopy (addition of more than one trocar), or () to open surgery [4,]. The secondary outcomes were operative time, estimated blood loss (EBL), postoperative time to oral intake, length of stay (LOS), and time of convalescence. Warm ischemia time and postoperative serum creatinine (SCr) levels of recipient grafts were assessed for the donor nephrectomy (DN) subgroup..4. Quality assessment and statistical analysis Studies were rated for the level of evidence provided according to criteria by the Centre for Evidence-Based Medicine in Oxford, UK [7]. The methodological quality of RCTs was assessed by the Cochrane risk of bias tool [8]. The methodological quality of retrospective studies was assessed by the modified Newcastle-Ottawa scale [9,], which consists of three factors: patient selection, comparability of the study groups, and assessment of outcome. A score of 9 (allocated as stars) was allocated to each study except RCTs. RCTs and observational studies achieving six or more stars were considered to be of high quality. All the meta-analyses were performed using Review Manager 5. (Cochrane Collaboration, Oxford, UK). The weighted mean difference (WMD) and odds ratio (OR) were used to compare continuous and dichotomous variables, respectively. All results were reported with 95% confidence intervals (CIs). For studies that presented continuous data as means and range values, the standard deviations were calculated using the technique described by Hozo et al. []. Statistical heterogeneity between studies was assessed using the chi-square test with significance set at p <., and heterogeneity was quantified using the I statistic.

3 EUROPEAN UROLOGY () [(Fig._)TD$FIG] The random-effects model was used if there was heterogeneity between studies; otherwise, the fixed-effects model was used [8]. Subgroup analyses were performed to compare LESS radical nephrectomy (LESS-RN), simple nephrectomy (SN), and DN with the respective conventional laparoscopic procedures. Sensitivity analyses were performed for highquality studies. Funnel plots were used to screen for potential publication bias.. Evidence synthesis Twenty-seven studies including 94 cases (487 cases for LESS-N and 7 cases for CL-N) fulfilled the predefined inclusion criteria and were included in the final analysis (Fig. ). Seventeen publications were full-text articles [, ], and publications were conference abstracts [ 4]. Examination of the references listed for these studies and for the review articles did not yield any further studies for evaluation. Agreement between the two reviewers was 95% for study selection and 9% for quality assessment of trials. PubMed: n = 7 Embase: n = 58 Cochrane: n = 9 Studies identified through initial searches of electronic databases: n = 9 Titles and abstracts screened: n = 5 Full-text articles screened: n = 79 Included studies: n = 7 Duplications: n = 9 Excluded studies: n = 44 - Irrelevant topics: n = 9 - Non-comparative studies: n = 95 - Animal models: n = 8 Excluded studies: n = 5 - Reviews or meeting abstracts: n = 4 - Editorials or letters: n = - Duplicate reports: n = - Abstracts data not extractable: n = Fig. Flow diagram of studies identified, included, and excluded... Characteristics of eligible studies The characteristics of included studies are shown in Table. Among the included studies, there were small sampled RCTs (level of evidence: b) [9,]; 9 retrospective studies compared contemporary series of patients (level of evidence: b) [,7,,,,4, 8,, 4,4]; and retrospective studies used historical series as controls (level of evidence: 4) [8,9,,,,4]. Six retrospective studies declared prospective data collection [7,,,,,4]. As for surgical indications, and studies were about RN [, 4,,,7 9,4] and partial nephrectomy [,4] for renal malignancies, respectively; studies[8,,] were about SN for nonfunctional kidney diseases; and another studies [,7,,8,9,4] were about DN. The remaining six studies [9,7,,4 ] included a mixture of those surgical procedures. The majority of studies used commercial single-port devices (ie, TriPort/QuadPort, R-Port, SILS Port, GelPort, Endocone, AnchorPort, and OCTO Port), and three studies [,,] also used homemade devices based on surgical gloves. In another two studies [9,7], the adjacent trocars were inserted through separate fascial sites within the same skin incision. Two studies [,4] used the da Vinci Surgical System... Methodological quality of included studies The quality of included studies was generally low. True randomization was used in only two RCTs. None of the retrospective studies adopted an appropriate protocol for treatment assignment, with allocation usually at the discretion of the physician. No studies provided information about allocation concealment or the blinding method. Matching criteria between the groups were variable, and little matching information was identified from the conference abstracts. Only six studies [,,4,,,8] mentioned the length of follow-up, and most of the studies provided only perioperative data. Methods for handling missing data and intention-to-treat analyses were not adequately described in the majority of studies... Primary outcomes... Perioperative complications Pooling the data from 8 studies [,7,, 9,,8,9,4] that assessed perioperative complications in 89 patients showed no significant difference between the LESS-N and CL-N groups (4.5% and 5.%; OR:.9; 95% CI,.4.7; p =.7) (Fig. ). Intraoperative and postoperative complication rates were available for studies [4,,9] and 4 studies [,7,,,7 9, ], respectively, and showed no significant differences between the two groups (7.% and.%; OR:.58; 95% CI,.8 7.7; p =.9; and.% and.9%; OR:.8; 95% CI,.5.; p =.4, respectively). When postoperative complications were further divided into minor (Clavien- Dindo grade I/II) and major (Clavien-Dindo grade III/IV/V) complications, there were still no significant differences between groups (7.7% and 7.7%; OR:.98; 95% CI,.5.7; p =.94; and.97% and 5.%; OR:.; 95% CI,..; p =., respectively) (Table ).... Conversion rate Two studies [7,9] used an additional - or -mm trocar for all cases in LESS-N. Three studies [9,,7] used an additional -mm trocar for liver retraction in right-side nephrectomies. Ten studies [7,,4,,7,9,,,,4] including 55 patients reported conversion events. The conversion rate was % (5 of 49 patients) in LESS-N, with.% of cases converting to reduced port laparoscopy,.% to

4 4 EUROPEAN UROLOGY () Table Characteristics of included studies Study Level of evidence Design Indications Patients, no. Ports for LESS Matching ô Follow-up, * mo, LESS/CL Quality score LESS CL Andonian et al. [] b R DN AnchorPort,,,4,7,9 NA $$$$$$$ Bazzi et al. [] b R PN 4 NA NA 8./. $$$ Best et al. [4] b R MP NA NA NA $$$ Canes et al. [7] b RP DN 7 7 R-Port,,,4,7 NA $$$$$$ Chan et al. [] b R MP 8 NA NA NA $$$ Derweesh et al. [] b RP MP 5 NA NA NA $$$ Flamand et al. [7] b R RN GelPort NA Perioperative $$$ Greco et al. [] 4 R RN Endocone,,,4,5,8,9..9/.. $$$$$$$ Hsueh et al. [8] b R RN 5 5 NA NA./9. $$$ Kim et al. [8] 4 R SN TriPort, NA $$$$$ Kurien et al. [9] b RCT DN R-Port,,,5,7 Perioperative RCT Lunsford et al. [8] b R DN GelPort,,,7 Perioperative $$$$$$ Mir et al. [7] b R MP 4 No y,,9 Perioperative $$$$$ Oh et al. [9] b R RN NA,,,4,8 Perioperative $$$$$$ Park et al. [] 4 R RN 9 8 Homemade/OCTO Port,,,4,5,,8 NA $$$$$$$ Rais-Bahrami et al. [4] b RP DN 7 NA,5 NA $$$ Raman et al. [9] 4 R MP No y,,8,9 Perioperative $$$$$$ Raybourn et al. [] b RP MP TriPort, Perioperative $$$$ Seo et al. [] b R RN Homemade/SILS-Port,,,4,,8,9 Perioperative $$$$$$$ Seo et al. [4] 4 R PN NA NA NA $$$ Tugcu et al. [] b RCT SN 4 SILS Port,,,4,9 RCT Wang et al. [] 4 RP DN GelPort,,,4,7,9 Perioperative $$$$$$$ Wang et al. [4] b R RN TriPort,,,4,5,8,9 9 4./8.. $$$$$$$ White et al. [] b RP RN SILS Port/GelPort,,,4,5,8,9.5 $$$$$$$ Woldrich et al. [4] b R RN NA NA NA $$$ Woldrich et al. [] b R SN 7 SILS Port, Perioperative $$$$$ Zhang et al. [] b R RN 5 Homemade,,,4,8,9 Perioperative $$$$$$$ LESS = laparoendoscopic single-site; CL = conventional laparoscopic; R = retrospective; RP = retrospective design, prospective data collection; RCT = randomized controlled trail; DN = donor nephrectomy; PN = partial nephrectomy; MP = mixed procedures; RN = radical nephrectomy; SN = simple nephrectomy; NA = data not available. * Mean or median. ô Matching: = age; = gender; = body mass index; 4 = kidney side; 5 = American Society of Anesthesiologists score; = previous abdominal surgery history; 7 = anatomic complexity (more than one artery, vein, and/or ureter); 8 = tumor size; 9 = single surgeon. y No single-port access device was used; the adjacent trocars were inserted through a single incision. Table Results of meta-analysis comparison of laparoendoscopic single-site nephrectomy and conventional laparoscopic nephrectomy Outcomes of interest Studies, no. LESS-N patients, no. CL-N patients, no. WMD/OR y (95% CI) p value * Study heterogeneity x df I,% p value * Primary outcomes Perioperative complications y (.4.7) Intraoperative complications y (.8 7.7) Postoperative complications 4.8 y (.5.) Minor (Clavien-Dindo grade I II) 4.94 y (.5.7) Major (Clavien-Dindo grade III V) 4. y (..) Conversion rate y (.87.45) Postoperative VAS score (.95 to.) <. Analgesic requirement, mg ô ( 8.59 to.97) <. Cosmetic satisfaction score 75.7 (.7.48) < Secondary outcomes Operative time, min (.7.8) Estimated blood loss, ml ( 9.9 to.7) Postoperative time to oral intake, d 9.9 (.5 to.4) Length of hospital stay, d 9 4. (.55 to.9) <. Time of convalescence, d ( 8.49 to.8) <. Warm ischemia time, min (.5 to.7) <. Postoperative SCr of recipient grafts, mmol/l (.78 to.9) LESS-N = laparoendoscopic single-site nephrectomy; CL-N = conventional laparoscopic nephrectomy; WMD/OR = weighted mean difference/odds ratio; df = degrees of freedom; CI = confidence interval; VAS = visual analog scale; SCr = serum creatinine. ô Morphine equivalents in milligrams. * Statistically significant results are shown in bold. y Odds ratio.

5 [(Fig._)TD$FIG] EUROPEAN UROLOGY () 5 LESS-N CL-N Odds ratio Odds ratio Study or subgroup Events Total Events Total Weight, % M-H, fixed (95% CI) M-H, fixed (95% CI).. Radical nephrectomy for renal cancer Hsueh TY, Oh TH, Park YH, Seo IY, Wang L, White MA, Zhang SD, Heterogeneity: χ = 5.7, df = ( p =.4); I ² = % Test for overall effect: z =.5 ( p =.58) (., 8.4) 4.75 (.8,.4). (.5,.). (.4,.94).7 (., 9.7). (.5, 8.57).7 (., 9.).8 (.7,.74).. Partial nephrectomy for renal cancer Bazzi W, Seo JT, (.7,.).4 (.4, 4.5).97 (.8,.49) 9 4 Heterogeneity: χ =., df = (p =.58); I² = % Test for overall effect: z =.7 ( p =.95).. Donor nephrectomy Andonian S, Canes D, Kurien A, Lunsford KE, Wang GJ, Heterogeneity: χ =.7, df = 4 (p =.5); I² = % Test for overall effect: z =.4 (p =.9) (., 8.4) 5.5 (.,.87). (., 4.7).7 (.,.59). (.57,.). (.,.)..4 Mixed procedures Best S, Chan J, Mir SA, Raybourn Iii, (.8,.58).55 (.9, 7.).89 (.,.8). (.5,.9).74 (.,.79) Heterogeneity: χ =.8, df = ( p =.); I² = % Test for overall effect: z =.7 (p =.5) Total (95% CI) Heterogeneity: χ =.9, df = 7 (p =.8); I ² = % Test for overall effect: z =. ( p =.7) Test for subgroup differences: =.8, df = (p =.85), I² = % χ.9 (.4,.7).. 5 Favors LESS-N Favors CL-N Fig. Forest plot and meta-analysis of perioperative complication rates. LESS-N = laparoendoscopic single-site nephrectomy; CL-N = conventional laparoscopic nephrectomy; M-H = Mantel-Haenszel method; CI = confidence interval. conventional laparoscopy or robotic surgery, and.% to open surgery. Reasons for conversions were difficult retraction (.% of converted cases), bleeding (.7%), difficult dissection (.%), failure to progress (%), and difficult access (.7%). The conversion rate was significantly higher in LESS-N than in CL-N (% compared with.%, p =.) (Fig. ). When only open conversions were analyzed, no significant difference was found between the two groups (.% compared with.%, p =.).... Postoperative pain Fourteen studies [7,,,,8,,9,4,4] including 99 patients evaluated postoperative pain using the VAS at different time points, ranging from the first postoperative day to the day of discharge. The pooled

6 [(Fig._)TD$FIG] EUROPEAN UROLOGY () LESS CL Study or subgroup Events Total Events.. Radical nephrectomy for renal cancer Park YH, Wang L, Woldrich J, Heterogeneity: χ =.9, df = (p =.7); I² = % Test for overall effect: z =.87 (p =.) Total Weight, % M-H, fixed (95% CI) Odds ratio.4 (.,.48).4 (.5, 74.) 7. (.,.) 4.4 (.9,.9) Odds ratio M-H, fixed (95% CI).. Donor nephrectomy Canes D, Kurien A, Wang GJ, Heterogeneity: χ =., df = (p =.88); I² = % Test for overall effect: z =.99 (p =.5) (., 78.8) 5.4 (., 8.9) 9.7 (.5, 7.4) 5.95 (., 4.5).. Simple nephrectomy for nonfunctional kidney Woldrich JM, Heterogeneity: Not applicable Test for overall effect: z =.9 (p =.7) (., 8.54) 4. (., 8.54)..4 Mixed procedures Chan J, Derweesh I, 9 Mir SA, 5 Heterogeneity: χ =., df = ( p =.99); I² = % Test for overall effect: z =.49 (p =.4) (.8, 8.79) 4.4 (., 9.48).5 (.4, 89.4) 4. (., 7.8) Total (95% CI) Heterogeneity: χ =., df = 9 (p =.99); I ² = % Test for overall effect: z =. (p =.) Test for subgroup differences: χ =.9, df = (p =.99), I² = % 4.8 (.87,.45).. Favors LESS Favors CL Fig. Forest plot and meta-analysis of conversion rates. LESS = laparoendoscopic single site; CL = conventional laparoscopic; M-H = Mantel-Haenszel method; CI = confidence interval. data showed significant lower VAS scores in the LESS-N group than the CL-N group (WMD:.48; 95% CI,.95 to.; p =.4) (Fig. 4). The pooled data of 4 studies [7,,,8,,,8,4 4] including patients showed that the LESS-N group had lower analgesic requirement than the CL-N group (WMD: 4.78 mg; 95% CI, 8.59 to.97; p =.) (Fig. 5)...4. Cosmetic satisfaction Two studies [7,4] reported a cosmetic satisfaction score on a scale, and the results of another study [9] that reported cosmetic satisfaction on a 4 scale were converted to a scale for comparison. Pooling the data of the 7 patients in these three studies showed significantly better cosmetic satisfaction scores in the LESS-N group than the CL-N group (WMD:.7; 95% CI,.7.48; p <.). Another study [] reported subjective scar satisfaction and reported that all patients who underwent LESS-RN were enthusiastic about the appearance of their scars (%), compared with of the patients in the CL-RN group (74.%) ( p =.)..4. Secondary outcomes.4.. Operative time and estimated blood loss Except for one conference abstract [4], all studies reported operative time for the 9 included patients, which was significantly longer in the LESS-N group than the CL-N group (WMD: 9.87 min; 95% CI,.7.8; p =.). EBL was reported in 4 studies [,,,,9 4]

7 [(Fig._4)TD$FIG] EUROPEAN UROLOGY () 7 LESS-N CL-N Mean difference Mean difference Study or subgroup Mean SD Total Mean SD Total Weight, % IV Random (95% CI) IV Random (95% Cl).. Radical nephrectomy for renal cancer Greco F, (.,.8) Oh TH, (.4,.) Park YH, (.,.7) Wang L, (.4,.7) White MA, (.77,.7) Woldrich J, (.8,.8) Zhang SD, (.,.5) (.,.9) Heterogeneity: τ² =.7; χ² =., df = (p <.); I ² = 8% Test for overall effect: z =.47 ( p =.).. Partial nephrectomy for renal cancer Seo JT, (.8,.8) 4..5 (.8,.8) Heterogeneity: Not applicable Test for overall effect: z =.55 (p =.58).. Donor nephrectomy Canes D, (.5,.75) Kurien A, (.55,.5) Lunsford KE, (.8,.) Wang GJ, (.,.45) (.84,.8) Heterogeneity: τ ² =.54; χ² = 7.95, df = (p =.4); I ² = 8% Test for overall effect: z =. (p =.99)..4 Simple nephrectomy for nonfunctional kidney Tugcu V, (.,.9) Woldrich JM, (.84,.84) (.4,.8) Heterogeneity: τ ² =.4; χ² =.5, df = (p =.); I ² = % Test for overall effect: z =.47 ( p =.4) Total (95% CI) (.95,.) Heterogeneity: τ ² =.59; χ² = 7.4, df = (p <.); I ² = 8% Test for overall effect: z =. ( p =.4) Test for subgroup differences: χ ² =.8,df = (p =.8),I ² =.% Favors LESS Favors CL Fig. 4 Forest plot and meta-analysis of postoperative pain measured by visual analog scale score. LESS-N = laparoendoscopic single-site nephrectomy; CL- N = conventional laparoscopic nephrectomy; SD = standard deviation; IV = inverse variance method; CI = confidence interval. including patients; the EBL was lower in the LESS-N group than the CL-N group, but this difference was not statistically significant (WMD:.99 ml; 95% CI, 9.9.7; p =.7)..4.. Postoperative time to oral intake, length of stay, and time of convalescence Six studies [,] reported postoperative time to oral intake in 4 patients, and the pooled data showed a significant difference favoring the LESS-N group (WMD:.9 d; 95% CI,.5 to.4; p =.). Pooling the data of 9 studies [7,,,8,4] including 795 patients that reported LOS showed a significant difference favoring the LESS-N group (WMD:. d; 95% CI,.55 to.9; p =.7). Four studies [7,,,] assessed time of convalescence in 7 patients and showed shorter convalescence time in the LESS-N group (WMD: 5.8 d; 95% CI, 8.49 to.8; p =.).

8 8 EUROPEAN UROLOGY () LESS CL Mean difference Mean difference Study or subgroup Mean, mg SD, mg Total Mean, mg SD, mg Total Weight, % IV, Random (95% CI, mg) IV, Random (95% CI, mg).8. Radical nephrectomy for renal cancer Greco F, ( 5.9,.44) Hsueh TY, ( 48.,.) Park YH, (.9, 9.) White MA, (.9, 9.7) Woldrich J, (.94,.4) 7. (.,.7) Heterogeneity: τ ² =.59; χ² =., df = 4 (p =.); I ² = 9% Test for overall effect: z =.78 ( p =.5).8. Partial nephrectomy for renal cancer Seo JT, ( 5.9, 8.9). ( 5.9, 8.9) Heterogeneity: Not applicable Test for overall effect: z =.8 ( p =.4).8. Donor nephrectomy Canes D, ( 7., 4.) Lunsford KE, ( 75.5, 7.49) Rais-Bahrami (.7,.5) Wang GJ, (.7,.4).4 ( 9.8, 9.5) Heterogeneity: τ ² = 9.4; χ² = 8.4, df = ( p =.); I² = 5% Test for overall effect: z =.4 (p =.).8.4 Simple nephrectomy for nonfunctional kidney Kim PH, (., 5.) Tugcu V, ( 4., 5.) Woldrich JM, (.47, 4.5).47 (.7, 5.4) Heterogeneity: τ ² = 7.; χ² = 8.8, df = ( p =.); I ² = 7% Test for overall effect: z =. (p =.87).8.5 Mixed procedures Raman JD, (.9, 8.9). (.9, 8.9) Heterogeneity: Not applicable Test for overall effect: z =. (p =.7) Total (95% CI) ( 8.59,.97) Heterogeneity: τ ² =.5; χ² =.5, df = (p<.); I ² = 79% Test for overall effect: z =.4 (p =.) Test for subgroup differences: χ ²=4.9,df =4(p =.),I ²=8.% 5 5 Favors LESS Favors CL Fig. 5 Forest plot and meta-analysis of analgesic requirement. LESS = laparoendoscopic single site; CL = conventional laparoscopic; SD = standard deviation; IV = inverse variance method; CI = confidence interval..5. Subgroup analysis Only two conference abstracts [,4] reported studies of partial nephrectomy, which made it difficult to perform analysis of this subgroup..5.. Laparoendoscopic single-site radical nephrectomy compared with conventional laparoscopic radical nephrectomy There were no significant differences in this subgroup analysis compared with the original analysis, except that no significant difference was found in the conversion rate between groups (8.8% compared with.%; OR: 4.4; 95% CI,.9.9; p =.)..5.. Laparoendoscopic single-site donor nephrectomy compared with conventional laparoscopic donor nephrectomy There were no significant differences in this subgroup analysis compared with the original analysis in postoperative VAS scores (WMD:.; 95% CI,.84.8; p =.99), operative time (WMD:.5 min; 95% CI, 7.57.;

9 EUROPEAN UROLOGY () 9 Table Sensitivity analysis comparison of laparoendoscopic single-site nephrectomy and conventional laparoscopic nephrectomy Outcomes of interest Studies, no. LESS-N patients, no. CL-N patients, no. WMD/OR y (95% CI) p value * Study heterogeneity x df I,% p value * Primary outcomes Perioperative complications 7 7. y (..) Intraoperative complications y (.8 7.7) Postoperative complications y (.49.48) Minor (Clavien-Dindo grade I II) y (.5.85) Major (Clavien-Dindo grade III V) y (..7).4.7. Conversion rate y (.4.78) Postoperative VAS score.5 (. to.) <. Analgesic requirement, mg ô (. to.8) Cosmetic satisfaction score 75.7 (.7.48) < Secondary outcomes Operative time, min (.74 9.) Estimated blood loss, ml ( 5.7 to.) Postoperative time to oral intake, d 9.9 (.5 to.4) Length of hospital stay, d (.9 to.4) <. Time of convalescence, d ( 8.49 to.8) <. Warm ischemia time, min (.5 to.7) <. Postoperative SCr of recipient grafts, mmol/l (.78 to.9) LESS-N = laparoendoscopic single-site nephrectomy; CL-N = conventional laparoscopic nephrectomy; WMD/OR = weighted mean difference/odds ratio; df = degrees of freedom; CI = confidence interval; VAS = visual analog scale; SCr = serum creatinine level. ô Morphine equivalents in milligrams. * Statistically significant results are shown in bold. y Odds ratio. p =.), LOS (WMD:.9 d; 95% CI,.7.8; p =.), analgesic requirement (WMD:.4 mg; 95% CI, ; p =.), or perioperative complication rates. Three studies [7,,9] including 84 patients reported the warm ischemic time and showed no significant difference between groups (WMD:.58 min; 95% CI,.5.7; p =.4). Four studies [7,,8,9] including 4 patients assessed the SCr of graft recipients and showed no significant [(Fig._)TD$FIG] difference between groups (WMD: 7. mmol/; 95% CI,.78.9; p =.)..5.. Laparoendoscopic single-site simple nephrectomy compared with conventional laparoscopic simple nephrectomy Subgroup analysis was not performed for perioperative complication rates because of insufficient data. There were no significant differences in this subgroup analysis SE(log[OR]).5.5 OR.. 5 Subgroups Radical nephrectomy for renal cancer Partial nephrectomy for renal cancer Donor nephrectomy Mixed procedures Fig. Funnel plots illustrating meta-analysis of perioperative complication rates. SE = standard error; OR = odds ratio.

10 EUROPEAN UROLOGY () compared with the original analysis in postoperative VAS score (WMD:.; 95% CI,.4.8; p =.4), operative time (WMD:.5 min; 95% CI, ; p =.8), LOS (WMD:. d; 95% CI,..8; p =.88), or analgesic requirement (WMD:.47 mg; 95% CI,.7 5.4; p =.87). Other comparisons revealed results similar to the original analysis... Sensitivity analysis and publication bias Two RCTs [9,] and retrospective studies [,7,9,,,8,,9] that scored six or more stars on the modified Newcastle-Ottawa scale were included in sensitivity analysis (Table ). There was no change in the significance of any of the outcomes except for EBL, which was shown to be significantly lower in the LESS-N group than the CL-N group (WMD: 8.4 ml; 95% CI, 5.7 to.; p =.4). The degree of between-study heterogeneity decreased slightly for operative time and LOS but not for postoperative VAS score, EBL, or analgesic requirement. Between-study heterogeneity remained statistically significant for postoperative VAS score, operative time, LOS, time of convalescence, analgesic requirement, and warm ischemia time. Figure shows a funnel plot of the studies included in this meta-analysis that reported perioperative complication rates. All studies lie inside the 95% CIs, with an even distribution around the vertical, indicating no obvious publication bias..7. Discussion This meta-analysis of RCTs and retrospective studies including 94 patients comparing the efficacy of LESS-N and CL-N showed that LESS was safe, with significantly reduced postoperative pain, lower analgesic requirement, shorter hospital stay, shorter recovery time, and better cosmetic outcome. We found no significant differences in perioperative complications, EBL, warm ischemia time, or postoperative SCr of recipient grafts. In the application of any new procedure, the safety of the patients is always of paramount importance. The pooled data of perioperative outcomes indicates that the LESS approach is safe and effective for nephrectomies. There was no significant difference in perioperative complications. The operative time was only slightly longer. These results were surprising, as LESS is more challenging for surgeons compared with conventional laparoscopy. This finding may represent stricter patient selection in the LESS-N group [,,7]. The populations of LESS-N were relatively young and not obese, with small tumor size and no complex anatomy. This characteristic introduced a selection bias. This finding, however, indicates that LESS-N is at least as safe and efficient as CL-N with appropriate patient selection. The conversion rate was significantly higher for LESS-N than CL-N. Features specific to the LESS technique (such as crossing or collision of instruments, lack of triangulation, and in-line vision) represent additional challenges for surgeons []. Five included studies [7,9,,7,9] used an additional - or -mm trocar (minilaparoscopy), which is still considered to be LESS according to current terminology [,4,5]. This strategy is effective to aid in triangulation, and the small punctures require no formal closure [5]. They present excellent cosmetic outcomes [5,4] and should be recommended for use in case of difficult dissection or difficult retraction. A conversion to reduced port laparoscopy or standard laparoscopy is needed when there is severe adhesion and difficulty in progression. When there is uncontrolled bleeding, conversion to open surgery is necessary to ensure patient safety. It has been wisely stated that sensitivity to the potential for complications is critical and that the threshold for conversion must be appropriately low [,5,]. Thus, when starting LESS, proper patient selection, adequate laparoscopic experience, and preferably a certain amount of LESS training are recommended to minimize complications and conversions [5]. Disease features, as well as patients features, are to be considered [,5]. Nevertheless, the development of new devices for LESS (eg, prebent instruments, streamlined and flexible optics, and magnetic anchors) will surely reduce the technical difficulties that were reported when use of this technique was just beginning []. The pooled data of postoperative outcomes suggest that LESS-N was associated with shorter time to oral intake, shorter LOS, and shorter time of convalescence. Given that there were differences in postoperative patient management preferences and hospital discharge criteria, whether these potential benefits can be proved in future welldesigned RCTs is not known. The pooled analysis of postoperative pain showed lower VAS scores and lower analgesic requirement for LESS-N compared with CL-N. As LESS-N reduces the number of skin incisions to only one, it seems reasonable to postulate that LESS is less invasive than conventional laparoscopy. However, a recent study [] demonstrated that the increase in stress parameters was associated with the trauma to muscles but not directly correlated with the sum of each single incision. Pain has both physical and psychological components. Patients in the LESS-N group knew they had undergone a newer and smaller incision procedure, so they might have tended to report lower VAS scores and requests for less analgesic. The actual benefit of LESS in terms of postoperative pain remains to be defined. Improved cosmesis is an apparent advantage of LESS. This finding is encouraging for certain patient groups, such as young female patients and living kidney donors. With no sacrifice to graft function, the benefits of improved cosmesis following LESS may increase donor enthusiasm, therefor decreasing barriers to donation. To assess any impact of study quality on the effect estimates, we performed a sensitivity analysis including only high-quality studies. The results were similar to those of the analysis. Although a meta-analysis of RCTs only would be ideal, the limited number of RCTs prevented us from reaching any definitive conclusions based on sensitivity analysis alone. Because of ethical concerns and patient expectations, it is difficult to conduct randomized trials comparing these surgical techniques; this situation highlights the importance of conducting meta-analyses.

11 EUROPEAN UROLOGY () Between-study heterogeneity was not significant for dichotomous outcomes but was significant for most of the continuous variables. Included studies adopted different surgical indications, matching criteria, single-port access devices, operative techniques, and measurement of outcomes. These differences might contribute to the significant between-study heterogeneity. Pooling of data using the random-effects model might reduce the effect of heterogeneity but does not abolish it. The present meta-analysis has the following limitations that must be taken into account. The main limitation is that all the included studies were retrospective, except for two RCTs with small sample sizes. Inadequate random sequence generation and blinding tended to increase the risk of bias. Ten included studies were conference abstracts, which usually do not provide complete information for each end point. In addition, the original meta-analysis was based on the assumption that the surgical subgroups (RN, DN, and SN) were similar enough to be assessed together. However, subgroup analysis yielded some different results compared with the original analysis. Future systematic reviews should evaluate different indications separately when enough literature is available. In addition, the included studies were carried out with different levels of surgical expertise. The different experience of the surgeons with the two different approaches could influence the outcomes. Finally, the followup period was generally short, so long-term outcomes of LESS-N, especially for oncologic safety of LESS-RN, remain to be proved. Nevertheless, this meta-analysis was conducted at an appropriate time, because enough data have accumulated for inspection by meta-analytical methods. We applied multiple strategies to identify studies, strict criteria to include and evaluate the methodological quality of the studies, and subgroup and sensitivity analysis to minimize the heterogeneity. A non-english study [] was included to minimize publication bias. Hence, we provide the most upto-date information in this area. 4. Conclusions This meta-analysis indicates that CL-N may be associated with a shorter operative time and decreased conversion rate and that LESS-N may be associated with reduced postoperative pain, lower analgesic requirement, shorter LOS, shorter recovery time, and better cosmetic satisfaction without compromising surgical safety. The two surgical techniques appear to be equivalent in terms of operative complications, EBL, warm ischemia time, and postoperative SCr of graft recipients. Nevertheless, despite our rigorous methodology, the inherent limitations of included studies prevent us from reaching definitive conclusions. Future large-volume, well-designed RCTs with extensive follow-up are awaited to confirm and update the findings of this analysis. Author contributions: Jian Huang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: J. Huang, Fan. Acquisition of data: Xu, Lin. Analysis and interpretation of data: Xu, Lin, Yin. Drafting of the manuscript: Fan, Lin, J. Huang. Critical revision of the manuscript for important intellectual content: Dong, H. Huang. Statistical analysis: Fan, Xu, Dong. Obtaining funding: None. Administrative, technical, or material support: Fan, H. Huang. Supervision: J. Huang. Other (specify): None. 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