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Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis
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Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis K. Tang a,b,d, D. Xia a,b,d, H. Li a,b, W. Guan a,b, X. Guo a,b, Z. Hu a,b, X. Ma c, X. Zhang c, H. Xu a,b,*, Z. Ye a,b a
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China b Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China c Department of Urology, PLA General Hospital, Military Postgraduate Medical College, Beijing, China Accepted 13 March 2014 Available online - - -
Abstract Aims: To evaluate the safety and efficacy of robot-assisted radical cystectomy (RARC) compared with open radical cystectomy (ORC) in the treatment of bladder cancer. Methods: A systematic search of Medline, Embase databases and the Cochrane Library was performed to identify studies that compared RARC and ORC and were published up to December 2012. Outcomes of interest included demographic and clinical characteristics, perioperative, pathologic variables and complications. Results: Although there was a significant difference in the operating time in favor of ORC (WMD: 70.69 min; p < 0.001), patients having RARC might benefit from significantly fewer total complications (OR: 0.54; p < 0.001), less blood loss (WMD: 599.03 ml; p < 0.001), shorter length of hospital stay (WMD: 4.56 d; p < 0.001), lower blood transfusion rate (OR: 0.13; p ¼ 0.002), less transfusion needs (WMD: 2.14 units; p < 0.001), shorter time to regular diet (WMD: 1.57 d; p ¼ 0.002), more lymph node yield (WMD: 2.18 n; p ¼ 0.001) and fewer positive lymph node (OR: 0.64; p ¼ 0.03). There was no significant difference between the RARC and ORC regarding positive surgical margins. Conclusions: In early experience, our data suggest that RARC appears to be a safe, feasible and minimally invasive alternative to its open counterpart when performed by experienced surgeons in selected patients. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Robotic-assisted; Open; Radical cystectomy; Bladder cancer; Meta-analysis
Introduction Bladder cancer (BC) is the fourth and fifth most commonly diagnosed malignancy in the United States and Europe, respectively.1 Open radical cystectomy (ORC) remains the gold standard of care for patients with muscleinvasive bladder cancer and for those with high-risk recurrent non-muscle-invasive disease, providing efficacy with regard * Corresponding author. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Tel./fax: þ86 27 836 63454. E-mail addresses: [email protected], [email protected] (H. Xu). d K. Tang and D. Xia contributed equally to this work.
to local control and long-term disease-free survival.2e7 Despite our better understanding of pelvic anatomy and improved surgical techniques, ORC is still associated with significant perioperative complications, including significant intraoperative blood loss even when performed by experienced surgeons, in part due to the long incision, prolonged abdominal wall retraction, prolonged exposure of the peritoneal surface with major fluid shifts and poor visibility, particularly in the depth of the pelvis and retrovesical area.8e10 In an attempt to minimize intraoperative blood loss and decrease perioperative complications of ORC, the most notable of advanced surgical techniques is the increased application of minimally invasive laparoscopic and robotassisted surgery in the management of urological disorders.
0748-7983/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2014.03.008 Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Abbreviations RARC ORC BC EBL LOS UTI GI MI DVT PE ASA WMD SMD OR CI FE RE RCT LOE NOS
robot-assisted radical cystectomy open radical cystectomy bladder cancer estimated blood loss length of hospital stay urinary tract infection gastrointestinal myocardial infarction deep vein thrombosis pulmonary embolus American Society of Anesthesiologists score weighted mean difference standardized mean differences odds ratio confidence interval fixed-effects random-effects randomized controlled trial level of evidence NewcastleeOttawa Scale.
The established advantages of laparoscopic surgery include decreased pain, shorter hospital stay, and decreased intraoperative blood loss compared with these things in conventional open surgery.11e14 There is still room for improvement, however, as the current laparoscopic technology is limited due to the lack of 3-dimensional visualization and poor ergonomics. The first experience with robot-assisted radical cystectomy was reported in 2003 by Menon et al.15 Since its introduction, RARC has been added to the armamentarium of minimally invasive surgery with an obvious advantage of 3-dimensional better perspective vision, 6 degrees of freedom of movement, and improved ergonomics to laparoscopic techniques.16 And RARC is increasingly being used in the management of bladder cancer.17,18 In recent years, a number of investigators have begun to report case series of minimally invasive robot-assisted approach to radical cystectomy compared with traditional open techniques. Their early experience demonstrated the surgical feasibility of this procedure with the potential of fewer complications, lower surgical blood loss, more rapid convalescence, and even hospital discharge.19e31 However, the short- and long-term outcomes of RARC vs. ORC have not been adequately assessed, and no standard conclusive data are available. Each approach has its own advantages and limitations, and no definitive conclusions regarding objective differences in outcomes have been reached to date. Therefore, we conducted a systematic review of the literature with a meta-analysis of the available published literature to compare RARC and ORC in terms of demographic and
clinical characteristics, perioperative, pathologic outcomes and complications. Methods Study selection A systematic review of the literature was performed to identify articles published form January 2006 to December 2012 comparing RARC with ORC. We conducted a systematic search of the electronic databases, including Medline, Embase databases, and Cochrane library, using the MESH search headings: “comparative studies”, “robot-assisted”, “open”, “cystectomy” and “bladder cancer”. The “related articles” function was used to broaden the search, and all abstracts, studies, and citations scanned were reviewed. Inclusion criteria and exclusion criteria To be included in the analysis, studies were required to: (i) compare RARC with ORC, (ii) report on at least one outcome of interest mentioned below, (iii) clearly document the technique as robot-assisted cystectomy, (iv) clearly document indications for cystectomy with bladder cancer, and (iv) a randomized controlled trial (RCT) or retrospective comparative study design. When two studies were published by the same institutions and/or authors with a potentially overlapping patient sample, the most recent and/or the most informative was included unless the articles were reporting on different outcomes or on different population. Studies were excluded in the meta-analysis if: (i) the inclusion criteria were not met, (ii) no outcomes of interest (specified later) were reported or were impossible to calculate or extrapolate the necessary data for either RARC or ORC from the published results, (iii) studies focusing on pure laparoscopic procedures and/or on single-site techniques, and (iv) children were included in the studies population. Data extraction and outcomes of interest Two reviewers (K.T. and H. X.) extracted independently the following data including: first author, year of publication, country, study interval, study design, indications for operation, number of patients who underwent RARC or ORC, rate of conversion from robot-assisted to open technique, characteristics of the study population, and outcomes of interest. All disagreements about eligibility were resolved by a third reviewer (X.Z.) by discussion until a consensus was reached. In all cases of missing or incomplete data, the corresponding authors were contacted, but no additional information were provided. The following outcomes were extracted to compare RARC and ORC.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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pulmonary (pneumonia & respiratory failure), neurologic, infectious complications (urinary tract infection [UTI] & sepsis), renal (renal failure & fistula/leak & ureteric obstruction), gastrointestinal [GI] (ileus & fistula/leak & clostridium difficile colitis), cardiac (myocardial infarction [MI]), miscellaneous and thromboembolic (deep vein thrombosis/pulmonary embolus [DVT/PE]). Study quality and level of evidence
Figure 1. Flow chart of studies identified, included, and excluded.
Demographic and Clinical characteristics: Demographic variables were series of characteristics that all described as patients’ baseline characteristics including: age, proportion of males, BMI, ASA score, previous abdominal surgery, history of radiation, neoadjuvant chemotherapy, clinical stage and diversion type (ileal conduit & ileal neobladder). Perioperative variables: Perioperative variables included operating time, estimated blood loss (EBL), length of hospital stay (LOS), blood transfusion rate, transfusion needs and time to regular diet. Pathologic and oncological variables: Pathologic and oncological variables included postoperative pathologic stage (pT0,Ta,Tis,T1, pT2, pT3, pT4), positive surgical margins, mean lymph node yield and positive lymph node. Postoperative complications variables: overall complications, Clavien classification IeV, and a series of comprehensive and meticulous variables of all complications including wound (wound infection & dehiscence),
The level of evidence (LOE) of included studies was rated according to criteria by the Centre for EvidenceBased Medicine in Oxford, UK.32 The methodological quality of RCTs was assessed by means of the Jadad score33 via three items (method of randomization, blinding and withdrawals/dropouts). The methodological quality of all non-randomized studies observational studies was assessed using the NewcastleeOttawa Scale (NOS).34,35 The NOS evaluated the quality of studies by examining three aspects of the study design: patient selection, comparability of the study groups, and assessment of outcomes. A score of 0e9 (allocated as stars) may be given to individual studies. Studies achieving a score of 7 or more stars indicated a higher quality. Two reviewers (K.T. and H. X.) independently assessed the quality of the studies and disagreement was resolved by consensus. Statistical analysis The present meta-analysis was performed according to the recommendations of the Cochrane Collaboration and the Quality of Reporting of Meta-analyses (QUORUM) guidelines.36 The weighted mean differences (WMDs)
Table 1 Characteristics of included studies. First author, year
Country Study interval Design
LOEc No. of patients: Conversion, RARC/ORC N (%)
Galich, 200619 Gondo, 201220 Khan, 201221 Knox, 201222 Martin, 201123 Nepple, 201124 Ng, 201025 Nix, 201026 Rhee, 200627 Richards, 201228 Sterrett, 200629 Styn, 201230
USA Japan UK USA USA USA USA USA USA USA USA USA
2000e2006 2008e2011 2003e2008 2006e2010 NA 2007e2010 2002e2008 NA 2003e2005 2008e2010 2000e2005 2007e2010
Prospective Retrospective Prospective Retrospective Prospective Retrospective Prospective Prospective Prospective Retrospective Retrospective Retrospective
3b 3b 3b 3b 3b 3b 3b 2b 3b 3b 3b 3b
13/24 11/15 48/52 58/84 19/14 36/29 83/104 21/20 7/23 20/20 19/33 30/14
0 1,2,3,8 NA 1,2,3,5,8,9 0 1,2,4,9 NA 1,2,3,4,5,6,7,8,9 NA 1,2,3,4 3/36 (8.3%) 1,2,3,6,8 NA 1,2,3,4,5,9 0 1,2,3,4,8,9 NA 1,2,3 0 1,2,3,4,5,6,7,9 NA 1,2,3 NA 1,2,3,4,5,6,7
Wang, 200731
USA
2006e2007
Prospective
3b
33/21
1/33 (3%)
Matching/ comparablea
1,2,3,4,5,7,8,9
Follow-up, mob: Quality scored RARC/ORCA NA 20.5 2.42 39.4 7.5/8 NA 14 (8e20) NA NA 18 25 NA 8 (1e25)/ 13.5 (0e37) NA
++++++ ++++++ +++++++ +++++++ +++++ +++++++ +++++ RCT +++++ +++++++ ++++++ +++++++ ++++++
RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy; RCT ¼ randomized controlled trail; NA ¼ data not available. a Matching/comparable variables: 1 ¼ age, 2 ¼ gender, 3 ¼ BMI, 4 ¼ ASA, 5 ¼ previous abdominal surgery history, 6 ¼ history of radiation, 7 ¼ neoadjuvant chemotherapy, 8 ¼ clinical stage, 9 ¼ a diversion type. b Mean SD or median (range). c Based on US Preventive Services Task Force grading system. d Based on NewcastleeOttawa Scale. Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 2. Forest plot and meta-analysis of organ confined cT2.
and the odds ratios (ORs) were used to compare continuous and dichotomous variables, respectively. If continuous variables were measured in different units, the standardized mean differences (SMDs) were used. All outcomes were reported with 95% CIs (95% confidence interval). For continuous variables (e.g., operating time and length of hospital stay), we calculated the difference in mean values and the 95% CI between the RARC and ORC. This method requires that the study report the standard errors of the mean, the standard deviations, or the CIs. However, some studies that did not report any of these parameters but presented continuous data as medians and ranges, under this circumstance we made an approximate transformation using the technique described by Hozo.37 For dichotomous variables derived from contingency tables (e.g., complication rate), the ORs and 95% CI were computed. An OR significantly <1 favored RARC, whereas an OR significantly >1 favored ORC. All p values are two-tailed with a significant level at 0.05. A fixed-effects (FE) meta-analysis was performed, and the quantity of heterogeneity was assessed using c2 and I2 statistics with significance set at p <0.10 providing evidence of significant heterogeneity, For outcomes detected with higher values of I2 and the c2 statistic signified
increasing levels of inconsistency between studies and significant interstudy heterogeneity, then a random-effects (RE) meta-analysis model was adopted. Egger’s test was used and funnel plots were explored to determine the presence of publication bias. Sensitivity analysis was carried out RCTs and highquality retrospective studies which achieving a score of 7 stars as referred foregoing. Variables were pooled only if outcomes reported by three or more studies in the overall meta-analysis. Statistical analysis was performed using Review Manager (RevMan) Version 5.1 (The Cochrane Collaboration, Oxford, London, UK) and the metareg procedure STATA 12.0 (StataCorp, College Station, TX). Results Characteristics of eligible studies Thirteen trials including 1011 cases (418 cases and 539 controls) assessing RARC vs. ORC fulfilled the predefined inclusion criteria and were considered suitable for metaanalysis including one RCT, seven prospective and five retrospective studies (Fig. 1).
Figure 3. Forest plot and meta-analysis of organ confined cT3.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Table 2 Overall analysis of demographic and clinical characteristics comparing RARC and ORC. Outcome of interest
Age (years) Proportion of males BMI (kg/m2) ASA score ASA Class 1e2 ASA Class 3e4 Previous abdominal surgery History of radiation Neoadjuvant chemotherapy Clinical stage Organ confined cT2 Non-organ confined cT3 Diversion type Ileal conduit Ileal neobladder
No. of studies
No. of patients, RARC/ORC
OR/WMD (95% CI)
13 13 12 6 5 4 6 4 4
418/539 418/539 370/476 213/223 259/360 176/256 255/344 161/225 164/233
1.69 1.45 0.35 0.25 1.41 0.64 0.68 0.45 0.83
Chi2
d.f.
I2
p-Value
Egger’s test ( p value)
0.004 0.02 0.37 0.53 0.06 0.08 0.03 0.12 0.46
27.84 14.76 48.79 21.32 7.35 6.96 7.49 1.93 2.53
12 12 11 5 4 3 5 3 3
57% 19% 77% 77% 46% 57% 33% 0% 0%
0.006 0.26 <0.001 <0.001 0.12 0.07 0.19 0.59 0.47
0.93 0.59 0.69 0.24 0.90 0.74 0.55 0.91 0.22
6 6
172/193 172/193
1.71 (1.01, 2.91) 0.57 (0.33, 0.97)
0.05 0.04
3.11 5.02
5 5
0% 0%
0.68 0.41
0.81 0.29
6 6
254/296 254/296
1.15 (0.77, 1.71) 1.17 (0.76, 1.78)
0.50 0.48
1.09 1.16
5 5
0% 0%
0.96 0.95
0.11 0.88
(0.50, 2.70)a (1.06, 1.97) (1.10, 0.41)a (0.11, 0.21)a (0.99, 2.02) (0.41, 1.02) (0.49, 0.96) (0.16, 1.22) (0.50, 1.37)
p-Value
Study heterogeneity
CI ¼ confidence interval; OR ¼ odds ratio; WMD ¼ weighted mean difference; RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy; ASA ¼ American Society of Anesthesiologists score. *Statistically significant results are shown in bold. a Values of WMD.
Quality of the studies and level of evidence For the observational studies, the NewcastleeOttawa Scale quality assessment method35 and the US Preventive Services Task Force grading system36 were utilized to assess the quality of every study included in our metaanalysis. Only one RCT scored level 2b, the remaining prospective and retrospective studies were all level 3b. Six studies21,22,24,26,28,30 scored 7 stars and were considered to be of high quality. Also, the demographic, rate of conversion to open, comparable variables of RARC vs. ORC and follow-up time were extracted individually from each study and listed Table 1.
Outcomes of demographic and clinical characteristics Patients undergoing RARC were older (OR: 1.69; 95% CI, 0.50e2.70; p ¼ 0.004), and have a higher proportion of males (OR: 1.45; 95% CI, 1.06e1.97; p ¼ 0.02), lower incidence of previous abdominal surgery (OR: 0.68; 95% CI, 0.49e0.96; p ¼ 0.03). There was a significant trend to choose more organ-confined cT2 in the RARC (OR: 1.17; CI, 1.01e2.91; p ¼ 0.05), more non-organ confined cT3 (OR: 0.57; 95% CI, 0.33e0.97; p ¼ 0.04). And there were no significant heterogeneity between studies with (c2 ¼ 3.11, 5 d.f., I2 ¼ 0%) for organ-confined cT2,
Figure 4. Forest plot and meta-analysis of operating time.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 5. Forest plot and meta-analysis of estimated blood loss (EBL).
(c2 ¼ 5.02, 5 d.f., I2 ¼ 0%) for non-organ confined cT3. There were no significant differences with respect to BMI, ASA score, history of radiation, neoadjuvant chemotherapy, ileal conduit and ileal neobladder. Figs. 2 and 3 show the forest plots for organ confined cT2 and non-organ confined cT3, respectively. Outcomes of perioperative variables Operating time and estimated blood loss (EBL) Pooled data from the 12 studies19e23,25e31 that reported operating time and EBL between RARC and ORC, and RARC was associated with longer operative time (WMD 70.69 min; 95% CI, 46.40e94.98; p < 0.001) and less blood loss (WMD: 599.03 ml; 95% CI, 881.29 to 316.76; p < 0.001 Table 2). Figs. 4 and 5 show forest plots for operating time and EBL.
Blood transfusion rate and transfusion needs We extracted blood transfusion rate from 8 studies19e22,27e30 and transfusion needs from 3 studies.26,28,32 There were statistically significant lower blood transfusion rate (OR: 0.13; 95% CI, 0.03e0.46; p ¼ 0.002) and less transfusion needs (WMD: 2.14 units; 95% CI, 2.68 to 1.59; p < 0.001) in the RARC group compared with ORC group. Figs. 6 and 7 show forest plots for blood transfusion rate and transfusion needs respectively. Postoperative recovery 12 studies19e23,25e31 on length of hospital stay (LOS), 4 studies21,23,27,32 on time to regular diet were reported respectively, and the pooled data showed a significant difference favoring the RARC group associating with shorter length of hospital stay (WMD: 4.56 d; 95% CI, 6.67 to 2.46; p < 0.001), shorter time to regular diet (WMD:
Figure 6. Forest plot and meta-analysis of length of hospital stay (LOS).
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 7. Forest plot and meta-analysis of blood transfusion rate.
1.57 d; 95% CI, 2.57 to 0.58; p ¼ 0.002 Table 3). Figs. 8 and 9 show the forest plots for LOS and time to regular diet respectively.
positive lymph node (OR: 0.64; 95% CI, 0.42e0.96; p ¼ 0.03; Fig. 13). Outcomes of complications
Outcomes of pathologic and oncological variables Pathologic stage 6 studies20,21,24,25,30,31 on pT0,Ta,Tis,T1, pT2, pT3, pT4, 12 studies20e29,31,32 on organ confined pT2 and nonorgan confined pT3eT4 were reported respectively, and the pooled data showed a significant difference the pathologic results with more organ confined pT2 (OR: 1.80; 95% CI, 1.16e2.80; p ¼ 0.009; Fig. 10) performed RARC and more non-organ confined pT3eT4 (OR: 0.57; 95% CI, 0.36e0.89; p ¼ 0.01; Fig. 11) in ORC. Positive surgical margins There was no significant difference between the RARC and ORC regarding positive surgical margins. Mean lymph node yield and positive lymph node RARC group had more lymph node yield (WMD: 2.18 n; 95% CI, 0.89e3.47; p ¼ 0.001; Fig. 12) and fewer
Overall complications and Clavien classification IeV Pooling data from 10 studies19e22,25e28,30,31 reported on overall complications, there was a statistically significant reduction in the overall complication rate in the RARC group compared with the ORC group (OR: 0.54; 95% CI, 0.40e0.72; p < 0.001), and there was no significant heterogeneity between studies (c2 ¼ 12.51, d.f. ¼ 9, I2 ¼ 28%, Table 5). Fig. 14 shows a forest plot for overall complications. A comprehensive and meticulous review of all complications using the Clavien classification system identified statistically significant differences with regard to Clavien II (OR: 0.57; 95% CI, 0.39e0.84; p ¼ 0.004) and IV (OR: 0.36; 95% CI, 0.14e0.94; p ¼ 0.04). Comprehensive and meticulous variables of all complications A comprehensive and meticulous classification of all complications showed that RARC had a lower incidence
Table 3 Overall analysis of perioperative outcomes comparing RARC and ORC. Outcome of interest
Operating time, min EBL, mL LOS, days Blood transfusion rate Transfusion needs, units Time to regular diet, days
No. of studies
No. of patients, RARC/ORC
WMD/OR (95% CI)
12 12 12 8 3 4
382/510 382/510 382/510 226/351 123/148 123/140
70.69 599.03 4.56 0.13 2.14 1.57
p-Value
Study heterogeneity Chi
d.f.
I
p-Value
Egger’s test ( p value)
62.31 890.69 415.27 41.94 1.87 43.83
11 11 11 7 2 3
82% 99% 97% 83% 0% 93%
<0.001 <0.001 <0.001 <0.001 0.39 <0.001
0.14 0.04 0.06 0.52 0.69 0.17
2
(46.40, 94.98) (881.29, 316.76) (6.67, 2.46) (0.03, 0.46)a (2.68, 1.59) (2.57, 0.58)
<0.001 <0.001 <0.001 0.002 <0.001 0.002
2
CI ¼ confidence interval; OR ¼ odds ratio; WMD ¼ weighted mean difference; RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy; EBL ¼ estimated blood loss; LOS ¼ length of hospital stay. *Statistically significant results are shown in bold. a Values of OR. Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 8. Forest plot and meta-analysis of transfusion need.
of wound infection (OR: 0.42; p ¼ 0.05), pneumonia (OR: 0.35; p ¼ 0.01), respiratory failure (OR: 0.17; p ¼ 0.01), sepsis (OR: 0.60; p ¼ 0.008), fistula/leak (OR: 0.26; p ¼ 0.03), MI (OR: 0.24; p ¼ 0.04) and miscellaneous (OR: 0.14; p ¼ 0.03). An interesting finding showed RARC was associated with a higher incidence of ureteric obstruction (OR: 4.05; p ¼ 0.009). There was no difference between the RARC and ORC with respect to the other complications (Table 5). Heterogeneity between studies was effectively decreased after this comprehensive and meticulous classification of all complications compared with the overall complications. Sensitivity analysis and publication bias Sensitivity analysis (Table 6) was carried out for studies matched for general variables by the method of higher quality studies. There was no change in the significance of any of the outcomes in sensitivity analysis performed by one RCT and nine high-quality retrospective studies. Heterogeneity between studies was effectively decreased by the method of sensitivity analysis to some consent. The funnel plots and Egger’s tests (Tables 2e5) revealed that significant publication bias existed in only two (EBL and positive surgical margins) of the 56 comparisons performed in the present analysis. Discussion The incidence of bladder cancer rises with age, peaking between age 50 and 70 years, and is three times more common in men than in women which could be certificated in
all the included studies. Respecting the patients requiring cystectomy are generally older, some of whom may not be suitable for RARC because of the need for CO2 insufflations and the steep Trendlenberg position required during the procedure. Selection bias therefore may exist in patients performed with RARC, as the surgeons may choose patients who are generally fitter to tolerate robotic technical ease. However, in this meta-analysis RARC seemed to have an older age (OR: 1.69; p ¼ 0.004) and there was no significant difference with respect to BMI which displayed there was no bias in patients selection for age and BMI. Conversely, RARC may have a potential advantage on the management of elderly patients. Patients with a history of prior surgery are also generally excluded, and our result showed a lower incidence of previous abdominal surgery (OR: 0.68; p ¼ 0.03) which demonstrated that. Additionally, in order to reduce the risk of positive margins, the selected patients may have lower stage (TaeT2N0) disease and we also found that there was a significant trend to choose more organ-confined cT2 in the RARC (OR: 1.17; p ¼ 0.05), more non-organ confined cT3 (OR: 0.57; p ¼ 0.04) in ORC and this is consistent with the pathologic results with more organ confined pT2 (OR: 1.80; p ¼ 0.009) performed RARC and more non-organ confined pT3eT4 (OR: 0.57; p ¼ 0.01) in ORC, respectively. On our present meta-analysis, no significant differences were found with regard to ASA score, history of radiation, neoadjuvant chemotherapy or diversion type. Our current study demonstrated that patients who underwent RARC lost less blood, were less likely to be transfused, with a consequent decrease in blood transfusion
Figure 9. Forest plot and meta-analysis of time to regular diet.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 10. Forest plot and meta-analysis of organ confined pT2.
needs, time to regular diet and were discharged from the hospital earlier than patients who underwent ORC. The operative time was longer (WMD 70.69 min; p < 0.001) when performed with RARC which likely reflects the early operative experience with radical cystectomy by the robotic method. Considering robot-assisted as a new procedure for cystectomy, increasing experience may improve operating time for RARC, and the learning curve showed the potential for gradual reduction in operating time is ongoing without compromising the surgical outcomes.38 With regard to the pathologic results, RARC was associated with a lower stage in terms of more organ confined pT2, less non-organ confined pT3eT4 especially
significant in pT4 and fewer positive lymph node. Lymphadenectomy not only provides the staging information but is considered to be curative in the patients with nodal metastases. Some authors regarded LN yield as an indicator of surgical quality with cystectomy.39 Reporting on the number of harvested lymph nodes has been inconsistent in all the included studies. It reflects the tendency that surgeons began to concentrate on execution of the operation and pay attention to the details with increasing expertise. The number of lymph nodes retrieved of RARC are larger comparable to numbers harvested in ORC. The possible explanation is that meticulous dissection due to 3D vision with better perspectives of anatomical structure and decreased
Figure 11. Forest plot and meta-analysis of organ confined pT3.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 12. Forest plot and meta-analysis of mean lymph node yield.
blood loss might give the surgeon the advantage of acquiring higher LN yield in the RARC group. Although there was selection bias in patients with a lower stage and the better 3D visualization facilitates better surgical precision in RARC, results from comparison of oncological outcomes in terms of positive surgical margins between RARC and ORC remained equivocal. It is worthy of concern when RARC conducted without selection bias what the positive surgical margins would be compared with ORC. As suggested by Donat,40 improving patient outcomes and surgical technique first require an accurate characterization of overall postoperative complications. In this meta-analysis, we attempted to perform a comprehensive and meticulous review of all complications after radical cystectomy using the Clavien system. To the end, this analysis presented a rigorous comparative series of complications between RARC and ORC. Patients undergoing RARC experienced fewer overall complications than those
undergoing ORC. The etiology of the lower complication rate in RARC may be related to lower EBL, less transfusion requirements and minimally invasive surgery which are highly correlated with complications. Complications evaluated based on the Clavien score identified statistically significant differences with regard to Clavien II and IV, but not significant for Clavien I, III, V. A comprehensive and meticulous classification of all complications showed that RARC had a lower incidence of wound, wound infection, pulmonary (pneumonia & respiratory failure), &infectious disease (sepsis), GI (fistula/leak) cardiac (MI) and miscellaneous. An interesting finding showed RARC was associated with a higher incidence of ureteric obstruction (OR: 4.05; p ¼ 0.009). There was no difference between the RARC and ORC with respect to dehiscence, neurologic, UTI, renal (renal failure & fistula/leak), ileus & clostridium difficile colitis and thromboembolic (DVT/PE). To assess any impact of study quality on the effect estimates, sensitivity analysis was performed for studies
Figure 13. Forest plot and meta-analysis of positive lymph node.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
K. Tang et al. / EJSO xx (2014) 1e13
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Table 4 Overall analysis of pathologic and oncological outcomes comparing RARC and ORC. Outcome of interest
Pathologic stage pT0,Ta,Tis,T1 pT2 pT3 pT4 Organ confined pT2 Non-organ confined pT3eT4 Positive surgical margins Mean lymph node yield, n Positive lymph node
No. of studies
No. of patients, RARC/ORC
OR/WMD (95% CI)
6 6 6 6 12 12 9 10 9
261/321 261/321 261/321 261/321 399/506 399/506 352/449 379/459 352/444
1.71 1.04 0.86 0.46 1.80 0.57 0.71 2.18 0.64
(0.91, (0.66, (0.58, (0.27, (1.16, (0.36, (0.43, (0.89, (0.42,
3.22) 1.65) 1.26) 0.77) 2.80) 0.89) 1.18) 3.47)a 0.96)
p-Value
0.10 0.85 0.44 0.003 0.009 0.01 0.19 0.001 0.03
Study heterogeneity Chi2
d.f.
I2
p-Value
Egger’s test ( p value)
13.79 4.30 9.18 4.72 21.53 21.37 5.72 34.60 6.43
5 5 5 5 11 11 8 9 8
64% 0% 46% 0% 49% 49% 0% 74% 0%
0.02 0.51 0.10 0.45 0.03 0.03 0.68 <0.001 0.60
0.11 0.36 0.19 0.65 0.82 0.86 0.003 0.40 0.59
CI ¼ confidence interval; OR ¼ odds ratio; WMD ¼ weighted mean difference; RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy. *Statistically significant results are shown in bold. a Values of WMD.
pathological and oncological results in a certain degree unconsciously. In addition, short follow-up time in some patients, marked heterogeneity for several continuous variables may have an influence on the confidence of the results more or less. Nevertheless, our study establishes the feasibility of performing RARC with efficacy comparable to that of conventional ORC. This present meta-analysis comparing RARC and ORC which was conducted at an appropriate time with enough data available for extraction by metaanalytical methods. We applied a series of as many as available variables to identify studies, strict criteria with two scales to evaluate the quality of the included studies, egger’s test to evaluate the publication bias and the method of sensitivity analysis to minimize the effects of heterogeneity. Here, we provide up-to-date information which
matched for available variables. There were no significant differences in the two sensitivity analysis compared with the original analysis. The heterogeneity was not significant for dichotomous outcomes but was significant for most of the continuous variables between studies. It had a downregulation in the sensitivity analysis to some extent. However, we should admit that there existing certain inherent limitations in the studies included in our metaanalysis that cannot be ignored when interpreting our data. The major limitation of this study was the limited number of well constructed prospective studies. Indeed, with only one exception, remaining studies included in our analysis were not designed appropriately. Second, the studies included in the analysis mostly had the risk of selection bias of a lower stage and influenced the Table 5 Overall analysis of complications comparing RARC and ORC. Outcome of interest
Overall complications Major complications Minor complications 1. Infectious complications Wound infection Pulmonary infection UTI GI infection Systemic sepsis 2. Wound Dehiscence 3. Neurologic 4. Renal fistula/leak 5. Ureteric obstruction 6. GI fistula/leak 7. Ileus 8. Thromboembolic DVT/PE
No. of studies
No. of patients, RARC/ORC
OR (95% CI)
10 6 7 5 4 5 5 3 4 3 5 5 3 6 6 4
356/473 241/295 274/316 242/281 209/260 242/281 242/281 189/240 194/229 189/240 263/301 230/280 189/240 263/301 263/301 209/260
0.54 0.40 0.57 0.35 0.42 0.32 0.11 0.15 0.17 0.36 0.52 0.87 4.05 0.60 0.85 0.61
(0.40, (0.08, (0.39, (0.17, (0.18, (0.10, (0.04, (0.03, (0.04, (0.09, (0.32, (0.49, (1.42, (0.39, (0.52, (0.24,
0.72) 1.91) 0.84) 0.73) 1.00) 1.09) 0.35) 0.68) 0.65) 1.50) 0.82) 1.55) 11.54) 0.93) 1.42) 1.52)
p-Value
<0.001 0.25 0.004 0.005 0.05 0.07 <0.001 0.01 0.01 0.16 0.006 0.64 0.009 0.02 0.54 0.29
Study heterogeneity Chi2
d.f.
I2
p-Value
Egger’s test ( p value)
12.51 22.27 9.41 1.74 1.24 0.36 1.26 0.43 0.35 2.50 3.39 2.79 0.25 3.00 2.61 1.49
9 5 6 4 3 4 4 2 3 2 4 4 2 5 5 3
28% 78% 36% 0% 0% 0% 0% 0% 0% 20% 0% 0% 0% 0% 0% 0%
0.19 <0.001 0.15 0.78 0.74 0.99 0.87 0.81 0.95 0.29 0.64 0.59 0.88 0.70 0.76 0.68
0.81 0.47 0.30 0.14 0.23 0.62 0.92 0.88 0.89 0.13 0.14 0.36 0.58 0.16 0.61 0.17
CI ¼ confidence interval; OR, odds ratio; RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy; UTI ¼ urinary tract infection; GI ¼ gastrointestinal; MI ¼ myocardial infarction; DVT ¼ deep vein thrombosis; PE ¼ pulmonary embolus. *Statistically significant results are shown in bold. Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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K. Tang et al. / EJSO xx (2014) 1e13
Figure 14. Forest plot and meta-analysis of overall complications rate.
Table 6 Sensitivity analysis of RCT and high-quality observational studies (7 stars) comparing RARC and ORC. Outcome of interest Organ confined cT2 Non-organ confined cT3 Operating time, min EBL, mL LOS, days Blood transfusion rate Organ confined pT2 Non-organ confined pT3eT4 Positive surgical margins Mean lymph node yield Positive lymph node Overall complications
No. of studies
No.of patients, RARC/ORC
OR/WMD (95% CI)
p-Value
3 3 5 5 6 5 6 6 5 6 5 5
115/133 115/133 197/276 197/276 204/299 183/279 233/305 233/305 212/258 233/305 212/280 197/276
1.09 (0.54, 2.23) 0.77 (0.37, 1.61) 72.58 (56.26, 88.90)y 490.31 (930.07, 50.56)y 4.50 (7.39, 1.61) y 0.06 (0.02, 0.20) 1.93 (1.29, 2.88) 0.54 (0.36, 0.79) 0.81 (0.43, 1.56) 2.68 (1.55, 3.82) y 0.73 (0.41, 1.29) 0.50 (0.34, 0.73)
Study heterogeneity 2
0.80 0.49 <0.001 0.03 0.002 <0.001 0.001 0.01 0.53 <0.001 0.28 0.02
2
Chi
d.f.
I
2.65 3.40 7.61 747.1 400.1 12.70 5.66 5.18 4.01 15.13 4.49 10.21
2 2 4 4 5 4 5 5 4 5 4 4
25% 41% 47% 99% 99% 68% 12% 4% 0% 67% 11% 61%
p-Value
Egger’s test (p value)
0.07 0.18 0.11 <0.001 <0.001 0.01 0.34 0.39 0.40 0.01 0.34 0.04
0.81 0.08 0.20 0.13 0.57 0.85 0.64 0.50 0.04 0.63 0.66 0.38
CI confidence interval; OR odds ratio; WMD weighted mean difference; RARC¼ robot-assisted radical cystectomy; ORC¼ open radical cystectomy. *Statistically significant results are shown in bold. y Values of WMD.
may worth reference on the role of RARC for bladder cancer compared with ORA. Conclusions Thirteen trials (418 cases and 539 controls) assessing RARC vs. ORC were considered suitable for metaanalysis including one RCT, seven prospective and five retrospective studies. There was a significant trend to choose more organ-confined cT2 in the RARC, more non-organ confined cT3, and this is consistent with the pathologic results with more organ confined pT2 performed RARC and more non-organ confined pT3eT4 in ORC, respectively. This meta-analysis indicates that, in appropriately selected patients having RARC may be associated with significantly fewer total complications, less blood loss, shorter length of hospital stay, lower blood
transfusion rate, less transfusion needs, shorter time to regular diet, more lymph node yield and fewer positive lymph nodes. In early experience, our data suggest that although associated with a longer operating time, RARC appears to be a safe, feasible and minimally invasive alternative to its open counterpart when performed by experienced surgeons in selected patients. However, in spite of our rigorous methodological review, because of the inherent limitations of the included studies and the long-term oncologic results are not available, further large sample prospective, multicentric, long-term follow-up studies and Randomized control trials should be undertaken to confirm our findings. Conflict of interest statement There is no conflict of interest in relation to this study.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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22. Knox ML, El-Galley R, Busby JE. Robotic versus open radical cystectomy: identification of patients who benefit from the robotic approach. J Endourol 2012;26:1–12. 23. Martin AD, Nunez RN, Castle EP. Robot-assisted radical cystectomy versus open radical cystectomy: a complete cost analysis. Urology 2011;77:621–5. 24. Nepple KG, Strope SA, Grubb 3rd RL, Kibel AS. Early oncologic outcomes of robotic vs. open radical cystectomy for urothelial cancer. Urol Oncol 2013;31:894–8. 25. Ng CK, Kauffman EC, Lee MM, et al. A comparison of postoperative complications in open versus robotic cystectomy. Eur Urol 2010;57: 274–82. 26. Nix J, Smith A, Kurpad R, Nielsen ME, Wallen EM, Pruthi RS. Prospective randomized controlled trial of robotic versus open radical cystectomy for bladder cancer: perioperative and pathologic results. Eur Urol 2010;57:196–201. 27. Rhee JJ, Lebeau S, Smolkin M, Theodorescu D. Radical cystectomy with ileal conduit diversion: early prospective evaluation of the impact of robotic assistance. BJU Int 2006;98:1059–63. 28. Richards KA, Hemal AK, Kader AK, Pettus JA. Robot assisted laparoscopic pelvic lymphadenectomy at the time of radical cystectomy rivals that of open surgery: single institution report. Urology 2010;76: 1400–4. 29. Sterrett S, Mammen T, Nazemi T, et al. Major urological oncological surgeries can be performed using minimally invasive robotic or laparoscopic methods with similar early perioperative outcomes compared to conventional open methods. World J Urol 2007;25:193–8. 30. Styn NR, Montgomery JS, Wood DP, et al. Matched comparison of robotic assisted and open radical cystectomy. Urology 2012;79: 1303–8. 31. Wang GJ, Barocas DA, Raman JD, Scherr DS. Robotic vs open radical cystectomy: prospective comparison of perioperative outcomes and pathological measures of early oncological efficacy. BJU Int 2008; 101:89–93. 32. Phillips B, Ball C, Sackett D, et al. Levels of evidence and grades of recommendation. Oxford Centre for Evidence-based Medicine. Web site: http://www.cebm.net/index.aspx?o¼1025 [accessed 26.04.12]. 33. Clark HD, Wells GA, Hu€et C, et al. Assessing the quality of randomized trials: reliability of the Jadad scale. Control Clin Trials 1999;20: 448–52. 34. Taggart DP, D’Amico R, Altman DG. Effect of arterial revascularization on survival: a systematic review of studies comparing bilateral and single internal mammary arteries. Lancet 2001;358:870–5. 35. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute. Web site: http://www.ohri. ca/programs/clinical_epidemiology/oxford.asp [accessed 15.03.12]. 36. Clarke M, Horton R. Bringing it all together: Lancet-Cochrane collaborate on systematic reviews. Lancet 2001;357:1728. 37. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 2005;5:13. 38. Pruthi RS, Smith A, Wallen EM. Evaluating the learning curve for robot-assisted laparoscopic radical cystectomy. J Endourol 2008;22: 2469–74. 39. Buscarini M, Josephson DY, Stein JP. Lymphadenectomy in bladder cancer: a review. Urol Int 2007;79:191–9. 40. Donat SM. Standards for surgical complication reporting in urologic oncology: time for a change. Urology 2007;69:221–5.
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Review
Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis K. Tang a,b,d, D. Xia a,b,d, H. Li a,b, W. Guan a,b, X. Guo a,b, Z. Hu a,b, X. Ma c, X. Zhang c, H. Xu a,b,*, Z. Ye a,b a
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China b Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China c Department of Urology, PLA General Hospital, Military Postgraduate Medical College, Beijing, China Accepted 13 March 2014 Available online - - -
Abstract Aims: To evaluate the safety and efficacy of robot-assisted radical cystectomy (RARC) compared with open radical cystectomy (ORC) in the treatment of bladder cancer. Methods: A systematic search of Medline, Embase databases and the Cochrane Library was performed to identify studies that compared RARC and ORC and were published up to December 2012. Outcomes of interest included demographic and clinical characteristics, perioperative, pathologic variables and complications. Results: Although there was a significant difference in the operating time in favor of ORC (WMD: 70.69 min; p < 0.001), patients having RARC might benefit from significantly fewer total complications (OR: 0.54; p < 0.001), less blood loss (WMD: 599.03 ml; p < 0.001), shorter length of hospital stay (WMD: 4.56 d; p < 0.001), lower blood transfusion rate (OR: 0.13; p ¼ 0.002), less transfusion needs (WMD: 2.14 units; p < 0.001), shorter time to regular diet (WMD: 1.57 d; p ¼ 0.002), more lymph node yield (WMD: 2.18 n; p ¼ 0.001) and fewer positive lymph node (OR: 0.64; p ¼ 0.03). There was no significant difference between the RARC and ORC regarding positive surgical margins. Conclusions: In early experience, our data suggest that RARC appears to be a safe, feasible and minimally invasive alternative to its open counterpart when performed by experienced surgeons in selected patients. Ó 2014 Elsevier Ltd. All rights reserved. Keywords: Robotic-assisted; Open; Radical cystectomy; Bladder cancer; Meta-analysis
Introduction Bladder cancer (BC) is the fourth and fifth most commonly diagnosed malignancy in the United States and Europe, respectively.1 Open radical cystectomy (ORC) remains the gold standard of care for patients with muscleinvasive bladder cancer and for those with high-risk recurrent non-muscle-invasive disease, providing efficacy with regard * Corresponding author. Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Tel./fax: þ86 27 836 63454. E-mail addresses: [email protected], [email protected] (H. Xu). d K. Tang and D. Xia contributed equally to this work.
to local control and long-term disease-free survival.2e7 Despite our better understanding of pelvic anatomy and improved surgical techniques, ORC is still associated with significant perioperative complications, including significant intraoperative blood loss even when performed by experienced surgeons, in part due to the long incision, prolonged abdominal wall retraction, prolonged exposure of the peritoneal surface with major fluid shifts and poor visibility, particularly in the depth of the pelvis and retrovesical area.8e10 In an attempt to minimize intraoperative blood loss and decrease perioperative complications of ORC, the most notable of advanced surgical techniques is the increased application of minimally invasive laparoscopic and robotassisted surgery in the management of urological disorders.
0748-7983/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2014.03.008 Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Abbreviations RARC ORC BC EBL LOS UTI GI MI DVT PE ASA WMD SMD OR CI FE RE RCT LOE NOS
robot-assisted radical cystectomy open radical cystectomy bladder cancer estimated blood loss length of hospital stay urinary tract infection gastrointestinal myocardial infarction deep vein thrombosis pulmonary embolus American Society of Anesthesiologists score weighted mean difference standardized mean differences odds ratio confidence interval fixed-effects random-effects randomized controlled trial level of evidence NewcastleeOttawa Scale.
The established advantages of laparoscopic surgery include decreased pain, shorter hospital stay, and decreased intraoperative blood loss compared with these things in conventional open surgery.11e14 There is still room for improvement, however, as the current laparoscopic technology is limited due to the lack of 3-dimensional visualization and poor ergonomics. The first experience with robot-assisted radical cystectomy was reported in 2003 by Menon et al.15 Since its introduction, RARC has been added to the armamentarium of minimally invasive surgery with an obvious advantage of 3-dimensional better perspective vision, 6 degrees of freedom of movement, and improved ergonomics to laparoscopic techniques.16 And RARC is increasingly being used in the management of bladder cancer.17,18 In recent years, a number of investigators have begun to report case series of minimally invasive robot-assisted approach to radical cystectomy compared with traditional open techniques. Their early experience demonstrated the surgical feasibility of this procedure with the potential of fewer complications, lower surgical blood loss, more rapid convalescence, and even hospital discharge.19e31 However, the short- and long-term outcomes of RARC vs. ORC have not been adequately assessed, and no standard conclusive data are available. Each approach has its own advantages and limitations, and no definitive conclusions regarding objective differences in outcomes have been reached to date. Therefore, we conducted a systematic review of the literature with a meta-analysis of the available published literature to compare RARC and ORC in terms of demographic and
clinical characteristics, perioperative, pathologic outcomes and complications. Methods Study selection A systematic review of the literature was performed to identify articles published form January 2006 to December 2012 comparing RARC with ORC. We conducted a systematic search of the electronic databases, including Medline, Embase databases, and Cochrane library, using the MESH search headings: “comparative studies”, “robot-assisted”, “open”, “cystectomy” and “bladder cancer”. The “related articles” function was used to broaden the search, and all abstracts, studies, and citations scanned were reviewed. Inclusion criteria and exclusion criteria To be included in the analysis, studies were required to: (i) compare RARC with ORC, (ii) report on at least one outcome of interest mentioned below, (iii) clearly document the technique as robot-assisted cystectomy, (iv) clearly document indications for cystectomy with bladder cancer, and (iv) a randomized controlled trial (RCT) or retrospective comparative study design. When two studies were published by the same institutions and/or authors with a potentially overlapping patient sample, the most recent and/or the most informative was included unless the articles were reporting on different outcomes or on different population. Studies were excluded in the meta-analysis if: (i) the inclusion criteria were not met, (ii) no outcomes of interest (specified later) were reported or were impossible to calculate or extrapolate the necessary data for either RARC or ORC from the published results, (iii) studies focusing on pure laparoscopic procedures and/or on single-site techniques, and (iv) children were included in the studies population. Data extraction and outcomes of interest Two reviewers (K.T. and H. X.) extracted independently the following data including: first author, year of publication, country, study interval, study design, indications for operation, number of patients who underwent RARC or ORC, rate of conversion from robot-assisted to open technique, characteristics of the study population, and outcomes of interest. All disagreements about eligibility were resolved by a third reviewer (X.Z.) by discussion until a consensus was reached. In all cases of missing or incomplete data, the corresponding authors were contacted, but no additional information were provided. The following outcomes were extracted to compare RARC and ORC.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
K. Tang et al. / EJSO xx (2014) 1e13
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pulmonary (pneumonia & respiratory failure), neurologic, infectious complications (urinary tract infection [UTI] & sepsis), renal (renal failure & fistula/leak & ureteric obstruction), gastrointestinal [GI] (ileus & fistula/leak & clostridium difficile colitis), cardiac (myocardial infarction [MI]), miscellaneous and thromboembolic (deep vein thrombosis/pulmonary embolus [DVT/PE]). Study quality and level of evidence
Figure 1. Flow chart of studies identified, included, and excluded.
Demographic and Clinical characteristics: Demographic variables were series of characteristics that all described as patients’ baseline characteristics including: age, proportion of males, BMI, ASA score, previous abdominal surgery, history of radiation, neoadjuvant chemotherapy, clinical stage and diversion type (ileal conduit & ileal neobladder). Perioperative variables: Perioperative variables included operating time, estimated blood loss (EBL), length of hospital stay (LOS), blood transfusion rate, transfusion needs and time to regular diet. Pathologic and oncological variables: Pathologic and oncological variables included postoperative pathologic stage (pT0,Ta,Tis,T1, pT2, pT3, pT4), positive surgical margins, mean lymph node yield and positive lymph node. Postoperative complications variables: overall complications, Clavien classification IeV, and a series of comprehensive and meticulous variables of all complications including wound (wound infection & dehiscence),
The level of evidence (LOE) of included studies was rated according to criteria by the Centre for EvidenceBased Medicine in Oxford, UK.32 The methodological quality of RCTs was assessed by means of the Jadad score33 via three items (method of randomization, blinding and withdrawals/dropouts). The methodological quality of all non-randomized studies observational studies was assessed using the NewcastleeOttawa Scale (NOS).34,35 The NOS evaluated the quality of studies by examining three aspects of the study design: patient selection, comparability of the study groups, and assessment of outcomes. A score of 0e9 (allocated as stars) may be given to individual studies. Studies achieving a score of 7 or more stars indicated a higher quality. Two reviewers (K.T. and H. X.) independently assessed the quality of the studies and disagreement was resolved by consensus. Statistical analysis The present meta-analysis was performed according to the recommendations of the Cochrane Collaboration and the Quality of Reporting of Meta-analyses (QUORUM) guidelines.36 The weighted mean differences (WMDs)
Table 1 Characteristics of included studies. First author, year
Country Study interval Design
LOEc No. of patients: Conversion, RARC/ORC N (%)
Galich, 200619 Gondo, 201220 Khan, 201221 Knox, 201222 Martin, 201123 Nepple, 201124 Ng, 201025 Nix, 201026 Rhee, 200627 Richards, 201228 Sterrett, 200629 Styn, 201230
USA Japan UK USA USA USA USA USA USA USA USA USA
2000e2006 2008e2011 2003e2008 2006e2010 NA 2007e2010 2002e2008 NA 2003e2005 2008e2010 2000e2005 2007e2010
Prospective Retrospective Prospective Retrospective Prospective Retrospective Prospective Prospective Prospective Retrospective Retrospective Retrospective
3b 3b 3b 3b 3b 3b 3b 2b 3b 3b 3b 3b
13/24 11/15 48/52 58/84 19/14 36/29 83/104 21/20 7/23 20/20 19/33 30/14
0 1,2,3,8 NA 1,2,3,5,8,9 0 1,2,4,9 NA 1,2,3,4,5,6,7,8,9 NA 1,2,3,4 3/36 (8.3%) 1,2,3,6,8 NA 1,2,3,4,5,9 0 1,2,3,4,8,9 NA 1,2,3 0 1,2,3,4,5,6,7,9 NA 1,2,3 NA 1,2,3,4,5,6,7
Wang, 200731
USA
2006e2007
Prospective
3b
33/21
1/33 (3%)
Matching/ comparablea
1,2,3,4,5,7,8,9
Follow-up, mob: Quality scored RARC/ORCA NA 20.5 2.42 39.4 7.5/8 NA 14 (8e20) NA NA 18 25 NA 8 (1e25)/ 13.5 (0e37) NA
++++++ ++++++ +++++++ +++++++ +++++ +++++++ +++++ RCT +++++ +++++++ ++++++ +++++++ ++++++
RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy; RCT ¼ randomized controlled trail; NA ¼ data not available. a Matching/comparable variables: 1 ¼ age, 2 ¼ gender, 3 ¼ BMI, 4 ¼ ASA, 5 ¼ previous abdominal surgery history, 6 ¼ history of radiation, 7 ¼ neoadjuvant chemotherapy, 8 ¼ clinical stage, 9 ¼ a diversion type. b Mean SD or median (range). c Based on US Preventive Services Task Force grading system. d Based on NewcastleeOttawa Scale. Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 2. Forest plot and meta-analysis of organ confined cT2.
and the odds ratios (ORs) were used to compare continuous and dichotomous variables, respectively. If continuous variables were measured in different units, the standardized mean differences (SMDs) were used. All outcomes were reported with 95% CIs (95% confidence interval). For continuous variables (e.g., operating time and length of hospital stay), we calculated the difference in mean values and the 95% CI between the RARC and ORC. This method requires that the study report the standard errors of the mean, the standard deviations, or the CIs. However, some studies that did not report any of these parameters but presented continuous data as medians and ranges, under this circumstance we made an approximate transformation using the technique described by Hozo.37 For dichotomous variables derived from contingency tables (e.g., complication rate), the ORs and 95% CI were computed. An OR significantly <1 favored RARC, whereas an OR significantly >1 favored ORC. All p values are two-tailed with a significant level at 0.05. A fixed-effects (FE) meta-analysis was performed, and the quantity of heterogeneity was assessed using c2 and I2 statistics with significance set at p <0.10 providing evidence of significant heterogeneity, For outcomes detected with higher values of I2 and the c2 statistic signified
increasing levels of inconsistency between studies and significant interstudy heterogeneity, then a random-effects (RE) meta-analysis model was adopted. Egger’s test was used and funnel plots were explored to determine the presence of publication bias. Sensitivity analysis was carried out RCTs and highquality retrospective studies which achieving a score of 7 stars as referred foregoing. Variables were pooled only if outcomes reported by three or more studies in the overall meta-analysis. Statistical analysis was performed using Review Manager (RevMan) Version 5.1 (The Cochrane Collaboration, Oxford, London, UK) and the metareg procedure STATA 12.0 (StataCorp, College Station, TX). Results Characteristics of eligible studies Thirteen trials including 1011 cases (418 cases and 539 controls) assessing RARC vs. ORC fulfilled the predefined inclusion criteria and were considered suitable for metaanalysis including one RCT, seven prospective and five retrospective studies (Fig. 1).
Figure 3. Forest plot and meta-analysis of organ confined cT3.
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Table 2 Overall analysis of demographic and clinical characteristics comparing RARC and ORC. Outcome of interest
Age (years) Proportion of males BMI (kg/m2) ASA score ASA Class 1e2 ASA Class 3e4 Previous abdominal surgery History of radiation Neoadjuvant chemotherapy Clinical stage Organ confined cT2 Non-organ confined cT3 Diversion type Ileal conduit Ileal neobladder
No. of studies
No. of patients, RARC/ORC
OR/WMD (95% CI)
13 13 12 6 5 4 6 4 4
418/539 418/539 370/476 213/223 259/360 176/256 255/344 161/225 164/233
1.69 1.45 0.35 0.25 1.41 0.64 0.68 0.45 0.83
Chi2
d.f.
I2
p-Value
Egger’s test ( p value)
0.004 0.02 0.37 0.53 0.06 0.08 0.03 0.12 0.46
27.84 14.76 48.79 21.32 7.35 6.96 7.49 1.93 2.53
12 12 11 5 4 3 5 3 3
57% 19% 77% 77% 46% 57% 33% 0% 0%
0.006 0.26 <0.001 <0.001 0.12 0.07 0.19 0.59 0.47
0.93 0.59 0.69 0.24 0.90 0.74 0.55 0.91 0.22
6 6
172/193 172/193
1.71 (1.01, 2.91) 0.57 (0.33, 0.97)
0.05 0.04
3.11 5.02
5 5
0% 0%
0.68 0.41
0.81 0.29
6 6
254/296 254/296
1.15 (0.77, 1.71) 1.17 (0.76, 1.78)
0.50 0.48
1.09 1.16
5 5
0% 0%
0.96 0.95
0.11 0.88
(0.50, 2.70)a (1.06, 1.97) (1.10, 0.41)a (0.11, 0.21)a (0.99, 2.02) (0.41, 1.02) (0.49, 0.96) (0.16, 1.22) (0.50, 1.37)
p-Value
Study heterogeneity
CI ¼ confidence interval; OR ¼ odds ratio; WMD ¼ weighted mean difference; RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy; ASA ¼ American Society of Anesthesiologists score. *Statistically significant results are shown in bold. a Values of WMD.
Quality of the studies and level of evidence For the observational studies, the NewcastleeOttawa Scale quality assessment method35 and the US Preventive Services Task Force grading system36 were utilized to assess the quality of every study included in our metaanalysis. Only one RCT scored level 2b, the remaining prospective and retrospective studies were all level 3b. Six studies21,22,24,26,28,30 scored 7 stars and were considered to be of high quality. Also, the demographic, rate of conversion to open, comparable variables of RARC vs. ORC and follow-up time were extracted individually from each study and listed Table 1.
Outcomes of demographic and clinical characteristics Patients undergoing RARC were older (OR: 1.69; 95% CI, 0.50e2.70; p ¼ 0.004), and have a higher proportion of males (OR: 1.45; 95% CI, 1.06e1.97; p ¼ 0.02), lower incidence of previous abdominal surgery (OR: 0.68; 95% CI, 0.49e0.96; p ¼ 0.03). There was a significant trend to choose more organ-confined cT2 in the RARC (OR: 1.17; CI, 1.01e2.91; p ¼ 0.05), more non-organ confined cT3 (OR: 0.57; 95% CI, 0.33e0.97; p ¼ 0.04). And there were no significant heterogeneity between studies with (c2 ¼ 3.11, 5 d.f., I2 ¼ 0%) for organ-confined cT2,
Figure 4. Forest plot and meta-analysis of operating time.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 5. Forest plot and meta-analysis of estimated blood loss (EBL).
(c2 ¼ 5.02, 5 d.f., I2 ¼ 0%) for non-organ confined cT3. There were no significant differences with respect to BMI, ASA score, history of radiation, neoadjuvant chemotherapy, ileal conduit and ileal neobladder. Figs. 2 and 3 show the forest plots for organ confined cT2 and non-organ confined cT3, respectively. Outcomes of perioperative variables Operating time and estimated blood loss (EBL) Pooled data from the 12 studies19e23,25e31 that reported operating time and EBL between RARC and ORC, and RARC was associated with longer operative time (WMD 70.69 min; 95% CI, 46.40e94.98; p < 0.001) and less blood loss (WMD: 599.03 ml; 95% CI, 881.29 to 316.76; p < 0.001 Table 2). Figs. 4 and 5 show forest plots for operating time and EBL.
Blood transfusion rate and transfusion needs We extracted blood transfusion rate from 8 studies19e22,27e30 and transfusion needs from 3 studies.26,28,32 There were statistically significant lower blood transfusion rate (OR: 0.13; 95% CI, 0.03e0.46; p ¼ 0.002) and less transfusion needs (WMD: 2.14 units; 95% CI, 2.68 to 1.59; p < 0.001) in the RARC group compared with ORC group. Figs. 6 and 7 show forest plots for blood transfusion rate and transfusion needs respectively. Postoperative recovery 12 studies19e23,25e31 on length of hospital stay (LOS), 4 studies21,23,27,32 on time to regular diet were reported respectively, and the pooled data showed a significant difference favoring the RARC group associating with shorter length of hospital stay (WMD: 4.56 d; 95% CI, 6.67 to 2.46; p < 0.001), shorter time to regular diet (WMD:
Figure 6. Forest plot and meta-analysis of length of hospital stay (LOS).
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Figure 7. Forest plot and meta-analysis of blood transfusion rate.
1.57 d; 95% CI, 2.57 to 0.58; p ¼ 0.002 Table 3). Figs. 8 and 9 show the forest plots for LOS and time to regular diet respectively.
positive lymph node (OR: 0.64; 95% CI, 0.42e0.96; p ¼ 0.03; Fig. 13). Outcomes of complications
Outcomes of pathologic and oncological variables Pathologic stage 6 studies20,21,24,25,30,31 on pT0,Ta,Tis,T1, pT2, pT3, pT4, 12 studies20e29,31,32 on organ confined pT2 and nonorgan confined pT3eT4 were reported respectively, and the pooled data showed a significant difference the pathologic results with more organ confined pT2 (OR: 1.80; 95% CI, 1.16e2.80; p ¼ 0.009; Fig. 10) performed RARC and more non-organ confined pT3eT4 (OR: 0.57; 95% CI, 0.36e0.89; p ¼ 0.01; Fig. 11) in ORC. Positive surgical margins There was no significant difference between the RARC and ORC regarding positive surgical margins. Mean lymph node yield and positive lymph node RARC group had more lymph node yield (WMD: 2.18 n; 95% CI, 0.89e3.47; p ¼ 0.001; Fig. 12) and fewer
Overall complications and Clavien classification IeV Pooling data from 10 studies19e22,25e28,30,31 reported on overall complications, there was a statistically significant reduction in the overall complication rate in the RARC group compared with the ORC group (OR: 0.54; 95% CI, 0.40e0.72; p < 0.001), and there was no significant heterogeneity between studies (c2 ¼ 12.51, d.f. ¼ 9, I2 ¼ 28%, Table 5). Fig. 14 shows a forest plot for overall complications. A comprehensive and meticulous review of all complications using the Clavien classification system identified statistically significant differences with regard to Clavien II (OR: 0.57; 95% CI, 0.39e0.84; p ¼ 0.004) and IV (OR: 0.36; 95% CI, 0.14e0.94; p ¼ 0.04). Comprehensive and meticulous variables of all complications A comprehensive and meticulous classification of all complications showed that RARC had a lower incidence
Table 3 Overall analysis of perioperative outcomes comparing RARC and ORC. Outcome of interest
Operating time, min EBL, mL LOS, days Blood transfusion rate Transfusion needs, units Time to regular diet, days
No. of studies
No. of patients, RARC/ORC
WMD/OR (95% CI)
12 12 12 8 3 4
382/510 382/510 382/510 226/351 123/148 123/140
70.69 599.03 4.56 0.13 2.14 1.57
p-Value
Study heterogeneity Chi
d.f.
I
p-Value
Egger’s test ( p value)
62.31 890.69 415.27 41.94 1.87 43.83
11 11 11 7 2 3
82% 99% 97% 83% 0% 93%
<0.001 <0.001 <0.001 <0.001 0.39 <0.001
0.14 0.04 0.06 0.52 0.69 0.17
2
(46.40, 94.98) (881.29, 316.76) (6.67, 2.46) (0.03, 0.46)a (2.68, 1.59) (2.57, 0.58)
<0.001 <0.001 <0.001 0.002 <0.001 0.002
2
CI ¼ confidence interval; OR ¼ odds ratio; WMD ¼ weighted mean difference; RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy; EBL ¼ estimated blood loss; LOS ¼ length of hospital stay. *Statistically significant results are shown in bold. a Values of OR. Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 8. Forest plot and meta-analysis of transfusion need.
of wound infection (OR: 0.42; p ¼ 0.05), pneumonia (OR: 0.35; p ¼ 0.01), respiratory failure (OR: 0.17; p ¼ 0.01), sepsis (OR: 0.60; p ¼ 0.008), fistula/leak (OR: 0.26; p ¼ 0.03), MI (OR: 0.24; p ¼ 0.04) and miscellaneous (OR: 0.14; p ¼ 0.03). An interesting finding showed RARC was associated with a higher incidence of ureteric obstruction (OR: 4.05; p ¼ 0.009). There was no difference between the RARC and ORC with respect to the other complications (Table 5). Heterogeneity between studies was effectively decreased after this comprehensive and meticulous classification of all complications compared with the overall complications. Sensitivity analysis and publication bias Sensitivity analysis (Table 6) was carried out for studies matched for general variables by the method of higher quality studies. There was no change in the significance of any of the outcomes in sensitivity analysis performed by one RCT and nine high-quality retrospective studies. Heterogeneity between studies was effectively decreased by the method of sensitivity analysis to some consent. The funnel plots and Egger’s tests (Tables 2e5) revealed that significant publication bias existed in only two (EBL and positive surgical margins) of the 56 comparisons performed in the present analysis. Discussion The incidence of bladder cancer rises with age, peaking between age 50 and 70 years, and is three times more common in men than in women which could be certificated in
all the included studies. Respecting the patients requiring cystectomy are generally older, some of whom may not be suitable for RARC because of the need for CO2 insufflations and the steep Trendlenberg position required during the procedure. Selection bias therefore may exist in patients performed with RARC, as the surgeons may choose patients who are generally fitter to tolerate robotic technical ease. However, in this meta-analysis RARC seemed to have an older age (OR: 1.69; p ¼ 0.004) and there was no significant difference with respect to BMI which displayed there was no bias in patients selection for age and BMI. Conversely, RARC may have a potential advantage on the management of elderly patients. Patients with a history of prior surgery are also generally excluded, and our result showed a lower incidence of previous abdominal surgery (OR: 0.68; p ¼ 0.03) which demonstrated that. Additionally, in order to reduce the risk of positive margins, the selected patients may have lower stage (TaeT2N0) disease and we also found that there was a significant trend to choose more organ-confined cT2 in the RARC (OR: 1.17; p ¼ 0.05), more non-organ confined cT3 (OR: 0.57; p ¼ 0.04) in ORC and this is consistent with the pathologic results with more organ confined pT2 (OR: 1.80; p ¼ 0.009) performed RARC and more non-organ confined pT3eT4 (OR: 0.57; p ¼ 0.01) in ORC, respectively. On our present meta-analysis, no significant differences were found with regard to ASA score, history of radiation, neoadjuvant chemotherapy or diversion type. Our current study demonstrated that patients who underwent RARC lost less blood, were less likely to be transfused, with a consequent decrease in blood transfusion
Figure 9. Forest plot and meta-analysis of time to regular diet.
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Figure 10. Forest plot and meta-analysis of organ confined pT2.
needs, time to regular diet and were discharged from the hospital earlier than patients who underwent ORC. The operative time was longer (WMD 70.69 min; p < 0.001) when performed with RARC which likely reflects the early operative experience with radical cystectomy by the robotic method. Considering robot-assisted as a new procedure for cystectomy, increasing experience may improve operating time for RARC, and the learning curve showed the potential for gradual reduction in operating time is ongoing without compromising the surgical outcomes.38 With regard to the pathologic results, RARC was associated with a lower stage in terms of more organ confined pT2, less non-organ confined pT3eT4 especially
significant in pT4 and fewer positive lymph node. Lymphadenectomy not only provides the staging information but is considered to be curative in the patients with nodal metastases. Some authors regarded LN yield as an indicator of surgical quality with cystectomy.39 Reporting on the number of harvested lymph nodes has been inconsistent in all the included studies. It reflects the tendency that surgeons began to concentrate on execution of the operation and pay attention to the details with increasing expertise. The number of lymph nodes retrieved of RARC are larger comparable to numbers harvested in ORC. The possible explanation is that meticulous dissection due to 3D vision with better perspectives of anatomical structure and decreased
Figure 11. Forest plot and meta-analysis of organ confined pT3.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 12. Forest plot and meta-analysis of mean lymph node yield.
blood loss might give the surgeon the advantage of acquiring higher LN yield in the RARC group. Although there was selection bias in patients with a lower stage and the better 3D visualization facilitates better surgical precision in RARC, results from comparison of oncological outcomes in terms of positive surgical margins between RARC and ORC remained equivocal. It is worthy of concern when RARC conducted without selection bias what the positive surgical margins would be compared with ORC. As suggested by Donat,40 improving patient outcomes and surgical technique first require an accurate characterization of overall postoperative complications. In this meta-analysis, we attempted to perform a comprehensive and meticulous review of all complications after radical cystectomy using the Clavien system. To the end, this analysis presented a rigorous comparative series of complications between RARC and ORC. Patients undergoing RARC experienced fewer overall complications than those
undergoing ORC. The etiology of the lower complication rate in RARC may be related to lower EBL, less transfusion requirements and minimally invasive surgery which are highly correlated with complications. Complications evaluated based on the Clavien score identified statistically significant differences with regard to Clavien II and IV, but not significant for Clavien I, III, V. A comprehensive and meticulous classification of all complications showed that RARC had a lower incidence of wound, wound infection, pulmonary (pneumonia & respiratory failure), &infectious disease (sepsis), GI (fistula/leak) cardiac (MI) and miscellaneous. An interesting finding showed RARC was associated with a higher incidence of ureteric obstruction (OR: 4.05; p ¼ 0.009). There was no difference between the RARC and ORC with respect to dehiscence, neurologic, UTI, renal (renal failure & fistula/leak), ileus & clostridium difficile colitis and thromboembolic (DVT/PE). To assess any impact of study quality on the effect estimates, sensitivity analysis was performed for studies
Figure 13. Forest plot and meta-analysis of positive lymph node.
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Table 4 Overall analysis of pathologic and oncological outcomes comparing RARC and ORC. Outcome of interest
Pathologic stage pT0,Ta,Tis,T1 pT2 pT3 pT4 Organ confined pT2 Non-organ confined pT3eT4 Positive surgical margins Mean lymph node yield, n Positive lymph node
No. of studies
No. of patients, RARC/ORC
OR/WMD (95% CI)
6 6 6 6 12 12 9 10 9
261/321 261/321 261/321 261/321 399/506 399/506 352/449 379/459 352/444
1.71 1.04 0.86 0.46 1.80 0.57 0.71 2.18 0.64
(0.91, (0.66, (0.58, (0.27, (1.16, (0.36, (0.43, (0.89, (0.42,
3.22) 1.65) 1.26) 0.77) 2.80) 0.89) 1.18) 3.47)a 0.96)
p-Value
0.10 0.85 0.44 0.003 0.009 0.01 0.19 0.001 0.03
Study heterogeneity Chi2
d.f.
I2
p-Value
Egger’s test ( p value)
13.79 4.30 9.18 4.72 21.53 21.37 5.72 34.60 6.43
5 5 5 5 11 11 8 9 8
64% 0% 46% 0% 49% 49% 0% 74% 0%
0.02 0.51 0.10 0.45 0.03 0.03 0.68 <0.001 0.60
0.11 0.36 0.19 0.65 0.82 0.86 0.003 0.40 0.59
CI ¼ confidence interval; OR ¼ odds ratio; WMD ¼ weighted mean difference; RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy. *Statistically significant results are shown in bold. a Values of WMD.
pathological and oncological results in a certain degree unconsciously. In addition, short follow-up time in some patients, marked heterogeneity for several continuous variables may have an influence on the confidence of the results more or less. Nevertheless, our study establishes the feasibility of performing RARC with efficacy comparable to that of conventional ORC. This present meta-analysis comparing RARC and ORC which was conducted at an appropriate time with enough data available for extraction by metaanalytical methods. We applied a series of as many as available variables to identify studies, strict criteria with two scales to evaluate the quality of the included studies, egger’s test to evaluate the publication bias and the method of sensitivity analysis to minimize the effects of heterogeneity. Here, we provide up-to-date information which
matched for available variables. There were no significant differences in the two sensitivity analysis compared with the original analysis. The heterogeneity was not significant for dichotomous outcomes but was significant for most of the continuous variables between studies. It had a downregulation in the sensitivity analysis to some extent. However, we should admit that there existing certain inherent limitations in the studies included in our metaanalysis that cannot be ignored when interpreting our data. The major limitation of this study was the limited number of well constructed prospective studies. Indeed, with only one exception, remaining studies included in our analysis were not designed appropriately. Second, the studies included in the analysis mostly had the risk of selection bias of a lower stage and influenced the Table 5 Overall analysis of complications comparing RARC and ORC. Outcome of interest
Overall complications Major complications Minor complications 1. Infectious complications Wound infection Pulmonary infection UTI GI infection Systemic sepsis 2. Wound Dehiscence 3. Neurologic 4. Renal fistula/leak 5. Ureteric obstruction 6. GI fistula/leak 7. Ileus 8. Thromboembolic DVT/PE
No. of studies
No. of patients, RARC/ORC
OR (95% CI)
10 6 7 5 4 5 5 3 4 3 5 5 3 6 6 4
356/473 241/295 274/316 242/281 209/260 242/281 242/281 189/240 194/229 189/240 263/301 230/280 189/240 263/301 263/301 209/260
0.54 0.40 0.57 0.35 0.42 0.32 0.11 0.15 0.17 0.36 0.52 0.87 4.05 0.60 0.85 0.61
(0.40, (0.08, (0.39, (0.17, (0.18, (0.10, (0.04, (0.03, (0.04, (0.09, (0.32, (0.49, (1.42, (0.39, (0.52, (0.24,
0.72) 1.91) 0.84) 0.73) 1.00) 1.09) 0.35) 0.68) 0.65) 1.50) 0.82) 1.55) 11.54) 0.93) 1.42) 1.52)
p-Value
<0.001 0.25 0.004 0.005 0.05 0.07 <0.001 0.01 0.01 0.16 0.006 0.64 0.009 0.02 0.54 0.29
Study heterogeneity Chi2
d.f.
I2
p-Value
Egger’s test ( p value)
12.51 22.27 9.41 1.74 1.24 0.36 1.26 0.43 0.35 2.50 3.39 2.79 0.25 3.00 2.61 1.49
9 5 6 4 3 4 4 2 3 2 4 4 2 5 5 3
28% 78% 36% 0% 0% 0% 0% 0% 0% 20% 0% 0% 0% 0% 0% 0%
0.19 <0.001 0.15 0.78 0.74 0.99 0.87 0.81 0.95 0.29 0.64 0.59 0.88 0.70 0.76 0.68
0.81 0.47 0.30 0.14 0.23 0.62 0.92 0.88 0.89 0.13 0.14 0.36 0.58 0.16 0.61 0.17
CI ¼ confidence interval; OR, odds ratio; RARC ¼ robot-assisted radical cystectomy; ORC ¼ open radical cystectomy; UTI ¼ urinary tract infection; GI ¼ gastrointestinal; MI ¼ myocardial infarction; DVT ¼ deep vein thrombosis; PE ¼ pulmonary embolus. *Statistically significant results are shown in bold. Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
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Figure 14. Forest plot and meta-analysis of overall complications rate.
Table 6 Sensitivity analysis of RCT and high-quality observational studies (7 stars) comparing RARC and ORC. Outcome of interest Organ confined cT2 Non-organ confined cT3 Operating time, min EBL, mL LOS, days Blood transfusion rate Organ confined pT2 Non-organ confined pT3eT4 Positive surgical margins Mean lymph node yield Positive lymph node Overall complications
No. of studies
No.of patients, RARC/ORC
OR/WMD (95% CI)
p-Value
3 3 5 5 6 5 6 6 5 6 5 5
115/133 115/133 197/276 197/276 204/299 183/279 233/305 233/305 212/258 233/305 212/280 197/276
1.09 (0.54, 2.23) 0.77 (0.37, 1.61) 72.58 (56.26, 88.90)y 490.31 (930.07, 50.56)y 4.50 (7.39, 1.61) y 0.06 (0.02, 0.20) 1.93 (1.29, 2.88) 0.54 (0.36, 0.79) 0.81 (0.43, 1.56) 2.68 (1.55, 3.82) y 0.73 (0.41, 1.29) 0.50 (0.34, 0.73)
Study heterogeneity 2
0.80 0.49 <0.001 0.03 0.002 <0.001 0.001 0.01 0.53 <0.001 0.28 0.02
2
Chi
d.f.
I
2.65 3.40 7.61 747.1 400.1 12.70 5.66 5.18 4.01 15.13 4.49 10.21
2 2 4 4 5 4 5 5 4 5 4 4
25% 41% 47% 99% 99% 68% 12% 4% 0% 67% 11% 61%
p-Value
Egger’s test (p value)
0.07 0.18 0.11 <0.001 <0.001 0.01 0.34 0.39 0.40 0.01 0.34 0.04
0.81 0.08 0.20 0.13 0.57 0.85 0.64 0.50 0.04 0.63 0.66 0.38
CI confidence interval; OR odds ratio; WMD weighted mean difference; RARC¼ robot-assisted radical cystectomy; ORC¼ open radical cystectomy. *Statistically significant results are shown in bold. y Values of WMD.
may worth reference on the role of RARC for bladder cancer compared with ORA. Conclusions Thirteen trials (418 cases and 539 controls) assessing RARC vs. ORC were considered suitable for metaanalysis including one RCT, seven prospective and five retrospective studies. There was a significant trend to choose more organ-confined cT2 in the RARC, more non-organ confined cT3, and this is consistent with the pathologic results with more organ confined pT2 performed RARC and more non-organ confined pT3eT4 in ORC, respectively. This meta-analysis indicates that, in appropriately selected patients having RARC may be associated with significantly fewer total complications, less blood loss, shorter length of hospital stay, lower blood
transfusion rate, less transfusion needs, shorter time to regular diet, more lymph node yield and fewer positive lymph nodes. In early experience, our data suggest that although associated with a longer operating time, RARC appears to be a safe, feasible and minimally invasive alternative to its open counterpart when performed by experienced surgeons in selected patients. However, in spite of our rigorous methodological review, because of the inherent limitations of the included studies and the long-term oncologic results are not available, further large sample prospective, multicentric, long-term follow-up studies and Randomized control trials should be undertaken to confirm our findings. Conflict of interest statement There is no conflict of interest in relation to this study.
Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008
K. Tang et al. / EJSO xx (2014) 1e13
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Please cite this article in press as: Tang K, et al., Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis, Eur J Surg Oncol (2014), http://dx.doi.org/10.1016/j.ejso.2014.03.008