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Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL)
EURURO-8624; No. of Pages 9 E U R O P E A N U RO L O GY X X X ( 2 019 ) X X X – X X X
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Bladder Cancer
Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL) Muhammad Shamim Khan a,b,*, Kawa Omar a, Kamran Ahmed b,c, Christine Gan a, Mieke Van Hemelrijck d, Rajesh Nair a, Ramesh Thurairaja a, Peter Rimington a, Prokar Dasgupta a,b a
Department of Urology, Guy's & St Thomas’ NHS Foundation Trust, London, UK;
c
Department of Urology, King's College Hospital, Denmark Hill, London, UK;
d
b
MRC Centre for Transplantation, King's College London, London, UK;
King's College London, School of Cancer and Pharmaceutical Studies,
Translational Oncology & Urology Research (TOUR), London, UK
Article info
Abstract
Article history: Accepted October 23, 2019
Background: The long-term oncological outcomes of laparoscopic (LRC) and roboticassisted radical cystectomy (RARC) are still maturing compared with open radical cystectomy (ORC). Objective: To evaluate the 5-yr oncological outcomes of patients recruited into the randomised trial of Open, Laparoscopic and Robot Assisted Cystectomy (CORAL) and extracorporeal urinary diversion. Design, setting, and participants: A review of prospectively maintained database of 60 patients with muscle-invasive bladder cancer (MIBC) or high-risk nonmuscle-invasive bladder cancer (HRNMIBC) who were previously randomised in the CORAL trial to receive ORC, RARC, or LRC. This trial was designed to compare the perioperative and early oncological outcomes of these techniques. Outcome measurements and statistical analysis: The outcomes of interest included 5-yr recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Kaplan–Meier curves were used to plot the recurrence and survival data. The curves between RFS, CSS, and OS were compared using the log-rank test. A two-sided p value <0.05 was considered significant. Results were analysed on the basis of intention to treat. Results and limitations: A total of 60 patients with either MIBC (n = 38) or HRNMIBC (n = 21) were randomised in the CORAL trial to receive ORC, RARC, or LRC. The 5-yr RFS was 60%, 58%, and 71%; 5-yr CSS was 64%, 68%, and 69%; and 5-yr OS was 55%, 65%, and 61% for ORC, RARC, and LRC, respectively. There was no significant difference in RFS, CSS, and OS between the three surgical arms. The principal limitation is the small sample size. Conclusions: There was no difference in 5-yr RFS, CSS, and OS rates of patients who underwent ORC, RARC, and LRC for management of bladder cancer. Minimally invasive techniques achieved equivalent oncological outcomes to the gold standard of ORC. However, the study was based at a single institution with a small sample size. Patient summary: Patients who agreed to participate in the randomised trial of either open, laparoscopic, or robotic-assisted radical cystectomy for bladder cancer did not have different cancer outcomes at 5 yr. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: James Catto Statistical Editor: Andrew Vickers Keywords: Robotic cystectomy Bladder cancer Open cystectomy
* Corresponding author. Department of Urology, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK. E-mail address: [email protected] (M.S. Khan).
https://doi.org/10.1016/j.eururo.2019.10.027 0302-2838/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Khan MS, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol (2019), https://doi.org/10.1016/j. eururo.2019.10.027
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1.
Introduction
outcomes (recurrence, bladder cancer-specific death, and overall death). To assess for competing outcomes (eg, death), Fine and Gray competing
Radical cystectomy, although a highly morbid procedure, remains the standard of care for muscle-invasive bladder cancer (MIBC) and high-risk nonmuscle-invasive bladder cancer (HRNMIBC) where bladder preservation treatments have failed [1,2]. Open radical cystectomy (ORC) is accepted as the gold standard because its long-term oncological outcomes are well-established [3,4]. In an endeavour to minimise the perioperative morbidity, minimally invasive radical cystectomy (MIRC) techniques such as laparoscopic (LRC) and robotic-assisted (RARC) radical cystectomy have been developed. The main findings from our previously published CORAL Trial demonstrated reduced blood loss and shorter hospital stay with the minimally invasive approaches. We found no significant differences in 90-d complication rates and oncological outcomes among the randomised groups [5]. Several other studies have shown lower complication rates for RARC compared with ORC [6–9], but evidence on the long-term oncological outcomes of MIRC is still maturing. This article aims to report long-term oncological outcomes of the three-arm CORAL trial (open, laparoscopic, and robotic), a randomised trial of radical cystectomy. 2.
Patients and methods
Patients’ eligibility for trial inclusion, the randomisation process, and the technical aspects of ORC, RARC, and LRC were previously described [5]. All operations were performed at Guy's Hospital London by three expert surgeons (MSK, PD, and PR) who were all well over their learning curves for their respective operative modalities. Urinary diversions were
risk regression was applied. All data analysis was performed using SPSS version 21 (IBM Corp, Armonk, NY, USA) and Statistical Analysis Systems (SAS) release 9.4 (SAS Institute, Cary, NC). Results were analysed on the basis of intention to treat.
3.
Results
A total of 60 patients agreed to participate in the study and were randomised to receive either ORC, LRC, or RARC. All 20 patients who were randomised to ORC underwent the assigned procedure. In the RARC arm, one patient was converted to ORC due to equipment failure. In the LRC group, one patient randomised to LRC was withdrawn from the trial after further review of the histology by the specialist bladder cancer pathologist team panel changed the diagnosis to small cell bladder cancer. Surgery was deemed unsuitable for this disease and the patient eventually underwent chemoradiotherapy. Of the remaining 19 patients in the LRC group, three were converted to RARC because of unavailability of the laparoscopic surgeon and another was converted intraoperatively to ORC due to large tumour size. In total, 59 patients underwent radical cystectomy in three surgical arms. In the follow-up period, one patient in the LRC group was lost to follow-up. Median follow-up for those in the ORC arm was 65.6 mo, whereas this was 86.6 mo in the RARC group and 83.8 in the LRC group. Median follow-up for the survivors was 104.7, 102.7, and 91.4 mo in the ORC, RARC, and LRC arms, respectively.
performed extracorporeally in both laparoscopic and robotic subgroups and pelvic lymph node (LN) dissection was performed in all arms.
3.1.
Patient characteristics
At each follow-up visit, patients had clinical examination and blood tests for full blood count and electrolytes, including renal function tests and bicarbonate. Patients were followed up with a computed tomogra-
Patient preoperative characteristics, surgical factors, and final pathologic stage are presented in Table 1.
phy scan of the chest, abdomen, and pelvis at 6 and 12 mo and then every 6 mo or 1 yr thereafter according to the final histopathological stage as
3.2.
Pathologic outcomes
per EAU Guidelines. A loopogram was performed at 3 mo to assess for uretero-enteric anastomosis stricture. Follow-up data on recurrence, pattern of recurrence, death, and cause of death were recorded prospectively from the end of the trial to March 31, 2019. Outcomes studied included recurrence-free survival (RFS), cancerspecific survival (CSS), and overall survival (OS). RFS is defined as the time from the date of radical cystectomy to either local recurrence (defined as disease recurrence within the true pelvis) or development of metastatic disease (disease recurrence outside the true pelvis) based on imaging or histology. CSS is defined as the time to death from bladder cancer after radical cystectomy. OS implies the length of time from the date of cystectomy to death from any cause. The cause of death was determined from death certificates obtained from the patient's general practitioner if the patient died outside the hospital. Positive margins in cystectomy on final histology are either ureteric, urethral (either a grossly visible tumour or carcinoma in situ [CIS] at the resection margin), or bladder soft tissue margins (STMs). Information regarding positive margins was recorded as part of the original CORAL trial. Kaplan–Meier curves were used to plot the recurrence and survival data. The curves between the RFS, CSS, and OS were statistically compared using the log-rank test. Moreover, a univariate Cox proportional hazards regression model was used to predict the three primary
In the ORC group, four patients had no residual disease (pT0) in the bladder, 10 had nonmuscle-invasive (NMIBC) residual tumours, and six had locally advanced disease (pT3 = 4 and pT4 = 2). In the RARC group, two patients had no residual cancer (pT0), nine had residual NMIBC, three had residual MIBC, and six locally advanced (pT3) tumours. Of the patients in the LRC group, three had no residual cancer (pT0), five nonmuscle-invasive tumours (NMIBC), three muscle-invasive tumours (pT2), and eight locally advanced disease (pT3 = 7 and pT4 = 1). Two of the 20 ORC patients (10%), three of the 20 RARC patients (15%), and one of the 19 LRC patients (5%) had positive surgical margins (PSMs). Of these, three had CIS at the distal urethral margin: one in the ORC group and two in the RARC group. These patients subsequently had interval urethrectomy but there was no residual cancer in the excised urethral stump. Three patients had positive STMs, one in each of the three surgical arms. Overall, we found no significant relationship between the surgical arm and PSMs.
Please cite this article in press as: Khan MS, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol (2019), https://doi.org/10.1016/j. eururo.2019.10.027
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Table 1 – Patient characteristics
Age, yr, median (Q1–Q3) BMI, kg/m2, median (Q1–Q3) Male, n (%) ASA grade, n (%) ASA 1 ASA 2 ASA 3 Neoadjuvant chemotherapy, n (%) Preoperative diagnosis NMIBC, n (%) MIBC, n (%) Diversion type Ileal conduit, n (%) Neobladder, n (%) Final pathologic stage T0 Ta/T1/Tis T2 T3 T4 LN yield (median, Q1–Q3) Positive LN
ORC (n = 20)
RARC (n = 20)
LRC (n = 19)
68 (58–74) 26.99 (23.76–30.44) 18 (90)
68 (65–74) 27.50 (24.00–31.00) 17 (85)
71 (63–75) 26.00 (24.00–27.59) 15 (79)
4 (20) 15 (75) 1 (5) 3 (15)
4 (20) 15 (75) 1 (5) 2 (10)
3 (16) 13 (68) 3 (16) 1 (5.26)
8 (40) 12 (60)
8 (40) 12 (60)
5 (26) 14 (74)
17 (85) 3 (15)
18 (90) 2 (10)
18 (95) 1 (5)
4 10 0 4 2 18.5 (14.0–25.0) 6 (30%)
2 9 3 6 0 14.5 (11.0–21.0) 3 (15%)
3 5 3 7 1 15.5 (12.0–22.0) 6 (31.5%)
ASA = American Society of Anesthesiologists; BMI = body mass index; LN = lymph node; LRC = laparoscopic radical cystectomy; MIBC = muscle-invasive bladder cancer; NMIBC = nonmuscle-invasive bladder cancer; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
Table 2 – Site of recurrence in the three surgical arms
Overall recurrence Local recurrence Distant recurrence Combination Upper tract recurrence
ORC
RARC
LRC
9/20 3/9 4/9 1/9 1/9
8/20 3/8 4/8 1/8 0/8
6/18 4/6 2/6 0/6 0/6
LRC = laparoscopic radical cystectomy; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
Mean LN yield was 19, 16, and 16 for ORC, RARC, and LRC, respectively. The differences in LN yield was only statistically significant (p = 0.01) between the ORC and LRC arms. LNs were involved by cancer in 30% (six/20), 15% (three/20), and 31% (six/19) in the ORC, RARC, and LRC groups, respectively. 3.3.
Oncological outcomes
Overall, 23/59 of patients had disease recurrence in the follow-up period up to March 31, 2019. There were nine/20 recurrences in the ORC group, eight/20 in the RARC group, and six/18 in the LRC group. The recurrences were classified
as local, distant metastasis, or a combination. The proportions of local, distant, and combination metastases occurring in each surgical arm are summarised in Table 2. Univariate Cox proportional hazards regression models did not show an effect of surgical procedure on recurrence, overall death, or bladder cancer-specific death (Table 3). These results are also graphically represented with Kaplan– Meier graphs in Figs. 1–3, respectively. The RFS, CSS, and OS are also not significantly different between the three surgical groups when comparing the data based on the modality of the operation the patients underwent. Additional assessment of competing risks did not reveal any other associations. Because of the small sample size of this study, the results of this modelling should be interpreted with caution. 4.
Discussion
Minimally invasive approaches in the treatment of benign or malignant conditions have been embraced widely in all surgical specialties, but none more so than in urology. The minimally invasive techniques provide important benefits such as reduced blood loss, quicker recovery, shorter hospital stay, and reduced wound complications [10,11]. However, aside from these perioperative benefits,
Table 3 – Hazard ratios and 95% confidence intervals for recurrence, overall death, and bladder cancer-specific death based on surgical procedure
Open radical cystectomy Robotic-assisted radical cystectomy Laparoscopic radical cystectomy
Recurrence
Overall death
1.00 (Reference) 1.13 (0.42–3.01) 0.83 (0.29–2.39)
1.00 (Reference) 0.72 (0.30–1.74) 0.83 (0.34–2.01)
Bladder cancer-specific death 1.00 (Reference) 0.75 (0.28–2.01) 0.60 (0.20–1.78)
Please cite this article in press as: Khan MS, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol (2019), https://doi.org/10.1016/j. eururo.2019.10.027
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Fig. 1 – Recurrence-free survival of ORC, RARC, and LRC. (A) Results from ITT analyses. (B) Results from per-treatment analyses. ITT = intention to treat; LRC = laparoscopic radical cystectomy; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
there is as yet little evidence to suggest that these approaches yield superior oncological outcomes, which are largely dependent on the local stage and biology of the disease, and perhaps the experience of the surgeons performing the procedures [10,11].
Traditional laparoscopy has inherent limitations as a result of four degrees of freedom of movement and poor ergonomics which put a lot of physical and mental strain on surgeons performing the surgery. As a result, it has gradually been replaced with robotic surgery which has
Please cite this article in press as: Khan MS, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol (2019), https://doi.org/10.1016/j. eururo.2019.10.027
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5
Fig. 2 – Cancer-specific survival of ORC, RARC, and LRC. (A) Results from ITT analyses. (B) Results from per-treatment analyses. ITT = intention to treat; LRC = laparoscopic radical cystectomy; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
the unique benefits of superior visualisation, higher degree of freedom of movement, and better ergonomics [12,13]. However, the installation and maintenance costs of current robotic surgical systems remain prohibitive and have attracted some criticism, particularly in the
“free-for-all” health care systems such as the National Health Service (NHS) in the UK. The benefit of robotic surgery continues to be debated even for procedures such as radical prostatectomy [14] and partial nephrectomy [15], but the robotic procedure which
Please cite this article in press as: Khan MS, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol (2019), https://doi.org/10.1016/j. eururo.2019.10.027
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Fig. 3 – Overall survival of ORC, RARC, and LRC. ITT = intention to treat; LRC = laparoscopic radical cystectomy; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
has come under the most scrutiny is radical cystectomy. This is following the publication of several randomised trials from both the United States and the UK showing minimal difference in outcomes between ORC and RARC except a reduced need for blood transfusions and a trend towards shorter length of stay in favour of RARC [5,16–19] (Table 4).
RARC has come under most scrutiny principally because of the hype created over the perceived benefits of robotassisted surgery. It may be argued that the surgical community had unrealistic expectations from this technology and anticipated a vast difference in outcomes compared with open surgery. As such, given that the benefits of robotic cystectomy reported to date have been marginal, and
Please cite this article in press as: Khan MS, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol (2019), https://doi.org/10.1016/j. eururo.2019.10.027
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Table 4 – Results from other randomised controlled trials comparing open and robotic cystectomy Study
Country
Number RARC/ORC
Parekh et al. [14] Nix et al. [15] Bochner et al. [16]
USA USA USA
20/20 21/20 60/58
Feasibility trial of RARC LN yield Perioperative complications
NS NA NA
NS NS NS
RAZOR trial, Parekh et al. [17]
USA
150/156
2-yr PFS
Lower in RARC
NS
Primary end point
BT
LOS
Complications
NS NS NS (except wound infection) NS
Positive margins
Yield median and significance
NS (5%/5%) NS (0/0) NS (3.3%/5.2%)
NS (11/23) NS (19/18) NS (19.5/18.9)
NS
NS
BT = blood transfusion; LN = lymph node; LOS = length of stay; NA = not available; NS = not significant; ORC = open radical cystectomy; PFS = progression-free survival; RARC = robotic-assisted radical cystectomy.
coupled with the high cost of robotic surgery, it has been a challenge to justify the introduction of robotic cystectomy in the NHS in the UK. To demonstrate the oncological safety of the technique, PSM and LN yield are considered two critical measures of surgical quality in cystectomy. Large studies have demonstrated that PSMs are important predictors of local recurrence and metastases, and consequently determine CSS [20,21]. Higher LN yield has also been shown to be associated with improved CSS [22–25]. Therefore, for MIRC to measure up to ORC in terms of oncological efficacy, it must be able to achieve equivalence in these two pathological measures. The rate of PSMs in large ORC series range from 1% to 6.3% [26,27]. Analysis of the International Robotic Cystectomy Consortium (IRCC) database of 702 patients have shown 8% PSM in RARC [28], whereas PSM in a big series of LRC was 5.8% [29]. The PSM rates reported in this study were 10% (two/20), 15% (three/20), and 5% (one/15) for ORC, RARC, and LRC, respectively. Although the PSM rate for RARC in particular seems high, three of the six patients with PSMs in fact had CIS at the distal urethral margin. As we previously explained, this is likely to be related to our practice of avoiding simultaneous urethrectomy except in patients with clinically overt disease in the urethra. In our experience patients who had simultaneous excision of the urethra suffered more pain from this part of the procedure than from the cystectomy itself. More importantly, we found no significant correlation between surgical modality and urethral PSM. This finding is in agreement with that from a meta-analysis of four randomised controlled trials comparing RARC and ORC [30]. The recently published RAZOR trial did find a greater incidence of positive bladder STMs in the robotic arm compared with the open arm, but the difference in overall positive margin rate between RARC and ORC in this study did not reach significance [19]. Herr et al. [31] proposed that at least 10–14 LNs need to be retrieved to adequately determine LN involvement status. Several studies have shown that RARC can achieve comparable LN retrieval with ORC [17,32,33]. A study based on the IRCC database for RARCs also found that surgeon volume is related to the probability of the patient undergoing extended LN dissection [34]. In our study all of the participating surgeons for each surgical arm were well beyond their indicative learning curves. The mean LN
yield was 18.8 in the ORC group, 16.3 in the RARC group, and 15.5 in the LRC group. The differences in LN yield between ORC and LRC were statistically significant (p = 0.01), but the difference between ORC and RARC was not significant. This is again in agreement with the aforementioned randomised controlled trials where there was no significant difference in LN yield between ORC and RARC [14–17]. We have found no significant difference in 5-yr RFS, CSS, and OS between the three surgical arms. Although several nonrandomised studies have reported long-term oncological outcomes of RARC [35,36] and LRC [29,37], these series demonstrated oncological outcomes that were comparable with those from the other historical series of ORC [4,38]. In summary, the principal advantage of MIRC lies in minimising the morbidity of cystectomy but can only achieve equivalent oncological outcomes compared with ORC. Thus, it is evident that oncological outcomes of cystectomy for urothelial cancer is largely dependent on the biology of the disease. Our long-term findings from this study, as well as the shorter-term studies that we have discussed earlier bear out this statement. Another aspect of concern has been the risk of tumour cell spillage with MIRC. In this cohort, none of the patients developed peritoneal metastasis or port site metastasis to suggest seeding from tumour spillage. We believe that the quest for reducing the morbidity of radical cystectomy should not stop, as these marginal benefits are likely to widen with the increasing trend towards performing intracorporeal urinary diversion. Limitations include surgeons being in a single specialist centre, small sample size, failure to deliver the treatment in allocated randomised groups, and early termination of the trial. 5.
Conclusions
Based on our observation, there was no difference in 5-yr RFS, CSS, and OS of patients who underwent ORC, RARC, and LRC. Minimally invasive techniques achieved similar oncological outcomes to the gold standard of ORC. However, the results need to be interpreted with caution due to the small sample size. These results from the only randomised trial comparing all three approaches with radical cystectomy should provide some reassurance to the clinicians and the patients.
Please cite this article in press as: Khan MS, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol (2019), https://doi.org/10.1016/j. eururo.2019.10.027
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Author contributions: Muhammad Shamim Khan had full access to all
[10] Soave A, Schmidt S, Dahlem R, et al. Does the extent of variant
the data in the study and takes responsibility for the integrity of the data
histology affect oncological outcomes in patients with urothelial
and the accuracy of the data analysis.
carcinoma of the bladder treated with radical cystectomy? Urol
Study concept and design: Khan, Dasgupta. Acquisition of data: Omar, Gan. Analysis and interpretation of data: Van Hemelrijck. Drafting of the manuscript: Khan, Dasgupta, Omar, Ahmed. Critical revision of the manuscript for important intellectual content: Khan, Dasgupta, Ahmed. Statistical analysis: Van Hemelrijck. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Khan. Other: None. Financial disclosures: Muhammad Shamim Khan certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or
Oncol Semin Orig Investig 2015;33:21, 21.e1–21.e9. [11] Bhindi B, Yu J, Kuk C, et al. The importance of surgeon characteristics on impacting oncologic outcomes for patients undergoing radical cystectomy. J Urol 2014;192:714–20. [12] Lanfranco AR, Castellanos AE, Desai JP, Meyers WC. Robotic surgery: a current perspective. Ann Surg 2004;239:14–21. [13] Hussain A, Malik A, Halim MU, Ali AM. The use of robotics in surgery: a review. Int J Clin Pract 2014;68:1376–82. [14] Yaxley JW, Coughlin GD, Chambers SK, et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study. Lancet 2016;388:1057–66. [15] Xia L, Wang X, Xu T, Guzzo TJ. Systematic review and meta-analysis of comparative studies reporting perioperative outcomes of robotassisted partial nephrectomy versus open partial nephrectomy. J Endourol 2017;31:893–909. [16] Parekh DJ, Messer J, Fitzgerald J, Ercole B, Svatek R. Perioperative
patents filed, received, or pending), are the following: None.
outcomes and oncologic efficacy from a pilot prospective random-
Funding/Support and role of the sponsor: None.
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Acknowledgements: Authors acknowledge the contribution from the bladder cancer specialist nurses (Kathryn Chatterton and Suzanne Amery) and Dr Fahim Ismail for their contribution regarding patient counselling and follow-up. We also acknowledge the contribution from Beth Russell for her help in the analysis and editing of the manuscript. PDG is grant funded by the MRC Centre for Transplantation, NIHR Biomedical Research Centre, KCL, The KCL-Vattikuti Institute of Robotic Surgery, EU, and the GSTT Charity.
ized clinical trial of open versus robotic assisted radical cystectomy. [17] 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. [18] Bochner BH, Dalbagni G, Sjoberg DD, et al. Comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: a randomized clinical trial. Eur Urol 2015;67:1042–50. [19] Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.
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[36] Yuh B, Torrey RR, Ruel NH, et al. Intermediate-term oncologic outcomes of robot-assisted radical cystectomy for urothelial carcinoma. J Endourol 2014;28:939–45. [37] Huang J, Lin T, Liu H, et al. Laparoscopic radical cystectomy with
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available at www.sciencedirect.com journal homepage: www.europeanurology.com
Bladder Cancer
Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL) Muhammad Shamim Khan a,b,*, Kawa Omar a, Kamran Ahmed b,c, Christine Gan a, Mieke Van Hemelrijck d, Rajesh Nair a, Ramesh Thurairaja a, Peter Rimington a, Prokar Dasgupta a,b a
Department of Urology, Guy's & St Thomas’ NHS Foundation Trust, London, UK;
c
Department of Urology, King's College Hospital, Denmark Hill, London, UK;
d
b
MRC Centre for Transplantation, King's College London, London, UK;
King's College London, School of Cancer and Pharmaceutical Studies,
Translational Oncology & Urology Research (TOUR), London, UK
Article info
Abstract
Article history: Accepted October 23, 2019
Background: The long-term oncological outcomes of laparoscopic (LRC) and roboticassisted radical cystectomy (RARC) are still maturing compared with open radical cystectomy (ORC). Objective: To evaluate the 5-yr oncological outcomes of patients recruited into the randomised trial of Open, Laparoscopic and Robot Assisted Cystectomy (CORAL) and extracorporeal urinary diversion. Design, setting, and participants: A review of prospectively maintained database of 60 patients with muscle-invasive bladder cancer (MIBC) or high-risk nonmuscle-invasive bladder cancer (HRNMIBC) who were previously randomised in the CORAL trial to receive ORC, RARC, or LRC. This trial was designed to compare the perioperative and early oncological outcomes of these techniques. Outcome measurements and statistical analysis: The outcomes of interest included 5-yr recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Kaplan–Meier curves were used to plot the recurrence and survival data. The curves between RFS, CSS, and OS were compared using the log-rank test. A two-sided p value <0.05 was considered significant. Results were analysed on the basis of intention to treat. Results and limitations: A total of 60 patients with either MIBC (n = 38) or HRNMIBC (n = 21) were randomised in the CORAL trial to receive ORC, RARC, or LRC. The 5-yr RFS was 60%, 58%, and 71%; 5-yr CSS was 64%, 68%, and 69%; and 5-yr OS was 55%, 65%, and 61% for ORC, RARC, and LRC, respectively. There was no significant difference in RFS, CSS, and OS between the three surgical arms. The principal limitation is the small sample size. Conclusions: There was no difference in 5-yr RFS, CSS, and OS rates of patients who underwent ORC, RARC, and LRC for management of bladder cancer. Minimally invasive techniques achieved equivalent oncological outcomes to the gold standard of ORC. However, the study was based at a single institution with a small sample size. Patient summary: Patients who agreed to participate in the randomised trial of either open, laparoscopic, or robotic-assisted radical cystectomy for bladder cancer did not have different cancer outcomes at 5 yr. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: James Catto Statistical Editor: Andrew Vickers Keywords: Robotic cystectomy Bladder cancer Open cystectomy
* Corresponding author. Department of Urology, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK. E-mail address: [email protected] (M.S. Khan).
https://doi.org/10.1016/j.eururo.2019.10.027 0302-2838/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Khan MS, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol (2019), https://doi.org/10.1016/j. eururo.2019.10.027
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1.
Introduction
outcomes (recurrence, bladder cancer-specific death, and overall death). To assess for competing outcomes (eg, death), Fine and Gray competing
Radical cystectomy, although a highly morbid procedure, remains the standard of care for muscle-invasive bladder cancer (MIBC) and high-risk nonmuscle-invasive bladder cancer (HRNMIBC) where bladder preservation treatments have failed [1,2]. Open radical cystectomy (ORC) is accepted as the gold standard because its long-term oncological outcomes are well-established [3,4]. In an endeavour to minimise the perioperative morbidity, minimally invasive radical cystectomy (MIRC) techniques such as laparoscopic (LRC) and robotic-assisted (RARC) radical cystectomy have been developed. The main findings from our previously published CORAL Trial demonstrated reduced blood loss and shorter hospital stay with the minimally invasive approaches. We found no significant differences in 90-d complication rates and oncological outcomes among the randomised groups [5]. Several other studies have shown lower complication rates for RARC compared with ORC [6–9], but evidence on the long-term oncological outcomes of MIRC is still maturing. This article aims to report long-term oncological outcomes of the three-arm CORAL trial (open, laparoscopic, and robotic), a randomised trial of radical cystectomy. 2.
Patients and methods
Patients’ eligibility for trial inclusion, the randomisation process, and the technical aspects of ORC, RARC, and LRC were previously described [5]. All operations were performed at Guy's Hospital London by three expert surgeons (MSK, PD, and PR) who were all well over their learning curves for their respective operative modalities. Urinary diversions were
risk regression was applied. All data analysis was performed using SPSS version 21 (IBM Corp, Armonk, NY, USA) and Statistical Analysis Systems (SAS) release 9.4 (SAS Institute, Cary, NC). Results were analysed on the basis of intention to treat.
3.
Results
A total of 60 patients agreed to participate in the study and were randomised to receive either ORC, LRC, or RARC. All 20 patients who were randomised to ORC underwent the assigned procedure. In the RARC arm, one patient was converted to ORC due to equipment failure. In the LRC group, one patient randomised to LRC was withdrawn from the trial after further review of the histology by the specialist bladder cancer pathologist team panel changed the diagnosis to small cell bladder cancer. Surgery was deemed unsuitable for this disease and the patient eventually underwent chemoradiotherapy. Of the remaining 19 patients in the LRC group, three were converted to RARC because of unavailability of the laparoscopic surgeon and another was converted intraoperatively to ORC due to large tumour size. In total, 59 patients underwent radical cystectomy in three surgical arms. In the follow-up period, one patient in the LRC group was lost to follow-up. Median follow-up for those in the ORC arm was 65.6 mo, whereas this was 86.6 mo in the RARC group and 83.8 in the LRC group. Median follow-up for the survivors was 104.7, 102.7, and 91.4 mo in the ORC, RARC, and LRC arms, respectively.
performed extracorporeally in both laparoscopic and robotic subgroups and pelvic lymph node (LN) dissection was performed in all arms.
3.1.
Patient characteristics
At each follow-up visit, patients had clinical examination and blood tests for full blood count and electrolytes, including renal function tests and bicarbonate. Patients were followed up with a computed tomogra-
Patient preoperative characteristics, surgical factors, and final pathologic stage are presented in Table 1.
phy scan of the chest, abdomen, and pelvis at 6 and 12 mo and then every 6 mo or 1 yr thereafter according to the final histopathological stage as
3.2.
Pathologic outcomes
per EAU Guidelines. A loopogram was performed at 3 mo to assess for uretero-enteric anastomosis stricture. Follow-up data on recurrence, pattern of recurrence, death, and cause of death were recorded prospectively from the end of the trial to March 31, 2019. Outcomes studied included recurrence-free survival (RFS), cancerspecific survival (CSS), and overall survival (OS). RFS is defined as the time from the date of radical cystectomy to either local recurrence (defined as disease recurrence within the true pelvis) or development of metastatic disease (disease recurrence outside the true pelvis) based on imaging or histology. CSS is defined as the time to death from bladder cancer after radical cystectomy. OS implies the length of time from the date of cystectomy to death from any cause. The cause of death was determined from death certificates obtained from the patient's general practitioner if the patient died outside the hospital. Positive margins in cystectomy on final histology are either ureteric, urethral (either a grossly visible tumour or carcinoma in situ [CIS] at the resection margin), or bladder soft tissue margins (STMs). Information regarding positive margins was recorded as part of the original CORAL trial. Kaplan–Meier curves were used to plot the recurrence and survival data. The curves between the RFS, CSS, and OS were statistically compared using the log-rank test. Moreover, a univariate Cox proportional hazards regression model was used to predict the three primary
In the ORC group, four patients had no residual disease (pT0) in the bladder, 10 had nonmuscle-invasive (NMIBC) residual tumours, and six had locally advanced disease (pT3 = 4 and pT4 = 2). In the RARC group, two patients had no residual cancer (pT0), nine had residual NMIBC, three had residual MIBC, and six locally advanced (pT3) tumours. Of the patients in the LRC group, three had no residual cancer (pT0), five nonmuscle-invasive tumours (NMIBC), three muscle-invasive tumours (pT2), and eight locally advanced disease (pT3 = 7 and pT4 = 1). Two of the 20 ORC patients (10%), three of the 20 RARC patients (15%), and one of the 19 LRC patients (5%) had positive surgical margins (PSMs). Of these, three had CIS at the distal urethral margin: one in the ORC group and two in the RARC group. These patients subsequently had interval urethrectomy but there was no residual cancer in the excised urethral stump. Three patients had positive STMs, one in each of the three surgical arms. Overall, we found no significant relationship between the surgical arm and PSMs.
Please cite this article in press as: Khan MS, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Three-arm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol (2019), https://doi.org/10.1016/j. eururo.2019.10.027
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Table 1 – Patient characteristics
Age, yr, median (Q1–Q3) BMI, kg/m2, median (Q1–Q3) Male, n (%) ASA grade, n (%) ASA 1 ASA 2 ASA 3 Neoadjuvant chemotherapy, n (%) Preoperative diagnosis NMIBC, n (%) MIBC, n (%) Diversion type Ileal conduit, n (%) Neobladder, n (%) Final pathologic stage T0 Ta/T1/Tis T2 T3 T4 LN yield (median, Q1–Q3) Positive LN
ORC (n = 20)
RARC (n = 20)
LRC (n = 19)
68 (58–74) 26.99 (23.76–30.44) 18 (90)
68 (65–74) 27.50 (24.00–31.00) 17 (85)
71 (63–75) 26.00 (24.00–27.59) 15 (79)
4 (20) 15 (75) 1 (5) 3 (15)
4 (20) 15 (75) 1 (5) 2 (10)
3 (16) 13 (68) 3 (16) 1 (5.26)
8 (40) 12 (60)
8 (40) 12 (60)
5 (26) 14 (74)
17 (85) 3 (15)
18 (90) 2 (10)
18 (95) 1 (5)
4 10 0 4 2 18.5 (14.0–25.0) 6 (30%)
2 9 3 6 0 14.5 (11.0–21.0) 3 (15%)
3 5 3 7 1 15.5 (12.0–22.0) 6 (31.5%)
ASA = American Society of Anesthesiologists; BMI = body mass index; LN = lymph node; LRC = laparoscopic radical cystectomy; MIBC = muscle-invasive bladder cancer; NMIBC = nonmuscle-invasive bladder cancer; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
Table 2 – Site of recurrence in the three surgical arms
Overall recurrence Local recurrence Distant recurrence Combination Upper tract recurrence
ORC
RARC
LRC
9/20 3/9 4/9 1/9 1/9
8/20 3/8 4/8 1/8 0/8
6/18 4/6 2/6 0/6 0/6
LRC = laparoscopic radical cystectomy; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
Mean LN yield was 19, 16, and 16 for ORC, RARC, and LRC, respectively. The differences in LN yield was only statistically significant (p = 0.01) between the ORC and LRC arms. LNs were involved by cancer in 30% (six/20), 15% (three/20), and 31% (six/19) in the ORC, RARC, and LRC groups, respectively. 3.3.
Oncological outcomes
Overall, 23/59 of patients had disease recurrence in the follow-up period up to March 31, 2019. There were nine/20 recurrences in the ORC group, eight/20 in the RARC group, and six/18 in the LRC group. The recurrences were classified
as local, distant metastasis, or a combination. The proportions of local, distant, and combination metastases occurring in each surgical arm are summarised in Table 2. Univariate Cox proportional hazards regression models did not show an effect of surgical procedure on recurrence, overall death, or bladder cancer-specific death (Table 3). These results are also graphically represented with Kaplan– Meier graphs in Figs. 1–3, respectively. The RFS, CSS, and OS are also not significantly different between the three surgical groups when comparing the data based on the modality of the operation the patients underwent. Additional assessment of competing risks did not reveal any other associations. Because of the small sample size of this study, the results of this modelling should be interpreted with caution. 4.
Discussion
Minimally invasive approaches in the treatment of benign or malignant conditions have been embraced widely in all surgical specialties, but none more so than in urology. The minimally invasive techniques provide important benefits such as reduced blood loss, quicker recovery, shorter hospital stay, and reduced wound complications [10,11]. However, aside from these perioperative benefits,
Table 3 – Hazard ratios and 95% confidence intervals for recurrence, overall death, and bladder cancer-specific death based on surgical procedure
Open radical cystectomy Robotic-assisted radical cystectomy Laparoscopic radical cystectomy
Recurrence
Overall death
1.00 (Reference) 1.13 (0.42–3.01) 0.83 (0.29–2.39)
1.00 (Reference) 0.72 (0.30–1.74) 0.83 (0.34–2.01)
Bladder cancer-specific death 1.00 (Reference) 0.75 (0.28–2.01) 0.60 (0.20–1.78)
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Fig. 1 – Recurrence-free survival of ORC, RARC, and LRC. (A) Results from ITT analyses. (B) Results from per-treatment analyses. ITT = intention to treat; LRC = laparoscopic radical cystectomy; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
there is as yet little evidence to suggest that these approaches yield superior oncological outcomes, which are largely dependent on the local stage and biology of the disease, and perhaps the experience of the surgeons performing the procedures [10,11].
Traditional laparoscopy has inherent limitations as a result of four degrees of freedom of movement and poor ergonomics which put a lot of physical and mental strain on surgeons performing the surgery. As a result, it has gradually been replaced with robotic surgery which has
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5
Fig. 2 – Cancer-specific survival of ORC, RARC, and LRC. (A) Results from ITT analyses. (B) Results from per-treatment analyses. ITT = intention to treat; LRC = laparoscopic radical cystectomy; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
the unique benefits of superior visualisation, higher degree of freedom of movement, and better ergonomics [12,13]. However, the installation and maintenance costs of current robotic surgical systems remain prohibitive and have attracted some criticism, particularly in the
“free-for-all” health care systems such as the National Health Service (NHS) in the UK. The benefit of robotic surgery continues to be debated even for procedures such as radical prostatectomy [14] and partial nephrectomy [15], but the robotic procedure which
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Fig. 3 – Overall survival of ORC, RARC, and LRC. ITT = intention to treat; LRC = laparoscopic radical cystectomy; ORC = open radical cystectomy; RARC = robotic-assisted radical cystectomy.
has come under the most scrutiny is radical cystectomy. This is following the publication of several randomised trials from both the United States and the UK showing minimal difference in outcomes between ORC and RARC except a reduced need for blood transfusions and a trend towards shorter length of stay in favour of RARC [5,16–19] (Table 4).
RARC has come under most scrutiny principally because of the hype created over the perceived benefits of robotassisted surgery. It may be argued that the surgical community had unrealistic expectations from this technology and anticipated a vast difference in outcomes compared with open surgery. As such, given that the benefits of robotic cystectomy reported to date have been marginal, and
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Table 4 – Results from other randomised controlled trials comparing open and robotic cystectomy Study
Country
Number RARC/ORC
Parekh et al. [14] Nix et al. [15] Bochner et al. [16]
USA USA USA
20/20 21/20 60/58
Feasibility trial of RARC LN yield Perioperative complications
NS NA NA
NS NS NS
RAZOR trial, Parekh et al. [17]
USA
150/156
2-yr PFS
Lower in RARC
NS
Primary end point
BT
LOS
Complications
NS NS NS (except wound infection) NS
Positive margins
Yield median and significance
NS (5%/5%) NS (0/0) NS (3.3%/5.2%)
NS (11/23) NS (19/18) NS (19.5/18.9)
NS
NS
BT = blood transfusion; LN = lymph node; LOS = length of stay; NA = not available; NS = not significant; ORC = open radical cystectomy; PFS = progression-free survival; RARC = robotic-assisted radical cystectomy.
coupled with the high cost of robotic surgery, it has been a challenge to justify the introduction of robotic cystectomy in the NHS in the UK. To demonstrate the oncological safety of the technique, PSM and LN yield are considered two critical measures of surgical quality in cystectomy. Large studies have demonstrated that PSMs are important predictors of local recurrence and metastases, and consequently determine CSS [20,21]. Higher LN yield has also been shown to be associated with improved CSS [22–25]. Therefore, for MIRC to measure up to ORC in terms of oncological efficacy, it must be able to achieve equivalence in these two pathological measures. The rate of PSMs in large ORC series range from 1% to 6.3% [26,27]. Analysis of the International Robotic Cystectomy Consortium (IRCC) database of 702 patients have shown 8% PSM in RARC [28], whereas PSM in a big series of LRC was 5.8% [29]. The PSM rates reported in this study were 10% (two/20), 15% (three/20), and 5% (one/15) for ORC, RARC, and LRC, respectively. Although the PSM rate for RARC in particular seems high, three of the six patients with PSMs in fact had CIS at the distal urethral margin. As we previously explained, this is likely to be related to our practice of avoiding simultaneous urethrectomy except in patients with clinically overt disease in the urethra. In our experience patients who had simultaneous excision of the urethra suffered more pain from this part of the procedure than from the cystectomy itself. More importantly, we found no significant correlation between surgical modality and urethral PSM. This finding is in agreement with that from a meta-analysis of four randomised controlled trials comparing RARC and ORC [30]. The recently published RAZOR trial did find a greater incidence of positive bladder STMs in the robotic arm compared with the open arm, but the difference in overall positive margin rate between RARC and ORC in this study did not reach significance [19]. Herr et al. [31] proposed that at least 10–14 LNs need to be retrieved to adequately determine LN involvement status. Several studies have shown that RARC can achieve comparable LN retrieval with ORC [17,32,33]. A study based on the IRCC database for RARCs also found that surgeon volume is related to the probability of the patient undergoing extended LN dissection [34]. In our study all of the participating surgeons for each surgical arm were well beyond their indicative learning curves. The mean LN
yield was 18.8 in the ORC group, 16.3 in the RARC group, and 15.5 in the LRC group. The differences in LN yield between ORC and LRC were statistically significant (p = 0.01), but the difference between ORC and RARC was not significant. This is again in agreement with the aforementioned randomised controlled trials where there was no significant difference in LN yield between ORC and RARC [14–17]. We have found no significant difference in 5-yr RFS, CSS, and OS between the three surgical arms. Although several nonrandomised studies have reported long-term oncological outcomes of RARC [35,36] and LRC [29,37], these series demonstrated oncological outcomes that were comparable with those from the other historical series of ORC [4,38]. In summary, the principal advantage of MIRC lies in minimising the morbidity of cystectomy but can only achieve equivalent oncological outcomes compared with ORC. Thus, it is evident that oncological outcomes of cystectomy for urothelial cancer is largely dependent on the biology of the disease. Our long-term findings from this study, as well as the shorter-term studies that we have discussed earlier bear out this statement. Another aspect of concern has been the risk of tumour cell spillage with MIRC. In this cohort, none of the patients developed peritoneal metastasis or port site metastasis to suggest seeding from tumour spillage. We believe that the quest for reducing the morbidity of radical cystectomy should not stop, as these marginal benefits are likely to widen with the increasing trend towards performing intracorporeal urinary diversion. Limitations include surgeons being in a single specialist centre, small sample size, failure to deliver the treatment in allocated randomised groups, and early termination of the trial. 5.
Conclusions
Based on our observation, there was no difference in 5-yr RFS, CSS, and OS of patients who underwent ORC, RARC, and LRC. Minimally invasive techniques achieved similar oncological outcomes to the gold standard of ORC. However, the results need to be interpreted with caution due to the small sample size. These results from the only randomised trial comparing all three approaches with radical cystectomy should provide some reassurance to the clinicians and the patients.
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Author contributions: Muhammad Shamim Khan had full access to all
[10] Soave A, Schmidt S, Dahlem R, et al. Does the extent of variant
the data in the study and takes responsibility for the integrity of the data
histology affect oncological outcomes in patients with urothelial
and the accuracy of the data analysis.
carcinoma of the bladder treated with radical cystectomy? Urol
Study concept and design: Khan, Dasgupta. Acquisition of data: Omar, Gan. Analysis and interpretation of data: Van Hemelrijck. Drafting of the manuscript: Khan, Dasgupta, Omar, Ahmed. Critical revision of the manuscript for important intellectual content: Khan, Dasgupta, Ahmed. Statistical analysis: Van Hemelrijck. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Khan. Other: None. Financial disclosures: Muhammad Shamim Khan certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or
Oncol Semin Orig Investig 2015;33:21, 21.e1–21.e9. [11] Bhindi B, Yu J, Kuk C, et al. The importance of surgeon characteristics on impacting oncologic outcomes for patients undergoing radical cystectomy. J Urol 2014;192:714–20. [12] Lanfranco AR, Castellanos AE, Desai JP, Meyers WC. Robotic surgery: a current perspective. Ann Surg 2004;239:14–21. [13] Hussain A, Malik A, Halim MU, Ali AM. The use of robotics in surgery: a review. Int J Clin Pract 2014;68:1376–82. [14] Yaxley JW, Coughlin GD, Chambers SK, et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: early outcomes from a randomised controlled phase 3 study. Lancet 2016;388:1057–66. [15] Xia L, Wang X, Xu T, Guzzo TJ. Systematic review and meta-analysis of comparative studies reporting perioperative outcomes of robotassisted partial nephrectomy versus open partial nephrectomy. J Endourol 2017;31:893–909. [16] Parekh DJ, Messer J, Fitzgerald J, Ercole B, Svatek R. Perioperative
patents filed, received, or pending), are the following: None.
outcomes and oncologic efficacy from a pilot prospective random-
Funding/Support and role of the sponsor: None.
J Urol 2013;189:474–9.
Acknowledgements: Authors acknowledge the contribution from the bladder cancer specialist nurses (Kathryn Chatterton and Suzanne Amery) and Dr Fahim Ismail for their contribution regarding patient counselling and follow-up. We also acknowledge the contribution from Beth Russell for her help in the analysis and editing of the manuscript. PDG is grant funded by the MRC Centre for Transplantation, NIHR Biomedical Research Centre, KCL, The KCL-Vattikuti Institute of Robotic Surgery, EU, and the GSTT Charity.
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