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Robotic-assisted, laparoscopic, and open radical cystectomy: surgical data of 1400 patients from The Italian Radical Cystectomy Registry on intraoperative outcomes

Introduction The Italian Radical Cystectomy Registry (Registro Italiano Cistectomie – RIC) aimed to analyse outcomes of a multicenter series of patients treated with radical cystectomy (RC) for bladder cancer. Material and methods An observational, prospective, multicenter, cohort study was performed to collect data from RC and urinary diversion via open (ORC), laparoscopic (LRC), or robotic-assisted (RARC) techniques performed in 28 Italian Urological Departments. The enrolment was planned from January 2017 to June 2020 (goal: 1000 patients), with a total of 1425 patients included. Chi-square and t-tests were used for categorical and continuous variables. All tests were 2-sided, with a significance level set at p <0.05. Results Overall median operative-time was longer in RARCs (390 minutes, IQR 335–465) than ORCs (250, 217–309) and LRCs (292, 228–350) (p <0.001). Lymph node dissection (LND) was performed more frequently in RARCs (97.1%) and LRCs (93.5%) than ORCs (85.6%) (p <0.001), with extended-LND performed 2-fold more frequently in RARCs (61.6%) (p <0.001). The neobladder rate was significantly higher (more than one-half) in RARCs. The median estimated blood loss (EBL) rate was lower in RARCs (250 ml, 165–400) than LRCs (330, 200–600) and ORCs (400, 250–600) (p <0.001), with intraoperative blood transfusion rates of 11.4%, 21.7% and 35.6%, respectively (p <0.001). The conversion to open rate was slightly higher in RARCs (6.8%) than LRCs (4.3%). Intraoperative complications occurred in 1.3% of cases without statistically significant differences among the approaches. Conclusions Data from the RIC confirmed the need to collect as much data as possible in a multicenter manner. RARCs proves to be feasible with perioperative complication rates that do not differ from the other approaches.


INTRODUCTION
In selected cases of high-risk non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) the optimal oncological is reached with radical cystectomy (RC) [1,2]: moreover, it is considered the gold standard. This surgery is complex, with significant morbidity, and it essentially consists of two phases, the destructive phase (removal of the bladder and the lymph nodes) and the reconstructive phase (urinary diversion), and each step is prone to complications. Therefore, RC is preferably performed in referral centers where the experience of the surgeon and the facilities allow to minimize the burden of this complex surgery. Open RC (ORC) has represented the gold standard approach for a long time; recently, the increased introduction of new technologies has led to minimally invasive approaches such as laparoscopic RC (LRC), and robotic-assisted RC (RARC) becoming more and more applied in this field. Surely, RARC represents a challenging procedure that can be improved with specific training and a skilled robotic team [3]. However, RARC is a suitable technique for both older and younger patients [4] and has shown promising rates of peri-operative and short-term outcomes compared to ORC: lower rates of minor perioperative complications, decreased blood loss and transfusion rate, faster gastrointestinal recovery, and shorter length of stay [5].
Despite several studies reporting comparable longterm oncological outcomes for RARC versus ORC [6][7][8][9], data on the long-term functional outcomes is sparse. No studies have directly compared urinary continence or sexual potency in patients receiving neobladder after RARC versus ORC. Not least, the economic burden of RARC is heavier than open surgery due to higher supply costs, but an effective cost-effective analysis is lacking to date. In a systematic review, Novara et al. demonstrated the safety, acceptable operative time other than relatively lower estimated blood loss (EBL), and relatively low transfusion rate for RARC compared to ORC and LRC [10]. Most intra-abdominal surgical procedures in urology are now performed robotically worldwide. The transition is gradual due to the high cost of the technology and the associated learning curve. The hope is that with more competition in the robotic technology space, the advent of new robotic companies will bring the overall costs down and will reduce the robotic technology healthcare disparities. The Italian Radical Cystectomy Registry (Registro Italiano Cistectomie -RIC) Protocol [11] aimed to accurately and comprehensively assess the out-comes of RC in order to improve current clinical knowledge. The aim of this study was to analyse intraoperative outcomes of a multicenter series of patients treated with RC for bladder cancer.

Study design and inclusion criteria
An observational, prospective, multicenter, cohort study was performed in order to constitute the RIC, a protocol with the aim to collect data from RC and urinary diversion via open, laparoscopic, or roboticassisted technique performed in the most important urological Departments of Italy. Inclusion criteria: male and female patients ≥18 years old, histologically proven diagnosis of bladder cancer deserving of RC surgery (according to EAU guidelines), signed informed consent. The enrolment was planned to be performed from January 1 st 2017 to June 30 th 2020, with a goal of 1000 patients, based on power calculations. The enrolment was discontinued before the planned deadline with the inclusion of 1400 patients. The RIC is an electronic registry of the 28-participating clinical centers. At each center, patient data was collected in accordance with Italian privacy laws, and entered into an online database by a coordinating physician. Data collection and entering was done using the Data Collection Form, which was designed by the Scientific and Steering Committees. The Data Collection Form was designed using either prespecified or open-ended responses for each question, to ensure homogeneity between centers. Patients' data were securely stored and kept anonymously using identification codes. The database was password protected. As data sharing is becoming increasingly important, the data was regularly transferred to a globally-accessible online platform. The trial was registered retrospectively on Clini-calTrials.gov on 14/01/2020 with reference number NCT04228198. Data collection was conducted in accordance with the World Medical Association Declaration of Helsinki. This study was approved on 25/06/2020 by Ethical Committee of the University of Padova (number: 0042389). All patients provide signed, informed consent.

Participating centers
All Italian urological departments that currently provide care for RC patients using all three (open, robotic-assisted, laparoscopic) approaches were invited to participate, on a voluntary basis, without additional funding for the centers or participants.
Patients underwent laparoscopic, robotic or open approach at the discretion of the surgeon. A physician at each center was assigned the management of the recruitment of patients, data collection, the entering of the data into the registry, the data security and the anonymity of the patients. Patients were enrolled at 28 centers across Italy.

Timeline and data collection
The scheduled enrolment of patients was performed as described in Figure 1. Patients' baseline and preoperative characteristics are described in Table 1. We collected surgical data on total surgery time, type of urinary diversion, median time for urinary diversion, conversion to open surgery, intraoperative bleeding, nerve sparing technique, lymphadenectomy (including its extension). The post-surgery follow-up was demanded to a subsequent evaluation (the scheduled follow-up is actually ongoing, and at this time is still incomplete).

Statistical analysis
Data were cleaned and checked for discrepancies by a statistician before analysis and dissemination. Chi-square and t-tests were used to compare categorical and continuous variables, respectively, between surgical technique groups. Statistical analyses were performed using Stata-SE 15 (StataCorp LP, College Station, TX, USA). All tests were 2-sided with a significance level set at p <0.05.

RESULTS
A total of 1425 patients were enrolled (1009 ORCs, 368 RARCs, 46 LRCs). Surgical characteristics are reported in Table 2 Lymph node dissection (LND) was performed in more cases during RARC (97.1%) and LRC (93.5%) than ORC (85.6%), with statistically significant differences (p <0.001). Moreover, LND was not performed up to 2-3 fold in ORC (14.5%) than in the two other types of RC. Regarding the type of LND, the limited dissection rate was similar among the three types of RC, while the rate of extended dissection was more than 2-fold higher in case of RARC (61.6%) compared to the two other RC types with statistically significant differences (p <0.001). The median time of LND was higher in case of RARC (80 minutes, IQR 60-100) than the two other types of RC, and in particular up to 2-fold higher by comparing RARC to ORC. The nerve sparing technique was performed in nearly one-third of RARC cases, while with regards to the other two techniques, almost all patients did not undergo the nerve-sparing technique. In the RARC group the rate of neobladders was significantly higher (more than one-half) compared to the two other approaches where the non-continent diversion was preferred in up to the 80% of cases.  The statistically significant differences demonstrated for overall population were confirmed after match-pairing analysis (Table 4).

DISCUSSION
The   [19]. Moreover, Albisinni et al. in a multicenter study, confirmed significantly longer operative time, fewer overall complications, less blood transfusions and analgesic use, less blood loss and a shorter LOS for LRC compared to ORC [20]. One of the most interesting data concerned the LND issue: it was performed more frequently in RARC (in almost all cases, up to 97.1%) and with a 2-fold higher rate of extended dissection compared to the other two approaches. This data might be justified by the lower disease stage of the cases performed with the robotic-assisted approach, but surely it reflected the need of an accurate and extended LND not only in terms of accurate diagnosis but also in a prognostic point of view. In our study LND was most frequently performed during RARC compared to ORC and LRC group. The absence of LND in 14.5% of patients in ORC group is essentially due to the high number of palliative surgeries presents in this group.
good perioperative profile in terms of intraoperative outcome. RARC and LRC show lower EBL compared to ORC. RARC is characterized by longer median OT probably explained by the learning curve of robotic approach other than by urinary diversion type utilized. Orthotopic neobladder is more likely used during robotic procedures. RC actually represents one of the most complex urological surgery, and the increasingly technological improvement represents the way to the employment of minimally invasive approaches to this major surgery. There are currently very few randomized control trials (RCTs) comparing the three considered approaches, and previous non-randomized studies had small sample sizes and short follow-up. The RCTs are the preferred study design for evaluating treatment efficacy, but there is also the need of comparison-effective studies: there are multiple factors that determine the choice and outcomes of surgical techniques in real-life clinical settings, including complex clinical decision making, patient and hospital characteristics, and surgical expertise. The RIC aimed to provide data to this rapidly developing field by creating a nationwide, multicenter registry with two-year post-surgery follow-up of bladder cancer patients treated with RC, with a comprehensive data collection on multiple outcomes. A direct comparison of RARC to ORC and LRC was not optimal based on previously published RCTs [12,13]; surgical RCTs are difficult to perform successfully, leading to methodological and practical issues: several biases might arise from low accrual rate, preferences of the patients, different skills of surgeons and team, different standardisation of the technique among centers and difficulties regarding the blinding of the procedures [14]. These reasons lead to the choice of a comparative effectiveness design alternative to an optimal surgical RCT. The ORC is a well-developed technique and it has represented the standard treatment for many years. RARC is increasingly performed [15], since many urologists are trained mainly in minimally invasive technique: the laparoscopic RC is challenging, therefore RARC might be the only minimally invasive alternative.
Recent systematic reviews comparing ORC and RARC reported lower rates of blood loss and an approximately one-day shorter length of hospital stay (LOS) in case of RARC, but with longer operative time. The complication rates seemed similar for both approaches but all published reviews suffer from low quality data.
In the systematic review performed by Novara et al., despite the post-operative complications being common, the authors reported a low risk of intraopera-patients might benefit more from the RARC approach [30]. The limitations of the study consisted of: short follow-up, different number of cases performed in different centers (with different surgical volumes), potential different protocols of reporting complications and different perioperative protocols, the cohorts were not balanced in terms of surgeon's experience, patient and tumour characteristics, the lack of propensity score matching and multiple regression analyses and aimed to control for the most important group differences and potential confounders. Nonetheless, statistics cannot replace prospective RCTs. Furthermore, not all surgeons conducted both RARC and ORC and no mid-or long-term follow-up was included to compare the oncological outcomes, which are currently ongoing.

CONCLUSIONS
RC still represents a challenging procedure and RARC is gaining its role in this important issue, despite some disadvantages but also thanks to a lot of advantages. Moreover, the initial results are corroborating what reported in the international background.
Data from the RIC Italian registry confirmed the need and the usefulness to collect as much data as possible in a multicenter manner. In the next years, this longitudinal study might represent a benchmark and the base for every further research in the context of RC.

DATA SHARINg STATEMENT
Will individual participant data be available (including data dictionaries)?
Yes What data in particular will be shared?
Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).
What other documents will be available?
Study protocol, statistical analysis plan, informed consent form, clinical study report, analytic code.
When will data be available (start and end dates)?
Immediately following publication. No end date.
With whom?
Researchers who provide a methodologically sound proposal.
For what types of analyses?
To achieve aims in the approved proposal.
Controversies in evaluating the clinical significance of LND still concern RC in general, and they are generally related to two main aspects of nodal dissection: therapeutic procedure and/or staging instrument. In general, studies comparing LND vs no LND reported a better oncological outcome for the LND group [21]. To date, the optimal extent of LND has not been established yet. In two high-volume center studies, the authors reported no difference in outcome between extended and super-extended LND [22]. In the LEA trial [23] the extended LND failed to show a significant advantage over limited LND in RFS, CSS, and OS but, differently, Mandel et al. and Bi et al., in meta-analyses, reported a beneficial outcome for (super)extended compared to limited or standard LND [24,25]. Moreover, Koppie et al. showed how the survival rates increase with the number of dissected lymph nodes [26], but regarding the optimal minimum number to be removed during surgery there are no data from RCTs. In retrospective studies, the removal of at least ten lymph nodes has been postulated as sufficient for evaluation of lymph node status, as well as being beneficial for OS [27]. In conclusion, extended LND might have a therapeutic benefit compared to less extensive LND, but due to study bias no firm conclusions have been drawn to date [28]. Among the advantages of RARC there are the higher manoeuvrability and the image amplification: these allowed to perform nerve sparing technique in nearly one-third of cases and the orthotopic continent neobladder in more than one-half of cases, and these rates appeared to be significantly higher compared to the other two techniques. RARC surely represents a costly procedure, but the non-inferiority in terms of surgical outcomes and the increasing opportunities from different and more and more competitive robotic-industry products might overcome the economic aspects. An open question concerns how the complications translate into costs and quality-adjusted life years, and if it possible to build scenarios in which RARC might become a gold standard treatment in terms of cost-effectiveness or at least cost-neutrality [29]. Furthermore, in a cohort of 267 patients treated with RARC and intracorporeal (ICUD) or extracorporeal (ECUD) urinary diversion, Mazzone et al. reported how Age-adjusted Charlson Comorbidity Index (ACCI) was associated with an increased risk of Clavien Dindo ≥2 (OR: 1.2, p = 0.006), by identifying a significant interaction term between ACCI and approach type (p = 0.04), where patients with ICUD had lower risk of CD ≥2 relative to those with ECUD with increasing ACCI. The authors tried to identify a recommendation from which

FUNDINg DETAILS
The Italian Radical Cystectomy Registry is an observational, nonprofit study. AB Medica provided an unconditional grant solely for the maintenance of the database. AB Medica has no involvement in the acquisition, control, or management of the data. The registry and all data are exclusively owned by the Steering Committee.
By what mechanism will data be made available?
To gain access, data requestors will need to sign a data access agreement

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.