Bladder cancer (BC) is the ninth most common type of cancer worldwide, and is sixth in Europe, with an age-standardized incidence of 17.7 per 100,000 and mortality rate of 5.2 per 100,000 among European men (1, 2). Tumor stage/grade is the factor most strongly predictive of outcomes even if the pathophysiology behind the aggressivity of high-risk BC has not yet been fully elucidated (3, 4). Poor clinical response of some patients can be caused by disease spread, understaging or inherent biological aggressiveness of the tumor (5, 6). Identification of new imaging strategies and prognostic biomarkers could better guide therapeutic options and identification of the molecular background of BC has improved our knowledge (tumor suppressor genes, oncogenes, cell cycle regulators, growth factors and receptors, and cell adhesion molecules) (7–10).

While recent large cohort studies have indicated that prevention of BC or prevention of advanced stages is the most effective way to reduce disease related morbidity and mortality, it remains that curative responses are necessary (11). Radical cystectomy (RC) is the only curative intervention available for advanced BC. It is performed for those patients affected by muscle-invasive bladder cancer (MIBC) or with a high-risk disease not responding to conservative treatment with trans-urethral resection followed by BCG (4). RC is a highly complex procedure, needing an experienced surgeon and centralization of care to enhance patient outcomes (12–15). Indeed, 13-67% of patients undergoing RC develop some type of complication (16–20), and while these rates of complications are high, they are also exceedingly variable.

Three techniques - open, robotic-assisted, and laparoscopic - can be used to complete RC. Robotic-assisted surgery is comparable to laparoscopic, and both seem to have better outcomes than open (21). A recent meta-analysis showed that open and robotic cystectomy have similar outcomes with regard to time to recurrence, positive margins, major com-plication rates, and quality of life; however, it seems that a robotic approach reduces the risk of blood transfusions and may reduce hospital stay (22). Even so, as of 2013, only one-quarter of RCs were being performed robotically in the US (23). Pre-surgical data, that can affect decision between techniques, are important and should be considered because can predict following complications. We speculate that a less invasive procedure can be easily performed in elderly patients, and with more comorbidities. To that end, we have designed a multicenter study in order to address these gaps in the current clinical knowledge.

The aim of the project is to investigate the pre-surgical outcomes of patients with bladder cancer who undergo radical cystectomy, comparing three different surgical techniques (robotic-assisted, laparoscopic, and open surgery).

An enrollment of 1000 patients was planned, but it was closed on February 2020 because, surprisingly, included patients exceeded original estimates. A total of 1400 patients undergoing radical cystectomy and urinary diversion via open, laparoscopic, or robotic-assisted technique were included. Patient enrollment, by center and technique, is detailed in Figure 2 and Table 1. Patients had a mean age of 69.9 years (SD 10.0) and 18.7% were female. Hypertension (55%), followed by anticoagulant use (35.1%) and other pathologies (35.4%) were the most common comorbidities. Preoperatively, nearly all (92.6%) were classified as grade 3 and two-thirds (65.7%) as pT2. Preoperative patient characteristics of the overall population are presented in Table 2.

In comparison of patients by surgical technique, significant differences were found. Roughly three-quarters of patients (n=999) underwent open surgery, while 25.3% (n=354) underwent robotic surgery, and the remaining 3.4% (n=47) underwent laparoscopic surgery (Table 3). Age differed significantly by group (p<.001), with those undergoing robotic surgery being the youngest. Patients also varied significantly on all comorbidities (and Charlson Comorbidity Index) except TIA. Additionally, there were differences in preoperative ASA score (p<.001), with a trend for open surgery patients to have a higher score. Similarly, they differed on preoperative G-stage classification (p=.003), with more laparoscopic patients being classified as G2, versus G3, which was more common among open and robotic patients. Moreover, patients who underwent robotic surgery had higher rates of preoperative neoadjuvant chemotherapy (p<.001) and BCG instillation (p<0.001), while open surgery patients had higher rates of palliative cystectomy (p<.001). Patients did not differ between groups on preoperative T-stage (p=.128) or concomitant CIS (p=.136).

The multivariable analysis predicting minimally invasive radical cystectomy (Open vs Robotic+ Laparoscopic) has been performed and reported in Table 4. Age and CCI were independently associated with minimally invasive surgery.

This first analysis from the Italian Radical Cystectomy Registry (RIC) reported preoperative results of advanced BC patients, comparing three RC techniques - open, robotic-assisted, and laparoscopic. This study was designed to assess, in a real-world context, factors associated with disease-related morbidity and mortality and effectiveness of the separate RC techniques. We found that among BC patients undergoing RC, those undergoing robotic procedures were younger and more likely to have undergone preoperative neoadjuvant chemotherapy and BCG instillation. Additionally, patients undergoing open and laparoscopic RC had a higher Charlson Comorbidities Index compared to patient undergoing robotic RC (p<.001). There were also significant differences in terms of grading and staging between patient groups, including laparoscopic patients having a lower G-stage classification and open patients having a higher ASA score. This suggests that laparoscopic patients, at least compared to open patients, have less advanced disease at the time of surgery.

In our study, BC patients undergoing robotic RC were younger. Conversely, Rai et al., in a Cochrane Review comparing robotic versus open radical cystectomy, showed no differences in patients age between robotic and open group (22).

These preliminary findings from this large prospective cohort study suggest that differences observed in disease-related morbidity and mortality between RC techniques may be related to preoperative patient clinical factors and characteristics. Although past studies have suggested that outcomes are similar among patient who undergo robotic and laparoscopic RC, some of these differences may be due to preoperative differences be-tween groups (21, 22). Currently, one study is attempting to disentangle what may be due to inherent differences versus technique in a randomized comparative effectiveness trial (24). However, it must be noted that surgeons must evaluate the safest and most effective technique for the patient based on a myriad of real-world factors. Although trending evidence suggests that robotic or laparoscopic surgery is preferable to open surgery, only 25% of BC patients undergo robotic surgery in the US (23), which is consistent with our findings. Therefore, understanding why most surgeries are still being done using an open technique and how this may affect patients is critical to improving outcomes.

This study has several strengths, including a large representative sample, a longitudinal design, and a real-world contextual setting. However, we must also consider that there are surgeon biases that may affect technique choice, which cannot be controlled. In fact, the decision between one technique and the others was completely under surgeon discretion. The difference in procedure and protocols among different institutions (which however is common in every multicenter study) is another potential selection bias. Additionally, although this sample is representative of southern Europe, the highest BC incidence and mortality rates are in high human development index countries (1), so findings from this study and future studies in the RIC may not be generalizable to these populations. Finally, because laparoscopic procedures are still uncommon, there were few patients (3.4%) in our cohort who underwent this type of intervention. We even believe that laparoscopic RC is the most complex technique, and probably for this reason the less performed. Therefore, power may have been and may be limited in analyzing results in this group. However, this study was designed to have sufficient power and, indeed, exceeded enrollment targets.

This study presented preliminary, preoperative results from RIC. RIC is even a prospective longitudinal study that will follow patients postoperatively and over the follow-up care period. As the study progresses, we will be able to investigate clinical factors and patient characteristics associated with both short- and long-term outcomes, as well as differences in outcomes based on technique used. This study will provide invaluable information that will help to inform physicians about the best care plans for advanced BC patients to reduce disease-related morbidity and mortality.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The study involving human participants was reviewed and approved by Ethical Committee of University of Padua (number: 0042389). The patients/participants provided their written informed consent to participate in this study.

AA, AB, RS, LC, and AM are on the Scientific Committee for the current project. WA and AP are on the steering committee for the current project. GMB, DD’A, MicC, KP, WA, AA, LB, AB, EB, MarC, GiuC, LC, UGF, EDB, AleS, CL, FDG, MM, OdC, MF, GM, AE, FDM, AG, CI, EM, GioC, AM, FM, RS, SS, CS, PP, ArmS, MSM, GP, PD, AlcS, DR, AC, AP provided patient data for the multicenter trial described in the article. All authors provided input into the planning of the protocol including the definition of inclusion criteria, variables and data collection. GMB, MicC, FDG, UGF and KP wrote the manuscript draft. All authors revised the draft.

The Italian Radical Cystectomy Registry is an observational, non-profit study. AB Medica provided an unconditional grant 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.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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