**Recovery from Anesthesia after Robotic-Assisted Radical Cystectomy: Two Di**ff**erent Reversals of Neuromuscular Blockade**

**Claudia Claroni 1,\*, Marco Covotta 1, Giulia Torregiani 1, Maria Elena Marcelli 1, Gabriele Tuderti 2, Giuseppe Simone 2, Alessandra Scotto di Uccio 3, Antonio Zinilli <sup>4</sup> and Ester Forastiere <sup>1</sup>**


Received: 22 September 2019; Accepted: 21 October 2019; Published: 24 October 2019

**Abstract:** During robot-assisted radical cystectomy (RARC), specific surgical conditions (a steep Trendelenburg position, prolonged pneumoperitoneum, effective myoresolution until the final stages of surgery) can seriously impair the outcomes. The aim of the study was to evaluate the incidence of postoperative nausea and vomiting (PONV) and ileus and the quality of cognitive function at the awakening in two groups of patients undergoing different reversals. In this randomized trial, patients that were American Society of Anesthesiologists physical status (ASA) ≤III candidates for RARC for bladder cancer were randomized into two groups: In the sugammadex (S) group, patients received 2 mg/kg of sugammadex as reversal of neuromuscolar blockade; in the neostigmine (N) group, antagonization was obtained with neostigmine 0.04 mg/kg + atropine 0.02 mg/kg. PONV was evaluated at 30 min, 6 and 24 h after anesthesia. Postoperative cognitive functions and time to resumption of intestinal transit were also investigated. A total of 109 patients were analyzed (54 in the S group and 55 in the N group). The incidence of early PONV was lower in the S group but not statistically significant (S group 25.9% vs. N group 29%; *p* = 0.711). The Mini-Mental State test mean value was higher in the S group vs. the N group (1 h after surgery: 29.3 (29; 30) vs. 27.6 (27; 30), *p* = 0.007; 4 h after surgery: 29.5 (30; 30) vs. 28.4 (28; 30), *p* = 0.05). We did not observe a significant decrease of the PONV after sugammadex administration versus neostigmine use. The Mini-Mental State test mean value was greater in the S group.

**Keywords:** anesthesia recovery periods; bladder cancer; cognitive impairment; gamma-cyclodextrins; neuromuscular blockade; robotic radical cystectomy

#### **1. Introduction**

The diffusion of robot-assisted laparoscopic techniques has made it possible to perform surgical procedures with greater precision, and has reduced the need for transfusions, postoperative complications and hospitalization time [1]. In particular, robot-assisted radical cystectomy (RARC) has rapidly spread as the gold standard in the treatment of urothelial tumors, becoming a credible alternative to open cystectomy which is burdened by a high rate of complications [2].

Due to the particular surgical conditions and because of its recent application, there still are many anesthetic implications that must be examined thoroughly—patients have to satisfy specific clinical requirements, identified through careful anesthesiologic assessments [3].

During RARC, the anesthesiologist must be prepared to manage any hemodynamic, cerebrovascular and respiratory changes resulting from the surgical conditions that the robotic procedure requires, such as the prolonged use of pneumoperitoneum, the steep Trendelenburg position in which the patient is placed, and the lengthening of surgical times [4]. In addition, an effective myoresolution until the final stages of surgery is necessary to establish ideal surgical conditions [5] and the factors that can impair the quality and time of awakening [6]. To overcome this effect, a reversal of neuromuscular blockade (NMB) is routinely used in our clinical practice.

Currently, the effectiveness of the rocuronium/sugammadex combination for the reversal of the NMB has been widely demonstrated in terms of time and quality of neuromuscular and respiratory functions [7,8].

Neostigmine has been associated with an increased incidence of postoperative nausea and vomiting (PONV), although there is no definitive agreement on the need to avoid its use to reduce the incidence of PONV [9]. On the other hand, neostigmine has an important muscarinic effect on gastrointestinal (GI) receptors, and, by increasing the availability of acetylcholine, increases the GI motility.

In our study, we investigated if the use of a different kind of NMB reversal can influence the early postoperative period after a prolonged major surgery, such as RARC, affected by alterations on mechanical ventilation, cerebral perfusion, and vascular resistances [10]. Our aim is particularly focused on PONV and ileus, with attention to the recent collective effort to build an enhanced recovery after surgery (ERAS) path applicable specifically in the interventions of RARC [11].

The hypothesis is that the continuous infusion of rocuronium followed by sugammadex administration as NMB reversal in patients undergoing robotic radical cystectomy can improve the quality of awakening in terms of postoperative outcomes and cognitive function, compared to use of neostigmine as reversal.

The primary end point was to compare the incidence of PONV. Secondary end points were postoperative cognitive functions and time to resumption of intestinal transit (ROI).

#### **2. Experimental Section**

A mono-center prospective, two-arm parallel, randomized trial was conducted at the IRCCS Regina Elena National Cancer Institute. The study was approved by the Central Ethics Committee Lazio1, in May 2017, with Protocol n. CE/2288/17, and registered with ClinicalTrial.gov identifier NCT03144453. The clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki.

#### *2.1. Patients and Procedures*

American Society of Anesthesiologists physical status (ASA) ≤III patients, candidates of RARC for bladder cancer, were enrolled after having given written informed consent. The exclusion criteria were age <18 years, inability to provide informed consent, BMI >30, and a history of cerebrovascular diseases.

Patients were randomly divided into two treatment groups by an operator who is not directly involved in the study using a specific dedicated software, developed in-house by a GW Basic (Microsoft Corporation, USA) programmer, which generates an assignment code verified immediately before arrival in the operating room. Surgeons were blinded to the intervention and blinded observers recorded the outcome.

In both groups, all patients were premedicated with midazolam 0.02 mg/kg and received dexamethasone 8 mg for anti-emesis. General anesthesia was induced with fentanyl 3–5 g/kg, propofol 2 mg/kg and a bolus of rocuronium 0.7 mg/kg was administered. After tracheal intubation, anesthesia was maintained with a mixture of sevoflurane/oxygen/air, adjusted to provide an end-tidal

sevoflurane of 1.5–2 vol.%, remifentanil was adapted according to a target-controlled infusion (TCI) range of 2–4 ng/mL. Curarization started with rocuronium 5 g/kg/min and was set to maintain the post-tetanic count between 1 and 2. At the end of surgery, after skin closure, neuromuscular function was allowed to recover spontaneously and, at reappearance of the second twitch (T2), patients received a NMB reversal.

In the sugammadex group (S group), at T2 reappearance, patients received 2 mg/kg of sugammadex.

In the neostigmine group (N group), at T2 reappearance, antagonization was obtained with the standard NMB reversal agent: neostigmine 0.04 mg/kg and atropine 0.02 mg/kg to block the peripheral muscarinic side-effects of neostigmine.

All patients were extubated when the train-of-four (TOF) ratio was 0.9 or higher.

Nasogastric tube was removed after surgery, before the awakening.

In both groups, fluid therapy regimen was mainly restrictive, with a basal infusion of crystalloid variable from 2 to 4 mL/kg/h. Mean arterial blood pressure (MAP) was regulated by titrating remifentanil and fluid administration in order to maintain target values between 65 and 95 mmHg.

The standard monitoring for all patients consisted of continuous ECG, heart rate (HR) and MAP measurements, pulse oximetry (SpO2), inspired and expired gas, and capnometry. Neuromuscular function was measured using a TOF-Watch acceleromyograph (Organon ltd, Dublin, Ireland). After induction of general anesthesia, but before administering any NMB agent, the calibration of the acceleromyograph was performed according to the manufacturer's guidelines. The ulnar nerve received neuromuscular stimulation via two electrodes applied to the skin of the distal underarm, to the left and to the right of the ulnar nerve.

The surgical procedure was performed routinely following the standards of the Department of Urology at our hospital [12].

After surgery, patients requiring rescue anti-emetic therapy received ondansetron 4 mg, which was followed by metoclopramide 20 mg, if necessary.

All patients received intravenous morphine patient-controlled analgesia using the CADD®-Solis device (Smith Medical, Kent, UK) postoperatively. Patient-controlled analgesia was set on the demand mode without a loading dose. The dose of morphine was set at 0.02 mg/kg with a time-lock interval of 15 min.

All patients received morphine 0.07 mg/kg and 1000 mg acetaminophen at the time of surgical wound closure, followed by 1000 mg intravenous acetaminophen every 6 h for up to 5 days.

#### *2.2. Measurements*

Baseline data were collected, which included risk of PONV by Apfel score, neoadjuvant chemotherapy, and anxiety and depression by the Hospital Anxiety and Depression Scale.

During anesthesia, main parameters (MAP, HR, SpO2 and etCO2) and time to recovery from NMB reversal were recorded. Duration of surgery, amount of opioid consumption, comorbidities, and total amount of intensive care unit admission were also observed.

In the postoperative period, PONV (intended as number of episodes of nausea, vomiting or bloating) was evaluated after 30 min in post-anesthesia care unit (PACU), 6 and 24 h after anesthesia.

The assessment of consciousness at awakening and postoperative cognitive function was carried out by The Observer's Assessment of Alertness/Sedation Scale (OASS) at 15 min, 30 min, and 1 h after anesthesia, and through the Mini Mental State test (MMSt) at 1 and 4 h after anesthesia.

Early postoperative pulmonary failure (including bronchospasm, postoperative PaO2 <60 mmHg, a PaO2:FIO2 ratio ≥ 300 mmHg, or arterial oxyhemoglobin saturation measured with pulse oximetry <90% and requiring oxygen therapy) was noted after 24 h after anesthesia.

Time to resumption of intestinal transit, defined as time to return of peristalsis and time to first passage of flatus, antiemetics, and morphine consumption were recorded. Nurses detected peristalsis and gastrointestinal symptoms every 2 h and patients were asked to warn staff of the perception of bowel activity.

#### *2.3. Statistical Analysis*

The primary outcome was the cumulative incidence of PONV in the first 6 postoperative hours. Based on data from our department after this type of surgery using single-drug PONV prophylaxis and reversal of neuromuscular block with neostigmine, and according with previous study [13,14], we estimated that experience PONV would be 30% in neostigmine group and 8% in the sugammadex group. Based on power = 80% and *a* = 0.05, a sample size of 98 patients at least (*n* = 49 per group) was required.

For scores continuous, we used a two-sample Kolmogorov–Smirnov test, while for the ordinal categorical variable we used the Mann–Whitney U-test. *P*-values ≤ 0.05 were regarded as statistically significant. Data were analyzed using SPSS software (IBM, New York, United States).

#### **3. Results**

In the period between May 2017 and December 2018, a total of 109 patients were randomized: 54 patients to the S group and 55 to the N group.

The flowchart of the patients who participated in the study is demonstrated in Figure 1. The demographics and clinical characteristics were balanced for both treatment arms and are presented in Table 1. Intraoperative and perioperative data recorded are shown in Table 2.

**Figure 1.** Patient disposition.

Time to recovery from TOF 2 to TOF ratio >0.9 was significantly lower in the S group. The incidence of early PONV was lower in the S group but not statistically significant (*p* = 0.711). The values were similar between the two groups for the incidence of late PONV.

The mean MMSt value was significantly higher in the S group compared with the N group at 1 h after anesthesia [mean and 25–75th percentile, 29.3 (29; 30) vs. 27.6 (27; 30); *p* = 0.007] and at 4 h after anesthesia [29.5 (30; 30) vs. 28.4 (28; 30); *p* = 0.048]. Thus, S group obtained better MMSt values during all measurements of time. The mean OASS value was significantly higher in the S group compared with the N group 1 h after the end of anesthesia (median and 25–75th percentile, 5 (5; 5) vs. 5 (4; 5); *p* = 0.02), but no differences were observed in the first measurement, 30 min after the end of anesthesia (Table 3).



BMI: body mass index; ASA: American Society of Anesthesiologists; COPD: chronic obstructive pulmonary disease; HADS: Hospital Anxiety and Depression Scale.


\* *p*-value < 0.05; EtCO2: end tidal CO2; SpO2: pulse oximetry; HR: heart rate; MAP: mean arterial pressure; TOF: train-of-four; PONV: postoperative nausea and vomiting; IQR: interquartile range.


**Table 3.** Consciousness at awakening and postoperative cognitive function.


In Figure 2, we can observe that the trend in both MMSt and OASS is different between the two groups. The MMSt trend remained steadily higher since the awakening, while the values of OASS in S group were significantly increased after the first postoperative hour. The incidence of postoperative pulmonary failure was similar in each group. There were no significant differences between the groups for time to resumption of intestinal transit. Postoperative ondansetron and metoclopramide were similar in each group, as well as analgesic consumption.

**Figure 2.** (**A**) MMSt and (**B**) OASS trend (error bars: 95% CI). Blue line: S group. Green line: N group.

#### **4. Discussion**

In our study, we attempted to evaluate the quality of recovery from anesthesia in two groups of patients who underwent robotic-assisted laparoscopic cystectomy. Prolonged myoresolution was carried out with continuous infusion of rocuronium: In one group, NMB reversal was obtained with sugammadex and in the other group, the association neostigmine/atropine was used.

Our results show that the incidence of PONV was greater in the N group, although non-statistically significant. Even time to resumption of intestinal transit was overlapping in the two groups.

In the past, studies concerning the reduction of PONV following the use of sugammadex have had conflicting results. Inhibiting cholinesterase action causes neostigmine increases concentration of acetylcholine, the principal excitatory neurotransmitter in the GI tract. Acetylcholine acts by increasing gastric secretions and esophageal pressure and increases the risk of symptoms such as nausea and vomiting, but also allows an increase in GI motility [15]. The prevention of PONV and the rapid restoration of intestinal function are fundamental topics in the development of ERAS protocols, which have shown efficacy in reducing complications and improving outcomes in many surgeries [16]. Nowadays, there are no definitive protocols specific to robotic surgery, and protocols applied in colorectal surgery are often used for cystectomy [10].

Our results agree with those of Peach et al. [17], which, in a large clinical trial of 304 women, did not find a lower incidence of PONV with the use of sugammadex compared with neostigmine. In contrast, Ya ˘gan et al. [13] found that the use of sugammadex had lower incidences of PONV in the first postoperative hour and less anti-emetic use at 24 h. In addition, in the study by Koyuncu et al. [18], sugammadex reduces PONV compared with neostigmine and atropine, but only slightly and transiently. While in the Ya ˘gan study [13], the population had undergone various types of surgery (more than half underwent head and neck surgery) and in the Koyuncu study [18] patient were candidates for extremity surgery, in the Peach study [17] patients underwent laparoscopic surgery, which, as in robotic cystectomy, involves a certain degree of postoperative ileus, a physiological arrest of GI transit in response to surgical stress and intestinal manipulation. Neostigmine can increase motility only if acetylcholine release and smooth muscle function are relatively preserved, while postoperative ileus induces the activation of presynaptic noradrenergic receptors and impairs the functionality of the enteric nervous system and the sympathetic nerves [19,20]. This could have determined the absence of the expected effects on intestinal and gastric motility.

Moreover, in the study by Ya ˘gan, neostigmine doses were higher than those used in our study [13], and the correlation between the neostigmine dose and PONV is now considered a key factor to control the symptoms [9].

Two scales were employed as awakening quality indicators: MMSt and OASS. The MMSt was considered to assess cognitive impairment because it is a rapid and simple to perform test that provides accurate measurements of cognitive status both in subjects with normal functions and in subjects with cognitive alterations [21], and its use to assess subtle changes in cognitive function after anesthesia is often reported [22].

Our results have unexpectedly shown a significant increase of the average value of MMSt in the considered time frames. The OASS mean value also significantly increased in the S group until 1 h after surgery.

The reversal action of sugammadex is based on the structure of cyclodextrins, consisting of a lipophilic central cavity able to encapsulate the steroid rings of the rocuronium molecule, forming an inactive complex that is no longer able to interact with the neuromuscular junction [23]. Based on its structural characteristics, the fact that the sugammadex molecule or the sugammadex/rocuronium complex could interact in any way with the anesthetic drugs or with the cholinergic system was excluded [24]. The apparent rapid awakening at a cognitive level, that some other authors and we have detected [25,26], could be explained in the light of the so-called Afferentation Theory [27], for which general activation of muscle receptors can induce a massive cerebral stimulation of the monoaminergic wakefulness centers. It is also known as the Spindle Theory [23], since it has been postulated that tension and stretch receptors in muscle spindles may be the terminations that transmit static and dynamic variations to the encephalon, acting on various cortical and mesencephalic areas. However, some studies have not been able to demonstrate changes in the depth of anesthesia after sugammadex administration [28], thus the results of studies regarding sugammadex's impact on recovery from general anesthesia remain conflicting and insufficient [29].

In the past, many studies demonstrated an existing relationship between the structure of cyclodextrins and neuroprotection: statins and cyclodextrins, influence the transmission of neural signals, interfering with the production of inflammatory molecules [30]. Ultimately, one could speculate that sugammadex gives an additional effect by interacting with the lipid molecules of the neuronal membrane, reducing exocytosis. This protective effect could be more readily detectable in a surgery, such as robotic cystectomy, which requires more than 2 h in steep Trendelenburg and alterations of cerebrovascular circulation due to prolonged pneumoperitoneum [10]. In the future, it could be interesting to analyze if the use of sugammadex can be optimized, employing it in elderly populations or in surgeries that require high abdominal pressure or extreme conditions.

A limit of our study mainly regards the same limitations related to the neurophysiological tests administered in the postoperative period. These tests may be subject to the learning effect bias and to the variability in the sessions following the preoperative one, considered baseline, and from one session to another. We tried to minimize this variability by administering the test in the same environment, with no external distractions, and patients who needed extra doses of opioids for pain were excluded.

#### **5. Conclusions**

In conclusion, our results were not able to demonstrate a significant decrease of the PONV or a more rapid ROI after sugammadex administration versus neostigmine use. We observed a significant increase in MMSt values, suggesting improved quality of awakening with the use of sugammadex in patients undergoing robotic radical cystectomy. Regarding OASS observations in both groups, we obtained higher values in the group receiving sugammadex. Further studies on elderly populations and different types of surgery will be needed in the future, especially with the aim to provide a comprehensive ERAS pathway for cystectomy based on the available evidence.

**Author Contributions:** Conceptualization, C.C. and E.F.; methodology, C.C.; formal analysis, C.C.; investigation, C.C., M.C. and G.T. (Giulia Torregiani); data curation, M.E.M., A.S.d.U., A.Z., G.T. (Gabriele Tuderti) and G.S.; writing—original draft preparation, C.C.; writing—review and editing, C.C., M.C. and G.T. (Giulia Torregiani); supervision, E.F.

**Funding:** This research received no external funding.

**Acknowledgments:** Editorial assistance was provided by Luca Giacomelli and Aashni Shah (Polistudium).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

### *Article* **Do Younger Patients with Muscle-Invasive Bladder Cancer have Better Outcomes?**

#### **Florian Janisch 1,2, Hang Yu 1, Malte W. Vetterlein 1, Roland Dahlem 1, Oliver Engel 1, Margit Fisch 1, Shahrokh F. Shariat 2,3,4,5,6,7, Armin Soave <sup>1</sup> and Michael Rink 1,\***


Received: 12 August 2019; Accepted: 11 September 2019; Published: 13 September 2019

**Abstract:** Urothelial cancer of the bladder (UCB) is usually a disease of the elderly. The influence of age on oncological outcomes remains controversial. This study aims to investigate the impact of age on UCB outcomes in Europe focusing particularly on young and very young patients. We collected data of 669 UCB patients treated with RC at our tertiary care center. We used various categorical stratifications as well as continuous age to investigate the association of age and tumor biology as well as endpoints with descriptive statistics and Cox regression. The median age was 67 years and the mean follow-up was 52 months. Eight patients (1.2%) were ≤40 years old and 39 patients (5.8%) were aged 41–50 years, respectively. In multivariable analysis, higher continuous age and age above the median were independent predictors for disease recurrence, and cancer-specific and overall mortality (all *p*-values ≤ 0.018). In addition, patients with age in the oldest tertile group had inferior cancer-specific and overall survival rates compared to their younger counterparts. Young (40–50 years) and very young (≤40 years) patients had reduced hazards for all endpoints, which, however, were not statistically significant. Age remains an independent determinant for survival after RC. Young adults did, however, not have superior outcomes in our analyses. Quality of life and complications are endpoints that need further evaluation in patients undergoing RC.

**Keywords:** bladder cancer; age; urothelial carcinoma; radical cystectomy; outcome; survival

#### **1. Introduction**

With an incidence of over 80,000 new cases and over 17,000 deaths estimated to occur in 2019 in the United States alone, urothelial cancer of the bladder (UCB) is the second leading genitourinary malignancy and a potentially lethal disease [1]. Compared with other malignancies, UCB is usually a disease of the elderly with a peak incidence among those in their 70s [2,3]. In fact, in general there is an increasing life expectancy in the US and Europe and in consequence, a potential further rise in UCB diagnoses is expected in the next few decades [4,5]. Ageing trends are of major scientific and clinical importance in any cancer including UCB, as the optimal management has great impact for each individuum and the public health system in general, especially in an expensive disease as UCB [6].

Despite the overwhelming incidence in elderly patients, UCB does also occur in a non-negligible number of young patients [3]. While the development of UCB in the elderly has been suggested to be driven by a cumulative lifetime exposure to environmentally, occupationally, or individually acquired carcinogens (e.g., smoking) [7–9], the factors for UCB in young patients remain rather inconclusive. Not only the diagnosis of UCB, particularly the need of RC with all its negative effects on quality of life has a significant impact on the psyche and more, especially in the younger. RC is more frequently offered in younger patients, due to their longer life expectancy, lower frailty resulting in lower adverse events and the superiority in survival outcomes of early compared to delayed RC [10]. Recent reports suggest superior UCB-specific outcomes in young and adolescent patients (15–39 years) [11].

The impact of patient age on oncological outcomes remains controversial and regional variabilities may be present that need to be considered in patient counselling and treatment planning. The aim of this study was to evaluate the impact of age on UCB outcomes after RC in a consecutive cohort of European patients, particularly focusing on the young and very young. We hypothesized that younger patients may have better oncologic outcomes as their disease may be earlier in their natural history and different as it may not have a large mutational burden.

#### **2. Material and Methods**

#### *2.1. Patient Population*

We retrospectively reviewed the medical records of 789 consecutive patients treated with RC and bilateral pelvic lymphadenectomy for UCB between 1996 and 2011 at our institution. Guideline adherent indications for RC were muscle invasive UCB or recurrent Ta, T1, or carcinoma in situ (CIS) refractory to transurethral resection of the bladder (TURB) with or without intravesical chemo- or immunotherapy. As neoadjuvant chemotherapy may be more frequently administered in younger patients, implementing an inherent bias of natural UCB history in age analyses, these patients were excluded upfront (*n* = 8). Moreover, 75 patients were excluded because of missing variables or follow-up, 30 patients with RC for non-malignant indication for RC, and seven patients with advanced, bladder infiltrating prostate cancer. In total, 669 patients remained for analyses. Overall, 147 patients (20.0%) received adjuvant chemotherapy (95% platinum-based) at the clinicians' discretion in accordance with the guidelines at the time. The study was approved by the local ethics committee.

#### *2.2. Follow-Up Regimen*

Follow-up strategy has been previously reported in detail [12,13]. In brief, patients were generally seen every three to four months for the first year after surgery, every six months from the second to fifth year, and annually thereafter. Follow-up included a history, physical examination and serum chemistry evaluation. Diagnostic imaging of the abdomen including the urinary tract and chest radiography were performed at least annually or when clinically indicated. Additional radiographic evaluations were performed when clinically indicated.

#### *2.3. Statistical Analysis*

Statistical analyses included demographic data on patients' age, ethnicity, gender, ASA status, pathologic tumor stage and grade, concomitant CIS, lymph node status, margin status, lymphovascular invasion, and adjuvant chemotherapy, respectively.

The co-primary endpoints were recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS), respectively. Disease recurrence was defined as local failure in the operative site, regional lymph nodes, or distant metastasis. Upper tract urothelial carcinoma was considered a metachronous tumor and not disease recurrence. Patients who did not experience disease recurrence were censored at time of last follow-up for recurrence-free survival analysis. Cancer-specific mortality was defined as death from UCB. The cause of death was determined by the treating physician, by chart review corroborated by death certificates, or by death certificates alone [14]. Perioperative mortality (i.e., death within 30 days of surgery) was censored at time of death for UCB-specific survival analyses.

Age was analyzed as a continuous variable, with a cut-off at median and tertiles, and using the cut-offs of 50 years. (dichotomized) and ≤40, 41–50, and >50 years (three categories), respectively. The different analytic approaches were used to optimally approach the definition of young age. There is no clear determination for UCB patients treated with RC in the urologic literature defining a patient as 'young' or 'very young'. However, there is a consensus among oncological experts that patients <50 years. are usually defined as 'young' and patients <40 years. defined as 'very young' [15]. Using median and tertiles as cut-off, we investigated the effects of age in our study population with homogenous sample distributions. Utilization of the dichotomized cut-off of 50 years. was based on previous reports that indicated superior survival outcomes in patients <50 years. The tri-categorical analyses uses cut-offs of <40 years and <50 years following predefined ranges indicated by the NCI in 2006 [15]. In addition, study results indicate significant outcome differences, suggesting these strata represent an ideal standard [11].

The Kolmogorov–Smirnov test was used to assess the normal distribution of variables. The Fisher's exact test and the chi-square test were used to evaluate the association between categorical variables. Differences in variables with a continuous distribution across categories were assessed using the Mann–Whitney U test (two categories) and Kruskal–Wallis test (three and more categories). Actuarial method was used to estimate RFS, CSS, and OS probabilities and the differences were assessed with the log rank test. Kaplan–Meier estimates were used to graphically display survival functions. Univariable and multivariable Cox regression models addressed time-to-event endpoint analyses. In all models, proportional hazards assumptions were systematically verified using the Grambsch–Therneau residual-based test. Multicollinearity was assessed with the variance inflation factor to test for possible confounding between relevant covariates. All reported *p*-values were two-sided, and statistical significance was set at *p* < 0.05. All statistical tests were performed with IBM SPSS Statistics 25 (IBM Corp., Armonk, NY, USA).

#### **3. Results**

#### *3.1. Association of Age with Clinical–Pathological Characteristics*

The median age of the study cohort was 67 years (interquartile range [IQR]: 59; 73), and 520 (78%) of the patients were male. In total, 622 patients (93.0%) were older than 50 years. Of those being <50 years, 39 patients (5.8%) were aged 41–50 years and 8 patients (1.2%) were younger than 40 years. Tertiles for age were ≤59 years (first tertile), 60–72 years (second tertile), and ≥73 years (third tertile), respectively. The descriptive clinicopathologic characteristics of the study cohort are presented in Table 1.


**Table 1.** Descriptive characteristics stratified by dichotomy age groups of 669 UCB patients treated with radical cystectomy


**Table 1.** *Cont.*

Comparing patients under and over 50, older patients presented with a significantly higher ASA score (*p* < 0.001). ASA scores increased significantly from patients ≤40 years to patients aged 41–50 and to ≥50 years (*p* < 0.001). There were no statistically significant differences in any other clinical–pathological variables irrespective of the stratification used.

#### *3.2. Association of Age with Disease Recurrence and Survival Outcomes*

The median follow-up was 52 months (IQR: 17; 78). During the follow-up period, 192 patients (32.4%) experienced disease recurrence, 175 patients (28.0%) died of UCB, and 257 patients (42.1%) died of any cause. The actuarial recurrence-free survival estimates at 2- and 5-years after RC were 64 ± 2% and 59 ± 2%, respectively. The actuarial cancer-specific survival estimates at 2- and 5-years after RC were 71 ± 2% and 61 ± 3%, respectively. The actuarial overall-specific survival estimates at 2 and 5-years after RC were 62 ± 2% and 50 ± 2%, respectively.

In the Kaplan–Meier analyses, no statistically significant difference was observed in recurrence-free survival (*p* = 0.49; Figure 1A), cancer-specific survival (*p* = 0.78; Figure 1C), and overall survival (*p* = 0.67; Figure 1E) between patients younger than 50 years, and those 50 and above. In categorical age group analyses, there was also no statistically significant difference in recurrence-free survival, cancer-specific survival and overall survival (*p* > 0.05 for all; Figure 1B,D,F) between patients 50 years and above, those between 41–50 years and those 40 and younger.

#### *3.3. Risk Factor Analyses for Disease Recurrence and Survival Outcomes*

All variables tested on multicollinearity had an VIF in the range of 1.1–2.9, indicating that no multicollinearity is present between factors included in the cox regression model. The results of univariable Cox regression analyses for different age stratifications are presented in Table 2. Higher continuous age was significantly associated with inferior recurrence-free (Hazard ratio (HR): 1.017; 95%CI: 1.002–1.032; *p* = 0.029), cancer-specific (HR: 1.023; 95%CI: 1.007–1.039; *p* = 0.005), and overall survival (HR: 1.030; 95%CI: 1.016–1.044; *p* < 0.001). In addition, patients older than the median (all *p* ≤ 0.01) and patients in the highest age tertile compared to patients in the second tertile

(all *p* ≤ 0.008) were significantly associated with inferior outcomes for all three endpoints. Analyses according to all age categories (i.e., ≤50 vs >50; ≤40 vs. 41–50 vs. >50, tertiles) revealed that patients in higher age categories were not associated with a higher risk for all endpoints (all *p* > 0.05).

The results of multivariable Cox regression analyses that adjusted for standard UCB clinic-pathological parameters (Table 3) showed that higher continuous age (RFS HR: 1.019; *p* = 0.018; CSS HR: 1.025; *p* = 0.004, and OS HR: 1.030; *p* < 0.001), age above the median of our cohort (RFS HR: 1.472; *p* = 0.014; CSS HR: 1.553; *p* = 0.008; and OS HR: 1.596; *p* = 0.001) and age in the third tertile (≥73 years) compared to the second age tertile (60–72 years) (RFS HR: 1.862; *p* = 0.005; CSS HR: 2.085; *p* = 0.001; OS HR: 2.256; *p* < 0.001) were all independently associated with worse outcomes for all three endpoints. In addition, CSS and OS of patients in the third tertile were also inferior compared to the outcomes of patients in the first age tertile (≤59 years) (CSS HR: 1.545; *p* ≤ 0.034; OS HR 1.728; *p* = 0.002).

**Figure 1.** Kaplan–Meier estimates of stratified age groups of elderly (≥50 years.) and young patients (<50 years.) (**A**,**C**,**E**), and stratified in three age groups of elderly (>50 years.) young (41–50 years.) and very young (≤40 years.) patients (**B**,**D**,**F**) for recurrence-free, cancer-specific, and overall survival, respectively.



Abbreviations: of the bladder. **Table 3.** Multivariable cox regression analysis of the effect of age on predicting recurrence-free survival, cancer-specific survival and overall survival of 669 patients with UCB and treated with radical cystectomy


All multivariablelymph node status, margin status, lymphovascular invasion, and adjuvant chemotherapy. Abbreviations: RFS = recurrence free survival; CSS = cancer specific survival; OS = overall survival; HR = hazard ratio; CI = confidence interval; UCB = urothelial carcinoma of the bladder.

#### **4. Discussion**

We found that young patients did not present with more favorable tumor biological features compared to their older counterparts. In addition, we did not find significantly superior survival outcomes for all three endpoints in favor of young patients. Therefore, we reject our hypothesis that young UCB patients with MIBC have better outcomes post-RC than the normal MIBC patient. This is in contrast to previous studies that reported better oncological outcomes in younger UCB populations [11,16,17]. Differences in results between our study and previous reports may be explained by different definition of young age, diverse race/ethnicity or distinct socioeconomic status, etc. [18]. Indeed, we found that higher continuous age and other strata defining patients as elderly were independently associated with inferior survival outcomes. Thus, while one end of the age spectrum does not better, the other end of the spectrum seems to have worse oncologic outcomes. Undeniably, this underscores the validity of our UCB cohort as these findings are in line with those of large, multicentric UCB series [19,20].

The relationship between age and prognosis of UCB remains controversial. In fact, there is no clear definition when a UCB patient is defined to be very young, young, old, or very old. A recent large US study reported that adolescents and young UCB patients (ages 15–39) [11] had superior cancer-specific and overall survival compared to their older counterparts. In another study, patients were stratified using a cut-off of 50 years with superior cancer-specific and overall survival in the younger group [16]. In our study we, therefore, used variable age stratifications and cut-offs to reflect the most comprehensive picture on the impact of age across a wide spectrum of definitions and results. Indeed, using this comprehensive approach, we only found differences in categorized outcome analyses when using the median age or age tertiles of our cohort. Of importance, the median age in our cohort was 67 years and the upper age tertile included patients above 73 years. Thus, despite depicting a statistical significance compared to 'younger patients' in our cohort, our data did not demonstrate superior outcomes in those patients usually defined to be young or very young.

From the biological rationale it intuitively seems reasonable that older patients may experience inferior outcomes. With increasing age, exposure to several environmental, occupational, and individually amenable (e.g., smoking) stressors accumulate over time [7,21,22]. In addition, especially elderly men often experience obstructive lower urinary tract symptoms with incomplete bladder drainage. In consequence, the potentially prolonged contact time to carcinogens excreted in the urine may induce accumulation of cellular events that can lead to neoplastic transformation and subsequently UCB development [20]. Moreover, younger patients tend to be healthier in general, with mostly good immunity and nutrition status, as well as fewer co-morbidities to tolerate the complications of cancers or treatment.

From a clinical perspective, our results are important, as recent studies found very young UCB patients to have a lower hazard of cancer-specific mortality compared to their older counterparts [11], suggesting that organ-sparing approaches may be a viable option in young patients [23–25]. Especially the prospect of incontinence, impotence and/or infertility due to radical cystectomy may lead to delay of therapy or a switch of strategy to a bladder sparing, multimodal approach. However, younger patients are more reluctant to undergo necessary diagnostics and treatments or comply with strict follow-up schedules, possibly affecting outcomes [26]. In agreement with our results, other investigators also found either no difference [27] or even worse outcomes, due to a higher rate of metastases [28], in patients ≤40 years. A potential reason for the disparity in findings of various studies including ours may be due to difference in ethnicities, regional varieties in treatment, different socioeconomic backgrounds, and other factors that we could not all adjust for in our analyses. However, despite our findings not providing a final answer on the influence of a very young age on UCB outcomes treated with RC, our results do generate hypotheses that warrant further investigation of this association in larger, multi-institutional, ideally prospective studies. Indeed, our findings support the surgical approach of radical cystectomy also in young and very-young patients, as our findings underscore the aggressive nature of UCB and no age-group had superior survival outcomes. Certainly, the reconstruction which affects quality of life and perceived self-image should be adopted to patients' preferences, and general and specific health factors [29].

Our study is not devoid of limitations. First and foremost, the retrospective and single-center nature may inevitably introduce some selection bias. Despite this being a large monocentric cohort of consecutive patients, the overall sample size is still limited, especially in the subgroup of very young patients. Nevertheless, we feel that our study still provides a representative insight on age-dependent prognostic outcomes for Europe. All patients in our study were Caucasians, which should be considered since ethnicity may influence survival in UCB [30,31]. We were unable to collect and adjust analyses for several predisposing risk factors of UCB, including smoking, occupational exposure, family history, insurance status, immunity or nutrition status, adjuvant therapies, or socio-economic factors that also may influence tumor biology or outcomes [22,32,33]. In addition, laboratory and molecular data was not available. However, from the clinical perspective, the latter information is usually not available in daily routine for patient counselling. Age in general does represent a competing risk for death particularly since older patients have a greater frailty and UCB patients often harbor important comorbidities [34–36]. However, due to sample size limitations, we were unable to perform competing-risk analyses. Consequently, a contemporary, European multicenter approach would be warranted to shed further insight on this relevant topic.

#### **5. Conclusions**

In conclusion, we found that young age at time of MIBC diagnosis does not result in better outcomes compared to typical age after RC. Higher age, however, remains an important prognostic factor for cancer-related endpoints in UCB and thus needs to be incorporated in therapeutic considerations. Radical cystectomy remains standard treatment for patients with muscle-invasive bladder cancer independent of age. Further studies to assess the differential effect of RC and the different types of urinary diversion on the health-related quality of life and metabolic consequences across age are necessary.

**Author Contributions:** Conceptualization, F.J. and M.R.; Data curation, M.R. and M.W.V.; Formal analysis, M.R. and H.Y.; Funding acquisition, M.R.; Investigation, F.J., H.Y. and M.R.; Methodology, M.R.; Project administration, A.S.; Resources, R.D.; Supervision, M.R. and M.F.; Validation, F.J., M.W.V. and O.E.; Visualization, A.S.; Writing—original draft, F.J., H.Y. and M.R.; Writing—review & editing, F.J., M.W.V., A.S., O.E., S.F.S., M.F. and M.R.

**Acknowledgments:** Hang Yu is supported by the China Scholarship Council.

**Conflicts of Interest:** Sharokh F. Shariat is consulting or advising the following: Astra Zeneca, BMS, Ferring, Ipsen, Jansen, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, Sanochemia, Urogen.

#### **References**


© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

### *Article* **Open Versus Robotic Cystectomy: A Propensity Score Matched Analysis Comparing Survival Outcomes**

**Marco Moschini 1,2,3, Stefania Zamboni 3, Francesco Soria 1,4, Romain Mathieu 1,5, Evanguelos Xylinas 6, Wei Shen Tan 7,8, John D Kelly 7,8, Giuseppe Simone 9, Anoop Meraney 10, Suprita Krishna 11, Badrinath Konety 11, Agostino Mattei 3, Philipp Baumeister 3, Livio Mordasini 3, Francesco Montorsi 2, Alberto Briganti 2, Andrea Gallina 2, Armando Stabile 2, Rafael Sanchez-Salas 12, Xavier Cathelineau 12, Michael Rink 13, Andrea Necchi 14, Pierre I. Karakiewicz 15, Morgan Rouprêt 16, Anthony Koupparis 17, Wassim Kassouf 18, Douglas S Scherr 19, Guillaume Ploussard 20, Stephen A. Boorjian 21, Yair Lotan 22, Prasanna Sooriakumaran 8,23 and Shahrokh F. Shariat 1,24,25,\***


Received: 14 June 2019; Accepted: 6 August 2019; Published: 9 August 2019

**Abstract:** Background: To assess the differential effect of robotic assisted radical cystectomy (RARC) versus open radical cystectomy (ORC) on survival outcomes in matched analyses performed on a large multicentric cohort. Methods: The study included 9757 patients with urothelial bladder cancer (BCa) treated in a consecutive manner at each of 25 institutions. All patients underwent radical cystectomy with bilateral pelvic lymphadenectomy. To adjust for potential selection bias, propensity score matching 2:1 was performed with two ORC patients matched to one RARC patient. The propensity-matched cohort included 1374 patients. Multivariable competing risk analyses accounting for death of other causes, tested association of surgical technique with recurrence and cancer specific mortality (CSM), before and after propensity score matching. Results: Overall, 767 (7.8%) patients underwent RARC and 8990 (92.2%) ORC. The median follow-up before and after propensity matching was 81 and 102 months, respectively. In the overall population, the 3-year recurrence rates and CSM were 37% vs. 26% and 34% vs. 24% for ORC vs. RARC (all *p* values > 0.1), respectively. On multivariable Cox regression analyses, RARC and ORC had similar recurrence and CSM rates before and after matching (all *p* values > 0.1). Conclusions: Patients treated with RARC and ORC have similar survival outcomes. This data is helpful in consulting patients until long term survival outcomes of level one evidence is available.

**Keywords:** bladder cancer; robotic-assisted; open; radical cystectomy; survival; propensity score

#### **1. Introduction**

Bladder cancer (BCa) is the second most common genitourinary malignancy with 81,190 estimated new diagnoses for 2018 in the United States alone [1]. Radical cystectomy (RC) with bilateral pelvic lymph node dissection (PLND) is the standard treatment for muscle invasive and very high risk non-muscle invasive BCa [2]. However, this procedure is associated with significant perioperative mortality and morbidity as a direct consequence of the complexity of the procedure and the characteristics of the population which is generally older and suffering from multiple comorbidities when compared to other surgical patients [3]. Minimally invasive surgeries, such as robotic assisted radical cystectomy (RARC), have been designed to improve surgical morbidity. Indeed, robotic-assisted radical surgery in urology has been shown to be associated with decreased blood loss, need for transfusion, and length of stay compared to open RC (ORC) in most studies [4–10].

While these perioperative benefits are generally accepted, the differential impact of RARC compared to ORC on survival outcomes remains debated with widely diverging opinions [4,11,12]. The RAZOR trial [13], a randomized, open-label, non-inferiority, phase 3 trial comparing ORC and RARC, found that RARC was non-inferior to open cystectomy for 2-year progression-free survival but did not report overall survival.

Given the shortage of prospective randomized trials comparing RARC to ORC, controlled data regarding the oncological risks and benefits are needed from well-designed retrospective multicenter studies.

Therefore, to address this unmet need, we collected complete data from BCa patients treated at academic centers to determine the impact of on survival outcomes of RARC compared to the standard ORC. We performed a propensity-matched analysis to limit the impact of selection bias on survival outcomes.

#### **2. Experimental Section**

#### *2.1. Patients and Methods*

We collected the data from 9757 patients treated with RC for non-metastatic UCB at 25 institutions. Patients were staged preoperatively with cross sectional imaging (mostly computerized tomography), bone scan when indicated and chest X-ray. Surgical specimens were processed according to standard pathologic procedures at each institution. Tumors were staged according to the 2009 American Joint Committee on Cancer-Union Internationale Centre le Cancer (AJCC/UICC) TNM classification. Tumor grade was assigned according to the 2003 WHO/International Society of Urologic Pathology (ISUP) consensus classification. STSM was defined as the presence of tumor at inked areas of soft tissue on the RC specimen [14,15]. Urethral and ureteral margins were not considered as STSM. Lymphovascular invasion (LVI) was defined as the presence of tumor cells within an endothelium-lined space without underlying muscular walls [16,17].

#### *2.2. Primary and Secondary End Points*

The primary end-point was to compare survival outcomes of RARC with ORC. The secondary end-point was to evaluate survival outcomes of BCa patients treated with RARC. Overall recurrence and cancer-specific mortality (CSM) were defined as disease recurrence and death from disease, respectively.

#### *2.3. Statistical Analyses*

Descriptive statistics of categorical variables focused on frequencies and proportions. Means, medians, and interquartile ranges (IQR) were reported for continuously coded variables. The Mann– Whitney and chi-square tests were used to compare the statistical significance of differences in medians and proportions, respectively. Fine and Gray multivariable competing risk analyses tested the impact surgical technique and survival outcomes. Owing to inherent differences between patients undergoing ORC and RARC in terms of baseline patient and disease characteristics, we used a 2:1 propensity score matched analysis to adjust for the effects of these differences. The use of the propensity score method reduces the customary bias associated with the conventional multivariable modeling approach. The variables adjusted for were administration of neoadjuvant chemotherapy (NAC), grade, pathological T stage, lymph node status and age at surgery Subgroup analyses were performed. Statistical significance was considered at *p* < 0.05. Statistical analyses were performed using SPSS v.22.0 (IBM Corp., Armonk, NY, USA) and STATA 14 (Stata Corp., College Station, TX, USA).

#### **3. Results**

#### *3.1. Clinicopathologic Characteristics (Entire Cohort)*

Demographics and pathologic characteristics of the cohort stratified by surgical approach are shown in Table 1. Overall, 767 (7.8%) patients were treated with RARC and 8990 (92.2%) with ORC and most of the patients were men (*n* = 7775, 80%); median age was: 68 years (IQR: 60–74). About half of the patients (*n* = 4248, 45%) harbored pathological stage T3-T4, 6.7% had positive STSM (*n* = 639) and 24% (*n* = 2276) had lymph node metastases. There were no differences in age at surgery and gender between RARC and ORC patients (all *p* values > 0.1). Conversely, patients treated with RARC were more likely treated with NAC (26% vs. 3.6%) compared to patients treated with ORC and had less advanced diseases (pT3-pT4 stage: 40% vs. 46% and lymph node metastasis 22% vs. 24%). RARC patients were less likely to receive adjuvant chemotherapy compared to ORC patients (13% vs. 21%).


**Table 1.** Clinicopathologic demographics of 9757 patients with bladder cancer treated with radical cystectomy according type of surgery.


**Table 1.** *Cont.*

RARC: robotic assisted radical cystectomy, ORC: open radical cystectomy, IQR: interquartile range, LNI: lymph node invasion, LVI: lymphovascular invasion.

#### *3.2. Clinicopathologic Characteristics (Adjusted Cohort)*

Demographics and pathologic characteristics of the cohort after propensity matching, stratified by surgical approach are reported in Table 2. After the propensity matching, 420 (33%) patients were treated with RARC and 840 (67%) with ORC; no differences were recorded between ORC and RARC patients considering age, gender, NAC usage, pathological T stage, pathologic grade, and lymph node invasion (all *p* > 0.1). On the other hand, patients treated with RARC recorded higher rate of positive STSM compared to ORC group (11% vs. 6.3%).

**Table 2.** Clinicopathologic characteristics of 1374 patients with bladder cancer treated with radical cystectomy, comparing robot assisted radical cystectomy (RARC) and open radical cystectomy (ORC) cohorts after propensity matching.



**Table 2.** *Cont.*

RARC: robotic assisted radical cystectomy, ORC: open radical cystectomy, IQR: interquartile range, LNI: lymph node invasion, LVI: lymphovascular invasion.

#### *3.3. Survival Analyses in the Entire Cohort (Unadjusted Cohort)*

The median follow-ups before and after propensity matching were 81 and 102 months, respectively. The 3-year recurrence rates, CSM and OM were 37% vs. 26%, 34% vs. 24% and 47% vs. 34% for ORC vs. RARC (Figure 1, all *p* values > 0.1), respectively. On multivariable Cox regression analyses adjusting for standard clinico-pathologic characteristics, no significant differences were found between RARC and ORC in overall recurrence and CSM (Table 3, *p* > 0.1).

*p*

**Figure 1.** Cumulative incidence of recurrence and cancer specific mortality on overall population of patients with non-metastatic bladder cancer (BCa) treated with radical cystectomy according the type of surgery (ORC vs. RARC).


**Table 3.** Multivariable competing risk analyses predicting the risk of overall recurrence and cancer specific mortality (CSM) in patients treated with radical cystectomy in overall patients.


**Table 3.** *Cont.*

CSM: cancer specific mortality, HR: Hazard ratio, CI: confidence interval, RARC: robotic assisted radical cystectomy, LVI: lymphovascular invasion.

#### *3.4. Survival Analyses after Propensity Matching (Adjusted Cohort)*

The 3-year recurrence and CSM were 31% vs. 29% and 27% vs. 26% for ORC vs. RARC, respectively (Figure 2, all *p* values > 0.3), respectively. On multivariable Cox regression analyses adjusting for standard clinicopathologic characteristics, RARC was again associated with similar overall recurrence and CSM compared to ORC (Table 4, *p* > 0.3).

**Table 4.** Multivariable competing risk analyses predicting the risk of overall recurrence and CSM in patients treated with radical cystectomy after propensity matching.


CSM: cancer specific mortality, HR: Hazard ratio, CI: confidence interval, RARC: robotic assisted radical cystectomy, LVI: lymphovascular invasion.

**Figure 2.** Cumulative incidence of recurrence and cancer specific mortality of patients with non-metastatic BCa treated with radical cystectomy according the type of surgery (ORC vs. RARC) after 2:1 propensity matching for age, pathological T stage, pathological N stage, neoadjuvant chemotherapy (NAC) and grade.

#### **4. Discussion**

The adoption of RARC is growing rapidly, but the majority of radical cystectomies continues to be performed by a conventional open approach. The majority of the current data from RARC series which tested perioperative and short term oncological outcomes did not test equivalence regarding long term survival outcomes [18–21]. Several retrospective series raised, indeed, some concerns regarding the oncological safety of the robotic approach [22]. On the other hand, two different prospective trials found no differences in survival outcomes between the two surgical approaches [13,23].

In this multicenter study, we evaluated the survival outcomes of the largest international cohort of bladder cancer patients treated with either ORC or RARC. Patients were treated in both European and American referral centers, collecting data from almost 1000 RARC and matching them with almost 9000 ORC patients. This manuscript follows two previous publications [10,21] from the same collaboration, evaluating for the first time the impact of survival and on peri-operative outcomes demonstrating an advantage of RARC in blood loss and length of stay. New centers were added to this manuscript in respect of the previous publications and the match of the final database was performed separately for each study on the bases of the main aim of each project.

We found that RARC and ORC share similar survival outcomes, both on univariable and multivariable analyses controlled for established prognostic factors. We performed propensity matching to minimize the risk of selection bias adjusting for pathological stage, lymph node status, and age at surgery. Even in this setting we confirmed that the RARC approach is associated with similar recurrence and CSM rates compared to ORC. These results were obtained with a median follow-up before and after propensity matching of 81 and 102 months, respectively. Similarly to our previous manuscript [21], we found a positive surgical margin status higher than 10% in patients treated with RARC. However, this was consistently higher than in patients treated with RARC compared to patients treated with ORC. Despite these differences, this had no impact on survival outcomes when adjusted for all the available confounders in the multivariable model.

Our results confirm the findings of the RAZOR trial [13], an open label, randomized, phase 3, non-inferiority trial comparing RARC versus ORC. A total of 152 patients were included in the ORC group and compared to 150 patients treated with RARC, reporting similar 2-year progression free survival rates. Bochner et al. [23], in a prospective, randomized trial compared 60 and 58 patients treated with RARC and ORC, respectively. No differences were found considering recurrence, cancer survival, or overall survival. Previously, Bochner et al. [18] reported in a single center prospective randomized trial, an advantage in terms of mean intraoperative blood loss for the RARC group but longer operative times compared to ORC. However, no survival outcomes were reported. Similarly, in the prospective

trial of Khan et al. [24] and Nix et al. [20] survival outcomes were not analyzed. Given the paucity of prospective data analyzing survival outcomes of RARC patients, new long term level one evidence are required.

Several retrospective series focused on mid-long-term survival outcomes [22,25]. Nguyen at al. [22] analyzed 383 consecutive patients treated with ORC (120) or RARC (263) between 2001 and 2014 at a single institution. With a median follow up of 30 months (for ORC) and 23 months (for RARC), they reported similar recurrence rates with an increasing risk of experiencing extrapelvic lymph node recurrence and peritoneal carcinomatoses for RARC patients. Our analyses did not include the type of recurrence limiting our ability to test this aspect; but we found a similar overall recurrence risk for patients treated with RARC when compared to ORC.

Hu et al. [25], using the SEER database compared 439 patients treated with RARC and 7308 treated with ORC. These authors observed an increasing trend in RARC utilization over the study period and with a median follow up of 44 months, they found no survival differences between the two techniques. However, as recognized by the authors themselves, they analyzed only a small RARC cohort treated by many different centers in their learning in some cases. In a recent systematic review and meta-analyses [26], five studies with a total of 540 participants were included. Authors found no differences in disease progression and local recurrences between patients treated with RARC and ORC. Finally, a recent large retrospective study analyzed the outcomes of RARC versus ORC in the selected population of patients who had received perioperative chemotherapy (in the neoadjuvant or adjuvant setting). No difference was found in multivariable analyses in the rate of positive surgical margins, rate of neobladder diversion, recurrence, and overall survival [27].

Our study represents the largest multicenter collaboration analyzing survival outcomes of patients affected by bladder cancer analyzing the effect of the RARC approach. Our analyses differentiate itself from previous reports including referral centers but excluding low case volume and learning curves which may lead to suboptimal outcomes. Our study comprises the largest available cohort to date analyzing survival outcomes in RARC patients. Despite several strengths, our study is not devoid of limitations. First and foremost, we recognize that our study is limited by its observational nature, and thus our results should be interpreted within the limits of its retrospective design. Second, we did not perform a central review of all specimens and therefore relied on the dedication and attention of the local uro-pathologists. Third, we did not include data regarding urinary diversion that might have an influence on survival outcomes. On the other hand, previous literature failed to prove any differences regarding different urinary diversion in RARC patients supporting the hypothesis of similar survival outcomes between these two groups [28]. Patients treated in academic centers are more prone to be treated with RARC as compared to ORC [8], moreover, differences exist regarding tumor characteristics, patient characteristics, and year of surgery (with an increasing tendency to perform a RARC) [29,30]. These elements can only partially be adjusted for with a propensity match analysis; we are aware that our results need to be confirmed in a controlled randomized trial. In this regard, a high proportion of RARC patients were found with pT0 disease at RC specimen, that might indicate a selection bias that can be only partially mitigated by the propensity matching analyses.

#### **5. Conclusions**

Patients treated with RARC were found with an increased rate of positive surgical margin compared to those treated with ORC. However, no differences regarding overall recurrence rate and survival were found between the two study groups. These results were confirmed in propensity score matched analyses adjusted for all the major confounders. High quality prospective trials are warranted to support the long-term oncological safety of RARC.

**Author Contributions:** M.M.: conceptualization, methodology, validation, formal analysis, investigation, data curation, writing original draft preparation, writing—review and editing; S.Z.: conceptualization, methodology, validation, formal analysis, investigation, data curation, writing—review and editing; F.S., R.M., E.X., W.S.T., J.D.K., G.S., A.M. (Anoop Meraney), S.K., B.K., A.M. (Agostino Mattei), P.B., L.M., F.M., A.B., A.G., A.S., R.S.-S., X.C., M.R., A.N., P.I.K., M.R. A.K., W.K., D.S.S., G.P., S.A.B., Y.L., P.S.: methodology, validation, data curation, writing—review and editing; S.F.S.: conceptualization, methodology, validation, investigation, data curation, writing—review and editing, project administration.

**Acknowledgments:** On behalf of the European Association of Urology-Young Academic Urologists (EAU-YAU), Urothelial carcinoma working group.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


#### *J. Clin. Med.* **2019**, *8*, 1192


© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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