was performed to identify independent predictors of survival.

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1 . JOURNAL COMPILATION 2010 Laparoscopic and Robotic Urology EARLY OUTCOMES FOR BUC PATIENTS TREATED WITH RRC KAUFFMAN ET AL. BJUI Early oncological outcomes for bladder urothelial carcinoma patients treated with robotic-assisted radical cystectomy Eric C. Kauffman, Casey K. Ng, Ming Ming Lee, Brandon J. Otto, Gerald J. Wang and Douglas S. Scherr Department of Urology, New York Presbyterian Hospital Weill Cornell Medical Center, New York, NY, USA Accepted for publication 12 March 2010 Study Type Therapy (case series) Level of Evidence 4 OBJECTIVE To determine oncological outcomes including early survival rates among unselected bladder urothelial carcinoma (BUC) patients treated with robotic-assisted radical cystectomy (RRC). PATIENTS AND METHODS Clinicopathologic and survival data were prospectively gathered for 85 consecutive BUC patients treated with RRC. The decision to undergo a robotic rather than open approach was made without regard to tumor volume or surgical candidacy. Kaplan Meier survival rates were determined and stratified by tumor stage and LN positivity, and multivariate analysis was performed to identify independent predictors of survival. RESULTS Patients were relatively old (25% >80 years; median 73.5 years), with frequent comorbidities (46% with ASA class 3). Of these patients 28% had undergone previous pelvic radiation or pelvic surgery, and 20% had received neoadjuvant chemotherapy. Extended pelvic lymphadenectomy was performed in 98% of patients, with on average 19.1 LN retrieved. On final pathology, extravesical disease was common (36.5%). Positive surgicalmargins were detected in five (6%) patients, all of whom had extravesical tumors with perineural and/or lymphovascular invasion, and most of whom were >80 years old. At a mean postoperative interval of 18 months, 20 (24%) patients had developed recurrent disease, but only three (4%) patients had recurrence locally. Disease-free, cancer-specific and overall survival rates at 2 years were 74%, 85% and 79%, respectively. Patients with low-stage/ln( ) cancers had significantly better survival than extravesical/ln( ) or any-stage/ln(+) patients, with stage being the most important predictor on multivariate analysis. CONCLUSION RRC can achieve adequately high LN yields with a low positive margin rate among unselected BUC patients. Early survival outcomes are similar to those reported in contemporary open series, with an encouragingly low incidence of local recurrence, however long-term follow-up and head-to-head comparison with the open approach are still needed. KEYWORDS bladder, carcinoma, lymph node, roboticassisted radical cystectomy INTRODUCTION Open radical cystectomy (ORC) with pelvic lymphadectomy (PLND) remains the goldstandard treatment for patients with muscleinvasive or recurrent high-grade nonmuscle-invasive bladder urothelial carcinoma (BUC). A durable cure is thus attainable in roughly 60% of patients, including half of those with extravesical disease and one-third of those with lymph node (LN) metastases [1]. Key predictors of survival include inherent features of the cancer, such as tumor stage, nodal status and lymphovascular invasion (LVI), in addition to variables specific to the cystectomy operation itself, namely surgical margin status, extent of lymphadenectomy and number of LN retrieved [1 8]. Yet, despite the oncological efficacy of ORC, perioperative morbidity presents a significant clinical challenge. Accordingly, there has been growing interest in minimally invasive alternatives to ORC. Relative to the gold-standard approach, robotic-assisted radical cystectomy (RRC) and laparoscopicassisted radical cystectomy (LRC) achieve significant reductions in operative blood loss, analgesic requirement and time to hospital discharge [9 13]. The potential advantages of RRC over LRC include enhanced dexterity and precision, superior three-dimensional visualization and a flatter learning curve [14]. In addition, we recently observed fewer postoperative complications after RRC relative to ORC in a nonrandomized head-to-head comparison at our institution [13] , doi: /j x x

2 EARLY OUTCOMES FOR BUC PATIENTS TREATED WITH RRC Total patients, n (%) 85 (100) Age, years Mean ± SD 72.1 ± 10.4 Median 73.5 Range Gender, n (%) Female 18 (21) Male 67 (79) Race, n (%) Caucasian 71 (84%) Other 14 (16%) BMI, kg/m 2 Mean ± SD 26.6 ± 4.0 Median 26.0 Range >25 kg/m 2, n (%) 52 (61) >30 kg/m 2, n (%) 18 (21) ASA class Mean ± SD 2.5 ± 0.5 Median 2 Range 2 4 3, n (%) 39 (46) Previous abdominal surgery, n (%) 29 (34) Previous pelvic surgery, n (%) 18 (21) Previous pelvic irradiation, n (%) 10 (12) Smoking history, 10 pack-year, n (%) 42 (49) Clinical stage, n (%) Ta, Tis 9 (11) T1 29 (34) T2 47 (55) Neoadjuvant chemotherapy, n (%) 17 (20) GC 9 (11) MVAC 6 (7) Other 2 (2) TABLE 1 Preoperative patient characteristics TABLE 2 Pathologic outcomes Total patients, n (%) 85 (100) Pathologic tumor stage, n (%) pt0 12 (14) Organ-confined 42 (49) pta 7 (8) Tis 11 (13) pt1 12 (14) pt2 12 (14) Extravesical 31 (36) pt3 25 (29) pt4 6 (7) Surgical margin positivity, n (%) 5 (6) Lymph nodes removed Mean ± SD 19.1 ± 10.0 Median 17 Range 0 56 Lymph node stage N0 72 (85) N1 3 (4) N2 10 (12) Carcinoma in situ, n (%) 40 (47) Lymphovascular invasion, n (%) 14 (16) Perineural invasion, n (%) 8 (9) Secondary histology, n (%) 12 (14)* Squamous cell carcinoma 10 (12) Glandular 4 (5) Sarcomatoid 1 (1) *Three patients had more than one secondary histology. TABLE 3 Clinical history and pathologic outcomes over time (according to case number) RRC case number Mean age, years Mean BMI However, despite the potential perioperative benefits, the oncological efficacy of the robotic approach to radical cystectomy remains largely unknown. Demonstration of similar oncological efficacy relative to ORC is critical to justify the continued use of RRC. While previous RRC case series suggest acceptable LN yields and negative margin rates, these studies are limited by small Previous pelvic surgery or radiotherapy, n (%) pt3/pt4, n (%) pn1/n2, n (%) (25.0) 9 (37.5) 5 (20.8) (29.2) 8 (33.3) 3 (12.5) (32.4) 14 (37.8) 5 (13.5) (28.2) 31 (36.5) 13 (15.3) BMI, body-mass index; RRC, robotic-assisted radical cystectomy. cohort sizes, a paucity of survival outcomes data, and significant selection bias for patients with low-stage disease and/or favorable surgical candidacy [9,15 18]. Oncological outcomes, particularly survival data, among unselected RRC patients are thus still needed. Here we describe oncological outcomes including early survival rates for a relatively large and unselected cohort of BUC patients undergoing RRC with PLND at our institution. Our goal was to more accurately define RRC oncological efficacy for comparison with contemporary ORC reports. PATIENTS AND METHODS PATIENTS From February, 2006 to September, 2008, 86 BUC patients underwent planned RRC and PLND with a single surgeon (D.S.S.) at our institution. One patient was excluded from analysis because of intra-operative conversion to ORC (before attempted cystectomy or PLND), after the initial laparoscopic surveillance demonstrated extensive metastasis of the ascending colon. Clinicopathologic and survival data were collected for all remaining 85 patients in a prospective fashion. During the same 2.7-year accrual period, 19 separate BUC patients underwent ORC with the same surgeon. All

3 KAUFFMAN ET AL. TABLE 4 Clinical, operative and pathologic characteristics of robotic-assisted radical cystectomy (RRC) patients with (a) positive surgical margins (n = 5), and (b) local recurrence (n = 3) (a) Case number Age, yrs BMI ASA class Previous pelvic surgery/xrt Neoadjuvant chemotherapy Surgery type Final pathology Recurrence T Stage LVI PNI N stage Local Distant No/No No NB T3 No Yes N1 N Y No/No Yes IC T3 No Yes N0 N N No/Yes No IC T3 Yes Yes N2 Y N No/No No IC T4 Yes No N0 N Y No/No No IC T3 Yes No N2 N N 13.8 (b) Case number Age, yrs BMI, kg/m 2 ASA class Previous pelvic surgery/radiotherapy Neoadjuvant chemotherapy Surgery type Final pathology T Stage LVI PNI Margin Recurrence Time, Site months No/Yes No IC T4 Yes No Positive 17 N0 L + D No/Yes Yes IC T4 No No Negative 14 N0 L No/No No NB T2 Yes No Radiotherapy 44 N1 L + D 6.6 ASA, American Society of Anesthesiologists; BMI, body-mass index; D, distant; IC, ileal conduit; L, local; LN, lymph node; LVI, lymphovascular invasion; NB, neobladder; PNI, perineural invasion. LN taken N stage patients were offered robotic and open approaches preoperatively, and the decision to undergo RRC was uninfluenced by oncological burden or factors related to surgical candidacy, including age, body-mass index (BMI), previous abdominal surgery/ radiation or other comorbidity/anesthesia risk. SURGICAL TECHNIQUE Variable Adjusted hazard ratio 95% CI P (a) T stage* 6.13 (2.05, 18.34) 1 LN density 4.91 (0.33, 73.36) LVI 1.96 (0.68, 5.67) 0.21 (b) pt stage* 5.25 (1.58, 17.51) 7 LN density 4.75 (0.46, 48.62) 0.19 LVI 2.04 (0.61, 6.81) TABLE 5 Multivariate analysis determination of independent predictors of (a) disease recurrence and (b) overall survival The RRC was performed using the Da Vinci Robotic System (Intuitive Surgical, Sunnyvale, CA, USA) as previously described [19]. Urinary diversion was performed extra-corporeally through a 5 7 cm incision extended from the peri-umbilical camera-port site after undocking the robotic system. For orthotopic neobladder reconstructions, the robot was redocked for the urethral neovesical anastomosis. The proximal limit of an extended PLND was defined as the aortic bifurcation. SURVEILLANCE Postoperative surveillance consisted of urine cytology, chest X-ray and abdominal/pelvic CT or MRI at approximately 6, 12, 18, 24 and 36 months after surgery. Patient symptoms prompted additional imaging. Recurrence was defined by positive urine cytology or radiographic lesion. Local recurrence included pelvic disease up to the level of the inferior mesenteric artery branch of the aorta, while *T3/T4 vs T0/Ta/Tis/T1/T2 (referent). Continuous variable. Using lymph node (LN) status (positive vs negative) instead of LN density in the models result in lower hazard ratios (near 1.0). Yes vs no (referent). distant recurrence involved any other site. Cause of death was determined by review of medical records, including death certificates and autopsy reports. SURVIVAL AND STATISTICAL ANALYSES Disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) were estimated by Kaplan Meier survival analysis and the log-rank test was used to compare DFS, CSS and OS by tumor stage (extravesical vs pt0/bladder confined) and LN status (positive vs negative). Multivariate Cox proportional hazards regression analysis was used to examine the independent effect of tumor stage (extravesical vs pt0/bladder confined), LN density (continuous variable), and LVI (yes/no) on DFS, CSS and OS (i.e. separate models for each survival endpoint). Multivariate Cox regression models were also repeated using LN status (positive/negative) in place of LN density. The associations between clinicopathologic/operative features and surgical margin status (positive vs negative) were examined by Fisher s exact test. All P values were two-sided with statistical significance evaluated at the 0.05 α level. All analyses were performed in SAS Version 9.2 (SAS Institute Inc., Cary, NC, USA) and Stata Version 10.0 (StataCorp, College Station, TX, USA). RESULTS Clinical characteristics of 85 patients undergoing RRC are shown in Table

4 EARLY OUTCOMES FOR BUC PATIENTS TREATED WITH RRC FIG. 1. Kaplan Meier survival after robotic-assisted radical cystectomy (RRC). (a) Diseasefree survival. (b) Cancer-specific survival. (c) Overall survival. Patients were relatively old, with one in four being >80 years old. The median cohort age was 73.5 years. The majority of patients were either overweight or obese (61%), and three patients (4%) had morbid obesity. Comorbid illnesses were common, with around half of a b Disease-free survival c Cancer-specific survival Overall survival all patients (46%) having an American Society of Anesthesiologists (ASA) class 3. Many patients (28%) had undergone prior pelvic (urologic, gynecologic or sigmoidorectal) surgery or irradiation, and one in five patients had received neoadjuvant chemotherapy. Forty percent of patients had received at least one of these treatments (pelvic surgery, radiation or chemotherapy). Intraoperatively, a majority of patients (71%) received a cutaneous urinary diversion, and the remainder (29%) underwent orthotopic reconstruction (neobladder). The median operative time for all surgeries was 6.0 h and the median blood loss was 400 ml. An extended PLND was performed in all but two patients whose dissections were limited owing to severe retroperitoneal fibrosis. Pathologic outcomes are summarized in Table 2. Thirty-one patients (36.5%) had extravesical primary tumors, 42 patients (49.4%) had bladder-confined cancers and 12 patients had no residual disease. LVI and perineural invasion (PNI) were detected in 16% and 9% of patients, respectively. A mean of 19.1 LN per patient was counted, and 13 patients (15%) had LN metastasis, most commonly involving multiple nodes. Clinicopathologic features of the cohort stayed consistent over time, (Table 3) and there were no differences between the 85 RRC patients and the 19 patients undergoing ORC during the same accrual period (data not shown). Surgical margins were positive in five patients (Table 4a). Three of these patients were >80 years old, and all five patients had extravesical tumors with aggressive histology, namely, LVI and/or PNI. Most patients with positive margins also had LN-positive disease. On univariate analysis, margin positivity was significantly associated with extravesical primary tumors (P < 0.01), LN positivity (P = 0.024), LVI (P = 0.032) and PNI (P < 0.01), and there was a non-significant trend towards association with age >80 years (P = 0.09). No association was observed with gender, race, obesity, previous abdominal or pelvic surgery, pelvic radiation, neoadjuvant chemotherapy or muscle-invasive clinical stage (P > 0.30 for each). PATIENT SURVIVAL Ten patients received adjuvant chemotherapy or radiation. At a mean follow-up of 18 months, 60 (71%) patients were alive without evidence of cancer, 7 (8%) were alive with recurrent disease, 13 (15%) were dead of recurrent cancer, and 5 (6%) were dead from other causes. Among the 20 (24%) patients with recurrence, only three occurred locally

5 KAUFFMAN ET AL. Two of these local recurrences occurred in patients with pt4 disease who had a preoperative history of pelvic irradiation (Table 4b). In patients with positive surgical margins, three of five recurred distantly at 4, 8 and 12 months postoperatively, while two remain alive without disease after 14 months and 32 months, with neither receiving any adjuvant therapy (Table 4b). Kaplan Meier survival for all patients is depicted in Fig. 1. At 1 year and 2 years postoperatively, the DFS rate for the cohort was 79.2% (95% CI = 68.3%, 86.7%) and 73.1% (95% CI = 60.6%, 82.2%), respectively, the CSS rate was 88.4% (95% CI = 78.9%, 93.8%) and 84.6% (95% CI = 73.5%, 91.3%), respectively, and the OS rate was 82.6% (95% CI = 72.4%, 89.3%) and 79.0% (95% CI = 67.7%, 86.7%), respectively. Stratification of survival outcomes by tumor stage (Fig. 2) supported significantly worse DFS, CSS and OS for patients with extravesical disease compared with patients with bladderconfined/pt0 disease (P < 01 for each). Similarly, stratification of survival outcomes by nodal status supported LN positivity association with a significant reduction in DFS and OS (P < 0.05 for each) and trending towards association with worse CSS (P = 0.13) (Fig. 3). When stratifying by both tumor stage and LN positivity simultaneously (Fig. 4), we observed significantly better DFS, CSS and OS for low-stage/ln( ) patients relative to either extravesical/ln( ) or any-stage/ln(+) patients (P < 5 for each). On multivariate analysis adjusting for LVI and LN positivity/density, tumor stage was the strongest predictor of patient survival (Table 5). DISCUSSION a b All others Disease-free survival P < 01 by log-rank test T3/T c All others T3/T Cancer-specific survival P < 01 Overall survival P < 01 All others T3/T FIG. 2. Kaplan Meier survival after robotic-assisted radical cystectomy (RRC) stratified by pathologic stage. (a) Disease-free survival. (b) Cancer-specific survival. (c) Overall survival. ORC is the gold-standard treatment for patients with muscle-invasive or recurrent high-grade non-muscle-invasive BUC. In addition to features inherent to the cancer, patient survival depends on characteristics of the cystectomy itself, such as margin status and extent of LN dissection [3,4,6]. In 2004, Herr et al. [20] proposed standards for these operative variables based on the oncological outcomes of 16 experienced ORC surgeons. Benchmark recommendations included a positive surgical margin rate of <10%, a standard or extended PLND rate of >75 80%, and the removal of >10 14 nodes. While intended for comparisons among different ORC surgeons/institutions, these standards All others also provide minimal guidelines for alternative approaches to radical cystectomy. Despite the growing popularity of RRC, it is unknown whether the robotic approach matches the oncological efficacy of ORC, particularly in unselected patients. Initial RRC studies reported no positive margins, but were limited by pilot-size cohorts (n = 13, n = 17) with predominantly early stage disease (LN positivity 5.9%) or favorable surgical candidacy (no pelvic irradiation or significant comorbidity) [9,15]. More recently, somewhat T3/T4 larger studies (n = 23, n = 50) have also reported 0% positive margin rates, in addition to adequate LN yields of >15, while providing initial survival data for RRC, including >90% disease-free survival rates at over 1 year after surgery [16,17]. However, a potentially confounding factor was the exclusion or otherwise under-representation of patients with multiple previous abdominal surgeries, pelvic radiation, advanced age, morbid obesity and/or other significant anesthetic risk. Furthermore, only around one in five BUC patients had pt3/pt4 disease roughly half

6 EARLY OUTCOMES FOR BUC PATIENTS TREATED WITH RRC FIG. 3. Kaplan Meier survival after robotic-assisted radical cystectomy (RRC) stratified by lymph node status. (a) Diseasefree survival. (b) Cancer-specific survival. (c) Overall survival. the incidence of contemporary ORC series [19 23]. Here we report oncological outcomes including 2-year survival data in one of the largest RRC series to date. In contrast to previous RRC studies we exercised no selection bias for patients with less oncological burden, as supported by our 36.5% incidence of pt3/pt4 disease despite frequent neoadjuvant chemotherapy, nearly a b LN Disease-free survival P = c LN P = 0.13 Cancer-specific survival P = 0.03 Overall survival LN LN double that of prior RRC reports [16,17], and within the 30 45% range of contemporary ORC studies [3,8,21 24]. Similarly, no selection bias was exercised with regard to surgical candidacy, with rates of obesity and ASA class 3 matching those of contemporary ORC series [24]. Furthermore, advanced patient age, a reported predictor of worse oncological outcomes after cystectomy [20], was common in our cohort, with 25% of patients being >80 years old and the mean/ median cohort age being among the highest in contemporary cystectomy literature nearly 10 years higher than in previous RRC reports [16,17]. Finally, 40% of our patients had a history of previous pelvic treatments (surgery/radiation/chemotherapy) shown to predispose to worse LN yields (well above the 15% average reported for high-volume ORC institutions), which further supports a lack of selection bias [20]. Among these unselected RRC patients, our findings indicate acceptable early oncological outcomes. Our positive margin rates meet the benchmark standards proposed by Herr et al. [20], at 6% overall (<10% recommended), 14% with extravesical disease (<15% recommended) and 6% among patients with previous pelvic treatments (<20% recommended). All positive margins occurred in the setting of extravesical disease with aggressive histology (LVI and/or PNI), and most often in the elderly (>80 years). The increased risk among elderly is also reported among ORC patients and may reflect the need to weigh oncological outcome against prolonged anesthesia among these higherrisk patients. For lymphadenectomy, despite the high incidence of previous pelvic treatments in our cohort, a 98% rate of extended PLND was achieved, meeting the proposed benchmark of >75 80%, and our mean LN retrieval of 19.1 similarly meets the recommended standard of >10 14, supporting the feasibility of a thorough PLND using a robotic approach [20]. This study is among the first reports of survival outcomes after RRC. While the outcomes remain early, demonstration of early oncological adequacy relative to contemporary ORC reports is critical to justify the continued use of the robotic approach. In that regard, our 2-year DFS, CSS and OS rates (73%, 85% and 79%, respectively) are virtually identical to the 2-year survival curve data of several large contemporary ORC series, providing strong support for the early oncological efficacy of RRC [1,7,23]. Stratification by tumor stage and LN positivity revealed significantly better survival for patients with organ-confined or LN-negative disease, demonstrating preservation of basic oncological tenants for radical cystectomy [1]. Despite our brief follow-up interval, the 2- year survival data provided here allows for adequate and clinically meaningful interpretation because of the relatively short time (7 18 months) to initial BUC recurrence

7 KAUFFMAN ET AL. that is typically observed following radical cystectomy [1,25,26]. While distant recurrence may reflect micrometastatic disease at the time of surgery, local recurrence invariably signifies inadequate surgical resection. In this respect, it is encouraging that only three patients (3.5%) recurred locally in this series, two of them following resection of pt4 disease in a previously irradiated pelvis. This incidence compares favorably with the 4 41% range reported among large ORC series, including a 15% average across >100 ORC institutions [1,3,7,25 27]. The follow-up interval of the current study, while relatively short, meets or surpasses the median time to local recurrence according to most cystectomy series, thus we anticipate the rate of local recurrence to remain acceptably low with further follow-up [7,25,26]. The present study had several limitations. While among the largest RRC series, our cohort remains relatively small compared with contemporary ORC series. Furthermore, longer follow-up data are needed before definitive conclusions on RRC oncological efficacy can be made. Finally, these findings reflect the experience of a single high-volume robotic surgeon and may have limited applicability to everyday clinical practice. CONCLUSION This study describes early oncological outcomes for RRC patients accrued without selection bias with regard to oncological burden or surgical candidacy. While it is difficult to definitively demonstrate the absence of selection bias in an uncontrolled setting, our lack of bias seems to be well supported by the frequent occurrence of advanced pathologic disease and a high incidence of certain clinical traits linked to poor oncological outcomes, such as advanced age and previous pelvic radiation/surgery. Among these RRC patients, oncological outcomes with respect to surgical margins, extent of LN dissection and LN retrieval all meet published benchmark recommendations for radical cystectomy. Furthermore, the 2- year survival outcomes match those of contemporary ORC series, with an encouragingly low rate of local recurrence. That said, more definitive long-term data are still needed, and ultimately head-to-head randomized comparisons will provide the most useful data. In the interim, this study a All others/ln T3/T4/LN b supports the continued use of RRC as an investigational alternative to ORC in the treatment of BUC patients. ACKNOWLEDGEMENTS Disease-free survival Statistical support was partially supported by the following grant: Clinical Translational Science Center (CTSC) (UL1-RR024996). T0/organ-confined, LN vs. : P < 01 T0/organ-confined, LN vs. T3/T4, LN : P < 01 vs. T3/T4, LN : P = 0.90 T0/organ-confined, LN vs. : P = 7 T0/organ-confined, LN vs. T3/T4, LN : P < 01 vs. T3/T4, LN : P = 0.54 All others/ln T3/T4/LN c All others/ln T3/T4/LN Cancer-specific survival Overall survival T0/organ-confined, LN vs. : P = 2 T0/organ-confined, LN vs. T3/T4, LN : P = 02 vs. T3/T4, LN : P = T0/organ-confined, LN T3/T4, LN CONFLICT OF INTEREST None declared. REFERENCES FIG. 4. Kaplan-Meier survival after robotic-assisted radical cystectomy (RRC) stratified by both pathologic stage and lymph node status. (a) Disease-free survival. (b) Cancer-specific survival. (c) Overall survival. 1 Stein JP, Lieskovsky G, Cote R et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results

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Kauffman, MD, Department of Urology, New York Presbyterian Hospital Weill Cornell Medical Center, 525 East 68th Street, Starr 900, New York, NY 10065, USA. erickauffman14@gmail.com Abbreviations: BMI, body-mass index; BUC, bladder urothelial carcinoma; CSS, cancerspecific survival; DFS, disease-free survival; LVI, lymphovascular invasion; ORC, open radical cystectomy; OS, overall survival; PLND, pelvic lymphadectomy; PNI, perineural invasion; RRC, robotic-assisted radical cystectomy