Raj S. Pruthi

Prospective Randomized Controlled Trial of Robotic versus Open Radical Cystectomy for Bladder Cancer: Perioperative and Pathologic Results

BACKGROUND In recent years, surgeons have begun to report case series of minimally invasive approaches to radical cystectomy, including robotic-assisted techniques demonstrating the surgical feasibility of this procedure with the potential of lower blood loss and more rapid return of bowel function and hospital discharge. Despite these experiences and observations, at this point high levels of clinical evidence with regard to the benefits of robotic cystectomy are absent, and the current experiences represent case series with limited comparisons to historical controls at best. OBJECTIVE We report our results on a prospective randomized trial of open versus robotic-assisted laparoscopic radical cystectomy with regard to perioperative outcomes, complications, and short-term narcotic usage. DESIGN, SETTING, AND PARTICIPANTS A prospective randomized single-center noninferiority study comparing open versus robotic approaches to cystectomy in patients who are candidates for radical cystectomy for urothelial carcinoma of the bladder. Of the 41 patients who underwent surgery, 21 were randomized to the robotic approach and 20 to the open technique. INTERVENTION Radical cystectomy, bilateral pelvic lymphadenectomy, and urinary diversion by either an open approach or by a robotic-assisted laparoscopic technique. MEASUREMENTS The primary end point was lymph node (LN) yield with a noninferiority margin of four LNs. Secondary end points included demographic characteristics, perioperative outcomes, pathologic results, and short-term narcotic use. RESULTS AND LIMITATIONS On univariate analysis, no significant differences were found between the two groups with regard to age, sex, body mass index, American Society of Anesthesiologists classification, anticoagulation regimen of aspirin, clinical stage, or diversion type. Significant differences were noted in operating room time, estimated blood loss, time to flatus, time to bowel movement, and use of inpatient morphine sulfate equivalents. There was no significant difference in regard to overall complication rate or hospital stay. On surgical pathology, in the robotic group 14 patients had pT2 disease or higher; 3 patients had pT3/T4 disease; and 4 patients had node-positive disease. In the open group, eight patients had pT2 disease or higher; five patients had pT3/T4 disease; and seven patients had node-positive disease. The mean number of LNs removed was 19 in the robotic group versus18 in the open group. Potential study limitations include the limited clinical and oncologic follow-up and the relatively small and single-institution nature of the study. CONCLUSIONS We present the results of a prospective randomized controlled noninferiority study with a primary end point of LN yield, demonstrating the robotic approach to be noninferior to the open approach. The robotic approach also compares favorably with the open approach in several perioperative parameters.

Molecular Stratification of Clear Cell Renal Cell Carcinoma by Consensus Clustering Reveals Distinct Subtypes and Survival Patterns

Clear cell renal cell carcinoma (ccRCC) is the predominant RCC subtype, but even within this classification, the natural history is heterogeneous and difficult to predict. A sophisticated understanding of the molecular features most discriminatory for the underlying tumor heterogeneity should be predicated on identifiable and biologically meaningful patterns of gene expression. Gene expression microarray data were analyzed using software that implements iterative unsupervised consensus clustering algorithms to identify the optimal molecular subclasses, without clinical or other classifying information. ConsensusCluster analysis identified two distinct subtypes of ccRCC within the training set, designated clear cell type A (ccA) and B (ccB). Based on the core tumors, or most well-defined arrays, in each subtype, logical analysis of data (LAD) defined a small, highly predictive gene set that could then be used to classify additional tumors individually. The subclasses were corroborated in a validation data set of 177 tumors and analyzed for clinical outcome. Based on individual tumor assignment, tumors designated ccA have markedly improved disease-specific survival compared to ccB (median survival of 8.6 vs 2.0 years, P = 0.002). Analyzed by both univariate and multivariate analysis, the classification schema was independently associated with survival. Using patterns of gene expression based on a defined gene set, ccRCC was classified into two robust subclasses based on inherent molecular features that ultimately correspond to marked differences in clinical outcome. This classification schema thus provides a molecular stratification applicable to individual tumors that has implications to influence treatment decisions, define biological mechanisms involved in ccRCC tumor progression, and direct future drug discovery.

Robotic Radical Cystectomy for Bladder Cancer: Surgical and Pathological Outcomes in 100 Consecutive Cases

PURPOSE Radical cystectomy remains the most effective treatment for patients with localized, invasive bladder cancer and recurrent noninvasive disease. Recently some surgeons have begun to describe outcomes associated with less invasive surgical approaches to this disease such as laparoscopic or robotic assisted techniques. We report our maturing experience with 100 consecutive cases of robotic assisted laparoscopic radical cystectomy with regard to perioperative results, pathological outcomes and surgical complications. MATERIALS AND METHODS A total of 100 consecutive patients (73 male and 27 female) underwent robotic radical cystectomy and urinary diversion at our institution from January 2006 to January 2009 for clinically localized bladder cancer. Outcome measures evaluated included operative variables, hospital recovery, pathological outcomes and complication rate. RESULTS Mean age of this cohort was 65.5 years (range 33 to 86). Of the patients 61 underwent ileal conduit diversion, 38 received a neobladder and 1 had no urinary diversion (renal failure). Mean operating room time for all patients was 4.6 hours (median 4.3) and mean surgical blood loss was 271 ml (median 250). On surgical pathology 40% of the cases were pT1 or less disease, 27% were pT2, 13% were pT3/T4 disease and 20% were node positive. Mean number of lymph nodes removed was 19 (range 8 to 40). In no case was there a positive surgical margin. Mean days to flatus were 2.1, bowel movement 2.8 and discharge home 4.9. There were 41 postoperative complications in 36 patients with 8% having a major complication (Clavien grade 3 or higher) and 11% being readmitted within 30 days of surgery. At a mean followup of 21 months 15 patients had disease recurrence and 6 died of disease. CONCLUSIONS We report a relatively large and maturing experience with robotic radical cystectomy for the treatment of bladder cancer providing acceptable surgical and pathological outcomes. These results support continued efforts to refine the surgical management of high risk bladder cancer.

Neoadjuvant Clinical Trial With Sorafenib for Patients With Stage II or Higher Renal Cell Carcinoma

PURPOSE The multitargeted tyrosine kinase inhibitor sorafenib is used for the treatment of advanced-stage renal cell carcinoma. However, the safety and efficacy of this agent have yet to be evaluated in the preoperative period, where there may be potential advantages including tumor downstaging. This prospective trial evaluates the safety and feasibility of sorafenib in the preoperative setting. PATIENTS AND METHODS Thirty patients with clinical stage II or higher renal masses, selected based on their candidacy for nephrectomy, underwent preoperative treatment with sorafenib. Toxicities, surgical complications, and tumor responses were monitored. RESULTS Of the thirty patients enrolled, 17 patients had localized disease and 13 had metastatic disease. After a course of sorafenib therapy (median duration, 33 days), a decrease in primary tumor size (median, 9.6%) and radiographic evidence of loss of intratumoral enhancement, quantified using a methodology similar to Choi criteria (median, 13%), was also observed. According to Response Evaluation Criteria in Solid Tumors, of the 28 patients evaluable for response, two patients had a partial response and 26 had stable disease, with no patients progressing on therapy. Toxicities from sorafenib were similar to that expected with this class of medication. All patients were able to proceed with nephrectomy and no surgical complications related to sorafenib administration were observed. CONCLUSION The administration of preoperative sorafenib therapy can impact the size and density of the primary tumor and appears safe and feasible. Further studies are required to determine if preoperative systemic therapy improves outcomes in patients undergoing nephrectomy for renal cell carcinoma.

The Learning Curve of Robot-Assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium

BACKGROUND Robot-assisted radical cystectomy (RARC) has evolved as a minimally invasive alternative to open radical cystectomy for patients with invasive bladder cancer. OBJECTIVE We sought to define the learning curve for RARC by evaluating results from a multicenter, contemporary, consecutive series of patients who underwent this procedure. DESIGN, SETTING, AND PARTICIPANTS Utilizing the International Robotic Cystectomy Consortium database, a prospectively maintained and institutional review board-approved database, we identified 496 patients who underwent RARC by 21 surgeons at 14 institutions from 2003 to 2009. MEASUREMENTS Cut-off points for operative time, lymph node yield (LNY), estimated blood loss (EBL), and margin positivity were identified. Using specifically designed statistical mixed models, we were able to inversely predict the number of patients required for an institution to reach the predetermined cut-off points. RESULTS AND LIMITATIONS Mean operative time was 386 min, mean EBL was 408 ml, and mean LNY was 18. Overall, 34 of 482 patients (7%) had a positive surgical margin (PSM). Using statistical models, it was estimated that 21 patients were required for operative time to reach 6.5h and 8, 20, and 30 patients were required to reach an LNY of 12, 16, and 20, respectively. For all patients, PSM rates of <5% were achieved after 30 patients. For patients with pathologic stage higher than T2, PSM rates of <15% were achieved after 24 patients. CONCLUSIONS RARC is a challenging procedure but is a technique that is reproducible throughout multiple centers. This report helps to define the learning curve for RARC and demonstrates an acceptable level of proficiency by the 30th case for proxy measures of RARC quality.

ICUD-EAU international consultation on bladder cancer 2012: Non-muscle-invasive urothelial carcinoma of the bladder

CONTEXT Our aim was to present a summary of the Second International Consultation on Bladder Cancer recommendations on the diagnosis and treatment options for non-muscle-invasive urothelial cancer of the bladder (NMIBC) using an evidence-based approach. OBJECTIVE To critically review the recent data on the management of NMIBC to arrive at a general consensus. EVIDENCE ACQUISITION A detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS The major findings are presented in an evidence-based fashion. We analyzed large retrospective and prospective studies. CONCLUSIONS Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy.

Analysis of intracorporeal compared with extracorporeal urinary diversion after robot-assisted radical cystectomy: Results from the international robotic cystectomy consortium

BACKGROUND Intracorporeal urinary diversion (ICUD) has the potential benefits of a smaller incision, reduced pain, decreased bowel exposure, and reduced risk of fluid imbalance. OBJECTIVE To compare the perioperative outcomes of patients undergoing extracorporeal urinary diversion (ECUD) and ICUD following robot-assisted radical cystectomy (RARC). DESIGN, SETTING, AND PARTICIPANTS We reviewed the database of the International Robotic Cystectomy Consortium (IRCC) (18 international centers), with 935 patients who had undergone RARC and pelvic lymph node dissection (PLND) between 2003 and 2011. INTERVENTION All patients within the IRCC underwent RARC and PLND as indicated. The urinary diversion was performed either intracorporeally or extracorporeally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Demographic data, perioperative outcomes, and complications in patients undergoing ICUD or ECUD were compared. All patients had at least a 90-d follow-up. The Fisher exact test was used to summarize categorical variables and the Wilcoxon rank sum test or Kruskal-Wallis test for continuous variables. RESULTS AND LIMITATIONS Of 935 patients who had RARC and PLND, 167 patients underwent ICUD (ileal conduit: 106; neobladder: 61), and 768 patients had an ECUD (ileal conduit: 570; neobladder: 198). Postoperative complications data were available for 817 patients, with a minimum follow-up of 90 d. There was no difference in age, gender, body mass index, American Society of Anesthesiologists grade, or rate of prior abdominal surgery between the groups. The operative time was equivalent (414 min), with the median hospital stay being marginally longer for the ICUD group (9 d vs 8 d, p=0.086). No difference in the reoperation rates at 30 d was noted between the groups. The 90-d complication rate was not significant between the two groups, but a trend favoring ICUD over ECUD was noted (41% vs 49%, p=0.05). Gastrointestinal complications were significantly lower in the ICUD group (p ≤ 0.001). Patients with ICUD were at a lower risk of experiencing a postoperative complication at 90 d (32%) (odds ratio: 0.68; 95% confidence interval, 0.50-0.94; p=0.02). Being a retrospective study was the main limitation. CONCLUSIONS Robot-assisted ICUD can be accomplished safely, with comparable outcomes to open urinary diversion. In this cohort, patients undergoing ICUD had a relatively lower risk of complications.

The Role of Laparoscopic and Robotic Cystectomy in the Management of Muscle-Invasive Bladder Cancer With Special Emphasis on Cancer Control and Complications

CONTEXT Minimally invasive radical cystectomy (MIRC) techniques for the treatment of muscle-invasive bladder cancer (BCa) are being increasingly applied. MIRC offers the potential benefits of a minimally invasive approach in terms of reduced blood loss and analgesic requirements whilst striving to provide similar oncologic efficacy to open radical cystectomy (ORC). Whether quicker recovery, shorter hospital stay, and a reduction in complications are routinely achieved with MIRC remains to be proved in prospective comparisons. OBJECTIVE To explore both laparoscopic radical cystectomy (LRC) and robot-assisted radical cystectomy (RRC), focusing specifically on the oncologic parameters and comorbidity of the procedures. Reported complications from major centres are identified and categorised via the Clavien system. Positive margins rates, local recurrence, and both cancer-specific survival (CSS) and overall survival rates are assessed. EVIDENCE ACQUISITION A comprehensive electronic literature search was conducted in November 2010 using the Medline database to identify publications relating to laparoscopic, robotic, or minimally invasive radical cystectomy. EVIDENCE SYNTHESIS There are encouraging short- to medium-term results for both LRC and RRC in terms of postoperative morbidity and oncologic outcomes. It seems possible in experienced hands to perform a satisfactory minimally invasive lymphadenectomy regarding lymph node counts and levels of dissection. Positive soft-tissue margins are similar to large open series for T2/T3 disease but inferior for bulky T4 disease. Local recurrence rates and CSS rates seem equivalent to ORC at up to 3 yr of follow-up; however, mature outcome data still need to be presented before definitive comparisons can be made. CONCLUSIONS Robotic and laparoscopic cystectomy has a growing role in the management of muscle-invasive BCa. Long-term oncologic results are awaited, and there are concerns over the ability of MIRC to treat bulky and locally advanced disease, making careful patient selection vital. Forthcoming randomised trials in this area will more fully address these issues.

Robotic-Assisted Laparoscopic Intracorporeal Urinary Diversion

BACKGROUND Recent small case series have now been reported for robotic-assisted laparoscopic radical cystectomy (RALRC). In most of these series, the urinary diversion has been performed in an extracorporeal fashion. There have been few case reports of an intracorporeal diversion and little description of the technique of such a procedure. OBJECTIVE In this paper, we report our initial experience with robotic-assisted laparoscopic intracorporeal urinary diversion, describing stepwise the surgical procedure itself and evaluating perioperative and pathologic outcomes of this novel procedure. DESIGN, SETTING, AND PARTICIPANTS We studied a single-institution case series of patients undergoing robotic-assisted cystectomy and intracorporeal urinary diversion for clinically localized urothelial carcinoma of the bladder (n=10) or for a noncompliant dysfunctional bladder refractory to more conservative management (n=2). Historical comparisons are also made to a consecutive case series of 20 patients undergoing robotic radical cystectomy and extracorporeal urinary diversion. SURGICAL PROCEDURE RALRC and intracorporeal urinary diversion, including ileal conduit (n=9) and orthotopic ileal neobladder (n=3). MEASUREMENTS The stepwise operative procedure is described in detail. Outcome measures evaluated in this series included operative variables, hospital recovery, and complication rate. Comparisons were made to a contemporaneous series of 20 patients who underwent a robotic cystectomy with extracorporeal diversion during this time period (from an experience of >100 robotic cystectomy patients since 2005). RESULTS AND LIMITATIONS Twelve patients (mean age: 60.9 yr) underwent an intracorporeal diversion. Mean operating-room time of all patients was 5.3h, and mean surgical blood loss was 221ml. Mean time to flatus, bowel movement, and hospital discharge was 2.2 d, 3.2 d, and 4.5 d, respectively. Eleven of the 12 patients were discharged on or before postoperative day 5. There were six postoperative complications in five patients (42%), with one complication being Clavien grade 3 or higher. The major limitations of the study are the small sample size and the nonrandomized nature of the compared treatment groups (intracorporeal vs extracorporeal), which limits the ability to directly compare the techniques at a high level of scientific confidence. CONCLUSIONS Our initial experience with robotic-assisted laparoscopic intracorporeal diversion appears to be favorable with acceptable operative and short-term clinical outcomes.

Reducing time to oral diet and hospital discharge in patients undergoing radical cystectomy using a perioperative care plan

OBJECTIVES To outline our current perioperative treatment of patients undergoing radical cystectomy and urinary diversion, which uses advancements in perioperative care to allow for early institution of an oral diet and early hospital discharge, and thereby overall improvement in patient recovery and outcome after this procedure. METHODS Forty consecutive patients underwent radical cystectomy and urinary diversion with curative intent from 2001 to 2002. A care plan was followed for all patients and included improvements in preoperative, intraoperative, and postoperative care. The preoperative care included limited outpatient bowel preparation with sodium phosphate solution and patient education. Operative modifications included reduced incision length, initial preperitoneal dissection, and the use of internal surgical stapling devices. The postoperative care included the use of prokinetic agents, early nasogastric tube removal, the use of non-narcotic analgesics, and early institution of an oral diet. The outcomes with regard to time to institution of an oral diet, tolerance of a regular diet, and hospital discharge were assessed. RESULTS The mean surgical time was 3.9 hours, and the mean estimated blood loss was 573 mL. The mean time to the institution of a clear liquid diet was 2.0 days and to a regular diet was 4.2 days. The mean time to hospital discharge was 5.1 days. No statistically significant differences were found in the time to resumption of a regular diet or to discharge between patients undergoing ileal conduits versus orthotopic ileal neobladders. Only 1 patient had any gastrointestinal dysfunction (ileus), and this patient was discharged on postoperative 7. No patient had any delayed complications involving problems with diet intolerance or other gastrointestinal dysfunction. The results of the current series were compared with those of historical controls. CONCLUSIONS Advancements in preoperative, intraoperative, and postoperative management have together been successfully used in our patient population to reduce morbidity and improve recovery with regard to the early institution of an oral diet and early hospital discharge.