Vitaly Margulis

Outcomes of radical nephroureterectomy: A series from the Upper Tract Urothelial Carcinoma Collaboration

The literature on upper tract urothelial carcinoma (UTUC) has been limited to small, single center studies. A large series of patients treated with radical nephroureterectomy for UTUC were studied, and variables associated with poor prognosis were identified.

Lymphovascular Invasion Predicts Clinical Outcomes in Patients With Node-Negative Upper Tract Urothelial Carcinoma

PURPOSEnTo assess the association of lymphovascular invasion (LVI) with cancer recurrence and survival in a large international series of patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC).nnnPATIENTS AND METHODSnData were collected on 1,453 patients treated with RNU at 13 academic centers and combined into a relational database. Pathologic slides were rereviewed by genitourinary pathologists according to strict criteria. LVI was defined as presence of tumor cells within an endothelium-lined space.nnnRESULTSnLVI was observed in 349 patients (24%). Proportion of LVI increased with advancing tumor stage, high tumor grade, presence of tumor necrosis, sessile tumor architecture, and presence of lymph node metastasis (all P < .001). LVI was an independent predictor of disease recurrence and survival (P < .001 for both). Addition of LVI to the base model (comprising pathologic stage, grade, and lymph node status) marginally improved its predictive accuracy for both disease recurrence and survival (1.1%, P = .03; and 1.7%, P < .001, respectively). In patients with negative lymph nodes and those in whom a lymphadenectomy was not performed (n = 1,313), addition of LVI to the base model improved the predictive accuracy of the base model for both disease recurrence and survival by 3% (P < .001 for both). In contrast, LVI was not associated with disease recurrence or survival in node-positive patients (n = 140).nnnCONCLUSIONnLVI was an independent predictor of clinical outcomes in nonmetastatic patients who underwent RNU for UTUC. Assessment of LVI may help identify patients who could benefit from multimodal therapy after RNU. After confirmation, LVI should be included in staging of UTUC.

Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration.

PURPOSEnThere is relatively little literature on adjuvant chemotherapy after radical nephroureterectomy in patients with upper tract urothelial carcinoma. We determined the incidence of adjuvant chemotherapy in high risk patients and the ensuing effect on overall and cancer specific survival.nnnMATERIALS AND METHODSnUsing an international collaborative database we identified 1,390 patients who underwent nephroureterectomy for nonmetastatic upper tract urothelial carcinoma between 1992 and 2006. Of these cases 542 (39%) were classified as high risk (pT3N0, pT4N0 and/or lymph node positive). These patients were divided into 2 groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine overall and cancer specific survival in the cohorts.nnnRESULTSnOf high risk patients 121 (22%) received adjuvant chemotherapy. Adjuvant chemotherapy was more commonly administered in the context of increased tumor grade and stage (p <0.001). Median survival in the entire cohort was 24 months (range 0 to 231). There was no significant difference in overall or cancer specific survival between patients who did and did not receive adjuvant chemotherapy. However, age, performance status, and tumor grade and stage were significant predictors of overall and cancer specific survival.nnnCONCLUSIONSnAdjuvant chemotherapy is infrequently used to treat high risk upper tract urothelial carcinoma after nephroureterectomy. Despite this finding it appears that adjuvant chemotherapy confers minimal impact on overall or cancer specific survival in this group.

Comparison of Oncologic Outcomes for Open and Laparoscopic Nephroureterectomy: A Multi-Institutional Analysis of 1249 Cases

BACKGROUNDnData regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce.nnnOBJECTIVEnWe compared recurrence and cause-specific mortality rates of ONU and LNU.nnnDESIGN, SETTING, AND PARTICIPANTSnThirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC).nnnMEASUREMENTSnUnivariable and multivariable survival models tested the effect of procedure type (ONU [n=979] vs LNU [n=270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, ureteral cuff management, previous urothelial bladder cancer, and previous endoscopic treatment.nnnRESULTS AND LIMITATIONSnMedian follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p<0.001) and less lymphovascular invasion (14.8% vs 21.3%, p=0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p=0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p<0.001] and 2.0 [p=0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p=0.1 for both).nnnCONCLUSIONSnShort-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Long-term follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC.

Surgical Morbidity Associated With Administration of Targeted Molecular Therapies Before Cytoreductive Nephrectomy or Resection of Locally Recurrent Renal Cell Carcinoma

PURPOSEnTargeted molecular therapies such as bevacizumab, sunitinib and sorafenib before surgical resection hold promise as rational treatment paradigms for patients with metastatic or locally recurrent renal cell carcinoma. To analyze the safety of this approach we evaluated surgical parameters and perioperative complications in patients treated with targeted molecular therapies before cytoreductive nephrectomy or resection of retroperitoneal renal cell carcinoma recurrence, and compared them to a matched patient cohort who underwent up-front surgical resection.nnnMATERIALS AND METHODSnWe evaluated surgical parameters and perioperative complications in 44 patients treated with targeted molecular therapies before cytoreductive nephrectomy or resection of local renal cell carcinoma recurrence, and in a matched cohort of 58 patients who underwent up-front surgery.nnnRESULTSnCohorts of patients treated with preoperative targeted molecular therapy and initial surgical resection were matched in terms of clinical characteristics, burden of metastatic disease and number of adverse prognostic factors. A total of 39 complications occurred in 17 (39%) patients treated with preoperative targeted molecular therapy and in 16 (28%) who underwent up-front resection (p = 0.287). There were no statistically significant differences in surgical parameters, incidence of perioperative mortality, re-exploration, readmission, thromboembolic, cardiovascular, pulmonary, gastrointestinal, infectious or incision related complications between patients treated with preoperative targeted molecular therapy and those who underwent up-front surgery. Duration, type and interval from targeted molecular therapy to surgical intervention were not associated with the risk of perioperative morbidity.nnnCONCLUSIONSnPreoperative administration of targeted molecular therapies is safe, and does not increase surgical morbidity or perioperative complications in patients treated with cytoreductive nephrectomy or resection of recurrent retroperitoneal renal cell carcinoma.

Impact of Lymph Node Dissection on Cancer Specific Survival in Patients With Upper Tract Urothelial Carcinoma Treated With Radical Nephroureterectomy

PURPOSEnWe examined the impact of lymphadenectomy on the clinical outcomes of patients with upper tract urothelial cancer treated with radical nephroureterectomy.nnnMATERIALS AND METHODSnData were collected on 1,130 consecutive patients with pT1-4 upper tract urothelial cancer treated with radical nephroureterectomy at 13 centers worldwide. Patients were grouped according to nodal status (pN0 vs pNx vs pN+). The choice to perform lymphadenectomy was determined by the treating surgeon. All pathology slides were reevaluated by dedicated genitourinary pathologists. Univariable and multivariable Cox regression models measured the association of nodal status (pN0 vs pNx vs pN+) with cancer specific survival.nnnRESULTSnOverall 412 patients (36.5%) had pN0 disease, 578 had pNx disease (51.1%) and 140 had pN+ disease (12.4%). The 5-year cancer specific survival estimate was lower in patients with pN+ compared to those with pNx disease (35% vs 69%, p <0.001), which in turn was lower than that in those with pN0 disease (69% vs 77%, p = 0.024). In the subgroup of patients with pT1 disease (345) cancer specific survival rates were not different in those with pN0 and pNx. In pT2-4 cases (813) cancer specific survival estimates were lowest in pN+, intermediate in pNx and highest in pN0 (33% vs 58% vs 70%, p = 0.017). When adjusted for the effects of standard clinicopathological features pN+ was an independent predictor of cancer specific survival (p <0.001). pNx was significantly associated with worse prognosis than pN0 in pT2-4 upper tract urothelial cancer only.nnnCONCLUSIONSnNodal status is a significant predictor of cancer specific survival in upper tract urothelial cancer. pNx is significantly associated with a worse prognosis than pN0 in pT2-4 tumors. Patients expected to have pT2-4 disease should undergo lymphadenectomy to improve staging and thereby help guide decision making regarding adjuvant chemotherapy.

Preoperative multivariable prognostic model for prediction of nonorgan confined urothelial carcinoma of the upper urinary tract

PURPOSEnWe created a prognostic tool for the accurate preoperative prediction of nonorgan confined upper tract urothelial carcinoma.nnnMATERIALS AND METHODSnA computerized data bank containing comprehensive information on 1,453 patients who underwent radical nephroureterectomy at 13 academic institutions was generated and continuously updated. This study comprised a subset of 659 patients in whom all appropriate preoperative prognostic variables (age, gender, race, symptoms, Eastern Cooperative Oncology Group performance status, primary tumor location, tumor architecture, tumor grade and history of previous bladder cancer) were available for statistical analysis. A multivariable logistic regression model containing relevant clinicopathological variables addressed the prediction of nonorgan confined stage disease (T3-4 and/or N+) at radical nephroureterectomy. A backward step-down selection process was applied to achieve the most informative and parsimonious model. Internal validation was performed using 200 bootstrap resamples.nnnRESULTSnPathological nonorgan confined urothelial carcinoma was found in 40% of patients. Grade, architecture and location of the tumor were independently associated with nonorgan confined disease. A nomogram including these 3 variables achieved 76.6% accuracy in predicting nonorgan confined upper tract urothelial cancer.nnnCONCLUSIONSnWe developed a simple and accurate prognostic tool for the prediction of locally advanced upper tract urothelial cancer. This preoperative prediction model can be used for designing clinical trials, selecting patients for preoperative systemic therapy and guiding the extent of concomitant lymph node dissection at nephroureterectomy.

Multi-Institutional Validation of the Predictive Value of Ki-67 Labeling Index in Patients With Urinary Bladder Cancer

Several small single-center studies have reported a prognostic role for Ki-67 labeling index in advanced urothelial carcinoma of the urinary bladder. To investigate whether Ki-67 was a useful biomarker of oncological outcome after radical cystectomy for urothelial carcinoma, we assessed its expression in tumor tissue from 713 patients treated with radical cystectomy and bilateral lymphadenectomy at six centers. A high Ki-67 labeling index was independently associated with established features of aggressive urothelial carcinoma, disease recurrence, and cancer-specific survival. Addition of Ki-67 labeling index improved the accuracy of standard multivariate outcome prediction models, as measured by Harrell concordance index, by 2.9% for disease recurrence and 2.4% for bladder cancer-specific survival (P < .001, two-sided Mantel-Haenszel) -- a statistically and potentially clinically significant margin. In conclusion, routine assessment of Ki-67 expression status along with assessment of other established predictors of urothelial carcinoma outcome has the potential to improve identification of patients who are at increased risk for disease progression after radical cystectomy and thus may benefit from perioperative systemic chemotherapy.

The extent of lymphadenectomy seems to be associated with better survival in patients with nonmetastatic upper-tract urothelial carcinoma: how many lymph nodes should be removed?

BACKGROUNDnThe role and extent of lymphadenectomy in patients with upper-tract urothelial carcinoma (UTUC) is debated.nnnOBJECTIVEnTo establish whether the number of lymph nodes (LNs) removed might be associated with better cause-specific survival in patients with UTUC.nnnDESIGN, SETTING, AND PARTICIPANTSnThe study included 552 consecutive patients who underwent radical nephroureterectomy (RNU) and lymphadenectomy between 1992 and 2006.nnnINTERVENTIONnPatients were treated with RNU and lymphadenectomy.nnnMEASUREMENTSnUnivariable and multivariable Cox proportional hazards regression models addressed the association between the number of LNs removed and cause-specific mortality (CSM). The number of LNs removed was coded as a cubic spline to allow for nonlinear effects. Finally, the most informative cut-off for the number of removed LNs was identified.nnnRESULTS AND LIMITATIONSnIn the entire population, the number of LNs removed was not associated with CSM in univariable (hazard ratio [HR]: 0.99; p=0.16) or in multivariable (HR: 0.97; p=0.12) analyses. In contrast, in the subgroup of pN0 patients (n=412), the number of LNs removed achieved the independent predictor status of CSM (HR: 0.93; p=0.02). Eight LNs removed was the most informative cut-off in predicting CSM (HR: 0.42; p=0.004). The inclusion of the variable defining dichotomously the number of removed LNs (< 8 vs > or = 8) in the base model (age, Eastern Cooperative Oncology Group performance status, pathologic stage, grade, architecture, and lymphovascular invasion) significantly increased the accuracy in predicting CSM (+1.7%; p<0.001).nnnCONCLUSIONSnThe extension of the lymphadenectomy in pN0 UTUC patients seems to be associated with CSM. Longer survival was observed in patients in whom at least eight LNs had been removed.

Tumour Necrosis Is an Indicator of Aggressive Biology in Patients with Urothelial Carcinoma of the Upper Urinary Tract

BACKGROUNDnPrognostic factors after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) are inconclusive, because most data in the literature have been obtained from small series.nnnOBJECTIVEnTo assess the association of tumour necrosis with cancer recurrence and survival in a large international series of patients treated with RNU.nnnDESIGN, SETTING, AND PARTICIPANTSnData were collected from 1425 patients treated with RNU at 13 centres and combined into a relational database. Pathologic slides were re-reviewed by genitourinary pathologists according to strict criteria. Extensive tumour necrosis was scored as >10% of the tumour area.nnnINTERVENTIONnPatients underwent either open or laparoscopic RNU. Lymph node dissection was performed in the presence of enlarged nodes.nnnMEASUREMENTSnRecurrence was defined as tumour relapse in the operative field, lymph node (LN) metastasis, and/or distant metastases. Bladder recurrences were not considered. Associations of extensive tumour necrosis with recurrence-free survival and cancer-specific survival were evaluated by univariate and multivariate analyses.nnnRESULTS AND LIMITATIONSnExtensive tumour necrosis was observed in 364 patients (25.5%) and was associated with advanced tumour stage, high tumour grade, sessile architecture, lymphovascular invasion (LVI), concomitant carcinoma in situ, and LN metastasis (p<0.0001 each). Extensive tumour necrosis was independently associated with disease recurrence and survival (p=0.037 and p=0.046, respectively) after adjusting for the effects of pathologic stage, grade, LVI, and LN status. The addition of extensive tumour necrosis to a base model comprising standard pathologic predictors marginally improved its predictive accuracy for both cancer-specific recurrence (1.5%) and survival (1.4%).nnnCONCLUSIONSnExtensive tumour necrosis is an independent predictor of clinical outcomes in patients who undergo RNU for UTUC. Assessment of tumour necrosis may help to identify patients who could benefit from multimodal therapy after RNU in the future. Evaluation of extensive tumour necrosis should be part of standard pathologic reporting.