Hendrik Isbarn

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.

Impact of Tumor Location on Prognosis for Patients with Upper Tract Urothelial Carcinoma Managed by Radical Nephroureterectomy

BACKGROUNDnThere is a lack of consensus regarding the prognostic significance of ureteral versus renal pelvic upper tract urothelial carcinoma (UTUC).nnnOBJECTIVEnTo investigate the association of tumor location on outcomes for UTUC in an international cohort of patients managed by radical nephroureterectomy (RNU).nnnDESIGN, SETTING, AND PARTICIPANTSnA retrospective review of institutional databases from 10 institutions worldwide identified patients with UTUC.nnnINTERVENTIONnThe 1249 patients in the study underwent RNU with ipsilateral bladder cuff resection between 1987 and 2007.nnnMEASUREMENTSnData accrued included age, gender, race, surgical approach (open vs laparoscopic), tumor pathology (stage, grade, lymph node status), tumor location, use of perioperative chemotherapy, prior endoscopic therapy, urothelial carcinoma recurrence, and mortality from urothelial carcinoma. Tumor location was divided into two groups (renal pelvis and ureter) based on the location of the dominant tumor.nnnRESULTS AND LIMITATIONSnThe 5-yr recurrence-free and cancer-specific survival estimates for this cohort were 75% and 78%, respectively. On multivariate analysis, only pathologic tumor (pT) classification (p<0.001), grade (p<0.02), and lymph node status (p<0.001) were associated with disease recurrence and cancer-specific survival. When adjusting for these variables, there was no difference in the probability of disease recurrence (hazard ratio [HR]: 1.22; p=0.133) or cancer death (HR: 1.23; p=0.25) between ureteral and renal pelvic tumors. Adding tumor location to a base prognostic model for disease recurrence and cancer death that included pT stage, tumor grade, and lymph node status only improved the predictive accuracy of this model by 0.1%. This study is limited by biases associated with its retrospective design.nnnCONCLUSIONSnThere is no difference in outcomes between patients with renal pelvic tumors and with ureteral tumors following nephroureterectomy. These data support the current TNM staging system, whereby renal pelvic and ureteral carcinomas are classified as one integral group of tumors.

Soft Tissue Surgical Margin Status is a Powerful Predictor of Outcomes After Radical Cystectomy: A Multicenter Study of More Than 4,400 Patients

PURPOSEnWe evaluated the association of soft tissue surgical margins with characteristics and outcomes of patients treated with radical cystectomy for urothelial carcinoma of the bladder.nnnMATERIALS AND METHODSnWe retrospectively collected the data of 4,410 patients treated with radical cystectomy and pelvic lymphadenectomy without neoadjuvant chemotherapy at 12 academic centers in the United States, Canada and Europe. A positive soft tissue surgical margin was defined as presence of tumor at inked areas of soft tissue on the radical cystectomy specimen.nnnRESULTSnPositive soft tissue surgical margins were identified in 278 patients (6.3%). On univariate analysis positive soft tissue surgical margin was significantly associated with advanced pT stage, higher tumor grade, lymphovascular invasion and lymph node metastasis (p <0.001). Actuarial 5-year recurrence-free and cancer specific survival probabilities were 62.8% +/- 0.8% and 69% +/- 0.8% for patients without soft tissue surgical margins vs 21.6% +/- 3.1% and 26.4% +/- 3.3% for those with positive soft tissue surgical margins (p <0.001). On multivariable analyses adjusting for the effect of standard clinicopathological features and adjuvant chemotherapy positive soft tissue surgical margin was an independent predictor of disease recurrence and cancer specific mortality (HR 1.52 and HR 1.51, p <0.001, respectively). Soft tissue surgical margin retained independent predictive value in subgroups with advanced disease such as pT3Nany, pT4Nany or Npositive.nnnCONCLUSIONSnPositive soft tissue surgical margin is a strong predictor of recurrence and eventual death from urothelial carcinoma of the bladder. Soft tissue surgical margin status should always be reported in the pathological reports after radical cystectomy. Due to uniformly poor outcomes patients with positive soft tissue surgical margins should be considered for studies on adjuvant local and/or systemic therapy.

Combination of Multiple Molecular Markers Can Improve Prognostication in Patients With Locally Advanced and Lymph Node Positive Bladder Cancer

PURPOSEnWe tested whether the combination of 4 established cell cycle regulators (p53, pRB, p21 and p27) could improve the ability to predict clinical outcomes in a large multi-institutional collaboration of patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder. We also assessed whether the combination of molecular markers is superior to any individual biomarker.nnnMATERIALS AND METHODSnThe study comprised 692 patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder treated with radical cystectomy and bilateral lymphadenectomy (median followup 5.3 years). Scoring was performed using advanced cell imaging and color detection software. The base model incorporated patient age, gender, stage, grade, lymphovascular invasion, number of lymph nodes removed, number of positive lymph nodes, concomitant carcinoma in situ and adjuvant chemotherapy.nnnRESULTSnIndividual molecular markers did not improve the predictive accuracy for disease recurrence and cancer specific mortality. Combination of all 4 molecular markers into number of altered molecular markers resulted in significantly higher predictive accuracy than any single biomarker (p <0.001). Moreover addition of number of altered molecular markers to the base model significantly improved the predictive accuracy for disease recurrence (3.9%, p <0.001) and cancer specific mortality (4.3%, p <0.001). Addition of number of altered molecular markers retained statistical significance for improving the prediction of clinical outcomes in the subgroup of patients with pT3N0 (280), pT4N0 (83) and pTany Npositive (329) disease (p <0.001).nnnCONCLUSIONSnWhile the status of individual molecular markers does not add sufficient value to outcome prediction in patients with advanced urothelial carcinoma of the bladder, combinations of molecular markers may improve molecular staging, prognostication and possibly prediction of response to therapy.

Characteristics and Outcomes of Patients with Clinical T1 Grade 3 Urothelial Carcinoma Treated with Radical Cystectomy: Results from an International Cohort

BACKGROUNDnManagement of T1 grade 3 (T1G3) urothelial carcinoma of the bladder (UCB), with its variable behaviour, represents one of the most difficult challenges for urologists and patients alike.nnnOBJECTIVEnTo evaluate the characteristics and long-term outcome of patients with clinical T1G3 UCB treated with radical cystectomy (RC).nnnDESIGN, SETTING, AND PARTICIPANTSnData from 1136 patients treated with RC for clinical T1G3 UCB without neoadjuvant chemotherapy were collected at 12 centres located in Europe, the United States, and Canada. Median age was 67 yr (range: 29-94), with a male-to-female ratio of 4:1.nnnMEASUREMENTSnPatients characteristics and outcome are evaluated.nnnRESULTS AND LIMITATIONSnOf the 1136 patients, 33.4% had non-organ-confined stage at cystectomy, and 16.2% had lymph node (LN) metastasis; 49.7% were upstaged after RC to muscle-invasive disease, while 21.4% were downstaged to lower than T1G3. Within a median follow-up of 48 mo, 35.5% of patients died of metastatic UCB.nnnCONCLUSIONSnApproximately half of the patients treated with RC without neoadjuvant chemotherapy for clinical T1G3 UCB are upstaged to muscle-invasive UCB. These rates support the inadequacy of clinical decision making based on current treatment paradigms and staging tools. Therefore, identification of patients with clinical T1G3 disease at high risk of disease progression is of the utmost importance, as these patients are likely to benefit from early RC.

The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: A North American validation

BACKGROUNDnA reclassification of the International Union Against Cancer (UICC) staging system for adrenocortical carcinoma (ACC) patients has recently been proposed by the European Network for the Study of Adrenal Tumors (ENSAT) to better discriminate between cancer-specific mortality (CSM) risk strata. We formally tested the validity of the modified staging system in a large North American population-based cohort.nnnMETHODSnKaplan-Meier survival curves depicted CSM rates in the overall population and after stratification according to the 2004 UICC or the 2008 ENSAT-staging system. Cox regression models addressing CSM tested the prognostic value of respectively the UICC or the ENSAT-staging system. Harrells concordance index quantified the accuracy of the standard versus the modified staging system.nnnRESULTSnIn the overall population (n=573), the CSM-free survival rates at 1, 3, and 5 years were, respectively, 62.9%, 47.0%, and 38.1%. No statistically significant differences in survival were recorded between 2004 UICC stages II and III patients (p=0.1). Conversely, a statistically significant difference was observed between 2008 ENSAT stage II and stage III patients (p<0.001). The 2008 ENSAT-staging system showed higher accuracy (83.0%) in predicting 3-year CSM rates, relative to the 2004 UICC-staging system (79.5%) (p<0.001).nnnCONCLUSIONnOur study corroborates the superior accuracy of the ENSAT-staging system for ACC relative to the 2004 UICC-staging system. In consequence, the 2008 ENSAT-staging system may warrant consideration in the next update of staging manuals.

Pathological results and rates of treatment failure in high‐risk prostate cancer patients after radical prostatectomy

Study Type – Therapy (outcomes research)

A Critical Appraisal of the Value of Lymph Node Dissection at Nephroureterectomy for Upper Tract Urothelial Carcinoma

OBJECTIVESnTo perform a population-based analysis of the potential staging or prognostic value (or both) of lymph node dissection (LND) in patients without nodal metastases vs no LND. In several previous reports, LND in patients with upper tract urothelial carcinoma (UTUC) treated with nephroureterectomy (NU) was associated with better survival relative to no LND (pN(x)), even in the absence of pathologically confirmed nodal metastases (pN(0)).nnnMETHODSnWithin the surveillance, epidemiology, and end results database, we identified 2824 patients treated with NU for UTUC between 1988 and 2004. CSM rates after NU were graphically explored using Kaplan-Meier plots. Univariable and multivariable Cox regression models tested the effect of N(0) vs N(x) stage on CSM, after adjusting for T stage, tumor grade, age, gender, primary tumor location, type, and year of surgery.nnnRESULTSnThe CSM-free survival rate at 5 years after NU was 81.2% and 77.8% respectively for pN(0) and pN(x) patients. In univariable analyses pN(x) vs pN(0) status was not associated with worse survival (HR: 1.19; P = .09). After adjustment for all covariates, pN(x) vs pN(0) status still failed to achieve independent predictor status (HR: 0.99; P = .9).nnnCONCLUSIONSnWe found no survival benefit related to the performance of LND in pN(0) patients, relative to pN(x) patients. Lack of standardized criteria for patients selection for LND and for pathological lymph node specimen evaluation represents some of the explanation for the observed discrepancy between the current finding and previous findings.

Discrepancy between clinical and pathological stage: External validation of the impact on prognosis in an international radical cystectomy cohort

Study Type – Prognosis (case series) Level of Evidenceu20034

Location of the Primary Tumor is Not an Independent Predictor of Cancer Specific Mortality in Patients With Upper Urinary Tract Urothelial Carcinoma

PURPOSEnThe prognostic significance of renal pelvis vs ureteral upper urinary tract urothelial carcinoma tumor location is controversial. We assessed the prognostic significance of upper urinary tract urothelial carcinoma tumor location in a large, population based data set.nnnMATERIALS AND METHODSnOur analyses relied on 2,824 patients treated with nephroureterectomy for upper urinary tract urothelial carcinoma within 9 SEER registries between 1988 and 2004. Univariable and multivariable models tested the effect of tumor location on cancer specific mortality rates. Covariates consisted of age, race, SEER registry, gender, type of surgery (nephroureterectomy with vs without bladder cuff removal), pT stage, pN stage, grade and year of surgery.nnnRESULTSnRelative to ureteral tumors renal pelvis tumors were of higher stage (T3/T4 disease 38.4% vs 57.9%, p <0.001) and had a higher rate of lymph node metastases (6.0% vs 9.8%, p = 0.003) at nephroureterectomy. The respective 5-year cancer specific mortality-free survival estimates were 81.0% vs 75.5% (p = 0.007). However, after multivariable adjustment tumor location failed to reach independent predictor status of cancer specific mortality (p = 0.8).nnnCONCLUSIONSnTo our knowledge this is the largest cohort in which the impact of upper urinary tract urothelial carcinoma tumor location on cancer specific mortality was examined. At nephroureterectomy renal pelvis tumors had significantly more advanced T and N stages compared to ureteral tumors. However, after adjustment for stage, grade and other covariates tumor location did not independently predict cancer specific mortality. Thus, the biological behavior of renal pelvis vs ureteral tumors is the same after nephroureterectomy as long as stage, grade, and other patient and tumor characteristics are accounted for.