Features Associated with Recurrence Beyond 5 Years After Nephrectomy and Nephron-Sparing Surgery for Renal Cell Carcinoma: Development and Internal Validation of a Risk Model (PRELANE score) to Predict Late Recurrence Based on a Large Multicenter Database (CORONA/SATURN Project)

Background

Approximately 10–20% of recurrences in patients treated with nephrectomy for renal cell carcinoma (RCC) develop beyond 5 yr after surgery (late recurrence).

Objective

To determine features associated with late recurrence.

Design, setting, and participants

A total of 5009 patients from a multicenter database comprising 13 107 RCC patients treated surgically had a minimum recurrence-free survival of 60 mo (median follow-up [FU]: 105 mo [range: 78–135]); at last FU, 4699 were disease free (median FU: 103 mo [range: 78–134]), and 310 patients (6.2%) experienced disease recurrence (median FU: 120 mo [range: 93–149]).

Interventions

Patients underwent radical nephrectomy or nephron-sparing surgery.

Outcome measurements and statistical analysis

Multivariable regression analyses identified features associated with late recurrence. Cox regression analyses evaluated the association of features with cancer-specific mortality (CSM).

Results and limitations

Lymphovascular invasion (LVI) (odds ratio [OR]: 3.07; p < 0.001), Fuhrman grade 3–4 (OR: 1.60; p = 0.001), and pT stage >pT1 (OR: 2.28; p < 0.001) were significantly associated with late recurrence. Based on accordant regression coefficients, these parameters were weighted with point values (LVI: 2 points; Fuhrman grade 3–4: 1 point, pT stage >1: 2 points), and a risk score was developed for the prediction of late recurrences. The calculated values (0 points: late recurrence risk 3.1%; 1–3 points: 8.4%; 4–5 points: 22.1%) resulted in a good-, intermediate- and poor-prognosis group (area under the curve value for the model: 70%; 95% confidence interval, 67–73). Multivariable Cox regression analysis showed LVI (HR: 2.75; p < 0.001), pT stage (HR: 1.24; p < 0.001), Fuhrman grade (HR: 2.40; p < 0.001), age (HR: 1.01; p < 0.001), and gender (HR: 0.71; p = 0.027) to influence CSM significantly. Limitations are based on the multicenter and retrospective study design.

Conclusions

LVI, Fuhrman grade 3/4, and a tumor stage >pT1 are independent predictors of late recurrence after at least 5 yr from surgery in patients with RCC. We developed a risk score that allows for prognostic stratification and individualized aftercare of patients with regard to counseling, follow-up scheduling, and clinical trial design.     

Impact of Smoking and Smoking Cessation on Outcomes in Bladder Cancer Patients Treated with Radical Cystectomy

Background

Cigarette smoking is the best-established risk factor for urothelial carcinoma development.

Objective

To elucidate the association of pretreatment smoking status, cumulative exposure, and time since smoking cessation on outcomes of patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC).

Design, setting, and participants

We retrospectively collected clinicopathologic and smoking variables, including smoking status, number of cigarettes per day (CPD), duration in years, and time since smoking cessation, for 1506 patients treated with RC for UCB. Lifetime cumulative smoking exposure was categorized as light short-term (≤20 CPD for ≤20 yr), light long-term (≤20 CPD for >20 yr), heavy short-term (>20 CPD for ≤20 yr), and heavy long-term (>20 CPD for >20 yr).

Intervention

RC and bilateral lymph node (LN) dissection without neoadjuvant chemotherapy.

Outcome measurements and statistical analysis

Logistic regression and competing risk analyses assessed the association of smoking with disease recurrence, cancer-specific mortality, and overall mortality.

Results and limitations

There was no difference in clinicopathologic factors between patients who had never smoked (20%), former smokers (46%), and current smokers (34%). Smoking status was associated with the cumulative incidence of disease recurrence (p = 0.004) and cancer-specific mortality (p = 0.016) in univariable analyses and with disease recurrence in multivariable analysis (p = 0.02); current smokers had the highest cumulative incidences. Among ever smokers, cumulative smoking exposure was associated with advanced tumor stages (p < 0.001), LN metastasis (p = 0.002), disease recurrence (p < 0.001), cancer-specific mortality (p = 0.001), and overall mortality (p = 0.037) in multivariable analyses that adjusted for standard characteristics; heavy long-term smokers had the worst outcomes, followed by light long-term, heavy short-term, and light short-term smokers. Smoking cessation ≥10 yr mitigated the risk of disease recurrence (hazard ratio [HR]: 0.44; p < 0.001), cancer-specific mortality (HR: 0.42; p < 0.001), and overall mortality (HR: 0.69; p = 0.012) in multivariable analyses. The study is limited by its retrospective nature.

Conclusions

Smoking is associated with worse prognosis after RC for UCB. This association seems to be dose-dependent, and its effects are mitigated by >10 yr smoking cessation. Health care practitioners should counsel smokers regarding the detrimental effects of smoking and the benefits of smoking cessation on UCB etiology and prognosis.     

CEACAM1: A Novel Urinary Marker for Bladder Cancer Detection

Background

Carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein; CEACAM1) is expressed in normal bladder urothelium and in angiogenically activated endothelial cells, where it exhibits proangiogenic properties.

Objective

The aim of this study was to evaluate the value of urinary CEACAM1 for detection of urothelial carcinoma of the bladder (UCB).

Design, setting, and participants

This prospective study included 175 patients.

Measurements

Immunohistochemistry for CEACAM1 was performed on UCB sections of 10 patients. Enzyme-linked immunosorbent assay (ELISA) for CEACAM1 was performed on urine specimens of healthy volunteers (n = 30), patients with benign prostatic hyperplasia (BPH; n = 5), severe cystitis (n = 5), non–muscle-invasive UCB (n = 72), muscle-invasive UCB (n = 21), or past history of UCB without evidence of disease (n = 42). Western blot analysis was performed on a subgroup of these subjects (n = 53).

Results and limitations

CEACAM1 immunostaining in normal urothelium disappears in noninvasive UCB but appears in endothelial cells of adjacent vessels. Western blotting revealed presence of CEACAM1 in the urine of no healthy volunteers, of 76% of noninvasive UCB patients, and of 100% of invasive UCB patients. ELISA analysis confirmed that urinary CEACAM1 levels were significantly higher in UCB patients compared with control subjects (median: 207 ng/ml vs 0 ng/ml; p < 0.001). The area under the curve for UCB detection was 0.870 (95% confidence interval [CI]: 0.810–0.931). In multivariable logistic regression analyses that adjusted for the effects of age and gender, higher CEACAM1 levels were associated with cancer presence (hazard ratio [HR]: 2.89; 95% CI: 2.01–4.15; p < 0.001) and muscle-invasive cancer (HR: 5.53; 95% CI: 1.68–18.24; p = 0.005). The cut-off level of 110 ng/ml yielded sensitivity of 74% and specificity of 95% for detecting UCB. Sensitivity was 88% for detecting high-grade UCB and 100% for detecting invasive-stage UCB. Larger studies are necessary to establish the diagnostic and prognostic roles of this highly promising novel marker in UCB.

Conclusions

Urinary CEACAM1 levels discriminate UCB patients from non-UCB subjects. Moreover, urinary levels of CEACAM1 increased with advancing stage and grade.     

Validation of the AJCC TNM Substaging of pT2 Bladder Cancer: Deep Muscle Invasion Is Associated with Significantly Worse Outcome

Background

The current TNM bladder cancer staging system stratifies bladder muscle invasion into superficial (pT2a) and deep (pT2b). Controversy exists regarding the significance of the extent of muscle invasion on clinical outcome.

Objective

Our aim was to compare the cancer-specific outcomes of patients with pT2 urothelial carcinoma of the bladder (UCB) at radical cystectomy (RC) in a large international cohort of patients.

Design, setting, and participants

The records of patients treated with RC for UCB at six centers were reviewed. Of the 2605 reviewed patients, 565 (21.7%) had pT2 disease. None of the patients received preoperative systemic chemotherapy or radiotherapy.

Measurements

Patients’ characteristics and outcome were evaluated.

Results and limitations

The median patient age in the entire group was 66.2 yr. Of the 565 patients with pT2 UCB, 249 patients (44.1%) had substage pT2a; 316 patients (55.9%) had pT2b. One hundred and eleven patients (19.6%) had metastases to regional lymph nodes. Median follow-up was 50.5 mo. Recurrence-free survival (73.2% vs 58.7%) and cancer-specific survival (78.0% vs 65.1%) estimates were significantly better for pT2a patients compared with those with pT2b (p = 0.002 and p = 0.001, respectively). Pathologic T2 substaging was associated with worse recurrence-free and cancer-specific survival after adjusting for the effects of standard pathologic features (p = 0.011 and p = 0.006, respectively). The statistical significance of these associations was reconfirmed in subgroup analysis limited to those patients with pathologically negative lymph nodes.

Conclusions

In this large international cohort, pathologic substaging helped to stratify patients with lymph node–negative pT2 UCB into statistically significantly different risk groups. These data support the value of the current American Joint Committee on Cancer TNM staging.     

Long-term Cancer-specific Outcomes of TaG1 Urothelial Carcinoma of the Bladder

Background

Few studies have investigated the natural history of TaG1 urothelial carcinoma of the bladder (UCB).

Objective

To assess the long-term outcomes of patients with TaG1 UCB and the impact of immediate postoperative instillation of chemotherapy (IPIC).

Design, setting, and participants

A retrospective analysis of 1447 patients with TaG1 UCB treated between 1996 and 2007 at eight centers. Median follow-up was 67.2 mo (interquartile range: 67.9). Patients were stratified into three European Association of Urology (EAU) guidelines risk categories; high-risk patients (n = 11) were excluded.

Intervention

Transurethral resection of the bladder with or without IPIC.

Outcome measurements and statistical analysis

Univariable and multivariable Cox regression models addressed factors associated with disease recurrence, disease progression, death of disease, and any-cause death.

Results and limitations

Of the 1436 patients, 601 (41.9%) and 835 (58.1%) were assigned to low- and intermediate-risk categories, respectively. The actuarial estimate of 5-yr recurrence-free survival was 56% (standard error: ±1). Advancing age (p = 0.04), tumor >3 cm (p = 0.001), multiple tumors (p < 0.001), and recurrent tumors (p < 0.001) were independently associated with increased risk of disease recurrence, whereas IPIC was associated with decreased risk (p = 0.001). The actuarial estimate of 5-yr progression-free survival was 95% ± 1. Advancing age (p < 0.001) and multiple tumors (p = 0.01) were independent risk factors for disease progression. Five-year cancer-specific survival was 98% ± 1. Advancing age (p = 0.001) and previous recurrence (p = 0.04) were associated with increased risk, whereas female gender (p = 0.02) was associated with decreased risk of cancer-specific mortality. Compared with low-risk patients, intermediate-risk patients were at significantly higher risk of disease recurrence, disease progression, and cancer-specific mortality (all p < 0.01). Limitations include the retrospective design of the study and the lack of a central pathology review.

Conclusions

TaG1 UCB patients experience heterogeneous risks of disease recurrence. We validated the EAU guidelines risk stratification in TaG1 UCB patients. IPIC was associated with a reduced risk of disease recurrence in patients with low- and intermediate-risk TaG1 UCB.     

Prognostic Role of Lymphovascular Invasion in Patients with Urothelial Carcinoma of the Upper Urinary Tract: An International Validation Study

Background

Lymphovascular invasion (LVI) identified following pathologic slide review has been shown to be an independent predictor of recurrence-free survival (RFS) and cancer-specific survival (CSS) in a multicenter series of patients undergoing radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). However, the validity of LVI in everyday practice, where pathologic re-review of all slides is uncommon, has not been assessed.

Objective

Our aim was to evaluate the prognostic role of LVI in an international cohort of patients treated with RNU for UTUC without pathologic slide review.

Design, setting, and participants

Data from 762 patients treated with RNU for UTUC without neoadjuvant chemotherapy were collected at nine centers located in Europe, Asia, and Canada.

Measurements

We evaluated patients’ characteristics, RFS, and CSS.

Results and limitations

LVI was present in 148 patients (19.4%). At a median follow-up of 34 mo, 23.5% of the patients developed disease recurrence and 19.8% died of UTUC. The 5-yr RFS and CSS rates were 79.3% and 82.1%, respectively, in the absence of LVI compared with 45.1% and 45.8%, respectively, in the presence of LVI (p values <0.0001). On multivariable Cox regression analyses, LVI was an independent predictor of RFS (hazard ratio [HR]: 3.3; p = 0.005) and CSS (HR: 5.9; p < 0.0001). Similarly, among patients with pN0/Nx disease, LVI was an independent predictor of RFS (HR: 2.1; p = 0.001) and CSS (HR: 2.3; p < 0.0001).

Conclusions

In a large multicenter series of patients treated with RNU for UTUC and for which no pathologic slide review was performed, LVI was present in approximately 20% and was an independent predictor of both RFS and CSS. LVI status should always be included in the pathologic report of RNU specimens, and patients with LVI should be considered for adjuvant therapy studies.     

Pretreatment Neutrophil-to-Lymphocyte Ratio Is Associated with Advanced Pathologic Tumor Stage and Increased Cancer-specific Mortality Among Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy

Background

Pretreatment neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been associated with adverse survival in a variety of malignancies. However, the relationship between NLR and oncologic outcomes following radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) has not been well studied.

Objective

To evaluate the association of preoperative NLR with clinicopathologic outcomes following RC.

Design, setting, and participants

We identified 899 patients who underwent RC without neoadjuvant therapy at our institution between 1994 and 2005 and who had a pretreatment NLR.

Outcome measurements and statistical analysis

Preoperative NLR (within 90 d prior to RC) was recorded. Recurrence-free, cancer-specific, and overall survival were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate Cox proportional hazard and logistic regression models were used to analyze the association of NLR with clinicopathologic outcomes.

Results and limitations

Median postoperative follow-up was 10.9 yr (interquartile range: 8.3–13.9 yr). Higher preoperative NLR was associated with significantly increased risks of pathologic, extravesical tumor extension (odds ratio [OR]: 1.07; p = 0.03) and lymph node involvement (OR: 1.09; p = 0.02). Univariately, 10-yr cancer-specific survival was significantly worse among patients with a preoperative NLR (≥2.7 [51%] vs <2.7 [64%]; p < 0.001). Moreover, on multivariate analysis, increased preoperative NLR was independently associated with greater risks of disease recurrence (hazard ratio [HR]: 1.04; p = 0.02), death from bladder cancer (HR: 1.04; p = 0.01), and all-cause mortality (HR: 1.03; p = 0.01).

Conclusions

Elevated preoperative NLR among patients undergoing RC is associated with significantly increased risk for locally advanced disease as well as subsequent disease recurrence, and cancer-specific and all-cause mortality. These data suggest that serum NLR may be a useful prognostic marker for preoperative patient risk stratification, including consideration for neoadjuvant therapy and clinical trial enrollment.     

Prognostic Value of Perinodal Lymphovascular Invasion Following Radical Cystectomy for Lymph Node–positive Urothelial Carcinoma

Background

Metastasis of urothelial carcinoma of the bladder (UCB) into regional lymph nodes (LNs) is a key prognosticator for cancer-specific survival (CSS) after radical cystectomy (RC). Perinodal lymphovascular invasion (pnLVI) has not yet been defined.

Objective

To assess the prognostic value of histopathologic prognostic factors, especially pnLVI, on survival.

Design, setting, and participants

A total of 598 patients were included in a prospective multicentre study after RC for UCB without distant metastasis and neoadjuvant and/or adjuvant chemotherapy. En bloc resection and histopathologic evaluation of regional LNs were performed based on a prospective protocol. The final study group comprised 158 patients with positive LNs (26.4%).

Intervention

Histopathologic analysis was performed based on prospectively defined morphologic criteria of LN metastases.

Outcome measurements and statistical analysis

Multivariable Cox proportional hazard regression models determined prognostic impact of clinical and histopathologic variables (age, gender, tumour stage, surgical margin status, pN, diameter of LN metastasis, LN density [LND], extranodal extension [ENE], pnLVI) on CSS. The median follow-up was 20 mo (interquartile range: 11–38).

Results and limitations

Thirty-one percent of patients were staged pN1, and 69% were staged pN2/3. ENE and pnLVI was present in 52% and 39%, respectively. CSS rates after 1 yr, 3 yr, and 5 yr were 77%, 44%, and 27%, respectively. Five-year CSS rates in patients with and without pnLVI were 16% and 34% (p < 0.001), respectively. PN stage, maximum diameter of LN metastasis, LND, and ENE had no independent influence on CSS. In the multivariable Cox model, the only parameters that were significant for CSS were pnLVI (hazard ratio: 2.47; p = 0.003) and pT stage. However, pnLVI demonstrated only a minimal gain in predictive accuracy (0.1%; p = 0.856), and the incremental accuracy of prediction is of uncertain clinical value.

Conclusions

We present the first explorative study on the prognostic impact of pnLVI. In contrast to other parameters that show the extent of LN metastasis, pnLVI is an independent prognosticator for CSS.     

Comorbidity and performance indices as predictors of cancer-independent mortality but not of cancer-specific mortality after radical cystectomy for urothelial carcinoma of the bladder

Background

Comorbidity and performance indices allow assessment of preoperative health status. However, the optimal tool for use in patients with urothelial carcinoma of the bladder (UCB) who are undergoing radical cystectomy (RC) has not yet been established.

Objective

To evaluate correlation of Adult Comorbidity Evaluation-27 (ACE27), Charlson Comorbidity Index, Age-Adjusted Charlson Comorbidity Index, Eastern Cooperative Oncology Group performance status, and American Society of Anesthesiologists (ASA) score with survival.

Design, setting, and participants

A retrospective multicenter study was carried out on 555 unselected consecutive patients who underwent RC for UCB from 2000 to 2010.

Intervention

RC with pelvic lymph node dissection in patients with UCB without neoadjuvant chemotherapy.

Outcome measurements and statistical analysis

Cox regression models were calculated with established variables to assess predictive capacity for cancer-specific mortality (CSM) and cancer-independent mortality (CIM).

Results and limitations

All indices were independent predictors for CIM but not for CSM. The ASA score was the only index that significantly increased the predictive accuracy of the predefined CIM model (+2.3%; p = 0.045). To create a clinically valuable tool, we devised a weighted prognostic model including age and the best prognosticators within the performance and comorbidity scores (ASA/ACE27 0–1/2–3). A 3-yr CIM rate of 8%, 26%, and 47% was calculated for the low-, intermediate-, and high-risk groups, respectively. Patients >75 yr of age with ASA 3/4 and ACE27 >1 exhibited a CIM risk seven times greater than patients ≤75 yr with ASA 1/2 and ACE27 0/1. This study is limited by the short follow-up and its retrospective nature.

Conclusions

Comorbidity and performance assessment is mandatory in the preoperative prediction of CIM for patients undergoing RC for UCB. The present results indicate that the ASA score is the tool of choice. External and prospective validation is warranted.     

Prospective Evaluation of a Molecular Marker Panel for Prediction of Recurrence and Cancer-specific Survival After Radical Cystectomy

Background

Retrospective studies demonstrated that cell cycle–related and proliferation biomarkers add information to standard pathologic tumor features after radical cystectomy (RC). There are no prospective studies validating the clinical utility of markers in bladder cancer.

Objective

To prospectively determine whether a panel of biomarkers could identify patients with urothelial carcinoma of the bladder (UCB) who were likely to experience disease recurrence or mortality.

Design, setting, and participants

Between January 2007 and January 2012, every patient with high-grade bladder cancer, including 216 patients treated with RC and lymphadenectomy, underwent immunohistochemical staining for tumor protein p53 (Tp53); cyclin-dependent kinase inhibitor 1A (p21, Cip1) (CDKN1A); cyclin-dependent kinase inhibitor 1B (p27, Kip1); antigen identified by monoclonal antibody Ki-67 (MKI67); and cyclin E1.

Intervention

Every patient underwent RC and lymphadenectomy, and marker staining.

Outcome measurements and statistical analysis

Cox regression analyses tested the ability of the number of altered biomarkers to predict recurrence or cancer-specific mortality (CSM).

Results and limitations

Pathologic stage among the study population was pT0 (5%), pT1 (35%), pT2 (19%), pT3 (29%), and pT4 (13%); lymphovascular invasion (LVI) was seen in 34%. The median number of removed lymph nodes was 23, and 60 patients had lymph node involvement (LNI). Median follow-up was 20 mo. Expression of p53, p21, p27, cyclin E1, and Ki-67 were altered in 54%, 26%, 46%, 15%, and 75% patients, respectively. In univariable analyses, pT stage, LNI, LVI, perioperative chemotherapy (CTx), margin status, and number of altered biomarkers predicted disease recurrence. In a multivariable model adjusting for pathologic stage, margins, LNI, and adjuvant CTx, only LVI and number of altered biomarkers were independent predictors of recurrence and CSM. The concordance index of a baseline model predicting CSM (including pathologic stage, margins, LVI, LNI, and adjuvant CTx) was 80% and improved to 83% with addition of the number of altered markers.

Conclusions

Molecular markers improve the prediction of recurrence and CSM after RC. They may identify patients who might benefit from additional treatments and closer surveillance after cystectomy.     

Extranodal Extension Is a Powerful Prognostic Factor in Bladder Cancer Patients with Lymph Node Metastasis

Background

Lymph node metastasis (LNM) is the most powerful pathologic predictor of disease recurrence after radical cystectomy (RC). However, the outcomes of patients with LNM are highly variable.

Objective

To assess the prognostic value of extranodal extension (ENE) and other lymph node (LN) parameters.

Design, setting, and participants

A retrospective analysis of 748 patients with urothelial carcinoma of the bladder and LNM treated with RC and lymphadenectomy without neoadjuvant therapy at 10 European and North American centers (median follow-up: 27 mo).

Intervention

All subjects underwent RC and bilateral pelvic lymphadenectomy.

Outcome measurements and statistical analysis

Each LNM was microscopically evaluated for the presence of ENE. The number of LNs removed, number of positive LNs, and LN density were recorded and calculated. Univariable and multivariable analyses addressed time to disease recurrence and cancer-specific mortality after RC.

Results and limitations

A total of 375 patients (50.1%) had ENE. The median number of LNs removed, number of positive LNs, and LN density were 15, 2, and 15, respectively. The rate of ENE increased with advancing pT stage (p < 0.001). In multivariable Cox regression analyses that adjusted for the effects of established clinicopathologic features and LN parameters, ENE was associated with disease recurrence (hazard ratio [HR]: 1.89; 95% confidence interval [CI], 1.55–2.31; p < 0.001) and cancer-specific mortality (HR: 1.90; 95% CI, 1.52–2.37; p < 0.001). The addition of ENE to a multivariable model that included pT stage, tumor grade, age, gender, lymphovascular invasion, surgical margin status, LN density, number of LNs removed, number of positive LNs, and adjuvant chemotherapy improved predictive accuracy for disease recurrence and cancer-specific mortality from 70.3% to 77.8% (p < 0.001) and from 71.8% to 77.8% (p = 0.007), respectively. The main limitation of the study is its retrospective nature.

Conclusions

ENE is an independent predictor of both cancer recurrence and cancer-specific mortality in RC patients with LNM. Knowledge of ENE status could help with patient counseling, clinical decision making regarding inclusion in clinical trials of adjuvant therapy, and tailored follow-up scheduling after RC.     

A Comparison of Postoperative Complications in Open versus Robotic Cystectomy

Background

Robotic cystectomy is an emerging alternative for treatment of invasive bladder cancer (BCa). However, reduction in postoperative morbidity relative to the open approach has not been demonstrated.

Objective

To compare complication rates in patients undergoing robotic versus open radical cystectomy (RC).

Design, setting, and participants

A prospective cohort study of 187 consecutive patients undergoing RC at our institution—104 open RC, 83 robotic RC.

Intervention

Open or robotic RC with urinary diversion.

Measurements

Demographic, perioperative, and complication data were recorded prospectively. Thirty-day and 90-d complication rates were assessed using the modified Clavien complication scale. Data were evaluated using χ² and multivariate logistic regression analyses.

Results and limitations

At 30 d, the open group demonstrated a higher overall complication rate (59% vs 41%; p = 0.04) as well as more major complications (30% vs 10%; p = 0.007). At 90 d, the overall complication rate was greater in the open group, but this was not statistically significant (62% vs 48%; p = 0.07). However, there was a significantly higher major complication rate in the open cohort (31% vs 17%; p = 0.03). When subjected to logistic regression analysis, robotic cystectomy was an independent predictor of fewer overall and major complications at 30 and 90 d. High American Society of Anesthesiologists (ASA) score (3–4) and longer surgical time were independent predictors of major complications. Though this is one of the largest published RC series, the sample size is relatively small. Moreover, despite the two patient cohorts being similarly matched, the study was not performed in a randomized fashion.

Conclusions

Patients undergoing robotic cystectomy experienced fewer postoperative complications than those undergoing open cystectomy. Robotic cystectomy is an independent predictor of fewer overall and major complications. Until long-term oncologic results are available, robotic cystectomy should still be considered investigational.     

Pathologic Nodal Staging Score for Bladder Cancer: A Decision Tool for Adjuvant Therapy After Radical Cystectomy

Background

Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the standard of care for high-risk non–muscle-invasive and muscle-invasive bladder cancer (BCa).

Objective

To develop a model that allows quantification of the likelihood that a pathologically node-negative patient has, indeed, no positive nodes.

Design, setting, and participants

We analyzed data from 4335 patients treated with RC and PLND without neoadjuvant chemotherapy at 12 international academic centers.

Interventions

Patients underwent RC and PLND.

Outcome measurements and statistical analysis

We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a pathologic (postoperative) nodal staging score (pNSS) that represents the probability that a patient is correctly staged as node negative as a function of the number of examined nodes.

Results and limitations

Overall, the probability of missing a positive node decreases with the increasing number of nodes examined (52% if 3 nodes are examined, 40% if 5 are examined, and 26% if 10 are examined). The proportion of having a positive node increased proportionally with advancing pathologic T stage and lymphovascular invasion (LVI). Patients with LVI who had 25 examined nodes would have a pNSS of 80% (pT1), 88% (pT2), and 66% (pT3–T4), whereas 10 examined nodes were sufficient for pNSS exceeding 90% in patients without LVI and pT0–T2 tumors. This study is limited because of its retrospective design and multicenter nature.

Conclusions

We developed a tool that estimates the likelihood of lymph node (LN) metastasis in BCa patients treated with RC by evaluating the number of examined nodes, the pathologic T stage, and LVI. The pNSS indicates the adequacy of nodal staging in LN-negative patients. This tool could help to refine clinical decision making regarding adjuvant chemotherapy, follow-up scheduling, and inclusion in clinical trials.     

Should Bladder Cuff Excision Remain the Standard of Care at Nephroureterectomy in Patients with Urothelial Carcinoma of the Renal Pelvis? A Population-based Study

Background

A large, multi-institutional, tertiary care center study suggested no benefit from bladder cuff excision (BCE) at nephroureterectomy in patients with upper tract urothelial carcinoma (UC).

Objective

We tested and quantified the prognostic impact of BCE at nephroureterectomy on cancer-specific mortality (CSM) in a large population-based cohort of patients with UC of the renal pelvis.

Design, setting, and participants

A cohort of 4210 patients with UC of the renal pelvis were treated with nephroureterectomy with (NUC) or without (NU) a BCE between 1988 and 2006 within 17 Surveillance, Epidemiology, and End Results registries.

Measurements

Cumulative incidence plots and competing risks regression models compared CSM after either NUC or NU. Covariates consisted of pathologic T and N stages, grade, age, year of surgery, gender, and race.

Results and limitations

Respectively, 2492 (59.2%) and 1718 (40.8%) patients underwent a nephroureterectomy with or without BCE. In univariable and multivariable analyses, BCE omission increased CSM rates in patients with pT3N0/x, pT4N0/x, and pT(any)N1-3 UC of the renal pelvis. For example, in patients with pT3N0/x disease, holding all other variables constant, BCE omission increased CSM in a 1.25-fold fashion (p = 0.04). Similarly, in patients with pT4N0/x disease, BCE omission resulted in a 1.45-fold increase (p = 0.02). The main limitation of our study is the lack of data on disease recurrence.

Conclusions

Nephroureterectomy with BCE remains the standard of care in the treatment of UC of the renal pelvis and should invariably be performed in patients with locally advanced disease. Conversely, patients with pT1 and pT2 disease could be considered for NU without compromising CSM. However, recurrence data are needed to fully confirm the validity of this option.     

Management of Localized Kidney Cancer: Calculating Cancer-specific Mortality and Competing Risks of Death for Surgery and Nonsurgical Management

Background

For elderly individuals with localized renal cell carcinoma (RCC), surgical intervention remains the primary treatment option but may not benefit patients with limited life expectancy.

Objective

To calculate the trade-offs between surgical excision and nonsurgical management (NSM) with respect to competing causes of mortality.

Design, setting, and participants

Relying on a cohort of Medicare beneficiaries, all patients with nonmetastatic node-negative T1 RCC between 1988 and 2005 were abstracted.

Intervention

All patients were treated with partial nephrectomy (PN), radical nephrectomy (RN), or NSM.

Outcome measurements and statistical analysis

Cancer-specific mortality (CSM) and other-cause mortality (OCM) rates were modeled through competing-risks regression methodologies. Instrumental variable analysis was used to account for the potential biases associated with measured and unmeasured confounders.

Results and limitations

A total of 10 595 patients were identified. In instrumental variable analysis, patients treated with PN (hazard ratio [HR]: 0.45; 95% confidence interval [CI], 0.24–0.83; p = 0.01) or RN (HR: 0.58; 95% CI, 0.35–0.96; p = 0.03) had a significantly lower risk of CSM than those treated with NSM. In subanalyses restricted to patients ≥75 yr, the instrumental variable analysis failed to detect any statistically significant difference between PN (HR: 0.48; p = 0.1) or RN (HR: 0.57; p = 0.1) relative to NSM with respect to CSM. Similar trends were observed in T1a RCC only.

Conclusions

PN or RN is associated with a reduction of CSM among older patients diagnosed with localized RCC, compared with NSM. The same benefit failed to reach statistical significance among patients ≥75 yr. The harms of surgery need to be weighed against the marginal survival benefit for some patients.     

Might Men Diagnosed with Metastatic Prostate Cancer Benefit from Definitive Treatment of the Primary Tumor? A SEER-Based Study

Background

Few data exist regarding the impact on survival of definitive treatment of the prostate in men diagnosed with metastatic prostate cancer (mPCa).

Objective

To evaluate the survival of men diagnosed with mPCa based on definitive treatment of the prostate.

Design, setting, and participants

Men with documented stage IV (M1a–c) PCa at diagnosis identified using Surveillance Epidemiology and End Results (SEER) (2004–2010) and divided based on definitive treatment of the prostate (radical prostatectomy [RP] or brachytherapy [BT]) or no surgery or radiation therapy (NSR).

Outcome measurements and statistical analysis

Kaplan-Meier methods were used to calculate overall survival (OS). Multivariable competing risks regression analysis was used to calculate disease-specific survival (DSS) probability and identify factors associated with cause-specific mortality (CSM).

Results and limitations

A total of 8185 patients were identified: NSR (n = 7811), RP (n = 245), and BT (n = 129). The 5-yr OS and predicted DSS were each significantly higher in patients undergoing RP (67.4% and 75.8%, respectively) or BT (52.6 and 61.3%, respectively) compared with NSR patients (22.5% and 48.7%, respectively) (p < 0.001). Undergoing RP or BT was each independently associated with decreased CSM (p < 0.01). Similar results were noted regardless of the American Joint Committee on Cancer (AJCC) M stage. Factors associated with increased CSM in patients undergoing local therapy included AJCC T4 stage, high-grade disease, prostate-specific antigen ≥20 ng/ml, age ≥70 yr, and pelvic lymphadenopathy (p < 0.05). The major limitation of this study was the lack of variables from SEER known to influence survival of patients with mPCa, including treatment with systemic therapy.

Conclusions

Definitive treatment of the prostate in men diagnosed with mPCa suggests a survival benefit in this large population-based study. These results should serve as a foundation for future prospective trials.

Patient summary

We used a large population-based cancer database to examine survival in men diagnosed with metastatic prostate cancer (mPCa) undergoing definitive therapy for the prostate. Local therapy (LT) appeared to confer a survival benefit. Therefore, we conclude that prospective trials are needed to further evaluate the role of LT in mPCa.     

Alvimopan Accelerates Gastrointestinal Recovery After Radical Cystectomy: A Multicenter Randomized Placebo-Controlled Trial

Background

Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS).

Objective

To assess the efficacy of alvimopan to accelerate GI recovery after RC.

Design, setting, and participants

We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics.

Intervention

Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo.

Outcome measurements and statistical analysis

The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed.

Results and limitations

Patients were randomized to alvimopan (n = 143) or placebo (n = 137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p < 0.0001), shorter mean LOS (7.4 vs 10.1 d; p = 0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p < 0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p = 0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy.

Conclusions

Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo.

Patient summary

This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety.

Trial registration

ClinicalTrials.gov identifier NCT00708201     

The Impact of Perioperative Blood Transfusion on Cancer Recurrence and Survival Following Radical Cystectomy

Background

While the receipt of a perioperative blood transfusion (PBT) has been associated with an increased risk of mortality for a number of malignancies, the relationship between PBT and survival following radical cystectomy (RC) for bladder cancer (BCa) has not been well established.

Objective

To evaluate the association of PBT with disease recurrence and mortality following RC.

Design, setting, and participants

We identified 2060 patients who underwent RC at the Mayo Clinic between 1980 and 2005. PBT was defined as transfusion of allogenic red blood cells during RC or postoperative hospitalization.

Outcome measurements and statistical analysis

Survival was estimated using the Kaplan-Meier method and was compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of PBT with outcome, controlling for clinicopathologic variables.

Results and limitations

A total of 1279 patients (62%) received PBT. The median number of units transfused was 2 (interquartile range [IQR]: 2–4). Patients receiving PBT were significantly older (median: 69 yr vs 66 yr; p < 0.0001), had a worse Eastern Cooperative Oncology Group performance status (p < 0.0001), and were more likely to have muscle-invasive tumors (56% vs 49%; p = 0.004). Median postoperative follow-up was 10.9 yr (IQR: 7.9–15.7). Receipt of PBT was associated with significantly worse 5-yr recurrence-free survival (58% vs 64%; p = 0.01), cancer-specific survival (59% vs 72%; p < 0.001), and overall survival (45% vs 63%; p < 0.001). On multivariate analyses, PBT remained associated with significantly increased risks of postoperative tumor recurrence (hazard ratio [HR]: 1.20; p = 0.04), death from BCa (HR: 1.31; p = 0.003), and all-cause mortality (HR: 1.27; p = 0.0002). Among patients who received PBT, an increasing number of units transfused was independently associated with increased cancer-specific mortality (HR: 1.07; p < 0.0001) and all-cause mortality (HR: 1.05; p < 0.0001). Limitations include selection bias and lack of standardized transfusion criteria.

Conclusions

We found that PBT is associated with significantly increased risks of cancer recurrence and mortality following RC. While external validation is required, continued efforts to reduce the use of blood products in these patients are warranted.     

Propensity-Matched Comparison of Morbidity and Costs of Open and Robot-Assisted Radical Cystectomies: A Contemporary Population-Based Analysis in the United States

Background

Radical cystectomy (RC) is a morbid procedure associated with high costs. Limited population-based data exist on the complication profile and costs of robot-assisted RC (RARC) compared with open RC (ORC).

Objective

To evaluate morbidity and cost differences between ORC and RARC.

Design, setting, and participants

We conducted a population-based, retrospective cohort study of patients who underwent RC at 279 hospitals across the United States between 2004 and 2010.

Outcome measurements and statistical analysis

Multivariable logistic and median regression was performed to evaluate 90-d mortality, postoperative complications (Clavien classification), readmission rates, length of stay (LOS), and direct costs. To reduce selection bias, we used propensity weighting with survey weighting to obtain nationally representative estimates.

Results and limitations

The final weighted cohort included 34 672 ORC and 2101 RARC patients. RARC use increased from 0.6% in 2004 to 12.8% in 2010. Major complication rates (Clavien grade ≥3; 17.0% vs 19.8%, p = 0.2) were similar between ORC and RARC (odds ratio [OR]: 1.32; p = 0.42). RARC had 46% decreased odds of minor complications (Clavien grade 1–2; OR: 0.54; p = 0.03). RARC had $4326 higher adjusted 90-d median direct costs (p = 0.004). Although RARC had a significantly shorter LOS (11.8 d vs 10.2 d; p = 0.008), no significant differences in room and board costs existed (p = 0.20). Supply costs for RARC were significantly higher ($6041 vs $3638; p < 0.0001). Morbidity and cost differences were not present among the highest-volume surgeons (≥7 cases per year) and hospitals (≥19 cases per year). Limitations include use of an administrative database and lack of oncologic characteristics.

Conclusions

The use of RARC has increased between 2004 and 2010. Compared with ORC, RARC was associated with decreased odds of minor but not major complications and with increased expenditures attributed primarily to higher supply costs. Centralization of ORC and RARC to high-volume providers may minimize these morbidity and cost differences.

Patient summary

Using a US population–based cohort, we found that robotic surgery for bladder cancer decreased minor complications, had no impact on major complications and was more costly than open surgery.     

Perioperative Blood Transfusion and Radical Cystectomy: Does Timing of Transfusion Affect Bladder Cancer Mortality?

Background

While perioperative blood transfusion (BT) has been associated with adverse outcomes in multiple malignancies, the importance of BT timing has not been established.

Objective

The objective of this study was to evaluate whether intraoperative BT is associated with worse cancer outcomes in bladder cancer patients treated with radical cystectomy (RC).

Design, setting, and participants

Outcomes from two independent cohorts of consecutive patients with bladder cancer treated with RC were analyzed.

Outcome measurements and statistical analysis

Recurrence-free survival, cancer-specific survival (CSS), and overall survival were estimated and multivariate analyses were performed to evaluate the association of BT timing with cancer outcomes.

Results and limitations

In the primary cohort of 360 patients, 241 (67%) received perioperative BT, including 162 intraoperatively and 79 postoperatively. Five-year CSS was 44% among patients who received an intraoperative BT versus 64% for patients who received postoperative BT (p = 0.0005). After multivariate analysis, intraoperative BT was associated with an increased risk of cancer mortality (hazard ratio [HR]: 1.93; p = 0.02), while receipt of postoperative BT was not (p = 0.60). In the validation cohort of 1770 patients, 1100 (62%) received perioperative BT with a median postoperative follow-up of 11 yr (interquartile range: 8.0–15.7). Five-year RFS (p < 0.001) and CSS (p < 0.001) were significantly worse among patients who received an intraoperative BT. Intraoperative BT was independently associated with recurrence (HR: 1.45; p = 0.001), cancer-specific mortality (HR: 1.55; p = 0.0001), and all-cause mortality (HR: 1.40; p < 0.0001). Postoperative BT was not associated with risk of disease recurrence or cancer death.

Conclusions

Intraoperative BT is associated with increased risk of bladder cancer recurrence and mortality.

Patient summary

In this study, the effects of blood transfusion on bladder cancer surgery outcomes were evaluated. Intraoperative blood transfusion, but not postoperative transfusion, was associated with higher rates of recurrence and cancer-specific mortality.