Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

PURPOSE: Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. METHODS: Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. RESULTS: Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. CONCLUSION: Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

Changes in the Perioperative Management and Outcomes of Patients With Upper Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy at Memorial Sloan Kettering Cancer Center: Over 20 Years of Experience.

INTRODUCTION: We evaluated surgical trends, perioperative management evolution, and oncologic outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) at a tertiary cancer center over a 24-year period. METHODS: Between 1995 and 2018, we evaluated 743 consecutive patients with UTUC who underwent RNU. Generalized additive models were used to estimate the associations between date of surgery and continuous outcomes using a linear model, dichotomous outcomes using a logit link, categorical outcomes using multinomial models, and 2- and 5-year survival outcomes using Cox proportional hazards models. RESULTS: Over the study period, preoperative diagnostic endoscopic biopsies increased from 10% to 66%, along with the proportion of patients who underwent RNU for high-grade disease from 55% to 91%. The rate of open RNU declined from 100% to 56% with a rise in minimally invasive approaches. Median lymph node yield increased with more retroperitoneal lymph node dissections performed. Neoadjuvant chemotherapy utilization increased with a contemporary utilization rate of 32%, coinciding with an increase in pT0 rate from 2% to 8%. Cancer-specific survival probabilities improved over the study period, while metastasis-free and overall survival remained stable. CONCLUSIONS: We found several changes in treatment patterns and outcomes for patients with UTUC over the past 2 decades. How individual alterations in management factors, such as patient selection, perioperative chemotherapy, lymphadenectomy, and salvage therapies, impact patient outcomes is challenging in the setting of multiple overlapping practice changes for this rare disease and warrants further investigation.

Smoking characteristics and years since quitting smoking of US adults diagnosed with lung and bladder cancer: A national health and nutrition examination survey analysis.

PURPOSE: Smoking is a recognized risk factor for bladder BC and lung cancer LC. We investigated the enduring risk of BC after smoking cessation using U.S. national survey data. Our analysis focused on comparing characteristics of LC and BC patients, emphasizing smoking status and the latency period from smoking cessation to cancer diagnosis in former smokers. MATERIALS AND METHODS: We analyzed data from the National Health and Examination Survey (2003-2016), identifying adults with LC or BC history. Smoking status (never, active, former) and the interval between quitting smoking and cancer diagnosis for former smokers were assessed. We reported descriptive statistics using frequencies and percentages for categorical variables and median with interquartile ranges (IQR) for continuous variables. RESULTS: Among LC patients, 8.9% never smoked, 18.9% active smokers, and 72.2% former smokers. Former smokers had a median interval of 8 years (IQR 2-12) between quitting and LC diagnosis, with 88.3% quitting within 0-19 years before diagnosis. For BC patients, 26.8% never smoked, 22.4% were active smokers, and 50.8% former smokers. Former smokers had a median interval of 21 years (IQR 14-33) between quitting and BC diagnosis, with 49.3% quitting within 0-19 years before diagnosis. CONCLUSIONS: BC patients exhibit a prolonged latency period between smoking cessation and cancer diagnosis compared to LC patients. Despite smoking status evaluation in microhematuria, current risk stratification models for urothelial cancer do not incorporate it. Our findings emphasize the significance of long-term post-smoking cessation surveillance and advocate for integrating smoking history into future risk stratification guidelines.

Total Margin Control Is Superior to Traditional Margin Assessment for Treatment of Low-Stage Penile Squamous Cell Carcinoma.

PURPOSE: Penile cancer is rare, with significant morbidity and limited literature assessing utility of peripheral and deep en face margin assessment (PDEMA) vs traditional margin assessment (vertical sections) on treatment outcomes. MATERIALS AND METHODS: This was a 32-year retrospective multicenter cohort study at 3 academic tertiary care centers. The cohort consisted of 189 patients with histologic diagnosis of in situ or T1a cutaneous squamous cell carcinoma of the penis at Brigham and Women's, Massachusetts General Hospital (1988-2020), and Memorial Sloan Kettering Cancer Center (1995-2020) treated with PDEMA surgical excision, excision/circumcision, or penectomy/glansectomy. Local recurrence, metastasis, and disease-specific death were assessed via multivariable Cox proportional hazard models. RESULTS: The cohort consisted of 189 patients. Median age at diagnosis was 62 years. Median tumor diameter was 1.3 cm. The following outcomes of interest occurred: 30 local recurrences, 13 metastases, and 5 disease-specific deaths. Primary tumors were excised with PDEMA (N = 30), excision/circumcision (N = 110), or penectomy/glansectomy (N = 49). Of patients treated with traditional margin assessment (non-PDEMA), 12% had narrow or positive margins. Five-year proportions were as follows with respect to local recurrence-free survival, metastasis-free survival, and disease-specific survival/progression-free survival, respectively: 100%, 100%, and 100% following PDEMA; 82%, 96%, and 99% following excision/circumcision; 83%, 91%, and 95% following penectomy/glansectomy. A limitation is that this multi-institutional cohort study was not externally validated. CONCLUSIONS: Initial results are encouraging that PDEMA surgical management effectively controls early-stage penile squamous cell carcinoma.

Evidence-Based Analysis of the Critical Steps of Radical Cystectomy for Bladder Cancer.

Radical cystectomy (RC) is an integral part of the management of patients with advanced-stage bladder cancer. This major oncologic operation is prone to complications resulting in morbidity and mortality. We analyzed the critical steps of open RC, performed an evidence-based review of these steps, and discussed our experience and approach. We conducted a literature review of the open RC technique, identified the critical steps that consistently appeared across different sources, and organized these steps into a framework. PubMed was queried with the critical steps as keywords for relevant articles published from 1 January 2013 to 1 August 2023. We utilized this query to conduct a systematic review of the literature using the outcomes of overall survival and 90-day complication rate. We developed the "Summary for the 10 Critical Operative Steps of Radical Cystectomy", a concise guide to the approach to open RC. When available, an evidence-based analysis of each critical step was performed. We also included additional components of cystectomy optimization such as pre-habilitation in the preoperative phase, standard versus extended lymphadenectomy, the vaginal-sparing approach to female radical cystectomy, patient-reported outcomes following urinary diversion, the use of a mesh for stoma formation, and the use of the ERAS protocol for postoperative care. An evidence-based assessment of RC may help provide valuable information to optimize surgical techniques and patient outcomes.

Anticoagulation prophylaxis patterns following retroperitoneal lymph node dissection for testis cancer.

INTRODUCTION: Retroperitoneal lymph node dissection (RPLND) is the standard of care for testicular cancer in various disease settings. Deep vein thrombosis (DVT) complications have been reported to occur in <1% of primary RPLND cases and up to 3% of postchemotherapy (PC-RPLND) cases. While prophylactic anticoagulation (AC) has been well-documented to reduce DVT rates in patients undergoing surgery in general, the benefit of prophylactic AC in RPLND has not been assessed. In this retrospective cohort study, we seek to address this unmet need by evaluating the rates and associated risk factors of DVT and pulmonary embolism (PE) with a national and institutional database, assess the changing patterns in DVT prophylaxis with postoperative AC following RPLND, and quantify the potential benefit of prophylactic AC in patients who have undergone RPLND using a risk-stratified approach. METHODS: The National Surgical Quality Improvement Program (NSQIP) database was queried for patients who underwent RPLND during the 10-year period from 2011 to 2021. An institutional database was queried for all patients undergoing RPLND from 2013 to 2022. Patient characteristics and operative outcomes were compared between the NSQIP and the institutional database. The institutional database was stratified by prior oncologic treatment (i.e., primary RPLND vs. PC-RPLND) and outcomes were compared. Postoperative AC rate was determined and trended by year. The use of postoperative AC and PE events were stratified by clinical stage. The absolute risk reduction (ARR) of AC prophylaxis on PE events and the number needed to treat (NNT) with AC prophylaxis to prevent a single PE event was determined. RESULTS: In total, the NSQIP database query resulted in 779 patients and our institutional database query resulted in 188 patients. The rate of DVT and PE was 1.2% and 0.5% vs. 2.1% and 1.6% in the NSQIP and institutional cohort, respectively. The rate of postoperative AC following RPLND in patients from the institutional database increased from 5% in 2013 to 43% in 2022 (P = 0.01). There were no statistically significant differences in complication rates, including bleeding events, chyle leaks, or hospital readmissions amongst patients who were prescribed AC at discharge and those who were not. No stage I patients developed PEs and no stage I patients were prescribed AC. The ARR for AC prophylaxis for development of PE was found to be 0.023 for the clinical stage II and stage III cohorts. The NNT to prevent a single PE with AC was 44 and 43 for the stage II and stage III cohorts, respectively. CONCLUSIONS: AC appears beneficial with minimal risk of harm after RPLND, especially in patients with higher risk of developing DVT/PE, highlighting the safety and efficacy of this regimen. There was a significant increase in the rate of AC prophylaxis at discharge amongst patients undergoing RPLND in the institutional database from 2013 to 2022. A risk-stratified protocol of postoperative AC following RPLND appears reasonable, and further prospective trials are warranted to formally confirm this recommendation.

Sequential intravesical gemcitabine/docetaxel provides a durable remission in recurrent high-risk NMIBC following BCG therapy.

PURPOSE: Bacillus Calmette-Guerin (BCG) is the standard of care for high-risk nonmuscle invasive bladder cancer (NMIBC), but half of patients develop disease recurrence. Intravesical regimens for BCG unresponsive NMIBC are limited. We report the safety, efficacy, and differential response of sequential gemcitabine/docetaxel (gem/doce) depending on BCG failure classification. METHODS: Multi-institutional retrospective analysis of patients treated with induction intravesical gem/doce (≥5/6 instillations) for recurrent high-risk NMIBC after BCG therapy from May 2018 to December 2021. Maintenance therapy was provided to those without high-grade (HG) recurrence on surveillance cystoscopy. Kaplan-Meier curves and Cox regression analyses were utilized to assess survival and risk factors for disease recurrence. RESULTS: Our cohort included 102 patients with BCG-unresponsive NMIBC. Median age was 72 years and median follow-up was 18 months. Six-, 12-, and 24-month high-grade recurrence-free survival was 78%, 65%, and 49%, respectively. Twenty patients underwent radical cystectomy (median 15.5 months from induction). Six patients progressed to muscle invasive disease. Fifty-seven percent of patients experienced mild/moderate adverse effects (AE), but only 6.9% experienced a delay in treatment schedule. Most common AE were urinary frequency/urgency (41%) and dysuria (21%). Patients with BCG refractory disease were more likely to develop HG recurrence when compared to patients with BCG relapsing disease (HR 2.14; 95% CI 1.02-4.49). CONCLUSIONS: In patients with recurrence after BCG therapy, sequential intravesical gem/doce is an effective and well-tolerated alternative to early cystectomy. Patients with BCG relapsing disease are more likely to respond to additional intravesical gem/doce. Further investigation with a prospective trial is imperative.

Impact of exercise on physical health status in bladder cancer patients.

INTRODUCTION: There is a scarcity of data on the impact of behavioral habits, such as exercise, on physical health in patients with bladder cancer. We investigated the association of exercise on self-reported physical health status and examined the prevalence of bladder cancer patients with sedentary lifestyle. METHODS: We examined cross-sectional data of participants diagnosed with bladder cancer within the Behavioral Risk Factor Surveillance System (BRFSS) from 2016-2020. Patient health status was surveyed using self-reported measures, such as the total days per month when their "physical health is not good." The primary outcome was patient-reported poor physical health for more than 14 days within a one-month period. RESULTS: Out of 2 193 981 survey participants, we identified 936 with a history of bladder cancer. Nearly one in three bladder cancer patients reported being sedentary within the last month, as a total of 307 (32.8%) patients reported no exercise within the last 30 days. The remaining 628 (67.2%) reported exercising for at least one day within the last month. In multivariable logistic regression model analysis, we found that exercise is protective for self-reported poor physical health status (odds ratio 0.37, 95% confidence interval 0.25-0.56, p<0.001). Patients that exercised were less likely to report bad physical health. CONCLUSIONS: Approximately one in three bladder cancer patients report no exercise within 30 days, suggesting a sedentary lifestyle. Patients that are active are less likely to self-report poor physical health status. Implementation of exercise programs for bladder cancer patients could be promising in improving health status.

Genomic heterogeneity as a barrier to precision oncology in urothelial cancer.

Precision oncology relies on the accurate molecular characterization of individual patients with cancer at the time of treatment initiation. However, tumor molecular profiles are not static, and cancers continually evolve because of ongoing mutagenesis and clonal selection. Here, we performed genomic analyses of primary tumors, metastases, and plasma collected from individual patients to define the concordance of actionable genomic alterations and to identify drivers of metastatic disease progression. We observed a high degree of discordance of actionable genomic alterations, with 23% discordant between primary and metastatic disease sites. Among chromatin-modifying genes, ARID1A mutations, when discordant, were exclusive to the metastatic tumor samples. Our findings indicate that the high degree of lesion-to-lesion genomic heterogeneity may be a barrier to precision oncology approaches for bladder cancer and that circulating tumor DNA profiling may be preferred to tumor sequencing for a subset of patients.

FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.

Pathologic stage as a surrogate for oncologic outcomes after receipt of neoadjuvant chemotherapy for high-grade upper tract urothelial carcinoma.

OBJECTIVE: Whether pathologic stage at radical nephroureterectomy (RNU) can serve as an appropriate surrogate for oncologic outcomes in patients with high-grade (HG) upper tract urothelial carcinoma (UTUC) treated with neoadjuvant chemotherapy (NAC) is not defined. We sought to determine whether patients who achieve pathologically non-muscle-invasive (ypT0, ypTa, ypT1, ypTis) HG UTUC after receipt of NAC exhibit oncologic outcomes comparable to those who are inherently low stage without chemotherapy. METHODS: We identified 647 UTUC patients who underwent RNU among 3 institutions from 1993to2016. Patients with low or unknown grade, pathologic muscle invasion, or receipt of adjuvant chemotherapy were excluded. We compared clinicopathologic data and oncologic outcomes between pT0-1 and ypT0-1 patients. Kaplan-Meier analysis was used to assess overall (OS), cancer-specific (CSS), and systemic recurrence-free (RFS) survival. Predictors of these endpoints were identified using Cox regression. RESULTS: 234 (43 ypT0-1, 191 pT0-1) patients with HG UTUC were included. Two patients exhibited pathologic complete response after NAC. OS (P = 0.055), CSS (P = 0.152), and RFS (P = 0.098) were similar between ypT0-1 and pT0-1 patients. Predictors of worse outcomes included African-American race (RFS, CSS, and OS), Charlson score (OS), and systemic recurrence (OS and CSS). CONCLUSIONS: Patients with HG UTUC who achieve ypT0-1 stage after NAC exhibit favorable oncologic outcomes comparable to those inherently non-muscle-invasive who do not receive chemotherapy. Improvements in clinical staging will play an important role in better defining candidacy for NAC in treating HG UTUC while minimizing overtreatment. Furthermore, pathologic stage may serve as an appropriate early surrogate for oncologic endpoints in designing clinical trials.

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts.

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.

Is there an oncological benefit to extended lymphadenectomy for muscle-invasive bladder cancer?

The full optimal extent of a pelvic lymph node dissection (PLND) at time of radical cystectomy (RC) has not yet been determined. The diagnostic role of LND is clear and is extremely important for identifying those who may benefit from adjuvant therapy. While retrospective analyses have demonstrated improved survival when the number of lymph nodes is increased and extended LNDs (eLNDs) are performed, these results have yet to be borne out in prospective randomized phase III trials. The recently published LEA AUO AB 25/02 trial is a promising attempt to determine the efficacy of eLND, but unfortunately falls short because of its limited design and therefore, did not demonstrate an improvement in recurrence-free survival (RFS). In an era of increased utilization of neoadjuvant chemotherapy (NAC) providing survival benefit, the ability to demonstrate improved survival with eLND is even more challenging. Currently, we are awaiting the results of SWOG S1011, expectations of achieving a positive trial with improved RFS remains unlikely.

Urinary Diversion Disparity Following Radical Cystectomy for Bladder Cancer in the Hispanic Population.

OBJECTIVE: To determine if disparities in quality of surgical care exist between Hispanics and non-Hispanics undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS: An observational cohort study was conducted retrospectively on patients who underwent radical cystectomy for urothelial carcinoma of the bladder at our institution between January 2005 and July 2018. Data was collected on demographic, clinical, and pathological characteristics of patients, including self-reported ethnicity. Univariable and multivariable logistic or linear regression analyses were used to evaluate the association of ethnicity with receipt of neoadjuvant chemotherapy, utilization of laparoscopic surgery, number of lymph nodes removed, and continent urinary diversion. RESULTS: We identified 507 patients in our database out of which, 136 (27%) were Hispanic and 371 (73%) were non-Hispanic. Compared to non-Hispanics, Hispanics had a higher body mass index (26.9 kg/m2 vs 28.2 kg/m2, P = .006) and lived further away from site of surgery (34 vs 96 miles, P = .02). No significant differences were observed in receipt of neoadjuvant chemotherapy, laparoscopic surgery, or number of lymph nodes removed during cystectomy between ethnicity groups. However, Hispanics were less likely than non-Hispanics to receive a continent urinary diversion on multivariable analysis (odds ratio 0.30, 95% confidence interval 0.10 - 0.92, P = .03). CONCLUSION: Disparity exists in the delivery of continent urinary diversions for Hispanic patients undergoing radical cystectomy for bladder cancer. Further investigation is needed to determine the potential causes for this disparity in care delivered.

Validating the predictors of outcomes after radical cystectomy for bladder cancer.

BACKGROUND: An assessment of surgical risk is essential for patient counseling and decision making, and it can provide rationale adjustment for patient populations as health care moves from a fee-for-service to a value-based reimbursement model. The modified Frailty Index (mFI) has been proposed as a risk-stratification tool for radical cystectomy (RC), and the objective of the current study was to validate this potential use of the mFI using an institutional cohort. METHODS: A retrospective review of all patients who underwent RC for bladder cancer was conducted at the authors' institution from 2012 to 2016. In addition to detailed clinicopathologic and treatment parameters, patients were categorized according to the mFI, the Charlson Comorbidity Index (CCI), and the American Society of Anesthesiologists (ASA) classification. Covariates were analyzed to determine associations with 1-month complication rates (according to the Clavien-Dindo system), 3-month readmission rates, hospitalization length, and hospitalization costs. RESULTS: In total, 346 patients were included in the analysis. The overall complication rate was 56.6%, the major (Clavien grade ≥3) complication rate was 19.4%, and the readmission rate was 27.9%. Receiver operating curve analysis demonstrated a weak association of all indices with major complications after RC: the area under the curve was 0.535 (95% confidence interval [CI], 0.460-0.611) for the ASA classification; 0.565 (95% CI, 0.485-0.645) for the CCI score; and 0.551 (95% CI, 0.471-0.631) for the mFI. There were no significant differences in the rate of major complications when stratifying the results according to the mFI, CCI, or ASA class. Length of hospitalization and associated costs were correlated with mFI. CONCLUSIONS: Frailty was not associated with postoperative complications and provided little additional predictive ability over the ASA classification and the CCI score. Further research is required to identify patients who are likely to suffer significant complications after RC.

Preoperative multiplex nomogram for prediction of high-risk nonorgan-confined upper-tract urothelial carcinoma.

BACKGROUND: Accurate risk stratification prior to radical nephroureterectomy remains a challenge with upper-tract urothelial carcinoma (UTUC). Herein, we generated an optimized preoperative tool predicting high-risk nonorgan-confined (NOC)-UTUC. MATERIALS AND METHODS: Retrospective evaluation of 699 patients undergoing radical nephroureterectomy at 3 academic centers. Multiplex preoperative patient, imaging, endoscopic, and laboratory values were evaluated. Model derivation and validation were based on a split-sample method. Patients were divided randomly into a development (training) cohort (70% of patients) and validation (test) cohort (30% of patients). Univariate and multivariate logistic regression addressed the prediction of NOC disease (pT3/pT4 and/or pN+) based on training cohort. A backward stepdown selection process achieved the most informative nomogram. The ROC analysis identified a cut-off point predicting high-risk disease. The test cohort served as "external" validation to verify the findings based on the training cohort. Bootstrap resampling was conducted for both internal and "external" validation to evaluate the model fitting. RESULTS: Total of 566 patients included for analysis, mean age 69.7 years, 85% Caucasian, 64% male, 62% high grade. NOC-UTUC was found in 184 (32.5%) patients on final pathology. Of 184 patients with NOC-UTUC, an equal number of renal pelvis and ureter only tumors (n = 74; 40.2% for each location) were noted; 36 (19.6%) had tumors in both locations. Multivariate model based on development cohort (n = 396) demonstrated clinical stage (odds ratio [OR] 14.0, P < 0.01), biopsy tumor grade (OR 3.3, P = 0.01), tumor architecture (OR 2.65, P = 0.09), and Hgb (OR 0.8, P = 0.02) level were independently associated with NOC disease. A preoperative nomogram incorporating these 4 variables achieved 82% accuracy, 48% sensitivity, and 95% specificity in predicting NOC-UTUC. The cut-off point for predicting high-risk disease was ≥0.49. CONCLUSIONS: We established and validated an accurate tool for the prediction of locally advanced NOC-UTUC. This preoperative nomogram can be used to more optimally select patients for preoperative systemic chemotherapy, and facilitate clinical trial enrollment.

Incidence and Outcomes of Delayed Targeted Therapy After Cytoreductive Nephrectomy for Metastatic Renal-Cell Carcinoma: A Nationwide Cancer Registry Study.

BACKGROUND: The optimal timing of targeted therapy (TT) initiation for metastatic renal-cell carcinoma (mRCC) is not clear. We used a nationwide cancer registry to determine clinical and social factors associated with delayed TT and to evaluate the association of a delayed approach with overall survival (OS). PATIENTS AND METHODS: We performed a retrospective observational study utilizing the National Cancer Data Base from 2006 to 2012 for patients diagnosed with mRCC (clear-cell histology) treated with cytoreductive nephrectomy and TT. Time to initiation of TT was defined as early (within 2 months), moderately delayed (2-4 months), delayed (4-6 months), and late (> 6 months). RESULTS: Of the 2716 patients included in the analysis, the median (interquartile range) time from diagnosis to initiation of TT was 2.1 (1.3-3.23) months. A total of 1255 patients (46.2%) had early TT, 1072 patients (39.5%) had moderately delayed TT, 284 patients (10.5%) had delayed TT, and 105 patients (3.9%) had late TT. Delay in TT initiation was not independently associated with OS in multivariable analysis. The time interval from diagnosis to TT initiation was not correlated with time from initiation of TT to death (r = 0.04, P = .08). CONCLUSION: We found that delayed initiation of TT was not an independent predictor of worse OS. Although this study is subject to limitations of observation study design and selection bias, the results are consistent with the notion that in carefully selected patients, outcomes might not be compromised with initial observation.