Cost-effectiveness of avelumab first-line maintenance therapy for adult patients with locally advanced or metastatic urothelial carcinoma in France.

BACKGROUND: This study evaluated the cost-effectiveness of avelumab first-line (1L) maintenance therapy plus best supportive care (BSC) versus BSC alone for adults with locally advanced or metastatic urothelial carcinoma (la/mUC) that had not progressed following platinum-based chemotherapy in France. METHODS: A three-state partitioned survival model was developed to assess the lifetime costs and effects of avelumab plus BSC versus BSC alone. Data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) were used to inform estimates of clinical and utility values considering a 10-year time horizon and a weekly cycle length. Cost data were estimated from a collective perspective and included treatment acquisition, administration, follow-up, adverse event-related hospitalization, transport, post-progression, and end-of-life costs. Health outcomes were measured in quality-adjusted life-years (QALYs) and life-years gained. Costs and clinical outcomes were discounted at 2.5% per annum. Incremental cost-effectiveness ratios (ICERs) were used to compare cost-effectiveness and willingness to pay in France. Uncertainty was assessed using a range of sensitivity analyses. RESULTS: Avelumab plus BSC was associated with a gain of 2.49 QALYs and total discounted costs of €136,917; BSC alone was associated with 1.82 QALYs and €39,751. Although avelumab plus BSC was associated with increased acquisition costs compared with BSC alone, offsets of -€20,424 and -€351 were observed for post-progression and end-of-life costs, respectively. The base case analysis ICER was €145,626/QALY. Sensitivity analyses were consistent with the reference case and showed that efficacy parameters (overall survival, time to treatment discontinuation), post-progression time on immunotherapy, and post-progression costs had the largest impact on the ICER. CONCLUSIONS: This analysis demonstrated that avelumab plus BSC is associated with a favorable cost-effectiveness profile for patients with la/mUC who are eligible for 1L maintenance therapy in France.

Predicting individual outcomes after radical cystectomy in urothelial variants with Cancer of the Bladder Risk Assessment (COBRA) score.

OBJECTIVE: To validate the Cancer of the Bladder Risk Assessment (COBRA) score in patients with urothelial variants. METHODS: Epidemiological, clinical, radiological, and anatomopathological data were collected from patients with urothelial carcinoma who underwent radical cystectomy at the Institute of Cancer of São Paulo between May 2008 and December 2022. Patients with the presence of at least 10% of any urothelial variants in the radical cystectomy specimens' anatomopathological exam were included in the study. The COBRA score and derivatives were applied and correlated with oncological outcomes. RESULTS: A total of 680 patients [482 men (70.9%) and 198 women (29.1%)]; 66 years (IQR 59-73) underwent radical cystectomy for bladder tumor, and of these patients, a total of 167 patients presented any type of urothelial variant. The median follow-up time was 28.77 months (IQR 12-85). The three most prevalent UV were squamous differentiation (50.8%), glandular differentiation (31.3%), and micropapillary differentiation (11.3%). The subtypes with the worst prognosis were sarcomatoid with a median survival of 8 months (HR 1.161; 95% CI 0.555-2.432) and plasmacytoid with 14 months (HR 1.466; 95% CI 0.528-4.070). The COBRA score for patients with micropapillary variants demonstrated good predictive accuracy for OS (log-rank P = 0.009; 95% IC 6.78-29.21) and CSS (log-rank P = 0.002; 95% IC 13.06-26.93). CONCLUSIONS: In our study, the COBRA score proved an effective risk stratification tool for urothelial histological variants, especially for the micropapillary urothelial variant. It may be helpful in the prognosis evaluation of UV patients after radical cystectomy.

A SEER-Medicare Based Quality Score for Patients With Metastatic Upper Tract Urothelial Carcinoma.

BACKGROUND: Population-based studies evaluating outcomes for metastatic upper tract urothelial carcinoma (mUTUC) are sparse and rarely capture both patients with de novo (synchronous) metastases and those who progress to metastatic disease (metachronous). Herein we evaluated the outcomes and costs associated with synchronous and metachronous mUTUC, utilizing a novel Methodology. Additionally, we created a guideline-based quality score to improve care in this space. PATIENTS AND METHODS: We identified all patients with mUTUC aged 66 years and older included in the SEER-Medicare linked database between 2004 and 2012. Achievement of 3 quality criteria was assessed: (1) cancer-specific survival (CSS)>12 months; (2) receipt of systemic therapy; (3) receipt of hospice/palliative care. Total healthcare and out-of-pocket costs were evaluated. Regression analyses were performed to assess characteristics associated with quality criteria and total healthcare costs. RESULTS: Of the 1223 patients identified, at least one quality criterion was met in just 40.2% and only 54 patients (4.4%) received palliative care. In multivariable analysis, patients with synchronous mUTUC (OR:0.55, 95%CI:0.41-0.72), and at least 3 comorbidities (OR:0.68, 95%CI:0.47-0.98) were less likely to achieve at least 1 quality criterion. Meeting at least 1 quality criterion was associated with increased costs ($94,677, 95%CI:87,702-101,652 versus $63,575, 95%CI:59,598-67,552). CONCLUSIONS: Less than half of patients with mUTUC met at least 1 quality criterion. Quality score achievement was associated with a modest increase in total healthcare spending. These findings not only provide guidance for future study of rare diseases using secondary data, but also highlight inadequacies in the current management of mUTUC.

Clinical and Economic Outcomes in Patients With Metastatic Urothelial Carcinoma Receiving First-Line Systemic Treatment (the IMPACT UC I Study).

BACKGROUND: The IMPACT UC I study assessed real-world treatment patterns, outcomes, healthcare resource utilization (HCRU), and costs in patients with metastatic urothelial carcinoma (mUC) receiving first-line (1L) systemic treatment after the FDA approval of 1L immune checkpoint inhibitor (ICI) monotherapy. PATIENTS AND METHODS: This retrospective study used 100% Medicare fee-for-service claims from 1/1/2015 to 6/30/2019 to identify patients aged ≥18 years diagnosed with UC with evidence of metastatic disease, continuously enrolled for 6 months before and after initial diagnosis. Patients were grouped by 1L treatment: cisplatin-containing chemotherapy, carboplatin-containing chemotherapy, ICI monotherapy, or nonplatinum-containing therapy. Unadjusted time on 1L treatment (TOT), overall survival (OS), HCRU, and total healthcare costs were analyzed. RESULTS: Of 18 888 patients with mUC, 8630 (45.7%) had received identified 1L systemic treatment; platinum-containing chemotherapy was the most common (cisplatin-containing chemotherapy, 37.6%; carboplatin-containing chemotherapy, 30.2%). Cisplatin- and carboplatin-containing chemotherapy had the shortest time-to-treatment initiation (median, 1.7-3.0 months) and longest TOT (median, 4.0-4.3 months). Median OS was longest with cisplatin-containing chemotherapy (20.0 months) and shortest with ICI monotherapy (7.6 months). Cisplatin- and carboplatin-containing chemotherapy were associated with highest HCRU; total healthcare costs were approximately 2-fold higher with ICI monotherapy vs other 1L treatments ($10 359 vs $5042-$5709 per patient per month). CONCLUSION: 1L platinum-containing chemotherapy resulted in the longest median OS and highest HCRU, whereas 1L ICI treatment had the shortest median OS and the highest costs. Over 50% of patients diagnosed with advanced UC (aUC) received no systemic therapy, highlighting the importance of optimal 1L treatment decisions in aUC.

Adenocarcinoma of the Bladder: Assessment of Survival Advantage Associated With Radical Cystectomy and Comparison With Urothelial Bladder Cancer.

PURPOSE: To evaluate the association between radical cystectomy (RC) and cancer-specific mortality (CSM) in patients diagnosed with adenocarcinoma of the bladder (ACB). Moreover, to directly compare the survival advantage of RC between ACB vs. urothelial bladder cancer (UBC). MATERIALS AND METHODS: Non-metastatic muscle-invasive ACB and UBC patients were identified within Surveillance, Epidemiology, and End Results database (SEER 2000-2018). All analyses were stratified between RC vs. no-RC, in either organ-confined (OC: T2N0M0) or non-organ-confined (NOC: T3-4N0M0 or TanyN1-3M0) stages. Propensity score matching (PSM), cumulative incidence plots, competing risks regression (CRR) analyses, and 3 months' landmark analyses were performed. RESULTS: Overall, 1,005 ACB and 47,741 UBC patients were identified, of whom 475 (47%) and 19,499 (41%) were treated with RC, respectively. After PSM, comparison between RC vs. no-RC applied to 127 vs. 127 OC-ACB, 7,611 vs. 7,611 OC-UBC, 143 vs. 143 NOC-ACB, and 4,664 vs. 4,664 NOC-UBC patients. 36-month CSM rates in RC vs. no-RC patients were 14 vs. 44% in OC-ACB, 18 vs. 39% in OC-UBC, 49 vs. 66% in NOC-ACB, and 44 vs. 56% in NOC-UBC patients. In CRR analyses, the effect of RC on CSM yielded a hazard ratio of 0.37 in OC-ACB, of 0.45 in OC-UBC, of 0.65 in NOC-ACB and of 0.68 in NOC-UBC patients (all P values<0.001). Landmark analyses virtually perfectly replicated the results. CONCLUSIONS: In ACB, regardless of stage, RC is associated with lower CSM. The magnitude of this survival advantage was greater in ACB than in UBC, even after control for immortal time bias.

Lymph node assessment technique matters in radical cystectomy for bladder cancer.

BACKGROUND: For patients undergoing radical cystectomy with pelvic lymph node dissection for urothelial cancer, a lymph node count of at least 16 is associated with improved cancer-specific and overall survival. Lymph node yield is presumed to relate directly to extent of dissection and surgical quality, however limited studies have reviewed the impact of the pathological assessment process of lymph nodes on lymph node yield. METHOD: A retrospective assessment of 139 patients who had radical cystectomy for urothelial cancer between March 2015 and July 2021 from Fiona Stanley Hospital (Perth, Australia) by a single surgeon was assessed. A change in pathological assessment process from assessment of only palpable lymph nodes to microscopic assessment of the entire submitted specimens occurred in August 2018. Patients were divided into two groups accordingly and other relevant demographic and pathological data was recorded. The impact of pathological processing technique on lymph node yield was assessed using the Student T test and logistical regression was used to assess the impact of other demographic variables. RESULTS: The mean lymph node yield was 16.2 nodes (IQR 12-23) in 54 patients in the pre-process change group compared to 22.4 nodes (IQR 15-28.4) in 85 patients in the post-process change group (P < 0.0001). 53.7% had 16 or more nodes in the pre-process change group compared to 71.3% in the post-process change group (P = 0.04). Age, BMI, and gender were not significant predictors of lymph node yield. CONCLUSION: The current study demonstrates that the microscopic assessment of all lymph node tissue detects significantly more lymph nodes than only examining palpably abnormal tissue. Pathologic assessment protocols should be standardized to this technique to ensure the utility of lymph node yield as a quality metric.

Animal model assessment of a new design for a coated mitomycin-eluting biodegradable ureteral stent for intracavitary instillation as an adjuvant therapy in upper urothelial carcinoma.

BACKGROUND: A major limitation in the treatment of upper urinary tract urothelial carcinoma is the limited use of adjuvant therapy due to the drawbacks of current techniques for intracavitary instillation. The aim was to assess, in a large animal model, a biodegradable ureteral stent coated with silk fibroin for mitomycin release, i.e. BraidStent-SF-MMC. METHODS: A total of 14 female pigs with a solitary kidney underwent initial urinalysis, blood chemistry, nephrosonographic, and contrast fluoroscopy assessment of the urinary tract. Later, the BraidStent-SF-MMC was placed retrogradely to assess the mitomycin urine concentration from 0-48 hours. Follow-up was performed weekly until complete stent degradation to assess the macroscopic and microscopic changes in the urinary tract, stent complications. RESULTS: The drug eluting stent released mitomycin for the first 12 h. The main complication was the release of obstructive ureteral coating fragments during the first to third week in 28.5 and 7.1% of animals, respectively, related to urinary pH<7.0, which destabilized the stent coating. Another complication was ureteral strictures between the fourth and sixth week in 21%. The stents were completely degraded by 6-7 weeks. There were no stent-related systemic toxic effects. The success rate was 67.5% and the complication rate was 25.7%. CONCLUSIONS: For the first time, we have shown that a biodegradable anti-cancer drug eluting stent, BraidStent-SF-MMC, provides controlled and well-tolerated release of mitomycin into the upper urinary tract in an animal model. Mitomycin release from a silk fibroin coating could be a compelling approach for adjuvant chemotherapy instillation in upper tract urothelial carcinoma management.

Assessment of association between lower ureteric excision technique and oncological outcomes for upper urinary tract urothelial carcinoma: retrospective analysis from the Scottish Renal Cancer Consortium.

PURPOSE: Nephroureterectomy(NU) remains the gold-standard surgical option for the management of upper urinary tract urothelial carcinoma(UTUC). Controversy exists regarding the optimal excision technique of the lower ureter. We sought to compare post-UTUC bladder tumour recurrence across the Scottish Renal Cancer Consortium(SRCC). METHODS: Patients who underwent NU for UTUC across the SRCC 2012-2019 were identified. The impact of lower-end surgical technique along with T-stage, N-stage, tumour location and focality, positive surgical margin, pre-NU ureteroscopy, upper-end technique and adjuvant mitomycin C administration were assessed by Kaplan-Meier and Cox-regression. The primary outcome was intra-vesical recurrence-free survival (B-RFS). RESULTS: In 402 patients, the median follow-up was 29 months. The lower ureter was managed by open transvesical excision in 90 individuals, transurethral and laparoscopic dissection in 76, laparoscopic or open extra-vesical excision in 31 and 42 respectively, and transurethral dissection and pluck in 163. 114(28.4%) patients had a bladder recurrence during follow-up. There was no difference in B-RFS between lower-end techniques by Kaplan-Meier (p = 0.94). When all factors were taken into account by adjusted Cox-regression, preceding ureteroscopy (HR 2.65, p = 0.001), lower ureteric tumour location (HR 2.16, p = 0.02), previous bladder cancer (HR 1.75, p = 0.01) and male gender (HR 1.61, p = 0.03) were associated with B-RFS. CONCLUSION: These data suggest in appropriately selected patients, lower ureteric management technique does not affect B-RFS. Along with lower ureteric tumour location, male gender and previous bladder cancer, preceding ureteroscopy was associated with a higher recurrence rate following NU, and the indication for this should be carefully considered.

Assessment of association between PD-L1 expression and clinicopathological characteristics of Indonesian patients with high grade bladder urothelial carcinoma.

INTRODUCTION: Urothelial carcinoma (UC) is the most common type of bladder cancer. One of the treatments that are currently being explored for UC involves the use of immune checkpoint inhibitors, especially those targeting PD-1/PD-L1 interaction. This interaction has been previously suggested to aid in the prediction of outcomes. This study was aimed to investigate PD-L1 expression in high grade UC cases in Indonesia, both at mRNA and protein levels, and assess its associated clinicopathological characteristics. MATERIALS AND METHODS: The study involved analysis of 51 formalin-fixed paraffin-embedded (FFPE) tissue samples, obtained from patients diagnosed with high grade UC. PD-L1 expression was measured using immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction. RESULTS: PD-L1 IHC staining was found to be positive in five (9.80%) cases. Upregulated expression of PD-L1 mRNA was reported in the patients belonging to older age group (p = 0.049) and mainly involved less invasive cases (p = 0.019), when compared with normoregulated group. Age was positively correlated with PD-L1 expression, as observed in IHC (r = 0.281, p = 0.046). In comparison to this, mitotic index was found to be inversely correlated with PD-L1 mRNA levels (r = -0.369, p = 0.008). CONCLUSION: IHC staining results showed that PD-L1 expression was lower as compared to previous studies, which might suggest poor response to anti PD-1/PD-L1 agents. The results of the study showed that higher mRNA levels were associated with lower proliferation and less invasive behavior. Thus, the study suggested the potential of PD-L1 mRNA levels to be used as a predictive factor for patient outcomes.

Comparing costs of renal preservation versus radical nephroureterectomy management among patients with non-metastatic upper tract urothelial carcinoma.

BACKGROUND: To describe overall and categorical cost components in the management of patients with non-metastatic upper tract urothelial carcinoma (UTUC) according to treatment. METHODS: We identified 4,114 patients diagnosed with non-metastatic UTUC from 2004 to 2013 in the Survival Epidemiology and End Results-Medicare linked database. Patients were stratified into renal preservation (RP) vs. radical nephroureterectomy (NU) groups. Total Medicare costs within 1 year of diagnosis were compared for patients managed with RP vs. NU using inverse probability of treatment-weighted propensity score models. RESULTS: A total of 1,085 (26%) and 3,029 (74%) patients underwent RP and NU, respectively. Median costs were significantly lower for RP vs. NU at 90 days (median difference -$4,428, Hodges-Lehmann [H-L] 95% confidence interval [CI], -$7,236 to -$1,619) and 365 days (median difference -$7,430, H-L 95% CI, -$13,166 to -$1,695), respectively. Median costs according to categories of services were significantly less for RP vs. NU patients by hospitalization, office visits, emergency room/critical care, consultations, and anesthesia. The only category which was significantly higher for RP vs. NU was inpatient visits ($1,699 vs. $1,532; median difference $152; HL 95% CI, $19-$286). CONCLUSIONS: Median costs were significantly lower for RP vs. NU up to 1-year and by hospitalization, office visits, emergency room/critical care, consultations, and anesthesia costs. In appropriately selected patients, such as patients with low-risk disease, these findings suggest the utility of RP as a suitable high-value management option in UTUC.

Contemporary Trends of Systemic Neoadjuvant and Adjuvant Intravesical Chemotherapy in Patients With Upper Tract Urothelial Carcinomas Undergoing Minimally Invasive or Open Radical Nephroureterectomy: Analysis of US Claims on Perioperative Outcomes and Health Care Costs.

INTRODUCTION: New evidence indicates that minimally invasive surgery (MIS) (laparoscopic or robotic-assisted [LNU, RANU]) reaches oncologic equivalence compared with Open Radical Nephroureterectomy (ORNU) for high-risk upper-tract urothelial carcinoma (UTUC). Recently, European Association of Urology (EAU) Guidelines suggested implementing neoadjuvant chemotherapy (NAC) to standard treatment to improve oncologic outcomes of high-risk UTUC. We aimed (1) To explore contemporary trends of MIS for RNU in the United States and to compare perioperative outcomes and costs with that of ORNU. (2) To determine the trends of NAC and postoperative intravesical chemotherapy (PIC) administration for high-risk UTUC and to assess their contribution to perioperative outcomes and costs. PATIENTS AND METHODS: The Optum Clinformatics Data Mart de-identified database was queried from 2003 to 2018 to retrospectively examine patients who had undergone LNU/RANU or ORNU with or without NAC and PIC. We evaluated temporal adoption trends, complications, and health care cost analyses. We obtained descriptive statistics and utilized multivariable regression modeling to assess outcomes. RESULTS: A total of n = 492 ORNU and n = 1618 LNU/RANU procedures were reviewed. The MIS approach was associated with a statistically significant lower risk of intraoperative complications (adjusted Odds Ratio [aOR], 0.48, 95% CI:0.24-0.96), risk of hospitalization costs (aOR: 0.62, 95% CI:0.49-0.78), and shorter hospital stay (aOR: 0.20, 95% CI:0.15-0.26) when compared to ORNU. Overall, adoption of NAC and PIC accounted for only n = 81 and n < 37 cases respectively. The implementation of NAC and higher number of cycles were associated with an increased probability of any complication rate (aOR: 2.06, 95% CI:1.26-3.36) and hospital costs (aOR: 2.12, 95% CI:1.33-3.38). CONCLUSION: MIS has become the approach of choice for RNU in the US. Although recommended by guidelines, neither NAC nor postoperative bladder instillation of chemotherapy has been routinely incorporated into the clinical practice of patients with UTUC.

Endoscopic Management of Low-Grade Upper Tract Urothelial Carcinoma: Characterizing the Long-term Burden of Care in Comparison to Radical Nephroureterectomy.

OBJECTIVE: To compare procedure burden, oncologic, surgical and renal-function outcomes between patients with low-grade upper urothelial cancer (UTUC) who were referred for either radical management (RM) or kidney-sparing endoscopic management (EM). PATIENTS AND METHODS: We retrospectively reviewed data of all patients treated for UTUC at our tertiary medical center between 2000 and 2018 and selected patients diagnosed with unilateral low-grade UTUC. RESULTS: Twenty-four patients were treated with EM and 37 with RM. Surgical and oncologic risk factors were similar between the arms except for tumor size. Mean follow-up was 4.9 ± 3.4 years. The 5-year overall-survival rate was 85% with EM and 84% with RM (P = .707). Metastasis-free and cancer-specific survival were also similar (P = .994, P = .960). End-of-follow-up average glomerular filtration rates were 58.7 ± 21.5 and 49.2 ± 22.1 mL/min/1.73 m2, respectively (P = .12). Ninety-two percent of patients managed endoscopically had local recurrences, with an average of 3.2 recurrences per patient. Four (17%) patients underwent salvage radical nephroureterectomy. Procedure burden was higher with EM, having 6.5 ± 4.4 operations and 344 ± 272 minutes under anesthesia compared with 1.9 ± 0.4 operations (P <.0001) and 213 ± 84 minutes under anesthesia (P = .031) with RM. Cost-of-care analysis revealed higher costs for EM in both private and publicly funded medical insurance plans. CONCLUSION: Patients undergoing endoscopic management had an 83% chance of preserving their kidney and an 81% chance of 5-year metastasis-free survival at a cost of 6.5 ± 4.4 operations during a mean follow-up of 4.9 ± 3.4 years. Our findings support EM for low-grade UTUC as a valid option from oncological aspects but highlight the associated costs.

Programmed death ligand-1 (PD-L1) immunohistochemical assessment using the QR1 clone in muscle-invasive urothelial carcinomas: a comparison with reference clones 22C3 and SP263.

Programmed death ligand-1 (PD-L1) immunohistochemical (IHC) status is used to predict which patients with metastatic urothelial carcinoma (UC) will respond to immunotherapy. We aimed to compare QR1(Quartett), 22C3 (Dako), and SP263 (Ventana) detection of PD-L1 expression in muscle-invasive UCs and determine the best scoring algorithm for assessment of PD-L1 expression when using the QR1 clone. Our study included 69 UCs. For SP263 and 22C3, PD-L1-positive tumor cell (TC) and/or immune cell (IC) percentages (TC%/IC%) and the Combined Positive Score (CPS) were assessed, respectively (positivity cut-offs of ≥ 25% and ≥ 10). For QR1, both interpretation systems were evaluated. The concordances between assays were calculated. PD-L1 IHC staining characteristics were comparable between QR1, 22C3, and SP263 in both conventional and variant histology UCs. We demonstrated strong or very strong correlations between clones; the strongest correlation for TCs was between QR1 and SP263 (r = 0.92; p = 0.001) and for ICs was between QR1 and 22C3 (r = 0.85; p = 0.001). Our comparative analysis of the scoring algorithms revealed very good concordances among the three assays (range 0.791-0.878); the highest concordance was between QR1 and SP263 when CPS was used as the scoring algorithm for QR1 (0.878; p < 0.001). Our study is the first to demonstrate that the QR1 clone can be used to evaluate PD-L1 status in UCs, with a very good agreement rate with the reference clones. QR1 appeared to be more similar to the SP263 clone. With regard to the scoring algorithm, when evaluating PD-L1 expression using QR1 clone, CPS performed better compared with the TC%/IC% score.

Treatment Patterns, Outcomes, and Costs Associated With Localized Upper Tract Urothelial Carcinoma.

Background: Upper tract urothelial carcinoma (UTUC) is a heterogeneous disease that presents a clinical management challenge for the urologic surgeon. We assessed treatment patterns, costs, and survival outcomes among patients with nonmetastatic UTUC. Methods: We identified 4114 patients diagnosed with nonmetastatic UTUC from 2004 to 2013 in the Survival Epidemiology, and End Results-Medicare population-based database. Patients were stratified into low- or high-risk disease groups. Median total costs from 30 days prior to diagnosis through 365 days after diagnosis were compared between groups. Overall and cancer-specific survival were evaluated using Cox proportional hazards regression. All statistical tests were 2-sided. Results: After risk stratification, 1027 (24.9%) and 3087 (75.0%) patients were classified into low- vs high-risk UTUC groups. Most patients underwent at least 1 surgical intervention (95.1%); 68.4% underwent at least 1 endoscopic intervention. Patients diagnosed with high- vs low-risk UTUC were more likely to undergo nephroureterectomy (83.6% vs 72.0%; P < .001); few patients with low-risk disease were exclusively managed endoscopically (16.9%). At 365 days after diagnosis, costs of care for high- vs low-risk UTUC were statistically significantly higher ($108 520 vs $91 233; median difference $16 704, 95% confidence interval [CI] = $11 619 to $21 778; P < .001). Those with high-risk UTUC had worse cancer-specific and overall survival compared with patients with low-risk UTUC (cancer-specific survival hazard ratio [HR] = 4.14, 95% CI = 3.19 to 5.37; overall survival HR = 1.78, 95% CI = 1.62 to 1.96). Conclusions: UTUC continues to be managed primarily with nephroureterectomy, regardless of risk stratification, and patients with high-risk UTUC have worse overall and cancer-specific survival. Substantial costs are associated with management of low- and high-risk UTUC, with the latter being more costly up to 1 year from diagnosis.

Development of a multiplex immuno-oncology biomarker and digital pathology workflow for assessment of urothelial carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICI) therapies have demonstrated significant benefit in the treatment of many tumors including high grade urothelial cancer (HGUC) of the bladder. However, variability in patients' clinical responses highlights the need for biomarkers to aid patient stratification. ICI relies on an intact host immune response. In this context, we hypothesize that key players in the antitumor immune response such as markers of activated cytotoxic T lymphocytes (CD8, granzyme-B) and immune suppression (FOXP3) may help to identify patients who will derive the greatest therapeutic benefit from ICI. A major obstacle for deployment of such a strategy is the limited quantities of tumor-derived biopsy material. Therefore, in this technical study, we develop a multiplex biomarker with digital workflow. We explored the (1) concordance of conventional single stain results using digital image analysis, and (2) agreement between digital scoring versus manual analysis. METHODS: (1) For concordance study of single and multiplex stains, triplicate core tissue microarrays of 207 muscle invasive, HGUC of bladder had sequential 4-micron sections cut and stained with CD8, FOXP3 and granzyme-B. An inhouse developed tri-chromogen multiplex immunohistochemistry (m-IHC) assay consisting of CD8 (green), granzyme B (brown), and FOXP3 (red) was used to stain the next sequential tissue section. (2) Agreement between manual and digital analysis was performed on 19 whole slide sections of HGUC cystectomy specimens. All slides were scanned using Aperio ScanScope AT Digital Scanner at 40X. Quantitative digital image analysis was performed using QuPath version 0.2.3 open-source software. Scores from triplicate cores were averaged for each HGUC specimen for each marker. Intraclass correlation coefficients were used to compare percent positive cells between the single- and multi-plex assays. Lin's concordance correlation coefficients were used for manual versus digital analysis. RESULTS AND CONCLUSIONS: m-IHC offers significant advantages in characterizing the host immune microenvironment particularly in limited biopsy tissue material. Utilizing a digital image workflow resulted in significant concordance between m-IHC and individual single stains (p < 0.001 for all assessments). Moderate to good agreements were achieved between manual and digital scoring. Our technical work demonstrated potential uses of multiplex marker in assessing the host immune status and could be used in conjunction with PD-L1 as a predictor of response to ICI therapy.

"Real-world" outcomes and prognostic indicators among patients with high-risk muscle-invasive urothelial carcinoma.

INTRODUCTION: There is no current standard of care for patients with high-risk muscle-invasive urothelial carcinoma (MIUC) after neoadjuvant chemotherapy and surgical resection or for those who cannot receive or decline cisplatin-based perioperative chemotherapy. Understanding current, real-world treatment patterns may help inform decisions from clinical, research, and population health management perspectives. We examined real-world treatment patterns, survival outcomes, and prognostic factors among Medicare beneficiaries with high-risk MIUC who did not receive adjuvant treatment after surgical resection. METHODS: We identified patients with high-risk MIUC in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database who underwent surgical resection (radical cystectomy and/or radical nephroureterectomy). Eligible patients had indicators of high-risk MIUC and surgical resection between 2001 and 2013. Demographic and clinical characteristics, including comorbidities, American Joint Commission on Cancer (AJCC) stage, tumor stage/grade and nodal status, and distribution of neoadjuvant treatment by the year of surgical resection were evaluated. Overall survival (OS) and disease-free survival (DFS) were assessed for the full cohort and by subgroups using Kaplan-Meier survival analysis. Adjusted Cox proportional hazards models were used to evaluate patient demographics and clinical characteristics associated with OS and DFS. RESULTS: A total of 665 patients were included in the analysis, with a mean age of 75.5 years; most were men (61%) and had AJCC stage IIIA disease (69%). Neoadjuvant treatment increased over the entire study period, both overall (from 12% to 46%) and cisplatin based (from 5% to 38%). Median OS for the entire cohort was 23.1 months (95% confidence interval: 18, 27); median DFS was 13.5 months (95% confidence interval: 11.3, 16.8). AJCC stage IIIB/IVA was the most significant predictor of poor prognosis for both OS and DFS, followed by non-white race and comorbidity burden. CONCLUSION: The prognosis for high-risk patients with MIUC remains poor, with significant risk of mortality within 2 years of radical cystectomy despite increasing use of neoadjuvant treatment. Unmet treatment needs persist for this difficult-to-treat patient population despite the increasing use of cisplatin-based neoadjuvant chemotherapy.

Response to Neoadjuvant Chemotherapy and Survival in Micropapillary Urothelial Carcinoma: Data From a Tertiary Referral Center and the Surveillance, Epidemiology, and End Results (SEER) Program.

BACKGROUND: Micropapillary urothelial carcinoma (MPC) is a rare urothelial carcinoma variant with conflicting data guiding clinical practice. In this study, we explored oncologic outcomes in relation to neoadjuvant chemotherapy (NAC) in a retrospective cohort of patients with MPC, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare. PATIENTS AND METHODS: We retrospectively identified patients with MPC or conventional urothelial carcinoma (CUC) without any variant histology undergoing radical cystectomy (RC) in our institution (2003-2018). SEER-Medicare was also queried to identify patients diagnosed with MPC (2004-2015). Clinicopathologic data and treatment modalities were extracted. Overall survival (OS) was estimated with the Kaplan-Meier method. Mann-Whitney-Wilcoxon and chi-square tests were used for comparative analysis and Cox regression for identifying clinical covariates associated with OS. RESULTS: Our institutional database yielded 46 patients with MPC and 457 with CUC. In SEER-Medicare, 183 patients with MPC were identified, and 63 (34%) underwent RC. In the institutional cohort, patients with MPC had significantly higher incidence of cN+ (17% vs. 8%), pN+ stage (30% vs. 17%), carcinoma-in-situ (43% vs. 25%), and lymphovascular invasion (30% vs. 16%) at RC versus those with CUC (all P < .05). Pathologic complete response (ypT0N0) to NAC was 33% for MPC and 35% for CUC (P = .899). Median OS was lower for institutional MPC versus CUC in univariate analysis (43.6 vs. 105.3 months, P = .006); however, MPC was not independently associated with OS in the multivariate model. Median OS was 25 months in the SEER MPC cohort for patients undergoing RC, while NAC was not associated with improved OS in that group. CONCLUSION: Pathologic response to NAC was not significantly different between MPC and CUC, while MPC histology was not an independent predictor of OS. Further studies are needed to better understand biological mechanisms behind its aggressive features as well as the role of NAC in this histology variant.

Noninvasive Detection of Urothelial Carcinoma by Cost-effective Low-coverage Whole-genome Sequencing from Urine-Exfoliated Cell DNA.

PURPOSE: Urothelial carcinoma is a malignant cancer with frequent chromosomal aberrations. Here, we investigated the application of a cost-effective, low-coverage whole-genome sequencing technology in detecting all chromosomal aberrations. EXPERIMENTAL DESIGN: Patients with urothelial carcinomas and nontumor controls were prospectively recruited in clinical trial NCT03998371. Urine-exfoliated cell DNA was analyzed by Illumina HiSeq XTen, followed by genotyping with a customized bioinformatics workflow named Urine Exfoliated Cells Copy Number Aberration Detector (UroCAD). RESULTS: In the discovery phase, urine samples from 126 patients with urothelial carcinomas and 64 nontumor disease samples were analyzed. Frequent chromosome copy-number changes were found in patients with tumor as compared with nontumor controls. A novel diagnosis model, UroCAD, was built by incorporating all the autosomal chromosomal changes. The model reached performance of AUC = 0.92 (95% confidence interval, 89.4%-97.3%). At the optimal cutoff, |Z| ≥ 3.21, the sensitivity, specificity, and accuracy were 82.5%, 96.9%, and 89.0%, respectively. The prediction positivity was found correlated with tumor grade (P = 0.01). In the external validation cohort of 95 participants, the UroCAD assay identified urothelial carcinomas with an overall sensitivity of 80.4%, specificity of 94.9%, and AUC of 0.91. Meanwhile, UroCAD assay outperformed cytology tests with significantly improved sensitivity (80.4% vs. 33.9%; P < 0.001) and comparable specificity (94.9% vs. 100%; P = 0.49). CONCLUSIONS: UroCAD could be a robust urothelial carcinoma diagnostic method with improved sensitivity and similar specificity as compared with cytology tests. It may be used as a noninvasive approach for diagnosis and recurrence surveillance in urothelial carcinoma prior to the use of cystoscopy, which would largely reduce the burden on patients.

Assessment of Luminal and Basal Phenotypes in Bladder Cancer.

Genomic profiling studies have demonstrated that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to frontline chemotherapy. We analyzed the mRNA expressions of signature luminal and basal genes in bladder cancer tumor samples from publicly available and MD Anderson Cancer Center cohorts. We developed a quantitative classifier referred to as basal to luminal transition (BLT) score which identified the molecular subtypes of bladder cancer with 80-94% sensitivity and 83-93% specificity. In order to facilitate molecular subtyping of bladder cancer in primary care centers, we analyzed the protein expressions of signature luminal (GATA3) and basal (KRT5/6) markers by immunohistochemistry, which identified molecular subtypes in over 80% of the cases. In conclusion, we provide a tool for assessment of molecular subtypes of bladder cancer in routine clinical practice.