bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional trends in the cost of transurethral bladder tumor resection in the outpatient and physician office setting.
Authors: Kokkotos Fotios , Buser Hannah , An Aimee , Ferrara Katherine
Published: February 2022

465

Background: TURBT is the standard surgical procedure for diagnosis, staging, and initial treatment of non-muscle invasive bladder cancer. This study aimed to identify current geographic trends associated with the use and cost of TURBT in Medicare beneficiaries. Methods: The Medicare Limited Data Set 100% sample of outpatient and 5% sample of carrier claims data from Q1 2019 to Q3 2020 was used for analysis. Patients who underwent TURBT were identified using CPT codes (55234, 52235, 52240). An analysis of variance (ANOVA) test was run comparing the difference in average claim payment amount, average beneficiary payment to physician, and average allowed charge amount between each region (West, Midwest, Northeast, and South). If the ANOVA test found a significant difference between regions, a t-test was run for all combinations of regions. Results: In the outpatient setting, we identified a total of 92,938 TURBT procedures between 2019 and Q3 2020, including 23,039 (Midwest), 19,890 (Northeast), 33,379 (South), and 16,630 (West). The average Medicare claim payment amount was $2,755 overall, $2,566 (Midwest), $2,866 (Northeast), $2,497 (South), and $3,092 (West). Beneficiaries paid an average of $605 in the Midwest, $673 in the Northeast, $572 in the South, and $697 in the West. The average total charge was $7,343, $7,189, $8,510, and $10,028 in the Midwest, Northeast, South, and West respectively. In the outpatient setting, there were no statistical differences for any cost related variables between the four regions. In the physician office setting, we identified 8,035 TURBT between 2019 and Q3 2020. There were 1,776, 1,577, 3,153, and 1,529 TURBT procedures in the Midwest, Northeast, South, and West, respectively. The average Medicare claim cost was $383 (Midwest), $372 (Northeast), $423 (South), and $417 (West). The average total allowed charges on the claim was $415 overall, and $392, $404, $430, and $432 in the Midwest, Northeast, South, and West, respectively. There was a significant statistical difference (p = 0.0154) for the average claim payment amount between the South and the Northeast. The two regions differed in average claim payment amount by $51 (95% CI: $15, $87). There was a significant difference in the average allowed charge amount between the South and Midwest (p = 0.019) and the West and Midwest (p = 0.016). Compared to the South, the Midwest had a lower average charge amount by $37 (95% CI: $9, $66). The West had a higher average charge amount than the Midwest by $40 (95% CI: $12, $68). Conclusions: This analysis demonstrated a significant difference in the cost of TURBT between regions in the physician office setting. The South had a significant higher claim payment amount than the Northeast. The allowed charge amount in the physician office setting for the South and the West were significantly higher than the Midwest.
Prospective validation of urine based FGFR screening by Uromonitor within the real-world clinicopathological register trial BRIDGister.
Authors: Wirtz Ralph M. , Veltrup Elke , Prazeres Hugo , Dias Carolina , Hake Roland , Eidt Sebastian , Vinagre Joao , Roggisch Jenny , Koch Stefan , Ecke Thorsten
Published: February 2022

471

Background: The objective of the present study was to prospectively evaluate FGFR mutation detetion in matched urine and tissue samples from patients suspicious of bladder cancer and undergoing first TURB within the framework of the BRIDGister RealWorld Experience trial. Methods: For this pilot study paraffin fixed pretreatment tissue samples from the first TURB of 48 pts participating in the BRIDGister trial and matched urine samples were prospectively collected and analyzed. RNA from FFPE tissues were extracted by commercial kits and analyzed by Therascreen FGFR IVD kit (Qiagen GmbH, Hilden). In addition urine samples were filtered at local urology and filters were shipped for central extraction of cellular DNA (Uromonitor, Porto). Concordance, Kruskal-Wallis, MannWhitney and Sensitivity/Specificity tests were analyzed by JMP 9.0.0 (SAS software). Results: The pilote cohort of the BRIDGister trial consisted of 47 patients (median age: 77, male 65% vs female 35%) of diverse clinical stages (benign lesions/no tumor 38%, pTa 23%, pT1 20%, pT2 19%) and WHO 1973 grade (G1 11%, G2 43%, G3 23%). Based on FFPE tissue testing using Therascreen FGFR IVD kit 10 out of 47 patients exhibited FGFR alterations (25%), while urine filtering for cellular components and subsequent PCR testing revealed 13 out of 40 matched urine sampels were FGFR positive (33%). Comparison with tissue testing as probable gold standard revealed 100% sensitivity, 90% specificity, 77% PPV, 100% NPV as well as high concordance (kappa 0,82, p < 0,0001). There were 3 patients being FGFR positive for Uromonitor from urine with no mutation found in the corresponding TUR biopsy. Conclusions: Filtering urine for cells and subsequent DNA extraction followed by PCR detection results in highly sensitive mutation testing being feasible with good concordance to matched tissue testing. Prospective testing validated the diagnostic accuracy of the Uromonitor FGFR test in a real world setting.
Distribution of immune-related adverse events (irAEs) across genitourinary (GU) malignancies.
Authors: Mar Nataliya , Slaught Matthew , Kaakour Dalia , Azizi Armon , Valerin Jennifer Brooke
Published: February 2022

480

Background: Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized management of GU malignancies. These agents are associated with a unique subset of toxicities that are immune-mediated, with a broad clinical spectrum that may affect any organ. Patients can also experience ³1 irAE involving multiple organ systems. Individual patient susceptibilities and type of CPI used may influence the incidence and type of irAEs that may develop. Wehypothesize that there are also differences in irAEs based on the histologic malignancy subtype. Methods: We performed a retrospective analysis of all patients with GU malignancies who received CPIs at the University of California Irvine using an outpatient oncology pharmacy database. Data was collected from 1/1/2020 to 6/30/2021. Patients were aged ³18 years and had a diagnosis of urothelial carcinoma (UC), renal cell carcinoma (RCC), prostate adenocarcinoma, or penile squamous cell carcinoma. Patients must have received ³1 dose of a CPI agent including ipilimumab (I), nivolumab (N), pembrolizumab (P), atezolizumab (At), avelumab (Av), durvalumab (D), and cemiplimab (C). Results: A total of 128 patients who received 141 unique CPI regimens were included. Documented irAEs were noted in 50.0% of patients and 18.4% had ³1 irAE. A total of 99 unique irAEs were recorded. In those who experienced irAEs, 92.2% of patients received CPIs in the metastatic setting and 7.8% in the adjuvant setting. In those who experienced irAEs, 12.5% of patients received combination CPIs with I+N, while 87.5% received single-agent CPI. In those who experienced irAEs, 46.8% of patients had UC, 50.0% had RCC, 1.6% had prostate cancer, and 1.6% had penile cancer. In those who experienced irAEs, 24.2% had skin rash or pruritis, 23.2% had endocrinopathies, 14.1% had colitis, 13.1% had other toxicity including arthritis, 12.0% had hepatitis, 3.9% had myositis, 2.9% had pneumonitis, 1.9% had neurologic toxicity including myasthenia gravis and encephalitis, 1.9% had carpal tunnel syndrome, 1.9% had nephritis, and 0.9% had autoimmune thrombocytopenia. Various irAEs for UC and RCC are summarized in Table. Conclusions: In this dataset, there were differences in type and incidence of irAEs in patients with UC and RCC, while the sample size was too small to draw conclusions about patients with prostate and penile cancer. Further investigation is needed involving other solid tumor types, including non-GU malignancies, to definitively answer this question.[Table: see text]
BCG efficacy in nonmuscle-invasive bladder cancer after prior radiation treatment for prostate cancer.
Authors: Durant Adri , Chang Yu-Hui , Faraj Kassem , Tyson Mark
Published: February 2022

482

Background: Prostate radiotherapy is associated with worse oncologic outcomes in patients with bladder cancer. This is thought to be secondary to microvascular damage resulting in propagation of inflammation. There is sparse data on the effect of prior radiotherapy on the efficacy of intravesical Bacillus Calmette-Guerin (BCG) in patients with non-muscle invasive bladder cancer (NMIBC). We sought to evaluate BCG response and outcomes in NMIBC patients who have previously undergone prostate radiotherapy compared to patients with no prior history of pelvic radiotherapy. Methods: This is a retrospective cohort study that includes patients who received intravesical BCG for NMIBC at our institution from 2001 to 2019. Data were collected on patient and pathologic characteristics. Patients were stratified into three cohorts: prior radiotherapy (RT), radical prostatectomy (RP), and no prostate cancer (No PCa). Wilcoxon rank sum test and Chi-squared test were used for comparison between groups. The primary endpoints included recurrence at one-year, progression to MIBC and progression to metastatic disease. Results: In 199 total patients who underwent BCG for NMIBC, 23 had a prior history of radiotherapy treatment for prostate cancer, while 17 underwent prior radical prostatectomy. Overall, 41.2% of patients had recurrence at one year. There was no difference in recurrence at one year between the cohorts: 42.8% No PCa, 29.4% RP and 39.1% RT; p = 0.56. There was also no difference in progression to MIBC (6.9% No PCA, 0% RP, and 8.7% RT) or progression to metastatic disease (6.9% No PCA, 5.9% RP and 4.3% RT) with p = 0.50 and 0.89 respectively. Conclusions: The efficacy of intravesical BCG does not appear to be modified by prior radiation treatment for prostate cancer in patients with NMIBC.[Table: see text]
SUB-urothelial durvalumab injection: 1 (SUBDUE-1)—Results from the first nine urothelial cancer patients using a dose-escalation schedule.
Authors: Hayne Dickon , Swarbrick Nicole , McCombie Stephen , Moe Andrew , Hawks Cynthia , Viswambaram Pravin , Conduit Ciara , Liow Elizabeth Chien Hern , Spalding Lisa , Bothe Jarrad , Ferguson Tom , Martin Andrew James , Davis Ian D. , Redfern Andrew David
Published: February 2022

483

Background: The sub-urothelial administration of checkpoint inhibitors has not been reported. This approach could be safer and more efficacious than systemic delivery for patients with non-muscle-invasive bladder cancer (NMIBC). Methods: This phase 1b study employed a 3+3 dose-escalation design to explore tolerability, safety and immunological efficacy of sub-urothelial durvalumab, a programmed death-ligand 1 (PDL1) monoclonal antibody. Eligible participants had high risk NMIBC or MIBC without prior chemotherapy or immunotherapy (BCG allowed) and were planned for cystectomy. Participants received 25/75/150mg durvalumab diluted in 25mL normal saline injected into the sub-urothelium at 25 locations (25x1mL injections), at least 2 weeks prior to radical cystectomy. Systematic four quadrant cold cup bladder biopsies were taken immediately prior to durvalumab injection and immediately prior to cystectomy. Tumour, if present, was biopsied before and after injection and bladder maps recorded. International Prostate Symptom Index (IPSS) and O’Leary symptom score at various time points and adverse events (AE) as per CTCAE (Version 4) were recorded. Relative changes in immune cell counts (RCI) on bladder biopsy for CD3, CD8, CD68 and CD168 expressing cells are reported (value >1.0 designating increase). Results: Nine participants were recruited; eight male (89%), 1 female; mean age 72 years (range 56 – 82). No dose-limiting toxicities were observed. No evidence of treatment-related effect on IPSS or O’Leary Symptom scores was seen. Fourteen AEs were reported by six (67%) patients: 10 were Grade 1, 3 Grade 2, 1 Grade 3. None were considered immune- or treatment-related by investigators. Transient elevation of peri-operative thyroid stimulating hormone was seen in two subjects, which normalised without intervention. No hepatitis was seen. All patients underwent planned cystectomy. RCI of different immune populations was calculated (see Table). Visible tumour was present in only 4 patients limiting interpretation of RCI. RCI varied significantly between cell types (p=0.008*). RCI numerically increased by dose but did not reach statistical significance (p=0.076**). A numeric increase in monocytes was seen at 150mg dose. RCI of different immune populations by dose of sub-urothelial durvalumab. Conclusions: Sub-urothelial injection of durvalumab was safe at all 3 dose levels without any drug-related adverse events. Immunological studies showed differential effects on immune cells with macrophage population most affected. Further studies investigating the role of 150mg sub-urothelial durvalumab in the management of NMIBC are planned. Clinical trial information: ACTRN12620000063910.[Table: see text]
CIMUC: Chemotherapy following Immune checkpoints inhibitors in patients with locally advanced or metastatic urothelial carcinoma (la/mUC).
Authors: Meynard Lucie , Dinart Derek , Flechon Aude , Saldana Carolina , Lefort Felix , Gravis Gwenaelle , Thiery-Vuillemin Antoine , Cancel Mathilde , Coquan Elodie , Ladoire Sylvain , Maillet Denis , Rolland Frederic , Boughalem Elouen , Martin Sophie , Laramas Mathieu , Crouzet Laurence , Abbar Baptiste , Falkowski Sabrina , Pouessel Damien , Roubaud Guilhem
Published: February 2022

492

Background: Immune checkpoints inhibitors (ICIs) have recently changed therapeutic landscape of la/mUC. Recent studies suggested an improvement of response to salvage chemotherapy (CT) after ICIs in several cancer types including urothelial carcinoma. We assumed that efficacy of CT rechallenge after ICIs may be improved compared to second-line CT without previous ICIs in patients (pts) with la/mUC. Methods: CIMUC is a French multicentric retrospective study including all pts with la/mUC initiating second or third-line CT from January 1st 2015 to June 30th 2020. Two groups of pts were defined: pts in group 1 (G1) were treated with a second-line CT without previous ICIs; pts in group 2 (G2) were treated with third line CT after ICIs. Primary endpoint was objective response rate (ORR: proportion of patients with complete or partial response, according to RECIST 1.1 criteria) in G2 versus G1. Secondary endpoints were progression-free survival (PFS), defined as time from initiation of second or third-line CT to disease progression or death from any cause, and toxicities. This study is supported by the French Genito Urinary Group (GETUG). Results: 553 pts were included. Baseline characteristics of the 2 groups are summarized in the Table. ORRs were 31% (95%CI [26.5-35.5]) and 29.2% (95%CI [21.9-36.6]) respectively in G1 and G2, without statistically significant difference (p=0.617), even after adjustment for Bellmunt risk factors (p=0.3214). In subgroups analysis, no difference in ORR was observed by type of CT (platinum or taxanes), duration of response (DOR) to first-platinum-based CT (< 12 months or ≥ 12 months) and FGFR-status. We did not identify any predictive factor of OR in G2 in multivariate analysis. Median PFS were 4.6 months (95%CI [3.88; 5.06]) and 4.86 months (95%CI [4.11; 5.45]), respectively in G1 and G2. Grade 3/4 hematologic toxicity occurred in 35% and 22.4%, respectively in G1 and G2. Conclusions: While ORR was not superior in G2 versus G1, pts derive comparable benefit in a further line of treatment (G2) in terms of ORR and PFS. Despite limits inherent to any retrospective study, CIMUC represents one of the largest retrospective studies in this setting.[Table: see text]
Sequential intravesical gemcitabine and docetaxel for BCG-naïve high-risk nonmuscle-invasive bladder cancer.
Authors: McElree Ian Mitchell , Steinberg Ryan L. , Mott Sarah L. , Martin Alexander C. , Richards Jordan , Gellhaus Paul T. , Nepple Kenneth G. , O'Donnell Michael A. , Packiam Vignesh T.
Published: February 2022

497

Background: Bacillus Calmette-Guerin (BCG) is currently recommended as adjuvant therapy following complete transurethral resection of bladder tumor (TURBT) for high-risk non-muscle invasive bladder cancer (NMIBC). However, continued BCG production shortages have precluded the use of BCG in many urologic practices. Efficacy of sequential intravesical gemcitabine and docetaxel (Gem/Doce) in the BCG failure setting has been reproduced across multiple institutions. In response to the continuing BCG shortage, Gem/Doce has been utilized at our institution in the BCG-naïve setting. We report the outcomes of a large cohort of patients with high-risk BCG-naïve NMIBC treated with Gem/Doce. Methods: We retrospectively identified all patients with BCG-naïve high-risk NMIBC who were treated with Gem/Doce from May 2013 through April 2021. We included patients with intent to receive 6 weekly intravesical instillations of sequential 1 gram gemcitabine and 37.5mg docetaxel after complete TURBT. Monthly maintenance of 2 years was initiated if disease free at first follow-up. The primary outcome was recurrence-free survival (RFS) and efficacy was evaluated in an intention-to-treat manner. Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as T-stage increase from Ta or CIS to T1 or development of muscle invasive or metastatic disease. Survival was assessed using the Kaplan-Meier method and log rank test, indexed from the first Gem/Doce instillation. Results: One hundred seven patients with median follow-up of 15 months were included in the analysis. There were 47 with any CIS, 55 with T1 disease, and 7 with micropapillary variant histology. Four patients did not complete a full induction cycle due to hematuria (3) and severe frequency/nocturia (1). 19 patients sustained a recurrence at any point during follow-up. RFS was 89%, 85%, and 82% at 6, 12, and 24 months, respectively. No difference in RFS was seen in patients with or without CIS (p = 0.42). No patients met criteria for either form of disease progression. One patient underwent cystectomy due to end-stage lower urinary tract symptoms, with final pathology pTisN0. No patients died of bladder cancer. Overall survival was 84% at 24 months. 46 patients reported any symptoms during treatment. Common side effects included urinary frequency/urgency (36%), hematuria (11%), and dysuria (8%). Conclusions: In a large cohort of high-risk, BCG-naïve NMIBC patients, Gem/Doce showed excellent efficacy (84% 2-year HG-RFS). These rates are similar to modern treatment naïve cohorts receiving BCG. Prospective comparative analysis of Gem/Doce in BCG-naïve populations is warranted.[Table: see text]
A multicenter real-life U.K. study of use of immunotherapeutic agents in metastatic urothelial cancer.
Authors: Das Prantik , Sharma Anand , Bhandari Ruchir , Lim JunHao , Ghose Aruni , Davies Jessica , Nair Ajith , Vasdev Nikhil , Moldawa Maja , Karimi Ahmad , Ward Colin , Richardson Alison , Singh Sadmeet , Peracha Amjad , Ahmed Shaista
Published: February 2022

504

Background: First-line chemotherapy for patients with cisplatin-ineligible metastatic urothelial carcinoma (mUC) is associated with short response duration and high toxicity. Pembrolizumab(PEM) and atezolizumab (ATZ) are associated with long-term, durable remissions as a first-line treatment of cisplatin-ineligible, PD-L1-positive patients with mUC. For patients who progressed during or after platinum-based chemotherapy, Immunotherapy also prolongs survival with less toxicity and better quality of life compared with further lines of chemotherapy. There have been no studies directly comparing the effectiveness of PEM to ATZ in mUC patients. Methods: A cohort of 112 patients from 3 UK centres were included. 62, previously untreated cisplatin ineligible mUC patients who showed PDL1 positivity were given either ATZ or PEM once every 3 weeks until progression. 49 patients who had initial platinum based chemotherapy subsequently had ATZ or PEM as second line treatment following their disease progression The primary endpoint was Overall Survival(OS) and secondary endpoints included objective rate(ORR), response duration and safety. Results: The median age was 69 ( Interquartile range 43-91) and 23% were female and 77% were male. Among, patients who received immunotherapy 1st line, 82% had baseline renal impairment(GFR < 60), and 18% had Eastern Cooperative Oncology Group performance status 2. For chemo naïve patients, median OS was 11.5 months for PEM and 5 months for ATZ respectively. ORR was 22 % for ATZ vs 50% for PEM and median duration of treatment was 4.5 and 2.5 months for PEM and ATZ respectively. When used in 2nd line median OS is 7 months for ATZ irrespective of PDL1 status and not reached for PEM yet. Grade 2 and above toxicities were reported in 18 % ATZ patients vs 10% in PEM patients, commonest were pneumonitis, tiredness, hepatitis and dermatitis. No treatment related deaths were reported. Conclusions: This study suggests that pembrolizumab has higher response rate and better survival compared to atezolizumab in cisplatin-ineligible patients with mUC and also in the 2nd line setting after disease progression following platinum based agents. Both agents were well tolerated.
Association of time to second-line (2L) immune-checkpoint inhibitors (ICI) and outcomes with ICIs in patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Makrakis Dimitrios , Talukder Rafee , Dawsey Scott , Carril Lucia , Stewart Tyler F. , Morales-Barrera Rafael , Park Joseph J. , Fulgenzi Claudia Angela Maria , Murgic Jure , Vather-Wu Naomi , de Kouchkovsky Ivan , Devitt Michael Edward , Di Lorenzo Giuseppe , Gupta Kavita , Tripathi Nishita , Zakopoulou Roubini , Tripathi Abhishek , Lu Eric , Grivas Petros , Khaki Ali Raza
Published: February 2022

505

Background: Current standard therapy for most pts with aUC is first-line (1L) platinum-based chemotherapy followed by ICI maintenance (or 2L if progression). Shorter time on 1L or between therapy lines may be a surrogate of more aggressive disease and poor outcome, but its prognostic role in ICI response is unclear. We hypothesized that shorter time until start of 2L ICI would be associated with worse outcomes in aUC. Methods: We performed a retrospective multi-institution cohort study in pts with aUC treated with 1L platinum-based chemotherapy, who later received 2L ICI. Pts receiving maintenance ICI were excluded. We calculated the time from start of 1L platinum chemotherapy to start of 2L ICI, dichotomizing the exposure into ≤6 months and >6 months. We compared overall response rate (ORR) to 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI between the two populations. ORR was compared among groups using multivariable logistic regression and PFS, OS using cox regression. Analysis was adjusted for calculated Bellmunt score. Results: From a total of 1283 pts, 462 received 1L platinum chemotherapy; among those, 350 received 2L ICI. After exclusions, 270, 269 and 260 pts were included in the ORR, PFS and OS analyses, respectively. Median age was 70 years, 78% men, 75% White, 74% with pure urothelial histology, 21% upper tract, 60% received cisplatin in 1L. Pts with time to 2L ICI ≤6 months had significantly higher Bellmunt scores (32% vs 22% score=2, 9% vs 3% score=3). ORR and PFS were comparable between pts with ≤ and >6 months to 2L ICI. However, OS was significantly longer for pts with >6 months to 2L ICI (median [m]OS 13 vs 7 months, p=0.002), (Table). Conclusions: Among pts with aUC treated with 2L ICI, time to 2L ICI ≤6 months from 1L platinum based chemotherapy was associated with similar ORR and PFS but shorter OS. Limitations include retrospective nature, patient selection, confounding factors. More studies are needed on the impact of platinum resistance in pts with aUC treated with ICIs.[Table: see text]
Survival outcomes with radical cystectomy (RC) in localized clinically node-positive bladder cancer (CNBC).
Authors: Perimbeti Stuthi , Jiang Changchuan , Deng Lei , Jatwani Karan , Kaur Anahat , George Saby , Chatta Gurkamal S. , Gopalakrishnan Dharmesh
Published: February 2022

520

Background: The role of RC in patients with CNBC remains unclear since most prospective clinical trials excluded them. Our study aims to evaluate overall survival (OS) in patients with CNBC treated with systemic chemotherapy (SC) with or without RC. Methods: We queried the National Cancer Database for adult patients who received SC for localized CNBC during the years 2004 to 2018. Patients with distant metastases, including to non-regional nodes, and those treated with radiation to the bladder or pelvic nodes were excluded. Chi-square and Mann Whitney U tests were used to compare frequency distributions. Cox proportional hazards analysis was employed for multivariate analysis of factors associated with OS. Results: A total of 8464 patients were identified – 3565 (42.1%) underwent RC + SC (RC+), while 4899 (57.9%) received only SC (RC-). Median age at diagnosis was 65y in the RC+ grp vs. 68y in the RC- grp ( P = 0.006). Majority of patients were Caucasian in both grps – 86.9% and 85.1%, respectively. 5y-OS was 34.1% in the RC+ grp vs. 36.1% in the RC- grp ( P = 0.06). On multivariate analysis, factors independently associated with OS were RC+ status (Hazard ratio (HR) 0.81, 95% CI 0.75-0.88, P < 0.001), advanced age (70-85y vs. 18-35y, HR 1.88, 95% CI 1.18-3.01, P < 0.001), female gender (HR 1.20, 95% CI 1.12-1.28, P = 0.001), African American (vs. Caucasian) race (HR 1.24, 95% CI:1.10-1.40, P = 0.0004), ≥ 2 comorbidities (HR 1.67, 95% CI 1.34-1.92, P = 0.001), annual income ( < $30,000 vs > $45,000, HR 1.24, 95% CI 1.13-1.37, P < 0.001), and insurance status (uninsured vs. private, HR 1.39, 1.15-1.67, P < 0.001). Conclusions: In this large retrospective analysis, among patients with localized CNBC who received SC, 5y-OS rates were comparable with or without RC. However, RC was associated with improved OS on multivariate analysis.[Table: see text]
Outcomes according to histological variants of urothelial carcinoma after neoadjuvant chemotherapy in the GETUG-AFU V05 VESPER trial.
Authors: Allory Yves , Culine Stephane , Krucker Clémentine , Harter Valentin , Pfister Christian ,   VESPER Trial Investigators
Published: February 2022

533

Background: The histological variants of urothelial carcinoma (UC) may impact the outcomes after neoadjuvant chemotherapy in muscle invasive bladder cancer (MIBC). Previous studies provided contradictory results because of bias related to their retrospective design. Our aim was to assess pathological response and 3-year (yr) progression free survival (PFS) according to UC variants for patients included within the French prospective Vesper clinical trial (NCT01812369). Methods: 493 patients received dose-dense Methotrexate, Vinblastine, Doxorubicin and Cisplatin (dd-MVAC) or Gemcitabine and Cisplatin (GC) after randomization in the VESPER trial. This ancillary study was restricted to 437 patients treated in neoadjuvant setting. A central pathological review of initial transurethral diagnostic specimens allowed to assess UC variants (if ≥10% tumor area) and the presence of tumor emboli, perineural invasion, and CIS. Results: Slides were available for central review in 303 cases. UC variants were present in 180 patients (59%). Tumor emboli, perineural invasion, and CIS were noticed in 119 (39%), 24 (8%) and 143 (47%) cases. In comparison with pure UC, the presence of UC variants was not associated with different complete pathological response (ypT0N0) (OR 0.78, 95% CI 0.48-1.27) or 3 yr PFS (HR 1.25, 95%CI 0.83-1.86). Tumor emboli were negatively associated with ypT0N0 (OR 0.57, 95%CI 0.35-0.95, p = 0.029), organ confined disease (OR 0.44, 95%CI 0.26-0.75, p = 0.002) and 3 yr PFS (HR 1.81, 95%CI 1.23-2.67, p = 0.003). Perineural invasion were negatively associated with organ confined disease (OR 0.29, 95%CI 0.12-0.68, p = 0.005) and 3 yr PFS (HR 2.54, 95%CI 1.47-4.40, p < 0.001). There was no association for CIS. Conclusions: In the VESPER trial, UC variants were not associated with distinct pathological response or 3 yr PFS after neoadjuvant chemotherapy. Future studies will determine whether molecular subtypes are associated or not with distinct outcome.
Clinical outcomes in advanced urothelial cancer (UC) patients who experienced immune-related adverse events (irAEs) after immune checkpoint inhibitor monotherapy (ICI).
Authors: Sanda Gregory E. , Shabto Julie M. , Goyal Subir , Liu Yuan , Martini Dylan J. , Nazha Bassel , Brown Jacqueline T , Yantorni Lauren Beth , Russler Greta , Caulfield Sarah , Joshi Shreyas S. , Narayan Vikram M. , Kissick Haydn , Ogan Kenneth , Master Viraj A. , Carthon Bradley Curtis , Kucuk Omer , Bilen Mehmet Asim
Published: February 2022

544

Background: Immune checkpoint inhibitors (ICIs) continue to demonstrate promise in treatment of advanced urothelial carcinoma (UC). Some patients undergoing ICIs experience immune related adverse events (irAEs) and may serve as a marker of response. We investigated the relationship between irAEs and clinical outcomes in UC patients treated with ICIs. Methods: A retrospective study of 70 UC patients treated with ICI monotherapies at Winship Cancer Institute from 2015-2020 was done. Overall survival (OS) and progression-free survival (PFS), defined as time from ICI initiation to death and clinical or radiographic progression, respectively as well as clinical benefit (CB), defined as best radiographic response of complete response, partial response, or stable disease for ≥ 6 months per RECIST v1.1, were used to measure clinical outcomes. Cox proportional hazards and multivariable analyses (MVA) were used to model associations with OS and PFS. Results: Most patients were male (70%) with a median age of 68.7 years (28.0-91.0). Most patients (95%) had urothelial carcinoma and most (81%) received at least 1 prior treatment. One third of patients had ECOG PS greater than or equal to 2. Of patients that experienced an irAE (35%), the most common were dermatologic (12.9%) and arthralgia (0.5%). In addition to significantly longer treatment duration, irAE patients had significantly increased OS (HR:0.38, 95% CI:0.18-0.79, p=0.009), significantly longer PFS (HR:0.27, 95% CI:0.14-0.53, p < 0.001), and significantly greater CB (OR:4.20, 95% CI:1.35-13.06, p=0.013). Patients who experienced dermatologic irAEs had significantly increased OS, PFS, and CB (Table). Conclusions: Our results demonstrate that UC patients undergoing ICI therapy who experience irAEs, especially dermatologic irAEs, had improved clinical outcomes. This suggests that irAEs may serve as a clinical biomarker of advantageous response in patients receiving ICI. Future prospective studies are needed for validation.[Table: see text]
Genomic sequencing for bladder urothelial carcinoma and its clinical implications for immunotherapy.
Authors: Kim Ryul , Lee Jeeyun , Kwon Ghee Young , Hong Jung Yong , Jeong Byong Chang , Park Se Hoon
Published: February 2022

551

Background: To explore the genomic and transcriptomic landscape of bladder cancer (BC) and its implication for treatment with an immune checkpoint inhibitor (ICI). Methods: We analyzed whole-exome and -transcriptome sequences of tumor samples from 64 BC patients who underwent surgical resection with either transurethral resection or radical cystectomy. For exploratory purposes, PD-L1 expression was evaluated in a subset of patients (n = 57) including those treated with ICI (n = 8). Results: We identified frequent molecular dysregulations in chromatin regulatory genes ( KDM6A, ARID1A, MLL2, and STAG2) and recurrent copy number alterations. Thirty-five samples (54.7%) were PD-L1-positive (PD-L1 combined positive score ≥ 1) with a significantly higher exonic tumor mutational burden (TMB) compared to PD-L1-negative BC samples ( P= 0.010). We observed that various immune-responsive pathways, including the PD-L1 signaling pathway, were enriched significantly in PD-L1-positive BCs. Interestingly, genes in the CTLA4 pathway were enriched significantly in PD-L1-positive BC as well. Among 8 patients who received ICI, progressive disease was confirmed in one patient, whose tumor had low exonic TMB, negative PD-L1 status, and a relatively colder microenvironment. Conclusions: Gaining new insights into the molecular landscape of BC will improve treatment strategies. Our analysis suggests a rationale for studying dual checkpoint inhibition against BC.
Tumor genomic landscape of locally advanced or metastatic urothelial carcinoma with squamous differentiation (UCS) compared to pure urothelial carcinoma (UC).
Authors: Tripathi Nishita , Jo Yeonjung , Sayegh Nicolas , Li Haoran , Nussenzveig Roberto , Haaland Benjamin , Thomas Vinay Mathew , Gupta Sumati , Maughan Benjamin L. , Swami Umang , Pal Sumanta K. , Grivas Petros , Agarwal Neeraj , Sirohi Deepika
Published: February 2022

553

Background: UCS is a common entity and usually managed similarly to pure UC but requires focused study. Limited data are available on the genomic profile of UCS. We hypothesized that UCS would have a distinct genomic landscape compared to UC. Methods: In this IRB-approved retrospective study, pts) with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Pts were determined to have UCS based on presence of any component of squamous differentiation. Pts with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of pts and variants of unknown significance were excluded from the analysis. test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction. Results: 87 pts were eligible and included. UCS (n=31) vs UC (n=56): median age, 66 vs 68 years; male vs female: 21/10 vs 48/8Genomic aberrations in both groups are listed in the. GA in KMT2D was found to be significantly enriched in UCS vs UC (15/31 vs 0/56, FDR <0.001, p value = <0.001). GA in CUL4A was numerically higher in UCS vs UC (4/31 vs 1/56, FDR= 0.444, p-value = 0.03). Tumor mutation burden the frequency of genomic aberrations per pt were not significantly different in the groups. Conclusions: While tumor GA in only KMT2D was significantly enriched in the UCS cohort, it is interesting to note that both KMT2D and CUL4A (higher frequency in UCS) are involved in epigenetic regulation. Identification of underlying molecular targets and biomarkers can guide further drug development in this population. Limitations include small sample size, selection and confounding biases. These hypothesis-generating data need external validation.[Table: see text]
Association of leucocyte levels in urine with tissue PD-L1 status and immune infiltration into basal bladder cancer subtype in the prospective real-world clinicopathological register trial Bladder BRIDGister.
Authors: Ecke Thorsten , Friedersdorff Frank , Veltrup Elke , Kilic Ergin , Hake Roland , Eidt Sebastian , Roggisch Jenny , Koch Stefan , Wirtz Ralph M.
Published: February 2022

560

Background: The objective of the present study was to evaluate whether preoperative standard urine parameters such as leucocyte count in urine samples dominate in particular molecular subtypes of bladder cancer and reflect the immune infiltration status in the tissue in matched urine and TUR biopsy samples from patients being suspicious of bladder cancer and undergoing first TURB within the prospective Real World Experience registry trial "BRIDGister". Methods: For this pilot study paraffin fixed pretreatment tissue samples from the first TURB of 48 pts participating in the BRIDGister trial and matched urine samples were prospectively collected and analyzed. RNA from FFPE tissues were extracted by commercial kits- Relative gene expression of subtyping markers (KRT5, KRT20) by standardized RT-qPCR systems for PD-1, PD-L1, CTLA4 (STRATIFYER Molecular Pathology GmbH, Cologne). In addition urine samples were analyzed for leucocyte and erythrocyte count. Spearman correlation, Kruskal-Wallis, MannWhitney and Sensitivity/Specificity tests were done by JMP 9.0.0 (SAS software). Results: The pilot cohort of the BRIDGister trial consisted of 48 patients (median age: 77, male 65% vs. female 35%) of diverse clinical stages (Benign lesions/no tumor 38%, pTa 23%, pT1 20%, pT2 19%) and WHO 1973 grade (G1 11%, G2 43%, G3 23%). Presence of leucocytes but not erythrocytes was negatively associated with KRT20 (r=-0.4249, p=0.0216) but positive with KRT5 (r=0.3704, p=0.0479). Moreover high levels of leucocytes in urine were positively associated with tumor expression of PD-L1 (r=0.5081, p=0.0041), PD-1 (r=0.5342, p=0.00024) and CTLA4 (r=0.4244, p=0.0194). In contrast there was no significant association of tumor PDL-1, PD-1 and CTLA4 expression with erythrocyte count in urine. Conclusions: Presence of leucotytes in urine is strongly associated with basal subtype and immune cell infiltration into early bladder cancer. As the presence of erythrcytes did not reveal these significant associations, the presence of leucocytes is not due to simple bleeding or tissue vulnerability. Moreover, the strong tumor subtype specificity further demonstrate the basal tumor specificity of urine leucocytes and therefore may be helpful for detecting and monitoring basal bladder cancer in a non invasive fashion. Given the prognostic value of tissue determination of PD-L1, PD-1 and CTLA4 quantitation on mRNA level, these results warrant further investigation to conclude on its impact on outcome prediction (BCG responsiveness, recurrence, progression, etc.), which will be prospectively analyzed in the framework of the ongoing multicenter BRIDGister Real World Experience trial.
Cost effectiveness of newly approved second/third-line agents in metastatic urothelial carcinoma (mUC).
Authors: Benjamin David Joseph , Lythgoe Mark , Raymakers Adam J N , Rezazadeh Arash
Published: February 2022

574

Background: Over the past years, the treatment landscape of platinum-refractory mUC has drastically changed with the advent of immunotherapy. More recently, several new agents including enfortumab, erdafitinib, and sacituzumab have received F.D.A. approval for the treatment of platinum-refractory mUC. It is unclear if these newly approved therapies may be cost prohibitive for patients and/or hospitals/clinics compared to the recommended NCCN category 1 second-line agent, pembrolizumab. Methods: Using acquisition costs from our home institution’s cancer center pharmacy department, we calculated the total cost of treatment for each agent. We used phase II clinical trial data to determine the median duration of treatment for each therapy. For weight-based therapies, we used 70 kg as the weight for an average human adult. Results: The three newly approved therapies for mUC have total acquisition costs in descending order as follows: enfortumab vedotin ($153,697.50), edafitinib ($131,642.62), and sacituzumab govitecan ($63,198.07). Enfortumab and sacituzumab likely have higher total costs given both therapies require infusion center use for administration, and are associated with infusion center administration fees. In comparison, pembrolizumab (standard of care per NCCN guidelines) has a total acquisition cost of $51,343.60. Conclusions: Based off median duration of treatment, pembrolizumab has the lowest total acquisition cost compared to the three newly approved therapies for mUC. Further statistical analysis of this data set is ongoing. In particular, analysis will include out-of-pocket costs for patients as well as quality-adjusted life years (QALY).[Table: see text]
Five-year survival comparison of different treatment modalities for muscle invasive urothelial carcinoma, squamous cell carcinoma and adenocarcinoma of the bladder: An analysis of the National Cancer Database.
Authors: Rivera Carlos , Jabbal Iktej Singh , Yaghi Marita , Landau Kevin Scott , Muruve Nicolas , Saravia Diana , George Tiffany L. , Nahleh Zeina A. , Arteta-Bulos Rafael
Published: February 2022

575

Background: Localized muscle invasive bladder cancer carries a significant recurrence and mortality rate. The purpose of this study was to compare 5-year overall survival (OS) of neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), RC alone, bladder preserving chemoradiotherapy (BPCRT) and radiation alone (RT) on selected histologies. Methods: We sampled the National Cancer Database (NCDB) for bladder cancer patients diagnosed with AJCC 7th Stage 2 and 3 for urothelial carcinoma (UC) including variant histologies, squamous cell carcinoma (SCC) and adenocarcinoma (AC) from 2004-2018 with definitive intent treatment. 5-year Kaplan-Meier survival plots were utilized to assess survival differences amongst treatment modalities and stratified by selected histologies. Multivariate cox regression models were used to compare hazard ratios and logistic regression analysis was performed for covariate analysis. A p-value <0.05 was considered statistically significant. Results: A total of 20,629 patients met inclusion criteria. The average age was 69.51 + 11.02 years, 68% were male. UC represented 94.1% of selected histologies, followed by 4.6% SCC and 1.3% AC. For all combined histologies, 5-year OS for patients with NAC followed by RC was 58%, 48% for RC alone, 33% for BPCRT and 10% for RT alone. RC alone provided a longer OS in the SCC and AC groups, 48% and 47% respectively (p<0.001). NAC followed by RC showed superior OS in the UC group (58%, p<0.001), with OS decreasing to 43% in SCC and 44% in AC. BPCRT showed lower 5-year OS in all selected histologies when compared to NAC followed by RC and RC alone (33% in UC, 27% in SCC and 24% in AC group). In all selected histologies, RT showed the lowest 5-year OS (10% in UC, 8% in SCC and 17% in AC group; p<0.001). Furthermore, covariables associated with lower 5-year survival were male sex (p<0.001) and TNM Stage 3 (p<0.001). Conclusions: NAC followed by RC showed improved 5-year OS for UC. The benefit of NAC was marginal for SCC and AC histology. RC is better than BPCRT for all histologies. RT alone showed inferior 5-year OS for all histologies.[Table: see text]
68ga-PSMA-11 patients with newly diagnosed and recurrent prostate cancer (Firefly).
Authors: Manogue Charlotte , Rauterkus Grant , Light Malcolm , Sussman Isabelle P. , Lieberman Alex , Huang Minqi , Davis Gaynelle , Barata Pedro C. , Layton Jodi Lyn , Lewis Brian E. , Harris Kendra Marie , Manning Hailey , Sartor A. Oliver
Published: February 2022

TPS189

Background: A primary challenge facing oncologists is the accurate identification of the source of the rising PSA in the recurrent disease setting and the failure of proper staging at the time of initial therapy. Current imaging modalities perform poorly in this regard. PSMA imaging is FDA approved but reimbursement remains a considerable issue for most patients. Methods: This is a phase II expanded access intermediate sized clinical trial using 68Ga-PSMA-11 (Telix Pharma cold kit) under our own Investigational New Drug (IND) with the FDA. Two cohorts are utilized, recurrent disease with a PSA > 0.2 or > 2.0 post-radiation, and newly diagnosed high risk localized disease and/or oligo-metastatic patients as assessed by conventional imaging. 300 patients will be allowed to enroll and 63 are enrolled to date. Patients will be injected with 1.8–2.2 MBq/kg body weight with 68Ga-PSMA-11 (per EANM guidelines). The lower and upper limits of the dose are set to 3 to 7 mCi respectively. Primary Objective(s): Utilize 68Ga-PSMA-11 PET images to define uptake location for localization of prostate cancer metastatic sites in patients prior to initial therapy and to utilize 68Ga-PSMA-11 PET images to define uptake location for localization of prostate cancer including both local recurrences and metastatic sites in patients with recurrent disease after initial therapy. Secondary Objectives: To assess the therapeutic consequences of 68Ga-PSMA-11 PET/CT imaging in prostate cancer patients with and without prior treatment. As such the planned therapies after the PSMA scan will be annotated and recorded. In addition, we aim to determine the number of patients with metastatic disease prior to initial therapy that was not diagnosed with conventional imaging and we aim to determine the locations of recurrent disease for those patients who have demonstrated PSA recurrence after curative therapy. Percentage of positive scans will be assessed for PSA values 0.2-0.5 ng/mL, > 0.5-1.0 ng/mL, > 1.0- > 2.0 ng/mL, and > 2 ng/mL. Results will be summarized descriptively with 95% confidence intervals. Localization of all lesions will be performed with regard to lymph nodes (pelvic versus non-pelvis), bones (by location), and other (by site). Treatment planning will be captured and quantified by radiation, surgery, hormonal therapy (type and duration), and/or observation at the time of the initial clinical visit after the PSMA scan and 6 months later. This trial is open and recruiting patients. Data analysis has not been performed. Clinical trial information: NCT04854369.
Part 1 results from NOVA-II, a randomized, double-blind, vehicle-controlled phase II study evaluating the safety and efficacy of OQL011 on VEGFR inhibitor associated hand-foot skin reaction in cancer patients.
Authors: Lacouture Mario E. , Patel Anisha B , LeBoeuf Nicole R. , Marathe Omkar Subhash , Leventhal Jonathan , Choi Jennifer N. , Lam Elaine Tat , Kaffenberger Benjamin S. , Voss Martin H , Webb Mark L , Tyler Robert Claude , Ju Juegang , Tang Hong , Luo Jie , Anadkat Milan J. , Vogelzang Nicholas J.
Published: February 2022

TPS396

Background: Hand-foot skin reaction (HFSR) is associated with the use of multi-targeted tyrosine kinase inhibitors sharing vascular endothelial growth factor receptor inhibitory (VEGFRi) activity (e.g., cabozantinib, regorafenib, sorafenib, sunitinib). HFSR affects the palms and soles with edema, erythema, hyperkeratosis, pain, and bullae/blisters impacting quality-of-life, activities of daily living, and consistent VEGFRi dosing. HFSR incidence differs among VEGFRi, ranging from 5-69% (all grades) and 1-19% (grade 3). Topical urea has marginal benefit, and to date, there are no regulatory authority approved HFSR treatments. The pathogenesis of HFSR has been partially associated with impaired vascular repair mechanisms resulting from inhibition of VEGF signaling. Nitric oxide (NO) has been reported to induce VEGF upregulation at a moderate concentration. We hypothesized that topical stimulation of VEGF signaling through OQL011, an NO donor, will safely and effectively mitigate HFSR. Methods: NOVA-II is a phase 2, double-blind, randomized vehicle-controlled trial evaluating the safety and efficacy of OQL011 for the treatment of moderate to severe HFSR. Subjects receiving a VEGFRi (either mono- or combination therapy) and have Grade ≥2 HFSR per NCI CTCAE v5.0 for palmar plantar erythrodysesthesia (PPE) were eligible. For Part 1, 31 subjects were randomized (2:1) and received 0.2% OQL011 topical ointment or vehicle TID for 6 weeks. The primary endpoint is the proportion of patients who achieve an NCI CTCAE v5.0 for PPE Grade 0 or 1 by Week 3. An investigator global assessment (IGA) scale is being developed to assess HFSR recovery, and a secondary endpoint will measure the proportion of patients who have improvement in HFSR severity and achieve an IGA score of clear (0) or almost clear (1) by Week 3 and/or Week 6. A Chi-square test will be used to detect a difference between the treatment arm and the vehicle-control arm. Additionally, the IGA score will be validated by assessing the inter- & intra-rater reliability. The correlation between IGA, NCI CTCAE v5.0 for PPE, and patient outcomes including Visual Analog Scale of Pain, HFSR Quality of Life questionnaire will also be reported. This study began enrolling patients in December 2019 and completed the last patient Visit in August 2021. Data lock, unblinding and data analysis will be completed by mid-November. Clinical trial information: NCT04088318.