bluuebunny/crossref_metadata_2025 huggingface dataset:
18F-PSMA1007 PET/CT in the context of biochemical recurrence of prostate cancer: An economical experience from a Latin American reference center.
Authors: Mogollon Maria Paula , Caicedo Juan Ignacio , Ramirez Natalia , Rojas Julian , Medina Camilo
Published: March 2023

47

Background: 25-30% of patients present with biochemical recurrence of prostatic adenocarcinoma (PCa) after primary tumor treatment. One of the options indicated for the study of recurrence is PET/CT PSMA. In our center we use the 18F-PSMA1007, which has a cost of approximately $1,342, while the alternative cost (68Ga-PSMA-11) is $2,422. The aim of this study is to evaluate the performance of 18F-PSMA-1007 PET/CT in patients with biochemical recurrence after definitive therapy. Methods: A cross-sectional study that included patients with a biochemical recurrence and who underwent 18F-PSMA1007 PET/CT in our center of reference between 2020-2022. Biochemical recurrence was defined as a PSA >0.1 ng/dL in prostatectomy and a value of nadir PSA + 2ng/ml in radiotherapy. Descriptive analysis was performed with frequencies for discrete variables, and central tendency and dispersion measures for continuous variables. Detection rates were evaluated according to primary tumor treatment and PSA values. To compare categorical variables, we use Chi-square and t-Test for continuous variables. This analysis was performed using SPSS statistical software. Results: A total of 154 patients were included, 84% (n=129) with radical prostatectomy and 16% (n=25) received management with radiotherapy. Of the first group, 75.2% had evidence of recurrence on 18F-PSMA-1007 PET/CT, while of the second group, 92% had evidence. The descriptive analysis is shown. A statistically significant difference was found in local recurrence and bone metastasis. In terms of metastases, 26,3% of post-surgical patients had bone metastasis and a higher percentage (52%) of those who underwent radiotherapy, with concomitant involvement of both the axial and appendicular skeleton in both groups. In the prostatectomy group, the detection rates for PSA levels <0.25, 0.25 - <0.5, 0.5-< 1, 1-2, 2 - < 5, 5 - <10, ≥10 were 12.5%, 48.3%, 79.2%, 84.2%, 96%,90% and 100% respectively. In the radiotherapy group, the detection rates for PSA levels 2 - <5, 5<10, ≥10 were 87,5%, 100% and 100%, respectively. Conclusions: 18F-PSMA-1007 PET/CT is an alternative option that offers similar detection ranges and is more economical than 68Ga-PSMA-11 in our population, allowing effective detection of biochemical PCa recurrence in central and remote locations, where fluorine is not consistently available. [Table: see text]
Response and outcomes of maintenance avelumab after platinum-based chemotherapy (PBC) in patients (pts) with advanced urothelial carcinoma (aUC): "Real world" experience.
Authors: Bakaloudi Dimitra Rafailia , Talukder Rafee , Makrakis Dimitrios , Agarwal Neeraj , Tripathi Nishita , Bamias Aristotelis , Zakopoulou Roubini , Brown Jason , Korolewicz James , Fulgenzi Claudia A.M. , Jindal Tanya , Murgic Jure , Fröbe Ana , Johnson Jeffrey , Drakaki Alexandra , Rodríguez-Vida Alejo , Rey-Cárdenas Macarena , Alonso Buznego Lucia Andrea , Khaki Ali Raza , Grivas Petros
Published: March 2023

472

Background: PBC followed by avelumab switch maintenance in non-progressors is the standard first line (1L) aUC treatment. We describe clinical features and outcomes in a ‘real-world’ cohort treated with avelumab maintenance for aUC. We hypothesized that outcomes would be similar with JavelinBladder100 trial data. Methods: This was a retrospective cohort study of pts from 12 sites who received 1L switch maintenance avelumab after no progression to PBC for aUC. We calculated overall response rate (ORR), median overall and progression-free survival (mOS, mPFS) using Kaplan Meier method from avelumab start. We also described OS and PFS for specific subsets using Cox regression. Results: We found 77 pts with aUC (78% pure, 22% mixed UC) with median age 68, 81% men, 91% White, 17% upper tract primary, 66% prior cisplatin, 17% liver metastasis (mets), 80% ECOG PS 0-1 at time of PBC start. There was a median of 6 weeks (range 1-30) from end of PBC to avelumab start; median follow-up time from avelumab start was 22 months (95%CI 16-24). ORR with avelumab maintenance: 28% (complete response [CR] 17%, partial response [PR] 11%), stable disease (SD) 32%; progression as best response 30% (10% unknown); mPFS 7 months (95%CI 5-9), mOS 22 months (95%CI 16-NR). Table shows HR for OS and PFS for specific subsets. Absence (vs presence) of liver mets (p=0.04), ECOG PS 0-1 (vs >1; p=0.01) and CR/PR (vs SD) to 1L PBC (p=0.03) were associated with longer OS. Conclusions:‘Real world’ outcomes with avelumab maintenance in pts with aUC align with JavelinBladder100 trial data (but higher ORR). Good PS, response to PBC and absence of liver mets are favorable prognostic factors. Limitations include moderate sample size, retrospective design, lack of randomization and central scan review, possible selection and confounding biases. Other studies (e.g. PATRIOT-II) can generate more data in pts on maintenance avelumab outside clinical trials. [Table: see text]
Time to event following bacillus Calmette-Guerin therapy initiation in Medicare beneficiaries with intermediate- to high-risk non-muscle invasive bladder cancer, 2010-2019.
Authors: Petrilla Allison A. , Silverstein Alison R. , Eccleston Anthony , Thompson Allison , Brinkmann Julia , Bello Temitope , Chang Jane , Cappelleri Joseph C , Chandrasekar Sanjana , Schroeder Amy L
Published: March 2023

473

Background: For patients with intermediate- to high-risk non-muscle invasive bladder cancer (NMIBC), standard of care includes transurethral resection (TURBT) followed by induction and maintenance intravesical immunotherapy with Bacillus Calmette-Guerin (BCG). This study describes characteristics and clinical outcomes of Medicare beneficiaries newly diagnosed with NMIBC who initiated BCG therapy following TURBT. Methods: Retrospective cohort study using Centers for Medicare and Medicaid-sourced Medicare Fee-for-Service medical/pharmacy claims (100% sample). Patient selection criteria: ≥1 bladder cancer diagnosis 2010-2019, no prior radiotherapy, systemic therapy, cystectomy, or metastasis in 6 months post-diagnosis, continuously enrolled in Medicare ≥12 months pre- and post-index (or death). Index date = date of first BCG instillation. A literature-based definition for adequate maintenance BCG defined adequate (≥7 instillations of BCG within 274 days of BCG initiation) and inadequate (remainder) BCG therapy for patient stratification. Events: time to BCG discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis. Provider access to BCG (due to supply shortage), patient tolerability, and NMIBC risk status are not captured in claims data. Results: Of 46,052 BCG-treated patients eligible for analysis, 19,859 (43.1%) received adequate BCG therapy. The two cohorts had similar baseline characteristics (Table) and median duration of follow up (46 months). Median (interquartile range [IQR]) time from NMIBC diagnosis to BCG initiation was 2.8 (8.2) months for adequate, 3.7 (14.4) months for inadequate BCG. Time from BCG initiation to discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis are reported in the table. Conclusions: Between 2010 and 2019, 57% of Medicare patients initiating BCG following diagnosis of NMIBC and TURBT may not have received adequate BCG therapy. Patients with inadequate BCG therapy had numerically shorter time to radical cystectomy, systemic therapy, radiation, and metastasis than those with adequate BCG therapy. Characteristics & Outcomes by Cohort. [Table: see text]
Neoadjuvant chemotherapy plus radical cystectomy (NAC-RC) versus trimodality therapy (TMT) in early-stage small cell bladder cancer: Comparison of outcomes.
Authors: Jatwani Karan , Roy Arya Mariam , Attwood Kristopher , George Anthony , Perimbeti Stuthi , Jiang Changchuan , Faisal Muhammad Salman , Muthusamy Kumarasamy Vasanthan , Chatta Gurkamal S. , Gopalakrishnan Dharmesh
Published: March 2023

476

Background: Small cell bladder cancer is a rare and aggressive histological variant with a paucity of data to guide the optimal management strategy in non-metastatic disease. NAC-RC and TMT (maximal transurethral resection of bladder tumor + chemoradiation) have been variably employed based on institutional preferences, and we aim to compare outcomes between these two approaches. Methods: We queried the National Cancer Database for adult patients with small cell bladder cancer diagnosed during the years 2004 to 2018. Patients with small cell histology and early-stage clinically node-negative bladder cancer (cT1-4N0M0) were included and divided into two groups based on the treatment strategy employed – NAC-RC or TMT. Patients who did not receive any definitive local therapy and those who received chemotherapy or radiation in the adjuvant setting were excluded. Fisher’s exact and Mann Whiney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed for multivariate analysis of factors associated with overall survival. Models were adjusted for age, sex, race, income, educational level, clinical T stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 1262 patients were identified – 629 (49.8%) underwent NAC-RC while 633 (50.2%) received TMT. Patients in the NAC-RC group were younger (median 67 vs. 74 years, P <0.001) and more frequently Males (81% vs 76%, p = 0.02). Clinical T stage was comparable between the groups (P = 0.38). Patients with private insurance (P < 0.001) and higher income tiers (P = 0.04) were more likely to receive NAC-RC in lieu of TMT. Overall survival in the NAC-RC group was significantly longer than the TMT group (median of 41.3 vs. 25.4 months, log-rank P < 0.001). On multivariable analysis, only the type of treatment modality employed was independently predictive of overall survival (Hazard Ratio of 1.22 for TMT, with 95% CI 1.05-1.43, P = 0.01). Conclusions: In early-stage clinically node-negative small cell bladder cancer, NAC-RC was associated with significantly longer overall survival compared to TMT.
Comparison of objective response rate and long-term overall survival in patients with treated immune checkpoint inhibitors in metastatic urothelial carcinoma.
Authors: Tural Deniz , Arslan Cagatay , Selcukbiricik Fatih , Olmez Omer Fatih , Akar Emre , Erman Mustafa , Ürün Yüksel , Erdem Dilek , Kilickap Saadettin
Published: March 2023

481

Background: In this study, we evaluated RECIST criteria-based objective response rate (ORR) as potential surrogate endpoints for overall survival (OS) in patients who were treated with immune checkpoint inhibitors therapy (ICT) and with long-term follow-up in metastatic urothelial carcinoma. Methods: The primary endpoint was overall ORR and OS, duration of treatment (DOR) with ICT. ORR was analyzed using Fisher’s exact test. Median follow-up and OS were estimated by using the Kaplan-Meier method. Results: The median follow-up time was 58 (1.15–71) months (mo). Progression developed in 94 (47%) patients during the first three months of treatment with ICT. The rate of complete response (CR) to ICT, partial response (PR) rate, and stable disease were 10% (n=20), 23% (n=46), and 20% (n=41), respectively. There was an imbalance in baseline characteristics between patients who had ORR and non-responder groups (Table). The 5–year OS rates for CR and PR were 73% and 23%, respectively. The median DOR for CR, PR, and SD were 51.8 mo% (44.5–59.1), 20.7mo (16.7–24.6), and 8.8 mo (5.5–12.1), respectively. Of the sixteen (80%) patients who had CR and 14 (30%) patients who had PR had an ongoing response at the time of the analysis. In univariate analysis, neutrophil-to-lymphocyte ratio (NLR) >3, liver metastases, ECOG PS ≥1, and hemoglobin levels below 10 mg/dl, PR, and CR were all significantly associated with OS. In multivariate analysis, liver metastases [HR=2.3; 95% CI 1.3-4.2; p < (0.004)] were independent related variable with short OS. Other hand, PR [HR=0.3; 95% CI 0.15-0.5; p < (0.001)] and CR [HR=0.06; 95% CI 0.014-0.27; p < (0.001)] were associated with improved OS. Conclusions: This five-year analysis of real-world data indicated a significant correlation between ORR, especially CR and OS in patients who received immune checkpoint inhibitors in metastatic urothelial cancer. Therefore, the identification of a potential surrogate marker for survival in patients treated with ICT would represent an important advance in the early identification of patients’ response or resistance to ICT.
Occurrence and prognostic significance of different histology relative to urinary tract tumors: A SEER population-based study.
Authors: Liu Haoyang , Chen Junru , Liu Zhenhua , Shen Pengfei , Zeng Hao
Published: March 2023

485

Background: To evaluate the prevalence and prognostic value of variant histology in urinary tract tumors according to primary location and metastatic status. Methods: Using the Surveillance, Epidemiology, and End Results registry (SEER, 2004-2015) databases, patients with urinary tract tumors were identified. Propensity Score Matching was used to balance the clinicopathologic features between different histologies. Kaplan-Meier plots were used to compare the cancer specific survival (CSS) and overall survival (OS) of different histologies. The cox regression analysis were also applied. Results: Of all 93,200 eligible patients with urinary tract tumors, 87,323 (93.7%) harbored bladder cancer (3,685 in M1 stage). Among them, urothelial tumors (UC) accounted for 96.67%, followed by squamous neoplasm (SCC), urachal carcinoma (Urachal), adenocarcinoma (Adeno), neuroendocrine tumors (NE) and tumor of Müllerian type (Müllerian). A total of 5877 (6.35%) harbored upper urinary tract tumors (950 in M1 stage). Among them, UC accounted for 96.39%, followed by SCC, Urachal, Müllerian, NE, Adeno. In patients with localized diseases, those with non-urothelial tumors had significantly worse prognosis in overall urinary tract tumors based on OS and CSS (P<0.001). In terms of specific histology in bladder cancer (BC), patients with UC had most favorable prognosis, followed by Adeno, Urachal and Müllerian, while those with SCC and NE were associated with the worst survival outcomes. In patients with upper urinary tract tumors (UUTT), those with Müllerian had the best survival outcomes, followed by UC, while those with NE, Adeno, SCC, and Urachal had relatively worse prognosis. In M1 stage, although there was a statistical difference in OS and CSS between all patients with urothelial and non-urothelial tumors (P<0.001), the 5-year survival rate (3.74%, 2.50%) and 5-year CSM (4.93%, 3.28%) were similar. In metastatic BC, there was no difference in OS among all histology. However, in terms of CSS, significant differences were still observed in patients with different histologies. In metastatic UUTT, no difference in survival was found among different histologies. After PSM, the similar results were observed in BC, while there is no statistical difference of survival among different histologies in UUTT, no matter the M stage. Cox analyses revealed that primary location, histology type, surgery, chemotherapy and M stage were the common and strong independent prognostic factors in both BC and UUTT. Conclusions: In urinary tract tumors, the incidence of different histology types between BC and UUTT is roughly similar. Overall, patient with variant histology have a worse prognosis than those with urothelial carcinoma. However, differences in survival among the histology types vary by primary location and metastatic status, especially the metastatic status.
Radical nephroureterectomy followed by adjuvant chemotherapy (RNU-AC) versus observation (RNU-O) in early-stage upper urinary tract cancers with variant histology (UUTC-VH).
Authors: Jatwani Karan , Muthusamy Kumarasamy Vasanthan , Roy Arya Mariam , Attwood Kristopher , George Anthony , Faisal Muhammad Salman , Perimbeti Stuthi , Chatta Gurkamal S. , Gopalakrishnan Dharmesh
Published: March 2023

487

Background: Upper urinary tract cancers (UUTC) are less frequent and associated with poorer stage-for-stage prognosis compared to bladder cancer, with variant histology being an independent predictor of inferior outcomes. The POUT trial included only patients with predominantly urothelial tumors. We aimed to compare outcomes among patients with UUTC-VH who were treated with RNU-AC vs. RNU-O. Methods: We queried the National Cancer Database for adult patients with UUTC-VH diagnosed between 2004 and 2018. Only patients who underwent RNU with node-negative disease on pathological staging (pT2-4N0M0) were included and divided into two groups based on the postoperative treatment strategy - RNU-AC and RNU-O. Patients who received neoadjuvant chemotherapy were excluded from analyses. Fisher’s exact and Mann Whiney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed for multivariate analysis of factors associated with overall survival. Models were adjusted for age, sex, race, income, educational level, clinical T stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 522 patients were identified – 133 (25.5%) received RNU-AC while 389 (74.5%) underwent RNU-O. Patients in the RNU-AC group were younger (median 69 vs. 76 years, P <0.001). Patients with small cell (15.8% vs 4.9%), micropapillary (9.8% vs 5.9%) and adenocarcinoma (9% vs 6.7%) histologies were more likely while those with squamous histology was less likely to receive AC (38.3% vs 50.6%) (p < 0.001 for all comparisons). A significant majority of patients in each T stage were treated with AC – 87.1% of pT1, 73.2% of pT2, and 68.4% of pT3 (P = 0.009). Overall survival in the RNU-AC and RNU-O groups were comparable (median of 27 vs 24.1 months, log rank-P = 0.63). On multivariable analysis, neither AC nor histological subtype were not independently predictive of OS (HR for AC = 0.96, 95% CI 0.74-1.24, P = 0.75). Conclusions: This is the largest study to date evaluating outcomes with AC after RNU in UUTC-VH since these patients were largely excluded from AC clinical trials. We observed that AC was not associated with improved overall survival after RNU in this population.
Neoadjuvant cisplatin-based chemotherapy followed by selective bladder preservation chemoradiotherapy (CRT) in muscle-invasive urothelial carcinoma of bladder (MIBC): A combined retrospective analysis of two prospective studies.
Authors: Hong Joohyun , Choi Daeho , Sung Hyun Hwan , Jeong Byong Chang , Park Se Hoon
Published: March 2023

496

Background: Bladder preservation CRT in patients with a clinical complete response (cCR) following neoadjuvant cisplatin-based chemotherapy is one of the promising treatment strategies for MIBC. A combined analysis of raw data from two prospective phase II studies was performed to better evaluate the feasibility of selective bladder preservation CRT. Methods: The analysis was based on primary efficacy data from two independent studies, including 76 MIBC patients receiving neoadjuvant chemotherapy followed by bladder preservation CRT. The efficacy data included metastasis-free survival (MFS) and disease-free survival (DFS). For the present analysis, starting point of survivals was defined as the date of commencing CRT. Results: Sixty-four patients received gemcitabine/cisplatin (GC) combination chemotherapy in neoadjuvant setting, and 12 received nivolumab plus GC. After completion of planned neoadjuvant chemotherapy, 66 patients with a cCR and 10 who did not have a cCR but refused surgery were treated with CRT. With a median follow-up of 45 (95% CI, 41-48) months, a total of 39 recurrences was observed (51%): metastatic (n=28) and within the urinary tract (n=11). Median DFS or MFS was not reached. The 12- and 24-month DFS rates were 81% and 66%, respectively. MFS rates at 12- and 24-month were 87% and 75%, respectively. Both DFS (P=0.055) and MFS (P=0.014; HR 0.38; 95% CI, 0.17-0.85) appeared to be affected by the achievement of a cCR. Conclusions: The strategy of neoadjuvant chemotherapy followed by selective bladder preservation CRT based on the cCR is feasible in the treatment of MIBC.
Sequential intravesical gemcitabine and docetaxel versus bacillus Calmette-Guérin for the treatment of high-risk, treatment-naïve, non-muscle invasive bladder cancer.
Authors: McElree Ian M. , Steinberg Ryan L. , Mott Sarah L. , O'Donnell Michael A. , Packiam Vignesh T.
Published: March 2023

497

Background: Due to ongoing bacillus Calmette-Guerin (BCG) shortages, sequential intravesical gemcitabine and docetaxel (Gem/Doce) has been increasingly utilized as first-line adjuvant treatment for patients with high-risk non-muscle invasive bladder cancer. Herein, we compared oncologic outcomes and tolerance of Gem/Doce versus BCG. Methods: We retrospectively identified 312 patients with high-risk, treatment-naïve, NMIBC treated at our institution between January 2011 and December 2021; 174 treated with BCG and 138 treated with Gem/Doce. After complete TURBT, patients received a 6 weekly intravesical induction regimen of Gem/Doce or BCG, followed by maintenance if disease free at first follow-up. The primary outcome was high-grade (HG) recurrence-free survival (RFS). Cox multivariable regression analyses were performed. Adverse events were reported using CTCAE v5. Results: Median follow-up for patients receiving Gem/Doce and BCG was 23 and 49 months, respectively. Baseline clinicopathologic characteristics were similar between groups, including presence of CIS (41% vs 44%, p=0.6) and T1 (37% vs 41%, p=0.5) disease for patients receiving Gem/Doce and BCG, respectively. HG-RFS estimates at 6, 12, and 24-months were 92%, 85%, and 81% for Gem/Doce and 76%, 71%, and 69% for BCG, respectively. On multivariable Cox regression analyses controlling for age, gender, treatment year, and presence of CIS, Gem/Doce treatment was associated with superior HG-RFS (HR 0.57, p=0.04) and RFS (HR 0.56, p=0.02) versus BCG (Table). Progression-free, cystectomy-free, cancer-specific, and overall survival were similar between groups. Induction BCG was associated with greater treatment discontinuation (9.2% vs 2.9%, p=0.02), dysuria (p=0.03), and arthralgias (p=0.02), but less bladder spasms (p<0.01) than Gem/Doce, respectively. Conclusions: In the setting of ongoing BCG production shortages, we found Gem/Doce to be an efficacious and well-tolerated alternative first-line therapy for high-risk NMIBC. Prospective randomized evaluation is being planned.
Safety and efficacy of immune checkpoint inhibitors (ICI) in advanced penile squamous cell carcinoma (PeCa): An international study from the Global Society of Rare Genitourinary Tumors (GSRGT).
Authors: El Zarif Talal , Nassar Amin , Jiang Lijuan , Pond Gregory Russell , Zhuang Tony , Velev Maud , Hahn Andrew Warren , Buti Sebastiano , Álvarez Pablo , McKay Rana R. , Vincenzi Bruno , El-Am Edward , Hui Gavin , Lee Jae-Lyun , Mouhieddine Tarek H. , Milowsky Matthew I. , Matthews Harrison , Barata Pedro C. , Apolo Andrea B. , Sonpavde Guru P.
Published: March 2023

5

Background: Management options for patients (pts) with advanced (locally advanced or metastatic) PeCa are limited. The GSRGT assembled an international cohort of pts with advanced PeCa treated with ICI to evaluate toxicity and clinical outcomes. Methods: We retrospectively collected data on pts with advanced PeCa receiving ≥1 cycle of ICI between 2015-2022 at 18 medical centers in the US, Europe, and Asia. Immune-related adverse events (irAE) were graded per the Common Terminology Criteria for Adverse Events v5.0. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Objective response rate (ORR) was determined by the clinical investigator per RECIST 1.1 criteria, whenever feasible. Results: Among 72 pts with advanced PeCa treated with ICI, 24 (33%) were Hispanic and 7 (10%) were Black. 60 (83%) pts had metastases while the remainder had locally advanced disease. The median age was 64 (inter-quartile range (IQR): 54,70) years and 48 (67%) had ECOG performance status ≥1. Most pts (n=60, 83%) were treated in the ≥2nd line setting and received pembrolizumab (n=23), nivolumab (n=15), cemiplimab (n=15), nivolumab and ipilimumab (n=7), or other anti-PD1/L1-based therapies (n=12). Among 37 pts with available data on HPV status, 24 (65%) were HPV+. 3 (4%) pts were HIV+. irAE of any grade occurred in 18 (25%) pts, 7 (10%) were grade ≥3, 7 (10%) required steroids, 6 (9%) required hospitalization, and 8 (11%) led to treatment discontinuation. The median OS and 24-month OS and median PFS and 24-month PFS were 9.4 (95%CI: 6.8, 12.8) months and 19.3% (95%CI: 9.2, 32.1) and 2.8 (95%CI: 2.1, 3.9) months and 11.2 % (95%CI: 4.9, 20.2), respectively. Among 66 pts evaluable for response, ORR was 7/66 (11%) (2 with complete response, 5 with partial response), and 16 (24%) pts had stable disease for a disease control rate of 35%. The median duration of response was 7.9 (IQR: 3, not reached) months. Conclusions: In the largest retrospective cohort of ICI-treated advanced PeCa, ICI showed no new safety signals, however, overall anti-tumor activity was limited. Future translational studies are needed to identify pts that are more likely to derive clinical benefit from ICI.
Comparison of costs incurred by patients treated with adjuvant nivolumab versus placebo for high-risk muscle-invasive urothelial carcinoma.
Authors: Yin Xin , Mitra Shreya , Patel Miraj Y , Ranjan Sandip , Bhandari Hitesh , Potluri Ravi , Rosenblatt Lisa
Published: March 2023

500

Background: The global, phase 3 CheckMate 274 trial showed significant and clinically meaningful benefit of adjuvant nivolumab (NIVO) treatment versus placebo (PBO) in reducing risk of disease recurrence or death in patients with muscle-invasive urothelial carcinoma (MIUC) at a high risk of recurrence after radical cystectomy. The implications of these benefits on costs associated with the treatment are unknown. Here, we estimate and compare per-patient medical and subsequent therapy costs in the United States for patients with high-risk MIUC initiating treatment with adjuvant NIVO or PBO. Methods: This analysis used individual data from all randomized patients for healthcare resources utilized (HCRU) from the CheckMate 274 trial. Medical (inpatient, lab, office visits, procedures, concomitant drugs) and subsequent treatment (surgery, radiotherapy, systemic therapy) resources were included, while the costs of NIVO were not included. US-based unit costs were applied to these resources and were obtained from Healthcare Cost and Utilization Project, Micromedex RED BOOK, and CMS databases, supplemented by inputs from published literature. HCRU was only captured on 2 follow-up visits after discontinuation of study therapy: follow-up 1 occurred approximately 35 days after the last dose or coinciding with the date of discontinuation, and follow-up 2 occurred approximately 80 days after follow-up 1. To align with data captured at follow-up visits, HCRU and related costs were analyzed from randomization to 12 months and 16 months. Costs were adjusted for censoring using the Kaplan–Meier sampling average estimator. Results: Total per-patient costs incurred by the NIVO-treated cohort (n = 353) were 6% lower than the PBO cohort (n = 356) over the 12-month period from randomization ($36K vs $38K) and 13% lower over the 16-month period from randomization ($41K vs $47K) (Table). The NIVO cohort, compared with placebo, had lower subsequent treatment costs ($2K vs $11K over 12 months, and $3K vs $18K over 16 months) despite higher medical costs ($34K vs $27K over 12 months, and $37K vs $29K over 16 months). Conclusions: Patients treated with adjuvant NIVO incurred lower total costs versus PBO, with the differential increasing over time. The slightly higher medical costs incurred by the NIVO cohort were offset by the substantially lower subsequent therapy costs. [Table: see text]
Enfortumab vedotin (EV) outcomes with and without immediate prior immune checkpoint inhibitor (ICI) in patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Koshkin Vadim S , Henderson Nicholas , Kilari Deepak , Jindal Tanya , Alhalabi Omar , Freeman Dory , Basu Arnab , Barata Pedro C. , Bilen Mehmet Asim , Zakharia Yousef , Emamekhoo Hamid , Shah Sumit , Milowsky Matthew I. , Davis Nancy B. , Gupta Shilpa , Hoimes Christopher J. , Grivas Petros , Bellmunt Joaquim , Campbell Matthew T , Alva Ajjai Shivaram
Published: March 2023

514

Background: EV is FDA-approved in pts with aUC and ≥1 prior therapy line. Data from EV-103 trial indicate robust response to first-line EV/pembrolizumab, suggesting potentially at least additive treatment effect with EV/ICI combination. Given the long half-life of ICIs, pts who start EV treatment immediately after ICI may potentially derive benefit from that therapy sequence. We hypothesized that the last systemic therapy prior to EV would impact outcomes, as pts treated with ICI immediately prior to EV would have superior outcomes relative to pts treated with chemotherapy (chemo). Methods: UNITE is a retrospective study of pts treated with EV at 16 US sites. Pt characteristics and outcomes were abstracted from EMR review at each site. Observed response was determined by investigators for evaluable pts with scans following ≥1 EV dose. Pts treated with EV monotherapy were divided into two groups based on whether they received chemo or ICI as the line of therapy immediately prior to EV, regardless of other therapy received. Chi-squared test was used to assess differences in pt characteristics and ORR while log-rank tests were used for OS and PFS measured from EV start. Results: Among 325 pts treated with EV monotherapy, 247 had chemo or ICI as immediate prior treatment, with 186 pts receiving ICI (Group A) and 61 pts receiving platinum-based chemo (Group B). In 247-pt cohort, ORR to EV was 52% and mPFS and mOS were 6 and 13 mos. Group B pts were younger, had more bone mets and higher Bellmunt risk factors, but were otherwise similar to Group A (Table). Most pts had both prior chemo and ICI in both group A (58%) and group B (84%). Group A pts had shorter time from last treatment (median 1.2 vs 3.2 mo, p<0.01), lower ORR to immediate prior treatment (16% vs 37%, p<0.01) and fewer prior therapy lines (mean 1.9 vs 2.6, p<0.01). Group A had superior ORR (58% vs 37%, p=0.02), mPFS (6.9 vs 4.8 mo, p=0.02) and mOS (15.2 vs 8.8 mo, p=0.01) from EV start vs Group B. Conclusions: Pts with aUC treated with EV had superior outcomes if they received ICI instead of chemo as immediate prior treatment, suggesting the hypothesis that this may represent an optimal therapy sequence or combination. These data need external validation as limitations include retrospective design, lack of randomization, and selection and confounding biases. [Table: see text]
Phase 2 open label study of durvalumab with neoadjuvant chemotherapy in variant histology bladder cancer.
Authors: Khaki Ali Raza , Fan Alice C. , Shah Sumit , Parikh Divya Ahuja , Chien Joanne , Moore Kaidi , Ruiz Shann Mika , Haas Denise , Fakhoury Laith , Del Toro Noël , Baker Paige , O'Brien Aidan , Srinivas Sandy
Published: March 2023

524

Background: The immune-responsive nature of bladder cancer has made it an active area of interest for novel applications of immune checkpoint inhibitors (ICIs), with multiple ICI agents approved in the metastatic setting and ongoing perioperative trials. Variant histology urothelial carcinoma is a rare, heterogenous, and aggressive disease category associated with poor prognosis and response to standard therapies. This investigator-initiated phase 2 trial explored the addition of durvalumab to neoadjuvant chemotherapy (NAC) in the setting of variant histology MIBC. Methods: Patients with cT2-T4a, N0-N1, M0 histologically-confirmed bladder cancer of variant histology who were candidates for platinum-based NAC and radical cystectomy were eligible for the study. Enrolled patients received durvalumab with each cycle of investigator’s choice of platinum NAC (ddMVAC, cisplatin/gemcitabine, or carboplatin/gemcitabine). The primary objective was to determine the safety and tolerability of each study treatment as assessed by the total number of adverse events of grade 3 or higher, judged by the investigator as probably or definitely related to durvalumab. Secondary objective was to determine the percent of subjects post neoadjuvant chemo immunotherapy who achieve tumor stage of pT2N0M0 or better at cystectomy. Target accrual was 24 patients. Results: Six patients were enrolled (the study closed early due to low accrual). Median age was 72 years, 17% were women, 67% were white, 33% were Asian. 50% received ddMVAC and 50% received carboplatin/gemcitabine. All patients completed the planned cycles of NAC and durvalumab (4 cycles) and 5/6 proceeded to radical cystectomy (one patient declined cystectomy). Three patients experienced a Grade 3 AE that was assessed by the investigator to be related to treatment (table). One patient with sarcomatoid and glandular histology had pathological complete response and one patient with papillary and 10% squamous had pT2N0 at cystectomy. Conclusions: The addition of durvalumab to platinum NAC for patients with variant-histology muscle invasive bladder cancer demonstrates a reasonable safety and tolerability profile. Further investigation into this combination is warranted in larger scale trials. Clinical trial information: NCT03912818 . [Table: see text]
Clinical features and prognosis of patients who undergo renal transplant with urothelial carcinoma.
Authors: Li Juan , Yan Xieqiao , Tang Bixia , Li Siming , Zhou Li , Xu Huayan , Guo Jun , Sheng Xinan
Published: March 2023

527

Background: Malignant tumor has been identified as one of the three major causes of death for kidney transplant recipients. This study collected the clinical data of UC patients after kidney transplantation in our center retrospectively, and explored the natural course of disease and response to systemic treatment of this special subgroup of patients. Methods: 1332 consecutive uc patients diagnosed pathologically in our department from 2012 to 2022 were collected, including 26 renal transplant pts. Data were collected, including gender, age, pathological grade, primary site, initial diagnosis stage, metastasis time, site, systemic treatment plan and response to treatment. Kaplan-Meier survival analysis was used to explore the survival and prognostic factors of uc patients after renal transplantation. Results: 1332 consecutive uc patients from Sep 2012 to Sep 2022 in our department were collected, including 26 pts (1.95%) after renal transplantation. 7 males (26.9%).，overall median age of diagnosis 59.0y (40-79y), 24 pathological high-grade (92.3%), 6 cases are with other differentiation (23%), 7 cases (63.65%) her2 IHC 2~3+ in 11 tested cases. Primary site includes 8 renal pelvis (30.8%), 7 ureter (26.9%), 3 bladder (11.5%) and 8 multiple (30.8%). T1, T2, T3, T4 and Tx accounted for 1 (3.8%), 8 (30.8%), 14 (53.8%), 0 and 3 (11.6%)，with lymph node metastasis in 2 (7.7%). Initial stage I, II, III and IV were 3.8%, 69.2%, 11.6% and 15.4% The median survival time of the four groups was 73.4, 38.0, 18.3 and 13.9 months respectively. The median disease-free survival time of 24 patients after radical surgery was 16.0 months (95% CI: 13.2-27.8m), and 11 patients (42.3%) relapsed within one year after surgery. Among systematic treatment, 24, 9 and 3 patients received the first-, second- and third line treatment. First-line includes nab-ptx+gem (7), ptx+gem+endo/bev (6), ptx+gem+cisplatin+endo/bev (4), gem+cisplatin (3), ADC (2 ), gem+carboplatin (1) and gem+oxa (1). Second-line includes nab-ptx based chemo (5), ADC (2), ptx+gem+cisplatin+endo (1) and ptx+sorafenib (1). Third-line includes nab-ptx +gem+cisplatin+bev (1), gem+cisplatin+sotan (1) and everolimus+cisplatin (1). The mPFS of first-, second-, and third-line were 6.5 months (95% CI: 6.4-17.7 m), 2.6 months (95% CI: 1.6-5.3 m) and 2.0 months (95% CI: 1.8-21 m). The mOS was 15.3 months (95% CI: 8.4-15.1 m), 11.6 months (95% CI: 5.0-16.3 m) and 8.0 months (95% CI: 1.6-13.0 m). The most common distant metastasis in late stage included lymph node in 16 cases (61.5%), lung in 12 cases (46.1%), bone in 7 cases (26.9%) and liver in 5 cases (19.2%). Conclusions: Urothelial carcinoma in renal transplant patients has higher degree of malignancy, nearly half of the patients have rapid recurrence and metastasis after operation. It seems these sub-group patients have higher her2 (IHC 2-3+) status.
Leptomeningeal metastases in prostate cancer: A systematic review.
Authors: Choe Sharon In Wha , Wang Jue
Published: March 2023

53

Background: Leptomeningeal metastasis (LM) is a rare complication of prostate cancer (PCa) that involves spread of malignant disease to the meninges and carries a poor prognosis. This review aimed to assess the clinical findings, treatments, and outcomes of LM cases reported in the literature. Methods: We performed a literature search for case reports in PubMed, Scopus, and ScienceDirect from database inception to June 2022 using keywords “leptomeningeal carcinomatosis AND prostate cancer” and “leptomeningeal metastases AND prostate cancer.” The reference lists of previously published reviews were also searched to identify additional articles. Results: We included 41 patients with a mean age (±SD, range) at diagnosis of 67.5 (8.4, 46-87) years. The most common presenting symptoms were headache (32%), leg weakness (24%), nausea (22%), vomiting (20%), vision complaints (17%), sensory abnormalities (17%), back pain (12%), and confusion (12%). The median time from initial PCa to LM diagnosis was 36 months (range 0-252) and was reported in 37 patients (90%). The median time of survival from LM to death was 1.7 months (range 4 days – 14 months) and was reported in 28 patients (68%). Four patients (13%) were still alive when the reports were written, including one who was alive at 16 months and another at 252 months. The median serum PSA (±SD, range) at time of diagnosis was 137.5 (507.9, 3.1-1500) ng/mL. The most common diagnostic tests were a combination of neuroimaging and CSF analysis (41%), neuroimaging only (32%), and autopsy only (12%). The most common imaging modalities used to aid diagnosis were MRI (65%) and CT (32%). CSF cytology was positive for malignant cells in 55% of 22 cases (54%) that reported cytology results. Thirty-four cases (83%) reported treatments, and the most common treatments were radiation (56%), steroids (32%), surgery (26%), hormonal therapy (21%), and chemotherapy (21%). Conclusions: LM is expected to become more prevalent with the overall increasing incidence of PCa with therapeutic advancements, yet it remains difficult to diagnose and treat. The findings of this review suggest that neurological symptoms in patients with advanced PCa should prompt providers to obtain neuroimaging to investigate possible LM.
Gene signatures for predicting the response to immune checkpoint inhibitor by integrating bulk and single-cell sequence data in patients with bladder cancer.
Authors: Chang Hyun , Kim Yongho , Lee Jeong Won , Jung Jin-Woo , Yoon Byung Il
Published: March 2023

535

Background: Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in bladder cancer (BC) therapy, only a limited fraction of patients benefit from it. Thus, we aim to establish gene signature (iGS) and develop a model that predicts the response of ICI for the patients with BC. Methods: We collected bulk RNA expression data from BC cohort (GSE176307) receiving ICI and single-cell sequencing data from patients with BC (GSE135337). Single-sample gene set enrichment (ssGSEA) analysis was used to develop predictive iGS. Clinical benefit of ICI was defined as a complete or partial response or stable disease at week 24. The gene ontology (GO) and pathway enrichment analysis were established through DAVID database. Logistic regression model was constructed with iGS and clinical factors. The final model was validated by the K-fold cross validation technique. Results: We integrated bulk RNA expression data and single-cell sequencing data, and identified subset of cells (N= 157) that were associated with the overall survival (OS) of patients receiving ICI. These cells were compared with all other cells, and 85 up-regulated differentially expressed genes (DEGs) were identified. DEGs were mainly enriched in 'antigen processing and presentation of exogenous peptide antigen via MHC class II', 'peptide antigen assembly with MHC class II protein complex' and 'immune response' in the biological process enrichment analysis. High iGS score, that was derived from ssGSEA, was significantly associated with longer OS in multivariate Cox regression analysis (Hazard ratio: 0.40, P = 0.02) Final prediction model for clinical benefit included iGS score [odds ratio (OR) = 3.89], tumor mutation burden (OR = 9.8) and age (OR = 0.93) with accuracy of 0.80 and an area under the receiver operator characteristic curve (AUROC) of 0.77. Conclusions: We showed the potential of iGS from bulk and single cell RNA sequencing for predicting clinical benefit of ICI in BC.
Antitumor immunity as the basis for durable disease-free, treatment-free survival (DDFTFS) in patients with metastatic urothelial cancer (mUC).
Authors: Anker Jonathan Forrest , Pal Sumanta Monty , Kim-Schulze Seunghee , Wang Huan , Halperin Rebecca , Uzilov Andrew , Saito Takuro , Hahn Noah M. , Patel Manishkumar , Qi Jingjing , Xie Hui , Bhardwaj Nina , Gnjatic Sacha , Galsky Matt D.
Published: March 2023

536

Background: Cisplatin-based chemotherapy has been associated with functional cures (i.e., DDFTFS) in a small subset of patients with mUC. However, the mechanistic basis for this phenomenon has remained elusive. Immune checkpoint blockade may enhance the ability of cisplatin-based chemotherapy to cure mUC, particularly if the latter is achieved by promoting antitumor immunity. From a phase II trial evaluating a phased schedule of gemcitabine and cisplatin (GC) followed by GC plus Ipilimumab (Ipi) for mUC, 4/36 patients were treatment-free disease-free >7 years after initiation of treatment. We sought to identify the immunological mechanisms associated with functional cure of such patients. Methods: Whole exome sequencing was performed on pre-treatment archival tumor tissue. Neoantigen binding affinity was predicted using NetMHCcons. Neoantigen-specific T cell response was assessed via IFNγ ELISpot assays after co-culture of patient-derived peripheral blood CD4+ and CD8+ T cells with autologous neoantigen-pulsed antigen presenting B cells. Serum protein soluble analytes were measured using the Olink Target 96 Immuno-Oncology Panel at the pre-treatment, post-GC, and post-GC+Ipi timepoints. Results: CD4+ and CD8+ neoantigen-specific T cell reactivity was measured at serial timepoints in 2 patients achieving DDFTFS and 5 patients not achieving DDFTFS. Strikingly, peripheral blood CD4+ and CD8+ T cell reactivity to a predicted neoantigen emerged on cycle 6 day 1 (after 2 cycles of GC followed by 4 cycles of GC + Ipi) in 2/2 patients achieving DDFTFS (variant in TP53 or DHX9) but in 0/5 patients not achieving DDFTFS. Peripheral serum proteomic analysis at serial timepoints (n = 35 patients) revealed that pre-treatment, patients achieving DDFTFS demonstrated an immune activated phenotype with elevations in cytotoxic adaptive immunity markers and immune checkpoints (Table). After the addition of Ipi, patients achieving DDFTFS demonstrated decreased markers of tumor-promoting inflammation but increased markers of adaptive immunity, co-stimulation, and cytotoxicity. Conclusions: Anti-tumor immunity may underlie functional cures achieved in patients with mUC treated with cisplatin-based chemotherapy +/- immune checkpoint blockade. Probing the mechanistic basis for DDFTFS may facilitate the identification of pre- and on-treatment features, and therapeutic components and sequences, necessary to extend this ultimate therapeutic goal to a larger subset of patients. [Table: see text]
EphA2 on urinary extracellular vesicles as a novel diagnostic marker for bladder cancer and its effect on the invasiveness of bladder cancer.
Authors: Tomiyama Eisuke , Fujita Kazutoshi , Kato Taigo , Hatano Koji , Kawashima Atsunari , Nonomura Norio
Published: March 2023

539

Background: An accurate and non-invasive test for diagnosing bladder cancer (BCa) is needed. Potential diagnostic markers include cancer-specific proteins in urinary extracellular vesicles (uEVs) secreted directly from BCa. In this study, we aimed to identify a uEV-based protein biomarker for the diagnosis of BCa and develop an ELISA for clinical application. In addition, we evaluated whether the identified EV protein exerts a cancer-promoting effect on BCa. Methods: Urinary EVs were isolated by ultracentrifugation with a sucrose cushion. Shotgun proteomics (TMT-labeled LC-MS/MS) was performed on uEVs from seven patients with BCa and four healthy individuals. Biomarker candidates were selected from the identified proteins and validated with targeted proteomics (SRM/MRM) of uEVs from 49 patients with BCa and 48 individuals without BCa. In addition, we developed an ELISA, without time-consuming ultracentrifugation, for quantifying the uEV-based protein biomarker and evaluated its diagnostic performance using urine samples from 46 patients with BCa and 46 individuals without BCa. The effect of the validated EV protein on BCa was also analyzed in vitro. Results: Shotgun proteomics identified 1960 proteins, of which 13 membrane proteins were significantly upregulated in the uEVs from patients with BCa. Among them, eight proteins were validated by target proteomics, and Ephrin type-A receptor 2 (EphA2) showed the best diagnostic performance (ROCAUC = 0.79). We developed EV-EphA2-CD9 ELISA as a simple assay for uEV-EphA2 measurement with clinical value, which showed good diagnostic performance (sensitivity: 60.9 %, specificity: 97.8%). Furthermore, the combination of EV-EphA2-CD9 ELISA and urine cytology improved the detection of BCa (sensitivity, 80.4 %; specificity, 97.8 %), which could reduce the frequency of cystoscopy at bladder cancer diagnosis and during follow-up. In addition, we demonstrated that EphA2 promotes the proliferation, invasion, and migration of BCa cells and that EV-EphA2 promotes the invasion of BCa cells. The invasion-promoting effect of EV-EphA2 was attenuated by knockdown of Ephrin-A1, the ligand of EphA2, on BCa cells or by prior exposure of Ephrin-A1 to EV-EphA2, suggesting that the signalling pathway via Ephrin-A1 toward BCa cells was involved in the cancer-promoting effect of EV-EphA2. Conclusions: We identified uEV-EphA2 as a novel diagnostic marker for BCa and established EV-EphA2-CD9 ELISA for uEV-EphA2 quantification, which enables the non-invasive early diagnosis of BCa in clinical practice. Furthermore, we revealed that exosomal EphA2 promotes the invasion of BCa via its ligand; Ephrin-A1 on BCa cells, suggesting that these may be potential therapeutic targets.