bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness-analysis of different treatment modalities in bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NIMBC).
Authors: Rieger Constantin , Schluechtermann Joerg , Storz Enno , Pfister David A. , Heidenreich Axel
Published: January 2024

556

Background: Elaborate treatment and repetitive surveillance makes bladder cancer to the most expensive cancer type over the lifetime of a patient with a peak in non-muscle invasive bladder cancer. Radical cystectomy (RC) as the Standard of Care in BCG unresponsive NMIBC is associated with a significant health-related quality-of-life burden (QALY). Gemcitabine/Docetaxel, Pembrolizumab or Hyperthermic Intravesical Chemotherapy (HIVEC) have recently been published as salvage treatment options trying to increase the rate of bladder preservation. Methods: We developed a Markov model from a payer´s perspective with the clinical data of single-arm studies for BCG unresponsive NMIBC (Gemcitabine/Docetaxel and Pembrolizumab) and our clinical data for patients receiving HIVEC (n=29) as intravesical salvage-chemotherapy. Costs were simulated with a non-commercial DRG-grouper, utilities were derived from comparable cost-effectiveness studies. We used a Monte-Carlo Simulation to identify the optimal treatment, comparing the incremental cost effectiveness ratios (ICER) in consideration of a willingness-to pay of 50.000 Euro/QALY. Results: Over a horizon of 10 years, Gemcitabine/Docetaxel, HIVEC and Pembrolizumab were associated with costs of 48.353 64.438 and 204.580 Euro, and QALY´s of 6.16, 6.48 and 6.00, resulting in an ICER of 26.482, 42.567 and 184.533 Euro in comparison to RC (costs: 21.871 Euro; QALY: 5.01). Monte-Carlo Simulation has identified HIVEC as the treatment of choice in the assumption of a WTP of <50.000 Euro. QALY gains in Gemcitabine/Docetaxel and especially HIVEC were mainly driven by bladder preservation and the low rate of progression. Conclusions: Considering a WTP of <50.000 Euro / QALY, Gemcitabine/Docetaxel and HIVEC are highly cost-effective therapy options in BCG unresponsive bladder cancer, while RC remains the cheapest option. At its current price, Pembrolizumab is only cost-effective with a price reduction of 70%.
Evaluating outcomes of sacituzumab govitecan (SG) in patients with urothelial cancer (UC), previously treated with enfortumab vedotin (EV).
Authors: Vlachou Evangelia , Johnson Burles Avner , Hahn Noah M. , Rourke Kelli , McConkey David James , Hoffman-Censits Jean H.
Published: January 2024

567

Background: SG is an antibody drug conjugate (ADC) FDA approved for treatment refractory UC with Response Rate (RR) of 27%. Many patients (pts) receive SG after disease progression (PD) on EV, another ADC commonly used in earlier lines of therapy. In the TROPHY study, 10/113 pts treated with SG received prior EV and RR was similar to that of the entire cohort. We present a real-world experience in pts treated with SG after EV. Methods: In this retrospective analysis, pts with aUC treated with SG following EV at Johns Hopkins were identified. Demographic and treatment details were extracted by chart review. RR [Complete Response (CR) + Partial Response (PR)] with 95% Confidence Interval (95%CI) were compared between pts who did and did not have response to EV and between subgroups of interest using the χ2 test. Response to EV was defined as physician-assessed CR or PR. Cox proportional hazard model analysis was used for comparing progression free (PFS) and overall (OS) survival for SG between groups. Results: 23 pts were identified, including 10 (43.5%) females and 19 (82.6%) white. Median age was 71.8 years (range: 46.3, 85.4). Primary tumor location was upper tract for 11 (47.8%) pts, lower tract for 11 (47.8%) and 1 pt had tumor in both sites. 11 (47.8%) pts had liver metastasis present at SG initiation. SG was 3rd line treatment for 5 (21.7%) pts and ≥ 4th line for 18 (78.3%). 4 (17.4%) pts had tumors with variant histology. RR for the entire cohort was 17.4%. Reason for discontinuation was PD in 16 (69.6%) pts and toxicity/functional decline in 7 (30.4%). The table summarizes RR in different subgroups. Median PFS for SG was 2.63 months among EV responders and 1.35 months for non-responders [Hazard Ratio (HR): 0.31, 95%CI: 0.12, 0.83, P = 0.02]. Median OS for SG was 5.36 months in EV responders and 5.78 months in non-responders (HR: 0.82, 95%CI: 0.27, 2.46, P= 0.7). No PFS or OS difference was found between subgroups: Upper vs lower tract primary tumor, liver metastasis presence vs absence, variant histology vs pure UC, estimated glomerular filtration rate (eGFR) ≥ 30 mL/min vs < 30. The small sample precluded multivariable analysis. Conclusions: To our knowledge this is the largest real-world cohort of pts with UC treated with SG post EV. A trend towards improved RR and PFS for SG was noted among EV responders. In our analysis clinical outcomes remained consistently similar across all subgroups, including pts with known poor prognosis risk factors. [Table: see text]
Experiences of patients with bladder cancer: A comparison of urban and rural areas.
Authors: Makaroff Lydia , Filicevas Alex , Hensley Patrick J. , Kamat Ashish M.
Published: January 2024

568

Background: Bladder cancer patients encounter unique challenges and advantages in urban and rural environments, significantly influencing their path from diagnosis to treatment. While numerous studies explore bladder cancer from clinical and therapeutic perspectives, there is a noticeable gap in research addressing patients' experiences based on geographical locale. This study aims to bridge this gap by offering a comparative analysis of urban versus rural experiences. Methods: The World Bladder Cancer Patient Coalition and IQVIA formulated an online survey, designed to capture the multifaceted experiences of bladder cancer patients. Available in various languages, the survey was accessible from October 2021 to February 2022. Responses underwent systematic analysis, with parameters including gender, time since diagnosis, age, region, and disease stage, forming the sub-analytical categories. Results: We received a total of 1,198 responses from 45 countries. Key findings are summarized in the table, highlighting the comparative experiences of urban and rural patients. Conclusions: Significant disparities emerge between urban and rural bladder cancer patients. Rural patients particularly face prolonged diagnosis times, less clear communication from healthcare providers, and experience greater challenges in accessing treatment. These findings underscore the need for a re-evaluation of communication strategies and healthcare infrastructure, especially in rural areas. This research serves as a stepping stone for further investigations aimed at fostering a more patient-centric approach to bladder cancer care. Limitations to consider involve the inherent biases of online survey distribution and the possibility of certain regions being underrepresented. [Table: see text]
Effect of body mass index (BMI) on efficacy of immune checkpoint inhibitors (ICIs) in patients with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Lynn David , Hobeika Charbel , Patgunarajah Ubenthira , Dawsey Scott , Pramod Nikhil , Wei Wei , Nair Monica , Maroli Kimberly , Martin Allison , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Nizam Amanda , Bonham Amanda , Mian Omar Y. , Pavicic Paul G. , Diaz-Montero C. Marcela , Gupta Shilpa
Published: January 2024

571

Background: There is emerging data on the role of BMI and outcomes of ICIs in various solid tumors, with underweight pts having worse outcomes to ICIs. The effect of BMI on efficacy of ICIs in pts with mUC is not clear. Methods: We identified 335 adult pts with mUC at the Cleveland Clinic treated who received >/= 2 cycles of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Patient characteristics including age, sex, race, primary site (bladder vs upper tract UC (UTUC)), tumor histology and pre-ICI treatment NLR values were collected. BMI was calculated and values were collected and compared to assess impact on overall (OS) and progression free survival (PFS) after ICI start date. BMI was broken down into four categories: underweight (BMI less than 18.5 kg/m2), normal weight (BMI between 18.5 and 24.9 kg/m2), obese (BMI 30 kg/m2 or greater) and overweight (BMI between 25 and 29.9 kg/m2). OS and PFS were estimated by Kaplan Meier method and compared using log rank test. Results: Median age of pts was 73 yrs (35-95) and 254 (76%) pts were males. 247 (74%) received P, 88 (26%) received A. We found that underweight pts had significantly worse OS compared to normal or higher BMI (2.32 vs 13.08 mos; p=0.001) as well a significantly worse PFS (1.61 vs 4.75 mos; p=0.02) (Table). Conclusions: In our large real-world cohort of pts with mUC receiving ICI, we report for the first time the effect of BMI on outcomes with ICI. Further prospective studies are warranted. [Table: see text]
Comparative cost-effectiveness of trimodal therapy and radical cystectomy for management of muscle-invasive bladder cancer.
Authors: Joyce Daniel D. , Wymer Kevin , Boorjian Stephen A. , Gore John L. , Khaki Ali Raza , Raldow Ann Caroline , Williams Stephen B. , Smith Angela B. , Sharma Vidit
Published: January 2024

572

Background: Bladder preservation with trimodal therapy (TMT), which consists of maximal transurethral resection of bladder tumors followed by chemoradiation, is now included in guidelines with radical cystectomy (RC) as options for definitive management of muscle-invasive bladder cancer (MIBC). Prospective randomized controlled trial data to help guide treatment selection are lacking, and prior efforts to bridge this knowledge gap have failed primarily due to poor accrual. A recent retrospective analysis comparing TMT to RC reported similar oncologic outcomes between these treatments when performed in highly selected patients. However, treatment toxicities and costs vary significantly between these management options. To investigate the impact of these outcomes on relative treatment value, we evaluated the comparative cost-effectiveness of TMT and RC for treatment of MIBC. Methods: Cost-effectiveness was compared between TMT and RC for patients with a solitary, muscle-invasive tumor less than 7cm, no or unilateral hydronephrosis, limited carcinoma in situ, and adequate bladder function (criteria utilized in a recent retrospective comparative series) using a microsimulation model with a 5-year horizon from a Medicare payer perspective. Additionally, a 10-year lifetime horizon was evaluated to better understand the impact of long-term outcome uncertainty on cost-effectiveness. Based on recently published multicenter retrospective propensity score matched data, metastatic progression and survival probabilities were assumed to be equivalent between treatments. Utility values and additional probabilities, including both short and long-term treatment toxicities, were obtained from published literature. Primary outcomes of interest included effectiveness measured in quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER) using a willingness-to-pay threshold of $100,000/QALY. One-way and probabilistic sensitivity analyses were performed to assess the robustness of the model. Results: At 5 years, the average cost was $32,286.35 higher for TMT versus RC. The average QALYs were 3.88 and 3.96 for RC and TMT respectively. TMT was not cost-effective at 5-year (ICER: $379,917.21/QALY) or 10-year (ICER: $222,704.78/QALY) time horizons. On one-way sensitivity analyses, TMT would become cost effective if: 1) TMT costs were less than $16,152; or 2) TMT resulted in a 13.3% improvement in metastasis free survival relative to RC. Conclusions: Although it resulted in similar quality and duration of life, TMT was not cost-effective relative to RC at 5 and 10 years given higher treatment costs. These findings support the role of both TMT and RC in management of MIBC and highlight the need for continued efforts to reduce healthcare costs associated with TMT.
Outcomes with neoadjuvant chemotherapy in bladder-preserving treatment for MIBC.
Authors: Glover Michael , Ewongwo Agnes , Usoz Melissa , Kornberg Zachary , Bagshaw Hilary , Shah Jay Bakul , Shah Sumit , Qian Yushen
Published: January 2024

577

Background: Trimodality bladder preservation is an acceptable alternative to radical cystectomy (RC) for muscle invasive bladder cancer (MIBC). Multiple retrospective studies have reported similar disease control rates and overall survival rates with chemoradiation (CRT), but the benefit of neoadjuvant chemotherapy (NAC) prior to CRT is not established. This study investigates the outcomes of CRT with or without NAC for management of MIBC. Methods: Retrospective analysis of 135 adult patients with muscle invasive bladder cancer evaluated in the Department of Radiation Oncology over 7 years (2016-2022). Patients were excluded if they did not receive NAC or if they underwent RC. Patients were treated with NAC followed by CRT. Overall survival (OS), progression-free survival (PFS), and metastasis-free survival (MFS) were calculated using Kaplan-Meier methods. Follow-up was censored at 36 months after treatment. Differences in survival outcomes by completion of status of NAC were analyzed using log-rank tests. All survival analyses were performed in SAS version 9.4. Results: Of the 135 evaluated patients, 38 were treated with NAC followed by CRT. The 24-month OS, PFS, and MFS were 76% [95% CI 62-92%], 60% [95% CI 46-79%], and 72% [95% CI 58-90%] respectively. The 24-month PFS in patients who received a full course of NAC was 66.0% [95% CI 50-87%]) and 38.0% [95 CI 15-92%] in those who did not complete NAC regimen. Overall PFS was significantly higher in the NAC cohort (log-rank p=0.03). There was no significant difference in OS between patients who completed prescribed course of NAC versus those who did not (log-rank p=0.48). Treatment was overall well tolerated with 28.2% of grade 2 or higher RT toxicity. Conclusions: NAC prior to CRT achieved excellent short term disease-free and survival outcomes in patients with non-metastatic MIBC. This analysis is limited by its retrospective nature but suggests that completion of NAC prior to CRT may be associated with lower rates of disease recurrence. [Table: see text]
Development of a novel machine learning-based predictive risk calculator for radical cystectomy.
Authors: Rajagopalan Aravind , Chua Kevin J. , Patel Hiren V. , Pfail John , Kaldany Alain , Fu Melinda , Elsamra Sammy , Jang Thomas L. , Pitt Henry , Ghodoussipour Saum
Published: January 2024

578

Background: Radical cystectomy (RC) is a standard treatment for patients with muscle invasive and certain high-risk non-invasive bladder cancers. Existing clinical risk calculators based for RC on standard regression methods have demonstrated poor, inaccurate predictions of post-operative risks and adverse outcomes. We aimed to build a risk calculator using novel machine learning methods to predict complication rates and other outcomes based on clinical characteristics of patients undergoing RC. Methods: Patients who had an RC for bladder cancer between 2019 and 2021 were pulled from the National Surgical Quality Improvement Database. Potential predictors included clinically meaningful characteristics such as patient demographics, pre-operative labs, comorbidities, pre-operative bowel and antibiotic preparations, and prior treatment history, as well as cystectomy-specific characteristics such as diversion type and surgical approach. Outcomes included risk of any complication, infectious complication, mortality, and readmissions. Logistic regression, random forest, and support vector machine algorithms were used to build predictive models. Models were optimized assessed with area under the ROC curve (AUROC) and average precision (AP). Results: 8,936 patients were included in the sample dataset. Random forest classifiers outperformed other models for predicting risk of any complication (AUROC = 0.662; AP = 0.66), infectious complication (AUROC = 0.615; AP = 0.20), and mortality (AUROC = 0.603; AP = 0.03). The logistic regression model best predicted readmissions (AUROC = 0.587; AP = 0.26). Top predictors of complication risk included operation time, glomerular filtration rate, and type of procedure (robotic vs. open). Infectious complication was best predicted by wound classification and diversion type, mortality was best predicted by BMI and operation time, and readmissions was predicted most by pre-existing renal failure and emergent cases. Conclusions: Machine learning-based risk calculators were more effective in predicting morbidity and mortality after RC compared to more standard predictive algorithms. Machine learning algorithms therefore demonstrate greater predictive potential when given a wide range of clinical characteristics. [Table: see text]
Adverse effects and discontinuation of pembrolizumab in BCG refractory non-muscle invasive bladder cancer.
Authors: Golijanin Borivoj , Malshy Kamil , Bhatt Vikas , Lagos Galina , Amin Ali , De Souza Andre Luiz , Cheng Liang , Mega Anthony E. , Golijanin Dragan
Published: January 2024

588

Background: Non-muscle invasive bladder cancer (NMIBC) is associated with high rates of recurrence and progression despite adequate intravesical treatment with Bacillus Calmette-Guerin (BCG). Pembrolizumab was found to be effective in treating BCG-refractory NMIBC in the KEYNOTE-057 trial with a 41% complete response after 3 months and minimal adverse effects. As a result it was approved by the FDA on January, 2020, for the treatment of high risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors in patients ineligible for or unwilling to undergo cystectomy. This study reports a single institution’s experience using pembrolizumab in BCG refractory patients with high-risk NMIBC. Methods: Records of NMIBC patients who commenced treatment with pembrolizumab between January 2020 and January 2023 at a single institution were retrospectively reviewed. Demographic and clinicopathologic information was collected. Kaplan-Meier curves were generated to calculate progression-free survival (PFS), and treatment-specific survival (TSS). The combined positive score (CPS) of PD-L1 was assessed for each case treated by pembrolizumab. Results: Out of 250 patients with NMIBC who were screened for the study, 18 met the inclusion criteria. The median age was 74.1 years (IQR=67.8 – 81.4), male to female ratio of 3.5:1. The median follow-up time was 17.5 months (IQR= 8.1–22.5). A previous history of CIS was present in all patients as well as second-line chemotherapy for BCG refractory disease. At the start of pembrolizumab, stage distribution was as follows: 1 (5.6%) cTa, 6 (33.3%) had CIS, and 11 (61.1%) cT1. After an average of 8.9 cycles, 72.2% (13/18) stopped treatment. 27.8% (5/18) are still undergoing treatment, with an average of 12.6 cycles (SD=10.4). 1 out of the 13 patients who stopped treatment had a complete response. The remaining reasons for termination of treatment are Grade 2 or higher immune-related adverse events in 53.8% (7/13), progression in 30.8% (4/13), and recurrence in 7.7% (1/13). Four patients ultimately required radical cystectomy which revealed 1 pTa, 1 pTis, 1 pT1, and 1 pT4. Only 1 patient had CPS of PD-L1 > 10. Conclusions: There were higher rates of toxicity from pembrolizumab for the treatment of BCG-refractory NMIBC than expected. More research is needed to better define the patients who are likely to benefit from this treatment. Pembrolizumab for BCG refractory NMIBC can have high rates of Grade 2 or higher adverse events leading to early withdrawal from treatment. Early discussion about radical surgery remains an important part of the treatment guidelines for BCG refractory NMIBC.
A real-world observational study characterizing patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) treated with or without androgen receptor pathway inhibitors (ARPIs).
Authors: Kolinsky Michael Paul , O'Sullivan Dylan E. , Boyne Devon J. , Brenner Darren R , Shokar Simran , Cheung Winson Y.
Published: January 2024

59

Background: mCSPC treatment is rapidly evolving with androgen deprivation therapy (ADT) plus ARPIs viewed as the standard of care for most pts. Data are needed to understand the real-world characteristics and treatment patterns of mCSPC (PC) pts in this dynamic field. This study aimed to define clinical features of mCSPC pts, estimate the proportion of pts receiving ARPIs, and evaluate clinical and demographic features associated with ARPI use. Methods: This retrospective cohort study used data from electronic health records and administrative databases in the province of Alberta, Canada. All newly diagnosed metastatic PC pts between 2017-2020 were identified. Pts were considered to have mCSPC if they initiated ADT within 30 days prior to, or at any time after diagnosis. ARPI exposure was defined as receiving ARPI within 180 days of initiating ADT. ARPI-naïve pts may have received ADT alone or other non-ARPI therapy (i.e., docetaxel) within 180 days of initiating ADT. Multivariable logistic regression was used to evaluate pt characteristics related to the receipt of ARPI. Overall survival (OS) was defined as the date of diagnosis to death from any cause or last known contact. Results: Of the 976 mCSPC pts identified, 33.5% received an ARPI. In ARPI exposed pts, the median time from ADT to ARPI start was 7.9 weeks and median time on ARPI was 13.1 months (mos). In multivariable analyses, ARPI use was associated with younger pt age, more recent diagnosis, fewer comorbidities, a higher metastatic burden, treatment centre, referral to a medical oncologist, and prior local therapy (all p<0.05). The median time to next therapy was 24.6 mos (95%CI=19.5-33.0) vs. 18.5 mos (95%CI+16.9-21.1), and median OS was 38.5 mos (95%CI=32.8-NA) vs. 34.2 mos (95%CI=33.3-38.8) for APRI exposed vs. ARPI-naive pts, respectively (p=0.03). Conclusions: This study identified factors associated with ARPI use in mCSPC, potentially allowing targeted efforts to improve ARPI uptake for pts in whom use is low. These findings are important as they reflect outcomes seen in real world pts.
Blue light cystoscopy versus white light cystoscopy for the detection of bladder cancer in China: An analysis of unpublished clinical trial and real-world data.
Authors: Li Hanzhong , Hu Hailong , Ma Lulin , Guo Jianming , Liu Xiuheng , Huang Jian , Guo Yonglian , Wen Jin , Zhang Shudong , Zhang Hongxian , Jiang Shuai , Liu Cheng , He Wang , Kang Xinli , Wang Fei
Published: January 2024

593

Background: Blue light cystoscopy (BLC) is superior to white light cystoscopy (WLC) in detection of bladder cancer, but no multi-center studies have been conducted in China with modern 4K LED equipment. The objective of this post hoc analysis of a randomized controlled trial (RCT) and a real-world study (RWS) was to compare BLC with WLC in the detection of bladder cancer and to determine the similarity between the RCT and RWS. Methods: In RCT (NCT05600322), patients with known or suspected bladder cancer were enrolled at seven hospitals in China from November 2022 to June 2023. In the prospective RWS, patients with known or suspected bladder cancer were enrolled at Hainan General Hospital from December 2022 to July 2023. Patients received intravesical HAL (Hexvix, Photocure ASA) and underwent WLC before BLC (System blue, Richard Wolf GmbH). Some patients were randomized to WLC to avoid observational bias. The primary endpoint was the proportion of patients with histologically confirmed tumors (Ta, T1, or CIS) who have at least one such lesion found by BLC but not by WLC. Secondary endpoints included, detection of CIS, lesion specific detection rate, false positive rates, and adverse events (AE). Results: 158 patients were enrolled in RCT, in which 37 patients were training patients, six patients were randomized to not undergo BLC, one patient withdrew. 114 patients remained in the full analysis set. 19 patients were enrolled in RWS. In patients confirmed with Ta, T1, or CIS, 42/97 patients (43.3%) in RCT and 4/12 patients (33.3%) in RWS had at least one confirmed lesion found by BLC but not by WLC (all p<0.0001). 11/114 patients (9.6%) with CIS in RCT and 1/14 patients (7.1%) with CIS in RWS showed at least 1 additional confirmed CIS lesion found by BLC but not by WLC. In RCT, detection rates for PUNLMP, CIS, Ta, T1 and T2-T4 tumors were NA, 94.7%, 100%, 98.2% and 100% for BLC and NA, 42.1%, 76.1%, 91.2% and 100% for WLC, respectively. In RWS, detection rates for PUNLMP, CIS, Ta, T1 and T2-T4 tumors were NA, 100%, 100%, 100% and 100% for BLC and NA, 50%, 81%, 100% and 100% for WLC, respectively. The false-positive rate was 23.2% and 16.0% for BLC and WLC in RCT and was 25.0% and 15.4% in RWS, respectively. In RCT, 200 AEs were observed in 95 patients, all mild to moderate, of which 191 were classified as unrelated to HAL. In RWS, 16 AEs were observed in 15 patients, all mild and were all unrelated to HAL. Conclusions: Both RCT and RWS confirm the superiority of BLC based on innovative LED technology with HAL over WLC in detection of bladder cancer in Chinese populations, especially CIS, and HAL is well tolerated. Clinical trial information: NCT05600322 .
Sequential endoluminal gemcitabine and docetaxel versus bacillus Calmette–Guérin for the treatment of high-grade upper tract urothelial carcinoma.
Authors: McElree Ian M. , Mott Sarah L. , Packiam Vignesh T. , O'Donnell Michael A. , Steinberg Ryan L.
Published: January 2024

613

Background: BCG is currently the only endoluminal treatment option for high-grade (HG) upper tract urothelial carcinoma (UTUC). Gemcitabine/Docetaxel (Gem/Doce) has shown promising efficacy as a treatment for HG UTUC, though a comparison to BCG is lacking. We report the outcomes of patients treated with endoluminal Gem/Doce versus BCG for non-invasive HG UTUC. Methods: A retrospective review of patients treated with Gem/Doce versus BCG for clinically non-invasive HG UTUC was performed. Treatment was instilled via nephrostomy or retrograde ureteral catheter. Induction instillations were performed weekly for 6 weeks. If disease free, maintenance therapy for Gem/Doce was monthly for 6 months and a single 3 week mini-cycle for BCG. Recurrence was defined as biopsy-proven disease or HG cytology. Progression was defined as development of muscle invasion, metastases, or death due to cancer. Results: The final cohort included 59 patients with 71 treated upper tract units; 36 received BCG and 35 received Gem/Doce. Median follow-up was 62 months in the BCG group and 29 months in the Gem/Doce group. Indication for treatment included a positive HG cytology in 78% and 89% of the BCG and Gem/Doce groups, respectively; the remaining patients in each group presented with pathologically-confirmed HG disease. The 2-year estimates for recurrence-free and nephroureterectomy-free survival were 57% and 87% for the BCG group and 56% and 100% for the Gem/Doce group, respectively (Table). Upon multivariable analysis, treatment with Gem/Doce was not associated with an increased risk of recurrence versus BCG (HR 0.78, 95%CI 0.33-1.85; p=0.57). In total, 19% of patients receiving BCG and 15% of patients receiving Gem/Doce experienced a grade 3+ adverse event. The development of any symptoms was not statistically different between treatment groups (p=0.28). There were two deaths recorded during the study period, one in each treatment group. Conclusions: Endoluminal Gem/Doce and BCG have similar oncological outcomes and major AE rates in the treatment of HG UTUC. Further prospective evaluation is warranted. [Table: see text]
Clinical outcomes of frontline GemFLP in advanced urachal and non-urachal adenocarcinomas of the urinary tract: The MD Anderson Cancer Center (MDACC) experience.
Authors: Moussa Mohammad Jad , Chen Adrienne H. , Grana Allison K. , Gao Jianjun , Shah Amishi Yogesh , Corn Paul Gettys , Tannir Nizar M. , Goswami Sangeeta , Wang Jianbo , Araujo John C. , Kamat Ashish M. , Navai Neema , Pettaway Curtis Alvin , Adibi Mehrad , Czerniak Bogdan , Guo Charles C. , Siefker-Radtke Arlene O. , Campbell Matthew T , Alhalabi Omar
Published: January 2024

630

Background: Adenocarcinomas of the urinary tract, including urachal (UA) and non-urachal (NUA) subtypes, are rare tumors. Triplet regimens combining gemcitabine, a taxane or 5-fluorouracil (5-FU)/leucovorin (L), and cisplatin (P), have been developed. Methods: We retrospectively reviewed records of patients receiving frontline (1L)GemFLP (Gemcitabine 200 mg/m2 IV on days 1 and 5; 5-FU 200 mg/m2 IV on days 1, 2, 3, 4, 5; L 10mg/m2 IV on days 1, 2, 3, 4, 5; P 20mg/m2 IV on days 1, 2, 3, 4, 5) in advanced UA and NUA at MDACC between 2003 and 2023. Advanced disease is defined as Sheldon stages IVA/IVB in UA and TNM stage IV in NUA. Imaging-based best overall responses (BOR) were complete (CR), partial (PR), stable (SD), progressive (PD) or non-evaluable (NE). Overall response rate (ORR) covers CR + PR, while disease control rate (DCR) covers CR + PR + SD. We report overall survival (OS) and progression-free survival (PFS) from GemFLP start. Results: Baseline characteristics of UA (n=40) and NUA (n=28) are in Table. In UA, bladder dome was primary location in 39 (97.5%). NUA pts had either bladder (11, 39.3%) or urethral (17, 60.7%) origin. BOR in 1L GemFLP are shown in Table. In UA, ORR is 20% and DCR is 72.5%. Median OS (mOS) is 19.8 months (95% CI: 12.2 - 30.6) and median PFS (mPFS) is 5.3 mo (95% CI: 3.1 – 6.3). In UA, pts with CR, PR, or SD have a significantly longer mOS than pts with PD [26 mo (16.2 – 35.6) vs. 7.7 mo (2.67 – 11.9), log-rank p <0.0001]. Meanwhile, in NUA, ORR is 35.7% and DCR is 75%. mOS is 12.95 mo (95% CI: 7.1-20.2) and mPFS is 5.3 mo (1.93 – 7.6). A similar significant survival benefit is seen in NUA pts with disease control versus pts with PD [17.6 mo (12.6 – 25.9) vs. 5 mo (2.63 – 7.1), p <0.0001]. Surgical consolidation was offered for 6 UA pts (3 PR, 3 SD), 3 of whom were regional N+ only, and for 4 NUA pts (1 CR, 1 PR, 2 SD) who were all regional N+ only. All except one showed residual pathological disease. Conclusions: 1L GemFLP is an active regimen in advanced UA and NUA, with a DCR of >70%. Pts with disease control (CR, PR, or SD) have a clear survival benefit compared to non-responders. 1L GemFLP might offer chances at surgical consolidation after disease control for pts with regional node-positive only disease, with larger cohorts needed to confirm findings. [Table: see text]
Outcomes with enfortumab vedotin in patients with advanced urothelial carcinoma and histology variants: Analysis of the UNITE study.
Authors: Jindal Tanya , Jiang Cindy Y. , Alhalabi Omar , Nguyen Charles B , Nizam Amanda , Basu Arnab , Bilen Mehmet Asim , Zakharia Yousef , Milowsky Matthew I. , Brown Jason R , Kilari Deepak , Emamekhoo Hamid , Hoimes Christopher J. , Khaki Ali Raza , Gupta Shilpa , Grivas Petros , Bellmunt Joaquim , Campbell Matthew T , Alva Ajjai Shivaram , Koshkin Vadim S
Published: January 2024

652

Background: Enfortumab vedotin (EV) is approved for patients (pts) with advanced urothelial carcinoma (aUC) but outcomes in pts with histology variants (HV) have not been well described. We hypothesized that presence of HV would impact EV treatment outcomes. Methods: UNITE is a multi-site retrospective study of pts with aUC treated with targeted agents, including 650 pts treated with EV regimens. We compared outcomes to EV monotherapy in pts with pure UC (pUC) relative to pts with any HV and with specific HVs. In pts with scans after > 1 cycle of EV, observed response rate (ORR) was assessed using χ2 test and logistic regression. Median progression-free survival (PFS) and overall survival (OS) from EV start were measured using the Kaplan Meier method and Cox proportional hazard test. Results: A total of 566 pts (366 with pUC; 200 with HV) from 17 US sites were treated with EV monotherapy. Median age was 70 years, 71% men, 87% Caucasian, 74% with ECOG PS 0/1 and 28% with liver mets. Median follow up was 21 mos from EV start, ORR was 49%, mPFS and mOS were 5.8 mos (95% CI: 5.29-6.67) and 12.2 mos (95% CI: 11.5 – 13.8), respectively. Pts with pUC had more visceral mets (69% vs 60%, p = 0.04) and liver mets (32% vs 21%, p =0.003) than pts with HV. No significant difference in outcomes were seen between pUC and pts with HV component (1-100%). Pts with predominant HV (50-99%; N=35), had numerically lower ORR relative to pUC pts (36% vs 52% OR 0.31, p <0.09), but no difference in mPFS or mOS. Pts with pure HV (pHV) (100%: N=14) had inferior outcomes relative to pts with pUC (ORR 0% vs 52%, p<0.001; mOS HR: 2.96 (95% CI: 1.60 – 5.46), p <0.001; mPFS HR: 1.9 (95% CI: 1.06 – 3.39), p=0.03). ORRs for specific HV are listed in the table. No significant difference in treatment outcomes were seen in pts with pUC vs any specific HV, except for NE HV which had inferior ORR (0% vs 52%; p=0.003). Conclusions: Responses to EV are noted in some aUC pts with HV, except for NE (any component) and pHV. Certain HV notable for poor outcomes, such as sarcomatoid and plasmacytoid, demonstrated responses to EV. These hypothesis-generating findings require further validation in studies with adequate sample size for specific HV, and in particular pHV. Evaluation of biomarkers, including Nectin4 expression, in HV is paramount. [Table: see text]
Applying fragmentomics profiles of urinary cell-free DNA for bladder cancer detection.
Authors: Zhang Ruiyun , Dong Hang , Gan Shuang , Tang Haoran , Zang Jingyu , Du Pan , Jia Shidong , Zhuang Guanglei , Chen Haige
Published: January 2024

671

Background: The liquid biopsy approach focusing on DNA molecules supports non-invasive diagnosis of bladder cancer. While utilizing cell-free DNA fragmentation characteristics for the cancer detection has shown potential in plasma, its applications in urine remained unexplored. Methods: We enrolled 70 patients with bladder cancer and 49 healthy individuals in this study. The urinary cell-free DNA (ucfDNA) was extracted and tested by PredicineSCORE, a low pass whole genome sequencing (LP-WGS) assay to identify tumor-specific features. The ucfDNA fragmentomics profiles including the coverage at specific region, length and end-motif of fragment was implemented. We also investigated the copy number variation and the inferred tumor fraction which was adjust by the Expectation-Maximum (EM) algorithm. Subsequently, an ensembled machine learning model were constructed for classification of bladder cancer and normal control. Results: We observed strong correlation between tumor fraction and specific features. The absolute correlation coefficient between tumor fraction with the LYL1 bonding sites relative depth, the insert size ratio of short reads, and the CCCA end motif were above 0.9, 0.75 and 0.7, respectively. To further assess the robustness of PredicineSCORE assay, we then diluted the tumor samples with tumor fraction ranging from 0.1% to 50% by manually mix reads from tumor samples into normal samples. By applied XGBoost algorithm, the performance (F1 score > 0.95) showed promising ability to distinguish tumor from normal samples. The limit of detection (LOD) was less than 1%, indicating heightened sensitivity compared to previously proposed models. Conclusions: The study suggests that urinary cell-free DNA fragmentomic profiling may enhance the precision of non-invasive bladder cancer detection.
Variant subtypes in bladder cancer and CA125-positive cancer cell state.
Authors: Yang Heiko , Song Hanbing , Allegakoen Paul , Lu Kevin L. , Gayle Janae , Stohr Bradley A. , Ding Chien-Kuang Cornelia , Chou Jonathan , Meng Maxwell , Porten Sima P. , Huang Franklin W.
Published: January 2024

694

Background: Variant subtypes in bladder cancer are clinically aggressive tumors associated with poor prognosis. The rarity of these tumors has made molecular characterization elusive. The aim of this study was to identify cell states unique to variant subtypes using single cell RNA sequencing. Methods: Fresh tissue was collected from bladder cancer patients undergoing surgery at our institution and sequenced using a bead-based single-cell RNA sequencing platform (SEQWELL). Tissue from histologic variants and high grade pure urothelial tumors were analyzed together for comparison. Pathologic diagnoses were independently confirmed. Analysis was performed using Seurat. Immunostaining validation was performed on a separately banked cohort. Bulk RNA sequencing data and clinical data were extracted and analyzed from The Cancer Genome Atlas (TCGA) database. Results: We generated a single cell RNA sequencing atlas of 9 variants (micropapillary, nested, squamous differentiation, pleomorphic giant-cell like, plasmacytoid, small cell) with 3 pure urothelial tumors for comparison. Our analyses reveal a tumor cell state shared among multiple variants that is characterized by highly specific expression of MUC16 (CA125) , KRT24, and WISP2 (Fig. 1). This cell state has transcriptional hallmarks of epithelial-mesenchymal transition and luminal-basal plasticity, and its signature is associated with poor survival and resistance to chemotherapy. Immunohistochemistry in a validation cohort demonstrates that CA125+ cells are found only in tumors with variant histology and not in conventional high-grade and low-grade urothelial carcinomas. Within variants tumors, CA125+ cells are more enriched in metastatic sites compared to the primary tumors, consistent with a more aggressive phenotype. Conclusions: A CA125+ cell state in variant subtypes in bladder cancer is associated with aggressive molecular features. Further investigation of this cell state is needed to define its role in the pathogenesis of variant tumors.
Survival outcomes in patients (pts) with prostatic cancer (PCa) based on pathologically confirmed sites of metastasis.
Authors: Galarza Fortuna Gliceida , Nazari Shayan , Swami Umang , Elliott Andrew , Gebrael Georges , Bagrodia Aditya , Puri Dhruv , Nabhan Chadi , McKay Rana R. , Antonarakis Emmanuel S. , Agarwal Neeraj
Published: January 2024

72

Background: In a meta-analysis of 9 phase III trials involving 8,820 pts with metastatic castration-resistant prostate cancer, overall survival progressively decreased from those with lymph node only disease to those with bone, lung, and liver metastases. Herein, we aimed to validate these results in a large real-world dataset based on pathologically confirmed site of metastasis. Methods: PCa tissue specimens derived from the primary Pca (PPCa) and metastatic sites were molecularly profiled by Caris Life Sciences (Phoenix, AZ). Overall survival (OS) was assessed using insurance claims data, with OS calculated from date of initial tumor diagnosis to death or lost to follow-up using Kaplan Meier estimates and log-rank test. Molecular and immunologic differences by specific metastatic site are presented in a companion abstract. All the analyses were done using CODEai. Results: 6,069 PCa specimens were included in the analysis [n= 3,411 prostate, n=1,634 non-visceral (bone and lymph node), n=1,029 visceral disease (lung, liver, peritoneum, brain, other.)]. PCa specimens (n=6,069) were stratified based on tumor biopsy site, including prostate (n= 3411), NV (bone and lymph node; n=1,631), and visceral (lung, liver, peritoneum, brain, other; n=1027) subgroups. The median OS from initial diagnosis was significantly longer for pts with PPCa compared to those with visceral metastatic PCa (median OS 70.2 vs 55.5 months; HR 1.42, 95% CI: 1.28-1.58, p<0.001) as well as non-visceral PCa (median OS 70.2 vs 63.9 months; HR 1.15, 95% CI: 1.05 – 1.27, p=0.004). The comparison of median OS by site of metastatic disease compared to bone metastasis is presented in the Table. Conclusions: We validate the results of prior studies in a real-world PCa population and show differential OS based on the site of metastases, with liver metastases associated with the shortest OS and lung metastases showing the longest OS. These data argue against combining liver and lung metastases into a single category of visceral metastases when visceral metastasis is used as stratification factor for randomized trials. [Table: see text]
Real world outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with lutetium-177-PSMA-vipivotide tetraxetan (Lu177-PVT).
Authors: Bergstrom Colin P , Song Hong , Ruiz Shann Mika , Chien Joanne , Moore Kaidi , Parikh Divya Ahuja , Shah Sumit , Fan Alice C. , Srinivas Sandy , Iagaru Andrei , Khaki Ali Raza
Published: January 2024

86

Background: Lu177-PVT is a novel radioligand, which was recently approved by the FDA to treat mCRPC. Real world data on its use and efficacy is limited. We aimed to build a new retrospective cohort of patients with mCRPC treated with 177Lu PSMA-617 in order to investigate clinical and pathological variables associated with treatment responses. Methods: We identified patients with a confirmed diagnosis of prostate cancer and were treated at Stanford University Medical Center with at least one dose of Lu177-PVT including trial patients. Data collection included demographic, clinicopathological and outcome variables. Statistical analysis was performed using Chi-squared and log-rank Kaplan-Meier analysis. Results: We identified 85 patients who met study criteria and were treated between March 2021 and June 2023, the median age was 66, 33% were non-white, median PSA at treatment initiation was 60, and 94% had osseous metastasis. Patients were pretreated with a median of six lines (range: 1-10) of prior therapy including local therapies; prostatectomy (28%), radiation (61%), brachytherapy (11%), taxane (78%), immunotherapy including checkpoint inhibitor and Sipuleucel-T (24%), PARP inhibitor (6%), and Radium-223 (15%). A majority of patients also received prior germline or somatic genetic testing (79%), with homologous recombination germline and somatic deficiencies present in 13% of patients. Of the identified cohort, 19 patients were still undergoing active treatment with Lu177-PVT at the time of data collection. Of the 66 patients not currently undergoing active Lu177-PVT treatment, 29 patients discontinued treatment due to progressive disease (44%) and 14 (21%) to toxicity related to 177Lu PSMA-617, completing a median of 4 cycles. 47 patients (71%) had an overall decline in their PSA from baseline, with 32 patients (49%) experiencing a decrease greater than fifty percent. Median overall survival of patients not actively receiving 177Lu PSMA-617 treatment was 366 days. Age, previous lines of therapy, and median time from diagnosis were not predictive of PSA treatment response (greater than fifty-percent reduction from baseline PSA). Conclusions: Lu177-PVT is a promising treatment for mCRPC in patients. Our results confirm ‘real-world’ activity of Lu177-PVT and align well with VISION study results, though real-world overall survival was comparatively shorter (12 months vs 15 months in VISION trial). Further investigation is warranted into predictors of response and toxicity.
Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC).
Authors: Choueiri Toni K. , Tomczak Piotr , Park Se Hoon , Venugopal Balaji , Ferguson Thomas , Symeonides Stefan N. , Hajek Jaroslav , Chang Yen-Hwa , Lee Jae-Lyun , Sarwar Naveed , Gurney Howard , Gross-Goupil Marine , Mahave Mauricio , Haas Naomi B. , Sawrycki Piotr , Zhang Tian , Cornell Jerry , Elfiky Aymen , Burgents Joseph E. , Powles Thomas
Published: January 2024

LBA359

Background: The randomized, multicenter, double-blind, phase 3 KEYNOTE-564 study (NCT03142334) showed that adjuvant pembrolizumab improved disease-free survival (DFS) compared with placebo following nephrectomy in participants (pts) with ccRCC at an increased risk of recurrence. We report results from the third prespecified interim analysis with a median follow-up of ~57 months. Methods: Pts were aged ≥18 years and had histologically confirmed ccRCC with or without sarcomatoid features, increased risk of recurrence, ECOG PS of 0 or 1, nephrectomy and/or metastasectomy ≤12 weeks before randomization, and no prior systemic therapy for RCC. Pts were randomly allocated 1:1 to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for ≥17 cycles (~1 year) or until disease recurrence, intolerable toxicity, or withdrawal of consent. DFS by investigator assessment was the primary end point. Overall survival (OS) was a key secondary end point. Safety was a secondary end point. Results: 994 pts were randomized 1:1 to pembrolizumab (n=496) or placebo (n=498). The median time from randomization to data cut-off date of September 15, 2023, was 57.2 months (range, 47.9−74.5). Statistically significant improvement in OS was observed with pembrolizumab vs placebo (medians not reached, HR 0.62, 95% CI 0.44−0.87; P=.0024). A total of 55 OS events were observed in the pembrolizumab arm and 86 in the placebo arm. The estimated OS rate at 48 months was 91.2% with pembrolizumab and 86.0% with placebo. OS benefit was observed across key subgroups, including in pts with M0 disease (HR 0.63, 95% CI 0.44−0.90) or M1 NED (HR 0.51, 95% CI 0.15−1.75), with PD-L1 CPS <1 (HR 0.65, 95% CI 0.31−1.38) or CPS ≥1 (HR 0.62, 95% CI 0.42−0.91), and with presence (HR 0.69, 95% CI 0.28−1.70) or absence (HR 0.57, 95% CI 0.39−0.84) of sarcomatoid features. The observed DFS benefit with pembrolizumab vs placebo was consistent with prior interim analyses (HR 0.72; 95% CI 0.59−0.87). No new safety signals were observed. Conclusions: After a median of ~57 months of follow-up, adjuvant pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in overall survival versus placebo in participants with RCC at increased risk of recurrence post surgery. KEYNOTE-564 is the first phase 3 study to show improved survival with any adjuvant therapy in RCC. These results continue to support adjuvant pembrolizumab as a standard of care. Clinical trial information: NCT03142334 .