bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative cost-effectiveness of alternative imaging and surveillance schedules for testicular seminoma in the TRISST trial.
Authors: Huo Dacheng , Huddart Robert A , Cafferty Fay Helen , Murphy Laura , Rustin Gordon J. S. , Sohaib Syed A , Schiavone Francesca , Kaplan Richard S. , Joffe Johnathan K , Sculpher Mark , Pedro Saramago
Published: March 2023

408

Background: Risk of radiation exposure from standard computed tomography (CT) surveillance is a major concern in the management of stage I seminoma testis patients. The TRISST randomized trial (NCT00589537) demonstrated that effective monitoring could be achieved with a reduced scan schedule or using Magnetic Resonance Imaging (MRI) instead of CT. Here, TRISST data is used to evaluate the economic consequences and health outcomes of different surveillance schedules in seminoma patients in the UK. Methods: 669 men were randomized to 4 surveillance groups undergoing 7 CTs over 5 years, 3 CTs over 3 years, 7 MRIs, or 3 MRIs of the retroperitoneum. Resource use (including investigations, scans, hospitalisations and treatment for relapse) and health outcomes data (EQ-5D 3L) on each patient were collected at baseline and over a period of 6 years after randomization. Health resources were costed using publicly available national unit costs. Within-trial mean total costs and quality-adjusted life years (QALYs) were estimated for each alternative schedule. Under the perspective of the UK health system, cost-effectiveness was evaluated using a cost per QALY gained framework. Probabilistic sensitivity analysis was used to reflect parameter uncertainty and evaluate results robustness. Results: Since only 82 men (12%) relapsed, most health resource consumption (76%) happened during the disease-free period. Patients undergoing 7 MRIs yielded, on average, slightly higher health benefits (5.20 QALYs) but at higher costs (GBP £6,632, see table). Compared to 7 CTs, 7 MRIs was estimated to have 63% probability of being cost-effective at a system willingness to pay threshold of £20k/QALY. 3 MRIs had similar costs and benefit to 7 CTs, whereas 3CTs was more expensive than 7 CTs and 3 MRIs, providing marginal additional benefits. Conclusions: Overall, small differences exist in total costs and total QALYs between different strategies. A 7 scan MRI schedule yielded more health benefits than other strategies, but at higher costs. Considering possible capacity constraints with MRI, the reduced radiation exposure relative to CT, and non-inferiority for clinical outcomes in the primary analysis, a 3 scan MRI schedule may be the best option to replace current CT-based longer surveillance practice. Clinical trial information: NCT00589537 . [Table: see text]
Geographic variation in utilization of doublet therapy for metastatic prostate cancer.
Authors: Washington Samuel L. , Cowan Janet E. , Zhao Shoujun , Rider Jennifer , Taylor Nicholas , Whyte Warren , Carroll Peter , Cooperberg Matthew R.
Published: March 2023

41

Background: Clinical trials for men with metastatic prostate cancer have supported the use of combination therapies to improve survival outcomes, with recent work showing increased benefit of triplet regimens. However, real-world utilization of doublet therapy ( i.e., androgen deprivation therapy (ADT) plus a novel hormonal therapy (NHT)) and variation in use according to geographic region have not been evaluated in detail. With recent data supporting the use of triplet regimens we must understand what factors already impact doublet therapy utilization before we can intensify treatment further. Using data aggregated from a national cohort of community and academic medical oncology practices, we characterized real-world utilization of doublet therapy and examined factors associated with its use, including geographic region. Methods: Using ConcertAI RWD, clinical data of men with metastatic prostate cancer was linked with state-level measures of socioeconomic factors and healthcare resources from the Area Health Resources File. Logistic regression was used to evaluate associations between clinical and community characteristics and receipt of doublet therapy (vs ADT alone) within 90 days of diagnosis; models were adjusted for clinical factors, state level factors (excluding hospital beds, poverty, and education due to collinearity), and geographic region. Odds ratios (ORs) with 95% confidence intervals were reported. Results: A total of 1,763 men with M1 disease were eligible, with a mean age of 68.6 years at diagnosis. Nearly half (48%) lived in the Southern region, 9.3% in North East, 18.6% in West, and 23.7% in Midwest. Roughly 13.8% were Black, and 1.3% American Indian, and 1.1% Asian. One-third received ADT alone (37.8%). Regression analysis for ADT+NHT vs. ADT included 1,604 men, of which 84.6% received doublet therapy. Geographic region [vs Southern: Midwest, OR 0.6, 95% CI 0.4-0.9; Northeast, OR 0.4, 95% CI 0.2-0.7], larger state population [(log-transformed) OR 0.09, 95 % 0.02-0.3], prior surgery or radiation (vs none, OR 1.7, 95% CI 1.3-2.3), greater urologist density [(log-transformed), OR 0.1, 95% CI 0.02-0.8] and radiation oncologist density [(log-transformed), OR 12.9, 95% CI 2.8-60.2] were significantly associated with receipt of doublet therapy compared to ADT alone. Conclusions: Receipt of doublet therapy was impacted by geographic region and regional availability of specialty care (i.e. urologist and radiation oncologist density), emphasizing the relationship between regional medical expertise and care implementation. As the drive to improve care grows, our study highlights how treatment remains influenced by where you live and the need for identifying actionable targets for intervention and organizational change at the regional level.
Gender specific differences in health-related quality of life for patients with bladder cancer following radical cystectomy.
Authors: Westhofen Thilo , Buchner Alexander , Schlenker Boris , Becker Armin , Stief Christian G. , Kretschmer Alexander
Published: March 2023

437

Background: Previous studies have shown pronounced gender specific differences regarding diagnosis and oncological outcome for patients with bladder cancer (BC). Current literature lacks evidence on gender specific differences in health-related quality of life (HRQOL) outcomes for patients with BC following radical cystectomy (RC). We aimed to assess those gender specific differences by providing HRQOL data from a large prospective propensity score-matched cohort of patients undergoing RC with a systematic follow-up of up to 10 yrs. Methods: 1498 consecutive patients [n=421 women, n=1077 men] who underwent RC at a large tertiary care center were included. A propensity-score matched analysis of 794 patients [n=397 women, n=397 men] was conducted applying the matching- variables “patient age”, “BMI”, “pT-stage” and “type of urinary diversion”. Exclusion criteria encompassed age <30 yr and RC due to benign diseases. HRQOL was assessed preoperatively, at 3 mo, then annually until a maximum follow-up of 120 months applying the validated EORTC QLQ-C30- as well as the bladder cancer-specific QLQ-BLM30- and FACT-BL-questionnaires. Separate modeling of longitudinal HRQOL for women and men was performed. Spearman’s rank correlation was applied to identify gender specific factors influencing HRQOL. Results: At baseline women and men showed no significant difference in general HRQOL assessed by the global health status domain (GHS) (p=.162). Women presented with worse mean emotional (p=.001) and cognitive (p=.007) functioning subscale. In the longitudinal analysis, a similar natural course of the GHS for women and men could be observed up to 36mo after RC (p-range: .107 - .856). Between 48mo and 96mo after RC, general HRQOL was significantly higher for men compared to women (p-range: .002-.045). At 12month a significant correlation between physical functioning or urinary continence and increased general HRQOL could equally be observed for men and women (each p< .05). No significant correlation was found between sexual functioning and increased general HRQOL. While a strong correlation between Social/Family wellbeing and increased general HRQOL was found for women (p=.001), no correlation was found for men (p=.103). Conclusions: The current study provides prospective data from a unique propensity score-matched contemporary patient cohort, which displays gender specific differences in the natural course of general HRQOL and its subdomains. Those data are important to guide gender specific treatment decision-making for patients with BC.
Uptake of maintenance immunotherapy and changes in upstream treatment selection in patients with advanced urothelial cancer (aUC).
Authors: Mamtani Ronac , Zhang Hanxi , Parikh Ravi Bharat , Cohen Aaron B. , Patel Khilna , Homet Moreno Blanca , Li Haojie , Imai Kentaro , Galsky Matt D. , Hubbard Rebecca A.
Published: March 2023

466

Background: In July 2020, the FDA approved avelumab, an immune checkpoint inhibitor (ICI), for maintenance treatment of aUC that has not progressed with first-line (1L) platinum-containing chemotherapy (chemo). Availability of avelumab may have influenced upstream treatment selection between 1L chemo and 1L ICI (pembrolizumab or atezolizumab). We described avelumab use in real-world practice and determined whether 1L treatment choice changed following its approval. Methods: This cohort study used Flatiron Health’s nationwide de-identified EHR-derived database. Included patients started 1L therapy for aUC in the US before (April 1 2017 to June 30 2020) or after (July 1 2020 to May 31 2022) avelumab approval. We calculated the proportion of patients initiating 1L chemo (carboplatin- or cisplatin-based) or ICI during the pre- and post- avelumab approval periods. Time trends were estimated using multinomial logistic regression for 1L treatment choice regressed on time modeled via a natural cubic spline, allowing for a discontinuity in the time trend at the time of FDA approval. Differences in probabilities of 1L treatment in July 2020 (immediately following approval) compared to June 2020 (immediately prior to approval) were calculated. Maintenance avelumab use was described among patients treated with 1L chemo in the post-approval period, and in a sensitivity analysis, among ‘maintenance eligible’ patients defined as those who were progression-free 28 weeks after 1L chemo start. Results: Among all 1L treatment initiators (n=3,507), the FDA approval of maintenance avelumab was followed by increased use of 1L carboplatin-based chemo (+9.9%; 95% CI 1.1-17.2%) but no significant changes in the use of ICI (-5.8%; 95% CI -15.9-4.4%) or cisplatin-based chemo (-4.2%; 95% CI -12.7-5.2%) (Table). Among patients treated with 1L platinum-chemo (n=485), probability of initiating maintenance avelumab increased over time. In the 22 months after approval, approximately 20.4% (n=99/485) of all 1L chemo-treated patients and 24.3% (n=78/321) of maintenance eligible patients received maintenance avelumab. Conclusions: We found modest uptake of maintenance avelumab for aUC after FDA approval. Potential reasons include limited clinician awareness of maintenance immunotherapy and/or patient preferences against long-term treatment after response to initial chemo. Our finding of higher treatment starts with carboplatin-based chemo in the post-maintenance period suggests increasing preference by clinicians of a strategy that provides patients an opportunity for two effective treatment options. Real-world data can provide important insights on community response to regulatory approvals. [Table: see text]
Assessment of treatment patterns and real-world outcomes following changes in the treatment paradigm for locally advanced/metastatic urothelial carcinoma (la/mUC) in the US.
Authors: Kirker Melissa , Abraham Anup , Vlahiotis Anna , Bhanegaonkar Abhijeet , Benjumea Darrin , Kim Chai , Sun Haiyan , Kearney Mairead , Chandrasekar Sanjana , Li Benjamin , Thakkar Sheena , Moon Helen H
Published: March 2023

468

Background: The standard-of-care first-line (1L) treatment for la/mUC is platinum-based chemotherapy (PBC) followed by avelumab 1L maintenance (1LM) in those who have not progressed following 1L PBC. This study aims to understand treatment patterns and real-world outcomes in patients with la/mUC in the US, including the early adoption of avelumab 1LM since its FDA approval in June 2020. Methods: Patients aged ≥18 years diagnosed with la/mUC between Jan 2015 and Jul 2021 were identified using electronic health records from the Flatiron Health database. Patient characteristics at baseline (la/mUC diagnosis) and clinical outcomes were described by 1L treatment received using the Kaplan-Meier method. Results: Of 4,387 patients included in this study, 3,706 (84.5%) received systemic treatments. Cisplatin-based therapy was the most common 1L therapy (33.3%), followed by carboplatin-based (30.9%) and immuno-oncology (IO) therapies (28.0%). Patients treated with cisplatin-based therapies had longer median progression-free survival compared with patients treated with carboplatin-based and IO therapies (8.0, 6.4, and 6.1 months, respectively). Median overall survival (mOS) in the treated cohort was 14.6 months from the initiation of 1L therapy. Patients treated with 1L cisplatin-based therapies had the longest mOS (18.3 months), followed by 1L IO therapies (14.6 months), and 1L carboplatin (13.2 months). Since July 2020, 89 patients received avelumab 1LM; the median follow-up time from the start of 1LM avelumab was 6.0 months and clinical outcomes data were immature. Of 1L-treated patients, 50.6% (n=1,874) moved onto second-line (2L) therapy during the study period. Notably, the cohort with the lowest 2L treatment rates were patients treated with 1L IO. The table demonstrates treatment sequences for this population. Conclusions: In this real-world cohort, most patients received standard-of-care platinum-based chemotherapy in 1L, with those on cisplatin-based therapy demonstrating the best outcomes. Early uptake of avelumab as 1LM was observed, and future analysis should examine the clinical outcomes of patients who received avelumab 1LM following 1L PBC. [Table: see text]
Comparative analysis of contemporary and past PSMA PET/CT results for recurrent prostate cancer in a high-volume Brazilian center.
Authors: Lages Dr. Paulo Sergio , Monteiro do Prado Junior Luciano , Fonseca Monteiro do Prado Leonardo , Carvalho Oliveira Bruno , Ramos Barra Renato , Silva Barbosa Michelle , Vargas Pivato de Almeida Daniel ,   Latin American Cooperative Oncology Group Genitourinary Tumors Division, LACOG-GU
Published: March 2023

51

Background: PSMA PET/CT scan (68Ga-PSMA PET/CT) has emerged as a highly accurate tool when assessing disease staging both for newly diagnosed localized high-risk prostate cancer and for recurrent disease, with treatment plan modification in up to two-thirds of patients. PSMA PET/CT is commercially available in Brazil since last decade and growing experience with this test has led to a more accurate analysis of the results over the years. Methods: We retrospectively reviewed the PSMA PET/CT scans results of patients undergoing the exam in all disease stages in a single institution in Brasilia, Brazil, between October 2015 and July 2022 and analyzed the results correlated with clinicopathological information (when available) in two separated timeframes for those in the recurrent disease setting. Results: Overall, more than 2,500 PSMA PET-CT scans were performed since October 2015. Between 2015 and 2019, 351 exams were performed, of which 303 in the setting of recurrent disease, while 297 tests were executed between 2021 and 2022, with 283 of them being done in the recurrent disease setting. Any clinicopathological information was available for 648 patients, of whom 586 underwent the test in the setting of recurrent disease following treatment of primary disease. Conclusions: There was a similar positivity rate among the clinicopathological characteristics analyzed in an indirect comparison of the two timeframes. It is remarkable the increased positivity rate among patients with lower levels of PSA in the contemporary dataset, which may reflect the learning curve of this image method. Among patients selected by Gleason grade, no definitive information can be extracted given the distinct PSA levels between patients in the two selected timeframes. [Table: see text]
Clinical results of a phase 1 study of intravesical EG-70 in patients with BCG-unresponsive NMIBC.
Authors: Steinberg Gary D. , Kalota Susan J. , Lotan Yair , Warner Loraine , Dauphinee Shauna , Mazanet Rosemary
Published: March 2023

512

Background: enGene is developing non-viral gene therapy platforms to deliver nucleic acids (plasmids) to epithelial mucosal tissues such as urothelium of urinary bladder. EG-70 is a nanoparticle formulation of plasmids that activates both innate and adaptive immune responses to activate the immune system within the bladder. The plasmid encodes both IL-12 and activators of the innate immune receptor RIG-I. EG-70 is administered intravesically to elicit local stimulation of anti-tumor immune responses providing durable efficacy in high grade non-muscle invasive bladder cancer (NMIBC) while avoidingsystemic toxicities. Methods: In the Phase 1 study(LEGEND; NCT04752722), escalating doses of EG-70 were administered intravesically to patients with BCG-unresponsive Carcinoma in situ (CIS) NMIBC on weeks 1 and 2 or weeks 1, 2, 5, 6 of 12-week treatment cycle. At the week 12 assessment, patients with stable disease (SD) or complete response (CR), as assessed by urine cytology, cystoscopy, and bladder biopsy, were allowed electively to remain on EG-70 for up to 3 additional 12-week cycles. Results: To date, 19 patients have been treated. There have been no DLTs. AEs (48 GR1, 17 GR 2 and 1 GR3) have been largely consistent with urinary tract instrumentation, and were not dose related. Eighteen patients have completed one cycle of EG-70, and 67% have achieved CR. Fifteen patients with CR or SD at the end of cycle 1 elected to receive additional treatment cycles (continuation rate of 15/18 ( 83%)). Durable CRs were seen at all dose levels. Patients who receive additional cycles are followed for durability of response (Table). Complete Response. Conclusions: These results demonstrate the safety, tolerability and durable therapeutic potential of intravesical EG-70 in patients with BCG-unresponsive CIS. A Phase 2 study will proceed in 2023. Clinical trial information: NCT04752722 . [Table: see text]
Neural network analysis of tumor and germline profiling to predict survival of muscle-invasive bladder cancer following radical cystectomy: An analysis of the Cancer Genome Atlas (TCGA).
Authors: Sonpavde Guru P. , Sadler Layne , Ravi Arvind , Nassar Amin , Lerner Seth P. , Varambally Sooryanarayana
Published: March 2023

546

Background: Following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC), recurrence is suboptimally associated with pathologic stage. A prognostic model that incorporates information from comprehensive genomic and transcriptomic data from germline and tumor tissues will improve the selection of high-risk patients (pts) for adjuvant therapy and tailored surveillance. Methods: Pts with MIBC in TCGA who underwent RC (without neoadjuvant chemotherapy) and with whole exome sequencing (WES) of tumor + normal, and tumor RNA-Seq were eligible. Germline variants were called and annotated using GATK4 and Variant Effect Predictor (VEP). Only high and moderate VEP-Impact variants contributed to burdens. Given that recurrence is associated with 5-year survival, pts were required to have data for survival at a landmark of 5 years post-RC or may have died within 5 years of RC. Patients who died <4 months of diagnosis were excluded since they may have died from post-operative complications. Dead patients were propensity-matched against alive patients by pathologic stage, adjuvant chemotherapy, gender, race, age and smoking. A linear artificial neural network was trained to predict 5-year survival using Artificial Intelligence Quality Control (AIQC)-a deep learning experience tracker. The samples were divided into 3 equally distributed subsets of alive and dead pts. The algorithm was trained on 50% of the dataset, evaluated on 40% and tested on 10%. The remaining 39 dead pts were used for additional holdout validation. The accuracy (percentage of correct prediction of death or survival) was reported. Results: A cohort of 117 pts were evaluable for 5 year survival. The cohort included 39 survivors that satisfied inclusion criteria, and 78 dead pts that were propensity matched against them (one set of 39 dead pts for training & evaluation, and a second set of 39 dead pts as an additional holdout). The binary classification neural network was trained on 38 samples to predict survival based on their most differentiated: germline alteration burdens + tumor alteration burdens + tumor gene expression. The differentially mutated genes most important to the algorithm were: PTPRN(n-m), TECTA(t-m), BPIFB1(n-m), SORL1(n-m), SLC39A5(n-m), and RBBP6(n-h) [t=tumor/ n=normal tissue origin | m=moderate/ h=high VEP impact]. The algorithm was 97% accurate on the 38 training samples, and 94% accurate across the 79 evaluation (validation, test and holdout) samples. Conclusions: Neural network analysis of germline and tumor profiling was validated to optimally differentiate between dead and surviving pts at 5 years following RC for MIBC. Further validation and application of this promising algorithm may advance precision medicine by permitting the selection of the most appropriate pts with high-risk MIBC for adjuvant therapy.
Risk analysis of open vs. robotic assisted radical cystectomy.
Authors: Simhal Rishabh Kumar , Wang Kerith Ruoyao , Shah Yash , Simon Daniel P , Mark James Ryan , Shah Mihir S , Gomella Leonard G. , Chandrasekar Thenappan , Lallas Costas D.
Published: March 2023

576

Background: Radical cystectomy (RC) is standard of care for muscle-invasive bladder cancer, but it comes with significant perioperative risk with half of patients experiencing major postoperative complications. Robot-assisted radical cystectomies (RARC) have aimed to decrease patient morbidity and have become increasingly adopted in North America. Currently, both open radical cystectomies (ORC) and RARC are frequently performed. To contribute to the existing literature using newly available data from the American College of Surgeons National Surgical Quality Improvement Project (NSQIP), representing one of the most recent, largest multi-institutional studies, while uniquely accounting for a variety of factors including type of urinary diversion, cancer staging, and neoadjuvant chemotherapy. Methods: RC procedures performed between 2019-2020 were identified in NSQIP and the corresponding Cystectomy Targeted database. Cases in the ORC group were planned open procedures, and cases in the RARC group were robotic with intra- or extracorporeal diversions, including unplanned conversion to open cases for intention-to-treat. Chi-square and t-tests were performed to compare baseline demographics and operative parameters. Multivariate analysis was performed for outcomes including major complications, minor complications, and 30-day mortality, while adjusting for operative approach, medical comorbidities, functional status, age, race, sex, BMI, ASA-classification, preoperative labs, type of urinary diversion, pathological staging, prior pelvic surgery or radiation, need for preoperative transfusion, preoperative sepsis, emergent or elective surgery, and recent chemotherapy. Results: 4,022 RC cases were identified. Of these, 3,146 (78.2%) received planned ORC while 876 (21.8%) received RARC. Baseline demographics of the patients who received ORC versus RARC were largely similar, with no significant difference in age or medical comorbidities. RARC was associated with longer operative times and shorter hospital length of stay compared to ORC. On multivariate analysis, ORC was associated with a higher rate of 30-day mortality [OR 3.1; 95% CI 1.3-7.2; p=0.009], reintubation, cardiac arrest, superficial wound infection, bleeding requiring transfusion [OR 4.7; 95%CI 3.6 - 6.1; p<0.001], prolonged postoperative nasogastric tube use, rectal injury, and ureteral fistula or urine leak compared to RARC. Conclusions: In the NSQIP database, ORC is associated with higher rates of 30-day mortality and operative complications, most notably bleeding, compared to RARC. This study is unique in the size of the cohorts compared, the timeliness of the data (2019-2020), and the ability to control for factors, such as type of urinary diversion, pathological bladder cancer staging, and use of neoadjuvant chemotherapy.
Changes in planned disease management after piflufolastat F18 PET/CT in men with biochemically recurrent prostate cancer and low PSA levels: A secondary analysis of results from the CONDOR study.
Authors: Pouliot Frederic , Gorin Michael A. , Rowe Steven P. , Saperstein Lawrence , Denes Bela Stephen , DiPippo Vincent A. , Stambler Nancy , Morris Michael J. , Siegel Barry A.
Published: March 2023

61

Background: Piflufolastat F 18 is a PSMA-targeted radiopharmaceutical approved in the US for imaging prostate cancer (PCa) patients both at the time of initial staging and at disease recurrence. In a phase 3 study of patients with biochemically recurrent (BCR) PCa, we reported that nearly two-thirds (63.9%; 131/205) of participants had a change in their intended disease management plan based on pre- and post-piflulfolastat F 18 PET/CT management questionnaires (MMQs) completed by the treating physicians. The clinical utility of piflufolastat F 18 scanning in men with very low/low PSA levels (<0.5 ng/mL) and a detection rate of ~36% has not been previously described. Here we report the changes in intended management in this subset of patients. Methods: Men ≥18 years of age with a rising PSA after definitive PCa therapy and negative or equivocal imaging were enrolled. A single ~9 mCi (333 MBq) dose of piflufolastat F 18 was administered followed by PET/CT from mid-thigh through skull vertex 1-2 hours later. Prior to scanning, the treating physicians completed a pre-PET MMQ to document the initial intended management plan for their patients based on available clinical information including baseline conventional imaging results. After PET, they completed a post-PET MMQ and recorded the management plan in light of PET findings. Treatment recommendations that differed from the pre-scan recommendations were reported as changes in the intended management plan. Results: 208 men (median PSA 0.8 ng/mL [range 0.17-98.45], n=202) underwent piflufolastat F 18-PET/CT. 200 evaluable patients had both a baseline PSA value and completed MMQs. Of 131 patients with a recorded change in intended management, 127 had an evaluable baseline PSA level. Of the 69 patients with baseline PSA levels ≤0.5ng/mL, 27 (39.1%) recorded a change in intended disease management based on positive (n=20) or negative (n=7) PET, including salvage local to systemic therapy (n=15); systemic to local therapy (n=3); observation to treatment (n=5); and treatment to observation (n=4). An additional 15 patients (21.7%) had recommended bidirectional change in management (e.g., salvage RT+ADT) and are excluded in this report. Specific treatment intensification/de-intensification plans are under investigation. Conclusions: The frequency of changes in intended disease management observed in BCR PCa patients with low baseline PSA levels (≤0.5ng/mL) was 39.1%. Both negative and positive PET/CT results impacted treatment recommendations and can provide useful and actionable information. Clinical trial information: NCT02981368 .
Evolution of systemic therapy from 2015 to 2019 for older patients in the United States with metastatic renal cell carcinoma.
Authors: Chow Ryan Dz-Wei , Long Jessica B. , Hassan Sirad , Wheeler Stephanie B. , Spees Lisa , Leapman Michael , Hurwitz Michael E. , McManus Hannah Dzimitrowicz , Gross Cary Philip , Dinan Michaela Ann
Published: March 2023

610

Background: Immune checkpoint inhibitors (IOs) and oral anti-cancer agents (OAAs) have demonstrated survival improvements in randomized trials of patients with metastatic renal cell carcinoma (mRCC). IOs were approved as second-line mRCC therapy in 2015 (nivolumab), followed by first-line approval in 2018 (ipilimumab/nivolumab). Real-world changes in overall treatment rates and IO usage have not been examined in patients over 65, who are often underrepresented in trials. Disparities in mRCC outcomes have persisted in the era of these novel therapies, raising the question of whether receipt of IOs and OAAs varies by race and ethnicity. Methods: We conducted a retrospective cohort study of Medicare beneficiaries over age 65 diagnosed with mRCC from 2015 through 2019 who were enrolled in fee-for-service Medicare Parts A, B, and D from 1 year prior to diagnosis through 1 year after presumed diagnosis or until death. We identified our cohort using diagnosis codes for primary or secondary kidney malignancy. We queried claims from 2014-2020, identifying receipt of IO, OAA, or other systemic therapies in the 2 months before through 1 year after diagnosis. Patients that received both IOs and OAAs were categorized as IO if both therapies were started within 60 days; otherwise, patients were categorized by the first therapy received. We assessed trends in treatment from 2015-2019, stratifying by race and ethnicity to compare non-Hispanic White (NHW) patients with Hispanic, Black, Asian, Pacific Islander, American Indian, Native Alaskan, or Other patients (grouped as non-NHW due to limited sample sizes). Results: We identified 15,407 patients who were diagnosed with mRCC between 2015-2019 and met study criteria. Non-Hispanic White patients comprised 84% of our sample. Receipt of IOs increased from 4% of patients in 2015 to 37% in 2019 ( P < .001). Among NHW patients, IO treatment receipt increased from 4% in 2015 to 38% in 2019 ( P < .001); for non-NHW patients, IO receipt grew from 3% in 2015 to 31% in 2019 ( P < .001). OAA usage decreased over time, from 31% of all patients in 2015 to 11% in 2019 ( P < .001). The percent of NHW patients treated with any systemic therapy increased from 51% in 2015 to 60% in 2019 ( P < .001), while there was no significant change for non-NHW patients (51% in 2015 to 54% in 2019; P = 0.27). Conclusions: Among Medicare beneficiaries, receipt of IO therapy for mRCC increased from 2015-2019. Receipt of any systemic therapy significantly increased over time for NHW patients, but not for non-NHW patients. [Table: see text]
CARINA interim analysis: A non-interventional study of real-world treatment sequencing and outcomes in patients with advanced renal cell carcinoma initiated on first-line checkpoint inhibitor-based combination therapy.
Authors: Nathan Paul D. , Allison Jennifer , Charnley Natalie , Michael Agnieszka , Moore Kathryn , Sharma Anand , Klair Bhupinder , Perrot Valérie , Larkin James
Published: March 2023

626

Background: First-line (1L) checkpoint inhibitor (CPI)-based combinations have become standard of care for patients with advanced renal cell carcinoma (aRCC). Data are required to inform optimal sequencing of aRCC therapies. CARINA is a non-interventional study of treatment sequencing and outcomes in patients with aRCC initiated on 1L CPI-based combination therapy. We report the results of a pre-planned interim analysis. Methods: We reviewed electronic prescribing records from participating UK specialist centers to identify patients (aged ≥ 18 years) with aRCC who received 2L therapy after 1L CPI-based combination therapy. The primary objective was to determine the treatment pathway for patients with aRCC who initiated treatment with a CPI-based combination and received subsequent therapy. Secondary objectives included treatment duration and objective response rate (ORR). Outcomes were evaluated for all patients (enrolled population [EP]) and for the patient subgroup who received 2L cabozantinib. Results: In total, 129 patients were eligible for inclusion in this interim analysis of the EP (mean [SD] age at diagnosis, 60.0 [9.9] years; 75.2% male; 77.3% clear-cell aRCC). Of these patients, 82.9% received 1L ipilimumab + nivolumab (Ipi + Nivo, n = 107) and 17.1% received axitinib + avelumab (Axi + Ave, n = 22); median (95% CI) duration of 1L treatment was 10.2 (9.1–17.1) weeks, ORR was 18.4%. The most commonly prescribed 2L therapies after Ipi + Nivo were cabozantinib (74.8%) and sunitinib (13.1%); the most commonly prescribed 2L therapies after Axi + Ave were lenvatinib + everolimus (45.5%) and cabozantinib (31.8%). Median (95% CI) duration of all 2L therapies was 23.6 (14.0–28.3) weeks, and median duration of 2L cabozantinib was 28.1 (20.1–37.1) weeks. ORR to 2L therapy was 30.4% for the EP, and 38.8% for the subgroup of patients who received 2L cabozantinib. Conclusions: In this interim analysis, the most commonly prescribed 2L therapies were cabozantinib and sunitinib after Ipi + Nivo, and lenvatinib + everolimus and cabozantinib after Axi + Ave. Antitumor response with 2L cabozantinib was observed after prior CPI-based therapy. Clinical trial information: NCT04957160 .
Financial toxicity in patients with metastatic renal cell carcinoma on combination therapy.
Authors: Staehler Michael D. , Ebrahimi Hedyeh , Vaishampayan Ulka N. , Rodler Severin , Pal Sumanta Monty , Battle Dena
Published: March 2023

651

Background: Combination therapy based on immunotherapy (IO) alone or in combination with oral tyrosine kinase inhibitors (TKI) has become the standard of frontline therapy in metastatic renal cell carcinoma (RCC). We sought to ascertain real world data on financial implications in RCC patients on combination therapy. Methods: An online survey was administered by Kidney Cancer Research Alliance (KCCure), a non-profit patient advocacy group, between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Multiple responses from the same patient were prohibited via anonymized IP address tracking. Select questions were directed at questions related to financial concerns as well as the validated 11-item COST measure and out-of-pocket spending patterns related to supplement purchases. Pearson’s correlation (r) and Kendal’s tau test were used to analyze the COST questionnaire, financial burden and hardship. Significance levels were 2 tailed. Results: 289 responders were on combination therapy (IO+IO or IO+TKI) (M:F, 145:143). Median age was 61 (range 19-89). 177 pts answered the COST questionnaire. Patients identified themselves as white (91%), living in the US (86.8%) and had a bachelor's degree or beyond (52.9%). 21.1%, 46.1%, and 32.6% lived in urban, suburban, and rural locations. The approximate annual household income was <50.000US$ in 17%, <100,000US$ in 41% and >200,000US$ in 15%. 61% had private insurance, 27% were on Medicare/Medicaid and 0.6% were uninsured. 14% reported that it was difficult or very difficult to pay their premiums. 31% were retired and 24% not able to work. 28% reported that their medical situation has not reduced their income at all and 26% claimed that their disease reduced their income very much. Significant financial, medical, behavioral, psychological and emotional hardship was reported by 15%, 26%, 12%, 19% and 24% of the patients respectively. The monthly out of pocket costs were independent of type of therapy with 50% of the patients reporting spendings of <50US$. 36% reported high out of pocket costs are a barrier to care. 44% have received financial support through a manufacturer or a foundation.22.4% of responders reported spending >$100/month on supplements, and 8.3% reported spending >$250/mo. Median COST score was 22 (range 4-36). COST score was significantly correlated to age, NCCN distress score, time since diagnosis and supplement intake (p<0.05). Conclusions: Systemic therapy imposes financial hardship on patients but does not seem to be worse with combination therapy in RCC. Route of administration is not influencing financial hardship. Patients are willing to pay for out supplements if their treatment is not causing financial harm.
Effect of RRx-001 on nephrotoxicity of cisplatin/etoposide in patients with solid tumors.
Authors: Abrouk Nacer , Cabrales Pedro , Oronsky Bryan , Caroen Scott , Reid Tony R.
Published: March 2023

657

Background: RRx-001 is a small molecule anticancer agent that preclinically protects non-malignant tissues, but not tumors, against the cytotoxicities of chemotherapy and radiation. In a completed, multicenter Phase 2 trial, QUADRUPLE THREAT, patients with previously platinum-treated extrapulmonary small cell cancer (SCC), high-grade neuroendocrine carcinoma (HGNEC), non-small cell lung cancer (NSCLC), and genitourinary cancer (GUC) received 4 mg IV RRx-001 followed by etoposide plus cisplatin or carboplatin (EP). In addition to overall survival (OS), and progression-free survival (PFS), this study also evaluated the possible prevention of nephrotoxicity by RRx-001. Methods: 90 patients with SCC, HGNEC, NSCLC, and GUC that previously received ≥2 lines of therapy including a platinum doublet were treated with 4 mg RRx-001 IV once per week. At progression, RRx-001 was discontinued and 40 patients were re-challenged with IV etoposide 80-100 mg/m2 (Days 1, 2, and 3) and cisplatin 60-80 mg/m2 on Day 1 for 4-6 cycles. The co-primary endpoints were PFS and OS. For all patients, serum creatinine (Cr), blood urea nitrogen (BUN), and electrolytes were determined prior to, during and after each treatment cycle. Results: After 2 cycles of chemotherapy, no patients experienced BUN elevations above 20 mg/dL and creatinine beyond 1.5 mg/dL. After four cycles of chemotherapy, 36/40 (90%) patients experienced no elevations of BUN above 20 mg/dL and creatinine above 1.5 mg/dL and none of the patients experienced > Grade 2 elevations of creatinine. 1/40 (2.5%) patients experienced Grade 3 hypomagnesemia (0 Grade 4). 3/40 (7.5%) patients were dose reduced or withdrawn from the trial due to platinum-related adverse events. No patients experienced renal-related serious adverse events (SAEs). One patient experienced a renal failure SAE, which was not drug related. The cumulative OS and PFS median of all the tumor types were 8.6 and 6.4 months, respectively. Conclusions: 20%-35% of patients develop acute kidney injury after cisplatin administration. Based on published clinical literature, approximately 33% of patients experience kidney injury just days following initial treatment (p = 0.0034, two-sided chi-square test comparing our study nephrotoxicity of 10% (4/40) in the first four cycles against 33% historical rate), and 20% of patients taking high-dose cisplatin experience severe renal dysfunction. The nephrotoxic effect of cisplatin is cumulative. In this heavily platinum-treated population, none of the patients were ineligible to receive cisplatin as scheduled because their serum creatinine levels had failed to return to < or = 1.5 mg/dL. RRx-001 pretreatment did not affect the antitumor effects of EP as assessed by PFS and OS. This dose of RRx-001 warrants further evaluation as a nephroprotectant that reduces the cumulative renotoxic effects of cisplatin but not its antitumor efficacy. Clinical trial information: NCT02489903 .
Evaluation of the safety and effectiveness of cryoablation in the treatment of renal angiomyolipoma related to tuberous sclerosis complex: The Cryo-TSC.
Authors: Kashiwagi Eiji , Hatano Takashi , Shimiz Kanichiro , Takamoto Atsushi , Tomita Koji , Osawa Takahiro , Sakuhara Yusuke , Hongo Fumiya , Hirota Tatsuya , Ushijima Yasuhiro , Asayama Yoshiki , Miki Jun , Kiyomi Fumiaki , Egawa Shin , Nasu Yasutomo , Shinohara Nobuo , Ukimura Osamu , Nakano Shuji , Arai Yasuaki , Eto Masatoshi
Published: March 2023

669

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease. Approximately 60%–80% of patients with TSC have bilateral angiomyolipoma (AML). Cryotherapy is one treatment option for renal tumors, but the safety and efficacy of cryotherapy for TSC–AML is not clear. We planned this study to establish the safety and efficacy of cryotherapy for TSC–AML. Methods: This was an open-label, single-arm phase II study to evaluate the safety and efficacy of cryotherapy for TSC–AML of 4 cm or less in diameter in patients at least 16 years old. The exclusion criteria were an inability to withdraw from mTOR inhibitor and failure to maintain rest during cryotherapy. mTOR inhibitors were withdrawn at least 7 days prior to cryotherapy and discontinued during the study period. Cryotherapy was performed using Cryohit (Galil Medical LTD, USA). Safety was assessed at 1, 2, 6, and 9 months after cryotherapy, and efficacy was assessed at 3 and 9 months after cryotherapy. The efficacy of cryotherapy was evaluated according to the modified RECIST or RECIST criteria. The primary endpoint was the disease control rate, and secondary endpoints included the overall response rate, safety, renal function, quality of life, and need for additional treatment. Results: The disease control and overall response rates were 100% and 93.3%, respectively. After 9 months of follow-up, the median creatine level was slightly increased by 0.06 mg/dL. Quality of life was stable, and no additional treatment was needed. Three Grade 3 adverse events (hematuria, chronic kidney disease, and aspartate aminotransferase elevation) were observed in three patients. Conclusions: Cryoablation is a safe and effective treatment option for TSC–AML. Clinical trial information: jRCTs072200039 .
Anti-PD1 plus oncolytic virus as first-line treatment option for metastatic renal cell carcinomas.
Authors: Park Jee Soo , Lee Myung Eun , Jang Won Sik , Kim Jongchan , Lee Namhee , Oh Keunhee , Ham Won Sik
Published: March 2023

675

Background: Although anti-programmed death (PD)1 and anti-cytotoxic T-cell lymphocyte (CTLA)-4 combination therapy is recommended as one of the first line treatment options for metastatic renal cell carcinoma (mRCC), immune checkpoint inhibitor (ICI) combination therapy leads to the increased immune-mediated adverse events (imAEs). Our group has reported the therapeutic potential of oncolytic virus, JX-594 in metastatic murine RCC model. In this study, we explored the effect of JX-594 plus anti-PD1 in comparison to the combination therapy of anti-PD1 and anti-CTLA-4. Methods: Early-stage and advanced-stage highly metastatic orthotopic murine RCC models developed by our group were used. Anti-PD1 with either JX-594 or anti-CTLA-4 were systemically injected through the peritoneum. Immunofluorescence analysis was performed to demonstrate the remodeling of the tumor immune microenvironment (TIME). Results: Both JX-594 plus anti-PD1 and ICI combination therapy significantly reduced primary tumor and metastatic tumor burden in lung and peritoneum compared to cytoreductive nephrectomy plus anti-PD1. For the early-stage and advanced-stage mRCC models, JX-594 plus anti-PD1 significantly decreased the primary tumor sizes and number of lung tumor nodules compared to ICI combination therapy only in the early-stage mRCC model ( P<0.01), but not in advanced-stage mRCC model ( P=0.07). The therapeutic benefit was significantly increased when JX-594 and anti-PD1 was sequentially injected compared to when JX-594 and anti-PD1 was injected simultaneously ( P<0.05). Notable imAEs were observed in 2/16 (12.5%) in ICI combination group, whereas no notable imAEs in JX-594 plus anti-PD1 group. JX-594 plus anti-PD1 induced changes in TIME of both early- and advanced-stage mRCC model. However, tumor-suppressing TIME was more notable in early-stage mRCC model, which increased tumor-infiltrating CD8+ T cells and tumor-suppressing M1 tumor-associated macrophages (TAM), and decreased tumor-promoting myeloid-derived suppressor cells (MDSCs) and M2 TAM. Conclusions: JX-594 plus anti-PD1 effectively reduced primary tumors and metastatic burdens similar to ICI combination therapy. Furthermore, imAEs significantly decreased in JX-594 plus anti-PD1 group, suggesting the potential benefit of JX-594 plus anti-PD1 for reserving ICI induced toxicities, especially by anti-CTLA-4.
Longitudinal detection of circulating tumor DNA in patients with advanced renal cell carcinoma.
Authors: Basu Arnab , Kollipara Revathi , Sudhaman Sumedha , Mahmood Tamara , Pajak Natalia , Carson Carcia , Dutta Punashi , Calhoun Mark , ElNaggar Adam , Liu Minetta C. , Ferguson James , Peyton Charles , Rais-Bahrami Soroush , Tan Alan
Published: March 2023

715

Background: Treatment response monitoring is key to effective disease management for patients with advanced (RCC) and can potentially improve clinical outcomes. Circulating tumor DNA (ctDNA) has shown promise as a biomarker in the early identification of treatment response in a variety of tumor types. Herein, we evaluated ctDNA-derived molecular residual disease (MRD) detection and dynamics in both clear cell (ccRCC) and non-clear cell (nccRCC) RCC patients treated with standard of care therapy and provide correlations with clinical outcomes. Methods: This was a multi-center retrospective analysis of real-world data obtained from commercial ctDNA testing (Signatera, Natera, Inc.), 41 patients (142 plasma samples) with high-risk resected or metastatic RCC were analyzed for ctDNA. Clinical data were collected on IMDC risk category, pathologic subtype, tumor stage and grade including the presence of sarcomatoid/rhabdoid features. Progression on radiological imaging was based on RECIST 1.1. criteria. Results: Of the 41 patients, 73% (30/41) had ccRCC and the remaining 27% (11/41) were nccRCC. Immunotherapy was administered as a single agent or in combination with other immune checkpoint inhibitor agents/targeted therapy in 78% (32/41) in either frontline or refractory settings. ctDNA detection at any time point was 70% (29/41) and patients were followed-up for a median of 26.4 weeks (range: 0.9-90.6) from the first ctDNA time point. Fourteen patients (34%) experienced disease progression during follow-up and all had ctDNA detected ahead of radiological progression (100% sensitivity) with a median lead time of 13.6 weeks (range: 1-39.7 weeks). Concordance between clinical outcome and ctDNA status (detected or not detected) was observed in 78% (32/41) of the patients, 12% (5/41) showed discordance, and imaging data is pending for 10% (4/41) at the time of analysis. Conclusions: Collectively, our study demonstrates high concordance between MRD status and subsequent clinical outcomes. MRD had 100% sensitivity for predicting subsequent radiographic progression with significant median lead time. MRD may serve as a valuable tool for monitoring patients on immunotherapy-based regimens for RCC.