bluuebunny/crossref_metadata_2025 huggingface dataset:
Societal benefits of surrogate outcomes to support reimbursement decisions: The case of prostate cancer.
Authors: de Feria Cardet Rafael , Davis Ian D. , Haas Marion , Laba Tracey-Lea , Goodall Stephen , De Abreu Lourenço Richard
Published: March 2023

372

Background: Incorporating surrogate outcomes for survival into economic evaluations for localized prostate cancer (LPC) has the potential to reduce the time needed to subsidise new therapies but may increase uncertainty regarding true benefit. The ICECaP study demonstrated that metastasis-free survival (MFS) is a strong surrogate of overall survival (OS) in LPC. We sought to model the benefits to society of earlier funding decisions, and to understand the context of societal trade-offs between aspects of drug value and time to reimbursement decision-making in LPC. Methods: Societal benefits were modelled using a 4-health state (biochemical recurrence (BCR), BCR-free, metastasis and death) partitioned survival model to evaluate the cost-effectiveness of abiraterone plus prednisolone (AAP) plus standard of care (SoC) compared to SoC alone in LPC. Survival outcomes were dependent on the ICECaP surrogacy relationship. Treatment pathways and costs reflected Australian practice and quality of life was informed by the literature. The model evaluated the difference between deciding to reimburse AAP now, based on MFS, versus wait for OS 3 years. Societal trade-offs were captured using a population based discrete choice experiment exploring the influence on preference for drug reimbursement of cost-effectiveness, cost to Government, adverse events, proportions expected to benefit, nature of benefits, the completeness of data and the time of follow-up. Preferences were analysed using mixed logit analyses. Results: The analysis of societal benefits showed that using MFS as a surrogate for OS could prevent 117 patients from recurrence, 30 from metastases and save 63 lives in the short-term when AAP is compared with SoC for LPC patients in Australia. Delaying the reimbursement decision for 3 years results in a loss of 4.48 years, 0.47 quality adjusted life years, and increase the cost to $11,558 per patient over the lifetime. The analysis of societal trade-offs reflected results from 1,003 community members and showed an inclination to favour reimbursing interventions that benefit a high proportion of patients (OR=2.10 CI 95%=1.91, 2.32), have a lower cost-effectiveness ratio (OR=0.81 CI 95%= 0.78, 0.88) and an aversion for evidence from ongoing studies (OR= 0.83 CI 95%= 0.78, 0.88). Conclusions: Using MFS as surrogate for funding decision in LPC is likely to produce benefits to society in terms of improved short and long-term outcomes. This contrasts with societal preferences to delay reimbursement decisions to increase certainty. This suggests, improved cost-effectiveness could be used to compensate for the uncertainty arising from the use of surrogate outcomes in reimbursement decisions. The use of evidence-based surrogate outcomes in economic evaluations to support reimbursement decisions can reduce the time it takes new interventions to become available improving the benefits to society.
Detection of intraductal carcinoma of the prostate (IDCP) cases focusing on high-grade prostatic intraepithelial neoplasia (PIN) findings regarding invasive carcinoma of the prostate.
Authors: Watanabe Ryuta , Sugihara Naoya , Kono Reina , Arai Osuke , Kakuda Toshio , Noda Terutaka , Nishimura Kenichi , Fukumoto Tetsuya , Miura Noriyoshi , Kurata Mie , Miyauchi Yuki , Kitazawa Riko , Haffner Michael C , Kikugawa Tadahiko , Saika Takashi
Published: March 2023

379

Background: Intraductal carcinoma of the prostate (IDCP) is a pathological pattern that involves atypical cells proliferating within the normal gland where basal cells are preserved. These exhibit cribriform morphology, a finding associated with poor prognosis. In addition to the TMPRSS2-ERG fusion gene, TP53, RB1, and PTEN deletions, and SPOP and HRR gene mutations, such as a BRCA mutations, are frequently detected in patients with IDCP. The National Comprehensive Cancer Network (NCCN) guidelines suggest that early genetic testing should be considered. However, IDCP recognition is notably low, and diagnosis requires skill. Methods: We selected 98 cases with "prostate cancer with high-grade prostatic intraepithelial neoplasia (PIN) in the background" by referring to the pathology reports of cases who underwent total prostatectomy for prostate cancer at our hospital between November 2011 and November 2021. Twelve cases were narrowed down to those that were considered suggestive of IDCP based on the pathology reports and reviewed by three pathologists to determine the presence of IDCP. These were additionally reviewed by three pathologists for the presence or absence of IDCP and a gene test of prostatectomy specimens was submitted for the relevant cases to determine the presence or absence of HRR gene mutations. Results: Five of the twelve cases were determined to be IDCP positive. The Gleason score of background prostate cancer was 4+3 in 3 cases, 4+4 in 1 case, and 4+5 in 1 case. Median postoperative follow-up was 37 months (22- 45 months); 3 of the 5 patients had no recurrence, 1 had recurrence at 2 years and 3 months resulting in additional local radio therapy (RT), and 1 patient died of other causes. Pathology genetic testing identified HRR-related genetic abnormalities, including BRCA mutations. Conclusions: We were able to establish IDCP cases from past high-grade PIN cases. As a number of HRR gene mutations of unknown pathological significance were detected, IDCP cases could be retrieved from past cases and genetic abnormalities could be identified efficiently. The findings of the study provide a possible approach to diagnose prostate cancer cases with genetic mutations at an early stage.
Characterization of lymph node metastases in prostate cancer.
Authors: Gottlieb Josh , Choe Jane , Chang Shu-Ching , Krasne David , Hoon Dave S. B. , Wilson Timothy
Published: March 2023

380

Background: Unlike lymph node (LN) staging in other malignancies, prostate cancer nodal staging does not characterize or quantify the LN tumor burden. Detailed characterization of LN metastases may provide improved prognostic information, which could assist in post-surgical management decisions. Methods: Clinical and pathologic information was retrospectively collected via electronic medical record from 66 patients with pathologically confirmed LN involvement after radical prostatectomy with pelvic lymph node dissection performed by a single surgeon. Tissue slides of all positive LNs were re-evaluated by a single pathologist in accordance with our institutional review board protocol. Poisson regression analyses and Cox proportional-hazard regression were performed to evaluate the association of risk factors with the number of positive nodes and the association of LN characteristics with biochemical recurrence (BCR)-free survival. Results: Median number of positive LNs per patient was 2 (IQR 1-3). Mean % positive LNs per patient was 8.9 (SD10.4). Mean cumulative size of all tumor deposits in all positive LNs per patient was 5.0mm (SD 4.8). Average % surface area of LN involved by tumor was 28%. 48 (73%) patients were alive without disease at median follow-up time of 38 months (IQR 26-50 months). Higher pre-surgery PSA, clinical stage T3-T4 versus T1-2, extraprostatic extension (EPE), seminal vesical involvement (SVI), and lymphovascular invasion (LVI) were significantly associated with higher incidence rate of nodal positivity. Larger mean size of largest LN deposits, mean size of total LN deposits, and mean % surface area of LN involved were significantly associated with worse BCR-free survival. There was no significant association for number of positive nodes, LN anatomical compartments, extranodal extension (ENE), span of ENE, and distance of ENE from LN capsule. Higher pre-surgery PSA and post-surgery Gleason grade were significantly associated with worse BCR-free survival. Conclusions: Our data shows that LN tumor burden is associated with worse BCR-free survival. Anatomical LN compartments and quantification of ENE did not show significant association with BCR. [Table: see text]
Polo-like kinase-1 as a potential prognostic marker of prostate cancer utilizing ORIEN data.
Authors: Nutalapati Snigdha , Wang Chi , Liu Alice X , Zhang Zhuwei , Colman Howard , Lam Elaine T. , Carpten John D. , Singer Eric A. , Adra Nabil , Devitt Michael Edward , Chahoud Jad , Tripathi Abhishek , Stratton Kelly Lynn , Myint Zin
Published: March 2023

384

Background: Polo-Like Kinase-1(PLK1) is one of the key regulators in G2/M cell cycle. Preclinical studies have shown that PLK1 might be involved in treatment resistance in prostate cancer (PCa). PLK1 overexpression by immunohistochemistry is associated with higher Gleason grade and thus PLK1 could play a role in PCa tumorigenesis. In this study, we utilized a different methodology by using RNA-seq PLK1 expression and correlated with clinical outcomes. Methods: Patients with all stages of prostate adenocarcinoma diagnosed between 2014 and 2020 from nine participating members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. Tumor RNA-seq was analyzed for PLK1 expression and associated with clinical data obtained from ORIEN AVATAR. PLK1 expression was stratified into high expression (defined as ≥75th percentile of PLK1 mRNA expression) vs. low expression (≤75th percentile). Univariate and multivariate Cox proportional hazard model were used to compare overall survival between patients with low vs high PLK1 expression adjusting for age, race, PSA and stage. Results: A total of 452 tumors were evaluated for PLK1 expression. Of those, 241 (53.3%) had high PLK1 and 211 (46.7%) had low PLK1 expression. Median age at diagnosis for high and low PLK1 expression was 64.5 and 63.2 years respectively. The majority of patients were Caucasian in both groups. In high PLK1 group, 93 (65%) had localized high risk/very high risk disease, 27 (19%) had localized intermediate risk, 20 (14%) had metastatic vs. 97 (63%), 38 (25%) and 18(12%) respectively in low PLK1 group. Gleason ≥ 8 and PSA <20 were seen slightly more in high PLK1 compared to low PLK1; 40% vs 33% and 96% vs.94% respectively. The median follow-up time was 2.74 years in low PLK1 group and 2.71 years in high PLK1 group. There was no difference between PLK1 low vs. high expression for age, race, stage, PSA and Gleason grade. There was no difference in overall survival between low PLK1 and high PLK1 expression by univariate analysis (p=0.86; HR 1.09) or after adjusting for multivariate analysis (p=0.85; HR 1.12). Conclusions: In our study, we did not find RNA-seq PLK1 expression as a potential prognostic marker for prostate cancer. There was no survival difference between low PLK1 vs. high PLK1 expression.
Healthcare utilization and outcomes in testicular cancer with and without HIV.
Authors: Deenadayalan Vaishali , Solipuram Vinod , Gupta Shweta
Published: March 2023

411

Background: Risk of testicular cancer (TC) was higher in HIV patients before combined antiretroviral therapy (cART) era. However the risk has decreased and outcomes reported to be similar since cART (PMID 17548695, 34592009). We evaluated the characteristics, outcomes, and healthcare utilization of patients with TC with and without HIV from a national sample. Methods: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database was queried to identify all TC patients with and without HIV from 2016-2019. The groups were compared for socio-demographic differences, medical comorbidities, inpatient mortality, length of stay (LOS), and total hospital charges (THC). Secondary outcomes included rates of orchiectomy, sepsis, septic shock, acute kidney injury, UTI, anemia, and protein energy malnutrition. Statistics were performed using t-test, univariate and multinomial logistic regression. Results: A total 265 admissions of HIV-TC and 29,450 non-HIV-TC were identified. HIV-TC patients were more likely to be in middle age group (45-65yrs) (38 vs 19% 40, p = 0.08) than non-HIV-TC who were younger <45yrs (76 vs 62%, p = 0.08). Compared to non-HIV-TC, HIV-TC patients were more likely to be Black (36% vs 5%, p<0.001), on Medicaid (47% vs 33%, p=0.002) or uninsured (12% vs 8%, p=0.002), treated at a teaching hospital (94% vs 84%, p=0.036). HIV-TC had a significantly higher comorbidity burden, prevalence of CKD and coinfection with Hepatitis B/C (all p<0.05). Other comorbidities and secondary outcomes were not significantly different. The overall adjusted all-cause mortality was not significantly different between groups (aOR = 0.6, 95% CI 0.08-4.24, p = 0.61), however on subgroup analysis mortality was significantly increased for blacks (aOR = 1.98, 95% CI 1.07-3.66, p = 0.02) and Asians (aOR = 1.84, 95% CI 1.05-3.21, p = 0.03) compared to Caucasians. Mean LOS (7 vs 6 days, p = 0.49) and THC ($68,766 vs $69,371, p = 0.17) were similar between cohorts. Conclusions: HIV-TC patients were older, in the middle age compared to more younger (<45 years) for non-HIV-TC patients. Although overall mortality and outcomes were similar between the groups, a racial disparity was seen with higher mortality in African American patients, the cause of which should be investigated in future studies.
Validation of AGR2 and KRT19 as specific proteins being significantly and differentially expressed in teratoma compared to necrosis in retroperitoneal lymph node resections after chemotherapy (pcRPLND).
Authors: Nestler Tim , Kremer Lara , von Brandenstein Melanie , Wittersheim Maike , Wagener-Ryczek Svenja , Paffenholz Pia , Mueller Stefan , Quaas Alexander , Hellmich Martin , Odenthal Margarete , Pfister David , Heidenreich Axel
Published: March 2023

412

Background: Metastatic non-seminomatous testicular tumor patients with residual retroperitoneal tumor masses > 1cm after chemotherapy are treated with pcRPLND. The goal of pcRPLND is to remove viable tumors (V) and teratoma (T), which are present in approximately 10% and 40% of cases, respectively. However, histopathologically, only scar/necrosis (N) is identified in the remaining 50% of patients. In those patients, surgical therapy is not necessary, resulting in a relevant overtreatment. So far, no adequate distinction between the histologies exists preoperatively. Recently, the first biomarker was described with miR371a-3p in serum, which is highly specific for V, but not for T. In 2022 we reported AGR2 and KRT19 to be significantly and differentially expressed in teratoma compared to necrosis in pcRPLND tissue on protein and mRNA level. The aim of this study was to validate these proteins on an independent cohort. Methods: All consecutive pcRPLND patients from 2021 who were treated in the University Hospital of Cologne, Germany, were selected (n=66). All patients had residual masses > 1 cm and normalized or plateaued tumor markers. For immunohistochemistry, the monoclonal antibodies KRT19 and AGR2 were applied to representative Formalin-Fixed Paraffin-Embedded tissue. To quantify the results, the H-score was used. The investigators were blinded to the final pathohistological results. Results: The cohort was composed of 66 patients, 23 patients with T, 24 patients with V and 19 patients with N. Significantly higher H-scores were shown for AGR2 and KRT19 when comparing T vs. N and T vs. V (both p < 0.0001). The discriminatory ability of the two proteins AGR2 and KRT19 was calculated by AUCs for T vs. N and was 1.0 in each case with a corresponding sensitivity and specificity for T of 100%. Conclusions: With AGR2 and KRT19, we could validate the two proteins that are significantly and differentially expressed in the pcRPLND specimen in the clinically relevant groups T vs. N. In perspective, these proteins could be targeted by radiolabeled ligands as a tracer in order to reliably distinguish patients with teratoma from those with necrosis by means of functional imaging. Thus, overtreatment with pcRPLND of patients with N could be safely reduced.
Contemporary analysis of complications after retroperitoneal lymph node dissection: Data from the National Surgical Quality Improvement Program 2006-2018.
Authors: Cahill Ellen , Chua Kevin J , Doppalapudi Sai Krishnaraya , Srivastava Arnav , Patel Hiren V , Balraj Vasundhara , Ghodoussipour Saum , Jang Thomas L
Published: March 2023

416

Background: Retroperitoneal lymph node dissection (RPLND) offers therapeutic and diagnostic value for patients with testicular cancer. Specific indications for RPLND include management of patients with stage I-II nonseminomatous germ cell tumors (NSGCT), advanced NSGCTs with post-chemotherapy masses, and seminomas with early metastatic disease. While RPLND is an invasive and complex operation, prior research suggests complication rates are relatively low and may vary based on patient characteristics and disease-related factors. We examined the incidence of complications after RPLND and aimed to determine risk factors associated with these complications. Methods: The National Surgical Quality Improvement Program (NSQIP) database from 2006-2018 was queried for RPLND in patients with testis cancer who were identified by ICD 9 and 10 codes. All reported postoperative complications were examined and categorized by type and organ system. Univariable and multivariable logistic regressions were performed to determine risk factors associated with complications. Results: 368 RPLND procedures over the 13 year interval met inclusion criteria. The overall complication rate was 23.91% (n=88). The most common complication was bleeding requiring transfusion (n=59, 16.03%). Risk factors associated with any complication included older age (OR 1.041, p=0.003), longer operative time (OR 1.007, p<0.001), and major concomitant procedure (OR 2.429, p=0.015). As shown in the table, risk factors associated with transfusion included older age (OR 1.040, p=0.019), longer operative time (OR 1.009, p<0.001), and major concomitant procedure (OR 3.296, p=0.004). Higher pre-operative hematocrit was associated with decreased risk of transfusion (OR 0.883, p<0.001). M+ (metastatic) disease and longer operative time were associated with an increased risk for wound, infectious, and respiratory complications. Conclusions: Based on our analysis, almost one in four patients undergoing RPLND experienced a complication. Bleeding requiring transfusion was the most common complication and was associated with patient age, preoperative hematocrit, operative time, and major concomitant procedure. Urologic surgeons may seek to optimize hematocrit prior to surgery, especially when major concomitant procedure may be necessary. [Table: see text]
The role of the size and number of index lesion in the diagnosis of clinically significant prostate cancer in patients with PI-RADS 4 lesions detected by multiparametric MRI of the prostate.
Authors: Kılıç Mert , Köseoğlu Ersin , Madendere Serdar , Vural Metin , Balbay Mevlana Derya , Esen Tarik
Published: March 2023

44

Background: This study aimed to evaluate the contribution of the size and number of the sampled lesions to the diagnosis of clinically significant prostate cancer (CSPC) in patients who had PI-RADS 4 lesions detected by multiparametric MRI (mpMRI) of the prostate and underwent in-bore biopsy (IB). Methods: In this retrospective study, data of 295 patients who underwent IB for PI-RADS 4-5 lesions between 2012 and 2021 were analyzed, and a total of 159 patients with only PI-RADS 4 lesions were included. Clinical and radiological data, including age, PSA level, previous biopsy information, and the size and the number of PI-RADS 4 lesions were recorded. Patients with a lesion classified as Grade Group 2 and above were considered to have CSPC. Univariate and multivariate regression analyses were used to evaluate the factors affecting the diagnosis of prostate cancer (PCa) and CSPC. Results: A great majority (86.8%) of the patients had undergone a biopsy for the first time. About three-fourths (71.7%) of the patients had PCa, and half (54.1%) had CSPC. In multivariate analysis, the relationship between PCa and age, index lesion size, low PSA levels, and first biopsy patients were found significant, while CSPC exhibited a significant relationship with age and first biopsy patients. When the patients were divided into three groups according to the index lesion size (<5 mm, 5-10 mm, and >10 mm), the prevalence of PCa was 64.3%, 67.5%, and 82.4% and the prevalence of CSPC was 42.9%, 51.2%, and 64.7% respectively. Conclusions: While the size of PI-RADS 4 lesions was significant in predicting PCa, it had no significance in detecting CSPC. The number of lesions was insignificant in predicting both conditions. However, the prevalence of PCa was high, especially in patients with PI-RADS 4 lesions larger than 10 mm, which in turn increased the probability of the lesion being Grade Group 2 or above. [Table: see text]
Early switching to pembrolizumab (Pe) during first-line platinum-based chemotherapy (PCT) in patients (pts) with metastatic urothelial carcinoma (mUC).
Authors: Endo Yuki , Kimura Go , Akatsuka Jun , Takeda Hayato , Yanagi Masato , Mikami Hikaru , Hasegawa Hiroya , Taniuchi Mami , Katsu Akifumi , Funato Ryota , Toyama Yuka , Kondo Yukihiro
Published: March 2023

452

Background: With the results of the Javelin bladder 100 trial, PCT followed by ICI has become the standard of care for pts with mUC. While more than half of the pts have progressive disease (PD) by the 4th cycle of PCT, in general, most these pts will receive ICI after 4th cycle of PCT. However, for pts who have PD before 4 cycles, additional PCT will not only be effective, but will also cause side effects and worsen immune environment. However, the outcome of early switching to ICI during 1st-line PCT has not been reported. Here, we investigated whether early switching to Pe may improve prognosis. We also examined the usefulness of serum CYFRA (sCY) as a prognostic marker of 2nd-line Pe in this study. Methods: Seventy pts with mUC received PCT followed by Pe from February 2018 to July 2022 at our institution. Among them 56 pts who had received PCT 3 cycles or less because of PD or unacceptable side effects were included in this study. During PCT, computed tomography (CT) was performed at the end of each cycle and PCT was continued until PD. If PD on CT was confirmed, 2nd-line Pe was initiated. Performance status, metastasis site, neutrophil-lymphocyte ratio, hemoglobin, and serum alkaline phosphatase, C-reactive protein, total protein, albumin, corrected calcium (Ca) and sCY before Pe were examined as possible prognostic factors for overall survival (OS). OS was analyzed by Kaplan-Meier curves and log-rank test. Multivariate analysis on prognostic factors was carried out using the Cox hazards model. Results: Median age was 73 (31-86). Twenty-seven pts (49%) received gemcitabine-cisplatin and 29 (51%) received gemcitabine-carboplatin for PCT. Twelve pts (21%) received 1 cycle of PCT, 2 cycles in 26 (46%) and 3 cycles in 18 (32%). During the median follow-up period of 14.6 (6.2-44.6) months (M), 30 pts (53.5%) had died. The median OS was 15.5M and the 1-year OS rate was 60%. The median PFS was 10.2M and the 1-year PFS rate was 46%. Objective response rate was 25% and 18 pts showed stable disease (32%) and 24 pts (43%) showed PD. On univariate analysis, sCY (p=0.001) and Ca (p=0.003) were the significant factors for OS. On multivariate analysis, sCY (HR 3.2, 95%CI [1.33-7.82], p=0.009) and Ca (HR2.3, (95%CI [1.02-5.22], p=0.046) were the significant factors for OS. Conclusions: Early switching to Pe during 1st-line PCT resulted in PFS of 10.2M and OS of 15.5M, which were longer than those of the KEYNOTE-045 trial (PFS 2M, OS 10M). Early introduction of Pe may be effective in the pts with mUC who are resistant to chemotherapy. sCY and Ca were suggested to be the useful prognostic factors for OS.
Clinical applications of urine- and blood-based genome wide copy number study from 1,000 patients with bladder and prostate cancer.
Authors: Dai Chao , Zheng Tiantian , Mo Wei , Bonora Giancarlo , Wang Amy , Luo Shujun , Zhou Kemin , Jia Shidong , Du Pan
Published: March 2023

459

Background: Liquid biopsy has become increasingly important in cancer diagnosis and disease progression monitoring. Copy number variation is an important characteristic for genitourinary cancer and many other cancer types, where bladder cancer was shown to have the largest copy number alternation among 33 human cancer types from TCGA. We developed PredicineCNB, a companion LP-WGS assay to robustly estimate genome-wide copy number burden (CNB) from plasma and urine clinical samples, which can provide longitudinal disease monitoring in a cost-effective way. Methods: By integrating both fragments coverage and fragments length from LP-WGS data, and quantifying copy number deviation at chromosome arm level, we greatly increase both sensitivity and specificity for CNB based cancer detection. Analytical evaluation was performed based on clinical plasma titration samples, and PredicineCNB has demonstrated high cancer detection sensitivity (LOD is 1%) with high specificity (> 99%), using DNA input amounts as low as 1ng. We also validated CNB using Predicine panel-based tumor fraction for more than 200 clinical samples, results demonstrated both are highly concordant with correlation coefficient 0.84. Results: We performed clinical evaluation of PredicineCNB on 700 patients with prostate cancer and 300 patients with bladder cancer. For clinical patients with longitudinal samples under different disease stages or drug treatments, we demonstrated a promising potential using PredicineCNB for monitoring dynamic changes in ctDNA, that are caused by copy number variation. For 12 different bladder cancer patients, each with at least two longitudinal samples, we observed that CNB declines as early as two weeks after treatment initiation, providing an early signal of molecular response to therapy. In addition, when comparing conventional radiology-based imaging with CNB, we found that an increase in CNB preceded clinical progression of disease in majority of patients; and CNB shows a positive correlation between cancer stage revealed by CT scan. Conclusions: We conducted a comprehensive clinical study using PredicineCNB in 1,000 patients with prostate and bladder cancers, demonstrating the promising clinical application of liquid biopsy-based genome-wide copy number changes in therapy monitoring.
The impact of blue light cystoscopy use among patients with non-muscle invasive bladder cancer in an equal access setting.
Authors: Das Sanjay , Gu Lin , Trustram Eve Claire , Parrish Joshua , De Hoedt Amanda Marie , McKee Chad , Aronson William , Freedland Stephen J. , Williams Stephen B.
Published: March 2023

461

Background: Prior studies suggest that white light cystoscopy (WLC) alone can fail to detect cases of non-muscle invasive bladder cancer (NMIBC) compared to blue light cystoscopy (BLC). We describe bladder cancer outcomes and the impact of BLC among NMIBC patients in an equal access setting. Methods: A total of 378 NMIBC patients within the Veterans Affairs system that had a CPT code for BLC from December 1, 2014 to December 31, 2020 were assessed. We determined recurrence rates and time to recurrence prior to BLC (i.e. after previous WLC if available) and following BLC. We used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine the association between race and recurrence, progression, and overall survival. Results: Of 378 patients with complete data, 43 (11%) were Black and 300 (79%) White. Median follow-up was 40.7 months from bladder cancer diagnosis. There were 194 (51%) patients with either TaHG or T1 without CIS; 52 (14%) had CIS with or without TaHG or T1; and 127 (34%) had TaLG only. A total of 239 (63%) patients received BCG at any point during the study. Median time to first recurrence following BLC was longer compared to WLC alone (40 (33-NE) vs. 26 (17-39) months). The risk of recurrence was significantly lower following BLC (Hazard Ratio (HR) 0.70; 95% Confidence Interval (CI) 0.54-0.90). There was no significant difference in recurrence (Hazard Ratio (HR) 0.83; 95% Confidence Interval (CI) 0.48-1.43), progression (HR 1.46; 95% CI 0.45-4.74), and overall survival (HR 0.69; 95% CI 0.29-1.65) following BLC by Black vs. White race. Conclusions: In this study from an equal access setting in the VA, we observed significantly decreased risk of recurrence and prolonged time interval to recurrence following BLC compared to WLC alone. There was no difference in any bladder cancer outcomes by race.
Baseline characteristics from a retrospective, observational, US-based, multicenter, real-world (RW) study of avelumab first-line maintenance (1LM) in locally advanced/metastatic urothelial carcinoma (la/mUC) (PATRIOT-II).
Authors: Grivas Petros , Barata Pedro C. , Moon Helen , Hutson Thomas E. , Gupta Shilpa , Sternberg Cora N. , Dave Vaidehi , Downey Chad , Shillington Alicia C. , Devgan Geeta , Kirker Melissa , Thakkar Sheena , Katzenstein Howard M. , Bhanegaonkar Abhijeet , Liu Frank , Brown Jason , Sonpavde Guru P.
Published: March 2023

465

Background: The JAVELIN Bladder 100 clinical trial demonstrated a significant overall survival and progression-free survival benefit with avelumab 1LM + best supportive care (BSC) vs BSC alone for la/mUC not progressing on platinum-based chemotherapy (PBC). PATRIOT-II aims to describe RW data for avelumab 1LM treatment (tx) of patients (pts) with la/mUC. Methods: PATRIOT-II collected data from pts with la/mUC treated in 37 geographically dispersed oncology practices/communities and academic centers in the US. Pts who initiated avelumab 1LM following PBC were retrospectively enrolled and will be followed up via medical record review for 52 weeks post avelumab 1LM initiation. This analysis focused on pt characteristics and tx data from la/mUC diagnosis through the PBC period and at avelumab 1LM initiation. Disease and PBC tx characteristics, as well as response to PBC, were assessed. All analyses were descriptive. Results: A total of 160 pts were enrolled (Table), 118 (74%) were white, non-Hispanic, 16 (10%), were Black, Asian, or Hispanic, and the rest unknown; 102 (64%) were current or former smokers. 77 (48%) were tested for PD-L1 via various assays, with 44 (57%) of those tumor samples reported as positive. 1L PBC was cisplatin-based in 100 (63%) of pts and carboplatin-based in 60 (38%). Pts received a median of 4 PBC cycles (interquartile range [IQR], 3-6) for a median of 13 weeks (IQR, 10-17). 31 (19%) discontinued PBC due to unacceptable side effects/toxicity. Best observed response was complete response in 21 (13%), partial response in 109 (68%), and stable disease in 17 (11%), with the remainder unknown. Median time to first imaging was 10 weeks (IQR, 5-14) after PBC initiation. 23 (14%) were hospitalized while receiving PBC, and 25 (16%) were seen in the emergency department. Pts proceeded to avelumab 1LM at a median of 4 weeks (IQR, 3-6) following PBC completion. Avelumab was administered at 800 mg every 2 weeks in 130 (81%), 10 mg/kg in 15 (9%), <800 mg in 8 (5%), and >800 mg in 7 (4%) pts. Conclusions: This ‘RW’ study offers valuable insights into characteristics and outcomes of pts with la/mUC treated in the US. Baseline factors, tx patterns and response to PBC were consistent with usual therapy paradigms in the 1L induction setting. Ongoing trials are evaluating the optimal number of PBC cycles and predictive biomarkers. Limitations include the retrospective nature, lack of randomization and central review, potential selection and confounding biases. [Table: see text]
Multi-center, retrospective study of first-line systemic therapy ± immune checkpoint inhibition for metastatic neuroendocrine carcinoma of the urinary tract.
Authors: Collier Katharine A. , Simon Nicholas I. , Taylor Amy K , Hemenway Gregory , Rose Tracy L , Eule Corbin Jeffrey , Tripathi Nishita , Rodman Christopher , Kalluri Uttam , Farooq Muhammad Zain , McKay Rana R. , Jain Rohit K. , Sonpavde Guru P. , Sweis Randy F. , Agarwal Neeraj , Lam Elaine T. , Zibelman Matthew R. , Emamekhoo Hamid , Apolo Andrea B. , Mortazavi Amir
Published: March 2023

467

Background: Neuroendocrine, small cell, or large cell carcinoma originating from the urothelium (uro-NE/SCC/LCC) is rare. Outcomes for metastatic disease are dismal. Treatment is extrapolated from small cell lung cancer, for which immune checkpoint inhibitors (ICIs) have modest activity. Preliminary activity has been reported with ICI for uro-NE. We aimed to compare real-world progression-free survival (PFS) and overall survival (OS) between ICI-containing and non-ICI-containing regimens in the first line (1L) metastatic setting for uro-NE/SCC/LCC. Methods: We performed a retrospective study at 11 cancer centers. Patients (pts) who received systemic therapy (2011-2021) for biopsy confirmed metastatic uro-NE/SCC/LCC were included. Pts with metastasis within 6 months of (neo)adjuvant chemotherapy (CT) (n=16) were excluded from 1L analyses. Results: 102 pts with metastatic uro-NE/SCC/LCC were evaluable. 17 (16.7%) had NE histology, 81 (79.4%) SCC, and 4 (3.9%) LCC. NE/SCC/LCC was mixed with urothelial histology in 19 (18.6%). Primary tumors were most often in the bladder (84.3%, n=86), less frequently upper tract (11.8%, n=12) or urethra (3.9%, n=4). 42 pts (41.2%) were previously treated for localized disease, the rest were de novo metastatic (n=60, 58.8%). Pts who received an ICI in any line (n=61) had significantly longer OS (p=0.038) than pts that never received an ICI (n=41). As shown in the table, in the 1L, ICI-containing regimens (n=33) resulted in significantly longer PFS, but not OS or ORR compared to non-ICI regimens (n=53). Subdividing 1L regimens into ICI without CT (n=14), CT without ICI (n=53), or ICI + CT (n=19), both PFS and OS were significantly different with similar ORR. ICI w/o CT had the longest median PFS and OS with an ORR 57.1% comparable to CT regimens. Of 61 pts that received ICI in any line, 14 (23.0%) had an immune-related adverse event of any grade; 11 (18.0%) received steroids. Conclusions: This is the largest ever report of ICI for metastatic uro-NE/SCC/LCC. ICIs were associated with improved outcomes with expected added toxicity. Further prospective investigation of ICI regimens is warranted. [Table: see text]
Oncologic outcomes in patients with residual invasive upper tract urothelial carcinoma following neoadjuvant chemotherapy.
Authors: Fletcher Sean A. , Pallauf Maximilian , Watts Emelia K. , Lombardo Kara A. , Campbell Jack A. , Mari Andrea , Rouprêt Morgan , Boorjian Stephen A. , Djaladat Hooman , Kikuchi Eiji , Soria Francesco , Rink Michael , Raman Jay D. , Abdollah Firas , Ploussard Guillaume , Hoffman-Censits Jean H. , McConkey David James , Shariat Shahrokh F. , Pradere Benjamin , Singla Nirmish
Published: March 2023

475

Background: Emerging evidence supports use of neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for appropriately selected patients with upper tract urothelial carcinoma (UTUC). However, oncologic outcomes have not been well characterized for patients with residual muscle-invasive disease after NAC. Methods: We used a multi-institutional cohort from 24 centers in the U.S., Europe, and Japan to retrospectively identify patients who underwent RNU for UTUC from 1985-2022 and had high-grade muscle-invasive disease. We stratified the cohort based on receipt of NAC (>ypT2 vs. >pT2). Exclusion criteria included receipt of adjuvant chemotherapy, concurrent cystectomy with RNU, and distant metastatic disease. Baseline characteristics were compared between groups. Kaplan-Meier survival analysis with log-rank test was used to compare differences in recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS). Multivariable Cox regression and Fine-Gray competing risk regression were used to determine predictors of these outcomes. Results: A total of 1,233 patients were included, 62 of whom received NAC prior to RNU. A platinum-based regimen was used in 90% of NAC recipients, and the median number of cycles administered was 4 (IQR: 3-5). Median follow-up time among all patients was 22 months (IQR: 8-47 mo.). NAC recipients were more likely to have pathologic node positivity (35% vs. 13%) and less likely to have positive tumor margins (8% vs. 28%). On Kaplan-Meier analysis, NAC recipients with residual >ypT2 disease had poorer outcomes than those with >pT2 disease (2-year RFS [NAC vs. no NAC]: 52% vs. 80%, p<0.001; 2-year OS: 60% vs. 78%, p=0.003; 2-year CSS: 61% vs. 86%, p<0.001). Multivariable analyses also showed a statistically significant association between residual muscle-invasive disease after NAC and poorer RFS, OS, and CSS (Table). Conclusions: NAC recipients with >ypT2 disease at RNU after exhibit poorer outcomes than stage-matched chemotherapy naïve counterparts. This may reflect effects of occult micrometastatic disease or chemoresistant primary tumors in non-responders. Our data highlight the need to improve prospective identification of candidates most likely to respond to NAC prior to RNU for UTUC in order to maximize its therapeutic benefit. [Table: see text]
Chemotherapy, immunotherapy, or combination first-line treatment for metastatic urothelial carcinoma of the bladder: A large real-world experience.
Authors: Ranganathan Sanjana , Riveros Carlos , Xu Jiaqiong , Geng Michael , Huang Emily , Anis Maryam , Muhammad Taliah , Zhang Jun , Efstathiou Eleni , Wallis Christopher J.D. , Sonpavde Guru P. , Satkunasivam Raj
Published: March 2023

477

Background: First-line therapy for metastatic urothelial carcinoma of the bladder (mUC) consists of platinum-based chemotherapy in most patients and PD1/L1 inhibitors in selected patients. Multiple combination chemo-immunotherapy trials failed to show a clear benefit over chemotherapy alone. We sought to use real-world data to evaluate clinical and sociodemographic factors associated with receipt of first-line chemotherapy, immunotherapy or combination chemo-immunotherapy treatment for metastatic bladder cancer and examined differences in overall survival (OS). Methods: We used the National Cancer Database to identify patients with stage IV UCB diagnosed between 2014 and 2018, who were treated with first-line immunotherapy, chemotherapy, or combination treatment. We performed multivariable logistic regression modeling to determine factors associated with treatment receipt. An extension of inverse probability treatment weighting (IPTW) obtained from multinomial logistic regression was used to balance clinical and sociodemographic differences between treatment groups. Adjusted Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression were used to evaluate the association between treatment and OS. Results: A total of 4,169 patients were identified in the cohort; 3,255 (78.1%) were treated with chemotherapy, 601 (14.4%) with immunotherapy, and 313 (7.5%) with combination treatment. Multivariable analysis identified increasing age (RRR: 1.07, 95% CI, 1.06-1.08), comorbidity burden (Charlson-Deyo 2, RRR: 1.65, 95% CI, 1.21-2.24 and Charlson-Deyo 3, RRR: 2.11; 95% CI, 1.51-2.93), and treatment at an academic facility (RRR: 1.26; 95% CI, 1.03-1.53) as independent predictors of receiving immunotherapy. Treatment at an academic facility (RRR: 1.29, 95% CI, 1.01-1.65) was associated with receipt of combination treatment. After IPTW, we found that combination therapy (hazard ratio [HR]: 0.72; 95% CI, 0.62-0.83), but not immunotherapy alone, was associated with improved survival compared to chemotherapy. These data are limited by inability to determine platinum eligibility, and residual confounding. Conclusions: Patients with older age and more comorbidities were more likely to receive immunotherapy than chemotherapy for first-line treatment of metastatic urothelial carcinoma of the bladder. Modest real-world utilization of chemo-immunotherapy was observed to be higher in academic centers and was associated with improved survival compared to chemotherapy. The study is limited by retrospective design; prospective data are necessary to identify patients who may benefit from combination chemo-immunotherapy.
Economic impact of bladder cancer (BC) in the United States (US).
Authors: Clark Otavio , Sarmento Tulio , Eccleston Anthony , Brinkmann Julia , Picoli Renato , Daliparthi Vamsi , Voss Jorine , Chandrasekar Sanjana , Thompson Allison , Chang Jane
Published: March 2023

479

Background: Incidence and mortality for BC has changed very little over the past 20 years. Approximately 40% of patients with high-risk non-muscle invasive BC eventually recur/progress. It is important to understand the economic impact of disease recurrence/progression in BC. Methods: An economic model was constructed to calculate the number of patients receiving each treatment modality at every stage of disease and their respective costs. Epidemiological data was based on the CancerMPact Patient Metrics (PM) database, and treatment modality data retrieved from CMP Treatment Architecture (TA), 2021 version. Resource utilization and costs were obtained from the medical literature and public data sources. Only direct costs were considered. Results: There were an estimated 83,532 newly diagnosed BC patients of all stages in 2021 with a projected total cost of treatment of $2,584,783,728. Average cost per patient varied from $19,521 (stage 0a) to $169,533 (metastatic disease) (Table). Cost profile differed substantially among the stages of disease. For the 75,760 patients that were expected to have a recurrence in 2021, an additional cost of $3,953,096,316 was estimated at an average cost per patient of $52,179. The expected total cost to treat newly diagnosed and newly recurrent patients is reported in this model, with the total cost in 2021 estimated to exceed $6.5 billion. Conclusions: Treatment and resource costs increase for BC as the disease recurs/progresses. More effective treatments earlier in the disease setting to delay recurrence/progression may reduce the economic burden associated with BC. [Table: see text]
Impact of 68Ga-PSMA PET/CT in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide.
Authors: Altavilla Amelia , Caroli Paola , Giunta Emilio Francesco , Scarpi Emanuela , Rossetti Virginia , Casadei Chiara , Lolli Cristian , Schepisi Giuseppe , Bleve Sara , Cursano Maria Concetta , Gasperoni Lorenzo , Matteucci Federica , De Giorgi Ugo
Published: March 2023

48

Background: 68Ga prostate specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA PET/CT) is a highly sensitive diagnostic tool to detect prostate metastatic sites even at low levels of Prostate Specific Antigen (PSA). We evaluated the impact of 68Ga-PSMA PET/CT in patients treated with enzalutamide as first-line therapy for mCRPC. Methods: In an observational prospective study, 67 consecutive mCRPC patients were treated with enzalutamide 160 mg once daily in first-line for mCRPC. 68Ga-PSMA PET/CT was performed at baseline, after 3 months, during follow-up and at PSA/clinical progression. Patients were evaluated on a monthly basis for serological PSA response and safety. We measured at baseline the sum of metabolic total volume (SMTV), mean standardized uptake volume (SSUVmean), maximum standardized uptake volume (SSUVmax) and total lesion activity (STLA), which is the product of SMTV and SSUVmean, for a maximum of 20 lesions. These parameters together with baseline PSA level, Eastern Cooperative Oncology Group performance status (ECOG PS), Gleason Score (GS) and age were analyzed by univariate and multivariate Cox regression models as potential predictors of progression-free survival (PFS) and overall survival (OS). Results: At the moment of the present analysis, 58 mCRPC patients were considered fully evaluable. The median age was 75 years (range, 47-91), ECOG PS was 0 in 47 cases (81%), 1-2 in 11 (19%), GS was <8 in 22 (38%), 8-10 in 36 (62%), the median baseline PSA was 2.66 µg/L (range 0.09-197). We observed a median SMTV of 5.73 cm3, median SSUVmax of 44.85, median SSUVmean of 25.80 and median STLA of 59.66. At the median follow-up of 52 months, median PFS was 28.9 months (95% CI 16.3-43.6), median OS was not reached (95% CI 36.8-not reached). In univariate analysis, SSUVmax and STLA were significant for PFS (p=0.015 and p=0.001, respectively) and OS (p=0.026 and p=0.019, respectively), while SSUVmean was significant only for OS (p=0.028). On multivariate analysis, STLA only remained significant for PFS (p<0.001) and OS (p=0.026). Conclusions: The assessment of mCRPC by 68Ga-PSMA PET/CT before starting enzalutamide was associated with longer median PFS and OS compared to prior studies using standard imaging only. STLA, expression of both volume and intensity of 68Ga-PSMA uptake, appeared the strongest parameter able to predict PFS and OS.
Surgery for urologic cancers after SARS-CoV-2 infection: Adverse outcomes and optimal delay.
Authors: Flitcroft Madelyn Anne , Verhagen Nathaniel , Shah Nayan , Johnson Scott , Kothari Anai
Published: March 2023

484

Background: Perioperative SARS-CoV-2 infection has been associated with increased adverse outcomes. Research conducted early in the COVID-19 pandemic suggested an 8 week delay after SARS-CoV-2 infection prior to undergoing surgery. The aim of this study is to determine if prior COVID-19 infection is an independent risk factor for adverse outcomes following surgery for urologic cancers. A secondary objective was to determine the optimal duration to delay surgery, specifically cystectomy, prostatectomy, or nephrectomy, after COVID-19 infection. Methods: Data from the National COVID Cohort Collaborative (N3C) data enclave was used to conduct this retrospective cross-sectional study. Patients with cancer diagnoses that underwent surgery for urologic cancers after January 2020 were included in the analyses. Urologic surgeries were queried using standard SNOMED concepts corresponding to cystectomy, nephrectomy, and prostatectomy. Patients were assessed for adverse postoperative events that were defined using standard SNOMED clinical concepts. COVID-19 positive patients were identified via the N3C Knowledge Store using positive lab measurement or a positive SARS-CoV-2 diagnosis. Analyses were conducted in the N3C data enclave. Results: The study cohort included 38,974 total patients with 15,216, 14,778, and 8,980, undergoing cystectomy, prostatectomy, and nephrectomy, respectively. 2,807 had a history of COVID-19 infection greater than 20 days prior to surgery. Prior history of COVID-19 was independently associated with adverse outcomes for cystectomy (OR 1.21 [1.03-1.43], p<0.05) and nephrectomy (OR 1.27 [1.06-1.52], p<0.05), but not prostatectomy (OR 1.14 [0.95-1.36]). Multivariable regression assessing time to surgery and risk for any adverse events, did not reveal significant benefit to waiting greater than 20 days after COVID-19 infection to operate. Conclusions: Patients with known prior COVID-19 infection who underwent surgical treatment of urologic cancers experienced increased risk of adverse surgical outcomes. Among this group, those who delayed surgery greater than 20 days after infection did not demonstrate decreased risk of these negative outcomes across the procedures studied. Optimal surgical delay in the treatment of urologic cancers after COVID-19 infection does not appear to be greater than 20 days.