The prognostic value of central pathology review in upper urinary tract cancer (UTUC) remains inadequately addressed in existing literature. In this study, we conducted an extensive central pathology review and presented its influence on multi-center UTUC studies. We conducted a retrospective review of patients who underwent radical nephroureterectomy or segmental resection for UTUC to determine eligibility for central pathology review. In the Taiwan UTUC Collaboration cohort, 377 cases met the criteria for pathology review. We assessed agreement between pathologists using both the total percentage of agreement and simple kappa statistics. The prognostic implications of original and review pathology for various parameters were examined using the Cox regression model. This study included 209 female and 168 male participants. Pathology review revealed substantial interobserver variability in pT staging, with a particularly high rate of pT2 cases being upgraded to pT3 upon central review (17/70 pT2 stage made by local pathologists were finally confirmed as pT3 disease by the review pathologist). The local pathologist cohort identified fewer significant histological predictors in survival models compared to the review pathology cohort. Advanced pT stage, perineural invasion (PNI), and positive surgical margin were independent predictors of poorer overall survival and cancer-specific survival. PNI, lymphatic vascular invasion, and positive surgical margin were independent predictors of disease recurrence. Substantial interobserver variability in histological assessment underscores the importance of centralized pathology review for both multi-center studies and accurate post-operative management of UTUC patients. Advanced stage, perineural invasion, and margin status were significant histological predictors of oncological outcomes.

OBJECTIVE: Adjuvant radiation therapy (ART) after radical cystectomy in locally advanced bladder cancer was revived after the advancement in precise radiation therapy that decreased the normal pelvic tissue radiation hazards. However, there are still scarce controlled randomized studies addressing this issue.
METHODS: One hundred thirty-one cystectomized urothelial bladder cancer patients were enrolled; 122 were randomized to receive ART of 50 Gy/25 fractions 4 weeks after cystectomy or cystectomy alone (CY). Sixty-two were included in the ART arm and 60 in the CY arm. Twenty-four ART and 30 CY patients received neoadjuvant chemotherapy. Eleven patients (9%) had cotenant neobladder diversion, 6 in ART, and 5 in CY arms. All ART patients were treated with intensity modulated radiation therapy with daily verification cone beam computed tomography. The median follow-up was 42.7 months.
RESULTS: The 3-year adjusted locoregional recurrence-free survival rate was higher in the ART arm, measuring 81% (95% CI, 69%-94%) compared with 71% (95% CI, 60%-80%; p = .0457). ART significantly improved the locoregional relapse-free rate in the cystectomy bed and the pelvic side wall (p = .016 and p = .001, respectively). The overall, event-free, and distant metastasis-free survival did not rank to the level of statistical significance in the 2 arms. Even though the acute side effects were slightly higher in ART, the late toxicities were almost equal in the 2 groups.
CONCLUSIONS: ART is safe and quite tolerable after radical cystectomy when using precise radiation techniques. These techniques significantly improved the locoregional recurrence-free survival but had insignificant improvement on the overall survival. ART did not affect the distant metastasis-free survival. Similar studies are performed in different centers around the world to confirm the value of ART in urothelial bladder cancer.

OBJECTIVE: Although recent trials involving first-line immune checkpoint inhibitors have expanded treatment options for patients with advanced urothelial carcinoma (aUC) who are ineligible for standard cisplatin-based chemotherapy, there exists limited evidence for whether trial efficacy translates into real-world effectiveness for patients seen in routine care. This retrospective cohort study compares differences in overall survival (OS) between KEYNOTE-052 trial participants and routine-care patients receiving first-line pembrolizumab monotherapy.
METHODS: A routine-care patient cohort was constructed from the Flatiron Health database using trial eligibility criteria and was weighted to balance EHR and trial patient characteristics using matching-adjusted indirect comparisons.
RESULTS: The routine-care cohort was older, more likely to be female, and more often cisplatin-ineligible due to renal dysfunction. ECOG performance status was comparable between the cohorts. Median OS was 9 months (95% CI 7-16) in the weighted routine-care cohort and 11.3 months (9.7-13.1) in the trial cohort. No significant differences between the Kaplan-Meier OS curves were detected (p = 0.76). Survival probabilities were similar between the weighted routine-care and trial cohorts at 12-, 24-, and 36- months (0.45 vs. 0.47, 0.31 vs. 0.31, 0.26 vs. 0.23, respectively). Notably, routine care patients had modestly lower survival at 3 months compared to trial participants (0.69 vs. 0.83, respectively).
CONCLUSIONS: Our results provide reassurance that cisplatin-ineligible aUC patients receiving first-line immunotherapy in routine care experience similar benefits to those observed in trial patients.

BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy.
METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors.
RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001).
CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.

UNASSIGNED: We initiated a biomarker-informed preoperative study of infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, in patients with localized upper tract urothelial carcinoma (UTUC), a population with high unmet needs and tumor with a high frequency of FGFR3 alterations.
UNASSIGNED: Patients with localized UTUC undergoing ureteroscopy or nephroureterectomy/ureterectomy were enrolled on a phase 1b trial (NCT04228042). Once-daily infigratinib 125 mg by mouth × 21 days (28-day cycle) was given for 2 cycles. Tolerability was monitored by Bayesian design and predefined stopping boundaries. The primary endpoint was tolerability, and the secondary endpoint was objective response based on tumor mapping, done after endoscopic biopsy and post-trial surgery. Total planned enrollment: 20 patients. Targeted sequencing performed using a NovaSeq 6000 solid tumor panel.
UNASSIGNED: From May 2021 to November 2022, 14 patients were enrolled, at which point the trial was closed due to termination of all infigratinib oncology trials. Two patients (14.3%) had treatment-terminating toxicities, well below the stopping threshold. Responses occurred in 6 (66.7%) of 9 patients with FGFR3 alterations. Responders had median tumor size reduction of 67%, with 3 of 5 patients initially planned for nephroureterectomy/ureterectomy converted to ureteroscopy. Median follow-up in responders was 24.7 months (14.9-28.9).
UNASSIGNED: In this first trial of targeted therapy for localized UTUC, FGFR inhibition was well tolerated and had significant activity in FGFR3 altered tumors. Renal preservation was enabled in a substantial proportion of participants. These data support the design of a biomarker-driven phase 2 trial of FGFR3 inhibition in this population with significant unmet clinical needs.

OBJECTIVE: Tislelizumab, a monoclonal antibody against programed death protein-1 (PD-1), has shown encouraging antitumor activity in urothelial cancer. This study was designed to assess the efficacy and safety of tislelizumab in urotelial cancer in a real-world setting.
METHODS: The study was a real-world retrospective study undertaken at Liaoning Cancer Hospital & Institute, China. Eligible patients were ≥18 years. Patients received 200-mg tislelizumab monotherapy intravenously every 3 weeks until the disease progressed to intolerable toxicity. Outcomes included an objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety.
RESULTS: Between March 2020 and December 2022, 33 patients were enrolled. The median follow-up was 10.17 (IQR 5.73-12.47) months. Of all 33 patients, ORR and DCR were 30.30% (95% CI 15.6%-48.7%) and 42.42% (95% CI 25.48%-60.78%), respectively. The median PFS was 5.73 (95% CI 3.27-13.00) months, with a 12-month PFS rate of 31.90% (95% CI 19.20%-53.00%). The median OS was 17.7 (95% CI 12.80-not reach) months, with a 12-month OS rate of 67.50% (95% CI 52.70%-86.40%). Eleven (33.33%) and 8 (24.24%) experienced ≥grade 3 treatment-related adverse events (TRAEs) and immune-related Aes, respectively. No treatment-related deaths occurred.
CONCLUSIONS: The excellent efficacy and controllable safety of tislelizumab in locally advanced or metastatic urothelial cancer suggest that it may be a promising therapeutic option for this population.

The ARON-2 study (NCT05290038) aimed to assess the real-world efficacy of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. This retrospective analysis reports the outcomes of urothelial carcinoma (UC) patients with bone metastases (BM). Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were reviewed from60 institutions in 20 countries. Patients were assessed for Overall Response Rate (ORR), Progression-Free Survival (PFS), and Overall Survival (OS). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 881 patients were included; of them, 263 (30%) presented BM. Median follow-up time was 22.7 months. Patients with BM showed both shorter median OS (5.9 months vs 13.1 months, p < 0.001) and PFS (3.5 months, vs 7.3 months, p < 0.001) compared to patients without BM. Patients who received bone targeted agents (BTAs) showed a significantly longer median OS (8.5 months vs 4.6 months, p = 0.003) and PFS (6.1 months vs 3.2 months, p = 0.003), while no survival benefits were observed among patients who received radiation therapy for BM during pembrolizumab treatment compared to those who did not. In multivariate analysis, performance status, concomitant liver metastases, and the lack of use of BTAs were significantly associated with worse OS and PFS. Bone involvement in UC patients treated with pembrolizumab predicts inferior survival. Poor performance status and liver metastases may further worsen outcomes, while the use of BTAs is associated with improved outcomes.

Patient-reported outcomes (PROs) are getting widely implemented, but little is known of the impact of applying PROs in specific cancer diagnoses. We report the results of a randomized controlled trial (RCT) of the active use of PROs in patients with locally advanced or metastatic bladder cancer (BC) undergoing medical oncological treatment (MOT) with focus on determining the clinical effects of using PROs during chemo- or immunotherapy compared to standard of care.
We recruited patients from four departments of oncology from 2019 to 2021. Inclusion criteria were locally advanced or metastatic BC, initiating chemo- or immunotherapy. Patients were randomized 1:1 between answering selected PRO-CTCAE questions electronically once weekly with a built-in alert-algorithm instructing patients of how to handle reported symptoms as a supplement to standard of care for handling of side effects (intervention arm (IA)) vs standard procedure for handling of side effects (control arm (CA)). No real-time alerts were sent to the clinic when PROs exceeded threshold values. Clinicians were prompted to view the completed PROs in the IA at each clinical visit. The co-primary clinical endpoints were hospital admissions and treatment completion rate. Secondary endpoints were overall survival (OS), quality of life (EORTC\'s QLQ-C30 and QLQ-BLM30) and dose reductions.
228 patients with BC were included, 76% were male. 141 (62%) of the patients had metastatic disease. 51% of patients in the IA completed treatment vs. 56% of patients in the CA, OR 0.83 (95% CI 0.47-1.44, p = 0.51). 41% of patients in the IA experienced hospitalization vs. 32% in the CA, OR 1.48 (95% CI 0.83-2.65, p = 0.17). OS was comparable between the two arms (IA: median 22.3mo (95% CI 17.0-NR) vs. CA: median 23.1mo (95% CI 17.7-NR). Patient and clinician compliance was high throughout the study period (80% vs 94%).
This RCT did not show an effect of PRO on completion of treatment, hospitalizations or OS for BC patients during MOT despite a high level of patient and clinician compliance. The lack of real-time response to alerts remains the greatest limitation to this study.

BACKGROUND: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab.
METHODS: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model.
RESULTS: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival.
CONCLUSIONS: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

We explored changes in perceptions of cure among patients with genitourinary (GU) cancers starting Immune checkpoint inhibitors (ICIs) therapy.
This longitudinal study assessed patients before starting therapy and 3-months later with a questionnaire that included patient perceptions of ICIs and the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety scale. General linear modeling was used to investigate changes in expectation of cure over time, and chi-square tests were used to determine the association between expectation of cure and perceptions of ICIs and anxiety.
A total of 45 patients were recruited (73% male, 84% diagnosed with renal cell carcinoma). The proportion of patients who possessed an accurate expectation of cure increased over time (55.6%-66.7%, P = .001). An accurate expectation of cure was associated with lower rates of anxiety over time. Patients with inaccurate expectation of cure reported more severe side effects and worse self-reported ECOG score at the follow-up assessment (P = .04).
We found that patients with GU metastatic cancer treated with ICI therapy have increasingly accurate expectations of cure over time. Accurate expectation of cure is associated with decreased anxiety. Further research is needed to fully explore this dynamic over time and help inform interventions that can help patients develop accurate expectations.