Effectiveness and safety of adjuvant treatment of tislelizumab with or without chemotherapy in patients with high-risk upper tract urothelial carcinoma: a retrospective, real-world study.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is a rare subset of urothelial cancers with poor prognosis. No consensus exists on the benefit of adjuvant immunotherapy for patients with UTUCs after nephroureterectomy with curative intent and the existing studies are limited. Herein, this study aimed to evaluate the effectiveness and safety of adjuvant treatment of tislelizumab with or without chemotherapy in patients with high-risk UTUC. METHODS: A retrospective study was conducted on 63 patients with high-risk UTUC who received tislelizumab with or without gemcitabine-cisplatin (GC) chemotherapy regimen after surgery between January 2020 and December 2022. Data on demographic and clinical characteristics, surgical, outcomes, prognostic factors, and safety were collected and analyzed. RESULTS: Among the 63 patients with high-risk UTUC, the median age was 66 years (interquartile range 57-72), with 33 (52%) being male. The majority of patients with staged pT3 (44%) and pN0 (78%) disease. Fifty-one patients (81%) received tislelizumab plus GC chemotherapy, and 12 (19%) were treated with tislelizumab monotherapy. After the median follow-up of 26 months (range 1-47), 49 (78%) patients achieved stable disease. The 2-year disease-free survival (DFS) and 2-year overall survival were 78.68% (95% CI: 60.02-87.07%) and 81.40% (95% CI: 68.76-89.31%), respectively. The cycles of GC chemotherapy were independent prognostic factors for survival, with higher DFS (hazard ratio = 0.68, 95% CI, 0.50-0.93; p = 0.016) observed in the subgroup undergoing ≥ 3 cycles versus < 3 cycles of GC chemotherapy. Fifty-eight patients (92%) experienced at least one treatment-related adverse event (TRAE), with grade 3-4 TRAEs occurring in 13%. The most common grade 3-4 TRAEs were decreased white blood cells, thrombocytopenia, and ulcers. CONCLUSIONS: The study demonstrates promising clinical benefits and a manageable safety profile of the tislelizumab-based adjuvant regimen for patients with high-risk UTUC. This suggests that adjuvant immunotherapy represents a potential therapeutic strategy for this population.

Comparison of different prediction tools for the risk of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma: a propensity-matched analysis.

OBJECTIVE: To compare the predictive performance of the current clinical prediction models for predicting intravesical recurrence (IVR) after radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively analysed upper tract urothelial carcinoma patients who underwent radical nephroureterectomy in our centre from January 2009 to December 2019. We used the propensity score matching (PSM) method to adjust the confounders between the IVR and non-IVR groups. Additionally, Xylinas' reduce model and full model, Zhang's model, and Ishioka's risk stratification model were used to retrospectively calculate predictions for each patient. Receiver operating characteristic (ROC) curves were generated, and the areas under the curves (AUCs) were compared to identify the method with the highest predictive value. RESULTS: We included 217 patients with a median follow-up of 41 months, of which 57 had IVR. After PSM analysis, 52 pairs of well-matched patients were included in the comparative study. No significant difference was found in clinical indicators besides hydronephrosis. The model comparison showed that the AUCs of the reduced Xylinas' model for 12 months, 24 months, and 36 months were 0.69, 0.73, and 0.74, respectively, and those of the full Xylinas' model were 0.72, 0.75, and 0.74, respectively. The AUC of Zhang's model for 12 months, 24 months, and 36 months was 0.63, 0.71, and 0.71, respectively, the performance of Ishioka's model is that the AUC of 12 months, 24 months and 36 months was 0.66, 0.71, and 0.74, respectively. CONCLUSION: The external verification results of the four models show that more comprehensive data and a larger sample size of patients are needed to strengthen the models' derivation and updating procedure, to better apply them to different populations.

National trends in clinical and pathologic staging for upper tract urothelial carcinoma: Implications for neoadjuvant chemotherapy.

INTRODUCTION: With growing support of perioperative chemotherapy for upper tract urothelial carcinoma (UTUC), current biopsy methods are challenging, and little is known as to the degree to which patients would appropriately receive neoadjuvant chemotherapy (NAC) from biopsy alone. Herein, we sought to assess the rates of appropriate clinical use of NAC and identify clinicopathologic factors associated with aggressive UTUC amongst patients undergoing radical nephroureterectomy (RNU) for clinically localized disease. METHODS: From 2004 to 2013, we identified all treatment naïve patients diagnosed with clinically localized, high grade UTUC (cTa-4Nx) who underwent RNU from the National Cancer Database (NCDB). Pathologic criteria for NAC (pT2-4N0,x; pTanyN1) from RNU represented the primary outcome. Bivariate and multivariable analyses were utilized to identify covariates associated with primary outcome to determine appropriate use of NAC. RESULTS: During the study interval, 5,362 patients were diagnosed with clinically localized UTUC and underwent RNU. Overall, 49.1% of patients presented with an unknown primary tumor stage (Tx) and 24.5% had invasive UTUC from biopsy. On multivariable analysis, upper tract tumor size was associated with invasive UTUC eligible for NAC (all P < 0.05). Amongst patients with cTx UTUC from biopsy, half of patients had pathologic noninvasive UTUC (pTa,is,1) from RNU and would be overtreated with NAC. CONCLUSION: Significant uncertainty persists in assigning primary upper tract tumor depth and represents a key barrier to widespread implementation of NAC for patients with high grade UTUC. Further research is needed to more accurately determine clinical criteria to identify patients for NAC.

PD-L1 Expression Reveals Significant Association With Squamous Differentiation in Upper Tract Urothelial Carcinoma.

OBJECTIVES: Limited literature is available on the tumor microenvironment (TM) of upper tract urothelial carcinoma (UTUC). This study comprehensively reviews programmed death 1 receptor (PD-1)-positive and CD8+ tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression on tumor epithelium (TE). METHODS: Seventy-two nephroureterectomy specimens were analyzed for PD-L1, PD-1, and CD8. One percent or more tumor and lymphohistiocyte PD-L1 expression was considered positive. TIL density by H&E was scored semiquantitatively from 0 to 3, and CD8+ and PD-1+ TILs were quantified in hotspots. RESULTS: Of the cases, 37.5% demonstrated PD-L1+ on TE. PD-L1+ TE showed an association with pathologic stage (P = .01), squamous differentiation (SqD) (P < .001), TILs by H&E (P = .02), PD-1+ peritumoral TILs (P = .01), and PD-L1+ peritumoral lymphohistiocytes (P = .002). Finally, there was a significant difference in PD-1+ peritumoral TILs in cases with SqD vs no SqD (P = .03). CONCLUSIONS: Aggressive UTUC is associated with a distinct TM. Furthermore, TM of UTUC-SqD was distinctly different from those with no SqD, warranting study in a larger cohort.

Impact of surgical waiting time on survival in patients with upper tract urothelial carcinoma: A national cancer database study.

PURPOSE: To evaluate the impact of surgical waiting time (SWT) on the survival outcome in patients with upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: We identified patients with nonmetastatic UTUC who underwent radical nephroureterectomy (RNU) between 2004 and 2013 in the National Cancer Database. The association between SWT and overall survival (OS) was evaluated using Cox proportional hazards regression. SWT was categorized into 6 groups: SWT ≤ 7 days, SWT 8 to 30 days, SWT 31 to 60 days, SWT 61 to 90 days, SWT 91 to 120 days, and SWT 121 to 180 days. Multivariable analyses were adjusted for patient, tumor, and facility-related factors. RESULTS: A total of 3,581 patients were included in the final overall cohort and 2,397 (66.9%) patients had the higher-risk disease (high-grade or ≥pT2). Multivariable Cox regressions showed that patients in the groups of SWT 31 to 60 days, SWT 61 to 90 days, and SWT 91 to 120 days had similar OS compared with patients who had SWT of 8 to 30 days in the overall cohort and higher-risk cohort. Patients with SWT 121 to 180 days had worse OS (HR = 1.61, 95% CI: 1.19-2.19, P = 0.002 in the overall cohort; HR = 1.56, 95% CI: 1.11-2.20, P = 0.010 in the higher-risk cohort). CONCLUSIONS: Increased SWT from diagnosis to RNU appears to be not associated with worse OS within 120 days after the diagnosis of UTUC but SWT>120 days may be associated with worsened survival. These findings might have important implications for trial design in the evaluation of neoadjuvant chemotherapy for UTUC and future clinical practice.

Is sarcopenia and sarcopenic obesity associated with clinical and pathological outcomes in patients undergoing radical nephroureterectomy?

PURPOSE: To investigate the association between sarcopenia and sarcopenic obesity on clinical, perioperative, and oncologic outcomes in patients with upper-tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). METHODS: Retrospective review of our institutional UTUC database was performed to identify all patients who underwent radical nephroureterectomy from 2002-2016. Skeletal Muscle Index (SMI) was measured at the L3 vertebral level and standardized according to patient height (cm2/m2). Sarcopenia was defined as<55cm2/m2 for men and<39cm2/m2 for women. Sarcopenic obesity was also assessed in patients with BMI>30kg/m2. Unadjusted logistic regression and Wilcoxon rank sum tests examined the relationship between sarcopenia and variables. RESULTS: A total of 100 patients (66 men and 34 women) with a mean age of 68 years, BMI of 30, Charlson comorbidity index of 4.0, tumor size of 3.5, and SMI of 50.8cm2/m2 were included. Furthermore, 42 patients (42%) were sarcopenic, and 18 patients (18%) had sarcopenic obesity. Median EBL was 150ml, OR duration was 322 minutes, and length of stay was 5.0 days. Sarcopenia was associated with several clinical factors including decreasing BMI, male sex, and coronary artery disease, albeit without association with any perioperative or oncologic outcomes. Sarcopenic obesity was similarly associated with several clinical variables including male sex, diabetes mellitus, hyperlipidemia, as well as increased EBL (P = 0.047) and non-bladder cancer disease relapse (P = 0.049). CONCLUSIONS: This contemporary cohort of patients undergoing RNU highlights the association of nonmodifiable risk factors with sarcopenia and disease relapse with sarcopenic obesity. Larger studies are necessary to further validate these observations.

Intravesical chemotherapy use after radical nephroureterectomy: A national survey of urologic oncologists.

To determine the use of prophylactic intravesical chemotherapy (pIVC) following radical nephroureterectomy (RNU) and barriers to utilization in a survey study of urologic oncologists. METHODS: A survey instrument was constructed, which queried respondents on professional experience, practice environment, pIVC use, and reasons for not recommending pIVC when applicable. The survey was electronically distributed to members of the Society of Urologic Oncology over an 8-week period. Survey software was used for analysis. RESULTS: The survey response rate was 22% (158 of 722). Half of the respondents were in practice for ≤10 years, while 90% performed ≤10 RNU cases annually. Of the 144 urologists regularly performing RNU, only 51% reported administering pIVC, including 22 exclusively in patients with a prior history of bladder cancer. One-third administered pIVC intraoperatively, whereas the remainder instilled pIVC at ≤3 (7%), 4 to 7 (37%), 8 to 14 (20%), and>14 (3%) days postoperatively. Almost all urologists noted giving a single instillation of pIVC. Agents included mitomycin-C (88%), thiotepa (7%), doxorubicin (3%), epirubicin (1%), and BCG (1%). Among respondents who did not administer pIVC, the most common reasons cited included lack of data supporting use (44%), personal preference (19%), and office infrastructure (17%). CONCLUSION: Only 51% of urologic oncologists report using pIVC in patients undergoing RNU. Reasons underlying this underutilization are multifactorial, thereby underscoring the need for continued dissemination of existing data and additional studies to support its benefits. Moreover, improving the logistics of pIVC administration may help to increase utilization rates.