Recent phase 3 randomized controlled trials (RCTs) demonstrate the promising impact of immune checkpoint inhibitor (ICI)-based combination therapies on locally advanced or metastatic urothelial carcinoma (UC). However, comparative data on the efficacy and toxicity of different ICI-based combinations are lacking. This study aims to compare the efficacy of first-line ICI-based combination therapies for locally advanced or metastatic UC using phase 3 RCT data. In November 2023, three databases were searched for RCTs evaluating oncological outcomes in patients with locally advanced or metastatic UC who were treated with first-line ICI-based combination therapies. Network meta-analysis (NMA) was conducted to compare outcomes, including overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), and treatment-related adverse events (TRAEs). Subgroup analyses were based on PD-L1 status and cisplatin eligibility. The NMA included five RCTs. Enfortumab vedotin (EV) + pembrolizumab ranked the highest for improving OS (100%), PFS (100%), ORR (96%), and CRR (96%), followed by nivolumab + chemotherapy. EV + pembrolizumab combination superiority held across PD-L1 status and cisplatin eligibility. In patients who are cisplatin-eligible, EV + pembrolizumab significantly improved OS (HR: 0.68, 95%CI 0.47-0.99) and PFS (HR: 0.67, 95%CI 0.49-0.92) compared to nivolumab + chemotherapy. Durvalumab + tremelimumab was the safest combination for severe TRAEs, and EV + pembrolizumab ranked second. Our analyses support EV + pembrolizumab combination as a first-line treatment for locally advanced or metastatic UC. Thus, EV + pembrolizumab may become a guideline-changing standard treatment.

• Klíčová slova
• Chemotherapy, Enfortumab vedotin, Immune checkpoint inhibitors, Metastasis, Urothelial carcinoma,
• MeSH
• humanizované monoklonální protilátky terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory kontrolních bodů * terapeutické užití   MeSH
• karcinom z přechodných buněk farmakoterapie   mortalita   patologie   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• monoklonální protilátky MeSH
• nádory močového měchýře farmakoterapie   patologie   mortalita   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• randomizované kontrolované studie jako téma MeSH
• urologické nádory farmakoterapie   mortalita   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• síťová metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• enfortumab vedotin MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• inhibitory kontrolních bodů * MeSH
• monoklonální protilátky MeSH
• pembrolizumab MeSH Prohlížeč

BACKGROUND AND OBJECTIVE: Given the uncertainty regarding the role of radical nephroureterectomy (RNU) as part of a multimodal treatment strategy for upper tract urothelial carcinoma (UTUC) patients with cN+ disease, we aimed to perform a systematic review and meta-analysis of the corresponding literature. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we identified 17 observational comparative and noncomparative studies, published between January 2000 and September 2024, evaluating UTUC patients with cTanyN+M0 disease (P) who received RNU as part of a multimodal treatment strategy (I), as compared with any treatment strategy if applicable (C), to assess oncological or postoperative outcomes (O). Meta-analyses were further performed, as appropriate. KEY FINDINGS AND LIMITATIONS: Overall, 15 studies evaluated the effectiveness of adding chemotherapy to RNU in the perioperative setting without specifying the exact timing of delivery (n = 1), in the induction setting (n = 14), or in the adjuvant setting (n = 5), while two studies evaluated the effectiveness of adding RNU to chemotherapy. Meta-analyses showed that the use of induction chemotherapy plus RNU versus RNU alone was associated with greater odds of pathological downstaging (risk ratio [RR] = 3.06; 95% confidence interval [CI] = [2.48-3.77]; p < 0.001; I2 = 0%; p = 0.44) and pathological complete nodal response (RR = 2.80; 95% CI = [2.03-3.86]; p < 0.001; I2 = 0%; p = 0.47) as well as prolonged overall survival (HR = 0.52; 95% CI = [0.42-0.64]; p < 0.001; I2 = 14%; p = 0.33) without any significant impact on the risk of overall (RR = 1.14; 95% CI = [0.79-1.64]; p = 0.48; I2 = 0%; p = 0.76) and major (RR = 0.48; 95% CI = [0.18-1.24]; p = 0.13; I2 = 0%; p = 0.87) postoperative complications. In addition, the use of induction chemotherapy plus RNU versus RNU plus adjuvant chemotherapy (HR = 0.58; 95% CI = [0.38-0.89]; p = 0.01) or chemotherapy alone (HR = 0.49; 95% CI = [0.32-0.76]; p = 0.001; I2 = 46%; p = 0.17) was associated with prolonged overall survival. Limitations include the observational design of all included studies. CONCLUSIONS AND CLINICAL IMPLICATIONS: The use of RNU could provide the greatest oncological benefits without any significant harm in selected UTUC patients with fit general condition and resectable cN+ disease responding to induction chemotherapy. PATIENT SUMMARY: In this report, we looked at the outcomes of radical surgery in combination with systemic chemotherapy for upper tract urothelial carcinoma with clinical evidence of dissemination to the surrounding lymph nodes. We observed that the use of radical surgery was associated with the greatest oncological benefits without any increased risk of postoperative complications in patients with fit general condition and resectable disease responding to induction chemotherapy. We conclude that the use of induction chemotherapy plus radical surgery could be the best multimodal treatment strategy for these patients.

• Klíčová slova
• Effectiveness, Induction chemotherapy, Lymph node metastasis, Radical nephroureterectomy, Upper tract urothelial carcinoma,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

CONTEXT: Adjuvant immune checkpoint inhibitors (ICIs) have recently emerged as guideline-recommended treatments of high-risk muscle-invasive urothelial carcinoma (MIUC). However, there is limited evidence regarding the optimal candidates and the differential efficacy of adjuvant ICI regimens. OBJECTIVE: To synthesize and compare the efficacy and safety of adjuvant ICIs for high-risk MIUC using updated data from phase III randomized controlled trials. EVIDENCE ACQUISITION: In April 2024, three databases were searched for eligible randomized controlled trials that evaluated oncologic outcomes in patients with MIUC treated with adjuvant ICIs. Pairwise meta-analysis (MA) and network meta-analyses were performed to compare the hazard ratios of oncological outcomes, including disease-free survival (DFS), overall survival (OS), and adverse events. Subgroup analyses were conducted on the basis of predefined clinicopathological features. EVIDENCE SYNTHESIS: Three randomized controlled trials that assessed the efficacy of adjuvant nivolumab, pembrolizumab, and atezolizumab were included in the MAs and network meta-analyses groups. Pairwise MAs showed that treatment with adjuvant ICIs significantly improved DFS [hazards ratio: 0.77, 95% confidence interval (CI): 0.66-0.90] as well as OS (hazards ratio: 0.87, 95% CI 0.76-1.00) in patients with MIUC compared with in the placebo/observation group. The DFS benefit was prominent in patients who underwent neoadjuvant chemotherapy (P = 0.041) and in those with bladder cancer (P = 0.013) but did not differ across programmed death-ligand 1 and lymph node status. Adjuvant ICI therapy was associated with increased risk of any (OR: 2.98, 95% CI 2.06-4.33) and severe adverse events (OR: 1.78, 95% CI 1.49-2.13). The treatment rankings revealed that pembrolizumab for DFS (84%) and nivolumab for OS (93%) had the highest likelihood of improving survival. CONCLUSIONS: Our analyses demonstrated the DFS and OS benefits of adjuvant ICIs for high-risk MIUC. Furthermore, patients with bladder cancer who underwent neoadjuvant chemotherapy appeared to be the optimal candidates for adjuvant ICIs regarding prolonged DFS. Adjuvant ICIs are the standard of care for high-risk MIUC, and differential clinical behaviors and efficacy will enrich clinical decision-making.

• MeSH
• adjuvantní chemoterapie metody   MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• karcinom z přechodných buněk * farmakoterapie   patologie   MeSH
• lidé MeSH
• nádory močového měchýře * farmakoterapie   patologie   MeSH
• síťová metaanalýza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• systematický přehled MeSH
• Názvy látek
• inhibitory kontrolních bodů * MeSH

BACKGROUND: Current European Association of Urology (EAU) guidelines support adjuvant intravesical Bacillus Calmette-Guérin (BCG) treatment after Transurethral Resection of Bladder Tumor (TURB) for intermediate- or high-risk Non-Muscle-Invasive Bladder Cancer (NMIBC) patients, aiming to reduce the risk of tumor recurrence. The quality of data, however, does not allow definitive conclusions on whether different strains and dosages of BCG have different efficacies on long-term survival outcomes. OBJECTIVE: To evaluate the long-term survival outcomes of different strains and dosages of BCG in patients with NMIBC. DESIGN, SETTING, AND PARTICIPANTS: All NMIBC patients treated with intravesical BCG therapy from 2001 to 2020 were identified using a territory-wide database in Hong Kong. INTERVENTION: BCG strains and dosages (Connaught strain 81 mg, Connaught strain 27 mg, Tokyo strain 80 mg, and Danish strain 30 mg) were retrieved from medical records. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall Survival (OS), Cancer-Specific Survival (CSS), Recurrence-Free Survival (RFS), and Progression-Free Survival (PFS) were analyzed using the Kaplan-Meier method. A multivariable Cox regression analysis was used to adjust potential confounding factors, and to estimate Hazard Ratio (HR) and 95% confidence interval (CI) of different BCG strains. A further subgroup analysis on adequate versus inadequate BCG treatment was performed. RESULTS AND LIMITATIONS: A total of 2602 NMIBC patients treated with intravesical BCG were identified. Among them, 1291 (49.6%) received Connaught strain 81 mg, 199 (7.6%) received Connaught strain 27 mg, 1014 (39.0%) received Tokyo strain, and 98 (3.8%) received Danish strain. The median follow-up was 11.0 years. No statistically significant differences in OS, CSS, RFS, and PFS were detected among the different groups. At the multivariable analysis, the Connaught strain 27 mg group was inferior to the Connaught strain 81 mg group in terms of OS (HR: 1.26, 95% CI: 1.05-1.51), CSS (HR: 1.69, 95% CI: 1.08-2.66), and PFS (HR: 1.86, 95% CI: 1.20-2.88). Adequate BCG treatment was associated with improved OS (HR: 0.82, 95% CI: 0.73-0.92), CSS (HR: 0.64, 95% CI: 0.47-0.86), RFS (HR: 0.80, 95% CI: 0.70-0.92), and PFS (HR: 0.52, 95% CI: 0.39-0.68). Among patients treated with adequate BCG, at the multivariable analysis the Connaught strain 27 mg group showed worse results than the Connaught strain 81 mg group in terms of CSS (HR: 1.93, 95% CI: 1.07-3.51). Compared with the Connaught strain 81 mg group, both Tokyo and Danish strains had similar survival outcomes in the whole cohort and the adequate BCG treatment subgroup. CONCLUSIONS: Our findings suggest that adequate BCG remains the most important factor in optimizing survival outcomes in patients with intermediate- and high-risk NMIBC. No significant differences in survival outcomes were observed between full-dose Connaught, Tokyo, and Danish strains. Reduced-dose Connaught strain was associated with the worst survival outcomes. PATIENT SUMMARY: We evaluated the efficacy of different strains and dosages of bacillus Calmette-Guérin (BCG) in patients with intermediate- or high-risk non-muscle-invasive bladder cancer in the past two decades in Hong Kong. We conclude no significant differences in long-term survival outcomes in terms of full-dose Connaught, Tokyo, and Danish strains, while reduced-dose Connaught strain was inferior to the full-dose group. Adequate BCG treatment benefits long-term survival.

• Klíčová slova
• Bacillus Calmette-Guérin, Cancer-specific survival, Non–muscle-invasive bladder cancer, Overall survival, Progression-free survival, Recurrence-free survival,
• MeSH
• adjuvancia imunologická terapeutické užití   aplikace a dávkování   MeSH
• aplikace intravezikální MeSH
• BCG vakcína * terapeutické užití   aplikace a dávkování   MeSH
• invazivní růst nádoru MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádory močového měchýře neinvadující svalovinu * mortalita   terapie   MeSH
• nádory močového měchýře * mortalita   terapie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Hongkong epidemiologie   MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• BCG vakcína * MeSH

Adjuvant immune checkpoint inhibitor therapies have radically altered the treatment landscape for renal cell carcinoma and urothelial carcinoma. However, studies have reported negative data regarding adjuvant immune checkpoint inhibitor therapies. Thus, this study aimed to assess the role of adjuvant immune checkpoint inhibitor therapy for both renal cell carcinoma and urothelial carcinoma. A systematic review and network meta-analysis were conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Multiple databases were searched for articles published as of February 2023. Studies were deemed eligible if they evaluated disease-free survival in patients with renal cell carcinoma and urothelial carcinoma receiving adjuvant immune checkpoint inhibitor therapy. Five studies met the inclusion criteria. In a network meta-analysis, pembrolizumab was shown to be the most effective regimen for patients with renal cell carcinoma, whereas nivolumab was found to be the most effective regimen for patients with urothelial carcinoma. Additionally, these results were consistently observed in a sub-analysis of the T stage. The present analysis provides findings that support the usefulness of adjuvant nivolumab therapy in urothelial carcinoma and adjuvant pembrolizumab therapy in renal cell carcinoma, in agreement with the currently available guidelines. However, the caveat is that the randomized controlled trials included in this analysis differed in important respects despite being similar in study design. Therefore, with these differences in mind, care needs to be taken when selecting patients for these immune checkpoint inhibitor therapies to maximize their benefits.

• Klíčová slova
• adjuvant immunotherapy, renal cell carcinoma, urothelial carcinoma,
• MeSH
• adjuvancia imunologická terapeutické užití   MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• karcinom z přechodných buněk * farmakoterapie   MeSH
• karcinom z renálních buněk * farmakoterapie   MeSH
• lidé MeSH
• nádory ledvin * farmakoterapie   MeSH
• nádory močového měchýře * MeSH
• nivolumab terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• síťová metaanalýza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• inhibitory kontrolních bodů MeSH
• nivolumab MeSH

OBJECTIVES: To address the association of perioperative surgical checklist across variable surgical expertise with transurethral resection of bladder tumour (TURBT) accuracy and oncological outcomes in non-muscle-invasive bladder cancer. PATIENTS AND METHODS: We relied on our prospective collaborative database of patients treated with TURBT between 2012 and 2017. Surgical experience was stratified into three groups: resident vs young vs expert consultants. The association of surgical experience with detrusor muscle (DM) presence and adherence to the standardised peri-procedural nine-items TURBT checklist was evaluated with logistic regression models. A Cox regression model was used to investigate the association of surgical experience with recurrence-free survival (RFS). RESULTS: A total of 503 patients were available for analysis. TURBT was performed by expert consultants in 265 (52.7%) patients, by young consultants in 149 (29.6%) and by residents in 89 (17.7%). Residents were more likely to have DM in the TURBT specimen than expert consultants (odds ratio [OR] 1.75, 95% confidence interval [CI] 1.03-2.99, P = 0.04). Conversely, no differences in DM presence were seen between young vs expert consultants (OR 1.09, 95% CI 0.71-1.70, P = 0.69). The median checklist completion rate was higher for both residents and young consultants when compared to experts' counterparts (56% and 56% vs 44%, P = 0.009). When focusing on patients receiving a second-look TURBT, the persistent disease was associated with resident status (OR 4.24, 95% CI 1.14-17.70, P = 0.037) at initial TURBT. Surgical experience was not associated with 5-years RFS. CONCLUSION: Surgeon's experience in the case of adequate perioperative surgical checklist implementation was inversely associated with the presence of DM in the specimen but directly linked to higher probability of persistent disease at re-TURBT, although no 5-year RFS differences were noted.

• Klíčová slova
• #BladderCancer, #blcsm, #uroonc, bladder cancer, non-muscle-invasive bladder cancer, resident, surgical experience, transurethral resection of bladder tumour,
• MeSH
• cystektomie MeSH
• kontrolní seznam MeSH
• lidé MeSH
• nádory močového měchýře * chirurgie   patologie   MeSH
• prospektivní studie MeSH
• transuretrální resekce močového měchýře MeSH
• ukazatele kvality zdravotní péče MeSH
• urologie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH