Perioperative platform for muscle-invasive bladder cancer trials: designs and endpoints.

PURPOSE OF REVIEW: This review explores the design and endpoints of perioperative platforms in clinical trials for muscle-invasive bladder cancer (MIBC). RECENT FINDINGS: The choice of clinical trial design in perioperative platforms for MIBC must align with specific research objectives to ensure robust and meaningful outcomes. Novel designs in perioperative platforms for MIBC integrate bladder-sparing approaches. Primary endpoints such as pathological complete response and disease-free survival are highlighted for their role in expediting trial results in perioperative setting. Incorporating patient-reported outcomes is important to inform healthcare decision makers about the outcomes most meaningful to patients. Given the growing body of evidence, potential biomarkers, predictive and prognostic tools should be considered and implemented when designing trials in perioperative platforms for MIBC. SUMMARY: Effective perioperative platforms for MIBC trials are critical in enhancing patient outcomes. The careful selection and standardization of study designs and endpoints in the perioperative platform are essential for the successful implementation of new therapies and the advancement of personalized treatment approaches in MIBC.

Cardiovascular events among men with prostate cancer treated with androgen receptor signaling inhibitors: a systematic review, meta-analysis, and network meta-analysis.

BACKGROUND: Androgen-receptor pathway inhibitors (ARPIs) have dramatically changed the management of advanced/metastatic prostate cancer (PCa). However, their cardiovascular toxicity remains to be clarified. OBJECTIVE: To analyze and compare the risks of cardiovascular events secondary to treatment of PCa patients with different ARPIs. METHODS: In August 2023, we queried PubMed, Scopus, and Web of Science databases to identify randomized controlled studies (RCTs) that analyze PCa patients treated with abiraterone, apalutamide, darolutamide, and enzalutamide. The primary outcomes of interest were the incidence of cardiac disorder, heart failure, ischemic heart disease (IHD), atrial fibrillation (AF), and hypertension. Network meta-analyses (NMAs) were conducted to compare the differential outcomes of each ARPI plus androgen deprivation therapy (ADT) compared to standard of care (SOC). RESULTS: Overall, 26 RCTs were included. ARPIs were associated with an increased risk of cardiac disorders (RR: 1.74, 95% CI: 1.13-2.68, p = 0.01), heart failure (RR: 2.49, 95% CI: 1.05-5.91, p = 0.04), AF (RR: 2.15, 95% CI: 1.14-4.07, p = 0.02), and hypertension (RR: 2.06, 95% CI: 1.67-2.54, p < 0.01) at grade ≥3. Based on NMAs, abiraterone increased the risk of grade ≥3 cardiac disorder (RR:2.40, 95% CI: 1.42-4.06) and hypertension (RR:2.19, 95% CI: 1.77-2.70). Enzalutamide was associated with the increase of grade ≥3 AF(RR: 3.17, 95% CI: 1.05-9.58) and hypertension (RR:2.30, 95% CI: 1.82-2.92). CONCLUSIONS: The addition of ARPIs to ADT increases the risk of cardiac disorders, including IHD and AF, as well as hypertension. Each ARPI exhibits a distinct cardiovascular event profile. Selecting patients carefully and vigilant monitoring for cardiovascular issues is imperative for those undergoing ARPI + ADT treatment.

Salvage therapies for biochemical recurrence after definitive local treatment: a systematic review, meta-analysis, and network meta-analysis.

PURPOSE: Recent advancements in the management of biochemical recurrence (BCR) following local treatment for prostate cancer (PCa), including the use of androgen receptor signaling inhibitors (ARSIs), have broadened the spectrum of therapeutic options. We aimed to compare salvage therapies in patients with BCR after definitive local treatment for clinically non-metastatic PCa with curative intent. METHODS: In October 2023, we queried PubMed, Scopus, and Web of Science databases to identify randomized controlled trials (RCTs) and prospective studies reporting data on the efficacy of salvage therapies in PCa patients with BCR after radical prostatectomy (RP) or radiation therapy (RT). The primary endpoint was metastatic-free survival (MFS), and secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: We included 19 studies (n = 9117); six trials analyzed RT-based strategies following RP, ten trials analyzed hormone-based strategies following RP ± RT or RT alone, and three trials analyzed other agents. In a pairwise meta-analysis, adding hormone therapy to salvage RT significantly improved MFS (HR: 0.69, 95% CI: 0.57-0.84, p < 0.001) compared to RT alone. Based on treatment ranking analysis, among RT-based strategies, the addition of elective nodal RT and androgen deprivation therapy (ADT) was found to be the most effective in terms of MFS. On the other hand, among hormone-based strategies, enzalutamide + ADT showed the greatest benefit for both MFS and OS. CONCLUSIONS: The combination of prostate bed RT, elective pelvic irradiation, and ADT is the preferred treatment for eligible patients with post-RP BCR based on our analysis. In remaining patients, or in case of post-RT recurrence, especially for those with high-risk BCR, the combination of ADT and ARSI should be considered.

Bladder sparing options for muscle-invasive bladder cancer.

PURPOSE OF REVIEW: This review critically evaluates the current state of bladder-sparing options in muscle-invasive bladder cancer (MIBC) and provides an overview of future directions in the field. RECENT FINDINGS: Bladder-sparing treatments have emerged as viable alternatives to radical cystectomy (RC) for selected patients with MIBC, especially in those who are unfit for RC or elect bladder preservation. Numerous studies have assessed the efficacy of trimodal therapy (TMT), with outcomes comparable to RC in a subgroup of well selected patients. Combining immunotherapy with conventional treatments in bladder-sparing approaches can yield promising outcomes. Current research is making significant progress in optimizing treatment protocols by exploring new combinations of systemic therapy agents, innovative drug delivery methods, and biomarker-based approaches. Furthermore, clinical markers of response are being tested to ensure adequate response assessment. SUMMARY: Bladder preservation promise to offer a viable alternative to RC for selected patients with MIBC with the potential to improve patient quality of life. Careful patient selection and ongoing research are essential to optimize patient selection, response assessment, and salvage strategies. As evidence continues to evolve, the role of bladder preservation in MIBC is likely to expand, providing patients with more treatment options tailored to their needs and preferences.

Differential effect of surgical technique on intravesical recurrence after radical nephroureterectomy in patients with upper tract urothelial cancer: a systematic review and Meta-analysis.

CONTEXT: Radical nephroureterectomy (RNU) with bladder cuff resection is the standard treatment in patients with high-risk upper tract urothelial cancer (UTUC). However, it is unclear which specific surgical technique may lead to improve oncological outcomes in term of intravesical recurrence (IVR) in patients with UTUC. OBJECTIVE: To evaluate the efficacy of surgical techniques and approaches of RNU in reducing IVR in UTUC patients. EVIDENCE ACQUISITION: Three databases were queried in January 2024 for studies analyzing UTUC patients who underwent RNU. The primary outcome of interest was the rate of IVR among various types of surgical techniques and approaches of RNU. EVIDENCE SYNTHESIS: Thirty-one studies, comprising 1 randomized controlled trial and 1 prospective study, were included for a systematic review and meta-analysis. The rate of IVR was significantly lower in RNU patients who had an early ligation (EL) of the ureter compared to those who did not (HR: 0.64, 95% CI: 0.44-0.94, p = 0.02). Laparoscopic RNU significantly increased the IVR compared to open RNU (HR: 1.28, 95% CI: 1.06-1.54, p < 0.001). Intravesical bladder cuff removal significantly reduced the IVR compared to both extravesical and transurethral bladder cuff removal (HR: 0.65, 95% CI: 0.51-0.83, p = 0.02 and HR: 1.64, 95% CI: 1.15-2.34, p = 0.006, respectively). CONCLUSIONS: EL of the affected upper tract system, ureteral management, open RNU, and intravesical bladder cuff removal seem to yield the lowest IVR rate in patients with UTUC. Well-designed prospective studies are needed to conclusively elucidate the optimal surgical technique in the setting of single post-operative intravesical chemotherapy.

Prospective non-randomized comparison of transurethral laser en bloc resection vs. conventional resection of bladder tumors larger than 3 cm.

BACKGROUND: En bloc resection of bladder tumor (ERBT) is an established surgical treatment method for patients with non-muscle invasive bladder cancer (NMIBC) in tumors less than 3 cm. Data regarding the efficacy and safety of ERBT on larger than 3 cm tumors are sparse and its efficacy compared to conventional transurethral resection (TURBT) remains unclear. The aim of this study was to prospectively compare the feasibility, safety and oncological outcomes of laser (Tm-fiber) ERBT and TURBT in patients with primary bladder lesions ≥3 cm. METHODS: A cohort of 45 patients who underwent surgery for primary NMIBC between February 2018 and March 2022 was collected prospectively. There was no randomization. All procedures were performed by two experienced surgeons. Inclusion criteria were as follows: age >18 years, primary Ta or T1 bladder tumor with a diameter of ≥3 cm, no more than 3 tumors and no history of upper tract urothelial carcinoma. Exclusion criteria were carcinoma in situ or invasion into muscle layer (≥T2). ERBT was performed with thulium fiber laser (IPG, Russia). Primary endpoints included efficacy with recurrence-free survival (RFS) at 3, 6 and 12 months. Secondary endpoints were safety parameters, perioperative data and specimen quality (the presence of muscle layer in specimens). RESULTS: Twenty-eight patients underwent laser ERBT and 17 conventional TURBT. The location and size of the tumors were comparable in both groups. The success rate was 93.3% in the ERBT group with two cases of conversion from ERBT to TURBT. Detrusor muscle was present in 92.8% patients in the ERBT group versus 70.5% in the TURBT group (P=0.04). Obturator nerve reflex was observed only in the TURBT group: 17.6% vs. 0.0% (P=0.02). The frequency of other complications was comparable between the two groups. RFS was not statistically different between the two methods at 3 (93.9% vs. 94.1%, P=0.87), 6 (89.3% vs. 82.3%, P=0.5) and 12 months (89.3% vs. 70.6%, P=0.11). CONCLUSIONS: Laser ERBT is a feasible and safe procedure to manage bladder tumors larger than 3 cm. While it seems safer than TURBT, its effect on efficacy remains to be assessed in larger trials.

Clinical Validation of the Intermediate-risk Non-muscle-invasive Bladder Cancer Scoring System and Substratification Model Proposed by the International Bladder Cancer Group: A Multicenter Young Academic Urologists Urothelial Working Group Collaboration.

BACKGROUND AND OBJECTIVE: Intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) encompasses a broad spectrum of disease, with heterogeneous outcomes in terms of disease recurrence and progression. The International Bladder Cancer Group (IBCG) recently proposed an updated scoring model for IR substratification that is based on five key risk factors. Our aim was to provide a clinical validation of the IBCG scoring system and substratification model for IR NMIBC. METHODS: This was an international multicenter retrospective study. Patients diagnosed with IR NMIBC between 2012 and 2022 and treated with transurethral resection of the bladder and adjuvant intravesical chemotherapy were included. According to the presence or absence of risk factors, patients with IR NMIBC were further categorized in IR-low (no risk factors), IR-intermediate (1-2 risk factors), and IR-high (≥3 risk factors) groups. The 1-yr and 3-yr rates for recurrence-free survival (RFS) and progression-free survival (PFS) were evaluated for each subgroup. Cox regression analyses were used to compare oncological outcomes between the groups. KEY FINDINGS AND LIMITATIONS: Of the 677 patients with IR NMIBC included in the study, 231 (34%), 364 (54%), and 82 (12%) were categorized in the IR-low, IR-intermediate, and IR-high groups, respectively. There were significant differences in RFS and PFS rates between these groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: We provide the first clinical validation of the IBCG scoring system and model for substratification of IR NMIBC. PATIENT SUMMARY: Our study demonstrates that patients with intermediate-risk non-muscle-invasive bladder cancer can be correctly classified into three distinct subgroups according to their risk of both disease recurrence and progression. Our results support use of this scoring system in clinical practice.

The Role of Mitomycin C in Intermediate-risk Non-muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVE: Intravesical mitomycin C (MMC) instillations are recommended to prevent recurrence of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC); however, the optimal regimen and dose are uncertain. Our aim was to assess the effectiveness of adjuvant MMC and compare different MMC regimens in preventing recurrence. METHODS: We performed a comprehensive search in PubMed, Scopus, and Web of Science in November 2023 for studies investigating recurrence-free survival (RFS) among patients with IR-NMIBC who received adjuvant MMC. Prospective trials with different MMC regimens or other intravesical drugs as comparators were considered eligible. KEY FINDINGS AND LIMITATIONS: Overall, 14 studies were eligible for systematic review and 11 for meta-analysis of RFS. Estimates of 1-yr, 2-yr, and 5-yr RFS rates were 84% (95% confidence interval [CI] 79-89%), 75% (95% CI 68-82%), and 51% (95% CI 40-63%) for patients treated with MMC induction plus maintenance, and 88% (95% CI 83-94%), 78% (95% CI 67-89%), and 66% (95% CI 57-75%) for patients treated with bacillus Calmette-Guérin (BCG) maintenance, respectively. Estimates of 2-yr RFS rates for MMC maintenance regimens were 76% (95% CI 69-84%) for 40 mg MMC (2 studies) and 66% (95% CI 60-72%) for 30 mg MMC (4 studies). Among the studies included, BCG maintenance provided comparable 2-yr RFS to 40 mg MMC with maintenance (78% vs 76%). RFS did not differ by MMC maintenance duration (>1 yr vs 1 yr vs <1 yr). CONCLUSIONS AND CLINICAL IMPLICATIONS: MMC induction and maintenance regimens seem to provide short-term RFS rates equivalent to those for BCG maintenance in IR-NMIBC. For adjuvant induction and maintenance, 40 mg of MMC appears to be more effective in preventing recurrence than 30 mg. We did not observe an RFS benefit for longer maintenance regimens. PATIENT SUMMARY: For patients with intermediate-risk non-muscle-invasive bladder cancer, bladder treatments with a solution of a drug called mitomycin C (MMC) seem to be as effective as BCG (bacillus Calmette-Guérin) in preventing recurrence after tumor removal. Further trials are needed for stronger evidence on the best MMC dose and treatment time.

Application of the ERAS guidelines in pediatric urological surgery: a systematic review.

INTRODUCTION: Consensus for Enhanced Recovery After Surgery (ERAS) in pediatrics has been achieved in neonatal intestinal surgery, yet it is not widely utilized in pediatric urology. We investigated the application of ERAS guidelines in pediatric urology, and determined its effects given the available level of evidence supporting the ERAS protocol in children. EVIDENCE ACQUISITION: A systematic literature review including series providing adoption of fast-track recovery protocols for pediatric urology procedures was carried out. Main outcome measures were study characteristics, adherence to the 19 ERAS items, complication rates and length of hospital stay. Sub-group analysis by surgery type (hypospadias versus major surgery) was performed. EVIDENCE SYNTHESIS: Nine series with data from 1272 surgical pediatric cases were included. An enhanced recovery pathway was applied in 67.3% of the reports. Two series included patients undergoing hypospadias repair and ERAS items were insufficiently reported. Studies including children undergoing major procedures mentioned a median of 15 ERAS items, yet applied a median of 11 items. Median compliance rate was 88.9% (range 50-100). More ERAS guideline items were reported (applied or mentioned) in the most recently published studies. CONCLUSIONS: There is limited reporting and use of the ERAS guidelines in urologic surgery particularly in hypospadias repair; whilst in major surgery in children, adherence and compliance rates vary widely. In more recent series there was an increase in ERAS items that have been mentioned and applied. Future research is needed to identify barriers and to overcome them in order to fully adopt and benefit from the ERAS pathway.

Preoperative Plasma Insulin-Like Growth Factor-I and Its Binding Proteins-Based Risk Stratification of Patients Treated With Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma.

INTRODUCTION: We evaluate the predictive and prognostic value of insulin-like growth factor-I (IGF-1), IGF binding protein-2 (IGFBP-2) and -3 (IGFBP-3) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). METHODS: This is a retrospective analysis of a multi-institutional database comprising 753 patients who underwent RNU for UTUC and had a preoperative plasma available. Logistic and Cox regression analyses were performed. The discriminative ability and clinical utility of the models was calculated using the lasso regression test, area under receiver operating characteristics curves, C-index, and decision curve analysis (DCA). RESULTS: Lower preoperative plasma levels of IGFBP-2 and -3 independently correlated with increased risks of lymph node metastasis, pT3/4 disease, nonorgan confined disease, and worse recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) (all P ≤ .004). The addition of both IGFBP-2 and -3 to a postoperative multivariable model, that included standard clinicopathologic characteristics, improved the model's concordance index by 10%, 9%, and 8% for RFS, CSS, and OS, respectively. On DCA, addition of both IGFBP-2 and -3 to base models improved their performance for RFS, CSS, and OS by a statistically and clinically significant margin. Plasma IGF-1 was not associated with any of outcomes. CONCLUSIONS: We confirmed that a lower plasma levels of IGFBP-2 and -3 both are independent and clinically significant predictors of adverse pathological features and survival outcomes in UTUC patients treated with RNU. These findings might help guide the clinical decision-making regarding perioperative systemic therapy and follow-up scheduling.

Clofarabine Has a Superior Therapeutic Window as compared to Gemcitabine in Preclinical Bladder Cancer Models.

Current standard-of-care systemic therapy options for locally advanced and metastatic bladder cancer (BC), which are predominantly based on cisplatin-gemcitabine combinations, are limited by significant treatment failure rates and frailty-based patient ineligibility. We previously addressed the urgent clinical need for better-tolerated BC therapeutic strategies using a drug screening approach, which identified outstanding antineoplastic activity of clofarabine in preclinical models of BC. To further assess clofarabine as a potential BC therapy component, we conducted head-to-head comparisons of responses to clofarabine versus gemcitabine in preclinical in vitro and in vivo models of BC, complemented by in silico analyses. In vitro data suggest a distinct correlation between the two antimetabolites, with higher cytotoxicity of gemcitabine, especially against several nonmalignant cell types, including keratinocytes and endothelial cells. Accordingly, tolerance of clofarabine (oral or intraperitoneal application) was distinctly better than for gemcitabine (intraperitoneal) in patient-derived xenograft models of BC. Clofarabine also exhibited distinctly superior anticancer efficacy, even at dosing regimens optimized for gemcitabine. Neither complete remission nor cure, both of which were observed with clofarabine, were achieved with any tolerable gemcitabine regimen. Taken together, our findings demonstrate that clofarabine has a better therapeutic window than gemcitabine, further emphasizing its potential as a candidate for drug repurposing in BC. PATIENT SUMMARY: We compared the anticancer activity of clofarabine, a drug used for treatment of leukemia but not bladder cancer, and gemcitabine, a drug currently used for chemotherapy against bladder cancer. Using cell cultures and mouse models, we found that clofarabine was better tolerated and more efficacious than gemcitabine, and even cured implanted tumors in mouse models. Our results suggest that clofarabine, alone or in combination schemes, might be superior to gemcitabine for the treatment of bladder cancer.

Adjuvant intravesical therapy in intermediate-risk non-muscle-invasive bladder cancer.

OBJECTIVE: To evaluate the impact of adjuvant therapy on oncological outcomes in patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC), as due to the poorly-defined and overlapping diagnostic criteria optimal decision-making remains challenging in these patients. PATIENTS AND METHODS: In this multicentre study, patients treated with transurethral resection of bladder tumour for Ta disease were retrospectively analysed. All patients with low- or high-risk NMIBC were excluded from the analysis. Associations between adjuvant therapy administration with recurrence-free survival (RFS) and progression-free survival (PFS) rates were assessed in Cox regression models. RESULTS: A total of 2206 patients with intermediate-risk NMIBC were included in the analysis. Among them, 1427 patients underwent adjuvant therapy, such as bacille Calmette-Guérin (n = 168), or chemotherapeutic agents, such as mitomycin C or epirubicin (n = 1259), in different regimens up to 1 year. The median (interquartile range) follow-up was 73.3 (38.4-106.9) months. The RFS at 1 and 5 years in patients treated with adjuvant therapy and those without were 72.6% vs 69.5% and 50.8% vs 41.3%, respectively. Adjuvant therapy was associated with better RFS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.70-0.89, P < 0.001), but not with PFS (P = 0.09). In the subgroup of patients aged ≤70 years with primary, single Ta Grade 2 <3 cm tumours (n = 328), adjuvant therapy was not associated with RFS (HR 0.71, 95% CI 0.50-1.02, P = 0.06). While in the subgroup of patients with at least one risk factor including patient age >70 years, tumour multiplicity, recurrent tumour and tumour size ≥3 cm (n = 1878), adjuvant intravesical therapy was associated with improved RFS (HR 0.78, 95% CI 0.68-0.88, P < 0.001). CONCLUSION: In our study, patients with intermediate-risk NMIBC benefit from adjuvant intravesical therapy in terms of RFS. However, in patients without risk factors, adjuvant intravesical therapy did not result in a clear reduction in the recurrence rate.

Infection risk reduction with povidone-iodine rectal disinfection prior to transrectal prostate biopsy: an updated systematic review and meta-analysis.

BACKGROUND: To prevent infectious complications after transrectal ultrasound-guided prostate biopsy (TRUS-PB), some studies have investigated the efficacy of rectal disinfection using povidone-iodine (PI) and antibiotic prophylaxis (AP). OBJECTIVE: To summarize available data and compare the efficacy of rectal disinfection using PI with non-PI methods prior to TRUS-PB. EVIDENCE ACQUISITION: Three databases were queried through November 2023 for randomized controlled trials (RCTs) analyzing patients who underwent TRUS-PB. We compared the effectiveness of rectal disinfection between PI groups and non-PI groups with or without AP. The primary outcomes of interest were the rates of overall infectious complications, fever, and sepsis. Subgroups analyses were conducted to assess the differential outcomes in patients using fluoroquinolone groups compared to those using other antibiotics groups. EVIDENCE SYNTHESIS: We included ten RCTs in the meta-analyses. The overall rates of infectious complications were significantly lower when rectal disinfection with PI was performed (RR 0.56, 95% CI 0.42-0.74, p < 0.001). Compared to AP monotherapy, the combination of AP and PI was associated with significantly lower risk of infectious complications (RR 0.54, 95% CI 0.40-0.73, p < 0.001) and fever (RR 0.47, 95% CI 0.30-0.75, p = 0.001), but not with sepsis (RR 0.49, 95% CI 0.23-1.04, p = 0.06). The use of fluoroquinolone antibiotics was associated with a lower risk of infectious complications and fever compared to non-FQ antibiotics. CONCLUSION: Rectal disinfection with PI significantly reduces the rates of infectious complications and fever in patients undergoing TRUS-PB. However, this approach does not show a significant impact on reducing the rate of sepsis following the procedure.

Impact of Preoperative Plasma Potassium Levels on Oncological Outcomes, Major Complications, and 30-Day Mortality in Bladder Cancer Patients Undergoing Radical Cystectomy.

INTRODUCTION AND OBJECTIVES: We examined the impact of preoperative plasma potassium levels (PPLs) on outcomes in patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB), hypothesizing that potassium imbalances might influence outcomes. PATIENTS AND METHODS: In this retrospective study, 501 UCB patients undergoing RC from 2009 to 2017 at a tertiary center were analyzed. Blood samples collected a week prior to surgery defined normal and abnormal PPL based on institutional standards. We assessed overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), postoperative complications, 30-day mortality, and non-organ confined disease. Kaplan-Meier estimates, Cox proportional hazards, logistic regression, and decision curve analyses (DCA) were employed. RESULTS: 63 (13%) patients had abnormal preoperative PPLs, with 50 (10%) elevated and 13 (2.5%) decreased. In a 59 months median follow-up, 152 (31%) had disease recurrence, 197 (39%) died from any cause, and 119 (24%) from UCB. Multivariable cox regression analyses adjusting for perioperative parameters demonstrated abnormal PPL was associated with worse OS (HR=1.9, P=0.009), CSS (HR=2.8, P<0.001) and RFS (HR=2.1; P=0.007). Elevated preoperative PPLs also demonstrated significant associations with adverse outcomes in OS, CSS, and RFS (all P<0.05). In multivariable logistic regression analyses, abnormal and elevated PPLs were not associated with 30-day mortality, major 30-day postoperative complications, positive nodal disease, pT3/4 stage, and non-organ confined disease (all P>0.05). CONCLUSION: Abnormal and elevated preoperative PPLs correlate with adverse oncologic outcomes in UCB patients treated with RC. Pending external validation, preoperative PPLs might be a cost-effective, easily obtainable supplemental biomarker for enriching accuracy of outcome prediction in this highly variable maladie.

A Systematic Review and Meta-analysis of the Impact of Local Therapies on Local Event Suppression in Metastatic Hormone-sensitive Prostate Cancer.

CONTEXT: It remains unclear to what extent the therapy of the primary local tumor, such as radical prostatectomy (RP) and radiation therapy (RT), improves overall survival in patients with low-volume metastatic hormone-sensitive prostate cancer (mHSPC). However, data suggest a benefit of these therapies in preventing local events secondary to local tumor progression. OBJECTIVE: To evaluate the efficacy of adding local therapy (RP or RT) to systemic therapies, including androgen deprivation therapy, docetaxel, and/or androgen receptor axis-targeted agents, in preventing local events in mHSPC patients compared with systemic therapy alone (ie, without RT of the prostate or RP). EVIDENCE ACQUISITION: Three databases and meeting abstracts were queried in November 2023 for studies analyzing mHSPC patients treated with local therapy. The primary outcome of interest was the prevention of overall local events (urinary tract infection, urinary tract obstruction, and gross hematuria) due to local disease progression. Subgroup analyses were conducted to assess the differential outcomes according to the type of local therapy (RP or RT). EVIDENCE SYNTHESIS: Overall, six studies, comprising two randomized controlled trials, were included for a systematic review and meta-analysis. The overall incidence of local events was significantly lower in the local treatment plus systemic therapy group than in the systemic therapy only groups (relative risk [RR]: 0.50, 95% confidence interval [CI]: 0.28-0.88, p = 0.016). RP significantly reduced the incidence of overall local events (RR: 0.24, 95% CI: 0.11-0.52) and that of local events requiring surgical intervention (RR: 0.08, 95% CI: 0.03-0.25). Although there was no statistically significant difference between the RT plus systemic therapy and systemic therapy only groups in terms of overall local events, the incidence of local events requiring surgical intervention was significantly lower in the RT plus systemic therapy group (RR: 0.70, 95% CI: 0.49-0.99); local events requiring surgical intervention of the upper urinary tract was significantly lower in local treatment groups (RR: 0.60, 95% CI: 0.37-0.98, p = 0.04). However, a subgroup analysis revealed that neither RP nor RT significantly impacted the prevention of local events requiring surgical intervention of the upper urinary tract. CONCLUSIONS: In some patients with mHSPC, RP or RT of primary tumor seems to reduce the incidence of local progression and events requiring surgical intervention. Identifying which patients are most likely to benefit from local therapy, and at what time point (eg, after response of metastases), will be necessary to set up a study assessing the risk, benefits, and alternatives to therapy of the primary tumor in the mHSPC setting. PATIENT SUMMARY: Our study suggests that local therapy of the prostate, such as radical prostatectomy or radiotherapy, in patients with metastatic hormone-sensitive prostate cancer can prevent local events, such as urinary obstruction and gross hematuria.

Impact of disease volume on survival efficacy of triplet therapy for metastatic hormone-sensitive prostate cancer: a systematic review, meta-analysis, and network meta-analysis.

BACKGROUND: Triplet therapy, androgen receptor signaling inhibitors (ARSIs) plus docetaxel plus androgen-deprivation therapy (ADT), is a novel guideline-recommended treatment for metastatic hormone-sensitive prostate cancer (mHSPC). However, the optimal selection of the patient most likely to benefit from triplet therapy remains unclear. METHODS: We performed a systematic review, meta-analysis, and network meta-analysis to assess the oncologic benefit of triplet therapy in mHSPC patients stratified by disease volume and compare them with doublet treatment regimens. Three databases and meeting abstracts were queried in March 2023 for randomized controlled trials (RCTs) evaluating patients treated with systemic therapy for mHSPC stratified by disease volume. Primary interests of measure were overall survival (OS). We followed the PRISMA guideline and AMSTAR2 checklist. RESULTS: Overall, eight RCTs were included for meta-analyses and network meta-analyses (NMAs). Triplet therapy outperformed docetaxel plus ADT in terms of OS in both patients with high-(pooled HR: 0.73, 95%CI 0.64-0.84) and low-volume mHSPC (pooled HR: 0.71, 95%CI 0.52-0.97). There was no statistically significant difference between patients with low- vs. high-volume in terms of OS benefit from adding ARSI to docetaxel plus ADT (p = 0.9). Analysis of treatment rankings showed that darolutamide plus docetaxel plus ADT (90%) had the highest likelihood of improved OS in patients with high-volume disease, while enzalutamide plus ADT (84%) had the highest in with low-volume disease. CONCLUSIONS: Triplet therapy improves OS in mHSPC patients compared to docetaxel-based doublet therapy, irrespective of disease volume. However, based on treatment ranking, triplet therapy should preferably be considered for patients with high-volume mHSPC while those with low-volume are likely to be adequately treated with ARSI + ADT.

First-line immunotherapy of metastatic renal cell carcinoma: an updated network meta-analysis including triplet therapy.

OBJECTIVE: To compare the differential efficacy of first-line immune checkpoint inhibitor (ICI)-based combined therapies among patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), as recently, the efficacy of triplet therapy comprising nivolumab plus ipilimumab plus cabozantinib has been published. PATIENTS AND METHODS: Three databases were searched in December 2022 for randomised controlled trials (RCTs) analysing oncological outcomes in patients with mRCC treated with first-line ICI-based combined therapies. We performed network meta-analysis (NMA) to compare the outcomes, including progression-free survival (PFS) and objective response rates (ORRs), in patients with intermediate- and poor-risk mRCC; we also assessed treatment-related adverse events. RESULTS: Overall, seven RCTs were included in the meta-analyses and NMAs. Treatment ranking analysis revealed that pembrolizumab + lenvatinib (99%) had the highest likelihood of improved PFS, followed by nivolumab + cabozantinib (79%), and nivolumab + ipilimumab + cabozantinib (77%). Notably, compared to nivolumab + cabozantinib, adding ipilimumab to nivolumab + cabozantinib did not improve PFS (hazard ratio 1.02, 95% confidence interval 0.72-1.43). Regarding ORRs, treatment ranking analysis also revealed that pembrolizumab + lenvatinib had the highest likelihood of providing better ORRs (99.7%). The likelihoods of improved PFS and ORRs of pembrolizumab + lenvatinib were true in both International Metastatic RCC Database Consortium (IMDC) risk groups. CONCLUSIONS: Our analyses confirmed the robust efficacy of pembrolizumab + lenvatinib as first-line treatment for patients with intermediate or poor IMDC risk mRCC. Triplet therapy did not result in superior efficacy. Considering both toxicity and the lack of mature overall survival data, triplet therapy should only be considered in selected patients.

Definitions, outcomes and perspectives for oligometastatic bladder cancer: towards a standardized terminology.

PURPOSE OF REVIEW: Oligometastatic (om) cancer is considered as a transitional state in between locally confined disease and widespread metastases, accessible to a multimodal treatment, combining systemic and local therapy. In urothelial bladder cancer (BCa), the definitions and the approaches to this condition are poorly standardised and mainly based on retrospective data. We aim to portray the framework for uro-oncologic terminology in omBCa and go through the latest evidence and the future perspectives. RECENT FINDINGS: Retrospective and registry data support the potential benefits of multimodality treatment for carefully selected omBCa patients, especially following a good response to systemic treatment. In 2023, a Delphi consensus has defined omBCa, allowing maximum three metastatic lesions, theoretically amenable to radical local treatment. In de-novo omBCa, surgical treatment of primary tumour might improve overall survival (OS), according to a matched registry analysis; also, consolidative radiotherapy was associated with better OS in two recent cohorts. Furthermore, metastasis-directed therapy (MDT) has shown high local control rates and promising OS (14.9-51 months) in a meta-analysis; benefits might be more pronounced for single-site omBCa and nodal or lung lesions. SUMMARY: From a clinical perspective, in de-novo omBCa, the local treatment of primary and metastatic sites might improve disease control and survival, in selected patients; in the oligorecurrent setting, MDT achieves good local symptom control with limited side effects; in selected cases, it could convey a survival benefit, too. From a research perspective, well designed prospective evidence is eagerly awaited, based on recently adopted shared definitions for omBCa.

Addition of neoadjuvant chemotherapy to a 'quadrifecta' composite in radical cystectomy.

OBJECTIVES: To evaluate the impact of incorporating neoadjuvant chemotherapy (NAC) into the 'quadrifecta' outcomes composite for reporting outcomes of radical cystectomy (RC) creating a pentafecta score. PATIENTS AND METHODS: This is a retrospective multicentre analysis of patients treated with RC, with or without NAC, for bladder cancer between 2002 and 2023. The primary outcome was the effect of adding NAC to a quadrifecta outcomes composite on cancer-specific (CSS) and overall survival (OS). The quadrifecta outcomes composite included a yield of ≥16 lymph nodes, negative soft tissue surgical margin, absence of major complication within 30 days from surgery, and no delay in RC. RESULTS: A total of 590 patients were included in the analyses. A total of 233 (39.5%) patients achieved all quadrifecta outcomes and 82 (13.9%) patients were additionally treated with NAC, achieving the pentafecta. Achieving the quadrifecta outcomes composite was significantly associated with better CSS (hazard ratio [HR] 0.49, 95% confidence interval [CI] 0.32-0.75; P = 0.001) and OS (HR 0.48, 95% CI 0.34-0.69; P < 0.01). The addition of NAC to the quadrifecta composite outcomes significantly improved the discrimination of patients more likely to have better CSS (HR 0.21, 95% CI 0.08-0.57; P = 0.002) and OS (HR 0.26, 95% CI 0.12-0.55; P < 0.01). CONCLUSION: We propose a new pentafecta that may serve as a tool for standardising outcomes reporting and measuring the quality of RC.