Benefit of Neoadjuvant Cisplatin-based Chemotherapy for Invasive Bladder Cancer Patients Treated with Radiation-based Therapy in a Real-world Setting: An Inverse Probability Treatment Weighted Analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) improves survival for patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. Studies on the potential benefit of NAC before radiation-based therapy (RT) are conflicting. OBJECTIVE: To evaluate the effect of NAC on patients with MIBC treated with curative-intent RT in a real-world setting. DESIGN, SETTING, AND PARTICIPANTS: The study cohort consisted of 785 patients with MIBC (cT2-4aN0-2M0) who underwent RT at academic centers across Canada. Patients were classified into two treatment groups based on the administration of NAC before RT (NAC vs no NAC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The inverse probability of treatment weighting (IPTW) with absolute standardized differences (ASDs) was used to balance covariates across treatment groups. The impact of NAC on complete response, overall, and cancer-specific survival (CSS) after RT in the weighted cohort was analyzed. RESULTS AND LIMITATIONS: After applying the exclusion criteria, 586 patients were included; 102 (17%) received NAC before RT. Patients in the NAC subgroup were younger (mean age 65 vs 77 yr; ASD 1.20); more likely to have Eastern Cooperative Oncology Group performance status 0-1 (87% vs 78%; ASD 0.28), lymphovascular invasion (32% vs 20%; ASD 0.27), higher cT stage (cT3-4 in 29% vs 20%; ASD 0.21), and higher cN stage (cN1-2 in 32% vs 4%; ASD 0.81); and more commonly treated with concurrent chemotherapy (79% vs 67%; ASD 0.28). After IPTW, NAC versus no NAC cohorts were well balanced (ASD <0.20) for all included covariates. NAC was significantly associated with improved CSS (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.14-0.56; p < 0.001) and overall survival (HR 0.56; 95% CI 0.38-0.84; p = 0.005). This study was limited by potential occult imbalances across treatment groups. CONCLUSIONS: If tolerated, NAC might be associated with improved survival and should be considered for eligible patients with MIBC planning to undergo bladder preservation with RT. Prospective trials are warranted. PATIENT SUMMARY: In this study, we showed that neoadjuvant chemotherapy might be associated with improved survival in patients with muscle-invasive bladder cancer who elect for curative-intent radiation-based therapy.

Carcinoma In Situ (CIS): Is There a Difference in Efficacy between Various BCG Strains? A Comprehensive Review of the Literature.

Introduction: Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is the standard of care for high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC) as well as for Carcinoma in situ (CIS). Evidence supports that the different BCG strains, despite genetic variability, are equally effective clinically for preventing the recurrence and progression of papillary NMIBC. The available evidence regarding possible differences in clinical efficacy between various BCG strains in CIS is lacking. Methods: We reviewed the literature on the efficacy of different BCG strains in patients with CIS (whether primary, secondary, concomitant, or unifocal/multifocal), including randomized clinical trials (RCTs), phase II/prospective trials, and retrospective studies with complete response rates (CRR), recurrence-free survival (RFS), or progression-free survival (PFS) as endpoints. Results: In most studies, being RCTs, phase II prospective trials, or retrospective studies, genetic differences between BCG strains did not translate into meaningful differences in clinical efficacy against CIS, regardless of the CIS subset (primary, secondary, or concurrent) or CIS focality (unifocal or multifocal). CRR, RFS, and PFS were not statistically different between various BCG strains. None of these trials were designed as head-to-head comparisons between BCG strains focusing specifically on CIS. Limitations include the small sample size of many studies and most comparisons between strains being indirect rather than head-to-head. Conclusions: This review suggests that the clinical efficacy of the various BCG strains appears similar, irrespective of CIS characteristics. However, based on the weak level of evidence available and underpowered studies, randomized studies in this space should be encouraged as no definitive conclusion can be drawn at this stage.

Integrating novel immunotherapeutic approaches in organ-preserving therapies for bladder cancer.

Bladder cancer (BC) is a prevalent malignancy with significant morbidity and mortality. Over the years, the landscape of bladder cancer treatment has witnessed notable advancements, particularly in the realm of immunotherapy. Immunotherapy has emerged as a promising adjunct to organ-preserving approaches, harnessing the immune system's potential to target and eliminate cancer cells. Organ preservation strategies offer viable alternatives to radical cystectomy to avoid the morbidities associated with radical surgery, as well as to respond to the needs of patients unfit for or who have refused surgery. However, the challenge lies in achieving durable disease control while minimizing treatment-related toxicities. This review highlights the significance of immune checkpoint inhibitors, such as anti-programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) antibodies, in the treatment of localized bladder cancer. The clinical efficacy of immune checkpoint inhibitors, as both neoadjuvant and adjuvant therapies in combination with radiation or chemotherapy, is discussed. Moreover, the potential of immunotherapies beyond immune checkpoint inhibition, including combinations with bacillus Calmette-Guérin (BCG) instillations and/or investigational gene therapies, is explored. Furthermore, the predictive value of the tumour immune microenvironment for the success of these strategies is examined. Understanding the complex interplay between tumour immunity and therapeutic interventions can aid in identifying predictive biomarkers and tailoring personalized treatment strategies. Further research and clinical trials are warranted to optimize the use of immunotherapy in conjunction with organ-preserving therapies, potentially leading to enhanced patient outcomes and quality of life.

Feasibility and Impact of Immunohistochemistry-based Molecular Subtyping for Muscle-invasive Bladder Cancer in Patients Treated with Radiation-based Therapy.

Background: Distinct molecular subtypes of muscle-invasive bladder cancer (MIBC) have been identified via gene expression profiling. Objective: We investigated the feasibility of a simple immunohistochemistry (IHC)-based Lund subtyping method and the association of MIBC subtypes with oncological outcomes for patients after bladder-preserving radiation-based therapy. Design setting and participants: Transurethral resected tumor tissues from 104 patients treated with radiation-based therapy were sampled on tissue microarray blocks. Outcome measurements and statistical analysis: The expression of KRT5, GATA3, and p16 proteins was scored via digital image analysis. Hierarchical clustering was used to classify tumors as the basal subtype or one of two luminal subtypes: genomically unstable (GU) or urothelial-like (URO). Subtypes were evaluated for association with complete response (CR), recurrence-free survival (RFS), and overall survival (OS). Results and limitations: The median OS was 43 mo (95% confidence interval 19-77) and median follow-up was 55 mo (interquartile range 39-75). Age and clinical stage had a significant impact on OS (p < 0.05). IHC-based subtype classification was feasible in most patients (89%). The subtype was basal in 23.6%, GU in 14.0%, URO in 31.2%, and unclassified in 31.2% of patients. No significant differences in CR, RFS, or OS were observed between the molecular subtypes. Limitations include the retrospective design and relatively small sample size. Conclusions: IHC-based molecular MIBC subtyping using a three-antibody algorithm is feasible in most patients treated with radiation-based therapy. MIBC subtype was not associated with response or survival. Further prospective studies are warranted to confirm the lack of association between molecular subtype and survival in patients treated with trimodal therapy. Patient summary: For patients with invasive bladder cancer treated with radiation-based therapy, we classified tumors into different subtypes using just three molecular stains. This method is cheaper and more widely available than the usual approach. However, we did not find an association between different cancer subtypes and survival.

The effect of cisplatin-based neoadjuvant chemotherapy on the renal function of patients undergoing radical cystectomy.

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). Cisplatin, however, can induce renal toxicity. Furthermore, RC is an independent risk factor for renal injury, with decreases in estimated glomerular filtration rate (eGFR) of up to 6 mL/min/1.73 m2 reported at one year postoperatively. Our objective was to evaluate the effect of cisplatin-based NAC and RC on the renal function of patients undergoing both. METHODS: We analyzed a multicenter database of patients with MIBC, all of whom received cisplatin-based NAC prior to RC. eGFR values were collected at time points T1 (before NAC), T2 (after NAC but before RC), and T3 (one year post-RC). eGFR and proportion of patients with eGFR <60 ml/min/1.73m2 (chronic kidney disease [CKD] stage ≥3) were compared between these time points. As all patients in this dataset had received NAC, we identified a retrospective cohort of patients from one institution who had undergone RC during the same time period without NAC for context. RESULTS: We identified 234 patients with available renal function data. From T1 to T3, there was a mean decline in eGFR of 17% (13 mL/min/1.73 m2) in the NAC cohort and an increase in proportion of patients with stage ≥3 CKD from 27% to 50%. The parallel cohort of patients who did not receive NAC was comprised of 236 patients. The mean baseline eGFR in this cohort was lower than in the NAC cohort (66 vs. 75 mL/min/1.73 m2). The mean eGFR decline in this non-NAC cohort from T1 to T3 was 6% (4 mL/min/1.73 m2), and the proportion of those with stage ≥3 CKD increased from 37% to 51%. CONCLUSIONS: Administration of NAC prior to RC was associated with a 17% decline in eGFR and a nearly doubled incidence of stage ≥3 CKD at one year after RC. Patients who underwent RC without NAC had a higher rate of stage ≥3 CKD at baseline but appeared to have less renal function loss at one year.

Phase 2 Trial of Atezolizumab in Bacillus Calmette-Guérin-unresponsive High-risk Non-muscle-invasive Bladder Cancer: SWOG S1605.

BACKGROUND: Although radical cystectomy (RC) is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC), many patients are ineligible for surgery or elect bladder preservation. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab in BCG-unresponsive high-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm phase 2 trial in patients with BCG-unresponsive high-risk NMIBC who were ineligible for or declined RC. INTERVENTION: Intravenous atezolizumab every 3 wk for 1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the pathological complete response (CR) rate for patients with carcinoma in situ (CIS) determined via mandatory biopsy at 6 mo. Event-free survival (EFS) at 18 mo for patients with non-CIS tumors and treatment-related adverse events (TRAEs) were key secondary endpoints. RESULTS AND LIMITATIONS: Of 172 patients enrolled in the trial, 166 received at least one dose of atezolizumab (safety analysis) and 129 were eligible (efficacy analysis). Of the 74 patients with CIS, 20 (27%) experienced a CR at 6 mo. The median duration of response was 17 mo, and 56% (95% confidence interval [CI] 34-77%) of the responses were durable to at least 12 mo. The 18-mo actuarial EFS rate among 55 patients with Ta/T1 disease was 49% (90% CI 38-60%). Twelve of 129 eligible patients experienced progression to muscle-invasive or metastatic disease. Grade 3-5 TRAEs occurred in 26 patients (16%), including three treatment-related deaths. The study was limited by the small sample size and a high rate of patient ineligibility. CONCLUSIONS: The efficacy of atezolizumab observed among patients with BCG-unresponsive NMIBC is similar to results from similar trials with other agents, but did not meet the prespecified efficacy threshold. Modest efficacy needs to be balanced with a significant rate of TRAEs and the risk of disease progression when considering systemic immunotherapy in early-stage bladder cancer. PATIENT SUMMARY: We tested intravenous immunotherapy (atezolizumab) in patients with high-risk non-muscle-invasive bladder cancer that recurred after BCG (bacillus Calmette-Guérin) treatment. Although we found similar outcomes to previous trials, the benefit of this therapy is modest and needs to be carefully balanced with the significant risk of side effects. This trial is registered on ClinicalTrials.gov as NCT02844816.

Chronic prednisone, metformin, and nonsteroidal anti-inflammatory drug use and clinical outcome in a cohort of bladder cancer patients undergoing radical cystectomy in Québec, Canada.

BACKGROUND: Studies have suggested a positive association between bladder cancer (BC) outcome and comedication use, including nonsteroidal anti-inflammatory drugs (NSAID), metformin, and prednisone use. To validate these associations, we evaluated whether these medications were associated with clinical outcome in a Canadian cohort of BC patients. METHODS: This is a retrospective cohort study on BC patients undergoing radical cystectomy (RC) in Québec province in 2000-2015, as registered in the provincial health administration databases. Medication use was considered chronic when prescribed for ≥ 1 year. Overall (OS), disease-specific (DSS) and recurrence-free (RFS) survival were compared using multivariable Cox proportional hazards models. Covariates included age, Charlson's comorbidity index, region of residence, year of RC, distance to hospital, hospital type, hospital and surgeon annual RC volume, neoadjuvant chemotherapy use, and type of bladder diversion, as well as mutual adjustment for concomitant comedication use (statins, NSAIDs, metformin, and prednisone). RESULTS: Of 3742 patients included, 293, 420, and 1503 patients chronically used prednisone, metformin, and NSAIDs before surgery, respectively. In multivariable analyses, preoperative prednisone use was associated with improved OS (HR 0.67, 95%CI 0.55-0.82), DSS (HR 0.58, 95%CI 0.45-0.76), and RFS (HR 0.61, 95%CI 0.47-0.78). Patients who chronically used metformin preoperatively had a worse OS (HR 1.29, 95%CI 1.07-1.55), DSS (HR 1.38, 95%CI 1.10-1.72), and RFS (HR 1.41, 95%CI 1.13-1.74). Preoperative, chronic NSAID use was not significantly associated with all clinical outcomes, with adjusted HRs for OS, DSS, and RFS of 1.10 (95%CI 0.95-1.27), 1.24 (95%CI 1.03-1.48), and 1.22 (95%CI 1.03-1.45), respectively. Directionality of findings was similar when stratifying by comedication use in the year following surgery. Results were similar after propensity-score matching too. CONCLUSIONS: In our Canadian cohort of BC undergoing RC, chronic prednisone use was associated with improved clinical outcomes, while metformin and NSAID were not.

Radiation-based Therapy for Muscle-invasive Bladder Cancer: Contemporary Outcomes Across Tertiary Centers.

BACKGROUND: Radiation therapy (RT) is an alternative to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To analyze predictors of complete response (CR) and survival after RT for MIBC. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter retrospective study of 864 patients with nonmetastatic MIBC who underwent curative-intent RT from 2002 to 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Regression models were used to explore prognostic factors associated with CR, cancer-specific survival (CSS), and overall survival (OS). RESULTS AND LIMITATIONS: The median patient age was 77 yr and median follow-up was 34 mo. Disease stage was cT2 in 675 patients (78%) and cN0 in 766 (89%). Neoadjuvant chemotherapy (NAC) was given to 147 patients (17%) and concurrent chemotherapy to 542 (63%). A CR was experienced by 592 patients (78%). cT3-4 stage (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.29-0.63; p < 0.001) and hydronephrosis (OR 0.50, 95% CI 034-0.74; p = 0.001) were significantly associated with lower CR. The 5-yr survival rates were 63% for CSS and 49% for OS. Higher cT stage (HR 1.93, 95% CI 1.46-2.56; p < 0.001), carcinoma in situ (HR 2.10, 95% CI 1.25-3.53; p = 0.005), hydronephrosis (HR 2.36, 95% CI 1.79-3.10; p < 0.001), NAC use (HR 0.66, 95% CI 0.46-0.95; p = 0.025), and whole-pelvis RT (HR 0.66, 95% CI 0.51-0.86; p = 0.002) were independently associated with CSS; advanced age (HR 1.03, 95% CI 1.01-1.05; p = 0.001), worse performance status (HR 1.73, 95% CI 1.34-2.22; p < 0.001), hydronephrosis (HR 1.50, 95% CI 1.17-1.91; p = 0.001), NAC use (HR 0.69, 95% CI 0.49-0.97; p = 0.033), whole-pelvis RT (HR 0.64, 95% CI 0.51-0.80; p < 0.001), and being surgically unfit (HR 1.42, 95% CI 1.12-1.80; p = 0.004) were associated with OS. The study is limited by the heterogeneity of different treatment protocols. CONCLUSIONS: RT for MIBC yields a CR in most patients who elect for curative-intent bladder preservation. The benefit of NAC and whole-pelvis RT require prospective trial validation. PATIENT SUMMARY: We investigated outcomes for patients with muscle-invasive bladder cancer treated with curative-intent radiation therapy as an alternative to surgical removal of the bladder. The benefit of chemotherapy before radiotherapy and whole-pelvis radiation (bladder plus the pelvis lymph nodes) needs further study.

Adaptive Immunity in Genitourinary Cancers.

CONTEXT: While urothelial and renal cell cancers have exhibited modest responses to novel immune checkpoint inhibitors targeting the programmed death ligand 1 and its receptor, response rates in patients with prostate cancer have remained poor. The factors underlying suboptimal outcomes observed in patients treated with novel immunotherapies are still to be resolved. OBJECTIVE: To review the literature and describe the key adaptive immune physiological events associated with cancer progression and therapeutic response in genitourinary (GU) cancers. EVIDENCE ACQUISITION: We performed a nonsystematic, collaborative narrative review to highlight recent advancements leading to the current state of knowledge on the critical mediators of antitumor adaptive immunity to GU cancers. Further, we discuss the findings on the pre- and post-treatment immunological events that either are unique to each of the three cancer types or exhibit overlapping clinical associations. EVIDENCE SYNTHESIS: Aging-associated immune function decline is a major factor underlying poor outcomes observed in patients treated with both conventional and novel immunotherapies. Other cancer immunobiological aspects associated with suboptimal responses in GU cancers include the overall tumor mutational burden, mutations in specific tumor suppressor/DNA damage repair genes (KDM6A, PTEN, STAG2, TP53, ATM, and BRCA2), and abundance of multiple functional states of adaptive immune cells and their spatiotemporal localization within the tumor immune microenvironment. Understanding these mechanisms may potentially lead to the development of prognostic and predictive biomarkers such as immune cell infiltration profiles and tertiary lymphoid structures (TLSs) that associate with variable clinical outcomes depending on the nature of the novel immunotherapeutic approach. Implementation of newer immune-monitoring technologies and improved preclinical modeling systems will augment our understanding of the host and tumor intrinsic factors contributing to the variability of responses to immunotherapies. CONCLUSIONS: Despite the tremendous progress made in the understanding of dynamic and static adaptive immune elements within the tumor immune landscape, several knowledge gaps remain. A comprehensive knowledge thus gained will lead to precision immunotherapy, improved drug sequencing, and a therapeutic response. PATIENT SUMMARY: We performed a collaborative review by a diverse group of experts in the field to examine our understanding of the events and crosstalk between cancer cells and the patient's immune system that are associated with responses to novel immunotherapies. An evolving understanding of tumor-intrinsic and host-related immune alterations, both before and after therapy, will aid in the discovery of promising markers of responses to immunotherapy as well as the development of unique therapeutic approaches for the management of genitourinary cancers.

Impact of Maximal Transurethral Resection on Pathological Outcomes at Cystectomy in a Large, Multi-institutional Cohort.

PURPOSE: While the presence of residual disease at the time of radical cystectomy for bladder cancer is an established prognostic indicator, controversy remains regarding the importance of maximal transurethral resection prior to neoadjuvant chemotherapy. We characterized the influence of maximal transurethral resection on pathological and survival outcomes using a large, multi-institutional cohort. MATERIALS AND METHODS: We identified 785 patients from a multi-institutional cohort undergoing radical cystectomy for muscle-invasive bladder cancer after neoadjuvant chemotherapy. We employed bivariate comparisons and stratified multivariable models to quantify the effect of maximal transurethral resection on pathological findings at cystectomy and survival. RESULTS: Of 785 patients, 579 (74%) underwent maximal transurethral resection. Incomplete transurethral resection was more frequent in patients with more advanced clinical tumor (cT) and nodal (cN) stage (P < .001 and P < .01, respectively), with more advanced ypT stage at cystectomy and higher rates of positive surgical margins (P < .01 and P < .05, respectively). In multivariable models, maximal transurethral resection was associated with downstaging at cystectomy (adjusted odds ratio 1.6, 95% CI 1.1-2.5). In Cox proportional hazards analysis, maximal transurethral resection was not associated with overall survival (adjusted HR 0.8, 95% CI 0.6-1.1). CONCLUSIONS: In patients undergoing transurethral resection for muscle-invasive bladder cancer prior to neoadjuvant chemotherapy, maximal resection may improve pathological response at cystectomy. However, the ultimate effects on long-term survival and oncologic outcomes warrant further investigation.

Association Between Antibiotic Prophylaxis Before Cystectomy or Stent Removal and Infection Complications: A Systematic Review.

CONTEXT: Patients undergoing radical cystectomy frequently suffer from infectious complications, including urinary tract infections (UTIs) and surgical site infections (SSIs) leading to emergency department visits, hospital readmission, and added cost. OBJECTIVE: To summarize the literature regarding perioperative antibiotic prophylaxis, ureteric stent usage, and prevalence of infectious complications after cystectomy. EVIDENCE ACQUISITION: A systematic review of PubMed/Medline, EMBASE, Cochrane Library, and reference lists was conducted. EVIDENCE SYNTHESIS: We identified 20 reports including a total of 55 306 patients. The median rates of any infection, UTIs, SSIs, and bacteremia were 40%, 20%, 11%, and 6%, respectively. Perioperative antibiotic prophylaxis differed substantially between reports. Perioperative antibiotics were used only during surgery in one study but were continued over several days after surgery in all other studies. Empirical use of antibiotics for 1-3 d after surgery was described in 12 studies, 3-10 d in two studies, and >10 d in four studies. Time to stent removal ranged from 4 to 25 d after cystectomy. Prophylactic antibiotics were used before stent removal in nine of 20 studies; two of these studies used targeted antibiotics based on urine cultures from the ureteric stents, and the other seven studies used a single shot or 2 d of empirical antibiotics. Studies with any prophylactic antibiotic before stent removal found a lower median percentage of positive blood cultures after stent removal than studies without prophylactic antibiotics before stent removal (2% vs 9%). CONCLUSIONS: We confirmed a high proportion of infectious complications after cystectomy, and a heterogeneous pattern of choice and duration of antibiotics during and after surgery or stent removal. These findings highlight a need for further studies and support quality prospective trials. PATIENT SUMMARY: In this review, we observed wide variability in the use of antibiotics before or after surgical removal of the bladder.

Obesity and Complication Risk From Radical Cystectomy: Identifying a Body Mass Index Threshold.

PURPOSE: There are conflicting reports regarding radical cystectomy complication risk from obesity subcategories, and a BMI threshold below which complication risk is notably reduced is undefined. A BMI threshold may be helpful in prehabilitation to aid patient counseling and inform weight loss strategies to potentially mitigate obesity-associated complication risk. This study aims to identify such a threshold and further investigate the association between BMI subcategories and perioperative complications from radical cystectomy. MATERIALS AND METHODS: Data were extracted from the Canadian Bladder Cancer Information System, a prospective registry across 14 academic centers. Five hundred and eighty-nine patients were analyzed. Perioperative (≤90 days) complications were compared between BMI subcategories. Unconditional multivariable logistic regression and cubic spline analysis were performed to determine the association between BMI and complication risk and identify a BMI threshold. RESULTS: Perioperative complications were reported in 51 (30%), 97 (43%), and 85 (43%) normal, overweight, and obese patients (P = .02). BMI was independently associated with developing any complication (OR 1.04 95% CI 1.01, 1.07). Predicted complication risk began to rise consistently above a BMI threshold of 34 kg/m2. Both overweight (OR 2.00 95% CI 1.26-3.17) and obese (OR 1.98 95% CI 1.24-3.18) patients had increased risk of complications compared to normal BMI patients. CONCLUSIONS: Complication risk from radical cystectomy is independently associated with BMI. Both overweight and obese patients are at increased risk compared to normal BMI patients. A BMI threshold of 34 kg/m2 has been identified, which may inform prehabilitation treatment strategies.

Disparities in Access to Novel Systemic Therapies in Patients With Urinary Tract Cancer: Propagating Access, Policies and Resources Uniformly.

After several decades of therapeutic stagnation, the treatment of patients with urothelial carcinoma has met a revolutionary wave, anticipated by the advent of immune-checkpoint inhibitors (ICI) and followed by newer therapeutic options in the post-ICI setting. These achievements were made in a very short time-frame, thus making the treatment of this disease particularly susceptible to geographical health disparity due to the differences in healthcare systems and approval processes of the regulatory authorities. Furthermore, additional barriers to access innovative care are represented by a limited coverage of clinical trials availability, that is consistent in focusing on selected geographical areas, across trials and clinical settings. Here, we present the current picture of new drug approvals in urothelial carcinoma worldwide, and we also focus our considerations onto the spectrum of ongoing trial inclusion possibilities, trying to understand what are the current gaps in clinical research and routine practice, identifying a way to move forward.

The Rate of Prostatic Involvement in Men Treated With Radical Cystectomy for Muscle Invasive Bladder Cancer.

PURPOSE: Radical cystoprostatectomy (RC) is one standard treatment for muscle-invasive bladder cancer (MIBC) in male patients. Another therapeutic option is trimodal therapy. Including the prostate in the trimodal therapy radiation therapy volume is based on MIBC surgical series showing prostatic stromal (PS) involvement. Our aim was to establish the rate of pathologic PS involvement by preoperative T stage in men treated with RC for MIBC. METHODS AND MATERIALS: We conducted a retrospective review of men with MIBC treated with RC between 2006 and 2019. Electronic medical records were reviewed, and preoperative clinical staging data were collected. χ2 test was done to test for a statistically significant difference in the rate of prostatic involvement between clinical tumor (cT) stages. Preoperatively identified carcinoma in situ, lymph node involvement, tumor location, and urethral involvement were also analyzed to see if they conferred a higher risk of PS involvement. Multivariate analysis using multiple logistic regression was performed. RESULTS: We identified 283 men with bladder cancer treated with RC. Patients with non-MIBC or incomplete medical data were excluded (n = 72). We analyzed 211 patients, and 46 (22%) had pathologic PS involvement. PS involvement by preoperative T stage was cT2 = 18%, cT3 = 23%, and cT4 = 48%. Twenty-nine (12%) patients had clinical lymph node involvement, of whom 19 (76%) had PS involvement. Thirty-four (16%) had urethral involvement, of whom 17 (50%) had PS involvement. Sixteen percent and 17% of percent of clinical T2 and T3 patients had bladder neck/trigone tumors, of whom 57% and 50% had prostatic involvement. Clinical T2 and T3 were not statistically different with regards to PS involvement (P = .385). Preoperative urethral involvement, lymph node involvement, cT4, and bladder neck/trigone location were statistically significant predictors of pathologic PS involvement (all P < .05). On multivariate analysis, only clinical urethral involvement was significant (P < .0001). CONCLUSIONS: The high rate of pathologic PS involvement seen in cT2 patients and the lack of ability of cT stage to predict PS involvement support routinely treating the prostate in trimodal therapy. Patients with preoperatively identified bladder neck/trigone tumors, urethral involvement, positive lymph nodes, or prostatic involvement are a subset at even higher risk of having pathologic PS involvement.

Oncological Outcomes for Patients Harboring Positive Surgical Margins Following Radical Cystectomy for Muscle-Invasive Bladder Cancer: A Retrospective Multicentric Study on Behalf of the YAU Urothelial Group.

Introduction: Adjuvant therapy has no defined role for patients with positive surgical margins (PSMs) following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). The aim of our study was to describe loco-regional recurrence-free survival (LRFS), metastatic-free survival (MFS), recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) and identify predictors of each endpoint in patients with PSMs following RC for MIBC. Methods: A collaborative retrospective cohort study was conducted on 394 patients with PSMs who underwent RC for MIBC between January 2000 and December 2018 at 10 tertiary referral centers. Patients receiving perioperative radiotherapy were excluded from the study. Kaplan−Meier curves were used to estimate patient survival. Cox regression analysis was used to identify predictors of survival. Results: Median age at surgery was 70 years (IQR 62−76) with 129 (33%) and 204 (52%) patients had pT3 and pT4 tumors, respectively. Nodal metastasis (pN+) was identified in 148 (38%). Soft tissue PSMs were found in 283 (72%) patients, urethral PSMs in 65 (16.5%), and ureteral PSMs were found in 73 (18.5%). The median follow-up time was 44 months (95% CI 32−60). Median LRFS, MRFS, RFS, CSS, and OS were 14 (95% CI 11−17), 12 (95% CI 10−16), 10 (95% CI 8−12), 23 (95% CI 18−33), and 16 months (95% CI 12−19), respectively. On multivariable Cox regression analysis, the pT3−4 stage, pN+ stage, and multifocal PSMs were independent predictors of LRFS, MRFS, RFS, and OS. Adjuvant chemotherapy improved all oncological outcomes studied (p < 0.05). The number of lymph nodes removed was independently associated with better LRFS, MRFS, and RFS. Advanced age at diagnosis was independently associated with worse OS. Conclusion: Patients with PSMs following RC have poor outcomes since half of them will recur within a year and will die of their disease. Among all PSMs types, patients with multifocal PSMs harbor the worst prognosis. We observed a benefit of adjuvant chemotherapy, but clinical trials evaluating innovative adjuvant strategies for these patients remain an unmet need.

Impact of Programmed Death-ligand 1 Expression on Oncological Outcomes in Patients with Muscle-invasive Bladder Cancer Treated with Radiation-based Therapy.

Background: No biomarkers are recommended for patients undergoing radiation-based therapy (RT) for muscle-invasive bladder cancer (MIBC). Objective: We aim to evaluate the predictive role of programmed death-ligand 1 (PD-L1) expression on the oncological outcomes of patients treated with RT for MIBC. Design setting and participants: A single-center retrospective analysis of tumor specimens collected through transurethral resection (TURBT) from 104 MIBC patients, implemented in a tissue microarray and stained with the SP263 PD-L1 clone (Ventana Medical Systems, Tucson, AZ, USA), was conducted. Two reviewers measured the PD-L1 H-score for tumor and immune cells. Intervention: RT (maximal TURBT followed by radiation and concurrent chemotherapy when eligible). Outcome measurements and statistical analysis: Logistic and Cox regression models were used to predict 3-mo complete response (CR) and overall survival (OS) after RT, respectively. Results and limitations: A total of 88 (85%) patients had cT2 disease and 39 (37.5%) had high immune cell PD-L1 expression. A CR was achieved in 68 (65%) patients. On the multivariable analysis (MVA), a higher clinical stage (p = 0.02) and a low immune cell PD-L1 H-score (p = 0.02) were associated with a decreased CR after RT. The median time to death was 43 mo (95% confidence interval 20-66). On Cox MVA, a high immune cell PD-L1 H-score (p = 0.0017) was associated with better OS, independently of performance status (p = 0.0005) or tumor stage (p = 0.0013). A high tumor cell PD-L1 H-score was not an independent predictor of CR or OS. Limitations of the study include the retrospective design. Conclusions: MIBC patients with high PD-L1 expression on immune cells appear to have better oncological outcomes following RT. Our results may aid in patient stratification for future clinical trial design. Patient summary: In this report, we evaluated the role of programmed death-ligand 1 (PD-L1) expressed on tumor and immune cells in the tumor microenvironment for patients treated with a bladder-sparing regimen. We found that PD-L1 overexpression on immune cells is able to predict a better response to radiation-based therapy.

Epidemiology of Renal Cell Carcinoma: 2022 Update.

CONTEXT: International variations in the rates of kidney cancer (KC) are considerable. An understanding of the risk factors for KC development is necessary to generate opportunities to reduce its incidence through prevention and surveillance. OBJECTIVE: To retrieve and summarize global incidence and mortality rates of KC and risk factors associated with its development, and to describe known familial syndromes and genetic alterations that represent biologic risk factors. EVIDENCE ACQUISITION: A systematic review was conducted via Medline (PubMed) and Scopus to include meta-analyses, reviews, and original studies regarding renal cell carcinoma, epidemiology, and risk factors. EVIDENCE SYNTHESIS: Our narrative review provides a detailed analysis of KC incidence and mortality, with significant variations across time, geography, and sex. In particular, while KC incidence has continued to increase, mortality models have leveled off. Among the many risk factors, hypertension, obesity, and smoking are the most well established. The emergence of new genetic data coupled with observational data allows for integrated management and surveillance strategies for KC care. CONCLUSIONS: KC incidence and mortality rates vary significantly by geography, sex, and age. Associations of the development of KC with modifiable and fixed risk factors such as obesity, hypertension, smoking, and chronic kidney disease (CKD)/end-stage kidney disease (ESKD) are well described. Recent advances in the genetic characterization of these cancers have led to a better understanding of the germline and somatic mutations that predispose patients to KC development, with potential for identification of therapeutic targets that may improve outcomes for these at-risk patients. PATIENT SUMMARY: We reviewed evidence on the occurrence of kidney cancer (KC) around the world. Currently, the main avoidable causes are smoking, obesity, and high blood pressure. Although other risk factors also contribute, prevention and treatment of these three factors provide the best opportunities to reduce the risk of developing KC at present.

Multicenter evaluation of neoadjuvant and induction gemcitabine-carboplatin versus gemcitabine-cisplatin followed by radical cystectomy for muscle-invasive bladder cancer.

PURPOSE: Cisplatin-based chemotherapy followed by radical cystectomy (RC) is recommended in patients with muscle-invasive bladder cancer (MIBC). However, up to 50% of patients are cisplatin ineligible. The aim of this study was to compare clinical outcomes after ≥ 3 cycles of preoperative gemcitabine-carboplatin (gem-carbo) versus gemcitabine-cisplatin (gem-cis). METHODS: We identified 1865 patients treated at 19 centers between 2000 and 2013. Patients were included if they had received ≥ 3 cycles of neoadjuvant (cT2-4aN0M0) or induction (cTanyN + M0) gem-carbo or gem-cis followed by RC. RESULTS: We included 747 patients treated with gem-carbo (n = 147) or gem-cis (n = 600). Patients treated with gem-carbo had a higher Charlson Comorbidity Index (p = 0.016) and more clinically node-positive disease (32% versus 20%; p = 0.013). The complete pathological response (pCR; ypT0N0) rate did not significantly differ between gem-carbo and gem-cis (20.7% versus 22.1%; p = 0.73). Chemotherapeutic regimen was not significantly associated with pCR (OR 0.99 [95%CI 0.61-1.59]; p = 0.96), overall survival (OS) (HR 1.20 [95%CI 0.85-1.67]; p = 0.31), or cancer-specific survival (CSS) (HR 1.35 [95%CI 0.93-1.96]; p = 0.11). Median OS of patients treated with gem-carbo and gem-cis was 28.6 months (95%CI 18.1-39.1) and 45.1 months (95%CI 32.7-57.6) (p = 0.18), respectively. Median CSS of patients treated with gem-carbo and gem-cis was 28.8 months (95%CI 9.8-47.8) and 71.0 months (95%CI median not reached) (p = 0.02), respectively. Subanalyses of the neoadjuvant and induction setting did not show significant survival differences. CONCLUSION: Our results show that a subset of cisplatin-ineligible patients with MIBC achieve pCR on gem-carbo and that survival outcomes seem comparable to gem-cis provided patients are able to receive ≥ 3 cycles and undergo RC.