Bladder Cancer Journal Vol. 6 Issue 2
Bladder cancer is the sixth most common malignancy in the United States and is associated with high morbidity and mortality rates. To date, no guidelines have been published that clearly establish bladder cancer management recommendations during the COVID-19 pandemic. In this short commentary, we strive to outline recommendations for treatment of both muscle invasive and non-muscle invasive disease based on data from various trials and prior studies while taking into account the potential lack of hospital resources available to physicians depending on their practice location.
Histologic Variants of Urothelial Carcinoma: Morphology, Molecular Features and Clinical Implications
Review of SWOG S1314: Lessons from a Randomized Phase II Study of Co-Expression Extrapolation (COXEN) with Neoadjuvant Chemotherapy for Localized, Muscle-Invasive Bladder CancerSalvage Hyperthermic Gemcitabine and Docetaxel Combination Chemotherapy After BCG Failure in Non-Muscle Invasive Bladder Cancer Patients
BACKGROUND: SWOG1314 is a randomized phase II study of co-expression extrapolation (COXEN) with neoadjuvant chemotherapy for localized, muscle-invasive bladder cancer. COXEN is a biomarker approach in which predictive biomarkers are developed using in vitro data, which may then be applied directly into a clinical testing application. Two separate Gene Expression Models (GEMs), one for the Methotrexate, Vinblastine, Doxorubicin, Cisplatin (MVAC) regimen and another for gemcitabine plus cisplatin (GC) were tested in S1314. The lessons learned from the development and operationalization of the S1314 clinical trial are described in detail, which may help to inform the future trials of predictive biomarkers for urothelial carcinoma in the neoadjuvant setting. Specific areas addressed include: The need for broad support from the bladder cancer community, planning for non-evaluable subjects, defining adequate neoadjuvant treatment, defining adequate tissue collection, setting expectations in phase II clinical studies of predictive biomarkers, and maximizing the impact of the samples collected in these studies for broader biomarker development. With a large number of newly available treatments in advanced urothelial carcinoma in the last few years, more investigations of these agents in the neoadjuvant setting is anticipated. There will be a great need for the development of predictive biomarkers in conjunction with the use of these agents in the preoperative setting. Insights from S1314 may provide useful information and lessons learned in this development.
BACKGROUND: Lack of appropriate models that recapitulate the diversity, heterogeneity, and tumor microenvironment of urothelial cancer (UC) is a limitation to preclinical models. Patient-derived xenograft (PDX) models are a promising tool to overcome some of these issues, and thus we present an up-to-date and comprehensive overview of UC PDX models to aid in their future use.
BACKGROUND: Bladder cancer patients who are insured experience improved outcomes. Medicaid expansion aimed to increase insurance coverage and improve access to care. However, the association between Medicaid expansion and stage at diagnosis or time to treatment for those with advanced bladder cancer is unknown.
Preoperative Risk Factors Predicting Postoperative Complications in Radical Cystectomy for Bladder Cancer
BACKGROUND: While radical cystectomy (RC) is the gold-standard treatment for patients with muscle-invasive bladder cancer, it is associated with a significant rate of complications. We aim to develop a prediction model to assess the risk of complications in the postoperative period using routinely collected data in the course of preoperative evaluation in patients undergoing RC for bladder cancer.
Detection of Muscle-Invasive Bladder Cancer on Biparametric MRI Using Vesical Imaging-Reporting and Data System and Apparent Diffusion Coefficient Values (VI-RADS/ADC)
Vesical Imaging-Reporting And Data System (VI-RADS) was proposed to detect muscle-invasive bladder cancer (MIBC).
To evaluate the performance of VI-RADS and additional value of apparent diffusion coefficient (ADC) values measured on diffusion-weighted magnetic resonance imaging (MRI) for detecting MIBC.
A total of 176 patients undergoing MRI (multiparametric in 97 [55%] and biparametric in 79 [45%]) before transurethral resection of bladder tumor for primary bladder cancer were retrospectively identified. MRI findings were scored according to VI-RADS. The standardized tumor ADC (sT-ADC: tumor ADC/gluteus maximus ADC) was calculated and used to account for the incompatibility among different MRI protocols. The accuracy of VI-RADS, sT-ADC and their combination to detect MIBC was assessed using the AUC of the ROC curve.
MIBC was pathologically confirmed in 46 patients (26%). AUC of VI-RADS to detect MIBC was 0.86. When cut-off of VI-RADS was set at≥3 and≥4, sensitivity/specificity were 78% /70% and 63% /96%, respectively. A lower sT-ADC (≤0.894) was significantly associated with muscle invasion (p < 0.01, AUC 0.79) with sensitivity 78% and specificity 79%. Combination of VI-RADS and sT-ADC improved the accuracy (AUC 0.94); sensitivity was 100% when VI-RADS≥3 or sT-ADC≤0.894 was considered positive, and specificity was 99% when VI-RADS≥4 and sT-ADC≤0.894 was considered positive. Incorporation of sT-ADC reduced under-staging of MIBC as VI-RADS < 3 by 100% and over-staging of non-MIBC as VI-RADS≥4 by 80%.
Incorporation of ADC values into VI-RADS improves accuracy to detect MIBC in primary bladder cancer patients.
Genomic Biomarkers and Underlying Mechanism of Benefit from BCG Immunotherapy in Non-Muscle Invasive Bladder Cancer
Optimal therapy for high-risk non-muscle invasive bladder cancer (NMIBC) includes intravesical instillation of Bacillus Calmette-Guérin (BCG). However, about 25-45% of patients do not benefit from BCG immunotherapy, and there is no biomarker to guide therapy. Also, many questions regarding BCG mechanisms of action remain unanswered.
To identify genomic biomarkers and characterize the underlying mechanism of benefit from BCG in NMIBC.
PATIENTS AND METHODS:
Pre-treatment archival index-tumors of 35 patients with NMIBC treated with BCG were analyzed by whole-exome sequencing (WES). Tumor mutation burden (TMB) and neoantigen load (NAL) were correlated with BCG response rate (RR) and recurrence-free survival (RFS). The presence of deleterious mutations in DNA damage response (DDR) genes was also compared between BCG-responsive (BCG-R, N = 17) and unresponsive (BCG-UR, N = 18) subgroups.
TMB and NAL were higher in BCG-R compared to BCG-UR patients (median TMB 4.9 vs. 2.8 mutations/Mb, P = 0.017 and median NAL 100 vs. 65 neoantigens, P = 0.032). Improved RR and RFS were observed in patients with high vs. low TMB (RR 71% vs. 28%, P = 0.011 and mRFS 38.0 vs. 15.0 months, P = 0.009) and with high vs. low NAL (RR 71% vs. 28%, P = 0.011 and mRFS 36.0 vs. 18.5 months, P = 0.016). The presence of deleterious mutations in DDR genes was associated with improved RFS (mRFS 35.5 vs. 11.0 months, P = 0.017).
In our cohort, improved outcomes after BCG immunotherapy were observed in patients with high TMB, high NAL and deleterious mutations in DDR genes. BCG may induce tumor-specific immune response by enhancing the recognition of neoantigens.
Extraperitoneal Antegrade vs Transperitoneal Open Radical Cystectomy: Single Center Experiences with 200 Cases
Radical cystectomy (RC) is one of the most complex surgeries and has a high rate of morbidity. Gastrointestinal complications are the most common type of complications. To reduce these complications some modifications have been described.
To evaluate perioperative outcomes of our extraperitoneal antegrade RC technique (EARTC), where the peritoneum is opened at the end of cystectomy just before of ileal reconstruction.
Group 1 included 120 patients who were operated with a standard RC technique and Group 2 included 80 patients who were operated with the EARC technique in this study. Groups were compared according to preoperative variables including patient characteristics, perioperative parameters, pathologic data, and postoperative overall and gastrointestinal complications.
There were no significant differences between the two groups in terms of preoperative characteristics and mean operative time. The group 1 has longer time for the exposure of abdominal cavity to the atmosphere (p < 0.01). Hospitalization time was significantly lower in Group 2 (p < 0.01). Concerning the rate of 90-day overall perioperative complication, no statistically significant difference was determined between the groups. Gastrointestinal complication was significantly higher in Group 1 (p:0.048). The average number of removed lymph nodes was similar between the groups (p:0.85). The time for recovery of bowel function, the time for passage of stool and the rate of postoperative ileus were significantly lower in Group 2 (p < 0.01, p < 0.01 and p < 0.043) respectively).
EARC provides advantages over the standard technique in terms of gastrointestinal symptoms and poses no disadvantage when the oncological outcome and operative difficulty were considered.
Transurethral resection of bladder tumor (TURBT) is fundamental to the diagnosis and management of bladder cancer. The impact of tumor size on perioperative outcomes is seemingly intuitive albeit incompletely defined.
To compare outcomes following TURBT of small, medium, and large tumors to determine if larger tumors truly resulted in a greater degree of complications.
The National Surgical Quality Improvement Project (NSQIP) Participant Use File (PUF) was queried to extract all TURBT cases performed from 2011–2015. CPT codes 52234 (small), 52235 (medium), and 52240 (large) were used to stratify the data into three cohorts. Outcomes of interest included any complications, hospital length of stay (LOS), reoperation within 30-days, 30-day readmission, and mortality.
17,839 patients who underwent TURBT were included. 44% had small (n = 7,805), 35% had medium (n = 6,240), and 21% had large tumors (n = 3,794). Univariate analysis revealed significant differences in complications, length of stay, reoperation rate, readmission at 30-days, and mortality when stratifying TURBT by tumor size (p < 0.0001). In the multivariable regression model, medium and large tumors were associated with significantly greater odds of a postoperative complication (OR = 1.37 and 1.64; p < 0.0001), reoperation (OR = 1.33 and 1.52; p = 0.019 and p = 0.002), readmission at 30-days (OR = 1.27 and 1.56; p = 0.001 and p < 0.0001), and death (OR = 1.65 and 2.59; p = 0.015 and p < 0.0001) compared to smaller tumors.
Larger tumor size (>5 cm) is associated with greater length of stay, reoperation, readmission, and death following TURBT. Patients should be counseled appropriately and likely warrant vigilant observation prior to and following hospital discharge.
Safety and Short-Term Oncological Outcomes of Thulium Fiber Laser En Bloc Resection of Non-Muscle-Invasive Bladder Cancer: A Prospective Non-Randomized Phase II Trial
Ongoing efforts aim at overcoming the challenges of conventional transurethral resection of bladder tumor (TURBT) such as the high recurrence rate, difficulty of pathologic interpretation and complications including wall injury.
To prospectively assess the safety and efficacy of Thulium fiber en bloc resection of bladder tumor (Tm-fiber ERBT) compared to TURBT.
MATERIALS AND METHODS:
The prospective non-randomized study included 129 patients with non-muscle-invasive bladder cancer (NMIBC) divided into two groups: 58 patients underwent conventional TURBT and 71 –Tm-fiber ERBT with FiberLase U1 (NTO IRE-Polus, Russia). Relapse-free survival (RFS), detrusor presence and complication rates were assessed. For multivariable analysis we used the Pearson chi-squared Hosmer-Lemeshow goodness of fit test; to compare survival –Cox regression analysis; for operative data comparison –chi-square test with Fisher’s correction; for survival analysis –the Kaplan–Meier method and logrank test.
RFS rates at 3 and 6 months were 84.5% and 67.2% for conventional TURBT versus 97.2% and 91.5% for Tm-fiber ERBT (p = 0.011 and p < 0.001, respectively). Detrusor muscle was present in 58.6% of cases treated with conventional
TURBT vs 91.6% for the Tm-fiber ERBT group (p < 0.001). The obturator nerve reflex and bleeding were noted in 17.2% and 10.3% of TURBT cases, respectively; and in none of cases treated with Tm-fiber ERBT. Limitations included the non–randomized nature and the small sample size.
Tm-fiber ERBT seems to be a safe and efficacious treatment option for NMIBC. Tm-fiber ERBT had fewer adverse events, was more likely to secure detrusor muscle in the specimen and resulted in better RFS rates than conventional TURBT. Based on these promising data, we have started a prospective randomized clinical trial comparing en bloc TURBT with conventional TURBT (ClinicalTrials.gov NCT03718754).
Non-Coding Mutations in Urothelial Bladder Cancer: Biological and Clinical Relevance and Potential Utility as Biomarkers
Building on previous studies to provide evidence for the inclusion of non-coding elements as potential biomarkers for urothelial bladder cancer (UBC) [2–6], Jeeta et al.  recently identified clinically relevant non-coding mutations in five genes (TBC1D12, GPR126, PLEKHS1, LEPROTL1 and WDR74). Clinical relevance was assessed by performing analyses of mutation frequencies across disease stages, association with clinical outcomes, distribution of mutations relative to one another, relative to mutational signatures, their effects on gene expression, and isoform usage. Substantiated by χ2 tests, logistic regression, and Cox proportional-hazards models, all of these analyses were informative. However, with regard to mutation frequencies, a more direct calculation of their cancer effect size— which accounts for underlying rates of mutation at each site and quantifies the somatic selection for each variant — could strengthen their conclusions regarding sites of genes that should or should not be included in UBC detection panels.