Healthcare Resource Utilization and Cost Burden of BCG-Treated Non-Muscle Invasive Bladder Cancer Patients in Germany: A Retrospective Claims Analysis.

Background: Intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) is typically managed with transurethral resection of the bladder tumour (TURBT) followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy; however, NMIBC patients can become refractory or unresponsive to BCG treatment, and/or progress to muscle-invasive bladder cancer (MIBC). Healthcare resource utilization (HCRU) and costs in these patient populations are high. Methods: A retrospective longitudinal cohort design of adult (≥18 years) patients with bladder cancer and BCG treatment (01/01/2012-31/12/2017) was conducted using data from a representative subset of the German statutory health insurance database. During the follow-up period after last BCG, patients were categorized into subgroups of No further NMIBC treatment, Continuous treatment for NMIBC, or MIBC evidence; HCRU and costs were tabulated for each subgroup and for the entire cohort. Results: A total of 1049 patients met the study inclusion criteria (mean age, 70.9 years; 84.8% male). Across the different subgroups, patients showing MIBC evidence had more than two times higher hospitalization rates compared to the other subgroups. Overall, the entire BCG-treated cohort's total direct medical cost including hospitalizations, outpatient care and drugs was €33.9 million and €9250 per patient-year. Cost for patients with MIBC evidence was much higher, at €17,983 per patient-year, than patients with No further NMIBC treatment (€6617) and patients with Continuous treatment for NMIBC (€7786). Across the subgroups, hospitalization was the largest driver of cost and contributed the most to cost for those with MIBC evidence. Conclusion: The overall cost burden of this BCG-treated cohort of 1049 patients is high (€38 million whereof 4.1 million are indirect costs) over a mean follow-up of 3.9 years; economic burden is especially substantial for patients who fail BCG treatment and those who progress.

A three-gene methylation marker panel for the nodal metastatic risk assessment of muscle-invasive bladder cancer.

PURPOSE: In this study, we aimed to identify a DNA methylation pattern suitable for prognosis assessment of muscle-invasive bladder cancer and to investigate metastasis-associated processes regulated by DNA methylation. METHODS: Genome-wide methylation analysis was performed on 23 muscle-invasive bladder tumors by microarray analysis. Validation was performed by the qAMP technique in two different patient cohorts (n = 32 and n = 100). mRNA expression was analyzed in 12 samples. Protein expression was determined using tissue microarrays of 291 patients. Bladder cancer cell lines T24 and 253JB-V were used for functional analyses. RESULTS: Microarray analyses revealed KISS1R, SEPT9 and CSAD as putative biomarkers with hypermethylation in node-positive tumors. The combination of the three genes predicted the metastatic risk with sensitivity of 73% and specificity of 71% in cohort 1, and sensitivity of 82% and specificity of 54% in cohort 2. mRNA expression differences were detected for KISS1R (p = 0.04). Protein expression of KISS1R was significantly reduced (p < 0.001). Knockdown of SEPT9v3 resulted in increased cell migration by 28% (p = 0.04) and increased invasion by 22% (p = 0.004). KISS1R overexpression resulted in decreased cell migration (25%, p = 0.1). CONCLUSIONS: We identified a methylation marker panel suitable to differentiate between patients with positive and negative lymph nodes at time of cystectomy. This enables a risk assessment for patients who potentially benefit from extended lymph node resection as well as from neoadjuvant chemotherapy and could improve the survival rates. Furthermore, we examined the impact of putative markers on tumor behavior. Hence, KISS1R and SEPT9 could represent a starting point for the development of novel therapy approaches.

A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment.

BACKGROUND: Neoadjuvant chemotherapy before cystectomy confers a survival benefit in bladder cancer, but it has not been widely adopted since most patients do not benefit and we are at present unable to predict those that do. Since the most important predictor of recurrence after cystectomy is pathologically positive nodes, our aim was to assess techniques that define this stage for the selection of patients for neoadjuvant chemotherapy. METHODS: We developed a gene expression model (GEM) to predict the pathological node status in primary tumour tissue from three independent cohorts of patients who were clinically node negative. From a subset of transcripts detected faithfully by microarrays from both paired frozen and formalin-fixed tissues (32 pairs), we developed both the GEM and cutoffs that identified patient strata with raised risk of nodal involvement by use of two separate training cohorts (90 and 66 patients). We then assessed the GEM and cutoffs to predict node-positive disease in tissues from a phase 3 trial cohort (AUO-AB-05/95; 185 patients). FINDINGS: We developed a 20-gene GEM with an area under the curve of 0·67 (95% CI 0·60-0·75) for prediction of nodal disease at cystectomy in AUO-AB-05/95. The cutoff system identified patients with high relative risk (1·74, 95% CI 1·03-2·93) and low relative risk (0·70, 95% CI 0·51-0·96) of node-positive disease. Multivariate logistic regression showed the GEM predictor was independent of age, sex, pathological stage, and lymphovascular space invasion (coefficient 9·81, 95% CI 1·64-18·00; p=0·019). INTERPRETATION: Selecting patients for neoadjuvant chemotherapy on the basis of risk of node-positive disease has the potential to benefit high-risk patients while sparing other patients toxic effects and delay to cystectomy. FUNDING: US National Cancer Institute (R01CA143971).

Is there standard chemotherapy for metastatic bladder cancer? Quality of life and medical resources utilization based on largest to date randomized trial.

A large multinational phase III trial performed during the late 1990s compared two systemic chemotherapy regimens gemcitabine plus cisplatin and methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) in more than 400 patients with advanced or metastatic urothelial cancer. This trial has been discussed to landmark the beginning of a new era following M-VAC polychemotherapy which has dominated treatment of advanced urothelial cancer throughout the previous decade. Despite the fact that gemcitabine/cisplatin combination therapy did not surpass M-VAC therapy in regard to patient survival as initially intended, this combination demonstrated a more favourable toxicity profile with improved tolerability and superior cost effectiveness, rendering this combination an attractive alternative to M-VAC. This review on the largest to date phase III trial for advanced or metastatic urothelial cancer will focus on issues of quality of life including indicators such as performance status and changes in body weight. Furthermore, data on medical resources utilization as accounted during systemic polychemotherapy and related toxic events will be reconsidered, particularly under the impression of decreasing health care resources worldwide.