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.

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.

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.

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.

Morphologic alterations post trimodal therapy in muscle-invasive urothelial carcinoma: understanding the impact of post-treatment changes on the pathological interpretation and their potential clinical correlates.

While surveillance biopsies play a critical role in management of patients with muscle invasive bladder cancer (MIBC) treated with trimodal therapy (TMT), their assessment is often confounded by pronounced post-treatment changes. The aim of this study was to characterize these morphologic alterations and their clinical implications. A single-center retrospective analysis of surveillance transurethral resection of bladder tumor (TURBT) samples was undertaken, assessing for post-treatment morphologic changes in non-neoplastic and neoplastic tissue, as well as the correlation between these changes and cancer recurrence and cancer-specific survival. The cohort consisted of 73 patients with 56 males (76.7%), with a median age of 72 years and stage cT2 in 84.9%. The median follow-up was 28 months (4-207 months), with 34 patients (46.6%) dead during follow-up. A wide spectrum of morphologic characteristics was documented in all post-TMT TURBTs, with most common features including fibrosis (63.0%), inflammation (56.2%), and epithelial denudation (45.2%). Presence of fibrosis inversely correlated with cancer-specific death (n = 68, p = 0.027). Among the 18 cases with residual MIBC, 12 cases (66.7%) showed morphologic changes in the neoplastic cells that deviated from usual morphology of urothelial carcinoma. Presence of these changes was enriched in patients with subsequent disease recurrence (n = 18, p = 0.05). Secondary pathology review identified two cases (2.7%) with diagnostic discrepancy, both due to omission of in situ component. Post-treatment changes in post-TMT TURBTs must be recognized to avoid diagnostic misinterpretation and accurately guide patient management. Also, poor cellular preservation and severe cytologic changes in the residual carcinoma are not associated with a better prognosis.

Role of Serum Lymphocyte-derived Biomarkers in Nonmetastatic Muscle-invasive Bladder Cancer Patients Treated with Trimodal Therapy.

BACKGROUND: The role of serum lymphocyte-based biomarkers, such as the neutrophil-to-lymphocyte (NLR), lymphocyte-to-monocyte (LMR), and platelet-to-lymphocyte (PLR) ratios, was previously studied in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy but remains underexplored in patients treated with trimodal therapy (TMT). OBJECTIVE: To analyze the impact of serum lymphocyte-based biomarkers on main oncological outcomes after TMT for MIBC. DESIGN SETTING AND PARTICIPANTS: A retrospective study, including 176 patients treated with TMT for nonmetastatic MIBC (cT2-4/cN0-2) between 2001 and 2017 at a tertiary academic center, was conducted. INTERVENTION: TMT, consisting of initial maximal transurethral resection of the bladder tumor, followed by radiotherapy with concurrent chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinicopathological characteristics, serum laboratory tests, and imaging reports were collected. NLR, LMR, and PLR were calculated before and at the end of TMT. Dynamic patterns of NLR, LMR, and PLR during TMT were studied. Multivariable regression models were performed to estimate the effect of these biomarkers on complete response (CR) to TMT and survival. RESULTS AND LIMITATIONS: The median age was 75 yr (interquartile range 66-82). Staging was cT2 in 156 (89%) and cN0 in 159 (90%) patients. A pretreatment NLR (pre-NLR) of ≥4.0 was independently associated with lower CR rates (odds ratio 0.32; p = 0.013). In addition, a pre-NLR of ≥4.0 was associated with worse cancer-specific survival (hazard ratio [HR] 1.88; p = 0.032) and overall survival (OS; HR 1.61; p = 0.033) together with other factors such as hydronephrosis, Eastern Cooperative Oncology Group performance status, and cT stage 3-4a. When both pre- and post-treatment variables were considered, an increase in NLR beyond 75% during TMT (HR 1.63; p = 0.035) was associated with worse OS. This study was limited by its retrospective design. CONCLUSIONS: A high pre-NLR value was independently associated with lower rates of CR and worse survival in MIBC patients undergoing TMT. Prospective validation is needed to implement NLR into clinical practice. PATIENT SUMMARY: In this study, we reported the oncological outcomes of patients with muscle-invasive bladder cancer treated with trimodal therapy. We found that the neutrophil-to-lymphocyte ratio, a cheap and available blood-derived biomarker, was associated with response to trimodal therapy and survival outcomes.

Trimodal therapy vs. radical cystectomy for muscle-invasive bladder cancer: A Canadian cost-effectiveness analysis.

INTRODUCTION: Trimodal therapy (TMT) is a suitable alternative to neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) for patients with muscle-invasive bladder cancer (MIBC). In this study, we conducted a cost-effectiveness evaluation of RC±NAC vs. TMT for MIBC in the universal and publicly funded Canadian healthcare system. METHODS: We developed a Markov model with Monte-Carlo microsimulations. Rates and probabilities of transitioning within different health states (e.g., cure, locoregional recurrence, distant metastasis, death) were input in the model after a scoped literature review. Two main scenarios were considered: 1) academic center; and 2) populational-level. Results were reported in life-years gained (LYG), quality-adjusted life years (QALY), and incremental cost-effectiveness ratio (ICER). A sensitivity analysis was performed. RESULTS: A total of 20 000 patients were simulated. For the academic center model, TMT was associated with increased effectiveness (both in LYG and QALY) at a higher cost compared to RC±NAC at five and 10 years. This resulted in an ICER of $19 746/QALY per patient undergoing the TMT strategy at 10 years of followup. For the populational-level model, RC±NAC was associated with higher effectiveness at 10 years, with an ICER of $3319/QALY per patient. This study was limited by heterogeneity within the studies used to build the model. CONCLUSIONS: In this study, TMT performed in academic centers was cost-effective compared to RC±NAC, with higher effectiveness at a higher cost. On the other hand, RC±NAC was considered cost-effective compared to TMT at the populational-level. Further studies are needed to confirm these results.

Impact of sarcopenia on outcomes of patients treated with trimodal therapy for muscle invasive bladder cancer.

OBJECTIVE: We sought to investigate the incidence of sarcopenia and its impact on main oncological outcomes in patients with muscle invasive bladder cancer (MIBC) treated with trimodal therapy (TMT). PATIENTS AND METHODS: This was a retrospective analysis of 141 MIBC patients treated with TMT in the period 2002 to 2018. Sarcopenia was identified through pretreatment computed tomography scans and defined as a skeletal muscle index of <55 cm2/m2 for men and <39 cm2/m2 for women. Body mass index (BMI)-adjusted definition of sarcopenia was used to evaluate for sarcopenic obesity. Uni- and multivariable analyses were performed to assess the impact of sarcopenia on initial complete response and overall survival (OS) to TMT. RESULTS: Median age at diagnosis was 73 years [range: 65-81] and median follow up was 32 months (Inter Quartile Range: 18-66). Median OS was 67 months (95% CI: 53-83). The incidence of sarcopenia and BMI-adjusted sarcopenia was 56.7% and 40.4%, respectively. On multivariable analysis, Eastern Cooperative Oncology Group performance status (HR = 2.37, 95% CI: 2.1-5.67, P = 0.001) and complete response to treatment (HR = 0.26, 95% CI: 0.14-0.049, P = 0.001] were independently associated with improved OS. Sarcopenia and BMI-adjusted sarcopenia were not independently associated with either complete response to TMT or OS. Similarly, in a subpopulation of 74 patients considered fit for radical cystectomy, we found that neither sarcopenia (P = 0.49) nor BMI-adjusted sarcopenia (P = 0.22) had an impact on OS. CONCLUSION: Sarcopenia and BMI-adjusted sarcopenia are prevalent in patients with MIBC undergoing TMT. TMT is a suitable treatment modality for patients with MIBC irrespective of their sarcopenia status.

Multiparametric magnetic resonance imaging for bladder cancer: a comprehensive systematic review of the Vesical Imaging-Reporting and Data System (VI-RADS) performance and potential clinical applications.

BACKGROUND: The Vesical Imaging-Reporting and Data System (VI-RADS) score is a novel standardized approach to image and report bladder cancer (BC) with multiparametric MRI (mpMRI). OBJECTIVES: To describe and evaluate the performance of the VI-RADS score using mpMRI and assess its potential clinical applications and limitations. METHODS: A systematic review was conducted using the MEDLINE and EMBASE electronic bibliographic databases between June 2020 and December 2020. All reports deemed relevant to describe the VI-RADS score and assess its performance and applications were retrieved. Results presentation stands as narrative, purely descriptive synthesis based on aggregate studies data. RESULTS: A total of 20 relevant studies were retrieved: three meta-analyses, five prospective studies, and twelve retrospective studies. The retrospective studies covered 1676 patients, while the prospective studies included a total number of 468 patients. Pooled sensitivity, specificity to differentiate muscle-invasive from non-muscle-invasive bladder cancer, ranged from 74.1% to 97.3%, and 77% to 100%, respectively. The chosen VI-RADS score thresholds for this discrimination varied across studies. The interreader agreement ranged from 0.73 to 0.95. Currently, the potential clinical applications of VI-RADS consist of initial BC risk stratification, assessment of neoadjuvant therapies response, and bladder sparing approaches, although further validation is required. CONCLUSIONS: The VI-RADS score helps to discriminate muscle invasive from non-muscle invasive BC with good performance and reproducibility. A simple algorithm based on four basic questions may enhance its popularization. Further studies are required to validate the clinical applications.

Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer.

Radiation therapy (RT) is used in the management of several cancers; however, tumor radioresistance remains a challenge. Polymorphonuclear neutrophils (PMNs) are recruited to the tumor immune microenvironment (TIME) post-RT and can facilitate tumor progression by forming neutrophil extracellular traps (NETs). Here, we demonstrate a role for NETs as players in tumor radioresistance. Using a syngeneic bladder cancer model, increased NET deposition is observed in the TIME of mice treated with RT and inhibition of NETs improves overall radiation response. In vitro, the protein HMGB1 promotes NET formation through a TLR4-dependent manner and in vivo, inhibition of both HMGB1 and NETs significantly delays tumor growth. Finally, NETs are observed in bladder tumors of patients who did not respond to RT and had persistent disease post-RT, wherein a high tumoral PMN-to-CD8 ratio is associated with worse overall survival. Together, these findings identify NETs as a potential therapeutic target to increase radiation efficacy.

Refining assessment of response to radiation-based therapy for muscle-invasive bladder cancer: Is post-treatment tumor bed biopsy always necessary?

INTRODUCTION: Radiation-based therapy (RT) has emerged as a suitable alternative to radical cystectomy (RC) and pelvic lymph node dissection for muscle-invasive bladder cancer (MIBC) patients. Routine biopsy after RT to rule out residual disease remains inconsistent across guidelines. Our objective was to review the significance of a bladder biopsy in terms of assessment of response post-RT and its potential impact on survival. PATIENTS AND METHODS: This was a single-center retrospective study on patients with MIBC (cT2-4aN0-2M0) treated with curative intent RT. A total of 169 patients with primary urothelial carcinoma were analyzed. Patients' demographic, clinical and pathological variables, imaging, cystoscopy, urine cytology, and biopsy reports after RT were collected and compiled. Whenever urine cytology was positive or cystoscopy showed any malignant-appearing lesion, the first assessment post-RT was considered suspicious for residual disease. A descriptive population analysis was reported. Cox regression multivariable analysis was performed to identify independent variables associated with survival outcomes. RESULTS: Median age was 75 years (interquartile range 66-82) and clinical staging was cT2 in 152 (90%) patients. Cytology and cystoscopy were normal in 140 (83%) after RT. Of patients with a control biopsy, residual MIBC was present in 3 (5%) and non-MIBC in another 6 (11%). On the contrary, a for-cause biopsy due to a suspicious assessment post-RT did not yield residual cancer in 45% of patients. Multivariable analysis showed that age (hazard ratio [HR] 1.04, P< 0.001), lymphovascular invasion (HR 1.68, P = 0.03) and a suspicious assessment after RT (HR 3.21; P< 0.001) were significantly associated with worse OS. This study was limited by its retrospective design. CONCLUSIONS: A routine biopsy after RT may be warranted to assess treatment response. This might be particularly important for patients who may benefit from early surgical intervention for residual MIBC. Further prospective studies are needed to confirm our findings.

Veia cava superior esquerda persistente: relato de caso / Persistent left superior vena cava: case report

O pleno conhecimento da anatomia vascular torácica é de suma importância para os profissionais envolvidos na realização de procedimentos invasivos como a punção de acesso venoso central. A persistência da veia cava superior esquerda é a malformação venosa torácica mais frequente, e seu diagnóstico costuma ser incidental. Apresentamos o caso de uma paciente de 14 anos em que o diagnóstico de veia cava superior esquerda persistente foi incidental em exame de imagem de controle após colocação de cateter venoso totalmente implantável. A paciente não apresentou dificuldade de infusão de quimioterapia pelo cateter e não houve complicações relacionadas ao cateter.

It is extremely important that health professionals involved in invasive procedures such as central venous access have a thorough knowledge of thoracic vascular anatomy. Persistent left superior vena cava is the most common congenital thoracic venous abnormality and is generally diagnosed as an incidental finding. We present the case of a 14-year-old female patient in whom a persistent left superior vena cava was diagnosed as an incidental finding of a control imaging exam after placement of a totally implantable venous catheter. The patient did not exhibit any difficulties with infusion of chemotherapy via the catheter and there were no complications related to the catheter.