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Urothelial carcinoma (UC) urgently requires new therapeutic options. Histone deacetylases (HDAC) are frequently dysregulated in UC and constitute interesting targets for the development of alternative therapy options. Thus, we investigated the effect of the second generation HDAC inhibitor (HDACi) quisinostat in five UC cell lines (UCC) and two normal control cell lines in comparison to romidepsin, a well characterized HDACi which was previously shown to induce cell death and cell cycle arrest. In UCC, quisinostat led to cell cycle alterations, cell death induction and DNA damage, but was well tolerated by normal cells. Combinations of quisinostat with cisplatin or the PARP inhibitor talazoparib led to decrease in cell viability and significant synergistic effect in five UCCs and platinum-resistant sublines allowing dose reduction. Further analyses in UM-UC-3 and J82 at low dose ratio revealed that the mechanisms included cell cycle disturbance, apoptosis induction and DNA damage. These combinations appeared to be well tolerated in normal cells. In conclusion, our results suggest new promising combination regimes for treatment of UC, also in the cisplatin-resistant setting.
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Apoptosis , Inhibidores de Histona Desacetilasas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Vejiga Urinaria , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Daño del ADN/efectos de los fármacos , Sinergismo Farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patologíaRESUMEN
Importance: Studies with nivolumab, an approved therapy for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy, demonstrate improved outcomes with added high-dose ipilimumab. Objective: To assess efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for mUC. Design, Setting, and Participants: In this phase 2 nonrandomized trial, patients with mUC composed 2 cohorts. Cohort 1 received first-line or second-/third-line nivolumab with escalating doses of ipilimumab, and cohort 2 received second-/third-line nivolumab with high-dose ipilimumab. Recruitment spanned 26 sites in Germany and Austria from August 8, 2017, to February 18, 2021. All patients had a 70% or higher Karnofsky Performance Score and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1. Interventions: All patients initiated 4 doses of 240-mg nivolumab (1× every 2 wk). Week 8 nonresponders received nivolumab + ipilimumab (1× every 3 wk). Cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab if no response. Due to safety concerns, cohort 1 treatment was halted, and first-line cohort 2 treatment was not pursued. Cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders continued with nivolumab maintenance but could receive nivolumab + ipilimumab for later progression. Main Outcomes and Measures: The primary end point was objective response rate. Results: The study comprised 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years): 86 in cohort 1 (42 first-line; 44 second-/third-line) and 83 in cohort 2. The median (IQR) follow-up times were 10.4 (4.2-23.5) months (first-line cohort 1), 7.5 (3.1-23.8) months (second-/third-line cohort 1), and 6.2 (3.2-22.7) months (cohort 2). Response rates to nivolumab induction were 12/42 (29%, first-line cohort 1), 10/44 (23%, second-/third-line cohort 1), and 17/83 (20%, cohort 2). Response rates to a tailored approach were 20/42 (48% [90% CI, 34%-61%], first-line cohort 1), 12/44 (27% [90% CI, 17%-40%], second-/third-line cohort 1), and 27/83 (33% [90% CI, 23%-42%], cohort 2). Three-year overall survival rates for first-line cohort 1, second-/third-line cohort 1, and cohort 2 using the Kaplan-Meier method were 32% (95% CI, 17%-49%), 19% (95% CI, 8%-33%), and 34% (95% CI, 23%-44%), respectively. Conclusions and Relevance: In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with mUC. Trial Registration: ClinicalTrials.gov Identifier: NCT03219775.
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Protocolos de Quimioterapia Combinada Antineoplásica , Ipilimumab , Nivolumab , Humanos , Nivolumab/uso terapéutico , Nivolumab/administración & dosificación , Ipilimumab/uso terapéutico , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Masculino , Anciano , Femenino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , Adulto , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias Urológicas/inmunología , Metástasis de la Neoplasia , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/inmunología , Inmunoterapia/métodos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/inmunologíaRESUMEN
Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label instillation therapy into the bladder. To reduce potential side effects, continuous efforts are made to optimise the therapeutic potential of drugs, thereby reducing the effective dose and consequently the pharmacological burden of the medication. We recently demonstrated that it is possible to significantly increase the therapeutic efficacy of mitomycin C against a bladder carcinoma cell line by exposure to non-toxic doses of blue light (453 nm). In the present study, we investigated whether the therapeutically supportive effect of blue light can be further enhanced by the additional use of the wavelength-specific photosensitiser riboflavin. We found that the gemcitabine-induced cytotoxicity of bladder cancer cell lines (BFTC-905, SW-1710, RT-112) was significantly enhanced by non-toxic doses of blue light in the presence of riboflavin. Enhanced cytotoxicity correlated with decreased levels of mitochondrial ATP synthesis and increased lipid peroxidation was most likely the result of increased oxidative stress. Due to these properties, blue light in combination with riboflavin could represent an effective therapy option with few side effects and increase the success of local treatment of bladder cancer, whereby the dose of the chemotherapeutic agent used and thus the chemical load could be significantly reduced with similar or improved therapeutic success.
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Luz Azul , Gemcitabina , Riboflavina , Neoplasias de la Vejiga Urinaria , Humanos , Adenosina Trifosfato/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Gemcitabina/farmacología , Peroxidación de Lípido/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Riboflavina/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
AIMS: This retrospective claims data study characterized real-world treatment patterns, healthcare resource utilization (HCRU), and costs in patients with metastatic urothelial carcinoma (mUC) in Germany. MATERIALS AND METHODS: Continuously insured adults with incident mUC diagnosis (=index; ICD-10: C65-C68/C77-C79) in 2015-2019 were identified from two German claims databases. Patients who received first-line (1 L) treatment within 12 months of index were divided into three mutually exclusive sub-cohorts: platinum-based chemotherapy (PB-CT), non-PB-CT, and immunotherapy (IO). Patient characteristics were assessed during a 24-month baseline period; treatments, HCRU, and costs (of the health insurance fund) per patient-year (ppy) were described during 12-month follow-up. RESULTS: We identified 3,226 patients with mUC (mean age, 73.8 years; male, 70.8%; mean Elixhauser Comorbidity Index, 17.6); 1,286 (39.9%) received 1 L treatment within 12 months of index. Of these, 825 (64.2%) received PB-CT, 322 (25.0%) non-PB-CT, and 139 (10.8%) IO. On average, treated patients had 5.1 hospitalizations ppy. Most UC-related hospitalizations ppy were observed in the PB-CT cohort (5.8), followed by the non-PB-CT (4.2) and IO (2.3) cohorts. Mean UC-related hospitalization costs ppy were 22,218 in the treated cohort, 24,294 in PB-CT, 19,079 in IO, and 18,530 in non-PB-CT cohorts. Cancer-related prescription costs ppy averaged 6,323 in treated patients, and 25,955 in IO, 4,318 in non-PB-CT, and 4,270 in PB-CT cohorts. LIMITATIONS: We recognized limitations in our study's sample selection due to unavailable mUC disease status data. We addressed this through an upstream feasibility study conducted in consultation with clinical experts to determine a suitable proxy. Proxies were also used to delineate treatment lines, switches, and discontinuations due to data absence. Furthermore, due to data restrictions, collective dataset analysis was not possible, prompting a meta-analysis for pooled results. CONCLUSIONS: The study shows that mUC is associated with significant HCRU and costs across different types of 1 L systemic therapy.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Adulto , Anciano , Humanos , Masculino , Atención a la Salud , Costos de la Atención en Salud , Seguro de Salud , Estudios Retrospectivos , FemeninoRESUMEN
PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.
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Moléculas de Adhesión Celular , Amplificación de Genes , Humanos , Moléculas de Adhesión Celular/genética , Masculino , Femenino , Anciano , Persona de Mediana Edad , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Hibridación Fluorescente in Situ , Variaciones en el Número de Copia de ADN , Anciano de 80 o más Años , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/genética , Neoplasias Urológicas/patología , NectinasRESUMEN
Aim: This study assessed real-world treatment in patients with metastatic urothelial carcinoma (mUC) in Germany. Materials & methods: Patients diagnosed with mUC from 2015 to 2019 were identified in two claims databases: AOK PLUS and GWQ. Results: 3226 patients with mUC were analyzed; 1286 (39.9%) received systemic treatment within 12 months of diagnosis (platinum-based chemotherapy: 64.2%). Factors associated with receiving treatment were: younger age, male sex, less comorbidity and recent diagnosis. In AOK PLUS and GWQ populations, unadjusted median overall survival (interquartile range) from diagnosis in treated patients was 13.7 (6.8-32.9) and 13.8 (7.1-41.7) months, and in untreated patients was 3.0 (1.2-10.8) and 3.6 (1.2-18.8) months, respectively. Conclusion: A significant proportion of patients with mUC in Germany receive no systemic treatment.
What is this article about? This article reports the results from a study in Germany between 2015 and 2019 that investigated how advanced bladder cancer that has spread to other organs was treated and how long people lived after diagnosis. The study looked at systemic therapies, which means treatments that affect the entire body.What were the results? Only 40% of people diagnosed with advanced bladder cancer received systemic treatment within the first 12 months. Of those who did receive systemic treatment, the majority received combination therapy that included a chemotherapy drug containing platinum (64%). Systemic treatment was more likely to be given to people who were younger, less sick, male, or more recently diagnosed. After 12 months, 56% of treated people were still alive, compared with 26% of people without treatment. On average, people who received systemic treatment lived for about 14 months, while people without systemic treatment lived for only 3 to 4 months.What do the results of the study mean? Many people with advanced bladder cancer in Germany do not receive systemic treatment. People who receive treatment are likely to live longer than those who do not receive treatment.
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Carcinoma de Células Transicionales , Humanos , Masculino , Femenino , Anciano , Estudios Retrospectivos , Alemania/epidemiología , Persona de Mediana Edad , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/secundario , Carcinoma de Células Transicionales/terapia , Resultado del Tratamiento , Anciano de 80 o más Años , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/patología , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/terapia , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Metástasis de la NeoplasiaRESUMEN
In the context of the COVID-19 pandemic, there has been a scarcity of resources with various effects on the care of cancer patients. This paper provides an English summary of a German guideline on prioritization and resource allocation for colorectal and pancreatic cancer in the context of the pandemic. Based on a selective literature review as well as empirical and ethical analyses, the research team of the CancerCOVID Consortium drafted recommendations for prioritizing diagnostic and treatment measures for both entities. The final version of the guideline received consent from the executive boards of nine societies of the Association of Scientific Medical Societies in Germany (AWMF), 20 further professional organizations and 22 other experts from various disciplines as well as patient representatives. The guiding principle for the prioritization of decisions is the minimization of harm. Prioritization decisions to fulfill this overall goal should be guided by (1) the urgency relevant to avoid or reduce harm, (2) the likelihood of success of the diagnostic or therapeutic measure advised, and (3) the availability of alternative treatment options. In the event of a relevant risk of harm as a result of prioritization, these decisions should be made by means of a team approach. Gender, age, disability, ethnicity, origin, and other social characteristics, such as social or insurance status, as well as the vehemence of a patient's treatment request and SARS-CoV-2 vaccination status should not be used as prioritization criteria. The guideline provides concrete recommendations for (1) diagnostic procedures, (2) surgical procedures for cancer, and (3) systemic treatment and radiotherapy in patients with colorectal or pancreatic cancer within the context of the German healthcare system.
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COVID-19 , Neoplasias Colorrectales , Neoplasias Pancreáticas , Asignación de Recursos , SARS-CoV-2 , Humanos , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/diagnóstico , COVID-19/epidemiología , Alemania , Asignación de Recursos para la Atención de Salud/organización & administración , Prioridades en Salud , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/epidemiología , Pandemias , Guías de Práctica Clínica como AsuntoAsunto(s)
Anticuerpos Monoclonales , Carcinoma de Células Transicionales , Neoplasias Urológicas , Humanos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológicoRESUMEN
Many systemic treatments used in genitourinary oncology negatively affect haematopoiesis, thus leading to neutropenia. Neutropenic patients are vulnerable to bacterial, and other infections. Often fever is the only symptom in these patients. Neutropenic fever is a major threat for these patients, as it may lead to life-threatening therapy complications that significantly impair the patient's quality of life, Moreover, it may also worsen the prognosis due to therapy delays or necessary dose modifications. Granulocyte colony stimulating factors (GCSF), which can improve neutrophil granulocyte formation, are used both for supportive treatment in febrile neutropenia and for its prophylaxis. The correct indication for such GCSF support depends on the general risk of febrile neutropenia of the therapy used, as well as on individual patient factors and the treatment intent (palliative vs. curative). Based on the current recommendations both of the German and international guidelines, this article aims to provide an up-to-date and practice-oriented overview of the use of GCSF in uro-oncology.
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Neutropenia Febril , Factor Estimulante de Colonias de Granulocitos , Humanos , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Calidad de Vida , Neutrófilos , Fiebre/tratamiento farmacológico , Fiebre/etiología , Fiebre/prevención & control , Neutropenia Febril/complicaciones , Neutropenia Febril/tratamiento farmacológicoRESUMEN
Clinical trials revealed significant antitumor activity for immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC). Due to their strict eligibility criteria, clinical trials include selected patient cohorts, and thus do not necessarily represent real-world population outcomes. In this multicentric, retrospective study, we investigated real-world data to assess the effectiveness of pembrolizumab and atezolizumab and to evaluate the prognostic value of routinely available clinicopathological and laboratory parameters. Clinical and follow-up data from mUC patients who received ICIs (01/2017-12/2021) were evaluated. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) were used as endpoints. Patients' (n = 210, n = 76 atezolizumab and 134 pembrolizumab) median OS and PFS were 13.6 and 5.9 months, respectively. Impaired ECOG-PS, the presence of visceral, liver or bone metastases, and hemoglobin levels were independently associated with poor OS and DCR. Furthermore, Bellmunt risk factors and the enhanced Bellmunt-CRP score were shown to be prognostic for OS, PFS and DCR. In conclusion, ICIs are effective treatments for a broad range of mUC patients. Our results confirmed the prognostic value of numerous risk factors and showed that Bellmunt risk scores can further be improved when adding CRP to the model.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , RadioinmunoterapiaRESUMEN
PURPOSE: In patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the Androgen Receptor Antagonizing Agent for Metastasis-free Survival (ARAMIS) trial, darolutamide significantly improved median metastasis-free survival by nearly 2 years and reduced the risk of death by 31% versus placebo, with a favourable safety/tolerability profile. This post hoc analysis of ARAMIS evaluated efficacy and safety in patients by number of comorbidities and concomitant medications. METHODS: Patients with nmCRPC were randomised 2:1 to darolutamide (n = 955) or placebo (n = 554) while continuing androgen-deprivation therapy. Overall survival (OS) and treatment-emergent adverse events (TEAEs) were evaluated in subgroups by median numbers of ongoing comorbidities and concomitant medications. HRs were determined from univariate analysis using Cox regression. FINDINGS: Median numbers of comorbidities and concomitant medications were 6 and 10, respectively, with 41.6% of patients having >6 comorbidities and 48.8% taking >10 concomitant medications. For patients with ≤ 6 and >6 comorbidities, darolutamide increased OS versus placebo (hazard ratio [HR] 0.65 and 0.73, respectively), and this benefit was consistent for cardiovascular, metabolic, and other comorbidities (HR range: 0.39-0.88). For patients taking ≤ 10 and >10 concomitant medications, increased OS was also observed with darolutamide versus placebo (HR 0.76 and 0.66, respectively), and the benefit was consistent across medication classes (HR range: 0.45-0.80). Incidences of TEAEs and TEAEs leading to treatment discontinuation with darolutamide were similar to placebo across subgroups by numbers of comorbidities and concomitant medications. CONCLUSIONS: The OS benefit and safety of darolutamide remained consistent with that observed in the overall ARAMIS population, even in patients with high numbers of comorbidities or concomitant medications. GOV REGISTRATION: NCT02200614. TWEETABLE ABSTRACT: Darolutamide increased overall survival versus placebo, and incidences of most adverse events were similar between treatments in patients with ≤ 6 or >6 comorbidities and those taking ≤ 10 or >10 concomitant medications.
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Antagonistas de Andrógenos , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Antagonistas de Andrógenos/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Pirazoles , PacientesRESUMEN
Background: Treatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials. Objective: To analyze the efficacy and safety of EV in a cohort of real-world patients. Design setting and participants: Retrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards. Outcome measurements and statistical analysis: Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results and limitations: The median age for the 125 eligible patients was 66 yr (range 31-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 for 76.0%, 2-4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20-12.80) and median PFS was 5.0 mo (95% confidence interval 4.34-5.67). For patients with ECOG PS of 0-1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up. Conclusions: Administration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC. Patient summary: Enfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment.
RESUMEN
Muscle-invasive urothelial carcinoma of the bladder (MIBC) has been treated with cisplatin-based chemotherapy for over 30 years. With the advent of immune checkpoint inhibitors, antibody drug conjugates and FGFR3 inhibitors new therapeutic options have been approved for patients with urothelial carcinoma (UC) and are still under investigation regarding association between patients' response and recently defined molecular subtypes. Unfortunately, similar to chemotherapy, only a fraction of UC patients responds to these new treatment approaches. Thus, either further new efficacious therapeutic options for treatment of individual subtypes or new approaches to overcome treatment resistance and to increase patients' response to standard of care treatment are needed.Epigenetic modifications of DNA and chromatin are known to mediate cellular plasticity or treatment resistance, and the responsible epigenetic regulators are frequently mutated or aberrantly expressed in UC. Thus, these enzymes provide targets for novel drug combination therapies to "episensitize" toward approved standard therapies by epigenetic priming. In general, these epigenetic regulators comprise writers and erasers like DNA methyltransferases and DNA demethylases (for DNA methylation), histone methyltransferases and histone demethylases (for histone methylation), as well as acetyl transferases and histone deacetylases (for histone and nonhistone acetylation). Such modifications, e.g., acetyl groups, are recognized by further epigenetic reader proteins, e.g., like the bromodomain and extra-terminal domain (BET) family proteins that often interact in multi-protein complexes and finally regulate chromatin conformation and transcriptional activity.Concurringly, epigenetic regulators target a plethora of cellular functions. Their pharmaceutical inhibitors often inhibit enzymatic activity of more than one isoenzyme or may have further noncanonical cytotoxic effects. Thus, analysis of their functions in UC pathogenesis as well as of the antineoplastic capacity of corresponding inhibitors alone or in combination with other approved drugs should follow a multidimensional approach. Here, we present our standard approach to analyze cellular effects of new epigenetic inhibitors on UC cells alone to define their potency and to conclude on putative reasonable combination therapy partners. We further describe our approach to identify efficacious synergistic combination therapies (e.g., with cisplatin or PARP inhibitors) that may have reduced normal toxicity through dose reduction, which can then be further analyzed in animal experiments. This approach may also serve as prototype for the preclinical evaluation of other epigenetic treatment approaches.
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Antineoplásicos , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Animales , Histonas/metabolismo , Cisplatino/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Metilación de ADN , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Epigénesis Genética , Cromatina/genética , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéuticoRESUMEN
Antibody drug conjugates (ADC) are a new class of agents that have been expanding the spectrum of treatment options in metastatic urothelial carcinoma only recently. Preliminary data suggest that these compounds may have the potential even to replace current standard treatments as platinum-based chemotherapies. To this end, current and future preclinical and translational evaluation of novel treatment strategies should consider these novel compounds in addition to current standard options as well. In this context, the following article will provide an overview of this new class of agents, starting with general information on molecular structure and mode of action, clinical use of ADCs in urothelial carcinoma, and ending with considerations for designing preclinical and translational experiments implementing ADCs.
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Carcinoma de Células Transicionales , Inmunoconjugados , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/secundario , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Inmunoconjugados/química , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
INTRODUCTION AND OBJECTIVE: BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, and CancerCheck® UBC® rapid VISUAL are urinary-based rapid tests. This multicenter study is the first study comparing all available rapid tests on a large cohort of bladder cancer patients and healthy controls in one setting. METHODS: In total 732 urine samples (second morning urine) in a real-world assessment have been analyzed. We evaluated clinical samples from 464 patients with histologically confirmed urothelial tumors of the urinary bladder (17 solitary CIS, 189 low-grade, 187 high-grade nonmuscle invasive, 71 high-grade muscle invasive), 77 patients with No Evidence of Disease (NED), and from 191 healthy controls. Urine samples were analyzed by the BTA stat®, NMP22® BladderChek®, UBC® Rapid Test point-of-care (POC) system using the concile Omega 100 POC reader, and CancerCheck® UBC® rapid VISUAL. Sensitivities and specificities were calculated by contingency analyses. RESULTS: All investigated urinary markers detected more pathological concentrations in urine of bladder cancer patients compared to tumor-free patients. The calculated diagnostic sensitivities for BTA stat®, NMP22® BladderChek®, UBC® Rapid Test, CancerCheck® UBC® rapid VISUAL, and cytology were 62.4%, 13.4%, 58.2%, 28.6%, 36.2% for low-grade, 83.4%, 49.5%, 84.5%, 63.1%, 71.2% for high-grade nonmuscle invasive, and 95.8%, 35.2%, 76.1%, 50.7%, 67.7% for high-grade muscle-invasive bladder cancer. The specificity was 67.9%, 95.5%, 79.4%, 94.4%, and 83.7%, respectively. The area under the curve (AUC) after receiver operating characteristics (ROC) analysis for high-grade non-muscle-invasive tumors was 0.757, 0.725, 0.819, 0.787, and 0.774, respectively. CONCLUSIONS: The analysis of more than 700 urine samples offers an objective view on urine-based rapid diagnostics. Elevated pathological concentrations of markers in urine of bladder cancer patients were detected in all investigated tests. The highest sensitivities for high-grade non-muscle-invasive tumors were calculated for BTA stat® and UBC® Rapid Test, whereas NMP22® BladderChek®, and cytology showed the highest specificities. BTA stat® and UBC® Rapid Test have the potential to be used as a clinical valuable urinary protein biomarker for the detection of high-grade non-muscle-invasive bladder cancer patients and could be included in the management of these tumors.
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Biomarcadores de Tumor , Neoplasias de la Vejiga Urinaria , Humanos , Biomarcadores de Tumor/orina , Neoplasias de la Vejiga Urinaria/patología , Proteínas Nucleares/orina , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Several studies indicate, particularly in the case of [18F]PSMA-1007, a relatively high rate of detection of ganglia in PSMA PET imaging. Ganglia are an integral part of the sympathetic portion of the autonomous nervous system. To date, no studies have directly compared [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 ganglionic uptake intra-individually and analyzed the underlying molecular and physical mechanisms of different detection rates. With this monocentric retrospective study, we sought to evaluate the intra-individual physiological ganglion uptake of these different PSMA ligands in evidence-based imaging for prostate cancer. METHODS: Our cohort consists of 19 male patients (median age 72 ± 9 with a range of 56-85) with biochemical recurrence of prostate cancer who underwent both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT in our clinic on the same scanner per standard care between March 2015 and March 2022. Tracer uptake was quantified according to maximum standardized uptake value (SUVmax) for both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT scans. Ganglia-to-background ratios (GBRs) were determined to quantify the image contrast through dividing the SUVmax of the ganglia by the background value (SUVmax of blood pool in the descending aorta, fatty tissue, and skeletal muscle in gluteal region). We used descriptive analyses for demographics and tumor characteristics and performed two-way repeated-measures ANOVA (analysis of variance) for SUV metrics including GBR measurements. RESULTS: In total, we examined 101 ganglia with [18F]PSMA-1007 scanning, localized mostly in pairs as stellate, coeliac, and sacral, of which 76 were also detected with [68Ga]Ga-PSMA-11 PET/CT scanning. There was no statistically significant difference in PSMA uptake in terms of SUVmax between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 (p value: 0.052). In contrast, the comparison of GBRs revealed a higher detectability rate of ganglia with [18F]PSMA-1007 imaging (p < 0.001). Furthermore, a separate comparison of ganglia with respect to their anatomical location also demonstrated statistically significant differences both within and between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 PET/CT scans. CONCLUSION: Given the impression of more accentuated [18F]PSMA-1007 uptake in ganglia compared with 68Ga-labelled counterparts, our study demonstrated that the better detectability of ganglia is not due to more intense [18F]PSMA-1007 uptake by these small structures but to much more favorable physical properties of the radionuclide 18F. The most relevant limitations of our study are its retrospective design and the small patient cohort.
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Guidelines can only give treatment recommendations for defined patient groups if high quality and meaningful evidence is available. However, patients included in clinical trials for the treatment of metastatic and/or locally advanced bladder cancer (mUC) are generally not representative for the spectrum of patients encountered in daily clinical practice. In particular, patients with different systemic pretreatments, variable prestudy responses or variable time to tumor progression are not sufficiently considered in trials and guideline recommendations. Accordingly, recommendations for the treatment of mUC patients with previous perioperative systemic therapy are lacking. To provide some guidance for daily uro-oncological practice despite the limited evidence, we sought to develop expert opinion-based treatment recommendations. These recommendations focus on palliative first-line therapy of mUC. Both perioperative pretreatment with classical cisplatin-based systemic therapy and/or immunotherapy, as well as the time to tumor recurrence have been considered.
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Neoplasias de la Vejiga Urinaria , Vejiga Urinaria , Humanos , Vejiga Urinaria/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Cisplatino/uso terapéutico , InmunoterapiaRESUMEN
BACKGROUND: Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. METHODS: TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. FINDINGS: Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0·0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. INTERPRETATION: Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. FUNDING: Bristol Myers Squibb.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Adulto , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Nivolumab/efectos adversos , Ipilimumab/efectos adversos , Carcinoma de Células Transicionales/tratamiento farmacológico , Platino (Metal) , Inmunoterapia/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
OBJECTIVES: The treatments for high-grade non-muscle invasive bladder cancer (NMIBC) vary between bladder preserving intravesical approaches and radical cystectomy. The impact of these treatments on health-related quality of life may vary widely. The purpose of this study was to elicit the general public's perspective on quality of life, measured as utility scores associated with treatment for Bacillus Calmette-Guerin (BCG)-unresponsive NMIBC and disease progression, for supporting economic evaluation of newly developed treatments for NMIBC. MATERIALS AND METHODS: Part I involved the development and testing of health states describing NMIBC, which was informed by a rapid review, expert input and a patient advisor. Part II involved elicitation of societal utility values for the different health states. Time trade-off (TTO) interviews were conducted with members of the UK general public. Five health states described different NMIBC scenarios including disease recurrence and progression. Participants ranked each health state, followed by the TTO valuation exercise. Descriptors included NMIBC symptom severity, impact and treatment characteristics. RESULTS: In total, 202 members of the general public participated. The mean age was 46 (standard deviation [SD] 14.6) years. Sample mean (SD) EQ-5D-5L visual analogue scale (VAS) and index scores were 83.2 (12.3) and 0.89 (0.18), respectively. Mean utilities were 0.781 for No High-Grade Recurrence, 0.586 for High-Grade Recurrence, 0.572 for > 1-Year Post-cystectomy and 0.283 for metastatic disease. The First Year Post-cystectomy path health state had a mean utility of 0.288. Pairwise comparisons found statistically significant differences between utilities (p < 0.001), except between High-Grade Recurrence and > 1-Year Post-cystectomy (p = 0.524). There were significant differences in utility scores by age and employment status. CONCLUSION: This study provides utility scores for health states describing living with NMIBC, which is associated with a significant health-related quality-of-life burden. These values address an existing gap in available data and have the potential to be used in models evaluating the cost-effectiveness of both current and newly developed treatments for bladder cancer.
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BACKGROUND: Primary retroperitoneal lymph node dissection (RPLND) for clinical stage (CS) IIA/B seminoma without adjuvant treatment is an experimental treatment to avoid radiotherapy- or chemotherapy-related toxicity from standard treatment. OBJECTIVE: The PRIMETEST trial aimed to prospectively evaluate the oncological efficacy and surgical safety of primary RPLND. DESIGN, SETTING, AND PARTICIPANTS: PRIMETEST is a single-arm, single-center prospective phase 2 trial. Patients with seminoma, unilateral retroperitoneal lymph node metastases <5 cm, and human chorionic gonadotropin levels <5 mU/ml were included. Patients with CS IIA/B seminoma at initial diagnosis, and recurrence under active surveillance or following adjuvant carboplatin for CS I disease were eligible. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Unilateral open or robot-assisted primary RPLND was performed. The primary endpoint of the study was progression-free survival (PFS) after 36 mo. The trial was considered positive if <30% of patients experienced a recurrence. RESULTS AND LIMITATIONS: Between 2016 and 2021, 33 patients were accrued (nine with primary CS IIA/B, 19 recurrences during active surveillance, and five recurrences following adjuvant carboplatin). Thirteen and 20 patients had CS IIA and IIB, respectively. Open and robot-assisted RPLND procedures were performed in 14 (42%) and 19 (58%) patients, respectively. After a median follow-up of 32 mo (interquartile range 23-46), ten recurrences were detected (30%, 95% confidence interval: 16-49%); thus, the primary endpoint was not met. Infield recurrences occurred in three of ten patients. The current analysis of risk factors could not identify the predictors of recurrence. Three of 33 patients (9%) presented with pN0. CONCLUSIONS: The PRIMETEST trial did not meet its primary endpoint. Nevertheless, PFS of 70% after a median follow-up of 32 mo suggests this approach to be of interest for highly selected patients. Selection criteria, however, need to be defined and validated in a larger prospective cohort of patients. Until then, surgery alone for the treatment of patients with CS IIA/B seminoma cannot be recommended outside of a clinical trial setting. PATIENT SUMMARY: In this study, we investigated primary surgery as an alternative to conventional treatment (chemotherapy or radiation therapy) in patients with metastatic seminoma. The primary objective of the study, to prevent at least 30% of patients from recurrence, was not met. However, certain patients may benefit from this approach and thereby avoid chemotherapy or radiation therapy. Predictive factors need to be analyzed to better select patients for this surgery-only approach.