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BACKGROUND: The first approvals of novel systemic therapies within recent years for metastatic hormone-sensitive (mHSPC) were mainly based on improved overall survival (OS) and time to castration resistance (ttCRPC) in mHSPC patients stratified according to CHAARTED low (LV) versus high volume (HV) and LATITUDE low (LR) versus high-risk (HR) disease. METHODS: Relying on our institutional tertiary-care database we identified all mHSPC stratified according to CHAARTED LV versus HV, LATITUDE LR versus HR and the location of the metastatic spread (lymph nodes (M1a) versus bone (M1b) versus visceral/others (M1c) metastases. OS and ttCRPC analyses, as well as Cox regression models were performed according to different metastatic categories. RESULTS: Of 451 mHSPC, 14% versus 27% versus 48% versus 12% were classified as M1a LV versus M1b LV versus M1b HV versus M1c HV with significant differences in median OS: 95 versus 64 versus 50 versus 46 months (p < 0.001). In multivariable Cox regression models HV M1b (Hazard Ratio: 2.4, p = 0.03) and HV M1c (Hazard Ratio: 3.3, p < 0.01) harbored significant worse than M1a LV mHSPC. After stratification according to LATITUDE criteria, also significant differences between M1a LR versus M1b LR versus M1b HR versus M1c HR mHSPC patients were observed (p < 0.01) with M1b HR (Hazard Ratio: 2.7, p = 0.03) and M1c HR (Hazard Ratio: 3.5, p < 0.01), as predictor for worse OS. In comparison between HV M1b and HV M1c, as well as HR M1b versus HR M1c no differences in ttCRPC or OS were observed. CONCLUSIONS: Significant differences exist between different metastatic patterns of HV and LV and HR and LR criteria. Best prognosis is observed within M1a LV and LR mHSPC patients.
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BACKGROUND: To evaluate the impact of prostate-specific antigen (PSA) nadir, PSA response and time to PSA nadir (TTN) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies. METHODS: Different PSA nadir cut-offs (including ultra-low PSA) were tested for OS analyses. Additionally, PSA response ≥99% was evaluated, as well as TTN categorized as <3 versus 3-6 versus 6-12 versus >12 months. Multivariable Cox regression models predicted the value of PSA nadir cut-offs, PSA response and TTN on OS. Sensitivity analyses were performed in de novo and high volume mHSPC patients. RESULTS: Of 238 eligible patients, PSA cut-offs of <0.2 versus 0.2-4.0 versus >4.0 ng/mL differed significantly regarding median OS (96 vs. 56 vs. 44 months, p < 0.01), as well as in subgroup analyses of de novo mHSPC patients and multivariable Cox regression models. A more stringent PSA cut-off of <0.02 versus 0.02-0.2 versus >0.2 ng/mL also yielded significant median OS differences (not reached vs. 96 vs. 50 months, p < 0.01), even after additional multivariable adjustment. A PSA response ≥99% was also significantly associated with better OS than counterparty with <99% response, even after multivariable adjustment (both p < 0.02). When TTN groups were compared, patients with longer TTN harbored more extended OS than those with short TTN (<3 vs. 3-6 vs. 6-12 vs. >12 months: 34 vs. 50 vs. 67 vs. 96 months, p < 0.01). Virtually similar results were observed in sensitivity analyses for high volume mHSPC patients. CONCLUSIONS: In times of combination therapies for mHSPC, a PSA nadir of respectively, <0.2 and <0.02 ng/mL are associated with best OS rates. Moreover, a relative PSA response ≥99% and a longer TTN are clinical important proxies for favorable OS estimates.
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Antígeno Prostático Específico , Neoplasias da Próstata , Humanos , Masculino , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Idoso , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Fatores de TempoRESUMO
Lymphoepithelioma-like carcinoma of the bladder (LELC-B) is a rare histologic subtype characterized by strong immune cell (IC) infiltrates. A better prognosis and favorable response rates to immune checkpoint inhibitors have been described. We aimed to characterize the molecular profiles and IC infiltration of LELC-B for a better understanding of its therapeutic implications. We identified 11 muscle-invasive bladder cancer cases with pure and mixed LELC-B. Programmed cell death ligand-1 (PD-L1) expression and mismatch repair proteins were evaluated using immunohistochemistry. We calculated the tumor mutational burden and characterized mutational profiles using whole-exome DNA sequencing data. Transcriptomic signatures were detected using the NanoString nCounter PanCancer IO360 Panel. Multiplex immunofluorescence of tumor microenvironment (PD-L1, PanCK, α-SMA, vimentin, CD45, and Ki67) and T cells (CD4, CD3, PD-1, CD163, CD8, and FoxP3) was used to quantify cell populations. All LELC-B cases were highly positive for PD-L1 (median tumor proportion score/tumor cell, 70%; range, 20%-100%; median combined positive score, 100; range, 50-100) and mismatch repair proficient and negative for Epstein-Barr virus infection. IC infiltrates were characterized by a high CD8+ T-cell count and high PD-1/PD-L1 expression on immune and tumor cells. LELC-B showed upregulation of signaling pathways involved in IC response. Most common mutations were found in chromatin remodeling genes causing epigenetic dysregulation. All LELC-B cases showed high tumor mutational burden with a median of 39 mutations/Mb (IQR, 29-66 mutations/Mb). In conclusion, LELC-B is a highly immunogenic tumor, showing strong upregulation of PD-1/PD-L1 and making immune checkpoint inhibitors a promising treatment option.
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OBJECTIVE: To investigate alterations of homologous recombination repair (HRR) and especially BReast CAncer 1/2 (BRCA1/2) gene on overall survival (OS). Moreover, to explore the effect of inhibition of poly(ADP-ribose)-polymerase (PARPi) as systemic therapy for metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Of all HRR-screened patients with metastatic prostate cancer, baseline characteristics were sampled. Kaplan-Meier estimates and multivariable Cox regression models predicted the effect of HRR/BRCA1/2 alterations on OS. RESULTS: Of 196 eligible patients, 61 (31%) harboured any HRR and 40 (20%) BRCA1/2 alterations. Of HRR alterations, 40 (66%) vs six (10%) vs five (8.2%) vs four (6.6%) vs two (3.3%) vs four (6.6%) were BRCA1/2 vs Ataxia-telangiectasia mutated kinase (ATM) vs checkpoint kinase 2 (CHEK2) vs cyclin-dependent kinase 12 (CDK12) vs Fanconi anaemia complementation Group A (FANCA) vs positive for other mutations. Of these, 30% received a PARPi. OS differed significantly between HRR-positive vs -negative patients. Specifically in hormone-sensitive prostate cancer, the median OS was 63 (HRR positive) vs 57 (BRCA1/2 positive) vs 113 months (HRR negative) (P ≤ 0.01). In mCRPC, OS was 42 (HRR positive) vs 41 (BRCA1/2 positive) vs 70 months (HRR negative) (P ≤ 0.01). HRR and BRCA1/2 alterations were associated with worse OS after multivariable adjustment. Finally, patients with mCRPC with BRCA1/2 mutation treated without PARPi harboured worse OS than patients with BRCA1/2 mutation and PARPi therapy (median OS: 33 vs 48 months, P < 0.03). CONCLUSION: Incidence of HRR alteration in a clinical real-world setting is high when using blood- and tissue-based tests. Patients with HRR/BRCA alterations have worse outcomes resulting in significant OS differences between HRR/BRCA-positive patients with mCRPC with and without PARPi usage vs HRR/BRCA-negative patients.
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BACKGROUND: Squamous cell carcinoma (SCC) of the urinary bladder is the most common non-urothelial variant histology. Currently, upfront radical cystectomy is the gold standard for non-metastatic SCC of the bladder. However, several studies have shown that SCC of the bladder is associated with higher aggressiveness and worse survival outcomes, such as progression-free and cancer-specific survival, relative to the urothelial histological subtype. Moreover, metastatic SCC seems to poorly respond to systemic treatments and/or radiotherapy. SUMMARY: This review summarizes the current knowledge and medical evidence regarding local and systematic treatment of mSCC of the bladder, including a case series of four initially locally advanced and later metastatic SCC patients of our tertiary care hospital. KEY MESSAGES: Despite being the second most common variant histology of bladder cancer, current therapies for SCC do not provide satisfactory therapeutic responses.
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Carcinoma de Células Escamosas , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Bexiga Urinária/patologia , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/patologia , Cistectomia , Carcinoma de Células Escamosas/terapia , Carcinoma de Células de Transição/cirurgiaRESUMO
INTRODUCTION: Despite the prospective randomized controlled JAVELIN Bladder 100 trial, no real-world evidence exists regarding tumor characteristics, adverse events (AEs), and survival of avelumab maintenance (AVM)-treated patients with partial/complete response or stable disease after previous platinum-based chemotherapy for advanced/metastatic urothelial carcinoma (mUC). METHODS: We relied on our institutional database to identify mUC patients who received AVM between January, 2021 and December, 2023. The main outcomes consisted of overall survival (OS) and progression-free survival (PFS) and were computed by Kaplan-Meier estimates. Stratification was performed according to programmed death ligand 1 (PD-L1) status. RESULTS: Overall, 24 AVM patients were identified at a median age of 71 (interquartile range [IQR]: 67-76) years, of which 67% were males. Of these, 63%, 21%, and 17% received AVM therapy for bladder cancer and upper tract urothelial carcinoma or both, respectively. PD-L1 status was positive in 45% of patients. During AVM treatment, AEs were observed in 33% of patients; however, they were limited to ≤2 grade AEs. At a median follow-up of eight (IQR 4-20) months, 71% of patients had progressed under AVM with median PFS of 6.2 months (confidence interval [CI]: 3.2-18.2). Median OS was 13.4 (CI: 6.9 - not reached [NR]) months. One-year OS after AVM was 52%. In PD-L1-positive patients, median PFS and OS were 6.4 (CI: 2.7 - NR) months and 13.4 (CI: 7.7 months - NR), respectively. CONCLUSION: AVM is associated with moderate AE rates. Despite similarities in baseline characteristics compared to trial-selected JAVELIN Bladder 100 mUC patients, AVM resulted in longer/similar PFS but significantly shorter OS in real-world setting.
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Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Masculino , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Idoso , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/secundário , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Taxa de Sobrevida , Quimioterapia de Manutenção , Estudos Retrospectivos , Metástase Neoplásica , Resultado do Tratamento , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To investigate characteristics and outcomes of oligometastatic hormone-sensitive prostate cancer (mHSPC) patients undergoing metastases-directed therapy (MDT) with external beam radiation therapy (EBRT). MATERIALS AND METHODS: We relied on an institutional tertiary-care database to identify mHSPC patients who underwent EBRT as MDT between 12/2019 and 12/2022. Main outcomes consisted of progression to metastatic castration-resistant prostate cancer (mCRPC) and overall mortality (OM). Oligometastatic was defined as ≤3 metastases and bone and/or lymph node deposits were treated with conventional doses up to 54 Gy or with hypofractionated stereotactic regimes of median 24 Gy (20-27 Gy). RESULTS: Overall, 37 patients treated with EBRT as MDT were identified. The median follow-up was 13 months. Median age at MDT was 71 years and 84% exhibited ECOG performance status 0. The median baseline PSA at diagnosis was 10 ng/mL. Overall, primary local therapy consisted of radical prostatectomy (65%), followed by external beam radiation therapy to the prostate (11%), focal therapy (8%), and palliative transurethral resection of the prostate (5%). Overall, 32% exhibited de novo oligometastatic mHSPC. Bone metastases were present in 78% versus 19% lymph node metastases versus 3% both. The distribution of targeted oligo-metastases was 62% versus 38% for respectively one metastasis versus more than one metastasis. Androgen deprivation therapy (ADT) was combined with MDT in 84%. Moreover, 19% received combination therapy with apalutamide/enzalutamide and 12% with abiraterone or docetaxel. The median time to mCRPC was 50 months. In incidence analyses, 13% developed mCRPC after 24 months. OM after 24 months was 15% in mHSPC patients receiving MDT. Significant OM differences were observed after stratification into targeted metastatic burden (<0.05). No high-grade adverse events were recorded during MDT. CONCLUSION: Our real-world data suggest that MDT represents a safe treatment option for well-selected oligometastatic mHSPC patients.
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Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Ressecção Transuretral da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/patologia , Antagonistas de Androgênios/uso terapêutico , Resultado do Tratamento , Hormônios/uso terapêuticoRESUMO
INTRODUCTION AND OBJECTIVE: Muscle-invasive urothelial bladder cancer (MIBC) is associated with limited response rates to systemic therapy, risk of recurrence and death. Tumor infiltrating immune cells have been associated with outcome and response to chemo-and immunotherapy in MIBC. We aimed to profile the immune cells in the tumor microenvironment (TME) to predict prognosis in MIBC and responses to adjuvant chemotherapy. METHODS: We performed multiplex immunohistochemistry (IHC) profiling and quantification of immune and stromal cells (CD3, CD4, CD8, CD163, FoxP3, PD-1, and CD45, Vimentin, αSMA, PD-L1, Pan-Cytokeratin, Ki67) in 101 patients with MIBC receiving radical cystectomy. We used uni- and multivariate survival analyses to identify cell types predicting prognosis. Samples were subdivided using K-means clustering for Treg and macrophage infiltration resulting in 3 clusters, Cluster 1: Treg high, cluster 2: macrophage high, cluster 3: Treg and macrophage low. Routine CD68 and CD163 IHC were analyzed with QuPath in an extended cohort of 141 MIBC. RESULTS: High concentrations of macrophages were associated with increased risk of death (HR 10.9, 95% CI 2.8-40.5; p < 0.001) and high concentrations of Tregs were associated with decreased risk of death (HR 0.1, 95% CI 0.01-0.7; p = 0.03) in the multivariate Cox-regression model adjusting for adjuvant chemotherapy, tumor and lymph node stage. Patients in the macrophage rich cluster (2) showed the worst OS with and without adjuvant chemotherapy. The Treg rich cluster (1) showed high levels of effector and proliferating immune cells and had the best survival. Cluster 1 and 2 both were rich in PD-1 and PD-L1 expression on tumor and immune cells. CONCLUSION: Treg and macrophage concentrations in MIBC are independent predictors of prognosis and are important players in the TME. Standard IHC with CD163 for macrophages is feasible to predict prognosis but validation to use immune-cell infiltration, especially to predict response to systemic therapies, is required.
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Antígeno B7-H1 , Linfócitos T Reguladores , Macrófagos Associados a Tumor , Neoplasias da Bexiga Urinária , Humanos , Músculos/patologia , Prognóstico , Receptor de Morte Celular Programada 1 , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Neoplasias da Bexiga Urinária/patologia , Linfócitos T Reguladores/imunologiaRESUMO
BACKGROUND: Molecular subtypes predict prognosis in muscle-invasive bladder cancer (MIBC) and are explored as predictive markers. To provide a common base for molecular subtyping and facilitate clinical applications, a consensus classification has been developed. However, methods to determine consensus molecular subtypes require validation, particularly when FFPE specimens are used. Here, we aimed to evaluate two gene expression analysis methods on FFPE samples and to compare reduced gene sets to classify tumors into molecular subtypes. METHODS: RNA was isolated from FFPE blocks of 15 MIBC patients. Massive analysis of 3' cDNA ends (MACE) and the HTG transcriptome panel (HTP) were used to retrieve gene expression. We used normalized, log2-transformed data to call consensus and TCGA subtypes with the consensusMIBC package for R using all available genes, a 68-gene panel (ESSEN1), and a 48-gene panel (ESSEN2). RESULTS: Fifteen MACE-samples and 14 HTP-samples were available for molecular subtyping. The 14 samples were classified as Ba/Sq in 7 (50%), LumP in 2 (14.3%), LumU in 1 (7.1%), LumNS in 1 (7.1%), stroma-rich in 2 (14.3%) and NE-like in 1 (7.1%) case based on MACE- or HTP-derived transcriptome data. Consensus subtypes were concordant in 71% (10/14) of cases when comparing MACE with HTP data. Four cases with aberrant subtypes had a stroma-rich molecular subtype with either method. The overlap of the molecular consensus subtypes with the reduced ESSEN1 and ESSEN2 panels were 86% and 100%, respectively, with HTP data and 86% with MACE data. CONCLUSION: Determination of consensus molecular subtypes of MIBC from FFPE samples is feasible using various RNA sequencing methods. Inconsistent classification mainly involves the stroma-rich molecular subtype, which may be the consequence of sample heterogeneity with (stroma)-cell sampling bias and highlights the limitations of bulk RNA-based subclassification. Classification is still reliable when analysis is reduced to selected genes.
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Biomarcadores Tumorais , Neoplasias da Bexiga Urinária , Humanos , Biomarcadores Tumorais/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Perfilação da Expressão Gênica/métodos , RNA , Músculos/patologiaRESUMO
PURPOSE: To determine the role of biopsy experience regarding a potential benefit of additional systematic biopsies and fusion failures during MRI-targeted biopsy of the prostate. SUBJECTS/PATIENTS AND METHODS: We retrospectively evaluated 576 men undergoing transrectal (MRI)-targeted biopsy of the prostate by seven residents in urology between November 2019 and March 2022. Benefit of systematic biopsies (detection of ISUP ≥ 2 PCa (clinically significant PCa (csPCa)) solely in systematic biopsies) and fusion failure (detection of csPCa during systematic biopsies in the area of a reported MRI-lesion and no detection of csPCa in targeted biopsy) were compared by growing biopsy experience levels. Multivariable regression analyses were calculated to investigate the association with benefit of systematic biopsies and fusion failure. RESULTS: The overall PCa detection rate was 72% (413/576). A benefit of systematic biopsies was observed in 11% (63/576); of those, fusion failure was seen in 76% (48/63). Benefit of systematic biopsies and fusion failure were more common among residents with very low experience compared to highly experienced residents (18% versus 4%, p = 0.026; 13% versus 3%, p = 0.015, respectively). Increasing biopsy experience was associated with less benefit from systematic biopsies (OR: 0.98, 95% CI 0.97-0.99) and less fusion failure (OR: 0.98, 95% CI 0.97-0.99). CONCLUSIONS: The benefit of systematic biopsies following targeted biopsy decreases with growing biopsy experience. The higher risk of fusion failure among inexperienced residents necessitates systematic biopsies to ensure the detection of csPCa. Further prospective trials are warranted before a targeted only approach can be recommended in routine clinical practice.
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Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/diagnóstico por imagem , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Biópsia Guiada por Imagem , Imageamento por Ressonância MagnéticaRESUMO
Glioblastoma (GBM) is an obligatory lethal brain tumor with a median survival, even with the best standard of care therapy, of less than 20 months. In light of this fact, the evaluation of new GBM treatment approaches such as oncolytic virotherapy (OVT) is urgently needed. Based on our preliminary preclinical data, the YB-1 dependent oncolytic adenovirus (OAV) XVir-N-31 represents a promising therapeutic agent to treat, in particular, therapy resistant GBM. Preclinical studies have shown that XVir-N-31 prolonged the survival of GBM bearing mice. Now using an immunohumanized mouse model, we examined the immunostimulatory effects of XVir-N-31 in comparison to the wildtype adenovirus (Ad-WT). Additionally, we combined OVT with the inhibition of immune checkpoint proteins by using XVir-N-31 in combination with nivolumab, or by using a derivate of XVir-N-31 that expresses a PD-L1 neutralizing antibody. Although in vitro cell killing was higher for Ad-WT, XVir-N-31 induced a much stronger immunogenic cell death that was further elevated by blocking PD-1 or PD-L1. In vivo, an intratumoral injection of XVir-N-31 increased tumor infiltrating lymphocytes (TILs) and NK cells significantly more than Ad-WT not only in the virus-injected tumors, but also in the untreated tumors growing in the contralateral hemisphere. This suggests that for an effective treatment of GBM, immune activating properties by OAVs seem to be of greater importance than their oncolytic capacity. Furthermore, the addition of immune checkpoint inhibition (ICI) to OVT further induced lymphocyte infiltration. Consequently, a significant reduction in contralateral non-virus-injected tumors was only visible if OVT was combined with ICI. This strongly indicates that for an effective eradication of GBM cells that cannot be directly targeted by an intratumoral OV injection, additional ICI therapy is required.
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Glioblastoma , Terapia Viral Oncolítica , Adenoviridae/genética , Adenoviridae/metabolismo , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glioblastoma/metabolismo , Camundongos , Receptor de Morte Celular Programada 1RESUMO
CONTEXT: Numerous health care organizations have established guidelines on diagnosis and treatment of bladder cancer. However, the lack of a standardized guideline development approach results in considerable differences of the guidelines' methodological quality. OBJECTIVE: To assess the methodological quality of all relevant clinical practice guidelines (CPGs) for urinary bladder cancer and provide a reference for clinicians in choosing guidelines of high methodological quality. EVIDENCE ACQUISITION: A systematic literature search was conducted in Medline via PubMed, 4 CPG databases, and 7 databases of interdisciplinary organizations. CPGs for non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) with the topics screening, pathology, diagnosis, treatment, and aftercare published in English language between 2012 and 2018 were included. The CPG quality was analyzed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. EVIDENCE SYNTHESIS: A total of 16 CPGs were included for the quality appraisal. Because of predefined criteria, 5 CPGs were "strongly recommended" (American Urological Association NMIBC, European Association of Urology [EAU] NMIBC, EAU MIBC, National Institute for Health and Care Excellence, and National Comprehensive Cancer Network), 4 CPGs were "weakly recommended" and 7 CPGs were "not recommended." CONCLUSIONS: The methodological quality of bladder cancer guidelines is diverse. Considering the rapid development of new therapies (e.g., immune checkpoint inhibitors), "living guidelines" of high methodological quality, such as the EAU NMIBC or MIBC guideline, will become more relevant in the future guideline's landscape.
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Guias de Prática Clínica como Assunto/normas , Projetos de Pesquisa/normas , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , HumanosRESUMO
BACKGROUND: Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer. METHODS: Study design: "RACE IT" (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb. Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11-15. Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15. Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up). Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy. Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy. Planned sample size: 33 patients, interim analysis after 11 patients. DISCUSSION: This trial aims to evaluate the safety and feasibility of the combined approach of preoperative PD-1 checkpoint-inhibitor therapy with concomitant radiation of bladder and pelvic region followed by radical cystectomy. The secondary objectives of therapy response and survival are thought to provide preliminary data for further clinical evaluation after successful completion of this trial. Recruitment has started in February 2019. TRIAL REGISTRATION: Protocol Code RACE IT: AB 65/18; EudraCT: 2018-001823-38; Clinicaltrials.gov: NCT03529890; Date of registration: 27 June 2018.
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Radioterapia Adjuvante , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Quimioterapia Adjuvante , Terapia Combinada , Cistectomia , Feminino , Humanos , Imunoterapia , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Of all urothelial carcinomas (UCs), 25% are muscle invasive and associated with a 5-year overall survival rate of 50%. Findings regarding the molecular classification of muscle-invasive urothelial carcinomas (MIUCs) have not yet found their way into clinical practice. OBJECTIVES: Prediction of molecular consensus subtypes in MIUCs with artificial intelligence (AI) based on histologic hematoxylin-eosin (HE) sections. METHODS: Pathologic review and annotation of The Cancer Genome Atlas (TCGA) Bladder Cancer (BLCA) Cohort (Nâ¯= 412) and the Dr. Senckenberg Institute of Pathology (SIP) BLCA Cohort (Nâ¯= 181). An AI model for the prediction of molecular subtypes based on annotated histomorphology was trained. RESULTS: For a five-fold cross-validation with TCGA cases (Nâ¯= 274), an internal TCGA test set (Nâ¯= 18) and an external SIP test set (Nâ¯= 27), we reached mean area under the receiver operating characteristic curve (AUROC) scores of 0.73, 0.8 and 0.75 for the classification of the used molecular subtypes "luminal", "basal/squamous" and "stroma-rich". By training on correlations to individual molecular subtypes, rather than training on one subtype assignment per case, the AI prediction of subtypes could be significantly improved. DISCUSSION: Follow-up studies with RNA extraction from various areas of AI-predicted molecular heterogeneity may improve molecular classifications and thereby AI algorithms trained on these classifications.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Carcinoma de Células de Transição/genética , Bexiga Urinária/patologia , Inteligência Artificial , Biomarcadores Tumorais/genética , Fenótipo , GenótipoRESUMO
The 5th edition of the World Health Organization (WHO) classification of tumors of the urinary tract and male genital organs introduced both general and specific changes in structure, classification, and nomenclature. This also applies to rarer tumors and tumor subtypes of the urinary system. Knowledge of these changes is relevant for routine histopathological work. This article provides an overview of the main new features of the rarer tumors and tumor subtypes of the urinary system in the new edition of the WHO classification.
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OBJECTIVE: The concept of lines of therapy (LOT) in cancer treatment is often considered for decision making in tumor boards and clinical management, but lacks a common definition across medical specialties. The complexity and heterogeneity of malignancies and treatment modalities contribute to an inconsistent understanding of LOT among physicians. This study assesses the heterogeneity of understandings of the LOT concept, its major dimensions, and criteria from the perspective of physicians of different specialties with an oncological focus in Germany. Semi-structured expert interviews with nine physicians were conducted and evaluated using qualitative content analysis. RESULTS: Most interviewees agreed that there is no single definition for LOT and found it difficult to explicate their understanding. A majority of experts stated that they had already encountered misunderstandings with colleagues regarding LOT and that they had problems with deciphering LOT from the medical records of their patients. Disagreement emerged about the roles of the following within the LOT concept: maintenance therapy, treatment intention, different therapy modalities, changing pharmaceutical agents, and therapy breaks. Respondents predominantly considered the same criteria as decisive for the definition of LOT as for a change in LOT (e.g., the occurrence of a progression event or tumor recurrence).
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Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Masculino , Feminino , Entrevistas como Assunto , Alemanha , Pessoa de Meia-Idade , Pesquisa Qualitativa , Adulto , Médicos/psicologiaRESUMO
BACKGROUND: The landscape of systemic therapies for metastatic hormone-sensitive (mHSPC) and castration resistant prostate cancer (mCRPC) extensively improved within the last decades resulting in a significantly prolonged overall survival. However, subgroup analyses of phase III trials suggest potentially different overall survival outcomes for older adults. METHODS: We relied on our institutional metastatic prostate cancer database to identify mHSPC and subsequently mCRPC patients. Older adults were stratified according to age groups 70-74 versus ≥75-79 versus ≥80 years at metastatic occurrence. Subsequently, uni- and multivariable time to mCRPC and overall survival analyses were performed. RESULTS: Of 494 older adults, 217 (44%) were 70-74 versus 180 (36%) 75-79 versus 97 (20%) ≥80 years old. Rates of local prostate cancer treatment differed significantly between all three groups (p < 0.01). Regarding mHSPC treatment, androgen receptor signaling inhibitors (ARSI) were administered in 30-39% of patients and docetaxel with 9% in age group 70-74 years and 6% and 3% in age groups 75-79 years and ≥80 years. Regarding mCRPC treatment, significant differences between treatment proportions were observed (p < 0.01). Most common treatment was ARSI for all three groups. Conversely, chemotherapy was more frequently administered in patients aged 70-74 (16%), relative to 4% and 3% in 75-79 year and ≥80 year aged patients. In univariable and multivariable time to mCRPC analyses, overall survival in mHSPC and OS in mCRPC analyses, no significant differences between all three age groups were observed (all p ≥ 0.3). CONCLUSIONS: Treatment patterns differ significantly between older adults with metastatic prostate cancer. However, these differences may not result in differences of overall life expectancy.
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Background and objective: With approval of novel systemic therapies within the past decade for metastatic hormone-sensitive (mHSPC) and castration-resistant (mCRPC) prostate cancer, patients may receive several therapy lines. However, the use of these treatments is under an ongoing change. We investigated contemporary treatment trends and progression-free (PFS) and overall (OS) survival of different therapy lines. Methods: Relying on our institutional tertiary-care database, we identified mHSPC and mCRPC patients. The main outcome consisted of treatment changes (estimated annual percentage change [EAPC]) within the past decade, as well as PFS and OS for different mHSPC and mCRPC treatment lines. Key findings and limitations: In 1098 metastatic patients, the median age was 70 yr with a median of two systemic therapy lines. For first-line mCRPC between 2013 and 2023, androgen deprivation monotherapy (ADT) monotherapy usage decreased significantly from 31% to 0% (EAPC -38.3%, p < 0.001), while the administration of chemotherapy increased from 16.7% to 33.3% (EAPC: +10.1%, p < 0.001). The PFS/OS rates of mHSPC patients was 21/67 mo, and those for first-, second-, third-, fourth-, fifth-, and sixth-line mCRPC patients were 11/47, eight of 30, seven of 24, six of 19, seven of 17, and seven of 13 mo, respectively. With an increased number of new combination therapy lines received, the median OS in mCRPC improved from 26 mo (one systemic treatment) to 52 mo (two or more lines of systemic treatment). Conclusions and clinical implications: Significant changes in treatment patterns could be observed for mHSPC and mCRPC patients within the past decade, and usage of ADT monotherapy has decreased rapidly in real-world practice. Moreover, PFS decreases significantly with every therapy line, and OS increases with the implementation of new therapies. Patient summary: Improvements in the real-world setting regarding the usage of combination therapies for metastatic hormone-sensitive and castration-resistant prostate cancer were made, which is reflected in contemporary survival outcomes.
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INTRODUCTION: Metachronous metastatic prostate cancer (mmPCa) patients harbor different characteristics and outcomes, relative to DeNovo metastatic PCa patients. Onset of metastatic disease might be influenced by primary PCa characteristics such as Gleason score (GS) or cancer stage, as well as overall survival (OS) by timing of metastatic onset. PATIENTS AND METHODS: We relied on an institutional tertiary-care database to identify mmPCa patients. Kaplan Meier and Cox Regression models tested for onset of metastases and OS, stratified according to GS, pathological stage and time to mmPCa. RESULTS: Of 341 mmPCa patients, 8% harbored GS6 versus 41% versus 51% GS7 and GS8-10. Median time to onset of metastatic disease was 79 versus 54 versus 41 months for GS6 versus GS7 versus GS8-10 (P = .01). Moreover, median time to onset of metastases was 64 versus 44 months for pT1-2 versus pT3-4 mmPCa patients undergoing radical prostatectomy (P = .027). In multivariable Cox regression models, higher GS and pT-stage was associated with earlier onset of metastases. Additionally, significant OS differences could be observed for time interval of < 24 versus 24-60 versus 60-120 versus ≥ 120 months between primary PCa diagnosis and onset of mmPCa. Specifically, median OS was 56 versus 69 versus 97 months versus not reached (P < .01) for these categories. In multivariable Cox regression, shorter time to metastatic onset was associated with shorter OS. CONCLUSION: Timing of mmPCa is strongly influenced by grading and pT-stage in real-life setting. OS benefits can be observed with longer time interval between primary PCa diagnosis and onset of mmPCa.
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BACKGROUND AND OBJECTIVE: With European Medicines Agency approval of PARP inhibitors in metastatic castration-resistant prostate cancer and ongoing trials in metastatic hormone-sensitive prostate cancer, detection of genetic alterations in BRCA1/2 and other homologous recombination repair genes has gained an important role. Our aim was to investigate the feasibility and comparability of comprehensive next-generation sequencing (NGS) of liquid biopsy (LB; circulating tumor DNA) and tumor tissue (TT) samples in a real-world clinical setting. METHODS: The study cohort consisted of 50 patients with metastatic prostate cancer (mPC) who had TT NGS performed for BRCA1/2 alterations and consent for additional LB NGS. The Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific, Waltham, MA, USA) was used for TT NGS. The Guardant360 83-gene assay (Guardant Health, Palo Alto, CA, USA) was used for LB NGS, including all types of somatic alterations, microsatellite instability, and blood tumor mutational burden. We calculated BRCA1/2 alteration rates and the negative percentage agreement (NPA) and positive percentage agreement (PPA) between TT and LB results. KEY FINDINGS AND LIMITATIONS: TT NGS was successful in 44/50 patients (88%), with pathogenic BRCA1/2 alterations detected in four (9%). LB NGS was successful in all 50 patients (100%), with BRCA1/2 alterations detected in ten (20%). In a subgroup analysis for the 44 patients with successful TT NGS, NPA was 85% and PPA was 50%. The median time between TT sample collection and blood sampling for NGS was 132 wk (IQR 94-186). The limited sample size and differences in the time of NGS assessment are limitations. CONCLUSIONS AND CLINICAL IMPLICATIONS: LB NGS resulted in a higher detection rate for BRCA1/2 alterations in comparison to conventional TT NGS (20% vs 9%). Ideally, BRCA1/2 testing should be based on both approaches to identify all patients with mPC eligible for PARP inhibitor therapy. PATIENT SUMMARY: Our study shows that genetic tests for both tumor tissue and blood samples results in higher rates of detection of BRCA1/2 gene alterations in patients with metastatic prostate cancer.