Neoadjuvant immunotherapy for muscle invasive urothelial bladder carcinoma: will it change current standards?
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ABSTRACT:
SUBMITTER: Renner A
PROVIDER: S-EPMC8273398 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeTo assess the safety and efficacy of gemcitabine and cisplatin as neoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy in muscle-invasive bladder cancer (MIBC).Materials and methodsPatients with clinical T2-T4aN0M0 MIBC eligible for radical cystectomy and cisplatin-based chemotherapy were treated with gemcitabine 1,000 mg/m² on days 1, 8 and 15, and cisplatin 70 mg/m² on day 1 every 28 days for 3 cycles. After clinical re-staging with computed tomography scans and cystoscopy, patients with clinical complete response (CR) were eligible to proceed without cystectomy and receive bladder preservation chemoradiotherapy involving weekly cisplatin 10 mg/m² and up to 70.2 Gy of radiation. The primary endpoint of the present prospective phase II study was metastasis-free survival (MFS).ResultsBetween Oct 2017 and Nov 2019, a total of 138 MIBC patients were enrolled and treated with neoadjuvant gemcitabine/cisplatin. Neoadjuvant chemotherapy was well-tolerated, with fatigue, nausea, and pruritus being the most commonly observed adverse events. After completion of planned neoadjuvant chemotherapy, 54 patients with a clinical CR and 10 patients who did not have CR but refused surgery received bladder preservation chemoradiotherapy. With a median follow-up duration of 34 months (95% confidence interval [CI], 32%-36%), the 3-year MFS rate in 64 chemoradiotherapy patients was calculated to be 70% (95% CI, 58%-82%).ConclusionsNeoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy based on the clinical CR was feasible and efficacious in the treatment of MIBC.
| S-EPMC8902424 | biostudies-literature
Project description:Despite aggressive treatment approaches, muscle-invasive bladder urothelial carcinoma (MIBC) patients still have a 50% chance of developing general incurable metastases. Therefore, there is an urgent need for candidate markers to enhance diagnosis and generate effective treatments for this disease. We evaluated four mRNA microarray datasets to find differences between non-MIBC (NMIBC) and MIBC tissues. Through a gene expression profile analysis via the Gene Expression Omnibus database, we identified 56 differentially expressed genes (DEGs). Enrichment analysis of gene ontology, Kyoto Encyclopedia of Genes and Genomes, and Reactome pathways revealed the interactions between these DEGs. Next, we established a protein-protein interaction network to determine the interrelationship between the DEGs and selected 10 hub genes accordingly. Bladder urothelial carcinoma (BLCA) patients with COL1A2, COL5A1, and COL5A2 alterations showed poor disease-free survival rates, while BLCA patients with COL1A1 and LUM alterations showed poor overall survival rates. Oncomine analysis of MIBC versus NMIBC tissues showed that COL1A1, COL5A2, COL1A2, and COL3A1 were consistently among the top 20 overexpressed genes in different studies. Using the TCGAportal, we noted that the high expression of each of the four genes led to shorter BLCA patient overall survival. It was evident that BLCA patients with an elevated high combined gene expression had significantly shorter overall survival and relapse-free survival than those with low combined gene expression using PROGgeneV2. Using Gene Expression Profiling Interactive Analysis, we noted that COL1A1, COL1A2, COL3A1, and COL5A2 were positively correlated with each other in BLCA. These genes are considered as clinically relevant genes, suggesting that they may play an important role in the carcinogenesis, development, invasion, and metastasis of MIBC. However, considering we adopted a bioinformatic approach, more research is crucial to confirm our results. Nonetheless, our findings may have important prospective clinical implementations.
| S-EPMC7784563 | biostudies-literature
Project description:The intra-tumor microbiome has recently been linked to epithelial-mesenchymal transition (EMT) in a number of cancers. However, the relationship between EMT and microbes in bladder cancer has not been explored. In this study, we profiled the abundance of individual microbe species in the tumor samples of over 400 muscle invasive bladder carcinoma (MIBC) patients. We then correlated microbe abundance to the expression of EMT-associated genes and genes in the extracellular matrix (ECM), which are key players in EMT. We discovered that a variety of microbes, including E. coli, butyrate-producing bacterium SM4/1, and a species of Oscillatoria, were associated with expression of classical EMT-associated genes, including E-cadherin, vimentin, SNAI2, SNAI3, and TWIST1. We also found significant correlations between microbial abundance and the expression of genes in the ECM, specifically collagens and elastin. Lastly, we found that a large number of microbes exhibiting significant correlations to EMT are also associated with clinical prognosis and outcomes. We further determined that the microbes we profiled were likely not environmental contaminants. In conclusion, we discovered that the intra-tumoral microbiome could potentially play a significant role in the regulation of EMT in MIBC.
| S-EPMC8344975 | biostudies-literature
Project description:This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.
| S-EPMC7935810 | biostudies-literature
Project description:We performed mass spectrometry-based proteomic analysis of urine samples of patients with BLCA with stroma invasion or muscle invasion to identify prognosis markers for use in liquid-based cytology (LBC).
2020-04-29 | PXD016437 | Pride
Project description:Muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC) are both major causes of morbidity and mortality. At diagnosis, MIBC is more likely to metastasize, but can often be treated with aggressive care. Standard treatment for MIBC patients is radical cystectomy but a select group of these individuals are not candidates for or will decline this treatment. Thus, bladder preservation therapy followed by combined chemoradiation may be considered. Despite the primary surgical management of MIBC, up to half of patients will obtain tumors at distant sites in the end and perioperative platinum-based chemotherapy comprises the standard of care. However, despite these aggressive treatment options, survival is poor and therefore, it is essential to combine local and systemic therapies. Therapeutic modalities contained cancer vaccines, immune checkpoint inhibitors and immunogenic therapy are emerging as alternatives to immunotherapy, and several drugs have recently been approved by the FDA. Currently, several trials of adjuvant immunotherapy based on checkpoint inhibitors that as monotherapy, inhibit the reaction between programmed death-receptor 1 (PD-1) and programmed death-receptor ligand 1 (PD-L1). Or combined therapies mixed with chemotherapy, radiation, or various immunotherapy are ongoing. This review summarizes the current state of immunotherapies and evolution of the chemotherapy landscape for MIBC perioperative treatment. Widespread research is currently being performed to investigate the role of perioperative immune checkpoint inhibition in both the neoadjuvant and adjuvant setting.
| S-EPMC8799279 | biostudies-literature
Project description:Radical cystectomy is the standard of care treatment for patients with localized muscle-invasive bladder cancer (MIBC). However, patients with MIBC experience high rates of relapse despite primary therapy, and perioperative strategy is an important treatment option. Cisplatin-based neoadjuvant chemotherapy was associated with improved prognosis, and adjuvant chemotherapy is also an important option for selected patients. However, perioperative chemotherapy is not effective in some patients. Moreover, the currently recommended perioperative treatment is cisplatin-based chemotherapy; approximately 50% of the patients are ineligilble for cisplatin treatment owing to various reasons such as medical comorbidities, poor performance status, and renal insufficiency. The recent success of treatment with immune checkpoint inhibitors (ICIs) suggests that ICIs is the new standard therapy for patients with metastatic bladder cancer. Furthermore, ICIs showed more favorable toxicity profiles than conventional cytotoxic chemotherapy. These results indicate that ICIs may play a role in the treatment of muscle-invasive disease, and many recent studies have been conducted in a perioperative setting. The present review aims to summarize and discuss the current perioperative strategy of immunotherapy focused on ICIs based on recent ongoing clinical trials.
| S-EPMC7807333 | biostudies-literature
Project description:A number of urinary bladder urothelial carcinoma (UB UC) mRNA-based classification systems have been reported. It also has been observed that treatment response and prognosis are different for each molecular subtype. In this study, cytokeratin (CK)5/6 and CK20 immunohistochemistry (IHC) were performed, and IHC-based subgroup classification was applied. UB UC was classified into CK5/6 single-positive (SP), CK20 SP, double-positive (DP) and double-negative (DN) subgroups, and transcriptional analysis was performed. The results of gene ontology (GO) terms and functional analysis using differentially expressed genes indicate that, CK5/6 SP and DP subgroups were enriched in cell migration, immune activation, interleukin 6-Janus kinase-signal transducer and activator of transcription 3 (IL6-JAK-STAT3) signaling pathway and tumor necrosis factor-α signaling via the nuclear factor-κB (NF-κB) signaling pathway signature gene. In addition, compared with the other subgroups, the DN subgroup showed inhibited cell movement, cell migration, and cell activation. Furthermore, in survival analysis, the CK5/6 SP subgroup was significantly associated with poor progression-free survival (p = 0.008). The results of our study indicate that the CK5/6 positive subgroup exhibited high gene expression signature related to aggressive behavior and exhibited worse clinical outcome.
| S-EPMC7828072 | biostudies-literature
Project description:The standard treatment for non-metastatic muscle-invasive bladder cancer (MIBC) is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy or trimodality therapy with chemoradiation in select patients. Pathologic complete response (pCR) to neoadjuvant chemotherapy is a reliable predictor of overall and disease-specific survival in MIBC. A pCR rate of 35-40% is attained with neoadjuvant cisplatin-based chemotherapy. With the approval of immune checkpoint inhibitors (ICIs) for the treatment of metastatic urothelial cancer, these agents are now being studied in the neoadjuvant setting for MIBC. We describe the results from clinical trials using single agent ICI, ICI/ICI and ICI/chemotherapy combination therapies in the neoadjuvant setting for MIBC. These single-arm clinical trials have demonstrated safety and pCR comparable to cisplatin-based chemotherapy. Neoadjuvant ICI is a promising approach for cisplatin-ineligible patients, and the role of adding ICIs to cisplatin-based chemotherapy is also being investigated in randomized phase III clinical trials. Ongoing biomarker research to suggest a response to neoadjuvant ICIs will also guide appropriate treatment selection. We also describe the studies using ICIs for adjuvant therapy and in combination with chemoradiation.
| S-EPMC8461126 | biostudies-literature
Project description:Urothelial carcinoma is a common malignancy that carries a poor prognosis when the disease includes muscle invasion. Metastatic urothelial carcinoma is almost uniformly fatal. The evidence behind treatment options in the neoadjuvant, adjuvant and metastatic settings are discussed in this manuscript, with a focused review of standard and investigational cytotoxic, targeted, and immunotherapy approaches. We have focused especially on neoadjuvant cisplatin-based therapy (supported by level one evidence) and on novel immunotherapy agents such as checkpoint inhibitors, which have shown great promise in early clinical studies.
| S-EPMC4647143 | biostudies-literature