Update on the Treatment of Metastatic Urothelial Carcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Bukhari N
PROVIDER: S-EPMC6011065 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Update on the Treatment of Metastatic Urothelial Carcinoma.
Bukhari Nedal N Al-Shamsi Humaid O HO Azam Faisal F
TheScientificWorldJournal 20180606
Platinum-based combination chemotherapy has been the standard of care in the first-line treatment of metastatic urothelial carcinoma (mUC). Treatment of metastatic disease following progression on platinum-based regimens has evolved significantly in the last few years. Clinical trials are currently ongoing to determine how best to use and sequence these treatments. In this minireview, we will review current first-line treatment options in both cisplatin fit and cisplatin unfit patients and advan ...[more]
Similar Datasets
Project description:Urothelial carcinoma is the fifth most common malignancy diagnosed each year in the United States. Neoadjuvant and adjuvant chemotherapy are given to decrease the risk of recurrent or metastatic disease with the more robust clinical data supporting the former. Bladder preservation utilizes a trimodality approach with maximal transurethral resection followed by concurrent chemotherapy and radiation and is appropriate for select patients. Gemcitabine and cisplatin is the current standard of care for first-line treatment in fit patients with metastatic disease. Optimal second-line therapy remains undefined, and targeted agents are under investigation. Clinical trial participation should be encouraged in patients with urothelial carcinoma of the bladder to help improve treatment regimens and outcomes. Synopsis. Chemotherapy is commonly used in the treatment of urothelial carcinoma of the bladder. This paper will review the role of chemotherapy in the neoadjuvant, adjuvant, bladder sparing, and metastatic settings.
| S-EPMC3217602 | biostudies-literature
Project description:Urothelial carcinoma (UC) is a frequently diagnosed tumor and an important cause of cancer deaths worldwide. Until a few years ago, despite the unquestioned role of platinum-based chemotherapy, therapeutic choices beyond the first line were limited and related to unsatisfactory outcomes. Metastatic UC has always been associated with a poor prognosis, with overall survival only slightly above a year. In the recent past, huge progress has been made in our understanding of the molecular and genomic disease characteristics, to enable stratification of patients in terms of prognosis and treatment responses. Unfortunately, we still do not have the perfect combination of clinical biomarkers to tailor the optimal treatment for each patient, despite making several efforts in this direction. The therapeutic arsenal has been augmented by immune checkpoint inhibitors (ICIs), which nowadays represent the backbone of the second-line setting. Equally revolutionary was the FDA's approval of erdafitinib, a potent fibroblast growth factor receptor (FGFR) inhibitor, the use of which is reserved for patients whose tumor harbors specific FGF pathway alterations. Recently, the therapeutic landscape of metastatic UC has been enhanced by the introduction of novel compounds, consisting of antibody-drug conjugates (ADCs). Enfortumab vedotin is an antibody targeting nectin-4, a cell adhesion molecule highly expressed in UC, conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Sacituzumab govitecan is a humanized monoclonal antibody targeting Trop-2, a transmembrane glycoprotein, conjugated to the active metabolite of irinotecan. These two compounds have received accelerated approval by the FDA in patients pretreated with platinum-based chemotherapy and immunotherapy. Several ongoing trials are investigating the role of ICIs combined with chemotherapy, antiangiogenic drugs, or other ICIs, as well as the efficacy of PARP inhibitors and target therapies, hoping to provide information for some important unmet needs. In this review, we aim to evaluate the current potential treatment options after first-line chemotherapy.
| S-EPMC9205436 | biostudies-literature
Project description:Urothelial carcinoma (UC) represents a common malignancy of the urinary system that can involve the kidneys, ureter, bladder, and urethra. Advanced/metastatic UC (mUC) tends to have a poor prognosis. UC ranks third in terms of human epidermal growth factor receptor 2 (HER2) overexpression among all tumors. However, multiple studies found that, unlike breast cancer, variable degrees of HER2 positivity and poor consistency between HER2 protein overexpression and gene amplification have been found. Trials involving trastuzumab, pertuzumab, lapatinib, afatinib, and neratinib have failed to prove their beneficial effect in patients with HER2-positive mUC, and a clinical trial on T-DM1 (trastuzumab emtansine) was terminated prematurely because of the adverse reactions. However, a phase II trial showed that RC48-ADC was effective. In this review, we provided an in-depth overview of the advances in the research regarding HER2-targeted therapy and the role of HER2 in mUC. Furthermore, we also discussed the prospects of potential strategies aimed at overcoming anti-HER2 resistance, and summarize the novel anti-HER2 approaches for the management of mUC used in recent clinical trials.
| S-EPMC10752798 | biostudies-literature
Project description:Metastatic renal cell cancer (mRCC) management has undergone a paradigm shift in recent decades. The first revolution came with the emergence of vascular endothelial growth factor inhibitors; there was a second wave with the unprecedented success of checkpoint inhibitors, and then the latest approach, which is becoming the new care standard in mRCC, of combining these two strategies in different ways. Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival (PFS), overall survival (OS), and objective response rate (ORR) in intermediate and high-risk patients. However, several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place, and so far, the only one for nivolumab/ipilimumab is the frontline setting. The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembroli-zumab/axitinib over sunitinib in favorable-risk mRCC, suggesting that it should no longer be the first line of choice in low-risk patients. Finally, the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS, OS, and ORR, providing a new first-line option among all International Metastatic RCC Database Consortium risk patients. Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib, cabozantinib/atezolizumab, and lenvatinib/pembrolizumab, providing promising grounds upon which to start phase III studies. In addition, other works are using novel therapeutic agents with different mechanisms of action, including telaglenastat (a glutaminase inhibitor), entinostat [an inhibitor of histone deacetylases (HDACs)], and olaparib and talazoparib, poly(ADP-ribose) polymerase inhibitors widely used in other tumors. However, some questions regarding mRCC management still need to be addressed, such as head-to-head comparisons between the current options, treatment sequencing, non-clear cell mRCC, and the role of biomarkers to ascertain the best treatment choice.
| S-EPMC8790301 | biostudies-literature
Project description:PurposeTo review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases.MethodsA PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion.ResultsThe management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients.ConclusionsThe management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.
| S-EPMC6777567 | biostudies-literature
Project description:Urothelial cancer (UC) is most commonly found in the urinary bladder, but can also appear in the upper urinary tract, where it is associated with several disease-specific challenges affecting its diagnosis, clinical staging, surgical management, and systemic therapy. A significant number of patients experience extra-vesical disease recurrence despite radical nephroureterectomy (RNU), leading to inevitable demise. Over the last years, the therapeutic armamentarium of UC has expanded with several systemic treatment options entering clinical care and deliver the potential to support a more individualized treatment in the near future. Currently, novel targeted therapies are emerging, accompanied with extensive biomarker research, which leads to a better understanding of the disease and therefore, reshaping the treatment landscape continuously and decisively. Though, systemic treatment of UTUC comes along with certain challenges that are specific to the disease, e.g., loss of renal function after RNU, which might result in ineligibility for a cisplatin-based chemotherapy. In this narrative review, the current standard of systemic treatment of UC in the perioperative and metastatic treatment setting are reported, with focus on UTUC. In addition, molecular aspects of UTUC, as well as future directions and specific implications for treatment of patients diagnosed with UTUC are discussed.
| S-EPMC8575594 | biostudies-literature
Project description:This study investigated the applicability of personalized peptide vaccination (PPV) for patients with metastatic upper tract urothelial cancer (mUTUC) after failure of platinum-based chemotherapy. In this single arm, open-label, phase II clinical trial, patients with mUTUC received PPV at a single institution. Personalized peptide vaccination treatment used a maximum of four peptides chosen from 27 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for six s.c. injections weekly as one cycle. The safety of PPV, as well as its influence on host immunity and effect on overall survival were assessed. Forty-eight patients were enrolled in this study. Personalized peptide vaccinations were well tolerated without severe adverse events. Median survival time was 7.3 months (95% confidence interval [CI], 5.3-13.1) with 13.0 months for patients receiving combined salvage chemotherapy (95% CI, 5.7-17.5) and 4.5 months for patients receiving PPV alone (95% CI, 1.7-10.1) (P = 0.080). Patients with positive CTL responses showed a significantly longer survival than patients with negative CTL responses (hazard ratio, 0.37; 95% CI, 0.16-0.85; P = 0.019). Multivariate Cox regression analysis showed that lower numbers of Bellmunt risk factors and lower levels of B-cell activating factor were significantly associated with favorable overall survival for patients under PPV treatment. This study indicated that PPV for patients with mUTUC after failure of platinum-based chemotherapy induced substantial peptide-specific CTL responses without severe adverse events and has the potential to prolong survival when combined with salvage chemotherapy. UMIN Clinical Trials Registry ID: 000001854.
| S-EPMC5715265 | biostudies-literature
Project description:Urothelial carcinoma (UC) is a chemosensitive disease with high response rates to platinum-based combination chemotherapy in locally advanced or advanced disease. However, de novo or emergence of cisplatin-resistance limits the duration of response, patients are frequently ineligible for cisplatin, and therapies tested thus far have minimal activity as second-line therapy. The first wave of clinical trials of novel agents and targeted therapy have modestly advanced the field and laid the foundations for future studies. These trials include the deployment of monoclonal antibodies and tyrosine kinase inhibitors that target mediators of angiogenesis and growth receptors. Novel cytotoxic agents have also been tested as single-agents in the second-line setting and together with the first-line combination of gemcitabine with cisplatin. To date, these novel agents have yet to demonstrate the ability to substantially improve the overall survival of patients with bladder cancer. Comparative trials of chemotherapy with or without a novel agent are ongoing and have the potential to improve upon current standard therapy. Moreover, state-of-the-art technologies have been developed that will likely identify the molecular alterations which drive both UC and platinum-resistance and in turn provide opportunities for drug development. The latter includes an interrogation of microRNAs and the integrated study of genetic mutations in extreme phenotypes of the disease. In essence, this ongoing work paired with physician and patient commitments to clinical trial participation will ultimately lead to advances in the care of patients with urothelial cancer.
| S-EPMC4587660 | biostudies-literature
Project description:The prognosis of patients with unresectable or metastatic urothelial carcinoma (UC) is poor. Platinum-based chemotherapy has been the standard first-line treatment in these patients for the past decade; however, the 5-year overall survival (OS) rate is only 13-22%. Recent advances in cancer immunology research have highlighted the pivotal role of the immune system in cancer development and progression, and new immune checkpoint inhibitors (ICIs) have demonstrated efficacy in a large variety of tumors including UC. Currently, five ICIs, including two anti-PD-1 antibodies (pembrolizumab and nivolumab) and three anti-PD-L1 antibodies (atezolizumab, avelumab, and durvalumab), have been granted approval by the US Food and Drug Administration (FDA) for patients with unresectable or metastatic UC who recurred or progressed after platinum-based chemotherapy. Among these agents, only pembrolizumab is supported by strong evidence from a large randomized Phase III trial (KEYNOTE-045). This trial demonstrated statistically significant improvements in OS for patients assigned to the pembrolizumab arm compared with the chemotherapy arm, both in the total population (HR 0.73; P=0.002) and in the population with high PD-L1 expression (HR 0.57; P=0.005). For patients with cisplatin-ineligible UC, pembrolizumab and atezolizumab were approved based on Phase II studies, with limitations on the use of these agents in patients with high tumor PD-L1 expression later imposed by the FDA. In conclusion, pembrolizumab may be a potential first-choice second-line therapy for unresectable or metastatic UC patients following platinum-based chemotherapy. Several Phase III trials are ongoing to evaluate the efficacy and toxicity of combination therapies of ICIs with chemotherapy, and ICIs with other ICIs with or without chemotherapy as first-line therapy. The results of these trials might redirect treatment strategies for patients with unresectable or metastatic UC.
| S-EPMC6526676 | biostudies-literature
Project description:BackgroundSecond-line therapy is frequently utilized for metastatic urothelial carcinoma, but there are limited data to guide this approach. While an assessment of overall survival based on registry data may not capture the impact of second- and third-line therapies on clinical outcome, this may be reflected in relative conditional survival (RCS).MethodsPatients with stage IV urothelial carcinoma diagnosed from 1990-2010 were identified from the Surveillance, Epidemiology and End Results (SEER) dataset. The association of clinicopathologic variables with disease specific survival (DSS) was explored through univariate and multivariate analyses. DSS in subgroups divided by time period (1990-2000 v 2001-2010) was compared using the Kaplan-Meier method and log-rank test. One-year RCS at annual landmarks up to 5 years was compared in subgroups divided by time period.ResultsOf 261,987 patients diagnosed with urothelial carcinoma from 1990-2010, 3,110 patients met criteria for the current analysis. Characteristics of patients diagnosed between 1990 and 2000 (n = 810) and 2001 to 2010 (n = 2,300) were similar and there was no significant difference in DSS between the two groups. On multivariate analysis, older age (age ≥ 80) was associated with shorter DSS (HR 1.79, 95%CI 1.48-2.15), but no association was found between time period of diagnosis and outcome. One-year RCS improved substantially through successive annual landmarks up to 5 years, but no differences were seen in subgroups divided by time of diagnosis.ConclusionsNo difference in RCS was observed amongst patients with stage IV urothelial carcinoma diagnosed from 1990-2000 and 2001-2010. A lack of difference in RCS (more so than cumulative DSS) may reflect a lack of progress in salvage therapies for the disease.
| S-EPMC4550434 | biostudies-literature