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1
Vias, Poorva, Ashish Saklani, Suman Singh, Anantika Thakur, and Era Sankhyan. "Perinephric and Ovarian Metastasis from Advanced Urothelial Carcinoma Bladder: Case Report of a Rare Dismal Disease." Asian Pacific Journal of Cancer Care 9, no. 1 (2024): 207–10. http://dx.doi.org/10.31557/apjcc.2024.9.1.207-210.
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Background: Metastatic urothelial carcinoma bladder at the time of diagnosis is a rare entity with lymph nodes, bones, lung and liver as common metastatic sites. Sometimes metastasis can be seen in various atypical sites.Case Presentation: Unusual location of metastasis can be seen in perinephric region, renal fascia and ovaries as seen in the described case. Primary urothelial carcinoma of ovary needs to be differentiated from the metastasis. There are no standard lines of management and the treatment needs to be individualised. Prognosis of metastatic urothelial carcinoma remains fatal with a limited life expectancy. Conclusion: We present a case of metastatic urothelial carcinoma bladder with metastasis to perinephric region and ovaries with her course of treatment.
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Wahyuni, Siska Dwiyantie, Sri Suryanti, Hasrayati Agustina, and Bethy Suryawathy Hernowo. "The Association of Clinicopathological Features with Metastatic Status in Infiltrative Urothelial Carcinoma of Bladder." Journal of Drug Delivery and Therapeutics 10, no. 6-s (2020): 99–102. http://dx.doi.org/10.22270/jddt.v10i6-s.4647.
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Background: Infiltrative urothelial carcinoma of bladder is an aggressive variant of bladder carcinoma. Most of the patients in their first encounter with doctors are diagnosed with advanced stages and many has metastasized. Metastasis is a process of malignant tumor cells migrating from its primary tumor location to other organs or sites inside the body via blood circulation or lymphatic system. Metastasis process is responsible for 90% cancer deaths compared to the primary tumor itself, infiltrative urothelial carcinoma of bladder. To reduce mortality, knowledge of the clinicopathological characteristics associated with metastasis is needed.
 Method: Research material used was clinical data and paraffin block from patients with metastatic and non-metastatic infiltrative urothelial carcinoma of bladder. Clinical data taken from Central Medical Record Installation and Urology Medical Record Installation Padjadjaran University/ Dr. Hasan Sadikin Hospital Bandung, Indonesia. Paraffin blocks were obtained from operations at Hasan Sadikin Hospital Bandung, Indonesia.Total data sample obtained were 40 samples, 20 samples are metastatic and another 20 are non-metastatic samples. Clinicopathological parameters included in the analysis were age, sex and pathalogical T stage.
 Result: Pathalogical T stage have associations with metastatic status with significant result with p value=0.035 (p<0.005).
 Conclusion: Pathalogical T stage was associated with the metastatic status of Infiltrative urothelial carcinoma of bladder and may play important roles during the metastatic process. Thus, it can be used as a predictor factor for the infiltrative urothelial carcinoma of bladder.
 Keywords: infiltrative urothelial carcinoma of bladder, metastastic, pathalogical T stage
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Rizzo, Alessandro, Veronica Mollica, Matteo Santoni, et al. "Impact of clinicopathological features on immune-based combinations for advanced urothelial carcinoma: a meta-analysis." Future Oncology 18, no. 6 (2022): 739–48. http://dx.doi.org/10.2217/fon-2021-0841.
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Aims: Immune checkpoint inhibitors (ICIs) have recently revolutionized the treatment landscape of metastatic urothelial carcinoma. The authors performed a meta-analysis aiming to evaluate the predictive value of Eastern Cooperative Oncology Group performance status, age, sex, liver metastasis and histology in trials comparing first-line ICI-based combinations with chemotherapy in metastatic urothelial carcinoma patients. Methods: Hazard ratios were analyzed. Results: ICI-based combinations significantly decreased the risk of death in several clinicopathological subgroups, including patients with no liver metastases (hazard ratio: 0.84; 95% CI: 0.74–0.95) and those with an Eastern Cooperative Oncology Group performance status of 0 (hazard ratio: 0.84; 95% CI: 0.72–0.97). Conclusion: The benefit of ICI-based combinations over chemotherapy in metastatic urothelial carcinoma was consistent across several clinicopathological subgroups, although a proportion of patients responded to chemotherapy alone.
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Apolo, Andrea Borghese, Howard L. Parnes, Ravi Amrit Madan, et al. "A phase II study of cabozantinib (XL184) in patients with advanced/metastatic urothelial carcinoma." Journal of Clinical Oncology 31, no. 15_suppl (2013): TPS4589. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps4589.
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TPS4589 Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. Activated MET can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in urothelial carcinoma pathogenesis. Cabozantinib inhibits primarily VEGFR2 and MET pathways. Cabozantinib has been approved by the FDA for the treatment of progressive metastatic medullary thyroid cancer, is in Phase 3 trials for metastatic castration-resistant prostate cancer and has demonstrated clinical activity in multiple solid tumors. We previously reported that shed MET levels in serum and urine of patients with urothelial carcinoma correlate with stage, presence of visceral metastases and urinary source and that cabozantinib is effective in reversing HGF-driven urothelial carcinoma cell growth and invasion. These data support the evaluation of cabozantinib in patients with metastatic urothelial carcinoma. Methods: This is a phase II study of oral cabozantinib 60mg daily given continuously in 28-day cycles. There are three study cohorts: [1] metastatic urothelial carcinoma [2] bone only metastatic urothelial carcinoma [3] metastatic non-urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. A maximum of 55 subjects will be enrolled. Up to 45 patients will be accrued to cohort 1.The remainder will be enrolled on exploratory cohorts 2 & 3. A two-stage single-arm phase II design will be employed. The primary objective is to determine the objective response rate in patients with metastatic urothelial carcinoma who have progressed on prior chemotherapy. Secondary objectives include progression free survival, safety and toxicity, and overall survival. Exploratory objectives include tumor tissue Met expression, shed MET levels in serum and urine, immune subsets, genetic biomarkers, molecular markers of angiogenesis and circulating tumor cells, correlation with clinical response parameters. Finally we will explore treatment evaluation with FDG and NaF PET/CT compared to standard imaging. This study is supported by the Cancer Therapy Evaluation Program (CTEP). NCT01688999 Clinical trial information: NCT01688999.
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Ullén, Anders, Firas Aljabery, Pär Dahlman, et al. "Swedish national guidelines on urothelial carcinoma: 2024 update on advanced and metastatic disease." Scandinavian Journal of Urology 60 (March 25, 2025): 76–82. https://doi.org/10.2340/sju.v60.43236.
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Objective: To overview and summarise the Swedish National Guidelines on Urothelial Carcinoma 2024. Methods: A narrative review of the updated guidelines was performed, highlighting new treatment recommendations for advanced and metastasized disease. Results: Compared to the previous guideline version, the current update includes recommendations for standardised radiological reporting when urothelial carcinomas are detected at CT-urography (CTU), to early identify locally advanced patients and accelerate the care pathway for these patients. The Swedish guidelines apply a more structured and liberal recommendation for the use of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography in patients with locally advanced urothelial carcinomas compared to the EAU-guidelines and recommend such examinations prior to transurethral resection. Improved outcomes for radical cystectomy in Sweden after centralised cystectomy care have led to a recommendation for performing more than six nephroureterectomies (NUs) per year for upper tract urothelial carcinomas (UTUC)-based associations with decreased use of invasive diagnostic modalities and better survival outcomes. Additionally, updated recommendations regarding adjuvant systemic therapies for muscle-invasive disease have been included. Whilst awaiting national regulatory approval for enfortumab vedotin/pembrolizumab, the present guideline version aligns with EAU-guidelines by endorsing cisplatin-gemcitabine-nivolumab as a new first-line treatment option in cisplatin-fit patients with unresectable or metastatic urothelial carcinoma. Conclusions: The current version of the Swedish national guidelines on urothelial carcinoma introduces standardised reporting at CTU to facilitate early identification of advanced disease, includes recommendations for centralisation of NU for UTUC and updated recommendations for adjuvant systemic treatment of muscle-invasive disease and endorses cisplatin-gemcitabine-nivolumab as a new first-line treatment option for non-resectable locally advanced and metastatic disease.
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Katims, Andrew B., Peter A. Reisz, Lucas Nogueira, et al. "Targeted Therapies in Advanced and Metastatic Urothelial Carcinoma." Cancers 14, no. 21 (2022): 5431. http://dx.doi.org/10.3390/cancers14215431.
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This review describes the current landscape of targeted therapies in urothelial carcinoma. The standard of care for advanced urothelial carcinoma patients remains platinum-based combination chemotherapy followed by immunotherapy. However, median overall survival for these patients is still <1 year and there is an urgent need for alternative therapies. The advent of next-generation sequencing has allowed widespread comprehensive molecular characterization of urothelial tumors and, subsequently, the development of therapies targeting specific molecular pathways implicated in carcinogenesis such as FGFR inhibition, Nectin-4, Trop-2, and HER2 targeting. As these therapies are demonstrated to be effective in the second-line setting, they will be advanced in the treatment paradigm to localized and even non-muscle invasive disease.
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Powels, Thomas, Park Se Hoon, Eric Voog, et al. "Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma." New Eng J Med 383, no. 13 (2020): 1218–30. https://doi.org/10.1056/NEJMoa2002788.
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BACKGROUND. Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance. METHODS. In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety. RESULTS. Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P=0.001). Avelumab also significantly prolonged overall survival in the PD-L1–positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1–positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively. CONCLUSIONS Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432. opens in new tab.)
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Rao, Arpit, and Manish R. Patel. "A review of avelumab in locally advanced and metastatic bladder cancer." Therapeutic Advances in Urology 11 (January 2019): 175628721882348. http://dx.doi.org/10.1177/1756287218823485.
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Urothelial carcinoma remains a devastating disease with a poor prognosis. Though immune therapy with Bacillus Calmette–Guérin (BCG) has been used for localized bladder cancer for years, only immune-checkpoint blockade with antiprogrammed cell-death 1 (anti-PD-1) and antiprogrammed cell-death ligand 1 (anti-PD-L1) inhibitors have demonstrated improvement in survival of patients with metastatic disease. Anti-PD-L1 antibody, avelumab, was recently given United States Food and Drug Administration (FDA) accelerated approval for the treatment of recurrent/metastatic urothelial carcinoma after failure of first-line chemotherapy, marking the fifth immune checkpoint inhibitor to be given FDA approval for the treatment of metastatic urothelial cancer. The following manuscript will review avelumab, its pharmacology, and the clinical experience that has led to its approval, as well as future plans for clinical development of avelumab for the treatment or urothelial cancer.
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Mainwaring, A. M., H. Wells, T. Banks, T. Ellul, and P. Bose. "Skeletal Muscle Metastasis to Vastus Lateralis from a Urothelial Carcinoma: A Case Report and Review of Its Diagnosis and Management." Case Reports in Urology 2019 (December 3, 2019): 1–4. http://dx.doi.org/10.1155/2019/8923780.
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Bladder cancer is a common genitourinary tract malignancy. Urothelial carcinoma is the most frequent type of bladder cancer and it commonly metastasises to lymph nodes, bone, lung and liver by a haematogenous route. Skeletal metastases are very rare and are usually present in patients with advanced metastatic disease. We present an unusual case of a 71-year-old male with a urothelial carcinoma metastasis to the vastus lateralis muscle 3 months following a cystoprostatectomy for muscle invasive bladder cancer.
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Yu, Chih-Chin, Po-Jung Su, and Yao-Chou Tsai. "Improved overall survival with immune checkpoint inhibitors in the treatment of metastatic urothelial carcinoma: A national retrospective comparative study." Journal of Clinical Oncology 42, no. 16_suppl (2024): e16550-e16550. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e16550.
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e16550 Background: Numerous randomized trials have illustrated the survival advantages of immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma. However, the application of ICI varies in different trials, encompassing first-line, second-line, monotherapy, combination with chemotherapy, or maintenance therapy. Real-world clinical practices often diverge from trial criteria. This study aims to evaluate the effectiveness of any ICI regimen in treating metastatic urothelial carcinoma using real-world data. Methods: This retrospective comparative study included patients diagnosed with locally advanced or metastatic urothelial carcinoma between January 2015 and July 2023, sourced from the Taiwan Upper Tract Urothelial Cancer and Bladder Cancer Collaboration Database. Patients with prior neo-adjuvant or adjuvant systemic therapy were excluded. Results: Among 427 patients, 152 (35.6%) who received any ICI as the first-line or second-line regimen constituted the ICI group, while the remaining 275 (64.4%) patients receiving only chemotherapy formed the chemotherapy group. Within the ICI group, 55 (36.2%) patients received monotherapy, 49 (32.2%) received combination therapy with chemotherapy, and 4 (2.6%) received maintenance therapy as the first-line regimen. The remaining 44 (28.9%) patients received ICI as the second-line regimen. No significant differences were observed in age, sex, performance status, renal function, tumor site, ratio of locally advanced disease, ratio of visceral metastasis, and ratio of previous radical surgery between the two groups. Median overall survival (OS) from the start of the first-line therapy was 15.8 months in the ICI group and 10.2 months in the chemotherapy group. Kaplan-Meier curves demonstrated that the ICI group exhibited superior OS and cancer-specific survival compared to the chemotherapy group (log-rank p= 0.009 and 0.004, respectively). In the multivariable analysis, the ICI group also demonstrated favorable outcomes in OS [hazard ratio (HR) 0.726, p=0.011] and cancer-specific survival (HR 0.67, p=0.004). Conclusions: Our study confirms the clinical efficacy of ICI in metastatic urothelial carcinoma. The use of ICI monotherapy or combination in the first-line or second-line regimen for metastatic urothelial carcinoma improves patient survival. [Table: see text]
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Qu, Mengnan, Li Zhou, Xieqiao Yan, et al. "Advances in HER2-Targeted Treatment for Advanced/Metastatic Urothelial Carcinoma." Bladder 10 (December 11, 2023): e21200012. http://dx.doi.org/10.14440/bladder.2023.871.
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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.
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Lemke, DNP, AGPCNP-BC, AOCNP, Emily. "Genitourinary Cancer: 2022 ASCO Annual Meeting Highlights for the Advanced Practitioner." Journal of the Advanced Practitioner in Oncology 13, no. 6 (2022): 596–602. http://dx.doi.org/10.6004/jadpro.2022.13.6.5.
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Emily Lemke, DNP, AGPCNP-BC, AOCNP®, of the Medical College of Wisconsin Cancer Center, comments on MET and CTLA-4 inhibitors for clear cell renal cell carcinoma, maintenance targeted therapy for patients with metastatic urothelial carcinoma, the landscape of metastatic hormone-sensitive prostate cancer, a consensus definition for platinum ineligibility, and PSMA-positive metastatic castration-resistant prostate cancer.
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Jackson-Spence, Francesca, Bernadett Szabados, Charlotte Toms, Yu-Hsuen Yang, Christopher Sng, and Thomas Powles. "Avelumab in locally advanced or metastatic urothelial carcinoma." Expert Review of Anticancer Therapy 22, no. 2 (2022): 135–40. http://dx.doi.org/10.1080/14737140.2022.2028621.
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Loriot, Yohann, Andrea Necchi, Se Hoon Park, et al. "Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma." New England Journal of Medicine 381, no. 4 (2019): 338–48. http://dx.doi.org/10.1056/nejmoa1817323.
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Houssiau, Hélène, and Emmanuel Seront. "The Evolution of Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma." Cancers 14, no. 7 (2022): 1640. http://dx.doi.org/10.3390/cancers14071640.
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Urothelial carcinoma is an aggressive cancer and development of metastases remains a challenge for clinicians. Immune checkpoint inhibitors (ICIs) are significantly improving the outcomes of patients with metastatic urothelial cancer (mUC). These agents were first used in monotherapy after failure of platinum-based chemotherapy, but different strategies explored the optimal use of ICIs in a first-line metastatic setting. The “maintenance” strategy consists of the introduction of ICIs in patients who experienced benefit from first-line chemotherapy in a metastatic setting. This allows an earlier use of ICIs, without waiting for disease progression. We review the optimal management of mUC in the era of ICIs, based on the key clinical messages arising from the pivotal trials.
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Benjamin, David J., Nataliya Mar, and Arash Rezazadeh Kalebasty. "Immunotherapy With Checkpoint Inhibitors in FGFR-Altered Urothelial Carcinoma." Clinical Medicine Insights: Oncology 16 (January 2022): 117955492211262. http://dx.doi.org/10.1177/11795549221126252.
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The treatment landscape of metastatic urothelial cancer (mUC) remained unchanged for over 30 years until the approval of immune checkpoint inhibitors (ICIs) in 2016. Since then, several ICIs have been approved for the treatment of mUC. In addition, recent molecular characterization of bladder cancer has revealed several subtypes, including those harboring fibroblast growth factor receptor (FGFR) mutations and fusion proteins. Erdafitinib, a pan-FGFR inhibitor, was approved for the treatment of metastatic/advanced UC in 2019. Some available evidence suggests ICI may have inferior response in advanced FGFR+ UC for unclear reasons, but may possibly be related to the tumor microenvironment. Several ongoing trials are evaluating erdafitinib in metastatic/advanced UC including the ongoing phase IB/II NORSE trial combining erdafitinib plus ICI, which may prove to offer a more robust and durable response in patients with FGFR+ metastatic/advanced UC.
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Andrews, Erik, Catherine Curran, Petros Grivas, et al. "Outcomes of advanced plasmacytoid urothelial carcinoma receiving systemic therapy." Journal of Clinical Oncology 38, no. 6_suppl (2020): 580. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.580.
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580 Background: Plasmacytoid urothelial carcinoma (pUC) is an aggressive variant with poor outcomes reported in small retrospective studies. Patients (pts) with plasmacytoid-predominant tumor histology have generally been excluded from clinical trials. Given the lack of systematic data regarding outcomes in metastatic pUC, we conducted a retrospective multicenter study to broadly examine outcomes. Methods: Pts who underwent any systemic therapy for metastatic pUC were eligible from collaborating institutions. Data were collected for demographics, clinical and pathological variables. Descriptive statistics were reported to examine tumor regression, time to treatment discontinuation or failure (TTF), and overall survival (OS). Results: 52 pts with metastatic pUC were evaluable from 7 institutions. The ECOG-PS ranged from 0-3 (median 1), median age was 65 (range 46 – 85), and 14 pmts (26.9%) were female. The histology consisted of predominant urothelial, predominant plasmacytoid, and pure plasmacytoid carcinoma in 35 (67.3%), 14 (26.9%) and 3 (5.8%) pts, respectively. The median OS for evaluable pts according to histology were 234 (n=21), 203 (n=11), and 12 (n=1) days (d), respectively. The sites of metastasis (mets) were liver +/- other, non-liver visceral +/- soft tissue/lymph node (ST/LN), and ST/LN only in 5 (9.6%), 36 (69.2%), and 11 (21.2%) pts, respectively. Cisplatin-based chemotherapy (cis-chemo), PD1/L1 inhibitor (i), or other non-cis-chemo was administered in 20 (41.7%), 13 (27.1%), and 15 (31.3%) pts, respectively (therapy unknown in 4 pts). Overall best response PR, CR, SD, and PD were seen in 3 (7%), 3 (7%), 7 (16.3%), and 30 (69.8%) pts, respectively. The overall median TTF and median OS were 91 and 232 d, respectively. The median TTF for cisplatin-based chemo, non-cisplatin based chemo and PD1/L1 inhibitors was 96.5, 122.5 and 73.5 d, respectively and the median OS was 236 (n=12), 221 (n=12) and 161 (n=8) d, respectively. Conclusions: The clinical outcomes of pts with metastatic pUC are dismal and appear worse than conventional UC without plasmacytoid component. Further progress will be possible only with better understanding of tumor biology and rational drug development.
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Nagata, Yujiro, Akinori Minato, Hisami Aono, et al. "Immunohistochemical Expression of p53 and FGFR3 Predicts Response to Enfortumab Vedotin in Metastatic Urothelial Carcinoma." International Journal of Molecular Sciences 25, no. 19 (2024): 10348. http://dx.doi.org/10.3390/ijms251910348.
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Locally advanced or metastatic urothelial carcinoma is a genomically and molecularly heterogeneous disease associated with various clinical outcomes. We aimed to evaluate the association between the status of p53/FGFR3 expression and the efficacy of enfortumab vedotin (EV) in metastatic urothelial carcinoma. We evaluated the association between p53 (abnormal vs. wild-type) or FGFR3 (high vs. low) expression determined by immunohistochemistry and response to EV in 28 patients with metastatic urothelial carcinoma. Overall, 60.7% showed abnormal p53, and 17.9% had high FGFR3 expression. The rates of objective response to EV were statistically higher in patients with abnormal p53 than in those with wild-type p53 (p = 0.038). Patients with pure urothelial carcinoma (n = 18) and low FGFR3 showed significantly better response to EV than those with high FGFR3. When the statuses of p53 and FGFR3 were combined, abnormal p53/low FGFR3 (vs. wild-type p53/high FGFR3) was strongly associated with favorable outcomes in both the entire cohort (p = 0.002) and in cases of pure urothelial carcinoma only (p = 0.023). Immunohistochemically abnormal p53 tumors were found to respond well to EV, while high FGFR3 tumors had a poorer response. Thus, p53 and FGFR3 are potential biomarkers for predicting response to EV treatment in patients with urothelial carcinoma.
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Rosenberg, Jonathan E., Peter H. O’Donnell, Arjun V. Balar, et al. "Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy." Journal of Clinical Oncology 37, no. 29 (2019): 2592–600. http://dx.doi.org/10.1200/jco.19.01140.
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PURPOSE Locally advanced or metastatic urothelial carcinoma is an incurable disease with limited treatment options, especially for patients who were previously treated with platinum and anti–programmed death 1 or anti–programmed death ligand 1 (PD-1/L1) therapy. Enfortumab vedotin is an antibody–drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma. METHODS EV-201 is a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti–PD-1/L1 therapy. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review. Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability. RESULTS Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti–PD-1/L1 therapy. Median duration of response was 7.6 months (range, 0.95 to 11.30+ months). The most common treatment-related adverse events were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), and dysgeusia (40%). No single treatment-related adverse events grade 3 or greater occurred in 10% or more of patients. CONCLUSION Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti–PD-1/L1 therapies.
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Xu, Huayan, Xinan Sheng, Xieqiao Yan, et al. "A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma." Journal of Clinical Oncology 38, no. 15_suppl (2020): e17113-e17113. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e17113.
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e17113 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). A phase II clinical study showed that RC48-ADC has a good effect on locally advanced or metastatic urothelial carcinoma with HER2-positive expression that failed standard chemotherapy. In the study, some patients with HER2-postive immunohistochemistry (IHC 2+) but negative FISH test still benefit from the treatment of RC48-ADC.The study was to evaluate the activity and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. Methods: This study is an open-label, single-center, one-arm, non-randomized phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary objectives were activity (ORR) and safety. Progress-free survival, disease control rate and overall survival will also be assessed. Results: As of February 2020, 8 patients were enrolled in the study. The median age was 65 years old. At baseline, most patients (6/8) had visceral metastasis. 6 (75%) patients had received≥2 lines treatment and 4 (50%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 25% (2/8) and the DCR was 75% (6/8). The ORR was 33.3% (2/6) in patients with visceral metastasis and was 50.0% (2/4) in liver metastasis patients. The ORR was 33.3% (2/6) in patients post to ≥ 2 lines of treatment and 25% (1/4) in patients post to immunotherapy. Common treatment-related AEs were AST increase (62.5%), ALT increase (50.0%), nausea (50.0%), leukopenia (37.5%), fatigue (37.5%), vomiting (37.5%), hypoesthesia (25.0%), alopecia (25.0%), and neutropenia (25.0%). Most of these AE were Grade 1 or 2. The AE of Grade 3 was neutropenia (12.5%). The SAE was CPK increased (12.5%). Conclusions: The study showed that RC48-ADC was safety and the ORR was 25% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. Clinical trial information: NCT04073602.
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Khalife, Nadine, Claude Chahine, Manal Kordahi, Tony Felefly, Hampig Raphael Kourie, and Khalil Saleh. "Urothelial carcinoma in the era of immune checkpoint inhibitors." Immunotherapy 13, no. 11 (2021): 953–64. http://dx.doi.org/10.2217/imt-2021-0042.
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Bladder cancer is the seventh most frequent cancer worldwide. The majority of patients present with nonmuscle invasive disease, while 20% of the patients are diagnosed with muscle-invasive bladder cancer. The treatment of nonmuscle invasive disease is endoscopic resection followed by intravesical adjuvant treatment for high risk patients. The standard treatment of localized muscle-invasive disease is neoadjuvant chemotherapy followed by radical cystectomy. Platinum-based chemotherapy is the first-line treatment in locally advanced or metastatic urothelial carcinoma. Immune checkpoint inhibitors have been approved for the treatment of metastatic urothelial carcinoma as second-line treatment or first-line in platinum-ineligible patients. Recently, pembrolizumab have been approved in bacillus Calmette–Guérin (BCG)-refractory nonmuscle invasive bladder cancer. This review summarizes the current evidence concerning immunotherapy in the treatment of urothelial carcinoma.
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Powles, Thomas, Se Hoon Park, Eric Voog, et al. "Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma." New England Journal of Medicine 383, no. 13 (2020): 1218–30. http://dx.doi.org/10.1056/nejmoa2002788.
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Chang, Sam S. "Re: Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma." Journal of Urology 203, no. 2 (2020): 251. http://dx.doi.org/10.1097/01.ju.0000614704.30826.9b.
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Polyakova, A. S., E. A. Sokolov, and D. Yu Pushkar. "Effectiveness of pembrolizumab in therapy of sarcomatoid variant of metastatic urothelial carcinoma. Clinical case." Cancer Urology 20, no. 4 (2025): 104–11. https://doi.org/10.17650/1726-9776-2024-20-4-104-111.
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Sarcomatoid variant of urothelial carcinoma is a rare histological subtype: it is diagnosed in 0.1–0.3 % of all neoplasms of the bladder. The standard 1st line therapy for all types of advanced urothelial carcinoma is chemotherapy which does not necessarily allow to achieve the best or complete responses, especially in the presence of sarcomatoid differentiation. High programmed cell death-ligand 1 (PD-L1) expression in this morphological subtype allows to assume better results of immunotherapy compared to chemotherapy. However, a large number of observations is necessary to confirm this hypothesis and suggest pembrolizumab immunotherapy as a standard 1st line therapy for metastatic urothelial carcinoma with sarcomatoid differentiation.
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Bingham, Nishan, H. James Wallace III, Joanne Monterroso, Claire Verschraegen, Brenda L. Waters, and Christopher J. Anker. "Urothelial Superior Vena Cava Syndrome with Limited Response to Radiation Therapy." Case Reports in Oncological Medicine 2015 (2015): 1–4. http://dx.doi.org/10.1155/2015/513685.
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Radiation therapy (RT) is the standard of care for cases of superior vena cava (SVC) syndrome secondary to metastatic adenopathy. Histologies vary in radiosensitivity and response time, making alternative therapies such as chemotherapy and/or intravenous stenting preferable alternative options for certain diagnoses. Metastatic urothelial carcinoma is a particularly rare cause of SVC syndrome with only 3 cases reported in the literature. Consequently, optimal management remains challenging, particularly in cases of high tumor burden. Here we present a case of highly advanced metastatic urothelial cancer with SVC syndrome and tracheal compression. The patient started urgent RT but expired midway through her treatment course due to systemic progression of disease, requiring SVC and tracheal stenting. The authors review the literature including discussion of the few other known cases of SVC syndrome due to urothelial carcinoma and a review of this histology’s response to RT. This experience suggests, that in cases of SVC syndrome with widespread advanced disease, stenting and chemotherapy with or without RT may be the most important initial treatment plan, depending on goals of care.
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Flaig, Thomas W., Philippe E. Spiess, Neeraj Agarwal, et al. "Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology." Journal of the National Comprehensive Cancer Network 18, no. 3 (2020): 329–54. http://dx.doi.org/10.6004/jnccn.2020.0011.
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This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non–muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non–muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.
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Torres-Jiménez, Javier, Víctor Albarrán-Fernández, Javier Pozas, et al. "Novel Tyrosine Kinase Targets in Urothelial Carcinoma." International Journal of Molecular Sciences 22, no. 2 (2021): 747. http://dx.doi.org/10.3390/ijms22020747.
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Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.
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Park, Rachel S., Lillian Werner, Heidi Greulich, et al. "Multidimensional investigation of HER2 in advanced urothelial carcinoma (UC)." Journal of Clinical Oncology 30, no. 15_suppl (2012): 4580. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4580.
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4580 Background: Incidence of Her2 positivity and association with overall survival (OS) are controversial in advanced UC. Activating Her2 mutations have been identified in other cancers, but they have not been previously reported in UC. We determined Her2 status by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and copy number gain (CNG) via array CGH of primary UC tumors from patients (pts) with metastatic disease. Targeted Her2 sequencing was performed at known mutation hotspots, and mutation effect was investigated in vitro. Methods: Tissue microarrays of formalin fixed paraffin-embedded tumor from 98 UC pts treated with platinum-based combination chemotherapy for metastatic disease were evaluated for Her2 protein and for Her2 gene amplification by using standard clinical protocols. Positive staining was defined as an IHC score of 3+ or a FISH ratio of ≥2 using scoring criteria established for evaluation of breast cancer. Her2 CNG was evaluated by aCGH with cutoff log base 2 ratio > 0.9. Mutation status was validated by hME sequencing. OS was measured from start of treatment for metastatic disease. Association of OS and Her2 status was assessed by a Cox regression model. NIH-3T3 cells with Her2 V777L were assessed for growth, invasion, and Her2 kinase activation. Results: 22% of pts had 3+ Her2 staining by IHC. 21% of pts had FISH amplification. These were concordant in 78% of pts. CNG was identified in 16% and was concordant with FISH and IHC 85% and 88% of the time, respectively. Her2 status by any modality showed no significant association with OS in either univariate [HR=0.94, 95% CI: (0.52, 1.70), p=0.83] or multivariate [HR=1.12, 95% CI: (0.61, 2.06), p=0.72] analysis. Her2 mutations (V777L and L755S) were identified in 2 pts (2%). In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and Her2 kinase constitutive activation. Conclusions: Her2 overexpression or amplification in the primary tumor does not predict OS in pts with metastatic UC. Other research has suggested that V777L sensitizes cells to lapatinib, while L755S leads to lapatinib resistance. These rare oncogenic Her2 mutations occur and may be therapeutic targets in selected pts.
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Ghatalia, Pooja, and Elizabeth R. Plimack. "Integration of Immunotherapy Into the Treatment of Advanced Urothelial Carcinoma." Journal of the National Comprehensive Cancer Network 18, no. 3 (2020): 355–61. http://dx.doi.org/10.6004/jnccn.2020.7539.
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Five new PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of metastatic urothelial carcinoma (UC): pembrolizumab, atezolizumab, durvalumab, nivolumab, and avelumab. Although cisplatin-based chemotherapy remains the recommended frontline option for cisplatin-eligible patients with metastatic UC, immunotherapy is now an available option in the second-line setting as well as the frontline setting for selected cisplatin-ineligible patients who are either unable to tolerate chemotherapy or PD-L1–positive. This review describes the updated clinical efficacy of these checkpoint inhibitors in the treatment of advanced UC and suggests how they can be sequenced in the context of available chemotherapeutic options.
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Bukhari, Nedal, Humaid O. Al-Shamsi, and Faisal Azam. "Update on the Treatment of Metastatic Urothelial Carcinoma." Scientific World Journal 2018 (June 6, 2018): 1–7. http://dx.doi.org/10.1155/2018/5682078.
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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 advances in first- and second-line treatments including chemotherapy and immunotherapy. This review reports key findings from the clinical trials especially highlighting the importance of PD-1 and PD-L1 inhibitors in the treatment of bladder/urothelial carcinomas.
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Molins, Joaquim Bellmunt, Lillian Werner, Marta Guix, et al. "PI3KCA mutations in advanced urothelial carcinoma: A potential therapeutic target?" Journal of Clinical Oncology 30, no. 15_suppl (2012): 4582. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4582.
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4582 Background: PI3KCA is frequently mutated in human cancer; however, information is scarce regarding its relevance in urothelial carcinoma (UC). We determined the prevalence of mutation and impact on clinical outcome of PI3KCA uniformly-treated patients with metastatic UC. Impact of PI3K and dual PI3K/mTOR inhibition was tested in vitro in UC cell lines with either H1047R or E545K mutation. Methods: 141 samples from invasive UC were scanned for mutations. Of those, complete clinical data was available from 85 cases treated with platinum-based combination chemotherapy for advanced or metastatic disease. DNA was extracted from FFPE material. Mutation status was determined by iPLEX sequencing and confirmed with hME sequencing. Overall survival (OS) was measured from beginning of treatment for metastatic disease to time of death or censored on the last known alive date. Cox proportional hazard model was used to assess the associations of PI3K mutational status and OS. Growth inhibitory effects of a specific PI3K inhibitor and a dual PI3K/mTOR inhibitor (both from Selleck) on UC cell lines with or without mutations were tested using MTT assays. Results: Mutations in the PI3KCA gene were observed in 14 (10%; 95% CI 6-16%) specimens. E545K was detected in all 14 specimens, though one specimen contained mutation at both E545K and H1047R. Among patients with clinical data, there was no statistically significant association between PI3KCA mutational status and OS (HR for having PI3KCA=0.49, 95% CI [0.15, 1.57], p-value 0.22). Preliminary in vitro experiments showed that cell growth was more potently inhibited with dual PI3K/mTOR inhibitors than with PI3K inhibitors. Conclusions: Mutations in the PI3KCA gene were detected in 10% of invasive UC and did not correlate with OS in patients with metastatic UC treated with platinum-based chemotherapy. PI3K inhibition in vitro impacts UC cell growth, though dual PI3K/mTOR inhibitors may have more significant effects than PI3K inhibition alone.
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Kawahara, Takashi, Akihito Hasizume, Koichi Uemura, et al. "Administration of Enfortumab Vedotin after Immune-Checkpoint Inhibitor and the Prognosis in Japanese Metastatic Urothelial Carcinoma: A Large Database Study on Enfortumab Vedotin in Metastatic Urothelial Carcinoma." Cancers 15, no. 17 (2023): 4227. http://dx.doi.org/10.3390/cancers15174227.
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Background: Enfortumab vedotin shows promise as a targeted therapy for advanced urothelial carcinoma, particularly in patients who have previously received platinum-based chemotherapy and an immune-checkpoint inhibitor. The EV-301 phase III trial demonstrated significantly improved overall survival and response rates compared to standard chemotherapy. However, more data, especially from larger real-world studies, are needed to further assess its effectiveness in Japanese patients. Methods: A total of 6007 urothelial cancer patients inducted with pembrolizumab as a second-line treatment were analyzed. Among them, 563 patients received enfortumab vedotin after pembrolizumab, while 443 patients received docetaxel or paclitaxel after pembrolizumab, and all were included in the study for efficacy as a life prolonging agent. Results: The enfortumab vedotin group showed a longer overall survival than the paclitaxel/docetaxel group (p = 0.013, HR: 0.71). In multivariate analysis, enfortumab vedotin induction was the independent risk factor for overall survival (p = 0.013, HR: 0.70). There were no significant differences in cancer-specific survival. Conclusions: Enfortumab vedotin prolonged the overall survival for Japanese advanced or metastatic urothelial carcinoma patients compared to paclitaxel or docetaxel after pembrolizumab treatment.
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Wahyuni, Siska Dwiyantie, Sri Suryanti, Hasrayati Agustina, and Bethy Suryawathy Hernowo. "CXCR4 and MMP-9 Immunoexpression are Associated with Metastasis in Infiltrating Urothelial Carcinoma of The Bladder." Indonesian Journal of Cancer 16, no. 3 (2022): 158. http://dx.doi.org/10.33371/ijoc.v16i3.892.
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Background: Infiltrating urothelial carcinoma of the bladder (IUCB) is an aggressive urinary tract cancer. Most of the patients were diagnosed with advanced stages, and many have metastasized. Metastasis is responsible for 90% of cancer deaths compared to the primary tumor itself. In previous research, the expression of CXCR4 and MMP-9 has been suggested to correlate with metastasis and prognosis in several cancers. This study aimed to analyze the association of CXCR4 and MMP-9 expression with metastasis in infiltrating urothelial carcinoma of the bladder. Methods: This cross-sectional study included 40 selected paraffin-embedded tissue blocks from histopathologically diagnosed IUCB patients, consisting of 20 cases of non-metastasizing and 20 cases of metastasizing IUCB. Immunohistochemical staining for CXCR4 and MMP-9 was performed in all cases. All data were analyzed using the Chi-Square test with p < 0.05 of a significant level and then processed using SPSS 24.0 for Windows.Results: High CXCR4 immunoexpression was found in 18 (45%) of all cases, and high MMP-9 immunoexpression was found in 19 (47.5%) cases. High immunoexpression of CXCR4 and MMP9 in infiltrating urothelial carcinoma of the bladder showed significant association with metastasis (p < 0.05). The stepwise logistic regression analysis revealed that both CXCR-4 and MMP-9 immunoexpressions were independent prognostic factors for metastasis.Conclusions: CXCR4 and MMP-9 play a role in the metastatic process in infiltrating urothelial carcinoma of the bladder.
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Wishahi, Mohamed. "Erdafitinib and checkpoint inhibitors for first-line and second-line immunotherapy of hepatic, gastrointestinal, and urinary bladder carcinomas: Recent concept." World Journal of Hepatology 16, no. 4 (2024): 490–93. http://dx.doi.org/10.4254/wjh.v16.i4.490.
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Cancer immunotherapy is administered for first-line, second-line, neoadjuvant, or adjuvant treatment of advanced, metastatic, and recurrent cancer in the liver, gastrointestinal tract, and genitourinary tract, and other solid tumors. Erdafitinib is a fibroblast growth factor receptor (FGFR) inhibitor, and it is an adenosine triphosphate competitive inhibitor of FGFR1, FGFR2, FGFR3, and FGFR4. Immune checkpoint inhibitors are monoclonal antibodies that block programmed cell death protein 1 (PD-1) and its ligand that exert intrinsic antitumor mechanisms. The promising results of first-line treatment of advanced and metastatic urothelial carcinoma with PD-1 blockades with single or combined agents, indicate a new concept in the treatment of advanced, metastatic, and recurrent hepatic and gastrointestinal carcinomas. Cancer immunotherapy as first-line treatment will improve overall survival and provide better quality of life. Debate is arising as to whether to apply the cancer immunotherapy as first-line treatment in invasive carcinomas, or as second-line treatment in recurrent or metastatic carcinoma following the standard chemotherapy. The literature in the field is not definite, and so far, there has been no consensus on the best approach in this situation. At present, as it is described in this editorial, the decision is applied on a case-by-case basis.
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Vitiello, Antonio, Francesco Ferrara, Ruggero Lasala, and Andrea Zovi. "Precision Medicine in the Treatment of Locally Advanced or Metastatic Urothelial Cancer: New Molecular Targets and Pharmacological Therapies." Cancers 14, no. 20 (2022): 5167. http://dx.doi.org/10.3390/cancers14205167.
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Many variants of urothelial cancer present diagnostic challenges and carry clinical implications that influence prognosis and treatment decisions. The critical issues of treatment-resistant clones are a crucial barrier to care in individuals affected by urothelial carcinoma. Laying the foundations for the resistance evolution, a wide mutational heterogeneity characterizes urothelial carcinoma, noticeable also in patients affected by a early stage disease. In recent years the growing knowledge of the pathogenesis and molecular paths underlying the onset and progression of urothelial cancer are leading to the development of new therapies based on immune checkpoints. Chemotherapy and immunotherapy both operate selectively by shaping the developmental trajectory of urothelial carcinoma in the course of the illness. To date, a promising new therapeutic treatment is represented by antibody-drug conjugates, therapeutic tools that exploit the targeted ability of an antibody to administer cytotoxic drugs directly to the tumor. Indeed, nowadays in the clinical setting there are several treatments available for the treatment of locally advanced or metastatic urothelial cancer, from classic chemotherapeutics such as Gemcitabine, Cisplatin and Carboplatin, Paclitaxel and Docetaxel, to Programmed cell death protein 1 (PD-1) or Programmed death-ligand 1 (PD-L1) inhibitors such as Atezolizumab, Avelumab, Nivolumab, Pembrolizumab, up to anti-nectin 4 Enfortumab Vedotin and Sacituzumab govitecan, which binds Tumor-associated calcium signal transducer 2 (Trop-2) and activates as a topoisomerase inhibitor. The aim of this work is to describe the molecular mechanisms underlying the onset of the urothelial cancer and provide an overview of the immunotherapies that can be used in the clinical setting to counteract it, deepening the efficacy and safety results of the pivotal studies and the place in therapy of these treatments.
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Wong, Yu-Ning, Samuel Litwin, David Vaughn, et al. "Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma." Journal of Clinical Oncology 30, no. 28 (2012): 3545–51. http://dx.doi.org/10.1200/jco.2012.41.9572.
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Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.
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Hanna, Kirollos S. "Updates and novel treatments in urothelial carcinoma." Journal of Oncology Pharmacy Practice 25, no. 3 (2018): 648–56. http://dx.doi.org/10.1177/1078155218805141.
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Urothelial Carcinoma (UC) is the second most common malignancy of the genitourinary system and is the sixth most common cancer in the USA. Over a decade prior to 2016, the standard of care for early disease consisted of transuretheral resection of the bladder tumor with or without intravesicular chemotherapy or immunotherapy. Systemic chemotherapies such as gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, cisplatin were reserved for recurrent, muscle-invasive, advanced or metastatic disease. Novel treatment approaches for UC have significantly impacted the management of patients. In 2016–2017, five immune checkpoint inhibitors marked a new paradigm in the treatment of UC for patients with advanced or metastatic disease or who are unable to tolerate platinum-based chemotherapy. Most recently, the U.S. Food and Drug Administration set restrictions on two commonly utilized checkpoint inhibitors, atezolizumab and pembrolizumab, in the first-line setting in patients with UC due to decreased survival associated with low expression of the protein programmed death ligand 1. Furthermore, Breakthrough Therapy Designations have been granted for enfortumab vedotin and erdafitinib for patients following platinum-based chemotherapy and those with fibroblast growth factor receptor mutated UC, respectively. Additional updates include dose-dense gemcitabine and cisplatin for muscle-invasive bladder cancer and preoperative checkpoint blockade. This article will review the available data on updates in the treatment of UC and future direction of therapies.
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Tambaro, Rosa, Marilena Di Napoli, Carmela Pisano, et al. "From clinical trials to clinical use of checkpoint inhibitors for patients with metastatic urothelial cancer." Immunotherapy 13, no. 1 (2021): 67–77. http://dx.doi.org/10.2217/imt-2020-0128.
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Monoclonal antibodies targeting the checkpoint inhibitors (CPIs), programmed cell death protein-1 or programmed cell death ligand-1, are changing the landscape of urothelial carcinoma therapeutics. Overall, clinical studies in metastatic or advanced urothelial cancer showed that CPIs provided a slight improvement in survival and a relevant advantage in safety, compared with chemotherapy. After reviewing published and ongoing trials, the authors discuss expected answers to unmet needs, with a special attention to the research of biological markers for patients with urothelial cancer eligible for treatment with CPIs in this article.
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Abdel-Malek, Raafat, Kyrillus S. Shohdy, Noha Abbas, Mohamed Ismail, Emad Hamada, and Yasser Abdel-Kader. "Safety of Vinflunine in Patients with Advanced Urothelial Carcinoma Refractory to Platinum-based Chemotherapy: A Prospective Pilot Study." Current Drug Safety 14, no. 1 (2019): 31–36. http://dx.doi.org/10.2174/1574886313666181001120752.
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Background: Several single chemotherapeutic agents have been evaluated as the second-line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess the safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to the previous toxicity of chemotherapy. Methods: This is an open-label, prospective, single-center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first-line platinum-based regimen for advanced or metastatic disease. Results: The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy. Conclusion: The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to the selected group of patients. However, this is a single institute experience in a limited number of patients.
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Aoun, Georges, Elie Hayek, and Ibrahim Nasseh. "Mandibular Metastasis of a Recurrent Poorly Differentiated Urothelial Bladder Carcinoma." Journal of Clinical Imaging Science 10 (May 2, 2020): 27. http://dx.doi.org/10.25259/jcis_46_2020.
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Metastatic lesions to the oral cavity are uncommon; they represent between 1 and 3% of all malignant oral neoplasms. In this article, we report a rare case of metastatic urothelial bladder carcinoma in the mandible detected on oral radiographic images and confirmed with multiple imaging modalities. A 67-year-old woman presented to our clinic suffering from pain in the right side of the mandible with a mild swelling. Panoramic radiograph revealed an ill-defined relatively radiolucent lesion in the right mandibular premolar-canine region presenting with permeative changes. Cone-beam computed tomography showed a relatively hypodense lesion with demineralization, interruption of the buccal cortices, and slight thickening and sclerosis of the buccal cortical bone. The patient was referred for further evaluation including additional advanced imaging radiographic techniques (MRI and PET scan) and clinical and histopathological examinations that lead to a final diagnosis of metastatic lesion from an underlying urothelial bladder carcinoma.
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Stecca, Carlos, Osama Abdeljalil, and Srikala S. Sridhar. "Metastatic Urothelial Cancer: a rapidly changing treatment landscape." Therapeutic Advances in Medical Oncology 13 (January 2021): 175883592110473. http://dx.doi.org/10.1177/17588359211047352.
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Despite significant progress, metastatic urothelial cancer remains an incurable condition with a limited life expectancy. Platinum-based chemotherapy is still the mainstay of treatment for metastatic disease, but immunotherapy, antibody drug conjugates, and targeted agents have shown encouraging results in several recent practice changing trials. In this review, we discuss the standard of care, recent therapeutic advances, ongoing clinical trials, and future perspectives in metastatic urothelial carcinoma.
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Bao, Yige, Xinyang Liao, Peng Zhang, Hao Zeng, Jiyan Liu, and Qiang Wei. "WUTSUP-02-II-Neo-Dis-Tis: Investigating the efficacy and safety of neoadjuvant tislelizumab plus disitamab vedotin with adjuvant tislelizumab in upper urinary tract carcinoma—A phase II multi-center study." Journal of Clinical Oncology 42, no. 4_suppl (2024): TPS718. http://dx.doi.org/10.1200/jco.2024.42.4_suppl.tps718.
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TPS718 Background: Upper tract urothelial carcinoma (UTUC) and urothelial bladder cancer (UBC) are frequently referred to as “disparate twins” despite their common tissue origin. They exhibit varying biological behaviors, prognostic outcomes, and responses to treatment. It is crucial to conduct dedicated clinical trials for UTUC as a separate entity rather than relying solely on UBC study results, giving that UTUC lags in evidence quantity and quality compared to UBC. Despite the superior outcomes of neoadjuvant treatment over adjuvant treatment in UBC trials, the currently available evidence for neoadjuvant therapy of UTUC remains limited in quantity and diversity, as the largest trial, POUT, is focused on adjuvant therapy. Additionally, the limited number of neoadjuvant trials for UTUC primarily utilize chemotherapy-based regimens, with little investigation into combination therapies. Of note, UTUC patients frequently have impaired renal functions, making a chemotherapy-independent approach a desirable alternative. On the other hand, given the short duration of neoadjuvant therapy, a combination therapy strategy appears to be necessary, especially with the increasing interest in immune therapy maintenance after surgery. Tislelizumab has demonstrated efficacy in patients with advanced or metastatic urothelial carcinoma. Disitamab Vedotin, a HER2-targeting antibody-drug conjugate (ADC), has demonstrated robust clinical efficacy in metastatic urothelial carcinoma patients with HER2 2+ or 3+ expression. Disitamab Vedotin in combination with PD-1 immunotherapy has shown remarkable results in locally advanced or metastatic urothelial carcinoma, regardless of HER2 expression, indicative of a synergistic effect between ADC and PD-1 immunotherapy. In this study, we aim to conduct a prospective phase II trial to investigate the efficacy and safety of neoadjuvant tislelizumab plus Disitamab Vedotin followed by adjuvant tislelizumab in patients with high-risk UTUC. Methods: This multi-center phase II trial aims to enroll 45 patients with histologically confirmed UTUC at clinical stage cT2-4N0M0 or cT1-4N1-2M0. Neoadjuvant therapy includes 4 cycles of Tislelizumab (200mg for each 3-week cycle) in combination with Disitamab Vedotin (2.0mg/kg for each 3-week cycle). Radical nephroureterectomy (including bladder cuff resection and regional lymph node dissection if indicated) will be performed if there is no obvious contraindication within 3-6 weeks after the final neoadjuvant therapy administration. Postoperative adjuvant treatment with 8 cycles of tislelizumab will be provided. The primary endpoint is pathological complete response rate. Secondary endpoints include overall survival, local recurrence free survival, distant metastasis free survival, FACT–G. Clinical trial information: ChiCTR2300067836 .
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Maestroni, Umberto, Stefania Ferretti, Francesco Dinale, et al. "A Renal Cancer with Intermediate Characteristics between Collecting (Bellini) Duct Carcinoma and Urothelial Carcinoma: Case Report and Review of the Literature." Tumori Journal 92, no. 6 (2006): 545–48. http://dx.doi.org/10.1177/030089160609200615.
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Collecting duct carcinoma of the kidney is a rare and aggressive neoplasm of the distal collecting tube, often metastatic at the time of the diagnosis, for which there is no established therapy. We herein describe the case of a 65-year-old man with a renal cancer with a particular immunohistochemical pattern and pathologic aspect. The lesion was diagnosed as a tumor borderline between a urothelial carcinoma with intraductal spreading and a collecting duct carcinoma with caly-ceal and pelvic spreading. The patient is disease-free 11 months after diagnosis, after radical surgery with adjuvant chemotherapy (carboplatine and gemcitabine) and radiotherapy of a local recurrence. Owing to the common embryologic origin of collecting duct and transitional urothelial cells, several authors have reported an association between collecting duct carcinoma and urothelial cancer. The literature is reviewed to evaluate drugs active against urothelial cancer (like ifosfamide, paclitaxel, carboplatin and gemcitabine). This field should be investigated in the future, in the framework of a neoadjuvant or adjuvant chemotherapy able to support radical surgery for local and advanced collecting duct carcinoma.
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Ogbuji, Vanessa, Irasema C. Paster, Alejandro Recio-Boiles, Jennifer S. Carew, Steffan T. Nawrocki, and Juan Chipollini. "Current Landscape of Immune Checkpoint Inhibitors for Metastatic Urothelial Carcinoma: Is There a Role for Additional T-Cell Blockade?" Cancers 16, no. 1 (2023): 131. http://dx.doi.org/10.3390/cancers16010131.
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Urothelial carcinoma (UC) is the most common form of bladder cancer (BC) and is the variant with the most immunogenic response. This makes urothelial carcinoma an ideal candidate for immunotherapy with immune checkpoint inhibitors. Key immune checkpoint proteins PD-1 and CTLA-4 are frequently expressed on T-cells in urothelial carcinoma. The blockade of this immune checkpoint can lead to the reactivation of lymphocytes and augment the anti-tumor immune response. The only immune checkpoint inhibitors that are FDA-approved for metastatic urothelial carcinoma target the programmed death-1 receptor and its ligand (PD-1/PD-L1) axis. However, the overall response rate and progression-free survival rates of these agents are limited in this patient population. Therefore, there is a need to find further immune-bolstering treatment combinations that may positively impact survival for patients with advanced UC. In this review, the current immune checkpoint inhibition treatment landscape is explored with an emphasis on combination therapy in the form of PD-1/PD-L1 with CTLA-4 blockade. The investigation of the current literature on immune checkpoint inhibition found that preclinical data show a decrease in tumor volumes and size when PD-1/PD-L1 is blocked, and similar results were observed with CTLA-4 blockade. However, there are limited investigations evaluating the combination of CTLA-4 and PD-1/PD-L1 blockade. We anticipate this review to provide a foundation for a deeper experimental investigation into combination immune checkpoint inhibition therapy in metastatic urothelial carcinoma.
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Chin, Sheray N., Tanya Foster, Gurendra Char, and Audene Garrison. "Concomitant Urothelial Cancer and Renal Tuberculosis." Case Reports in Urology 2014 (2014): 1–3. http://dx.doi.org/10.1155/2014/625153.
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We report a case of coexisting urothelial cancer and renal tuberculosis in the same kidney. The patient is a 72-year-old female with a remote history of treated pulmonary tuberculosis who presented with haematuria, initial investigation of which elucidated no definitive cause. Almost 1 year later, a diagnosis of metastatic urinary tract cancer was made. The patient received chemotherapy for advanced collecting duct type renal cell carcinoma, based on histological features of renal biopsy. Subsequent confirmatory immunostains however led to a revised diagnosis of urothelial cancer, necessitating a change in chemotherapy regimen. A diagnosis of ipsilateral renal tuberculosis was made based on TB-PCR testing of renal biopsy tissue and anti-TB therapy was coadministered with chemotherapy. The patient died 9 months after diagnosis of metastatic urothelial cancer.
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Hutterer, Georg C., and Martin Pichler. "Advanced/metastatic urothelial carcinoma of the bladder and upper urinary tract." memo - Magazine of European Medical Oncology 12, no. 4 (2019): 324–28. http://dx.doi.org/10.1007/s12254-019-00532-9.
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Goncalves, L., J. Gramaça, A. R. Freitas, et al. "Real world data from Avelumab in Advanced or Metastatic Urothelial Carcinoma." European Urology Open Science 57 (November 2023): S308. http://dx.doi.org/10.1016/s2666-1683(23)01513-6.
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Teo, Min Yuen, Kenneth Seier, Irina Ostrovnaya, et al. "Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers." Journal of Clinical Oncology 36, no. 17 (2018): 1685–94. http://dx.doi.org/10.1200/jco.2017.75.7740.
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Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens. Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free and overall survival. Results Sixty patients with urothelial cancer enrolled in prospective trials of anti-PD-1/PD-L1 antibodies met inclusion criteria. Any DDR and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001). A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations (80%) compared with DDR alterations of unknown significance (54%) and in those whose tumors were wild-type for DDR genes (19%; P < .001). The correlation remained significant in multivariable analysis that included presence of visceral metastases. DDR alterations also were associated with longer progression-free and overall survival. Conclusion DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma. These observations warrant additional study, including prospective validation and exploration of the interaction between tumor DDR alteration and other tumor/host biomarkers of immunotherapy response.
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Demianets, Roksolana, Dong Ren, Roozbeh Houshyar, Giovanna A. Giannico, and Cary Johnson. "Primary Adenosquamous Carcinoma of the Prostate." Diagnostics 14, no. 6 (2024): 645. http://dx.doi.org/10.3390/diagnostics14060645.
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Prostate cancer accounts for 29% of malignant diagnoses among men in the United States and is the second leading cause of death from cancer. Effective screening methods and improved treatment have decreased the mortality rate significantly. This decreased mortality rate, however, does not apply to all histologic variants. Adenosquamous carcinoma of the prostate is an extremely aggressive neoplasm with no current known curative therapy. It is often diagnosed after chemotherapy, radiation, or androgen deprivation therapy for traditional prostatic adenocarcinomas. Primary carcinomas of the prostate with squamous features include, but are not limited to, pure squamous cell carcinoma and adenocarcinoma mixed with squamous cell carcinoma (SCC). Important distinguishable clinical features of adenosquamous carcinoma include normal prostate-specific antigen (PSA) levels, even with advanced disease and osteolytic versus osteoblastic metastatic lesions in adenocarcinoma. Additional entities to consider in the differential diagnosis are squamous metaplasia of the prostate, secondary involvement of pure SCC, and urothelial carcinoma with squamous differentiation. Here, we present a de novo case of adenosquamous carcinoma in a 48-year-old man who rapidly developed extensive metastatic disease.
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Salous, Tareq, Rebecca Hassoun, Sandra K. Althouse, Stephanie Schneck, Jennifer King, and Nabil Adra. "Neuropathy, skin rash, and hyperglycemia as predictors of response to enfortumab vedotin in locally advanced and metastatic bladder and upper tract urothelial carcinoma." Journal of Clinical Oncology 43, no. 5_suppl (2025): 771. https://doi.org/10.1200/jco.2025.43.5_suppl.771.
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771 Background: Enfortumab vedotin (EV) in combination with pembrolizumab is FDA approved for treatment of locally advanced and metastatic urothelial cancer. Neuropathy, skin rash, and hyperglycemia are common side effects of EV. We evaluated the impact of presence of neuropathy, skin rash, and hyperglycemia on progression free survival (PFS) in patients (pts) with bladder or upper tract urothelial carcinoma treated with EV. Methods: The Indiana University bladder cancer database was queried for pts with locally advanced and metastatic bladder and upper tract urothelial carcinoma who were treated with EV with or without pembrolizumab. Pts with variant histology were included. Toxicities were documented throughout the course of treatment. Association of neuropathy, skin rash and hyperglycemia and PFS were compared to patients without any of the side effects using the log-rank test. Results: Between 2018-2024, a total of 83 pts were treated with EV with at least 2 doses. The median age was 69 years (range, 39-89). 47 pts had EV + pembrolizumab, while 36 pts had EV as single agent. 43 pts received EV as 1st, 28 pts as 2nd, 10 pts as 3rd, and 2 pts as 4th line of treatment. Metastatic sites were lymph nodes in 42 pts, lungs in 34 pts, bones in 29 pts, liver in 16 pts, and brain in 7 pts. Median follow-up from the start of EV treatment was 14 months (range, 1-33). Neuropathy was reported in 30 (36%) pts, skin rash in 32 (39%) pts, and hyperglycemia in 6 (7%) pts. The median PFS in patients who did not experience neuropathy/skin rash/hyperglycemia was 4.5 months (95% CI, 2.4-11.0), 10.6 months (95% CI, 7.2-15.7) in pts who experienced neuropathy (P = 0,01), 8.6 months (95% CI, 7.3-20.2) in pts who experienced skin rash (P = 0.01), and 15.9 months (95% CI, 5.1-15.9) in pts who experienced hyperglycemia (P = 0.03). Conclusions: The presence of neuropathy, skin rash, or hyperglycemia in patients with metastatic bladder or upper tract urothelial carcinoma treated with EV was associated with improved PFS.