Management of bladder cancer: current and emerging strategies.

Huntsman Cancer Institute at the University of Utah, Salt Lake City, USA.
Drugs (Impact Factor: 4.34). 02/2009; 69(9):1173-87.
Source: PubMed


Cancer of the urinary bladder is the fifth most prevalent solid tumour in the US. Urothelial carcinoma is the most common form of bladder cancer, accounting for about 90% of cases. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. Urothelial carcinoma is a chemo-sensitive disease, with a high overall and complete response rate to combination chemotherapy. In the setting of muscle-invasive urothelial carcinoma, use of neoadjuvant chemotherapy is associated with overall survival benefit. The role of adjuvant chemotherapy in this setting is yet to be validated. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients. Currently, there is no standard second-line therapy for patients in whom first-line chemotherapy for metastatic disease has failed. Many newer chemotherapeutic agents have shown modest activity in urothelial carcinoma. Improved understanding of molecular biology and pathogenesis of urothelial carcinoma has opened avenues for the use of molecularly targeted therapies, several of which are being tested in clinical trials. Currently, several novel drugs seem particularly promising including inhibitors of the epidermal growth factor receptor pathway, such as cetuximab, and inhibitors of tumour angiogenesis, such as bevacizumab and sunitinib. Development of reliable molecular predictive markers is expected to improve treatment decisions, therapy development and outcomes in urothelial carcinoma. Funding of and participation in clinical trials are key to advancing the care of urothelial cancer patients. Current and emerging strategies in the medical management of urothelial carcinoma are reviewed.

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    • "Cisplatin in combination with gemcitabine represents the first-line adjuvant treatment option for patients with locally advanced or metastatic bladder cancer. New chemotherapeutic strategies, involving receptor tyrosine kinase inhibitors, are currently investigated in preclinical models and in clinical studies [4,5]. Thus, despite the surgical and chemotherapeutic treatment options the severity of the disease and the poor prognosis urge for the discovery of new markers for disease progression as well as new insights into the pathophysiology of bladder cancer progression. "
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    ABSTRACT: Urothelial bladder cancer is the ninth most common cancer. Despite surgical and chemotherapeutic treatment the prognosis is still poor once bladder cancer progresses to a muscle-invasive state. Discovery of new diagnostic markers and pathophysiologic effectors might help to contribute to novel diagnostic and therapeutic options. The extracellular matrix microenvironment shaped by the extracellular matrix critically affects tumor cell and stroma cell functions. Therefore, aim of the present study was to assess the possible implication of the small leucine-rich proteoglycan biglycan in progression of human urothelial bladder cancer. For this purpose tumor biopsies of 76 bladder cancer patients with different tumor stages (pTa, pT1-T4) were investigated with respect to biglycan expression and correlated with a long-term (10 years) clinical follow-up. Interestingly, higher biglycan mRNA expression was associated with higher tumor stages and muscle invasiveness. In vitro knock-down of endogenous biglycan in human urothelial carcinoma cells (J82 cells) increased proliferation, whereas addition of recombinant biglycan and overexpression of biglycan inhibited tumor cell proliferation. In line with this growth-inhibitory effect of biglycan, transplantation of J82 cells after knock-down of biglycan resulted in significantly increased growth of subcutaneous xenograft tumors in nude mice in vivo. Furthermore, treatment with two anti-proliferative, multi-receptor tyrosine kinase inhibitors-sunitinib and sorafenib-strongly upregulated biglycan expression. Collectively, the experimental data suggest that high biglycan expression is associated with reduced tumor cell proliferation. In accordance, Kaplan-Meier analysis revealed higher 10-year survival in patients with high biglycan mRNA expression in tumor biopsies. In conclusion, the present data suggest that biglycan is an endogenous inhibitor of bladder cancer cell proliferation that is upregulated in response to anti-proliferative tyrosine kinase inhibitors. In addition, high biglycan expression is associated with favorable prognosis.
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