Sequencing of agents for metastatic renal cell carcinoma: can we customize therapy?

Context: The expanding armamentarium of agents for the therapy of advanced clear cell renal cell carcinoma (RCC) warrants further investigation of optimal patient selection.

Objective: To analyze the second and subsequent line of targeted therapies for advanced RCC while integrating clinical and molecular markers and imaging.

Evidence Acquisition: Data were acquired from research published in peer-reviewed literature or presented at major conferences.

Novel agents for advanced bladder cancer.

Conventional front-line platinum-based combination chemotherapy yields high response rates but suboptimal long-term outcomes for advanced transitional cell carcinoma. Salvage therapy is an unmet need with disappointing outcomes. The emergence of novel biologic agents offers the promise of improved outcomes.

Neoadjuvant chemotherapy preceding cystectomy for bladder cancer.

Background: Occult micrometastasis at the time of radical cystectomy leads predominantly to distant failures in patients with locally advanced, muscle-invasive transitional cell carcinoma of the bladder.

Objectives: Data supporting neoadjuvant chemotherapy for locally advanced bladder cancer are reviewed.

Results: Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power.

Phase II study of azacitidine to restore responsiveness of prostate cancer to hormonal therapy.

Epigenetic alterations, including methylation of key tumor suppressor genes, may play a role in the progression of prostate cancer to a castration-refractory state. Azacitidine, an agent approved for the treatment of myelodysplastic syndromes, appears to exert its antineoplastic effects partly by hypomethylating DNA that leads to the reversal of gene silencing. It is hypothesized that the addition of azacitidine to complete androgen blockade may restore the responsiveness of progressive prostate cancer to hormonal therapy.

Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma.

Background: The recent approvals of sunitinib, sorafenib and temsirolimus have revolutionized the management of renal cell carcinoma (RCC). Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR-1, 2 and 3, platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta and c-kit.

Objective: Data supporting the development of pazopanib for RCC are reviewed.

Current optimal chemotherapy for advanced urothelial cancer.

Conventional frontline cisplatin-based combination chemotherapy with gemcitabine and cisplatin, or traditional or dose-dense methotrexate, vinblastine, doxorubicin and cisplatin, yields high response rates but few durable remissions for advanced urothelial cancer. Salvage therapy is generally disappointing with few responses. A significant proportion of patients exhibit renal dysfunction, entailing carboplatin-based regimens that appear inferior to cisplatin-based regimens, which warrants a special focus In this population.