Abstract
Pazopanib controls disease in over half of patients with relapsed or refractory urothelial cancer.
Major finding: Pazopanib controls disease in over half of patients with relapsed or refractory urothelial cancer.
Clinical relevance: High circulating levels of interleukin-8 were associated with shorter overall survival.
Impact: Pazopanib warrants further study in randomized clinical trials, perhaps in a more selected population.
First-line platinum-based chemotherapy is moderately effective in urothelial cancers, but most patients ultimately experience disease progression and have minimal responses to second-line single-agent or combination chemotherapy. New treatment modalities for relapsed and refractory urothelial cancers are therefore needed, and due to the highly vascular nature of urothelial cancers, targeted antiangiogenic agents are of particular interest. Necchi and colleagues conducted an open-label, single-group phase II trial of pazopanib, a multitarget kinase inhibitor with antiangiogenic activity, in 41 patients with urothelial cancer, approximately half of whom were heavily pretreated and classified as cisplatin refractory. The primary endpoint was a confirmed objective response (including partial and complete responses), and secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), disease control (objective response plus stable disease), and circulating levels of angiogenic factors. Partial responses were confirmed in 7 patients, 4 of whom had aggressive upper urinary tract tumors. An additional 14 patients had stable disease, meaning that 21 patients treated with pazopanib achieved disease control. The median PFS was 2.6 months, the median OS was 4.7 months, and after more than a year, 6 patients were still alive and 4 were progression free. High baseline and posttreatment circulating levels of interleukin (IL)-8, a known contributor to the compensatory mechanism of resistance to the antiangiogenic agent sunitinib, were significantly associated with shorter overall survival, suggesting that IL-8 levels may be used to identify patients likely to benefit from pazopanib treatment. Pazopanib was generally well tolerated, although changes in bulky tumor masses induced fistulizations in 6 patients, 1 of whom died. Although patients presenting with bulky disease may be at increased risk for adverse effects, these findings provide support for further clinical evaluation of pazopanib in advanced, refractory urothelial cancer.
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