Existing randomized studies suggest that methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) chemotherapy should be the standard neoadjuvant regimen for high-risk UC patients.
However, cisplatin plus gemcitabine is a reasonable alternative based on similar efficacy in the setting of metastatic disease and is associated with far less toxicity. Meta-analysis of neoadjuvant studies evaluating cisplatin-based regimens demonstrates a 6.5% absolute improvement in five-year overall survival. Similar robust data for the subpopulation of patients with locally advanced UC are not available, but clinical experience indicates a compelling need for novel therapeutic strategies.
Recognizing this, we have initiated a neoadjuvant protocol for this patient population that uses sunitinib, a novel oral inhibitor of multiple tyrosine kinase receptors, including those of vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor (PDGF), stem cell factor (KIT), and Fms-like tyrosine kinase (FLT3). The conceptual and experimental rationale for the use of sunitinib for patients with UC is arguably as strong as that for kidney cancer, in which this drug has recently demonstrated promising results.
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In the UC protocol, patients receive sunitinib 50 mg p.o. daily for four weeks, followed by two weeks off (one cycle). Patients will then undergo standard radical cystectomy and bilateral lymph-node dissection at the completion of the entire cycle of sunitinib (Day 42+/- 2). The primary end point of this study is to determine the efficacy and safety of sunitinib in the neoadjuvant setting. Clinical activity is defined as the rate of complete pathologic responses observed.
Early experience has been provocative, with some pathologic downsizing observed. In addition to efficacy, this experience will also be closely monitored for systemic and surgical safety, a relevant concern given that agents targeting VEGF might theoretically affect wound or anastomotic healing as well as vascular integrity.
Christopher J. Weight, MD, Andrew J. Stephenson, MD, Michael Gong, MD, PhD, Amr F. Fergany, MD, Eric A. Klein, MD, Robert Dreicer, MD, and Jorge A. Garcia, MD, also contributed to this article.
