Topical overview New approaches in advanced renal cell carcinoma

Metastatic renal cell carcinoma (RCC) has long been a model of a tumor nearly uniformly resistant to all available therapies. Standard, but largely unsatisfactory, treatment for metastatic RCC consists of cytokine therapy, interleukin-2 (IL-2), and/or interferon–alpha (IFNA). IL-2 can be given in high-dose bolus regimens, resulting in an overall complete response rate of 6% to 7% and a durable complete response rate of 4% to 5% in appropriately selected patients. Furthermore, because the vast majority of patients derive no ultimate benefit from high-dose IL-2, no overall survival advantage in comparison to low-dose cytokine regimens has been observed in randomized trials. Low-dose cytokine regimens have a lower overall and durable complete response rate, although a modest survival advantage of IFNA versus inactive therapy has been shown in randomized trials. Investigators have attempted to augment the benefit of cytokine therapy in a myriad of ways: combination therapy with other cytokines or chemotherapy; dose modification; administration of other immunologically active cells, such as lymphokine-activated killer cells or tumor-infiltrating lymphocytes; or through selection of patients most likely to benefit. None of these approaches has resulted in a significant advance over cytokine monotherapy. Recently, a more thorough understanding of the molecular pathogenesis of RCC has identified rational therapeutic targets, possibly turning RCC into a model disease for targeted therapy. Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene (through mutation or methylation) is observed in the majority of clear cell RCC. The resulting VHL gene silencing leads to induction of hypoxiaregulated genes, including vascular endothelial growth factor (VEGF). VEGF is the most potent pro-angiogenic protein yet discovered, leading to increased vascular permeability and endothelial cell proliferation/migration. VEGF exerts this biologic effect through interaction with a series of VEGF receptors (VEGF-R) on the endothelial cell surface. Thus, therapeutic strategies have recently emerged in RCC that block the action of VEGF through either binding the VEGF protein or blocking the VEGF-R. Bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA) is a recombinant, humanized monoclonal antibody that binds and neutralizes all biologically active isoforms of VEGF. The clinical use of bevacizumab has been investigated in a randomized trial in which 116 cytokinerefractory patients with metastatic, clear cell RCC were randomized to receive placebo, low-dose (3 mg/kg) bevacizumab, or high-dose (10 mg/kg) bevacizumab given intra