Recent advances and future directions in the management of metastatic renal cell carcinoma.

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment for patients with metastatic RCC (mRCC). Multikinase inhibitors (sunitinib and sorafenib) and the inhibitors of mammalian target of rapamycin (temsirolimus and everolimus) have recently shown superiority over IFN-alpha or placebo; and bevacizumab + IFN-alpha have demonstrated improved activity when compared to IFN-alpha alone in patients with mRCC. Newer anti-vascular endothelial growth factor (VEGF) agents such as axitinib, pazopanib and cediranib are currently under investigation to expand and elucidate future treatment options. Several studies have investigated the synergistic potential of TKIs with a view to blocking multiple signalling pathways simultaneously, but this approach has resulted in a significant increase in toxicity. Sequential TKI administration has demonstrated encouraging results but the optimal sequence of TKIs is yet to be determined. Studies combining TKIs with immunotherapy have resulted in varying degrees of success; with bevacizumab + IFN-alpha being the only studies with positive outcomes. The purpose of this review is to summarize the current evidence supporting the role of TKIs and to discuss potential future directions in the management of mRCC. The role of TKIs as monotherapy, in combination with immunotherapy or other TKIs (combined or sequential approach) will be discussed.