Treatment Approaches in Renal Cell Carcinoma: Past, Present, and Future Perspectives

Treatment of localised renal cell carcinoma (RCC) is well established, and surgical resection is curative for most patients. However, for patients with either metastatic disease or whose local disease subsequently metastasises, treatment options have until recently been limited to cytokine therapy or chemotherapy, both of which are ineffective in the majority. As a result, prognosis has been poor for patients with metastatic RCC (mRCC). A better understanding of the pathogenesis of RCC has led to the development and application of therapies targeted at key molecules involved in angiogenesis, which is an integral part of tumour growth and invasion. Research has shown that mutations in the von Hippel-Lindau (VHL) tumour suppressor gene lead to increased expression of vascular endothelial growth factor (VEGF), an angiogenic factor that is frequently over-expressed in clear-cell RCC, and which is believed to contribute to the hypervascularity of RCC. Therefore, novel therapeutics have been developed that target proteins in the VHL–VEGF pathway, with the aim of inhibiting angiogenesis. These agents include sunitinib, sorafenib, temsirolimus, and bevacizumab, all of which improve clinical outcomes compared with immunotherapy or placebo. Although patients with mRCC are now offered a better prognosis, several questions remain: how do we optimise clinical use of these novel agents, how do we identify patients most likely to benefit from targeted therapies, and can combination therapies further improve outcomes? This article reviews the past and present treatment for mRCC and considers the future challenges.