Metastatic renal cell carcinoma: update on epidemiology, genetics, and therapeutic modalities

Abstract

The treatment of advanced renal cell carcinoma (RCC) remains a major therapeutic challenge for clinicians. Despite advances in the understanding of the immunobiology of RCC and the availability of several novel targeted agents, there has been little improvement in the survival of patients with metastatic RCC. This review will focus on the recent understanding of risk factors and treatment options and outcomes of metastatic RCC, in particular, targeted therapeutic agents that inhibit vascular endothelial growth factor and mammalian target of rapamycin pathways. Prospective studies are required to determine whether sequential targeted therapy will further improve progression-free survival in RCC. Ongoing research to develop novel agents with better tolerability and enhanced efficacy in the treatment of metastatic RCC is required.

Keywords: cytokines; immunotherapy; metastatic renal cell carcinoma; targeted treatment.

Figure 1

Age-standardized incidence rates of renal cell carcinoma according to sex and country. Notes: Data extracted from Cancer Research UK. Original source of data from Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr. Accessed July 16, 2013.

Figure 2

Incidence rates of renal cell carcinoma stratified by age-group. Notes: Data extracted from Cancer Research UK. Original source of data from Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr. Accessed July 16, 2013.

Figure 3

Site of actions of targeted therapy used in the treatment of metastatic renal cell carcinoma. Notes: The tumor cell possesses inactive Von Hippel–Lindau (VHL), permitting the production of heterodimerized hypoxia-inducible factor (HIF) under normoxic conditions. Mammalian target of rapamycin (mTOR) activation further facilitates HIF production. HIF and S6 contribute to gene activation, leading to production of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), both of which act upon the endothelial cell to promote angiogenesis. Bevacizumab targets only VEGF, whereas sunitinib and sorafenib target VEGF receptors as well as PDGF and c-kit. Temsirolimus and everolimus inhibit the mTOR signaling pathway. Dendritic cells (DCs) are crucial in antitumor immunity, and mature DCs interact with both innate immune cells and antigen-specific T cells to elicit an immune response against tumor antigens. Tumor-derived factors such as VEGF, interleukin (IL)-6, and IL-8 may inhibit DC maturation, therefore escaping immune surveillance. Nontargeted therapies such as interferon (IFN)-α (by promoting maturation of DCs) and DC-based vaccination (by presenting tumor antigens to induce an antigen-specific cytotoxic T-cell response) are other effective treatment options for metastatic renal cell carcinoma. Abbreviations: MHC, major histocompatibility complex; PI3-K, phosphatidylinositide 3-kinase; MIP, macrophage inflammatory protein; X, site of action; VEGF, vascular endothelial growth factor; FKBP, FK-binding protein; IGF, insulin-like growth factor, PDGFR, platelet-derived growth factor receptor.

Figure 4

Overview of the relationship between dendritic cells and effector cells. Notes: Immature conventional or plasmacytoid DCs mature in response to appropriate stimuli (eg, microbial products, TLR ligands). Mature DCs secrete immunoregulatory cytokines (including IFN-α and IL-12), and through cell–cell interactions modulate effector cell response including NK cells and B and T cells, as well as providing positive feedback to DCs to initiate ongoing activation and maturation. Activated effector cells could in turn modulate DC activation, maturation, and survival, as well as enhancing other effector cell functions through the production of cytokines (IFN-γ) and/or via cell–cell contact. Abbreviations: DC, dendritic cell; IFN, interferon; IL, interleukin; NK, natural killer; CTL, cytotoxic T lymphocyte; T_reg cells, regulatory T cells; Th, T helper; TLR, Toll-like receptor; TNF, tumor necrosis factor.