The prognosis and treatment outcome of patients with advanced renal cell carcinoma have substantially improved with the multitude of currently available molecularly targeted therapies. The rapid addition of novel therapeutic options has made the treatment algorithm complex and has created a significant challenge for the community oncologist, who is faced with selecting a drug for a given patient from a growing list of agents. The optimal treatment sequence remains to be determined, and effective management of side effects and toxicities is currently the key. These targeted therapies are associated with toxicity profiles that are classically distinct from those associated with conventional chemotherapy agents. In order to help community oncologists optimize patient outcomes, this review summarizes clinical issues associated with specific therapies and the background pivotal data.
Approximately 58,240 patients were diagnosed with and 13,040 died of cancer of the kidney and renal pelvis in 2010,1 and the incidence of this cancer is reported to be increasing.2 Renal cell carcinoma (RCC), originating within the renal cortex, constitutes about 85% to 90% of primary renal tumors. The most common subtype of RCC is clear cell carcinoma, arising from the proximal tubule, and constitutes approximately 75% to 85% of new diagnoses.
Biology of Renal Cell Carcinoma
The past several decades have witnessed a significant increase in the understanding of the biology of RCC, leading to development of many new therapeutic targets and a greater availability of newer drugs for RCC management. A majority of kidney cancers are believed to be related to changes in a gene called von Hippel–Lindau (VHL). A loss of functional VHL
gene results in an increased amount of a protein known as hypoxia-inducible factor, which thereafter leads to highly vascular tumors. Overexpression of hypoxia-inducible factor in kidney cancer is also related to stimulation of a receptor called the mammalian target of rapamycin (mTOR). Both the vascular endothelial growth factor (VEGF) and the mTOR pathways clearly provide opportunities for the development of molecularly targeted drugs in RCC (Figure
Figure. Mechanism of Action of Targeted Therapies in Renal Cell Carcinoma
Reprinted with permission from Courtney et al. Curr Oncol Rep. 2009;11(3):218-226.
GF indicates growth factor; GFR, growth factor receptor; HIF, hypoxia-inducible factor; mTORC1, mTORC2, mammalian target of rapamycin complexes 1 and 2; PDK1, phosphoinositide-dependent kinase-1; PI3K, phosphatidylinositol 3-kinase; SDF, stromal cell-derived factor; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau.
Historical Treatment of Advanced Renal Cell Carcinoma
Dramatic and sustained remissions had been seen occasionally in RCC patients with medications known to invoke immune responses. Until only about five years ago, immunotherapeutic agents such as interleukin-2 or interferon alfa were the mainstay of initial treatment of RCC. It is thought that immunotherapeutic agents cause killing of tumor cells by activated T cells and natural killer cells. Among the various immunotherapeutic strategies used to treat advanced RCC, high-dose bolus interleukin-2 induced durable remissions in about 15% to 20% of patients, but its use had been limited by severe toxicity and the need for specialized care (eg, admission to an intensive-care unit) during treatment. Therefore, this treatment approach was largely restricted to carefully selected patients with optimal organ function, who could withstand the possibility of severe hypotension.3
Subsequently, lower-dose interleukin-2 regimens were used to decrease toxicity, but they appeared to be less effective. Response rates (about 10%-15%) have also been seen with low-dose interleukin-2 and interferon alfa.
Targeted Agents in Renal Cell Carcinoma
Better understanding of the molecular biology of RCC led to identification of new therapeutic targets, which in turn led to development of molecular therapies that have now been integrated into the routine treatment algorithm of patients with advanced RCC. These novel therapies targeting the VEGF or the mTOR pathway are both more active as well as less toxic than immunotherapies that were used before.
The importance of angiogenic pathways in the biology of RCC is now well established. As with many other tumors, RCC must induce new blood vessels in order to receive nutrients and oxygen required for progressive cancer growth. VEGF is the strongest proangiogenic protein, and inhibiting VEGF has been proven to be of clinical value in many malignancies, including metastatic RCC.