advanced renal cell carcinoma
Hitting the target with novel systemic therapies

M. Neil Reaume, BSc, MSc, MD, FRCPC and Christina M. Canil, MD, FRCPC

Renal cell carcinoma is the seventh most common cancer in Canada, with an estimated 4600 new cases diagnosed in 2006.1 Approximately 95% of cases are sporadic (i.e. not hereditary). Risk factors include smoking, obesity, hypertension, acquired cystic kidney disease and exposure to trichloroethylene.

 

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Top-line summary
Renal cell carcinoma (RCC) is a common malignancy. Many patients already have locally advanced or metastatic disease when first diagnosed. In addition, patients with localized disease are at significant risk of progression despite surgical treatment. Chemotherapy is generally ineffective, while immunotherapy benefits only a small minority of patients and is associated with significant toxicity. The von Hippel- Lindau (VHL) gene is commonly mutated in RCC. Understanding the interaction of the VHL gene and cellular signalling pathways affecting angiogenesis has led to the development of targeted therapies. Three agents — bevacizumab, sorafenib and sunitinib — have demonstrated activity against the vascular endothelial growth factor (VEGF) pathway and improved progression-free survival in clinical trials of patients with advanced disease. The U.S. Federal Drug Administration (FDA) and Health Canada have approved sorafenib and sunitinib for the treatment of advanced RCC. A fourth targeted agent, temsirolimus, also downregulates the VEGF pathway through inhibition of mTOR kinase. This is the only targeted agent to have shown improved overall survival in a clinical trial of patients with advanced RCC, however the study was restricted to a poor-risk population. Research is ongoing to assess the role of targeted agents in combinations with chemotherapy, immunotherapy and other targeted therapies.
 
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