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  • image Renal cell carcinoma (RCC) predominantly occurs later in life, with 70% of all cases diagnosed between the ages of 55 and 84 years.
  • image The most established risk factors for RCC are smoking, obesity, and hypertension.
  • image Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is the hallmark of the most common type of RCC, the clear cell subtype.
  • image More than 50% of RCC cases are diagnosed by incidental findings on routine imaging for unrelated reasons.
  • image The Memorial Sloan-Kettering Cancer Center Prognostic Factors Model for Survival classifies patients into low-, intermediate-, and high-risk groups based on five clinical factors and can predict survival in untreated patients and those treated with immunotherapy and targeted agents.
  • image Surgical removal of the primary tumor, either by total or partial nephrectomy, is the preferred initial treatment for all stages of RCC.
  • image Immunotherapy used to be considered first-line therapy for metastatic RCC but has largely been replaced by targeted agents because of their improved efficacy and tolerability.
  • imageSunitinib and pazopanib are oral small molecule inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor and are each treatment options as first-line therapy for metastatic RCC.
  • image The VEGFR–tyrosine kinase inhibitor axitinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus are both second-line therapy options for metastatic RCC patients who progress on a targeted therapy or cytokine-based therapy first-line regimen.
  • imageTemsirolimus is an IV administered mTOR inhibitor indicated for first-line therapy in patients with high-risk metastatic RCC.

On completion of the chapter, the reader will be able to:

  1. Review the epidemiology, tumor histology, and molecular pathogenesis of renal cell carcinoma (RCC).

  2. Describe the pathophysiology of RCC with a focus on the roles of von Hippel-Lindau (VHL) and hypoxia inducible factor (HIF).

  3. Compare and contrast historical treatments for RCC with newer targeted drug therapy in terms of mechanism of action, methods of administration, adverse effects, and efficacy.

  4. Describe the mechanistic approaches by which targeted small molecule inhibitors interfere with the pathophysiology of RCC.

Renal cell carcinoma (RCC) is a less common malignancy that, until recently, had few treatment options that were poorly tolerated and resulted in few positive outcomes for patients. However, treatment for the disease has been revolutionized by an increased understanding of the pathophysiology of RCC. Clear cell is the predominant subtype of RCC and is the result of inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene on chromosome 3p25, which leads to increased production of growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), and others responsible for angiogenesis and cell growth.1 Before 2005, the primary therapy option for patients with advanced RCC after nephrectomy was immunotherapy with few responses and high toxicity. However, seven new drugs have been approved as first- or second-line therapy for RCC: sorafenib, sunitinib, temsirolimus, bevacizumab (in combination with interferon-α [IFN-α]), everolimus, pazopanib, and axitinib.27 Each drug is an ...

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