Therapeutic options in the management of renal cell carcinoma

Approximately 31,000 new cases of renal cell carcinoma (RCC) are diagnosed in the United States each year and 30% to 40% of these will eventually become metastatic disease. The primary tumor often grows to considerable size before symptoms are apparent, which could explain the high rate of metastatic RCC (mRCC). The median survival of mRCC after diagnosis is 8 to 12 months and the 5-year survival is less than ideal. Traditionally, surgery has been the treatment of choice for mRCC. Chemotherapeutic agents tested so far have been disappointing, perhaps because of a high expression of the multidrug resistance gene or the high content of glutathione in RCC cells. However, the spontaneous regression of mRCC in some cases suggests that these tumor cells are responsive to immunologic mechanisms. Initial interest has focused on two cytokines, interferon-alpha (IFN-alpha) and interleukin-2 (IL-2), with response rates ranging from 15% to 20%. Both IL-2 and IFN-alpha are pleiotropic compounds with specific effects on many leukocyte subsets, in addition to directly affecting tumor proliferation, angiogenesis, and antigen expression. The mechanisms by which these immunoenhancing cytokines exert antitumor effects are still unknown. However, many agree that activation of T cells and natural killer cells is a pivotal part of the antitumor efficacy. For example, some investigators have found that pretreatment levels of natural killer cells and T cells predict a response to IL-2 and IFN-alpha in mRCC. Others report a relationship between activation of peripheral blood lymphocytes and response to cytokine therapy. Expansion of activated T cells in blood during treatment with these two cytokines seems to relate to clinical efficacy in patients with RCC.