Treatment Strategies in Metastatic Renal Cell Carcinoma

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Abstract
Prognosis of metastatic renal cell carcinoma (RCC) remains highly unfavorable. Treatment with chemotherapeutic agents, radiation or hormones has been largely unsuccessful. The natural history of renal cell carcinoma is highly variable and may be characterized by late relapse after nephrectomy, prolonged stabilization of metastatic disease, and spontaneous regression. These features suggest that host immune mechanisms play an important role in the regulation of tumor growth. Hence, therapeutic strategies including cytokines, adoptive immunotherapy, gene therapy, and monoclonal antibodies (MAB) are being evaluated, aiming at modulating the host immune response. Interferons (IFN) have been widely used in the treatment of metastatic renal cell carcinoma, objective responses are achieved in approximately 12%, but complete remissions are rare. Treatment with high-dose intravenous interleukin-2 (IL-2) results in higher response rates but is associated with considerable toxicity. Combination therapy with IFN-α and IL-2 is clinically more effective than single-agent treatment. Multidrug regimens adding 5-fluoro-uracil and 13-cis-retinoic acid to the IFN-α / IL-2 combination show encouraging results. Preliminary data from trials with tumor-infiltrating lymphocytes (TIL), autolymphocyte therapy with activated memory-T cells (ALT), ex vivo primed cytotoxic T cells (CTL) or dendritic cells are promising. In gene therapy, ex vivo gene transfer into tumor cells subsequently serving as a tumor cell vaccine is investigated. In addition, intralesional in vivo gene therapy is examined in an effort to boost immunogenicity of the tumor cells. A monoclonal antibody (G250) against RCC cells has been developed and is evaluated for its diagnostic and therapeutic potential. Despite all efforts, curative results are still rare and a standard therapy for metastatic RCC is not available. If palliation is not reliably achieved with systemic therapy, tumor-related symptoms must be approached with aggressive supportive therapy. Therapy-related impact on the quality of life will become an increasingly important issue. All patients should be treated in the context of controlled studies whenever possible since, despite the encouraging results of new treatment strategies, their further assessment in large randomized trials remains a priority.

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