TREATMENT OF METASTATIC RENAL CELL CARCINOMA Nephrectomy Approximately one third of patients with RCC have metastatic disease at the time of initial diagnosis (synchronous metastatic disease), and 40% to 50% will develop distant metastases after initial diagnosis. The value of nephrectomy has been examined retrospectively in patients with synchronous metastases. Prospective controlled trials have also examined the value of nephrectomy. Initially, the rationale for nephrectomy included palliation for severe bleeding, pain, and paraneoplastic symptoms. In addition, there have been occasional patients who demonstrate regression of metastases after nephrectomy; the frequency of this finding has been estimated as 1% to 2%). These responses have been predominantly in pulmonary nodules, with a median duration of approximately 6 months. Several retrospective studies suggested that prior nephrectomy was a good prognostic factor for patients with metastatic RCC, but concerns about selection bias predominated. About 10% to 30% of patients undergoing cytoreductive nephrectomy were unable to receive systemic therapy because of postoperative medical complications or rapid cancer progression Selection of patients for nephrectomy followed by cytokine therapy in the setting of advanced disease must be careful—this is not a pathway that should be used indiscriminately. Individuals with advanced symptoms (performance status ≥ 2), metastases in critical areas (central nervous system, spinal cord compression), major organ dysfunction, and significant comorbid illnesses are not candidates for such approaches. The role of this approach in patients with non–clear cell carcinoma is not well defined. Hormonal Therapy The use of hormonal therapy for patients with metastatic RCC has minimal value. It was originally thought that progestational agents would be useful since they inhibit the growth of diethylstilbestrol-induced renal tumors in Syrian hamsters. Unfortunately, the collective experience with medroxyprogesterone acetate, androgens, and antiestrogens has shown that such preclinical models of renal cancer do not correlate with human RCC. Although the initial clinical trials using progestins for patients with advanced RCC looked promising, studies using modern objective response criteria have demonstrated only limited activity. Two multicenter randomized trials tested oral medroxyprogesterone acetate as initial therapy for patients with metastatic RCC. Response rates to medroxyprogesterone acetate were uniformly low (2.0% and 2.5%, respectively), and overall median survival of the patients varied from 6.0 months to more than 15.0 months. The difference in survival probably reflects patient entry criteria used in the two studies rather than a true difference in biologic responsiveness. Therefore, whereas progestational agents may be useful for symptom palliation, they do not appear to have any significant value in the treatment of patients with metastatic RCC. Chemotherapy Multiple clinical trials performed during the 1980s established RCC as a prototype of a chemotherapy-resistant tumor.. The overall response rate in this review was 18.5%, but protocols incorporated immunotherapy in combination with chemotherapy, and this probably accounts for the marginal increase in activity. In the past, it has been suggested that the fluoropyrimidines or vinblastine might have antitumor activity in patients with metastatic RCC. However, when vinblastine was tested in a randomized prospective setting, the response rate was 2.5% in 81 patients receiving chemotherapy alone, and overall survival was inferior to the combination of vinblastine and interferon alfa. Virtually every other cytotoxic agent has been tested for this disease, either alone or in combination with other chemotherapeutic approaches, almost uniformly with discouraging results. Radiation Therapy Radiation therapy has been used primarily as adjuvant treatment after radical nephrectomy and for palliation of metastatic lesions. Most studies have failed to demonstrate improvement in survival or a reduction in local recurrence rates after postoperative radiation therapy. At present, the main role of radiation therapy for patients with metastatic RCC is for the palliation of symptomatic osseous metastases. Radiation therapy has also been combined with surgery for the treatment of vertebral body metastases with spinal cord compression, allowing substantially reduced blood loss. Standard radiation therapy may also be employed for palliation of brain metastases. Stereotactic radiosurgery has shown promise for the treatment of select patients with brain metastases, thereby avoiding the risks associated with craniotomy. Cytokines and Immunologic Therapy The therapeutic potential of cytokines and immunotherapy has been investigated for the last 30 years in patients with metastatic RCC and has shown real but limited efficacy. The demonstration of T-cell infiltrates the development of T-cell lines (CD8+) with specificity for autologous tumor and the finding of tumor-associated antigens on renal tumors that are MHC restricted provide laboratory evidence for a specific antitumor immune response. Coincident with these observations, a series of clinical trials demonstrated the antitumor activity of cytokines such as interferon alfa and IL-2 in patients with advanced disease. Targeted Agents The VHL gene has been cloned, functions of the protein have been elucidated, and a high frequency of mutations or epigenetic silencing of this gene in sporadic clear cell carcinoma has been recognized. These findings led to a series of studies identifying the VEGF and PDGF pathways as molecular targets in this tumor. These growth factors bind to receptor tyrosine kinases that regulate cell proliferation and survival and can promote tumor-associated angiogenesis and growth. Inhibition of the VEGF and PDGF signaling pathways may therefore inhibit angiogenesis and tumor progression. A series of agents inhibiting VEGF or tyrosine kinase receptors such as VEGFR types 1 to 3 and PDGFR are now under investigation and appear to have antitumor effects in renal cancer patients.
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