Cytokine therapy with interferon-alpha or interleukin-2 (IL-2) has been shown to induce objective responses, and interferon-alpha appears to have a modest impact on survival in selected patients. Interferon-alpha has approximately a 15% objective response rate in appropriately selected individuals. In general, these patients have nonbulky pulmonary and/or soft tissue metastases with excellent PS ratings of zero or one, according to the ECOG rating scale, and the patients show no weight loss. The interferon-alpha doses used in studies reporting good response rates have been in an intermediate range (6-20 million units 3 times weekly). A Cochrane analysis of six randomized trials, with a total of 963 patients, indicated a HR for survival of 0.78 (CI, 0.67-0.90) or a weighted average improvement in survival of 2.6 months.[Level of evidence: 1iiA]
High-dose IL-2 produces a similar overall response rate to interferon-alpha, but approximately 5% of patients had durable complete remissions.[12,13,14,15,16,17] IL-2 has never been shown in a randomized controlled trial to result in longer survival. The current use of high-dose IL-2 mainly derives from the fact that it is the only systemic therapy that has been associated with inducing durable complete remissions, albeit in a small fraction (about 5%) of patients who are eligible for this treatment. The optimum dose of IL-2 is unknown. High-dose therapy appears to be associated with higher response rates but with more toxic effects. Low-dose inpatient regimens have activity against renal cell carcinoma with fewer toxic effects, especially hypotension, but have not been shown to be superior to placebo or any alternative regimen with regard to survival or quality of life. Outpatient subcutaneous administration has also demonstrated responses with acceptable toxic effects but, again, with unclear survival or quality of life benefit. Combinations of IL-2 and interferon-alpha have been studied, but outcomes have not been better with high-dose or low-dose IL-2 alone.[20,21]
Antiangiogenic and Other Targeted Therapy
A growing understanding of the biology of cancer in general, and renal cell carcinoma in particular, has led to the development and U.S. Food and Drug Administration (FDA) approval of six new agents targeting specific growth pathways. Two of the approved targeted therapies block the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth, division, and survival.
Temsirolimus, an intravenously administered mTOR inhibitor, was shown to result in prolonged OS compared with interferon-alpha in a phase III randomized controlled trial that enrolled intermediate- and poor-risk patients. The trial enrolled patients with a variety of subtypes of renal cell carcinoma and was not restricted to clear cell kidney cancer. The HR for death was 0.73 (95% CI, 0.58-0.92, P = .008), making temsirolimus the only therapy for renal cell carcinoma to have clearly been shown to result in longer OS than interferon-alpha using conventional statistical analysis.