Drs. Rini and Bukowski do an excellent job of updating and commenting on the rapidly evolving field of therapy for metastatic renal cell carcinoma (RCC). Dr. Bukowski has been a leader in the field for nearly 30 years and thus has a unique perspective on the remarkable progress that has been made between first-generation (hormones, chemotherapy, vaccines, interferon), second-generation (high-dose interleukin-2 [IL-2, Proleukin], allogeneic stem cell transplantation), and third-generation (sorafenib [Nexavar], sunitinib [Sutent], temsirolimus [Torisel]) therapies.

Underlying Biology
Drs. Rini and Bukowski review the fundamental role of the von Hippel-Lindau (VHL) protein in renal cancer. The VHL protein regulates the hypoxia-inducible factor (HIF) protein, and HIF, in turn, regulates nearly 200 genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and a number of other important genes/proteins controlling the growth of renal cancer and normal endothelial cells. Understanding of the biology of renal cancer and the endothelial cell led to the development of antiangiogenic therapy beginning in the late 1990s. Early trials with the aspergillus endothelial cell toxin fumagillin were negative.[1]

However, a sentinel paper by Dr. James Yang and colleagues at the National Cancer Institute (NCI) reported clear-cut responses and stabilization of disease with bevacizumab (Avastin) compared to placebo.[2] Within that same time period, two small-molecule inhibitors of the VEGF pathway, sorafenib and sunitinib, completed phase I trials[3,4] and began to demonstrate activity in renal cancer phase II trials.

At the June 2004 meeting of the American Society of Clinical Oncology (ASCO), three important papers were presented: Dr. Ratain demonstrated an objective prolongation of time to disease progression with sorafenib in a randomized discontinuation trial,[5] Dr. Hainsworth showed that the combination of bevacizumab and erlotinib (Tarceva) had strong anti-RCC activity,[6] and Dr. Motzer showed the strikingly positive phase II data for sunitinib in RCC.[7] Thus, by 2004 three antiangiogenic agents—bevacizumab, sorafenib, and sunitinib—were known to be active against RCC. In 2006/2007, Dr. Hudes added a fourth agent, temsirolimus, to the list of active agents.[8]

Definitive Trials
In the ensuing 4 years, we have seen the full publication of four definitive phase III trials in RCC. Sunitinib vs interferon in first-line metastatic disease showed an improvement in the median progression-free survival (PFS) from 5 to 11 months. Sorafenib vs placebo in second-line metastatic disease showed an improvement in median PFS from 2.8 to 5.5 months and an improvement in overall survival from 14.3 to 17.8 months (with censoring before crossover, which reduced the significance of the overall survival). The mammalian target of rapamycin (mTOR)-inhibiting agent temsirolimus vs interferon in first-line poor-risk disease showed an improvement in PFS from 3.1 to 5.8 and an improvement in overall survival from 7.3 to 10.8 months.[8] Bevacizumab/interferon vs placebo/interferon in first-line metastatic disease showed an improvement in median PFS from 5.4 to 10.2 months with no difference in overall survival yet with the median survival being in excess of 19.8 months.[9]

Two other key papers and abstracts in the past 4 years have included a randomized phase II trial led by Dr. Bukowski, showing that bevacizumab had independent activity in first-line RCC therapy that was not enhanced by adding erlotinib,[10] and a 2008 abstract by Dr. Rini and the Cancer and Leukemia Group B (CALGB), showing that bevacizumab/interferon vs interferon in first-line metastatic disease improved median PFS from 5.2 to 8.5 months.[11] In the three studies using interferon as a control, interferon demonstrated a consistent median PFS of about 5 months. In each study of an antiangiogenic agent alone or in combination, the antiangiogenic arm showed a PFS of 8.5 to 11 months. Overall survivals have not yet been reached in most of these studies but are expected to favor antiangiogenic therapy and to range from 15 to 24 months.

Thus, in the past 3 years we have seen dramatic improvement across the board in the management of patients with metastatic RCC. As Drs. Rini, Bukowski, and others point out,[11-15] despite this good news, the sobering reality is that there are very few complete responses, that IL-2 is apparently the only curative therapy, that the cumulative cost and toxicity of these agents is substantial, and that nearly every patient with metastatic disease will require second, third, fourth, or further lines of therapy.

Ongoing Studies
Drs. Rini and Bukowski summarize ongoing clinical investigations of metastatic RCC and point out some substantial issues. For example, we do not yet know which sequence is most effective. Should sorafenib or sunitinib be used first? Clearly, the weight of clinical evidence favors sunitinib, but is that always the case? In the expanded-access studies of these agents, the objective response rates for both drugs were in the single digits.[16,17] What about rapid sequential treatments with the alternative drug (ie, an AB-AB type regimen)? We also do not know the mechanisms of drug resistance, nor do we know how to predict sensitivity of individual patients to these drugs.

The authors comment that the roles of third-line therapy, new drugs, and combination therapy are still unclear. They only briefly mention the use of continuous sunitinib, which is likely to be less toxic and probably equivalent to intermittent sunitinib.[18] A randomized phase II investigation of intermittent vs continuous sunitinib is due to close at the end of April 2008.

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