“Medicinal treatment is of no avail. When the growth is small and the patient in good condition removal of the organ may be undertaken, but the percentage of cases of recovery is very small.”

Sir William Osler on Renal Cell Cancer in Principles and Practice of Medicine, Published in 1892 


In most circumstances, any scientist would be delighted to write something that would still be true more than 100 years later. However, when truthful words describe the futility of treatment for a particular illness, they are less of a tribute to the writer’s sagacity than a painful indictment of the slow progress of medical science.
Progress in understanding and treating renal cell cancer has been gradual over the past 20 years, but in the past 3 years progress has greatly accelerated. In the 1980s, it was first noted that a small fraction of patients with metastatic renal cell cancer would respond to treatment with either interferon (IFN)-α or interleukin (IL)-2, particularly at high doses, and that some patients had durable complete remissions that lasted for up to 20 years. Unfortunately, despite considerable effort, it was not possible to distinguish patients who were likely to respond from those unlikely to respond before applying the treatment. And because the treatment, especially with high doses of IL-2, produces high grade toxicity in nearly all patients, many have experienced toxicity without benefit.
Cancer research over the past 20 years has unveiled essential information on cellular abnormalities in renal cell cancer. In most clear cell cancers – which account for 75% of renal malignancies – the function of the von Hippel-Lindau (VHL) gene is lost, leading to activation of the cellular pathway of response to hypoxia. Among the cellular responses to hypoxia are induction of the hypoxia-inducible factor (HIF) and an effort to increase the blood supply by producing factors required for neoangiogenesis, including vascular endothelial growth factor (VEGF); Met; various chemokines (chemoattractant cytokines); and chemokine receptors. New agents that target some of the signaling pathways involved in angiogenesis and the hypoxia response are inducing effective responses in some patients with renal cell cancer.
Among these active new agents are bevacizumab, a monoclonal antibody against VEGF (together with interferon-α); sorafenib, an inhibitor of a number of tyrosine kinases including VEGF receptors 1 and 2, B-raf, and PDGF-β receptors; sunitinib, an inhibitor of Src, VEGF receptors, fibroblast growth factor receptor, and PDGF receptors; and temsirolimus, an mTOR inhibitor involved in regulating protein synthesis and a number of other signaling pathways. All these agents produce partial responses lasting for several months in 10-40% of patients. In the case of temsirolimus, the median overall survival has been prolonged by more than 3 months.
These gains appear to be modest, but they hint at the possibility of developing appropriate sequences or combinations of current agents to increase response rates and survival in advanced renal cell cancer. Much work remains to be done. New classes of agents and some ideas for rational combinations of agents need to be tested. Just as combination chemotherapy approaches are found to have synergistic effects in some settings, it is also possible that mechanism-based rationales for combinations of new targeting agents will be developed. Perhaps a receptor blocker plus an intracellular kinase inhibitor in an auxiliary pathway will produce synergistic tumor cell damage. Or, perhaps blocking a growth factor and applying a chemokine will be effective. We have many new tools but we do not yet know how to use them optimally.
Accordingly, enrolling patients in ongoing clinical studies remains the most important way to build on recent progress. If clinical trial participation is out of the question, the available data suggest an approach to optimize an individual patient’s chances of response. These data are discussed here in detail by experts in the field who have carried out the seminal clinical studies. Dr. Ronald Bukowski and his colleagues from the Renal cancer 6 Cleveland Clinic have reviewed the data on sunitinib. Dr. Martin Gore and his colleagues from the Royal Marsden Hospital have reviewed the data on sorafenib. Finally, Dr. Cora Sternberg and colleagues discuss temsirolimus and provide an overview of evidencebased decision-making using the currently available data.
It is likely that the treatment of renal cell cancer will continue to progress with relative rapidity. We seem to be in the midst of what Stephen Jay Gould would call a “punctuated equilibrium” in the evolution of cancer treatments in general and renal cell cancer in particular. A punctuated equilibrium is a period of rapid change that occurs between longer periods of relatively slow change. Whether or not this is an overly optimistic assessment of our current status, one thing is certainly true. We cannot write about stateof- the-art treatment for renal cell cancer in 2008 with the certainty that the current reality will be the same in 2108. And for that we can all be thankful.