Another Step Toward the Cure of Metastatic Renal Cell Carcinoma?

In the era of an embarrassment of riches for the treatment of metastatic renal cell cancer (mRCC), why do we need an article— much less an accompanying editorial—about the activity of S-1 (Taiho Pharmaceutical, Tokyo, Japan), a fluorinated pyrimidine in mRCC? With the US Food and Drug Administration approval in 2009 of everolimus, pazopanib, and bevacizumab/interferon to treat mRCC, to add to the agents already approved—namely interleukin 2, sunitinib, sorafenib, and temsirolimus—is S-1 needed, and does it get us closer to a cure? Among the eight approved agents, there are only three broad mechanisms of action: immune stimulation, inhibition of mammalian target of rapamycin (mTOR), and inhibition of the vascular endothelial growth factor (VEGF) signaling pathway. The sequential, combined, and repeated use of these agents has at least doubled the median overall survival of good, intermediate, and poor risk mRCC (20%, 70%, and 10%, respectively) in the United States and Canada. For example, patients with intermediate risk in the cytokine era (pre2005) had an expected survival of 10 months but now have an estimated survival of 25 to 30 months. However, these figures come from centers of excellence that treat large numbers of patients with mRCC. Results from phase III prospective, community-based studies suggest that the median survival is closer to 18 to 20 months—still an impressive improvement for the 5-year period since sorafenib was first approved. A closer look at the agents and the numerous mRCC phase III trials that led to their US Food and Drug Administration approvals suggests that complete remissions are extremely rare and that the median time to progression (or progression-free survival [PFS]) is roughly 8 to 11 months and shorter if the patient’s characteristics include adverse clinical features. Subsequent use of an agent with a different mechanism of action (such as mTOR inhibition) will often induce a second period of remission or stable disease that lasts a somewhat shorter period of time. A third-line agent (often a different agent but also one that inhibits the VEGF pathway) will commonly induce a third period of remission or stable disease; but that period lasts an even shorter period of time. By the time the fourthor fifthline therapy for mRCC is needed, few options are available for patients. Because they have enjoyed prolonged periods of disease control and freedom from cancer symptoms, our patients continue to ask for more high-quality time. Perhaps fluorinated pyrimidine therapy will give select patients such time, but are we getting closer to a cure? The mechanism by which mRCC becomes resistant to the VEGF and mTOR inhibiting agents is under intense investigation. Early data suggests that upregulation or overexpression of a variety of receptors and growth factors on the endothelial cells (such as interleukin 8 or basic fibroblast growth factor receptor) may play a role. Alternatively, the tumor cells themselves may alter their repertoires of the panoply of growth factors that they produce. Whatever the mechanism, the clinical result is clear: continued neovascularization and angiogenesis occurs even when the major factors, such as VEGF or platelet-derived growth factor, are blocked at the endothelial cell or pericyte level. It is also becoming clear that, although these targeted agents are highly effective in targeting the neovascular endothelium and controlling cancer progression, they are not addressing a fundamental issue— namely the persistence and resistance of kidney cancer cells in the face of these agents, perhaps in a dormant state. To fully eradicate the cancer, alternative measures are needed. One approach has been to use surgical excision of all metastatic sites, but that is impossible for a significant majority of patients. A second approach might be to activate the immune system against the cancer. Interleukin 2 is able to induce complete remissions in select patients with mRCC, but it seems difficult to give to patients previously treated with mTORor VEGF-inhibiting agents. It is thus used predominately as a first-line therapy, although that is true only in less than 10% of patients with mRCC. A third approach might include using agents that specifically target the clear-cell RCC cells. Although the specific mutation driving RCC has been identified within the von HippelLindau/hypoxia-inducible factor pathway, hypoxia-inducible factor inhibitors are just entering phase I trials, and no trials in RCC have been reported. A fourth approach has traditionally been to use chemotherapy that nonspecifically targets the RCC cells. Chemotherapy remains the standard of care for the majority of disseminated human malignancies. Although the targets of such agents are multiple, the result is lethal damage to the tumor cell DNA, leading to eradication of the cancer. The paradigm suggests that combinations of DNA targeting agents are needed to effect cure. For example, the recent discovery of the DNA targeting agents, poly(ADPribose)polymerase antibody inhibitors, and their synergy in improving the outcome of patients with breast cancer when added to a gemcitabine/carboplatin regimen affirms the ongoing value of that paradigm. However, the paradigm of chemotherapy in RCC has been largely disappointing. The classic review by Yagoda et al found that only the fluorinated pyrimidines had modest activity (5% to 10% JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 28 NUMBER 34 DECEMBER 1 2010