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Controversies and Challenges Surrounding Treatment for Renal Cell Carcinoma

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Sunitinib can delay tumor progression, prolong survival, and improve quality of life among patients with advanced and metastatic renal cell carcinoma (mRCC), making it a promising tool for the management of this challenging late-stage malignancy. Preclinical studies have raised concerns that sunitinib might change tumor biology in ways that could hasten disease progression and metastasis after therapy is discontinued.

However, a new analysis of data from a pivotal phase 3 clinical trial, published in the Feb. 21 issue of Cell Reports, ‘unequivocally' demonstrates that those concerns appear to have been misplaced. While more research is needed, the animal study findings in question are also unlikely to have clinical implications for similar agents, such as sorafenib or pazopanib, according to the authors of this study.

Nevertheless, other emerging challenges in the management of mRCC demand more attention. While prognosis and longer survival times for advanced RCC have improved, there is an emerging need for the development of comprehensive, interdisciplinary care strategies in order to deal with new clinical challenges such as poor patient compliance when managing treatment toxicities.

Vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs) promote neoangiogenesis—the growth of new vasculature—during early development, wound healing, and tumorigenesis.1 The oral antiangiogenic tyrosine kinase inhibitor sunitinib, a VEGFR inhibitor, targets other molecular pathways as well, and can delay disease progression and prolong survival, and it appears to enhance quality of life among patients with advanced and mRCC.2,3

Sunitinib was approved by the US Food and Drug Administration (FDA) in 2006 for the treatment of mRCC and imatinib-resistant gastrointestinal stromal tumors (GIST).1,4  A few years later, in 2011, sunitinib was also approved by the FDA for treatment of unresectable or metastatic progressive neuroendocrine pancreatic tumors.5 

A large randomized phase 3 trial found superior progression-free survival (PFS) for patients receiving sunitinib versus interferon-α (IFN-α; 11 months vs. 5 months; P<0.001), and identified an association with longer median overall survival (OS) among patients administered sunitinib (OS, 26.4 vs. 21.8 months; P=0.049).2 The authors concluded that the survival outcomes spotlighted “improved prognosis in patients with RCC in the era of targeted therapy.”2

Other targeted agents approved for treating advanced RCC include sorafenib, everolimus, temsirolimus, bevacizumab, and pazopanib.6  A recent Cochrane systematic review of 28 published randomized clinical trials of targeted agents for advanced RCC found that overall, while agents that target the VEGF and mTOR pathways rarely achieve complete responses and are therefore not curative, they do tend to improve PFS in first- and second-line settings; in fact, several studies in the review showed modest improvements of OS.7  These OS benefits of the agents reviewed might be underestimated in crossover design trials, the review's authors noted, as patients switch to antiangiogenic agents from control-arm therapies.7

Accelerated Metastasis Concerns Misplaced

The age-adjusted annual incidence rate of RCC has risen from 7.6 per 100,000 in 1988 to 11.7 per 100,000 in 2006, an annual increase of 2.39%.8  While incidence rates for localized RCC have climbed from 3.8 per 100,000 in 1988 to 8.2 per 100,000 in 2006, advanced and mRCC rates have declined from 2.1 to 1.6 per 100,000.8 Mortality rates increased during that time for localized RCC (1.3 to 2.4 per 100,000) but declined slightly for mRCC (1.8 to 1.6 per 100,000).8  Given the encouraging clinical trial data that has been published since 2006, it seems reasonable to anticipate longer patient survival times for mRCC.

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