Advances in the Management of Metastatic Renal Cell Cancer
Introduction
Renal cell carcinoma (RCC) represents a therapeutic challenge. In 2008, an estimated 54 390 new cases of RCC were diagnosed, and the disease accounted for approximately 13 010 deaths in the United States [1]. RCC comprises multiple subtypes, each with a distinct phenotype, clinical course, and response to treatment [2]. Most research is focused on clear-cell RCC, which represents >75% of all histologic subtypes. Papillary RCC is the second most common subtype, followed by chromophobe RCC, accounting for 15% and 5% of all subtypes, respectively. Patients with von Hippel-Lindau (VHL) disease commonly develop RCC, specifically the clear-cell type [2], [3].
With regard to the management of RCC, surgery is the primary treatment approach for localised RCC. Metastatic RCC (mRCC) is generally resistant to chemotherapy, radiation therapy and hormone therapy, and is associated with a poor prognosis. Immunotherapy using the cytokines interleukin-2 (IL-2) and/or interferon-α (IFN-α) has been the standard treatment for patients with mRCC over the past 20 yr. Cytokine therapy appears to be associated with low response rates of approximately 15% and a median overall survival (OS) of 10–12 mo, but only in patients with good prognostic features [4], [5].
More recently, the role of the VHL/hypoxia-inducible factor (VHL/HIF) pathway has been strongly implicated in RCC. Several molecules of this signalling pathway, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-α (TGF-α), and the mammalian target of rapamycin (mTOR), have been identified. These molecules play a critical role in tumour angiogenesis and tumour cell proliferation and have led to the development of promising new, rationally designed, molecularly targeted agents for treatment of mRCC [6]. Targeted agents such as sunitinib, bevacizumab, temsirolimus, sorafenib, and everolimus have shown potential in randomised phase 3 trials for treatment of mRCC (Table 1). In these trials, IFN-α has been used as a baseline for assessment of new therapies, and patients were stratified according to the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria [7].
This paper was based on presentations given at a symposium on advances in the management of mRCC that was held during the 2nd World Congress on Controversies in Urology (CURy) on 6 February 2009 in Lisbon, Portugal. Data were retrieved from original articles, review articles, and abstracts on the management of mRCC.
Section snippets
First-line treatment of metastatic renal cell carcinoma
Sunitinib is an orally administered tyrosine kinase inhibitor (TKI) with activity against VEGF receptors, PDGF receptors, c-kit, and FLT-3. In a landmark phase 3 trial, sunitinib demonstrated statistically superior efficacy over IFN-α as first-line treatment of good- or intermediate-risk patients with clear-cell mRCC (Table 1) [8]. Figlin et al. [9] presented at the American Society of Clinical Oncology (ASCO) 2008 annual meeting the final OS data of this phase 3 trial. Sunitinib appears to
Sequential therapy versus combination therapy with targeted agents
There are now many potentially active agents in mRCC with different molecular targets, which raises important questions regarding sequencing and combination therapies. However, to date, few data have been reported supporting either strategy. Two retrospective studies demonstrated that sequential use of sorafenib–sunitinib appears to be more effective than sunitinib–sorafenib for treatment of advanced RCC [17], [18]. Dudek et al. [17] recently hypothesised that drug resistance emerging after
Conclusions
There is a strong rationale for targeting angiogenesis and multiple pathways in mRCC. Currently, several targeted agents have been evaluated in randomised phase 3 trials and are available for treatment of mRCC. Sunitinib and bevacizumab plus IFN-α can be considered as a first-line treatment of mRCC with good or intermediate prognosis, whereas temsirolimus has proven antitumour activity in poor-risk patients. With regard to second-line treatment of mRCC, sorafenib and everolimus seem to
Conflicts of interest
Cora N. Sternberg received honoraria from Novartis. Joaquim Bellmunt has participated in advisory boards of Roche and received honoraria from Novartis. Viktor Grünwald received honoraria from Roche, Pfizer, and Novartis; a research grant from Wyeth; and is a consultant for Roche, Pfizer, and Novartis. James Larkin received honoraria from Novartis. Peter Mulders received honoraria from AstraZeneca, Bayer, Roche, Novartis, Gen-Probe, Antigenics, and Pfizer.
Funding support
None.
Acknowledgments
The authors are grateful to Ismar Healthcare NV for their assistance in writing the manuscript.
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