Author Proof 1 www.expert-reviews.com ISSN 1473-7140 © 2011 Expert Reviews Ltd 10.1586/ERA.10.XX Clinical Trial Report The increased availability of diagnostic imag- ing techniques has highlighted an increase in the incidence of renal cell carcinoma (RCC) – which accounts for 80% of all kidney cancers – worldwide. Tumor staging at diagnosis ranges from small, low-stage tumors to more advanced neoplasms [1–5] . Although 5-year relative survival rates have increased by approximately 10% in the last decades, survival has depended largely on the stage at diagnosis: patients with local- ized disease had a 5-year survival of >80%, but in those with distant metastatic RCC 5-year survival is <10% [6–8] . The increase in overall survival was due, at least in part, to improved surgical techniques [9–11,101] . Until recently, cyto- kines (IL-2 or IFN- a), have been the mainstay of systemic treatment despite low response rates and signiicant toxicity [11,12] . Since 2005, six targeted therapies for advanced/metastatic RCC were approved by both the US FDA and European Medicines Association (EMEA). Of these, three are multi- targeted tyrosine kinase inhibitors (TKIs) – sorafenib (SO), sunitinib (SU) and pazopanib (PZ), two are oral mTOR inhibitors – temsiro- limus (TS) and everolimus (EV), and one is the anti-VEGF monoclonal antibody bevacizumab (BV), normally administered with IFN- a [13] . These new agents improved the progression- free survival (PFS) and overall survival (OS) in several subgroups of patients; however, expert opinion on the optimal therapeutic strategy is divided. Two main therapeutic approaches – the use of these new agents in combination or sequen- tially – have been studied to maximize ef icacy and tolerability. Sequential therapy is the current standard of care in the treatment of advanced RCC as existing combination regimens have a high incidence of adverse events without a sub- stantial increase in ef icacy, although cl inical trials of combination therapy are still ongoing [102–105] . The use of sequential therapy provides a number of important advantages – patients who are refractory to one or more targeted agent(s) may beneit from treatment with a dif- ferent agent; there is no/limited cross-resistance between agents and patients experiencing disease G Procopio †1 , E Verzoni 1 , R Iacovelli 1 , V Guadalupi 1 , F Gelsomino 1 and R Buzzoni 1 Fondazione IRCCS ‘Istituto Nazionale dei Tumori’, Medical Oncology, Via G. Veneziani 1, 20133 Milan, Italy † Author for correspondence: Tel.: +39 02 2390 2557 Fax: +39 02 2390 2149 giuseppe.procopio@istitutotumori.mi.it Targeted therapies have improved survival in patients with metastatic renal cell cancer (RCC); however, expert opinion on the optimal therapeutic strategy is divided. This retrospective study evaluates different sequential schemes of targeted therapies in 310 patients with advanced/ metastatic RCC who received different systemic agents – sorafenib, sunitinib, bevacizumab, everolimus, temsirolimus and axitinib – alone or in different sequences, until disease progression or intolerable toxicity (median follow-up: 37 months). The median overall survival (OS) was 22 months and the 5-year OS was 23.4%; differential therapeutic schemes were not associated with differences in OS. A worse performance status, no nephrectomy and a poor-risk classiication according to the Motzer criteria was associated with a shorter OS. These indings support the use of targeted therapies in the treatment of RCC, even in a large unselected population from a single institution, and suggest that treatment should be tailored to meet individual circumstances and needs. KEYWORDS: Targeted therapies used sequentially in metastatic renal cell cancer: overall results from a large experience Expert Rev. Anticancer Ther. 11(11), 1–xxx (2011)