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Review Article| Volume 8, ISSUE 10, P809-814, November 2009

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Treatment Algorithms in Metastatic Renal Cell Carcinoma, Including the Potential Role of the Novel Oral Mammalian Target of Rapamycin Inhibitor Everolimus

  • Jean-Jacques Patard
    Correspondence
    Corresponding author. Department of Urology, Rennes University Hospital, rue Henri le Guillou, 35033 Rennes, France. Tel.: +33 2 99 28 42 70; Fax: +33 6 82 28 41 13.
    Affiliations
    Department of Urology, Rennes University Hospital, Rennes, France
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Published:September 10, 2009DOI:https://doi.org/10.1016/j.eursup.2009.08.004
Treatment Algorithms in Metastatic Renal Cell Carcinoma, Including the Potential Role of the Novel Oral Mammalian Target of Rapamycin Inhibitor Everolimus
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      Abstract

      Context

      Few treatment options were available for metastatic renal cell carcinoma (mRCC) until the development of novel targeted agents directed against angiogenesis and tumour growth.

      Objective

      This review discusses current targeted therapies for mRCC and outlines the position of everolimus, a novel, orally administered inhibitor of the mammalian target of rapamycin (mTOR), in current treatment algorithms.

      Evidence acquisition

      Medical literature was retrieved from PubMed during January 2009. Additional relevant articles were included from the bibliographies of retrieved literature.

      Evidence synthesis

      Targeted treatment for mRCC can be categorised for the following patient groups: previously untreated patients, those refractory to immunotherapy or chemotherapy, and those refractory to vascular endothelial growth factor (VEGF)–targeted therapy. Sunitinib and bevacizumab (combined with interferon alfa) are generally considered first-line treatment options in patients with favourable or intermediate prognosis. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, one recommendation is to switch to an agent with a different mechanism of action or molecular target, for example, an mTOR inhibitor. Everolimus (RAD001) has shown promising efficacy in the first phase 3 clinical trial in patients with mRCC with favourable, intermediate, and poor risk whose disease had progressed on VEGF-targeted therapy.

      Conclusions

      Increasing clinical evidence is clarifying appropriate first- and second-line treatment with targeted agents for patients with mRCC. Based on good results of published phase 3 clinical data, the potential use of everolimus in the second-line setting has been recognised in recent (2008 and 2009) guidelines, including those of the European Society of Medical Oncology, the European Association of Urology, the European Organisation for Research and Treatment of Cancer Genitourinary Group, the Spanish Oncology Genitourinary Group, the French Urology Association, the UK consensus guidelines, the National Comprehensive Cancer Network (United States), and Cancer Care Ontario (Canada).

      Keywords

      1. Introduction

      Renal cell carcinoma (RCC) originates in the renal cortex and accounts for approximately 90% of renal tumours [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ]. In 2002, there were approximately 200 000 new kidney cancer cases worldwide [

      International Agency for Research on Cancer. GLOBOCAN database 2002. CANCERMondial Web site. http://www-dep.iarc.fr. Accessed June 2009.

      ]. RCC mainly affects patients >40 yr of age, occurring predominantly in the seventh and eighth decades of life [
      • Motzer R.J.
      • Bander N.H.
      • Nanus D.M.
      Renal-cell carcinoma.
      N Engl J Med. 1996; 335: 865-875
      ]. Clear-cell carcinoma represents the majority (75–85%) of RCC cases and, therefore, is often explored in clinical trials [
      • Motzer R.J.
      • Bander N.H.
      • Nanus D.M.
      Renal-cell carcinoma.
      N Engl J Med. 1996; 335: 865-875
      ,
      • Costa L.J.
      • Drabkin H.A.
      Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies.
      Oncologist. 2007; 12: 1404-1415
      ]. Furthermore, 25–30% of patients have metastatic RCC (mRCC) at diagnosis, which is associated with poor prognosis (eg, 5-yr relative survival is estimated at approximately 10%) and is notoriously resistant to conventional radiation therapy or chemotherapy [
      • Motzer R.J.
      • Bander N.H.
      • Nanus D.M.
      Renal-cell carcinoma.
      N Engl J Med. 1996; 335: 865-875
      ,

      National Cancer Institute. Surveillance, Epidemiology and End Results (SEER) cancer statistics review: kidney and renal pelvis cancer; 5-yr relative survival rates, 1999–2005. http://seer.cancer.gov/csr/1975_2006/browse_csr.php?section=11&page=sect_11_table07.html. Accessed June 2009.

      ].
      Until recently, few treatment options were available for mRCC, and patients who became refractory to standard-of-care treatments faced a particularly dismal outlook. The need for more effective treatments and increased understanding of pathogenic processes—for example, the involvement of the von Hippel-Lindau and hypoxia-inducible factor pathway in clear-cell RCC [
      • Kim W.Y.
      • Kaelin W.G.
      Role of VHL gene mutation in human cancer.
      J Clin Oncol. 2004; 22: 4991-5004
      ]—led to the development of novel targeted therapies directed against angiogenesis and tumour growth [
      • Patard J.J.
      • Pouessel D.
      • Culine S.
      New therapies in renal cell carcinoma.
      Curr Opin Support Palliat Care. 2007; 1: 174-179
      ]. Several of these therapies, including sunitinib, sorafenib, temsirolimus, and bevacizumab, are available for clinical use and are revolutionising the treatment of mRCC [
      • Ravaud A.
      • Wallerand H.
      • Culine S.
      • et al.
      Update on the medical treatment of metastatic renal cell carcinoma.
      Eur Urol. 2008; 54: 315-325
      ]. In addition, everolimus (RAD001) gained US Food and Drug Administration approval in March 2009 for the treatment of patients with advanced RCC after failure of treatment with sunitinib or sorafenib. European Union approval for use of everolimus in patients with advanced RCC whose disease progressed on or after treatment with vascular endothelial growth factor (VEGF)–targeted therapy was granted in August 2009.
      This article discusses current targeted treatment approaches in the first- and second-line mRCC settings as well as modifications to existing treatment algorithms based on recently available data from trials investigating everolimus.

      2. Evidence acquisition

      Medical literature was retrieved from PubMed during January 2009. Additional relevant articles were included from the bibliographies of retrieved literature.

      3. Evidence synthesis

      3.1 Current treatment approaches utilising novel targeted agents

      At present, treatment for mRCC with molecularly targeted agents can be broadly divided into the following categories: previously untreated patients, those refractory to immunotherapy or chemotherapy, and those who have failed treatment with VEGF-targeted therapy [
      • Maluf F.C.
      • Fernandes G.S.
      • Kann A.G.
      • Aguilar-Ponce J.L.
      • de la Garza J.
      • Buzaid A.C.
      Exploring the role of novel agents in the treatment of renal cell carcinoma.
      Cancer Treat Rev. 2008; 34: 750-760
      ]. An important consideration that influences treatment decisions is the Memorial Sloan-Kettering Cancer Centre (MSKCC) prognostic risk stratification system, which is widely used to define patient profiles and provide an indication of overall survival (OS) [
      • Motzer R.J.
      • Mazumdar M.
      • Bacik J.
      • Berg W.
      • Amsterdam A.
      • Ferrara J.
      Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
      J Clin Oncol. 1999; 17: 2530-2540
      ,
      • Leibovich B.C.
      • Cheville J.C.
      • Lohse C.M.
      • et al.
      A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.
      J Urol. 2005; 174: 1759-1763
      ,

      Coppin C, Le L, Porzsolt F, Wilt T. Targeted therapy for advanced renal cell carcinoma. Cochrane Database Syst Rev 2008:CD006017.

      ]. In this system, five prognostic factors are used to categorise patients with mRCC into three risk groups: favourable (no risk factors), intermediate (one or two risk factors), and poor (three or more risk factors) [
      • Motzer R.J.
      • Mazumdar M.
      • Bacik J.
      • Berg W.
      • Amsterdam A.
      • Ferrara J.
      Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
      J Clin Oncol. 1999; 17: 2530-2540
      ]. Median OS times were shown to be separated by ≥6 mo between each of the three risk groups [
      • Motzer R.J.
      • Mazumdar M.
      • Bacik J.
      • Berg W.
      • Amsterdam A.
      • Ferrara J.
      Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
      J Clin Oncol. 1999; 17: 2530-2540
      ].

      3.2 Treatment-naïve patients

      Clinical trials assessing the efficacy and safety of the oral mammalian target of rapamycin (mTOR) inhibitor everolimus in the first-line setting are currently underway. RECORD-2 is a randomised phase 2 trial comparing everolimus plus bevacizumab with bevacizumab plus interferon alfa (IFN-α) in patients with previously untreated mRCC [

      Safety and efficacy of bevacizumab plus RAD001 versus interferon alfa-2a and bevacizumab in adult patients with kidney cancer (L2201) [identifier NCT00719264]. ClinicalTrials.gov Web site. http://www.clinicaltrials.gov/ct2/show/NCT00719264. Accessed June 2009.

      ]. RECORD-3 is an open-label, multicentre, phase 2 study comparing first-line everolimus followed by second-line sunitinib versus the opposite sequence (first-line sunitinib followed by second-line everolimus) in the treatment of patients with mRCC [

      Efficacy and safety comparison of RAD001 versus sunitinib in the first-line and second-line treatment of patients with metastatic renal cell carcinoma (RECORD3) [identifier NCT00903175]. ClinicalTrials.gov Web site. http://www.clinicaltrials.gov/ct2/show/NCT00903175. Accessed June 2009.

      ]. With its oral administration route, everolimus has the potential to be more acceptable to patients than temsirolimus, which requires weekly intravenous infusion. Everolimus has shown activity in patients with favourable, intermediate, and poor MSKCC risk whose disease had progressed on a VEGF-targeted therapy (sorafenib or sunitinib or both) [
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
      Lancet. 2008; 372: 449-456
      ], which helps to confirm the activity of mTOR inhibitors in mRCC.

      3.2.1 Treatment-naïve patients with favourable or intermediate prognosis

      Sunitinib is a tyrosine kinase inhibitor (TKI) that acts mainly on the VEGF receptor (VEGFR) and platelet-derived growth factor receptor. In a phase 3 trial of sunitinib versus IFN-α in untreated patients with mRCC [
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
      N Engl J Med. 2007; 356: 115-124
      ,
      • Figlin R.A.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Overall survival with sunitinib versus interferon (IFN)-alfa as first-line treatment of metastatic renal cell carcinoma (mRCC).
      J Clin Oncol. 2008; 26 (abstract 5024)
      ,
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
      J Clin Oncol. 2009; 27: 3984-3990
      ], sunitinib demonstrated significant improvements in objective response rate (ORR; independent review, 39% vs 8%; p < 0.000001) [
      • Figlin R.A.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Overall survival with sunitinib versus interferon (IFN)-alfa as first-line treatment of metastatic renal cell carcinoma (mRCC).
      J Clin Oncol. 2008; 26 (abstract 5024)
      ], median progression-free survival (PFS; 11 mo vs 5 mo; p < 0.001), and OS (26.4 mo vs 20.0 mo; hazard ratio [HR]: 0.808; p = 0.036; crossover data censored) [
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
      J Clin Oncol. 2009; 27: 3984-3990
      ]. These data have led to sunitinib being recommended as a first-line therapy for patients with mRCC [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ] (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Treatment schematic for patients with metastatic clear-cell renal cell carcinoma in the first-line setting based on the most recent European guidelines [
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ]. Cytokines, including high-dose interleukin-2 (IL-2), are recommended only for a specific subset of patients in European Organisation for Research and Treatment of Cancer Genitourinary (EORTC-GU) Group, United Kingdom consensus guidelines, French Urology Association (AFU), and European Society for Medical Oncology (ESMO) guidelines [
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ]. Sunitinib has shown efficacy across all patient risk groups and is therefore recommended as a potential alternative to temsirolimus by AFU, EORTC-GU and ESMO [
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ]. EORTC-GU and AFU guidelines also recommend sorafenib as an option for patients ineligible for treatment with other agents [
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ].
      IFN-α = interferon alfa.
      Bevacizumab, a monoclonal antibody targeting VEGF directly, has shown efficacy in combination with IFN-α in two phase 3 trials in patients with previously untreated mRCC [
      • Escudier B.
      • Pluzanska A.
      • Koralewski P.
      • et al.
      Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.
      Lancet. 2007; 370: 2103-2111
      ,
      • Escudier B.J.
      • Bellmunt J.
      • Negrier S.
      • et al.
      Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-a2a (IFN) in metastatic renal cell carcinoma (mRCC).
      J Clin Oncol. 2009; 27 (abstract 5020)
      ,
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.
      • et al.
      Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: results of overall survival for CALGB 90206.
      J Clin Oncol. 2009; 27 (abstract LBA5019)
      ,
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.E.
      • et al.
      Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206.
      J Clin Oncol. 2008; 26: 5422-5428
      ]. In the first of these studies, median PFS was 10.4 mo for bevacizumab plus IFN-α compared with 5.5 mo for IFN-α alone (p < 0.0001) [
      • Escudier B.J.
      • Bellmunt J.
      • Negrier S.
      • et al.
      Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-a2a (IFN) in metastatic renal cell carcinoma (mRCC).
      J Clin Oncol. 2009; 27 (abstract 5020)
      ]. No significant difference in OS was observed (23.3 mo vs 21.3 mo; p = 0.1291) [
      • Escudier B.J.
      • Bellmunt J.
      • Negrier S.
      • et al.
      Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-a2a (IFN) in metastatic renal cell carcinoma (mRCC).
      J Clin Oncol. 2009; 27 (abstract 5020)
      ]. Consistent results were seen in the second study, performed by the Cancer and Leukemia Group B, with median PFS of 8.4 mo and 4.9 mo, respectively (p < 0.0001) [
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.
      • et al.
      Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: results of overall survival for CALGB 90206.
      J Clin Oncol. 2009; 27 (abstract LBA5019)
      ]. No significant difference in OS was observed (18.3 mo vs 17.4 mo; p = 0.069) [
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.
      • et al.
      Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: results of overall survival for CALGB 90206.
      J Clin Oncol. 2009; 27 (abstract LBA5019)
      ]. The PFS benefits seen in these trials are similar to those obtained with sunitinib in patients with advanced RCC who were previously untreated [
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
      N Engl J Med. 2007; 356: 115-124
      ] and suggest that bevacizumab plus IFN-α is another acceptable and effective therapy in the first-line setting [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ] (Fig. 1).

      3.2.2 Treatment-naïve patients with poor prognosis

      Temsirolimus is an intravenously administered inhibitor of mTOR. A randomised phase 3 trial compared monotherapy with temsirolimus versus IFN-α versus temsirolimus plus IFN-α as a first-line treatment in patients with mRCC and poor prognosis [
      • Hudes G.
      • Carducci M.
      • Tomczak P.
      • et al.
      Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
      N Engl J Med. 2007; 356: 2271-2281
      ]. Patients were required to have at least three of six predictors of short survival according to a prognostic factor scheme modified from the MSKCC model [
      • Hudes G.
      • Carducci M.
      • Tomczak P.
      • et al.
      Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
      N Engl J Med. 2007; 356: 2271-2281
      ]. Patients who received temsirolimus alone, compared with those who received IFN-α alone or the combination, had greater PFS (5.5 vs 3.1 vs 4.7 mo, respectively), OS (10.9 vs 7.3 vs 8.4 mo), and ORR (8.6% vs 4.8% vs 8.1%). The results of this trial justify mTOR as a target for cancer treatment, and recent European guidelines recommend that temsirolimus be considered as a first-line treatment in poor-risk patients [
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ] (Fig. 1).

      3.3 Cytokine-refractory patients

      Sorafenib is a small-molecule inhibitor of VEGFR and related receptors and also inhibits the intracellular signalling enzyme Raf kinase. In a placebo-controlled phase 3 trial involving patients with mRCC who had failed previous cytokine therapy, a PFS advantage for sorafenib of 5.5 mo versus 2.8 mo (p < 0.001) was observed [
      • Escudier B.
      • Eisen T.
      • Stadler W.M.
      • et al.
      Sorafenib in advanced clear-cell renal-cell carcinoma.
      N Engl J Med. 2007; 356: 125-134
      ,
      • Bukowski R.M.
      • Eisen T.
      • Szczylik C.
      • et al.
      Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: survival and biomarker analysis.
      J Clin Oncol. 2007; 25 (abstract 5023)
      ]. Partial responses (PR) were reported as the best response in 10% of patients receiving sorafenib and in 2% of placebo recipients (p < 0.001). The disease control rate was higher for sorafenib than placebo (62% vs 37%; p < 0.001) [
      • Escudier B.
      • Eisen T.
      • Stadler W.M.
      • et al.
      Sorafenib in advanced clear-cell renal-cell carcinoma.
      N Engl J Med. 2007; 356: 125-134
      ]. An improved OS with sorafenib was observed after censoring placebo patients who had crossed over to sorafenib (17.8 mo vs 14.3 mo; p = 0.0287) [
      • Bukowski R.M.
      • Eisen T.
      • Szczylik C.
      • et al.
      Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: survival and biomarker analysis.
      J Clin Oncol. 2007; 25 (abstract 5023)
      ]. Based on the results of this trial, sorafenib is recommended as a second-line agent in cytokine-refractory patients [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ] (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Treatment schematic for patients with metastatic clear-cell renal cell carcinoma in the second-line setting based on the most recent European guidelines [
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ]. Sorafenib is currently the recommended first choice in patients refractory to cytokines [
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ], while sunitinib is recommended as an alternative option in this setting by the European Organisation for Research and Treatment of Cancer Genitourinary (EORTC-GU) Group, the European Society for Medical Oncology (ESMO), and the French Urology Association (AFU) [
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ]. The AFU also names bevacizumab plus interferon alfa as a possible alternative to sorafenib in this setting
      [
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ]
      . Everolimus is the recommended first-choice treatment in patients refractory to vascular endothelial growth factor (VEGF)–targeted therapy [
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ].
      The efficacy of sunitinib in a total of 169 patients with mRCC who progressed on prior cytokine therapy was demonstrated in two phase 2 trials [
      • Motzer R.J.
      • Rini B.I.
      • Bukowski R.M.
      • et al.
      Sunitinib in patients with metastatic renal cell carcinoma.
      JAMA. 2006; 295: 2516-2524
      ,
      • Motzer R.J.
      • Michaelson M.D.
      • Redman B.G.
      • et al.
      Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma.
      J Clin Oncol. 2006; 24: 16-24
      ]. Across the two trials, PR was reported in 34–40% of patients, and a median PFS of 8.3–8.7 mo was observed [
      • Motzer R.J.
      • Rini B.I.
      • Bukowski R.M.
      • et al.
      Sunitinib in patients with metastatic renal cell carcinoma.
      JAMA. 2006; 295: 2516-2524
      ,
      • Motzer R.J.
      • Michaelson M.D.
      • Redman B.G.
      • et al.
      Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma.
      J Clin Oncol. 2006; 24: 16-24
      ]. Taken together, these data indicate that either sorafenib or sunitinib may be valid second-line treatment options for patients who have failed prior cytokine-based therapies, and this strategy is recommended by recent guidelines [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ] (Fig. 2).

      3.4 Patients refractory to vascular endothelial growth factor–targeted therapy

      Substantial clinical benefit has been afforded by novel TKIs, including sunitinib and sorafenib, to patients with mRCC. However, the therapy is not curative, and there is a large unmet medical need for patients refractory to VEGF-targeted therapy. Appropriate second-line treatment approaches are required for these patients (Fig. 2). One possibility would be to switch to an agent with a different mechanism of action or molecular target—for example, an mTOR inhibitor such as everolimus—and this strategy is supported by data from the RECORD-1 trial [
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
      Lancet. 2008; 372: 449-456
      ].
      In this phase 3 trial, patients receiving everolimus (10 mg once daily; n = 272) had significantly prolonged PFS versus those on placebo (n = 138; 4.0 mo vs 1.9 mo; HR: 0.30; p < 0.0001) [
      • Motzer R.J.
      • Escudier B.
      • Oudard S.
      • et al.
      Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
      Lancet. 2008; 372: 449-456
      ]. The end of double-blind analysis from this trial indicated a further improvement in PFS with everolimus treatment (4.90 mo [n = 277] vs 1.87 mo [n = 139]; HR: 0.33; p < 0.001) [
      • Escudier B.
      • Ravaud A.
      • Oudard S.
      • et al.
      Phase-3 randomized trial of everolimus (RAD001) vs placebo in metastatic renal cell carcinoma [abstract 72].
      Ann Oncol. 2008; 19 (viii45)
      ]. PFS benefit following treatment with everolimus was maintained across patients with favourable (n = 120), intermediate (n = 235), or poor (n = 61) MSKCC risk. At the end of double-blind analysis, median OS was 14.78 mo in the everolimus group and 14.39 mo in the placebo group [

      Motzer R, Kay A, Figlin R, et al. Updated data from a phase III randomized trial of everolimus (RAD001) versus PBO in metastatic renal cell carcinoma (mRCC). ASCO 2009 Genitourinary Cancers Symposium [abstract 278]. American Society of Clinical Oncology Web site. http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_session_presentations_view&confID=64&sessionID=11. Accessed June 2009.

      ]. Crossover from placebo to the active treatment arm was allowed after disease progression, potentially confounding OS; 81% of placebo recipients who progressed crossed over to everolimus treatment.

      3.5 Guidelines for the treatment of metastatic renal cell carcinoma

      Recent European and American guidelines that have provided algorithms for first- and second-line treatment options in mRCC are the European Organisation for Research and Treatment of Cancer Genitourinary Group (EORTC-GU) [
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ]; the European Association of Urology (EAU) [

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ]; the Spanish Oncology Genitourinary Group (SOGUG) [
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ]; the European Society for Medical Oncology (ESMO) [
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ]; the French Urology Association (AFU) [
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ]; UK consensus guidelines [
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ]; Cancer Care Ontario (CCO; Canada) [

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ], and the National Comprehensive Cancer Network (NCCN; United States) [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ] (Table 1). Based on efficacy and safety results, sunitinib monotherapy and bevacizumab in combination with IFN-α may be considered first-line treatment options in patients with metastatic or unresectable clear-cell RCC and favourable or intermediate prognosis according to MSKCC criteria [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ]. In the second-line setting, sorafenib treatment is recommended for patients with mRCC refractory to cytokines, and everolimus treatment is recommended for patients refractory to VEGF-targeted therapy [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ]. Recommendations for the treatment of clear-cell mRCC from the most recent European guidelines (EAU, EORTC-GU, ESMO, SOGUG, AFU, and UK guidelines) are summarised in Fig. 1, Fig. 2[
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ].
      Table 1Recent guidelines for systemic treatment of metastatic clear-cell renal cell carcinoma

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      GuidelinesFirst-line treatmentSecond-line treatment
      Good or intermediate prognosisPoor prognosisPrior cytokine treatmentPrior VEGF-targeted therapy
      European
       ESMO
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      		Sunitinib or bevacizumab + IFN-α

      Option: Cytokines* (including high-dose IL-2)      		Temsirolimus

      Option: Sunitinib      		Sorafenib

      Option: Sunitinib      		Everolimus
       EAU

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      		Sunitinib or bevacizumab + IFN-α (grade A)Temsirolimus (grade A)Sorafenib (grade A)Everolimus (grade A)
       EORTC-GU
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      		Sunitinib (Level 1b) or bevacizumab + IFN-α (Level 1a)Temsirolimus (level 1b)Sorafenib (level 1b)

      Option: Sunitinib      		Everolimus (level 1b)
       SOGUG
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      		Sunitinib or bevacizumab + IFN-αTemsirolimusSorafenibEverolimus
       AFU
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      		Sunitinib or bevacizumab + IFN-α or cytokines*

      Option: Sorafenib      		Temsirolimus

      Option: Sunitinib      		Sorafenib

      Option: Sunitinib or bevacizumab + IFN-α      		Everolimus
       UK
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      		Sunitinib or bevacizumab + IFN-α or cytokines*TemsirolimusSorafenibEverolimus
      North American
       CCO

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      		Sunitinib or bevacizumab + IFN-αTemsirolimusSorafenibEverolimus
       NCCN

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      		Sunitinib (category 1)

      Bevacizumab + IFN-α (category 1)

      Temsirolimus (category 1 for poor-prognosis; category 2B for selected patients of other risk groups)

      High-dose IL-2* (selected patients, category 2A)

      Sorafenib (selected patients, category 2A)      		Sorafenib or sunitinib (category 1)

      Option: Temsirolimus (category 2A)      		Everolimus (category 1)

      Options: Sorafenib (category 2A)

      Temsirolimus (category 2B)

      Sunitinib (category 2A)
      IFN-α or high-dose IL-2 or bevacizumab (category 2B)

      Low-dose IL-2 ± IFN (category 3)
      VEGF = vascular endothelial growth factor; ESMO = European Society of Medical Oncology; INF-α = interferon alfa; IL-2 = interleukin-2; EAU = European Association of Urology; EORTC-GU = European Organisation for Research and Treatment of Cancer Genitourinary Group; SOGUG = Spanish Oncology Genitourinary Group; AFU = French Urology Association; CCO = Cancer Care Ontario; NCCN = National Comprehensive Cancer Network; mRCC = metastatic renal cell carcinoma.
      * Cytokines are recommended only for selected patients with good prognosis.
      The EAU classifies recommendations for the treatment of metastatic renal cell carcinoma as grades A–C, modified from grades of recommendation developed by the Oxford Centre for Evidence-Based Medicine

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ,

      Oxford Centre for Evidence Based Medicine. Centre for Evidence Based Medicine Web site. http://www.cebm.net. Accessed June 2009.

      .
      The EORTC-GU classifies evidence based on levels (1–5) developed by the Oxford Centre for Evidence Based Medicine
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,

      Oxford Centre for Evidence Based Medicine. Centre for Evidence Based Medicine Web site. http://www.cebm.net. Accessed June 2009.

      .
      The NCCN gives recommendations based on evidence categories 1–3

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      .
      Some guidelines also suggest alternative agents. Cytokines (including high-dose interleukin-2 [IL-2]) are named as an option for first-line treatment of selected patients with mRCC with good prognosis in the EORTC-GU, ESMO, AFU, and UK guidelines [
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ]. Furthermore, sunitinib is suggested as a possible alternative to temsirolimus as first-line treatment in patients with poor prognosis and also as an alternative to sorafenib as a second-line treatment after cytokines [
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ]. For patients previously treated with bevacizumab, treatment with sunitinib appears effective in a proportion of cases and is acknowledged in the EORTC-GU guidelines [
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • George D.J.
      • Michaelson M.D.
      • Rosenberg J.E.
      • et al.
      Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoma (mRCC): updated results and analysis of circulating biomarkers.
      J Clin Oncol. 2007; 25 (abstract 5035)
      ]. For patients refractory to mTOR inhibitors, the EAU suggests enrolment in a clinical trial [

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ].
      The NCCN proposes a number of options for first- and second-line systemic treatment for relapse or stage IV and medically or surgically unresectable clear-cell RCC based on evidence categories from 1 to 3 [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ]. In addition to the preferred treatment based on category 1 evidence outlined above (Fig. 1, Fig. 2, Table 1), the NCCN also suggests alternative options for selected patients in the first-line setting, such as high-dose IL-2 or sorafenib (both category 2A), temsirolimus (category 2B), enrolment in a clinical trial, or best supportive care. In the second-line setting, everolimus is the only recommended treatment supported by category 1 evidence; other options suggested by the NCCN include sorafenib (category 2B following TKI), sunitinib (category 2A following TKI), temsirolimus (category 2A following cytokine therapy and category 2B following TKI), IFN-α (category 2B), high-dose IL-2 (category 2B), bevacizumab (category 2B), low-dose IL-2 with or without IFN-α (category 3), enrolment in a clinical trial, or best supportive care.
      For patients with non–clear-cell histology, suggested agents include temsirolimus, sorafenib, and sunitinib (NCCN, EORTC-GU, UK guidelines, and ESMO) [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ]. The NCCN also includes chemotherapy or best supportive care as options [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ], whereas the EORTC-GU also suggests bevacizumab plus IFN-α (good or intermediate risk) or high-dose IL-2 (sufficiently good performance status) as options in patients with non–clear cell RCC [
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ].

      4. Conclusions

      The increasing amount of evidence with targeted agents is helping to clarify the first- and second-line treatment approaches in patients with mRCC and different prognostic risk factors. Recent clinical studies form the basis for new treatment guidelines for mRCC. In particular, recent data from the phase 3 trials with temsirolimus and orally administered everolimus establish mTOR inhibitors as a valid therapeutic approach for mRCC in poor-risk patients and in those who have failed treatment with VEGF-targeted therapy. These agents are included as valid and recommended treatment options in recent European guidelines [
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ].
      Although immunotherapy with high-dose IL-2 should still be considered for low-risk patients, this group represents a small proportion of the population of mRCC patients [
      • Maluf F.C.
      • Fernandes G.S.
      • Kann A.G.
      • Aguilar-Ponce J.L.
      • de la Garza J.
      • Buzaid A.C.
      Exploring the role of novel agents in the treatment of renal cell carcinoma.
      Cancer Treat Rev. 2008; 34: 750-760
      ]. Therefore, the majority of patients should receive VEGF-targeted agents. In the first-line setting, sunitinib appears the most viable option for favourable- and intermediate-risk patients, with evidence also supporting bevacizumab (plus IFN-α), while temsirolimus should be considered for poor-risk patients [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ]. Although sorafenib is not recommended for first-line therapy, it is currently the drug of choice in the second-line setting, following the results of the phase 3 trials in cytokine-refractory patients [

      NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

      ,
      • Bellmunt J.
      • Calvo E.
      • Castellano D.
      • et al.
      Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
      Cancer Chemother Pharmacol. 2009; 63: S1-13
      ,
      • Nathan P.
      • Wagstaff J.
      • Porfiri E.
      • Powles T.
      • Eisen T.
      UK guidelines for the systemic treatment of renal cell carcinoma.
      Br J Hosp Med (Lond). 2009; 70: 284-286
      ,
      • Mejean A.
      • Lebret T.
      Prise en charge of metastatic renal carcinoma.
      Prog Urol. 2008; 18: S298-308
      ,

      Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

      ,
      • de Reijke T.M.
      • Bellmunt J.
      • van Poppel H.
      • Marreaud S.
      • Aapro M.
      EORTC-GU group expert opinion on metastatic renal cell cancer.
      Eur J Cancer. 2009; 45: 765-773
      ,
      • Escudier B.
      • Kataja V.
      Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
      Ann Oncol. 2009; 20 (iv81–2)
      ,

      Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

      ,
      • Escudier B.
      • Eisen T.
      • Stadler W.M.
      • et al.
      Sorafenib in advanced clear-cell renal-cell carcinoma.
      N Engl J Med. 2007; 356: 125-134
      ]. However, there is increasing evidence for the mTOR inhibitor everolimus as a therapeutic option after failure of VEGF-targeted therapy; in this second-line patient population, it is the only drug with evidence of efficacy from a large phase 3 trial.
      The role of surgery in the management of patients with mRCC in the era of emerging effective systemic targeted therapies remains to be fully defined. Ongoing clinical studies are evaluating these novel agents in the adjuvant setting. It will be essential to continue to update treatment algorithms as further evidence on current targeted agents becomes available, especially their sequential use and possible combinations. The resulting optimal use of these agents will help improve clinical benefits and tailor treatment regimens for each individual patient.

      Conflicts of interest

      Dr. Patard is a consultant for Baxter, Bayer, Pfizer, Wilex, and Wyeth. The author did not receive an honorarium or consultancy fee for writing this manuscript.

      Funding support

      Novartis Farma S.p.A. (Italy) funded the publication of this paper.

      Acknowledgements

      Medical writing assistance was provided by David Collison and Simone Blagg with funding from Novartis Farma S.p.A. (Italy).

      References

      1. NCCN clinical practice guidelines in oncology: kidney cancer. National Comprehensive Cancer Network Web site. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 2009.

        View in Article

      2. International Agency for Research on Cancer. GLOBOCAN database 2002. CANCERMondial Web site. http://www-dep.iarc.fr. Accessed June 2009.

        View in Article
        • Motzer R.J.
        • Bander N.H.
        • Nanus D.M.
        Renal-cell carcinoma.
        N Engl J Med. 1996; 335: 865-875
        View in Article
        • Costa L.J.
        • Drabkin H.A.
        Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies.
        Oncologist. 2007; 12: 1404-1415
        View in Article

      5. National Cancer Institute. Surveillance, Epidemiology and End Results (SEER) cancer statistics review: kidney and renal pelvis cancer; 5-yr relative survival rates, 1999–2005. http://seer.cancer.gov/csr/1975_2006/browse_csr.php?section=11&page=sect_11_table07.html. Accessed June 2009.

        View in Article
        • Kim W.Y.
        • Kaelin W.G.
        Role of VHL gene mutation in human cancer.
        J Clin Oncol. 2004; 22: 4991-5004
        View in Article
        • Patard J.J.
        • Pouessel D.
        • Culine S.
        New therapies in renal cell carcinoma.
        Curr Opin Support Palliat Care. 2007; 1: 174-179
        View in Article
        • Ravaud A.
        • Wallerand H.
        • Culine S.
        • et al.
        Update on the medical treatment of metastatic renal cell carcinoma.
        Eur Urol. 2008; 54: 315-325
        View in Article
        • Maluf F.C.
        • Fernandes G.S.
        • Kann A.G.
        • Aguilar-Ponce J.L.
        • de la Garza J.
        • Buzaid A.C.
        Exploring the role of novel agents in the treatment of renal cell carcinoma.
        Cancer Treat Rev. 2008; 34: 750-760
        View in Article
        • Motzer R.J.
        • Mazumdar M.
        • Bacik J.
        • Berg W.
        • Amsterdam A.
        • Ferrara J.
        Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
        J Clin Oncol. 1999; 17: 2530-2540
        View in Article
        • Leibovich B.C.
        • Cheville J.C.
        • Lohse C.M.
        • et al.
        A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.
        J Urol. 2005; 174: 1759-1763
        View in Article

      12. Coppin C, Le L, Porzsolt F, Wilt T. Targeted therapy for advanced renal cell carcinoma. Cochrane Database Syst Rev 2008:CD006017.

        View in Article

      13. Safety and efficacy of bevacizumab plus RAD001 versus interferon alfa-2a and bevacizumab in adult patients with kidney cancer (L2201) [identifier NCT00719264]. ClinicalTrials.gov Web site. http://www.clinicaltrials.gov/ct2/show/NCT00719264. Accessed June 2009.

        View in Article

      14. Efficacy and safety comparison of RAD001 versus sunitinib in the first-line and second-line treatment of patients with metastatic renal cell carcinoma (RECORD3) [identifier NCT00903175]. ClinicalTrials.gov Web site. http://www.clinicaltrials.gov/ct2/show/NCT00903175. Accessed June 2009.

        View in Article
        • Motzer R.J.
        • Escudier B.
        • Oudard S.
        • et al.
        Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
        Lancet. 2008; 372: 449-456
        View in Article
        • Motzer R.J.
        • Hutson T.E.
        • Tomczak P.
        • et al.
        Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
        N Engl J Med. 2007; 356: 115-124
        View in Article
        • Figlin R.A.
        • Hutson T.E.
        • Tomczak P.
        • et al.
        Overall survival with sunitinib versus interferon (IFN)-alfa as first-line treatment of metastatic renal cell carcinoma (mRCC).
        J Clin Oncol. 2008; 26 (abstract 5024)
        View in Article
        • Motzer R.J.
        • Hutson T.E.
        • Tomczak P.
        • et al.
        Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
        J Clin Oncol. 2009; 27: 3984-3990
        View in Article
        • Bellmunt J.
        • Calvo E.
        • Castellano D.
        • et al.
        Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.
        Cancer Chemother Pharmacol. 2009; 63: S1-13
        View in Article
        • Nathan P.
        • Wagstaff J.
        • Porfiri E.
        • Powles T.
        • Eisen T.
        UK guidelines for the systemic treatment of renal cell carcinoma.
        Br J Hosp Med (Lond). 2009; 70: 284-286
        View in Article
        • Mejean A.
        • Lebret T.
        Prise en charge of metastatic renal carcinoma.
        Prog Urol. 2008; 18: S298-308
        View in Article

      22. Hotte S, Waldron T, Bjarnason G, et al. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. Cancer Care Ontario Web site. http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=43559. Accessed June 2009.

        View in Article
        • de Reijke T.M.
        • Bellmunt J.
        • van Poppel H.
        • Marreaud S.
        • Aapro M.
        EORTC-GU group expert opinion on metastatic renal cell cancer.
        Eur J Cancer. 2009; 45: 765-773
        View in Article
        • Escudier B.
        • Kataja V.
        Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up.
        Ann Oncol. 2009; 20 (iv81–2)
        View in Article

      25. Ljungberg B, Hanbury DC, Kuczyk MA, et al. Guidelines on renal cell carcinoma. European Association of Urology Web site. http://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/RCC.pdf. Accessed June 2009.

        View in Article
        • Escudier B.
        • Pluzanska A.
        • Koralewski P.
        • et al.
        Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.
        Lancet. 2007; 370: 2103-2111
        View in Article
        • Escudier B.J.
        • Bellmunt J.
        • Negrier S.
        • et al.
        Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV) + interferon-a2a (IFN) in metastatic renal cell carcinoma (mRCC).
        J Clin Oncol. 2009; 27 (abstract 5020)
        View in Article
        • Rini B.I.
        • Halabi S.
        • Rosenberg J.
        • et al.
        Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: results of overall survival for CALGB 90206.
        J Clin Oncol. 2009; 27 (abstract LBA5019)
        View in Article
        • Rini B.I.
        • Halabi S.
        • Rosenberg J.E.
        • et al.
        Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206.
        J Clin Oncol. 2008; 26: 5422-5428
        View in Article
        • Hudes G.
        • Carducci M.
        • Tomczak P.
        • et al.
        Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
        N Engl J Med. 2007; 356: 2271-2281
        View in Article
        • Escudier B.
        • Eisen T.
        • Stadler W.M.
        • et al.
        Sorafenib in advanced clear-cell renal-cell carcinoma.
        N Engl J Med. 2007; 356: 125-134
        View in Article
        • Bukowski R.M.
        • Eisen T.
        • Szczylik C.
        • et al.
        Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: survival and biomarker analysis.
        J Clin Oncol. 2007; 25 (abstract 5023)
        View in Article
        • Motzer R.J.
        • Rini B.I.
        • Bukowski R.M.
        • et al.
        Sunitinib in patients with metastatic renal cell carcinoma.
        JAMA. 2006; 295: 2516-2524
        View in Article
        • Motzer R.J.
        • Michaelson M.D.
        • Redman B.G.
        • et al.
        Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma.
        J Clin Oncol. 2006; 24: 16-24
        View in Article
        • Escudier B.
        • Ravaud A.
        • Oudard S.
        • et al.
        Phase-3 randomized trial of everolimus (RAD001) vs placebo in metastatic renal cell carcinoma [abstract 72].
        Ann Oncol. 2008; 19 (viii45)
        View in Article

      36. Motzer R, Kay A, Figlin R, et al. Updated data from a phase III randomized trial of everolimus (RAD001) versus PBO in metastatic renal cell carcinoma (mRCC). ASCO 2009 Genitourinary Cancers Symposium [abstract 278]. American Society of Clinical Oncology Web site. http://www.asco.org/ASCOv2/MultiMedia/Virtual+Meeting?&vmview=vm_session_presentations_view&confID=64&sessionID=11. Accessed June 2009.

        View in Article
        • George D.J.
        • Michaelson M.D.
        • Rosenberg J.E.
        • et al.
        Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoma (mRCC): updated results and analysis of circulating biomarkers.
        J Clin Oncol. 2007; 25 (abstract 5035)
        View in Article

      38. Oxford Centre for Evidence Based Medicine. Centre for Evidence Based Medicine Web site. http://www.cebm.net. Accessed June 2009.

        View in Article

      Article info

      Publication history

      Published online: September 10, 2009

      Identification

      DOI: https://doi.org/10.1016/j.eursup.2009.08.004

      Copyright

      © 2009 European Association of Urology. Published by Elsevier Inc. All rights reserved.

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