Systemic Therapy for Advanced Renal Cell Carcinoma

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Therapeutic Advances in Medical Oncology http://tam.sagepub.com/ Review: Systemic therapy for advanced renal cell carcinoma James M.G. Larkin, Emma L.S. Kipps, Ceri J. Powell and Charles Swanton Therapeutic Advances in Medical Oncology 2009 1: 15 DOI: 10.1177/1758834009338430 The online version of this article can be found at: http://tam.sagepub.com/content/1/1/15 Published by: http://www.sagepublications.com Additional services and information for Therapeutic Advances in Medical Oncology can
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    http://tam.sagepub.com/  Therapeutic Advances in Medical Oncology  http://tam.sagepub.com/content/1/1/15Theonline version of this article can be found at:DOI: 10.1177/17588340093384302009 1: 15 Therapeutic Advances in Medical Oncology  James M.G. Larkin, Emma L.S. Kipps, Ceri J. Powell and Charles Swanton Review: Systemic therapy for advanced renal cell carcinoma Published by:  http://www.sagepublications.com can be found at: Therapeutic Advances in Medical Oncology  Additional services and information for   http://tam.sagepub.com/cgi/alerts Email Alerts:    http://tam.sagepub.com/subscriptions Subscriptions:  http://www.sagepub.com/journalsReprints.nav Reprints:    http://www.sagepub.com/journalsPermissions.nav Permissions:    http://tam.sagepub.com/content/1/1/15.refs.html Citations:  What is This?- Jul 1, 2009Version of Record>>  by guest on October 9, 2011tam.sagepub.comDownloaded from   Systemic therapy for advanced renalcell carcinoma James M.G. Larkin, Emma L.S. Kipps, Ceri J. Powell and Charles Swanton Abstract  : Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and isrefractory to cytotoxic chemotherapy  immunotherapy has until recently been the standard ofcare for advanced disease. Randomised trials reported in the last 5 years have demonstratedthat a number of agents including the monoclonal antibody, bevacizumab, and the kinaseinhibitors  sorafenib sunitinib, temsirolimus and everolimus  are active in advanced RCC.Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediatorof angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGFand platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus andeverolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitiniband temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively.In the second-line setting, everolimus has shown benefit over placebo in patients who progressfollowing treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demon-strated efficacy in comparison with placebo in patients with immunotherapy-refractory disease.We review here recent clinical trial data and discuss future developments in the systemictreatment of RCC including combination and sequential therapy, adjuvant therapy, the role ofbiomarkers and the prospects for the development of rational mechanism-directed therapyin this disease. Keywords  : renal cell carcinoma, bevacizumab, sorafenib, sunitinib, temsirolimus, everolimus Biology and pathology of renal cell carcinoma Renal cell carcinoma (RCC) is a rare tumourwith a rising incidence, currently accountingfor approximately 3% of all cancers in the USA[Jemal et al. 2007]. Affected individuals maypresent with symptoms and signs of localised dis-ease such as loin pain or haematuria but the diag-nosis is increasingly made incidentally as a resultof imaging performed for unrelated reasons. Upto a third of patients present with advanced dis-ease and a third of patients treated surgically withcurative intent relapse with advanced disease.Poor performance status, anaemia, high serumcalcium and metastases in multiple organs arepoor prognostic factors in advanced disease[Bukowski et al. 2004]. The average survival forpatients with advanced RCC is approximately 12months [Motzer et al. 2004] although the diseasehas a variable natural history: rapidly progressivedisease is often seen but disease stability off treat-ment for prolonged periods of time and sponta-neous regressions are both well documented[Escudier et al. 2007a; Oliver et al. 1989]. Thefact that disease stability is not uncommon meansthat single-arm therapeutic studies in advancedRCC need to be interpreted with caution aspatient selection has a significant effect on out-come. Randomised studies are therefore neces-sary to draw firm conclusions.RCC is histologically heterogeneous: approxi-mately three quarters of tumours are of the clearcell subtype while papillary, chromophobe,medullary and collecting duct subtypes accountfor the remainder. These distinctions are impor-tant because clear cell histology is associated withdysfunction of the Von Hippel Lindau (VHL)gene in the majority of cases [Kaelin, 2007] butthis association for other histological subtypes isless well understood. The product of the VHL gene (pVHL) is a component of an ubiquitinligase complex that mediates the cellular responseto hypoxia. In normoxic conditions pVHL isbound to hypoxia inducible factor-1  (HIF-1  ) http://tam.sagepub.com 15 Therapeutic Advances in Medical Oncology Review  Ther Adv Med Oncol  (2009) 1(1) 15  27DOI: 10.1177/1758834009338430 ! The Author(s), 2009.Reprints and permissions:http://www.sagepub.co.uk/ journalsPermissions.navCorrespondence to: James M.G. Larkin Department of Medicine,Royal Marsden Hospital,London SW3 6JJ, UK  james.larkin@rmh.nhs.ukEmma L.S. Kipps Department of Medicine,Royal Marsden Hospital,London SW3 6JJ, UK Ceri J. Powell Department of ClinicalOncology, Royal MarsdenHospital, LondonSW3 6JJ, UK Charles Swanton CR-UK TranslationalCancer TherapeuticsLaboratory, LondonResearch Institute,44 Lincoln’s Inn Fields,London WC2A 3PX, UK  by guest on October 9, 2011tam.sagepub.comDownloaded from   and HIF-2  which become ubiquitinated andtagged for degradation in the proteasome. Inhypoxic conditions or in the absence of pVHL,HIF-1  accumulates, leading to the productionof growth factors such as platelet-derived growthfactor (PDGF), transforming growth factor  (TGF-  ) and vascular endothelial growth factor(VEGF). Activation of the mammalian targetof rapamycin (mTOR) also leads to increasedexpression of HIF-1 a [Brugarolas, 2007]. Allthese factors stimulate cellular proliferation andangiogenesis resulting in growth and progressionof renal cell cancers and as such, constitute a pos-sible therapeutic target in this subset of tumours. Systemic treatment of advanced renal cellcarcinoma Introduction Negligible response rates have been reported forthe treatment of advanced RCC with chemother-apy [Yagoda and Bander, 1989] and hormonetherapy [MRC RE01, 1999]. Higher responserates (10  20%) have been reported with subcu-taneous interferon therapy in patients with goodperformance status [MRC RE01, 1999] and suchtreatment was regarded, until recently, as thestandard of care for advanced disease. Since2003, a number of novel agents have shown effi-cacy in the treatment of RCC and these data arereviewed below. Immunotherapy  Immunotherapy is active in the treatment of bothRCC and melanoma. Both diseases are relativelyrefractory to cytotoxic chemotherapy in compar-ison with other solid tumours but neither thisresistance nor the sensitivity of immunotherapyis well understood. High dose intravenous inter-leukin-2 results in complete responses in approx-imately 5  10% of patients with advanced RCC.Disease control is prolonged in 70  80% of thissubset [Rosenberg et al. 1998] but this treatmentcauses substantial toxicity and has not been eval-uated against standard treatments in randomisedtrials. A survival benefit has been reported in theMedical Research Council (MRC) RE01 rando-mised trial for patients with advanced RCC trea-ted with subcutaneous interferon at a dose of 10 MU three times a week in comparison withmedroxyprogesterone acetate (MPA) 300mgorally per day [MRC RE01, 1999]. Median over-all survival for the interferon arm was 8.5 monthsin comparison with 6 months for the MPA arm.Given that the administration of immunotherapycan be of clear benefit in a small subset but isassociated with significant toxicity [Parton et al. 2006], there is a need to define the mechanism of action of such treatment and to identify possiblemarkers of response in order to identify patientsthat may benefit [Atkins et al. 2005]. Monotherapy with novel agents  Six randomised studies of single agent therapywith novel agents in advanced RCC have beenreported since 2003 (Table 1). Bevacizumab  Bevacizumab is a monoclonal anti-body against VEGF, a key regulator of angiogen-esis [Ferrara et al. 2003], a process necessary forthe growth of solid tumours [Folkman, 1972].Bevacizumab has shown activity in breast cancer[Miller et al. 2007], colorectal cancer [Hurwitz et al. 2004] and nonsmall cell lung cancer[Sandler et al. 2006] in combination with cyto-toxic chemotherapy but little activity as a singleagent has been reported. In contrast, in advancedRCC treatment with bevacizumab as a singleagentledtoanincrease intime todisease progres-sion in comparison with placebo in a three-armrandomised phase II study in the second-linesetting reported in 2003 [Yang et al. 2003]. Onehundred and sixteen patients were treatedintravenously with placebo or bevacizumab ata dose of 3mg/kg or 10mg/kg every 2 weeks.Time to progression was significantly prolongedin the ‘high dose’ bevacizumab group in compar-ison with the placebo group (4.8 versus 2.5months, hazard ratio ¼ 2.55, p < 0.001) but thedifference between ‘low dose’ bevacizumab andplacebo was not statistically significant. The trialwas stopped early on the basis of these dataalthough only four responses to treatment occurred(responserate10%,allinthe‘highdose’arm)andno survival benefit was demonstrated. Bevacizu-mab was generally well tolerated: the main toxici-ties were asymptomatic proteinuria (25%) andhypertension (14%). This pivotal trial providedproof of the principle that VEGF is a clinicallyrelevant therapeutic target in RCC. Sunitinib  Sunitinib is an orally administeredinhibitor of the c-KIT, FLT-3, PDGFR andVEGFR2 tyrosine kinases that is active in thetreatment of gastrointestinal stromal tumors(GISTs) after failure of imatinib therapy [Prenen et al. 2006]. A dose of 50mg orally once a day for4weeksfollowedbya2weekbreakwastherecom-mended phase II dose based on two phase Istudies [Faivre et al. 2006; O’Farrell et al. 2003]. Therapeutic Advances in Medical Oncology  1 (1) 16 http://tam.sagepub.com  by guest on October 9, 2011tam.sagepub.comDownloaded from   The results of a phase III trial comparing sunitinibwith interferon-  in the first-line treatment of patients of performance status 0 or 1 with favour-able and intermediate prognosis advanced clearcell renal carcinoma were reported early in 2007[Motzer et al. 2007b]. The administration of sunitinib resulted in superior response rates (31% versus 6%, p < 0.001) and median progression-freesurvival (11 versus 5 months, hazard ratio (HR)0.42, 95% confidence interval (CI) 0.32 to 0.54,  p < 0.001). Adverse events were similar in bothgroups except that 5  10% of patients in the suni-tinib group had grade three or four (i.e. severe orlife-threatening) diarrhoea, hypertension or hand-foot syndrome (  p < 0.05). Grade three or fourneutropaenia and thrombocytopaenia were alsomore common in the sunitinib group, occurringin about 10% of patients (  p < 0.05). Grade threeor four fatigue was seen in 7% of patients in thesunitinib group and 12% in the interferon group(  p < 0.05). Quality of life was also significantlybetter in the sunitinib than the interferon group(  p < 0.001). An update on the survival analysiswas more recently published in abstract form[Figlin et al. ASCO 2008, Abstract 5024].Overall survival analysis showed a median survivalof 26.4 months in the sunitinib group and 21.8months in the interferon group (HR 0.821,  p ¼ 0.051).Additionaldatawerepresentedindicat-ing that many patients initially assigned to inter-feron either crossed over to sunitinib or, morelikely, received subsequent sunitinib or otheractive treatments after progression. The medianoverall survival analysis in patients who did notreceive any second-line therapy was 28.1 versus 14.1 months (  p ¼ 0.0033) in favour of sunitinib.Asaresultofthesedata,sunitinibisnowconsideredstandard first-line therapy for patientswith favour-able and intermediate prognosis advanced RCC.There are also nonrandomised data fromphase II trials to support the use of sunitinib asa second-line therapy in patients who are intoler-ant of or resistant to cytokine therapy. Rosenberg[Rosenberg et al. , ASCO 2007, Abstract 5095]reported the results of two phase II trials[Motzer et al. 2006a; 2006b]. Of 168 patients,45% had an objective response with a medianprogression free survival of 8.4 months. Sorafenib  Sorafenib is orally administered andinhibits the BRAF and CRAF (Raf-1) nonrecep-tor serine threonine kinases, components of theRAF/MEK/ERK signalling cascade. Althoughoften involved in tumour cell survival and prolif-eration, it is unknown if dysfunction of this path-way specifically is relevant to RCC. Sorafenibalso inhibits the V600E BRAF mutant which iscommonly present in melanoma [Davies et al. 2002] but is not reported in RCC [Nagy et al. 2003]. A number of receptor tyrosine kinasesknown to be involved in angiogenesis andtumourigenesis such as VEGFR2, Flt-3, c-KITand PDGFR are also inhibited by sorafenib[Wilhelm et al. 2004] and sorafenib is the first-line treatment of choice in hepatocellular carci-noma on the basis of an overall survival benefit ina phase III study [Llovet et al. 2008].Three randomised trials have evaluated sorafenibin the treatment of advanced RCC [Escudier et al. 2007a; Szczylik et al. , ASCO 2007,Abstract 5025; Ratain et al. 2006]. The phase IIevaluation of sorafenib in advanced RCC was ini-tially conducted in a randomised discontinuationtrial (RDT) in the second-line setting [Ratain et al. 2006]. The RDT design distinguishes theefficacy of a study drug from slow disease growth[Stadler et al. 2005; Rosner et al. 2002]. All par-ticipants initially are treated with the study drug(stage 1) and those with stable disease after apredetermined interval undergo double-blindedrandomisation between continued therapy andplacebo (stage 2). Participants responding to Table 1. Randomised studies of novel single agent therapy in advanced renal cell carcinoma.Agent(s) Comparator(s) TrialphaseLine oftherapy n ReferenceBevacizumab(high dose)1. Placebo2. Bev (low dose)II 2nd 116 [Yang et al. 2003]Sorafenib IFN-  II 1st 189 [Escudier et al. 2009]Sorafenib Placebo II 2nd/3rd 202 [Ratain et al. 2006]Sorafenib Placebo III 2nd 903 [Escudier et al. 2007a]Sunitinib IFN-  III 1st 750 [Motzer et al. 2007b]Everolimus Placebo III 2nd 410 [Motzer et al. 2008a] Bev, bevacizumab; IFN, interferon. JMG Larkin, ELS Kipps et al  . http://tam.sagepub.com 17  by guest on October 9, 2011tam.sagepub.comDownloaded from 
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