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Updated recommendations from the Spanish Oncology Genitourinary Group on the treatment of advanced renal cell carcinoma

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The speed at which targeted therapies are being developed and incorporated into the treatment of advanced renal cell carcinoma (RCC) is surprising. After decades in which the only systemic treatment options available for advanced disease were
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  Updated recommendations from the Spanish OncologyGenitourinary Group on the treatment of advanced renalcell carcinoma Emiliano Calvo  &  Pablo Maroto  &  Xavier García del Muro  &  Miguel Ángel Climent  & José Luis González-Larriba  &  Emilio Esteban  &  Rafael López  &  Luis Paz-Ares  & Joaquim Bellmunt  &  Daniel Castellano Published online: 17 July 2010 # Springer Science+Business Media, LLC 2010 Abstract  The speed at which targeted therapies are beingdeveloped and incorporated into the treatment of advancedrenal cell carcinoma (RCC) is surprising. After decades inwhich the only systemic treatment options available for advanced disease were interleukin-2 and interferon- α  , inthe last decade, six new targeted therapies have emergedshowing meaningful clinical benefits to patients withadvanced RCC through phase III trials. Recently, theSpanish Oncology Genitourinary Group issued its first  public statement of recommendations for the optimalmanagement of advanced RCC. However, most pivotal phase III trials on which these recommendations were based have been updated and/or fully reported. Moreover, anew multikinase inhibitor, pazopanib, has emerged withgood quality clinical data. In this report, we review in depththe latest phase III data of targeted therapies for advancedRCC and update our recommendations. Furthermore, wehypothesize about the best environment for patients withadvanced RCC to receive cancer therapy. Keywords  Renal cell carcinoma.Spanish OncologyGenitourinary Group.Cancer treatment  1 Introduction It is estimated that every year, there are almost 58,000 newcases of renal cell carcinoma (RCC) and 13,000 deaths dueto the disease in the USA [1]. Approximately 30% of  patients with a new diagnosis present with advanceddisease. Until recently, treatment of advanced RCC waslimited to cytokine therapies, such as interleukin-2 (IL-2) E. CalvoHospital de Madrid-CIOCC,Madrid, SpainP. MarotoHospital de la Santa Creu i San Pau,Barcelona, SpainX. G. del MuroInstitut Català d ’ Oncologia,Barcelona, SpainM. Á. Climent Instituto Valenciano de Oncología,Valencia, SpainJ. L. González-LarribaHospital Clínico San Carlos,Madrid, SpainE. EstebanHospital Universitario Central de Asturias,Oviedo, SpainR. LópezComplexo Hospitalario Universitario de Santiago,A Coruña, SpainL. Paz-AresHospital Virgen del Rocío,Sevilla, SpainJ. Bellmunt Hospital del Mar,Barcelona, SpainD. Castellano ( * )Medical Oncology Service, Hospital Universitario 12 de Octubre,Avda. De Córdoba, s/n,28041 Madrid, Spaine-mail: cdanicas@hotmail.comCancer Metastasis Rev (2010) 29 (Suppl 1):S1  –  S10DOI 10.1007/s10555-010-9231-6  and interferon- α   (IFN- α  ), which produce modest objectiveresponse rates (ORR) and substantial toxicities.Due to better understanding of the molecular pathwaysinvolved in the development of RCC, six new targetedtherapies have emerged in the last decade. Sunitinib,sorafenib, and pazopanib produce their anticancer effect  by blocking the intracellular domain of vascular endothelialgrowth factor (VEGF) receptor, while bevacizumab bindsto circulating VEGF protein, preventing interaction with itsreceptors, without affecting it directly. Lastly, both temsir-olimus and everolimus are analogues of rapamycin, whichinhibit mammalian target of rapamycin (mTOR), a tyrosinekinase involved in the intracellular signalling pathways of cellular growth, proliferation, and hypoxic stress response.Recently, the Spanish Oncology Genitourinary Group(SOGUG) issued its first public statement of recommenda-tions for the optimal management of advanced RCC [2].However, at the time the paper was published, most pivotal phase III trials on which these recommendations were based have been updated and/or fully reported. Moreover, anew multikinase inhibitor, pazopanib, has emerged withnew good quality clinical data. Because of this, an updateof our previous recommendations is now reported.In this report, we have analyzed in depth the latest phaseIII data of targeted therapies for advanced RCC, specificallyin the elderly and/or frail patient populations, in patientswith severe concomitant diseases (renal, hepatic, or cardiacdysfunction), and in patients without prior nephrectomy or with non-clear RCC. Lastly, we hypothesize about the best environment for patients with advanced RCC to receivecancer therapy. The objective of this review is to issue newupdated recommendations from SOGUG for the optimalmanagement of patients with advanced RCC based on phase III data. 2 Update on prognostic and predictive markersfor advanced RCC Information about prognostic and predictive factors iscrucial to improve outcomes in patients with RCC receivingnovel treatment strategies. Reasons that support this viewinclude the modest to nonexistent response of RCC tostandard cytotoxic, endocrine, and cytokine therapy [3]; the aggressiveness that characterizes these tumors [4]; and the specific mechanism of action of new targeted therapies that render them inefficient when certain markers are not expressed.There are multiple studies that have allowed theidentification of prognostic factors for metastatic RCC [5  –  7]. These factors may be classified into biological, clinical,and histological prognostic factors. Biological factorsinclude laboratory abnormalities, such as anemia, hypercal-cemia, liver dysfunction, neutrophilia, thrombocytosis, andelevation of proinflammatory markers ( i.e ., erythrocytesedimentation rate, C-reactive protein, ferritin, and  α  1-antitrypsin levels) [5]. Clinical prognostic factors include Eastern Cooperative Oncology Group performance status(ECOG PS), localization and number of metastases, time todiagnosis, disease-free interval, metastasis-free interval,tumor burden, prior nephrectomy, and prior therapy [2, 5]. Finally, histological factors include nuclear grade, size or shape, histological subtypes (clear cell, papillary, chromo- phobe, oncocytoma, or collecting duct tumors), and the presence of sarcomatoid features [5]. Outcome models integrating these prognostic factors have been considered indepth by SOGUG [2], and thus will not be further discussedhere.Additionally, there are a number of molecular bio-markers that are being investigated in RCC (Table 1),including VEGF levels; expression of hypoxia induciblefactor (HIF); expression of B7-H1, B7-H4, and B7x; phosphatase and tensin homologue deleted from chromo-some 10 (PTEN); and carbonic anhydrase IX (CAIX), avon Hippel  –  Lindau-mediated enzyme expressed in most cases of RCC [8]. Many of these biomarkers are associatedwith pathological changes, and because of this, they mayalso constitute therapeutic targets [9]. The last 5 years have seen an increase in the number of clinical trials aimed at developing prognostic nomograms based on clinical and molecular biomarkers rather than onclinical markers alone. A recent report by Escudier   et al  .[10] demonstrated that VEGF levels correlate with ECOG PS and with the Memorial Sloan  –  Kettering Cancer Center (MSKCC) score. In another study, Heng  et al  . [11]validated the use of the MSKCC nomogram to predict overall survival (OS) in patients with RCC treated withVEGF-targeted therapy. In addition, they demonstrated that neutrophil and platelet counts were also independent  predictive factors of shortened survival, and thus should be incorporated into clinical trials which evaluate theseagents.One of the most prolific areas of research in the last fewyears is the search for genetic patterns or imprints that allow the identification of tumors with poor prognosis, even before they develop adverse clinical manifestations, to beused as prognostic factors in clinical practice (Table 1). In arecent study, tumors of 282 patients who underwent nephrectomy for RCC were cytogenetically analyzed andcorrelated with pathological factors and disease-free sur-vival [12]. After data analysis, Klatte  et al  . [12] found that tumors with loss of 3p presented at lower TNM stages,whereas loss of 4p, 9p, and 14q were associated with higher TNM stage, higher grade, and greater tumor size; lastly,loss of chromosome Y led to improved progression-freesurvival (PFS) in patients with metastatic disease. In the S2 Cancer Metastasis Rev (2010) 29 (Suppl 1):S1  –  S10  multivariate analysis, only loss of chromosome 9p wasshown to be an independent prognostic factor. 3 Updated results of targeted therapies for patientswith advanced RCC In a previous report issued by the SOGUG, the main resultsfrom randomized phase II and phase III trials of systemictherapies for advanced RCC, including immunotherapy,multikinase inhibitors, anti-VEGF therapies, and mTOR inhibitors, were thoroughly analyzed [2]. The present report is focused on relevant data reported since then.3.1 Multikinase inhibitorsTyrosine kinase inhibitors (TKIs) such as sunitinib, sor-afenib, and pazopanib produce their anticancer effects by blocking the intracellular domain of VEGF receptors. 3.1.1 Sunitinib Sunitinib (Sutent®, Pfizer) is an oral multitargeted tyrosinekinase that inhibits multiple receptors such as VEGF-1,VEGF-2, and VEGF-3 as well as platelet-derived growthfactor receptor (PDGFR)- α   and PDGFR- β , stem cell factor (KIT), and Fms-like tyrosine kinase-3 (FLT-3) receptors. Inthe last years, sunitinib has been demonstrated to yield highORR in patients with cytokine-refractory advanced RCC intwo phase II trials [13, 14]. Sunitinib has also been shown to be superior to IFN- α  asfirst-line treatment of patients with RCC [15, 16]. Very recently, final results of a pivotal phase III trial including750 treatment-naïve patients with advanced RCC have beenreported [17] (Table 2). Patients treated with sunitinib (50 mg once a day for 4 weeks followed by a 2-week rest)achieved a median PFS, which was the primary end point of the study, of 11.0 months, whereas patients who receivedIFN- α   (9 MIU three times a week) achieved a median PFSof 5.0 months (HR, 0.539; 95% CI, 0.451  –  0.643;  p <0.001). Compared with IFN- α  , secondary end points weresignificantly better in the sunitinib arm, as in the case of theORR (47%  vs  12%, respectively;  p <0.001), or showed astrong trend towards significance, as in the case of medianOS (26.4  vs  21.8 months, respectively; HR, 0.821; 95% CI,0.673  –  1.001;  p =0.051). Importantly, 33% of patients in theIFN- α   arm received sunitinib after progression, and another 32% of them received other VEGF inhibitors. Thus, whenthe survival analysis was performed only in those patientsfrom both arms who did not receive any post-study cancer  Table 1  Prognostic and predictive biomarkers in renal cell carcinomaBiomarkers Expression level Prognosis PredictivePrognostic molecular Akt [47] High cytoplasmic levels Poor survivalB7x [48] High Advanced tumor stageCAIX [49, 50] Low Poor survival COX-2 [51] Low No response; poor survivalHepatocyte growth factor [52] High Poor survivalHIF [53] High Poor survivalKi67 [54] High Poor survival p21 [55] High Poor survival p53 [56, 57] High Higher recurrence rate PTEN [47, 56] Low Poor survival VEGF [58] High serum levels Shorter PFSPredictive molecular CAIX [56] High Good response to immunotherapyCOX-2 [56] High Good response to immunotherapyHIF-1 α  /HIF-2 α   [59] High Good response to sunitinibPredictive geneticLoss of chromosomes 4, 9, or 17p [60] NA No response to IL-2Various nsSNPs [61] NA Significant toxicity with sunitinibVHL loss of function mutation [62] NA Good response to VEGF therapy CAIX   carbonic anhydrase IX,  COX-2  cyclooxygenase-2,  HIF   hypoxia inducible factor,  IL-2  interleukin-2,  nsSNPs  non-synonymous singlenucleotide polymorphisms,  PFS   progression-free survival,  PTEN   phosphatase and tensin homologue deleted from chromosome 10,  VEGF  vascular endothelial growth factor,  VHL  von Hippel  –  LindauCancer Metastasis Rev (2010) 29 (Suppl 1):S1  –  S10 S3  Table 2  Main efficacy data from phase III trials with targeted therapies for advanced or metastatic renal cell carcinomaPhase Treatment Patients Setting ORR (%) PFS (months) OS (months)Multikinase inhibitorsSunitinibMotzer   et al  . [16, 17] III Sunitinib 750 First-line 47 11.0 26.4 IFN- α   12;  p <0.001 5.0;  p <0.001 21.8;  p =0.051SorafenibEscudier   et al  . [10] III Sorafenib 903 Second-line (after cytokines) 10 5.5 17.8Placebo 2;  p <0.001 2.8;  p <0.01 15.2; NSPazopanibSternberg  et al  . [29] III Pazopanib 435 First and second-line (after cytokines) 30 9.2 Not reachedPlacebo 3; NR 4.2;  p <0.001 14.7; NSAnti-VEGF antibodiesBevacizumabEscudier   et al  . [35] III Bevacizumab+IFN- α   649 First-line 31 10.4 22.9IFN- α   12;  p <0.0001 5.5;  p <0.0001 20.6; NSRini  et al  . [34, 36] III Bevacizumab+IFN- α   732 First-line 26 8.4 18.3IFN- α   13;  p <0.0001 4.9;  p <0.0001 17.4;  p =0.097mTOR inhibitorsTemsirolimusHudes  et al  . [39] III IFN- α   626 First-line 5 3.1 7.3Temsirolimus Poor prognosis 9; NS 5.5;  p <0.001 10.9;  p =0.0088; NS 4.7; NS 8.4;  p =0.70Temsirolimus+IFN- α  EverolimusMotzer   et al  . [43] III Everolimus 362 Second-line (after TKIs) 3 4.0 Not reachedPlacebo 0 1.9;  p <0.0001 8.8;  p =0.233  IFN- α  interferon-alpha,  NR  not reported,  NS   non-significant,  ORR  objective response rate,  OS   overall survival,  PFS   progression-free survival,  RCC   renal cell carcinoma,  TKIs  tyrosine kinaseinhibitors  S 4   C  a n c  e r M e  t   a  s  t   a  s i    s R e  v  (   2   0  1   0    )   2   9    (    S  u  p  pl   1    )    :   S 1   –  S 1   0    treatment, median OS with sunitinib was twice that of IFN- α   (28.1  vs  14.1 months, respectively; HR, 0.647; 95% CI,0.483  –  0.870;  p <0.003).Within the same phase III trial, Cella  et al.  [18] analyzed and compared health-related quality of life (HRQoL) resultsobtained in patients who received sunitinib with thoseobtained in patients treated with IFN- α  . It was concludedthat in addition to providing significantly superior efficacyto IFN- α   therapy, sunitinib offered a better HRQoLaccording to different scales and subscales such as theFunctional Assessment of Cancer Therapy (FACT) andFACT-Kidney Symptom Index, among others. Moreover,results from an expanded-access trial which included 4,564 patients with previously treated and untreated metastaticRCC confirmed that the safety profile of sunitinib wasmanageable, even in populations who usually are under-represented in clinical trials such as elderly or patients with poor performance status [19, 20]. Sunitinib has been approved by the Food and DrugAdministration (FDA) and the European Medicines Agency(EMEA) for the treatment of advanced or metastatic RCC[21, 22]. The recommended dose is 50 mg once daily, administered for four consecutive weeks, followed by a2-week rest period, to complete a 6-week cycle. Doseadjustments should be made in 12.5 mg steps, and theminimum dose should not be below 25 mg. Treatment withsunitinib requires close monitoring to detect early signs of congestive heart failure, prolonged QT interval, arterialhypertension, and hemorrhagic events. Thyroid dysfunctionmay also occur in patients treated with sunitinib. 3.1.2 Sorafenib Sorafenib (Nexavar®, Bayer Pharmaceuticals) is an orallyactive multikinase inhibitor that blocks VEGFR-1,VEGFR-2, VEGFR-3, PDGFR- β , as well as FLT-3 andKIT receptors. As second-line treatment of advanced RCCafter cytokines failure, sorafenib has had its activity andsafety demonstrated in a previous phase II study [23]. Based on these findings, a randomized, double-blind, phaseIII trial comparing sorafenib (400 mg twice a day) with placebo as second-line treatment was performed in 903 patients with cytokine-refractory advanced RCC [24]. The primary endpoint of this study was OS, and secondaryendpoints included PFS and ORR.Based upon results of the first planned interim analysis,in which sorafenib provided a clear benefit to patients interms of PFS, patients on the placebo arm were allowed tocrossover and receive sorafenib after progression. As aconsequence, 48% of patients initially assigned to the placebo arm were treated with sorafenib, which probablyconfounded the results of the survival analysis. Thus, in thefinal analysis of survival [10], sorafenib was not superior to  placebo (17.8  vs  15.2 months, respectively; HR, 0.88; 95%CI, 0.74  –  1.04;  p =0.104; Table 2). However, when patientsassigned to the placebo arm who received sorafenib after  progression were excluded from the analysis, sorafenib wasassociated with a significantly longer survival in compar-ison with placebo (17.8  vs  14.3 months, respectively; HR,0.78; 95% CI, 0.62  –  0.97;  p =0.0287). Secondary endpointsof the study also were significantly better in the sorafenibarm in comparison with the placebo arm in terms of PFS(5.5  vs  2.8 months, respectively; HR, 0.44; 95% CI, 0.35  –  0.55;  p <0.01) and ORR (10%  vs  2%, respectively;  p <0.001) [10]. As first-line treatment, sorafenib (400 mg twice a day)was compared with IFN- α   (9 MIU three times a week) in arandomized phase II trial including 189 patients withadvanced RCC [25]. Although several endpoints such asdisease control rate, quality of life, and safety were improvedin the sorafenib arm with respect to the IFN- α   arm, PFS,which was the primary endpoint, was similar in both arms(5.7  vs  5.6 months, respectively; HR, 0.88;  p =0.50).Based on these results, sorafenib is currently approved by the FDA and by the EMEA for the treatment of patientswith advanced RCC who have failed prior IFN- α   or IL-2therapy or are considered unsuitable for those therapies [26,27]. The recommended dose of sorafenib is 400 mg twice aday, as long as clinical benefit is observed or untilunacceptable toxicity. Dose may be reduced to 400 mgonce a day or to 400 mg on alternate days. Precautions at the time of administration are similar to those for other TKIs and, therefore, special attention should be paid to theemergence of cardiac events, bleeding, gastrointestinal perforation, or arterial hypertension. 3.1.3 Pazopanib Pazopanib (Votrient®, GlaxoSmithKline) is an oral multi-kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3,PDGFR- α   and - β , fibroblast growth factor receptor (FGFR)-1 and -3, KIT, IL-2 receptor inducible T-cellkinase, leukocyte-specific protein tyrosine kinase, andtransmembrane glycoprotein receptor tyrosine kinase [28].In a previous international, multicenter, randomized,double-blind, phase III trial (VEG105192), 435 patientswith clear cell advanced RCC (233 treatment-naïve and 202with no more than one previous cytokine-based treatment)were included and treated with 800 mg of pazopanib oncedaily ( n =290) or placebo ( n =145) [29]. Patients werestratified according to performance status, prior nephrecto-my, or prior cytokine therapy. The study's primary endpoint was PFS. Secondary endpoints included OS, RR, andsafety.Baseline characteristics of both arms were well balanced.Forty-two percent of patients were ECOG PS 0, and 58% Cancer Metastasis Rev (2010) 29 (Suppl 1):S1  –  S10 S5
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