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Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer

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For almost the last two decades, interleukin-2 and interferon-α have been the only systemic treatment options available for metastatic renal cell carcinoma. However, in recent years, five new targeted therapies namely sunitinib, sorafenib,
  Cancer Chemother Pharmacol (2009) 63 (Suppl 1):S1–S13DOI 10.1007/s00280-009-0955-3  1 3 CONSENSUS STATEMENT Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer Joaquim Bellmunt · Emiliano Calvo · Daniel Castellano · Miguel Ángel Climent · Emilio Esteban · Xavier García del Muro · José Luis González-Larriba · Pablo Maroto · José Manuel Trigo Published online: 4 March 2009 ©  Springer-Verlag 2009 Abstract For almost the last two decades, interleukin-2and interferon-   have been the only systemic treatmentoptions available for metastatic renal cell carcinoma.However, in recent years, W ve new targeted therapiesnamely sunitinib, sorafenib, temsirolimus, everolimusand bevacizumab have demonstrated clinical activity inthese patients. With the availability of new targetedagents that are active in this disease, there is a need tocontinuously update the treatment algorithm of the dis-ease. Due to the important advances obtained, the SpanishOncology Genitourinary Group (SOGUG) has consideredit would be useful to review the current status of the dis-ease, including the genetic and molecular biology factorsinvolved, the current predicting models for developmentof metastases as well as the role of surgery, radiotherapyand systemic therapies in the early- or late management of the disease. Based on this previous work, a treatmentalgorithm was developed. Introduction Cancer of the kidney and renal pelvis constitute approxi-mately 2% of all oncological diseases of which most arerenal cell carcinomas (RCCs). The incidence of RCCranges between 12 cases per 100,000 people in some Euro-pean countries and 1.5 within India. In the United Statesalone, more than 50,000 people are diagnosed with thedisease each year and 12,000 deaths are attributable to it [1].Itis the third leading cause of death amongst genitourinarymalignancies and ranks 12th amongst cancer deaths overall[1]. The median age at diagnosis is around 60–65years andit a V  ects twice as many men as women. J. Bellmunt ( & )Medical Oncology Service, Hospital del Mar, Passeig Maritim 25, 08003 Barcelona, Spaine-mail: jbellmunt@imas.imim.esE. CalvoMedical Oncology Service, Hospital del Vall d’Hebron, Barcelona, SpainD. CastellanoHospital 12 de Octubre, Madrid, SpainM. Á. ClimentOncology Medical Service, Instituto Valenciano de Oncología, Valencia, SpainE. EstebanMedical Oncology Service, Hospital Universitario Central de Asturias, Oviedo, SpainX. García del MuroMedical Oncology Service, Institut Català d’Oncologia, Barcelona, SpainJ. L. González-LarribaMedical Oncology Service, Hospital Clínico San Carlos, Madrid, SpainP. MarotoMedical Oncology Service, Hospital de la Santa Creu i San Pau, Barcelona, SpainJ. M. TrigoMedical Oncology Service, Hospital Virgen de la Victoria, Malaga, Spain  S2Cancer Chemother Pharmacol (2009) 63 (Suppl 1):S1–S13  1 3 Risk factors for RCC Several potential risk factors for RCC have been identi W edin epidemiological studies. Some of the most solid ones aresmoking, obesity, hypertension, occupational exposure andintake of certain antihypertensive drugs [2]. Heavy smokers (more than 20cigarettes/day) have a risk, i.e. 1.5–2.0timeshigher than that observed in people who have never smoked[3]. Also, higher body mass index and elevated blood pres-sure independently increase the long-term risk of RCC.Obese people usually have increase serum concentrationsof free estrogens, which have been linked to RCC in animalstudies [4]. Additionally, hypertension may increase a vari-ety of angiogenic and other growth factors that may beinvolved in renal carcinogenesis [4]. An increased risk of RCC has also been reported in association with occupa-tional exposure to petroleum products or heavy metals suchas iron or steel (for exposures longer than 3years) [5]. Genetics and molecular biology of RCC It is estimated that RCC is inherited in » 4% of patients andis sporadic in srcin in 96% of patients [6]. In spite of that, di V  erent genetic anomalies have been identi W ed in most of the patients a V  ected. Hence, RCC is considered to comprisea group of di V  erent tumours including clear-cell (75%),papillary (12%), chromophobe (4%), oncocytoma (4%),collecting duct (1%) and other unclassi W ed (3–4%) tumours[6]. Each of them has a distinct phenotypic appearance and molecular characteristics. The pathogenesis of clear-cellRCC is associated with loss of function of the von Hippel–Lindau (VHL) gene and overproduction of the hypoxia-inducible factor (HIF). Under normal oxygen conditions,the VHL gene product binds to a complex of proteins con-taining the hydroxylated   subunits of HIF (HIF-1   andHIF-2  ) for HIF destruction [7]. Under hypoxic conditions,HIF-   is not hydroxylated, and therefore it is not recogni-sed by the protein pVHL. Hence, HIF accumulates andbinds to HIF-   in the nucleus, resulting in an increasedtranscription of di V  erent genes, such as vascular endothelialgrowth factor (VEGF), platelet-derived growth factor(PDGF), transforming growth factor beta (TGF  ) anderythropoietin. Even under normoxic conditions, the VHLgene may have mutations that avoid the binding that leadsto HIF degradation. To emphasise the key role of the VHLgene in RCC, it is important to know that the VHL gene ismutated in » 70% of patients with RCC; additionally, VHLis silenced in another 20% of patients [8].Papillary RCC is an inherited RCC characterised by apredisposition to develop multiple, bilateral papillary renaltumours. Type I papillary RCC is associated with multiplemutations of the MET gene on chromosome 7, which mayhave e V  ects on both the VHL gene and HIF [9]. In contrast,type II papillary RCC is associated with the inhibition of the enzyme fumarate hydratase, which is related to HIFhydroxylation, due to a mutation in chromosome 1. It isthought that this mutation may be responsible for hereditaryleiomyomatosis and RCC [7].One additional familial syndrome named Birt-Hogg-Dubé (BHD) has recently been described and associatedwith RCC. BHD is an autosomal, dominantly inheritedgenodermatosis that predisposes to W brofolliculomas, kid-ney neoplasms, lung cysts, and spontaneous pneumothorax.Patients with BHD are at risk for multiple renal tumoursthat are often malignant and which can metastasise [10].Genetic studies have led to the localisation of the BHDgene, and current studies are trying to explain how a muta-tion in the BHD gene may lead to chromophobe RCC [7].In summary, the genetic pathways of RCC are complexand may be interconnected. However, the understanding of the biology and the molecular basis of RCC is of greatimportance to W nd out how the disease develops and tooptimise the design of new disease-speci W c therapies forthese patients. Diagnosis and staging of RCC Symptoms of renal cancer often do not become apparentuntil the disease has progressed beyond the initial stages.The most de W ning symptom is haematuria, but there maybe other less speci W c symptoms such as unexplained weightloss, fatigue, swelling of the ankles and the legs, X ank massand/or X ank pain. In spite of that, half of RCC cases are dis-covered to date purely by chance, because imaging tech-niques such as ultrasound scan or abdominal computedtomography (CT) are becoming more common [5]. When a RCC is suspected, a series of tests and studiesneed to be performed to con W rm the diagnosis of RCC andto evaluate whether the disease has spread outside the kid-ney. This process includes a complete physical examinationof the patient, speci W cally to detect supraclavicular adenop-athies, abdominal masses, lower extremity oedema or sub-cutaneous nodules. Laboratory analysis should include acomplete blood cell count, a liver function assessment, cal-cium, creatinine, a coagulation pro W le and urinalysis. Inaddition, CT of the abdomen and pelvis and chest imaging(either by radiography or a CT scan) should be performed,if not already done. In contrast, bone scans should only becarried out in cases of elevated serum alkaline phosphataseor bone pain. Similarly, CT or magnetic resonance imaging(MRI) of the brain are recommended only in cases whereother symptoms suggest brain metastases [11]. However,the de W nitive diagnosis of RCC is made through biopsy or,in the case of a high risk of bleeding, through surgery.  Cancer Chemother Pharmacol (2009) 63 (Suppl 1):S1–S13S3  1 3 The most commonly used staging system for RCC is theTNM (tumour, node, metastases) system of the AmericanJoint Committee of Cancer (AJCC) [12]. Once TNM cate-gories have been assigned, the information obtained is com-bined to assign an overall stage of I, II, III or IV, in order togroup together RCC patients with similar prognosis, andtherefore patients that should be treated in a similar way.Thus, stage I includes patients with tumours of less than7cm, limited to the kidney, without lymph node involve-ment and without metastases (T1a–T1b, N0, M0). Stage IIincludes tumours larger than 7cm, but still limited to thekidney, without spread to lymph nodes or distant sites(T2N0M0). In stage III, the main tumour is of any size andhas reached the adrenal gland, the fatty tissue around thekidney, the renal vein, and/or vena cava; however, it hasnot spread beyond the W brous capsule of the kidney(Gerota’s fascia), lymph nodes or distant organs (T3a–T3c,N0, M0). Also, stage III includes tumours of any size thathave spread to nearby lymph nodes, but not to distantlymph nodes, distant organs or beyond Gerota’s fascia(T1a–T3c, N1, M0). Finally, stage IV includes tumourswhich have spread beyond Gerota’s fascia, with or withoutnearby lymph node involvement and without distant metas-tases (T4, N0–N1, M0). In addition, stage IV includestumours of any size that have spread to distant lymphnodes, but not to distant organs (any T, N2, M0) or tumoursof any size, with or without nearby or distant lymph nodeinvolvement, which have spread to other distant organs(any T, any N, M1).According to the United States National Cancer DataBase (NCDB), 48% of patients have an early-stage RCC atdiagnosis (9% of patients with stage I and 39% of patientswith stage II). Additionally, 16 and 25% are stages III andIV, respectively [13]. The role of surgery in localised and metastatic RCC If RCC is detected in earlier stages, when surgical treat-ment may be curative, the 5-year survival rate of patientswith RCC is around 88–100%. In contrast, when diagnosisis made in more advanced stages, the 5-year survivaldecreases to 20% or less [14]. These facts point out theimportance of surgery in the treatment of RCC. Thus, radi-cal nephrectomy remains the mainstay of the initial treat-ment for patients with RCC without evidence of metastaticdisease [6]. Nephron-sparing surgery (NSS), through open surgicalpartial nephrectomy or a laparoscopic partial nephrectomy,is also an established approach for certain patients withsmall, localised RCC, and in these patients similar long-term survival rates have been observed [15]. Although opensurgical partial nephrectomy is usually the most commonapproach for NSS, laparoscopic partial nephrectomy isincreasingly used in those patients with relatively small andperipheral RCC. This technique gives a minimally invasivesurgical approach with lower postoperative narcotic use,morbidity and hospital stays compared to the open surgicalapproach [15].In contrast to the management of other solid tumours inadvanced stages such as breast or lung cancer, surgery isalso performed in advanced RCC [16]. This approach is  justi W ed because cytoreductive nephrectomy not only helpsto control the symptoms but also seems to improvepatients’ survival [17, 18]. Two similar prospective, ran- domised clinical trials have been performed in Europe andin the United States to demonstrate the bene W t of cytore-ductive nephrectomy prior to immunotherapy in metastaticRCC. In a study performed by the Southwest OncologyGroup (SWOG), 241 metastatic RCC patients were ran-domised to either interferon-   (IFN-  ) alone or nephrec-tomy followed by IFN-   [17]. Patients who underwentsurgery plus immunotherapy obtained a survival advantageof 3.0months over those who received immunotherapyalone (8.1 vs. 11.1months,  p =0.012). Similarly, in a studyperformed by the European Organization for Research andTreatment of Cancer (EORTC), 85 patients with metastaticRCC were randomised to either IFN-   alone or nephrec-tomy followed by IFN-   [18]. The median survival wasagain signi W cantly higher for patients who underwent sur-gery plus immunotherapy (17.0 vs. 7.0months, HR: 0.54,95% CI: 0.31–0.94). As expected, the strongest bene W t wasobserved in those patients with better performance status.Although the reasons why cytoreductive nephrectomyimproves survival of patients with advanced RCC remainunknown, this approach has been widely incorporated intothe clinical practice. It is important, however, to selectpatients properly, i.e. patients with good performance sta-tus, without evidence of central nervous system metastases,aggressive extrarenal disease, and/or other important medi-cal comorbidities [19].Metastasectomy also has an important role in advancedRCC. Thus, resection of solitary metastases after recurrenceof RCC has led to long-term survival in 30% of patients[20]. Favourable predictors of survival for these patientsincluded a single site of W rst recurrence, curative resectiondisease and a long disease-free interval. Moreover, patientswith single or multiple resectable lesions [21], or patientswho have achieved a su Y cient decrease in tumour load aftersystemic therapy such as sunitinib [22], may also bene W tfrom metastasectomy. In this regard, two clinical cases of cytokine-refractory metastatic RCC in whom sunitinib wasadministered have been recently reported. Both patientsachieved an important decrease in tumour burden. Subse-quently, surgical resection of metastasis allowed them toachieve a long-term complete response [22].  S4Cancer Chemother Pharmacol (2009) 63 (Suppl 1):S1–S13  1 3 The role of radiotherapy in localised and metastatic RCC Many patients with large primary cancers have a signi W cantrisk of local relapse after surgery. Because of this, severalrandomised trials have assessed the role of pre- or postoper-ative radiotherapy in RCC [23–26]. Although all of these trials were small and probably underpowered, none of themshowed a signi W cant bene W t from radiotherapy. Moreover,in one of these trials [25, 26], postoperative radiotherapy was associated with a high rate of severe complications,and some of them led to patient death. For inoperable RCConly, stereotactic radiotherapy may have a role, but there isonly one retrospective study which supports this approach[27].These studies suggest that the only role that radiotherapymay have in RCC is in the metastatic setting and for pallia-tive purposes, i.e. patients with brain or bone metastases. Inpatients with RCC with multiple bone metastases, radio-therapy appears to control pain in the short term and pre-vent fractures [28]. Brain metastases from RCC may causesigni W cant morbidity and mortality and, traditionally,whole-brain radiotherapy has been used in those patients.More recently, advances in radiation oncology, stereotacticradiosurgery and hypofractionated stereotactic radiother-apy, have been utilised for RCC brain metastases, deliver-ing excellent outcomes [29]. Stereotactic radiotherapy mayalso be considered as a therapeutic option to surgery inpatients with a limited number of metastases, as local treat-ment in RCC with an indolent presentation or as a methodof reducing tumour burden prior to medical treatment [30].On the other hand, targeting tumour vasculature agentssuch as sunitinib, sorafenib, and bevacizumab, which haverecently been approved for renal cancer therapy, have astrong biological rationale in radiation therapy. Thus, pre-clinical studies have consistently showed an increase inradiosensitization with combined treatment. Nevertheless,the optimal biological doses of antiangiogenic agents withradiotherapy are still unknown, as well as its clinical safetyand e Y cacy. Early clinical trials are needed to minimise thevolume of irradiated normal organs and to establish safedose–volume parameters for phase II–III clinical trials [31]. Adjuvant systemic therapies for stage I–III RCC To date, systemic therapy after radical nephrectomy inpatients with RCC has not demonstrated an improvement insurvival [7]. RCC in the metastatic setting is highly resis-tant to systemic chemotherapy [32], and therefore it has noteven been tested in the adjuvant setting. Immunotherapywith IFN-   or interleukin-2 (IL-2) does not appear to pro-vide signi W cant bene W ts to patients after complete surgicalresection [33–35]. In a previous trial, 283 patients were ran- domised either to IFN-   or to watchful waiting after radicalnephrectomy plus lymphadenectomy [34]. Patientsremained on treatment until recurrence or toxicity. After10years of follow-up, median survival was 7.4years in theobservation group and 5.1years in treatment arm(  p =0.09). Relapse-free survival was similar in bothgroups. In a multivariate analysis, only performance status,nodal status and tumour stage were signi W cant prognosticfactors for survival. In another prospective trial, 68 patientswith resected locally advanced or metastatic RCC were ran-domised to observation or to one course of high-dose IL-2after surgery [33]. High-dose IL-2, although feasible, didnot result in a signi W cant bene W t. Recently, preliminaryresults of one of the biggest randomised trials have alsoindicated that adjuvant IFN-   does not seem to add anybene W ts in the treatment of patients with stage II and IIIRCC [35]. Other systemic therapies such as vaccines, anti-bodies or targeted therapies are being evaluated nowadaysin the adjuvant setting [36–38]. These results suggest that clinical observation shouldremain the standard of care in patients with RCC who haveundergone surgery. This watchful waiting approach shouldinclude several procedures such as physical examinations,chest X-ray and abdominal ultrasound, as well as blood lab-oratory analyses (including blood urea nitrogen, serum cre-atinine, calcium levels, lactate dehydrogenase [LDH] andliver function tests), which should be complemented withabdominal and chest CT scans [11]. However, there is noconsensus on which tests and studies need to be performedand at what intervals. It is assumed that a strong e V  ortshould be made during the W rst 3–5years, and subsequentlythat the frequency of the follow-ups should depend on thespeci W c risk of relapse of each patient [39]. Predicting models for development of metastasesin RCC Between 20 and 30% of patients with localised RCC willexperience disease relapse after surgery, most of themwithin the W rst 3years. Thus, prognostic information isessential in the clinical management of RCC. Currently,RCC prognosis is based on standard clinical and pathologi-cal parameters such as the performance status of thepatients, tumour stage (which evaluates tumour size, nodalstatus and metastatic lesions), nuclear grade of tumour cells(such as Fuhrman Nuclear Grade) [40] and histological type of the tumour (i.e. clear-cell, papillary, chromophobe,oncocytoma or collecting duct tumours). More recently, themolecular characterisation of tumours has allowed the iden-ti W cation of other more speci W c prognostic factors, such ascarbonic anhydrase IX [41], loss of phosphatase and tensin  Cancer Chemother Pharmacol (2009) 63 (Suppl 1):S1–S13S5  1 3 homolog (PTEN), or tumour expression of certain mole-cules such as B7H1 and B7H4, which are known to inacti-vate local immune cells [7].All the prognostic factors mentioned may be evaluatedseparately or together to facilitate the decision-making pro-cess. Thus, W ve prognostic models have been recentlyreported to predict the outcome of patients with localisedRCC after nephrectomy. All of them consider clinical and/ or pathologic variables. The Johns Hopkins Hospital hasdeveloped a biostatistical prognostic model for postopera-tive RCC using the records of 296 patients which was basedpurely on clinical variables, allowing a non-invasive preop-erative evaluation of the risk of recurrence [42]. The Memorial Sloan-Kettering Cancer Center (MSKCC) hasdeveloped a nomogram using variables of 601 patients suchas symptoms, histology, tumour size and pathologicalstage, which was able to predict the 5-year probability of treatment failure [43]. The nomogram was internally vali-dated. The Mayo Clinic developed a scoring system forpatients with only clear-cell RCC which was able to associ-ate TNM stage, tumour size, nuclear grade and histologicaltumour necrosis with cancer-speci W c survival (SSIGNscore) [44]. A fourth model was developed by the Univer-sity of California Los Angeles (UCLA) using the medicalrecords of 661 patients, and was called the UCLA Inte-grated Staging System (UISS). Along with the TNM stage,it takes into account the Fuhrman grade and the EasternCooperative Oncology Group (ECOG) performance statusto stratify RCC patients into low-, intermediate- or high-risk categories of disease relapse [45]. This model was alsovalidated externally. A prospective large-scale trial with4,202 patients with localised and metastatic tumoursshowed that UISS was an accurate predictor of survival forpatients with localised RCC, but that it was less accurate inthe subset of patients with metastatic RCC due to heteroge-neity in the patients and the treatments evaluated [46].Finally, an Italian group has constructed a recurrence riskformula with two clinical variables such as asymptomatic/ symptomatic presentation and tumour size [47]. In a later study, the Italian group compared the discrimi-nating accuracy of their model (Cindolo formula) withthree of the four previously mentioned prognostic models[48]. The SSIGN score could not be calculated because, in many patients, the information regarding histologicaltumour necrosis was not available. Thus, 2,404 medicalrecords of patients from six European sites were retrospec-tively reviewed. For each patient, four prognostic scoreswere calculated. The Johns Hopkins Hospital’s score andthe Cindolo formula used exclusively clinical variablesand could be calculated preoperatively. The MSKCC scoreand the UISS score used clinical and pathologic variablesand were calculated postoperatively. All models con W rmedtheir ability to discriminate between categories with di V  erentprognoses. The conclusion was that the postoperativescores can discriminate between prognoses substantiallybetter than preoperative ones. Overall, the MSKCC wasfound to be the most accurate, although the UISS also per-formed well [48]. Systemic therapies for metastatic RCC As mentioned before, classical systemic therapies witheither chemotherapy or radiotherapy for the advancedstages of the disease have failed to improve patient out-come. Traditionally, metastatic RCC patients have beentreated with immunotherapy agents, mainly IFN-   and IL-2, with low clinical bene W t and poor safety pro W le. In thelast few years, new targeted therapies against the kinasesinvolved in the pathogenesis of RCC have been developedand rapidly incorporated into the standard clinical practice.ImmunotherapyFor patients with stage IV RCC, di V  erent combinations anddosages of IFN-   and IL-2, both as single agent or in com-bination, have been tested. In a randomised trial, subcutane-ous IFN-  , in comparison with oral medroxyprogesteroneacetate, demonstrate a small bene W t in overall survival (OS)(8.5 vs. 6.0months,  p =0.017). However, patients whoreceived IFN-   had more symptoms of toxicity and a lowerquality of life [49]. Additionally, patients treated with IFN-   rarely showed complete or long-lasting responses.The response to high-dose IL-2 can be achieved in up to20% of patients, of which 5% of them could be consideredlong-lasting responses [50]. In spite of that, two large phase III trials in which high-dose IL-2 was compared with low-dose IL-2 or a combination of IFN-   plus low-dose IL-2were unable to demonstrate any bene W t regarding survival[51, 52]. Additionally, higher morbidity was observed in the high-dose arm. In fact, the administration of high-doseIL-2 requires a careful assessment by a physician due to theincidence of capillary leak syndrome and hypotension [53].Therefore, it is considered that intensive care would beadvisable during high-dose IL-2 administration and that30–50% of patients would require treatment with vasopres-sor agents to treat hypotension. Additionally, the Pro-gramme Etude Rein Cytokines (PERCY) Quattro trial wasdesigned to evaluate the e Y cacy of both cytokines, IFN-  and IL-2, in metastatic renal cancer patients with intermedi-ate prognosis in comparison with medroxyprogesterone ace-tate [54]. The results observed in 492 patients included wereIFN-   and IL-2 that did not provide any survival bene W t.Moreover, they induced a signi W cant increase of toxicity.In a retrospective analysis of six clinical trials in which463 patients received IFN-   as W rst-line systemic therapy
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