Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract

Renal cell carcinoma (RCC) accounts for 2%–3% of all adult malignancies, representing the seventh most common cancer in men and the ninth most common cancer in women [1.Rini B.I. Campbell S.C. Escudier B. Renal cell carcinoma.Lancet. 2009; 373: 1119-1132Abstract Full Text Full Text PDF PubMed Scopus (1117) Google Scholar]. Worldwide, there are ∼209 000 new cases and 102 000 deaths per year. The incidence of all stages of RCC has increased over the past several years, contributing to a steadily increasing mortality rate per unit population. Active and passive cigarette smoking is an established risk factor for RCC as well as hypertension. However, anti-hypertensive medications such as diuretics are not independently associated with RCC development. RCC also appears to be more common in patients with obesity, end-stage renal failure, acquired renal cystic disease and tuberous sclerosis. Approximately 2%–3% of RCC are hereditary and several autosomal dominant syndromes are described, each with a distinct genetic basis and phenotype, the most common one being Von Hippel Lindau disease. In recent years, many new genes associated with RCC have been reported (such as PBRM1, SETD2, BAP1). Their roles in pathogenesis and as prognostic biomarkers are currently under investigation. The proportion of small and incidental renal tumours has significantly increased owing to the widespread use of abdominal imaging e.g. ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI). More than 50% of RCCs are currently detected incidentally. However, some patients with RCC still present with clinical symptoms, such as flank pain, gross haematuria and palpable abdominal mass (the classical triad); metastatic symptoms like bone pain or lung nodules; or paraneoplastic syndromes, such as hypercalcaemia, unexplained fever, erythrocytosis or wasting syndromes. Physical examination alone directs further examinations especially when symptoms and signs mentioned above are present. Suspicion of RCC should prompt laboratory examinations of serum creatinine, haemoglobin, leukocyte and platelet counts, lactate dehydrogenase and serum-corrected calcium, in addition to other symptom derived tests [IV, B]. Inflammatory syndrome tests such as C-reactive protein (CRP) and erythrocyte sedimentation rate have been suggested. Some of these tests are prognosticators for survival and used for risk assessment (see later). Most cases of RCC are strongly suspected by imaging. Diagnosis is usually suggested by ultrasonography and further investigated by CT scan, which allows for assessment of local invasiveness, lymph node involvement or other metastases. MRI may provide additional information in investigating local advancement and venous involvement by tumour thrombus. MRI may also be useful in situations where i.v. contrast cannot be used. For accurate staging of RCC, abdominal and chest CT or MRI is mandatory [III, A]. Chest CT is the most sensitive approach for chest staging [III, A]. Unless indicated by clinical or laboratory signs or symptoms, the use of bone scan or CT (or MRI) of the brain is not recommended for routine clinical practice [III, A]. Positron emission tomography is not a standard investigation in the diagnosis and staging of RCC [I, B]. A renal tumour core biopsy provides histopathological confirmation of malignancy with high sensitivity and specificity. A diagnostic biopsy is especially required before treatment with ablative therapies [III, B]. It is also indicated in patients with metastatic disease before commencing systemic treatment [III, B]. The final histopathological diagnosis, classification, grading and evaluation of prognostic factors are based on the nephrectomy specimen when available. Due to a better understanding of the correlation between chromosomal alterations, histological subtypes and molecular pathway abnormalities, researchers now recognise new morphological variants of RCC. The distinct molecular pathway abnormalities demonstrated by these novel variants may provide new therapeutic targets. In order to classify these novel variants of RCC, the International Society of Urological Pathology (ISUP) coordinated a consensus conference in 2012, which proposed the Vancouver classification [2.Srigley J.R. Delahunt B. Eble J.N. et al.The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia.Am J Surg Pathol. 2013; 37: 1469-1489Crossref PubMed Scopus (756) Google Scholar] (Table 1).Table 1Vancouver RCC classification Clear-cell renal cell carcinoma Multi-locular clear-cell renal cell neoplasm of low malignant potential Papillary renal cell carcinoma Chromophobe renal cell carcinoma Hybrid oncocytic chromophobe tumour Carcinoma of the collecting ducts of Bellini Renal medullary carcinoma MiT family translocation renal cell carcinomaXp11 translocation renal cell carcinomat(6;11) renal cell carcinoma Carcinoma associated with neuroblastoma Mucinous tubular and spindle cell carcinoma Tubulocystic renal cell carcinoma Acquired cystic disease-associated renal cell carcinoma Clear-cell papillary (tubulopapillary) renal cell carcinoma Hereditary leiomyomatosis-associated renal cell carcinoma Renal cell carcinoma, unclassifiedReprinted from the American Journal of Surgical Pathology [2.Srigley J.R. Delahunt B. Eble J.N. et al.The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia.Am J Surg Pathol. 2013; 37: 1469-1489Crossref PubMed Scopus (756) Google Scholar]. Copyright © 2013, with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health. Open table in a new tab Reprinted from the American Journal of Surgical Pathology [2.Srigley J.R. Delahunt B. Eble J.N. et al.The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia.Am J Surg Pathol. 2013; 37: 1469-1489Crossref PubMed Scopus (756) Google Scholar]. Copyright © 2013, with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health. The more important conclusions of the consensus conference are as follows: •Clear-cell RCC is the most frequent subtype of sporadic RCC in adults (70%–85%) [3.Patard J.J. Leray E. Rioux-Leclercq N. et al.Prognostic value of histologic subtypes in renal cell carcinomas: a multicenter experience.J Clin Oncol. 2005; 23: 2763-2771Crossref PubMed Scopus (556) Google Scholar], with loss of 3p and the classical clear aspect of the cells due to glycogen and lipids in their cytoplasm.•The multi-locular cystic RCC, composed entirely of numerous cysts lined by clear cells, without solid tumoural areas, is considered as a neoplasm of low malignant potential.•Papillary RCC (7%–15%) shows distribution of malignant cells around capillary cores (papillae) in 50%–70% of the tumour as well as Trisomy 7, 12, 16, 17, 20, loss of Y chromosome but no 3p loss [4.Delahunt B. Eble J.N. Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors.Mod Pathol. 1997; 10: 537-544PubMed Google Scholar]. In 73% of cases, cells have scarce cytoplasm and are classified as type I. In 42% of cases, cells show eosinophilic cytoplasm and are classified as type II. Some pathologists prefer to sub-classify papillary tumours according to nucleolar size [5.Sika-Paotonu D. Bethwaite P.B. McCredie M.R. et al.Nucleolar grade but not Fuhrman grade is applicable to papillary renal cell carcinoma.Am J Surg Pathol. 2006; 30: 1091-1096Crossref PubMed Scopus (114) Google Scholar].•Chromophobe RCC (5%–10%) is made up of typical polygonal cells with a clear delimitation of the cytoplasmic membrane and reticular cytoplasm. The tumour shows loss in chromosomes 1, 2, 6, 10, 13, 17 and 21.•A hybrid oncocytoma/chromophobe RCC may be present in Birt–Hogg–Dubé syndrome and in sporadic cases.•Collecting duct RCC (Bellini tumours) constitutes <1% of RCC and derives from the medullary distal nephron or Bellini ducts. The typical morphology of the cells is a high nuclear grade, eosinophilic cytoplasm with predominantly tubular arrangement. Desmoplasia without other RCC subtype or urothelial cell carcinoma is mandatory.•Medullary RCC shows loss of INI1 and of genes involved in the hypoxia-inducible factor (HIF)1&agr; pathway.•Microphthalmia-associated transcription (MiT) familial translocation RCC includes translocation of Xp11.2 with TFE3 gene fusion and the t(6;11)(p21;q12) translocation with TFEB gene fusion [6.Argani P. Lal P. Hutchinson B. et al.Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay.Am J Surg Pathol. 2003; 27: 750-761Crossref PubMed Scopus (493) Google Scholar].•Mucinous tubular and spindle cell carcinoma is a low-grade and indolent tumour which only exceptionally metastasises to lymph nodes. •Tubulocystic RCC is an indolent tumour composed of packed tubules and cysts lined by cuboidal or hobnail cells with abundant eosinophilic cytoplasm and large nuclei showing prominent nucleoli.•Acquired cystic disease-associated RCC is often diagnosed at an early stage and is composed of eosinophilic cells with cribriform architecture and intra-tumoural oxalate crystals.•Clear-cell (tubulo) papillary RCC does not demonstrate 3p loss and is unrelated to clear-cell RCC. The papillary growth pattern, expression of CK7 and CAIX and lack of AMACR expression are diagnostic. Published data indicate an indolent evolution.•Hereditary leiomyomatosis RCC is a papillary RCC with peculiar pseudo-viral nucleoli. It is an entity under debate. Other emerging entities, which are not yet formally accepted, are the thyroid-like follicular RCC, succinate dehydrogenase B mutation-associated RCC and ALK translocation RCC. Of course some RCCs still remain unclassified. Each of the most frequent morphological genetic RCC subtypes correlates with a specific molecular pathway. Examples include:•The hypoxia-inducible pathway (clear-cell, papillary type II through the FH gene).•The mTOR signalling pathway (clear-cell and papillary type II).•The c Met-RAF-MEK-ERK pathway (papillary type I and translocation RCC). The 2012 ISUP consensus conference proposed a new grading classification based on the size of the nucleolus [7.Delahunt B. Cheville J.C. Martignoni G. et al.The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters.Am J Surg Pathol. 2013; 37: 1490-1504Crossref PubMed Scopus (480) Google Scholar], which correlates well with prognosis and shows good interobserver reproducibility. The following recommendations were made:•The nucleolar grading system should be used in clear-cell and papillary RCC.•In chromophobe RCC, it is only necessary to report sarcomatoid features or the presence of an anaplastic component.•Although some of the novel variants have marked nucleolar atypia, the nucleolar grading system is only recommended for the assessment of anaplastic areas. The Union for International Cancer Control tumour–node–metastasis staging system should be used (Table 2).Table 2Staging of RCC [Union for International Cancer Control (UICC) tumour–node–metastasis (TNM) classification of malignant tumours [8.Edge S.B. Byrd D.R. Compton C.C. AJCC Cancer Staging Handbook. 7th edition. Springer, New York, NY2010Google Scholar]TPrimary tumourTXPrimary tumour cannot be assessedT0No evidence of primary tumourT1Tumour ≤7 cm in greatest dimension, limited to the kidney T1aTumour ≤4.0 cm T1bTumour >4.0 cm but ≤7.0 cmT2Tumour >7.0 cm in greatest dimension, limited to the kidney T2aTumour >7 cm but ≤10 cm T2bTumour >10 cm, limited to the kidneyT3Tumour extends to major veins or peri-nephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota's fascia T3aTumour grossly extends into the renal vein or its segmental (muscle-containing) branches, or tumour invades peri-renal and/or renal sinus fat (peri-pelvic) but not beyond Gerota's fascia T3bTumour grossly extends into the vena cava below the diaphragm T3cTumour grossly extends into the vena cava above the diaphragm or invades the wall of the vena cavaT4Tumour invades beyond Gerota's fascia (including contiguous extension into the ipsilateral adrenal gland)NRegional lymph nodesNXRegional lymph nodes cannot be assessedN0No regional lymph node metastasisN1Metastasis in regional lymph node(s)MDistant metastasescM0Clinically no distant metastasiscM1Clinically distant metastasispM1Pathologically proven distant metastasis, e.g. needle biopsyStage grouping Stage IT1N0M0 Stage IIT2N0M0T3AnyM0 Stage IIIT1–3N1M0T4AnyM0 Stage IVAnyAnyM1Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com. Open table in a new tab Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com. RCC is recognised as having a very variable natural history. Risk assessment models have been developed to provide prognostic information for patients and to inform the eligibility and risk stratification designs of clinical trials. Two systems can be used to assess the risk of progression in localised tumours: the stage, size grade and necrosis (SSIGN) score [9.Leibovich B.C. Blute M. Cheville J.C. et al.Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.Cancer. 2003; 97: 1663-1671Crossref PubMed Scopus (557) Google Scholar] and the University of California Los Angeles Integrated Staging System (UISS) [10.Patard J.J. Kim H.L. Lam J.S. et al.Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study.J Clin Oncol. 2004; 22: 3316-3322Crossref PubMed Scopus (290) Google Scholar]. These systems are described in Tables 3 and 4. In SSIGN, risk points are accumulated as noted in Table 3 and added up to provide a risk score.Table 3Stage, size grade and necrosis (SSIGN) score for localised RCCFeatureScorePathological T category of primary tumour (TNM 2002)pT1a0pT1b2pT23pT3a–44Regional lymph node status (TNM 2002)pNx or pN00pN1 or pN22Tumour size (cm)<100≥101Nuclear grade1 or 203143Histological tumour necrosisNo0Yes1ScoresGroup5-year metastasis-free survival (%)0–2Low risk97.13–5Intermediate risk73.8≥6High risk31.2Reprinted from [9.Leibovich B.C. Blute M. Cheville J.C. et al.Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.Cancer. 2003; 97: 1663-1671Crossref PubMed Scopus (557) Google Scholar] with permission of John Wiley & Sons, Inc. Open table in a new tab Table 4University of California Los Angeles Integrated Staging System (UISS) risk groups and 5-year disease-specific survivalPatient groupPrognostic groupT stageFuhrman's gradeECOG status5-year disease-specific survival (%)Localized disease (N0, M0)Low risk11–2091.1Intermediate risk11–21 or more80.413–4Any2AnyAny31Any32–4AnyHigh32–41 or more54.74AnyAnyMetastatic diseaseLow riskN1M0AnyAny32N2M0/M11–20Intermediate riskN2M0/M11–21 or more19.530, 1 or more40HighN2M0/M141 or more0From: Renal Cancer by Tim Eisen (2010), Chapter 3 ‘Assessment of treatment options in renal cancer’ by Martin Gore & Sheeba Irshad, pp. 19–35 Table 3.1 from p. 22. By permission of Oxford University Press. Open table in a new tab Reprinted from [9.Leibovich B.C. Blute M. Cheville J.C. et al.Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.Cancer. 2003; 97: 1663-1671Crossref PubMed Scopus (557) Google Scholar] with permission of John Wiley & Sons, Inc. From: Renal Cancer by Tim Eisen (2010), Chapter 3 ‘Assessment of treatment options in renal cancer’ by Martin Gore & Sheeba Irshad, pp. 19–35 Table 3.1 from p. 22. By permission of Oxford University Press. The SSIGN score compared favourably with the UISS score in predictive accuracy in a series of patients who had surgically resected clear-cell RCC. On the other hand, the UISS provides prognostic predictions for both localised and metastatic disease. Further prospective data will be available from the current adjuvant trials for patients with high and intermediate risk RCC. Prognostic models were first built when immunotherapy was the standard therapy. The Memorial Sloane Kettering Cancer Centre (MSKCC) or Motzer score was the standard system. The MSKCC score has now been validated and updated for use in the current era of targeted therapies as the Heng or International Metastatic RCC Database Consortium (IMDC) criteria [11.Heng D.Y. Xie W. Regan M.M. et al.Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.J Clin Oncol. 2009; 27: 5794-5799Crossref PubMed Scopus (1453) Google Scholar]. Patients are stratified according to the presence of six risk factors:•Karnofsky performance status (PS) <80%•Haemoglobin <lower limit of normal•Time from diagnosis to treatment of <1 year•Corrected calcium above the upper limit of normal•Platelets greater than the upper limit of normal•Neutrophils greater than the upper limit of normal The number of risk factors present is added up and the risk is stratified as follows:Tabled 1Number of risk factorsRisk groupMedian overall survival (OS), months2-year OS (%)0Favourable43751–2Intermediate27533–6Poor8.8 7 Open table in a new tab This prognostic model has been recently validated also in second line. It should be noted that work continues to improve risk score models. Although there are many potential biomarkers under investigation, none has yet been validated for general use in the prognostic or predictive assessment of RCC. It is notable that multiple series have suggested that the presence of PBRM1 mutations confer a favourable prognosis, whilst mutations of BAP1 confer a poor prognosis. The small proportion of patients whose tumours exhibited both BAP1 and PBRM1 mutations had the worst survival of all [12.Kapur P. Peña-Llopis S. Christie A. et al.Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation.Lancet Oncol. 2013; 14: 159-167Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar]. Partial nephrectomy is recommended as the preferred option in organ confined tumours measuring up to 7 cm (elective indication). Partial nephrectomy can be performed via open, laparoscopic or coelioscopic robot-assisted approaches. In patients with compromised renal function, solitary kidney or bilateral tumours, partial nephrectomy is also the standard of care, with no tumour size limitation (imperative indication). Laparoscopic radical nephrectomy is recommended if partial nephrectomy is not technically feasible [13.MacLennan S. Imamura M. Lapitan M.C. UCAN Systematic Review Reference Group; EAU Renal Cancer Guideline Panel et al.Systematic review of oncological outcomes following surgical management of localised renal cancer.Eur Urol. 2012; 61: 972-993Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar]. Radio frequency or cryoablative treatments are options in patients with small cortical tumours (≤3 cm), especially for patients who are frail, present a high surgical risk, and those with a solitary kidney, compromised renal function, hereditary RCC or multiple bilateral tumours. Long-term oncological results are now available with low recurrence rates and excellent cancer-specific survival [14.Psutka S.P. Feldman A.S. McDougal W.S. et al.Long-term oncologic outcomes after radiofrequency ablation for T1 renal cell carcinoma.Eur Urol. 2013; 63: 486-492Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar]. Active surveillance is an option in elderly patients, with significant comorbidities, or those with a short life expectancy and solid renal tumours measuring <40 mm with emerging new data about tumour growth rate [15.Jewett M.A. Mattar K. Basiuk J. et al.Active surveillance of small renal masses: progression patterns of early stage kidney cancer.Eur Urol. 2011; 60: 39-44Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar]. Laparoscopic radical nephrectomy is the preferred option. Open radical nephrectomy remains the standard of care even though laparoscopic approach can be considered. Systematic adrenalectomy or extensive lymph node dissection is not recommended when abdominal CT shows no evidence of adrenal or lymph node invasion. There is no recommended adjuvant treatment, although at least four tyrosine kinase inhibitor (TKI)-based adjuvant trials have been now completed. Results will not be available before 2015. Neoadjuvant approaches are still experimental, especially for resectable tumours, and should not be routinely proposed outside of clinical trials. Many studies have demonstrated that such approaches are relatively safe, with modest median tumour downsizing and no proven benefit in terms of disease-free survival. See Table 5.Table 5Summary of recommendations for the treatment of localised and locally advanced RCCRecommendationLevel and grade of recommendationsPartial nephrectomy is recommended for the treatment of all T1 tumours if negative margins are obtained and risk of morbidity is acceptable.III, CLaparoscopic radical nephrectomy is the preferred option for the treatment of organ confined RCC (stages T1T2N0N×M0) when partial nephrectomy is not feasible.II, BRoutine adrenalectomy and lymph node dissection are not required for all radical nephrectomies.III, DOpen radical nephrectomy with the goal of obtaining negative margins is still the standard of care for locally advanced RCC.III, CAblative treatments are options in: patients with small cortical tumours (≤3 cm) and age >70 years, high surgical risk, solitary kidney, compromised renal function, hereditary RCC or multiple bilateral tumours.III, CActive surveillance is an option in patients ≥75 years, with significant comorbidities and solid renal tumours measuring <40 mm.III, C Open table in a new tab In the era of immunotherapy, cytoreductive nephrectomy was recommended in patients with good PS [I, A] [16.Flanigan R.C. Mickisch G. Sylvester R. et al.Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis.J Urol. 2004; 171: 1071-1076Crossref PubMed Scopus (675) Google Scholar]. Whether this recommendation will remain with current targeted therapies is currently being investigated in two prospective trials. In routine practice, cytoreductive nephrectomy is recommended in patients with good PS and large primary tumours with limited volumes of metastatic disease, and for patients with a symptomatic primary lesion. Cytoreductive nephrectomy is not recommended in patients with poor PS. Metastasectomy can be considered and performed after multidisciplinary review for selected patients with solitary or easily accessible pulmonary metastases, solitary resectable intra-abdominal metastases, a long disease-free interval after nephrectomy, or a partial response in metastases to immunotherapy or targeted therapy. Recent retrospective and nonrandomised studies of patients with metastatic RCC (mRCC) have demonstrated a prolonged median survival in those with metachronous lung metastases and an interval of at least 2 years [17.Karam J.A. Rini B.I. Varella L. et al.Metastasectomy after targeted therapy in patients with advanced renal cell carcinoma.J Urol. 2011; 185: 439-444Crossref PubMed Scopus (104) Google Scholar]. Metastasectomy may provide a possible survival benefit for a select group of patients with lung metastases only, a long metachronous disease-free interval and a response to immunotherapy/targeted therapy before resection. No systemic treatment is recommended after metastasectomy. Recommendations mainly relate to clear-cell histology, since most of the pivotal trials have been done in this common histological subtype (Table 6). In addition, recommendations will differ according to risk stratification (see above). It should be emphasised that many of the pivotal trials (such as Temsirolimus phase 3, RECORD-1 or COMPARZ) have flaws, and have raised questions, but can lead to well-accepted recommendations.Table 6Algorithm for systemic treatment in mRCCHistology and settingRisk groupStandardOptionClear-cell first lineGood or intermediate riskSunitinib [I, A]High-dose IL2 [III, C]Bevacizumab + IFN-α [I, A]Sorafenib [II, B]Pazopanib [I, A]Bevacizumab + low-dose IFN-α [III, A]Poor riskTemsirolimus [II, A]Sunitinib [II, B]Sorafenib [III, B]Clear-cell second linePost cytokinesAxitinib [I, A]Sunitinib [III, A]Sorafenib [I, A]Pazopanib [II, A]Post TKIsAxitinib [I, B]Sorafenib [II, A]Everolimus [II, A]Clear-cell third linePost 2 TKIsEverolimus [II, A]Post TKI and mTORSorafenib [I, B]Other TKI [IV, B]Rechallenge [IV, B]Non-clear-cell histologyTemsirolimus [III, B]Sunitinib [III, B]Sorafenib [III, B] Open table in a new tab Because some RCC have a very indolent course, a period of observation before starting treatment should be considered, especially in patients with limited tumour burden and few symptoms. Indeed, the outcome of patients who crossed over to an active agent after a brief period of treatment with placebo, within placebo-controlled phase III trials, indirectly supports this option [II, C]. Three treatments have demonstrated efficacy in pivotal phase 3: bevacizumab [combined with interferon-alpha (IFN-α)], sunitinib and pazopanib [18.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: 2103-2111Abstract Full Text Full Text PDF PubMed Scopus (1999) Google Scholar, 19.Motzer R. Hutson T.E. Tomczak P. et al.Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.N Engl J Med. 2007; 356: 115-124Crossref PubMed Scopus (4970) Google Scholar, 20.Sternberg C.N. Davis I.D. Mardiak J. et al.Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial.J Clin Oncol. 2010; 28: 1061-1068Crossref PubMed Scopus (2024) Google Scholar]. All three drugs have been registered based on improvement of progression-free survival (PFS) over either IFN-α or placebo. More recently, pazopanib has been shown not to be inferior to sunitinib in a large phase III trial [21.Motzer R.J. Hutson T.E. Cella D. et al.Pazopanib versus sunitinib in metastatic renal-cell carcinoma.N Engl J Med. 2013; 369: 722-731Crossref PubMed Scopus (1335) Google Scholar]. Considering all published trials, the level of recommendation for these three options is considered to be [I, A] for all three regimens. Sorafenib [II, B], high-dose interleukin-2 [III, C] and low-dose IFN-α combined with bevacizumab [III, A] are options. Single-agent IFN-&agr;, the losing arm of three randomised, controlled trials, should no longer be regarded as a standard option [I, D]. Temsirolimus is currently the only drug with level I evidence of activity in this patient population [II, A] [22.Hudes G. Carducci M. Tomczak P. et al.Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.N Engl J Med. 2007; 356: 2271-2281Crossref PubMed Scopus (3228) Google Scholar]. The pivotal trial demonstrated improvement of OS compared with IFN-α or combination of temsirolimus and IFN-α. Based on subgroup analysis from the pivotal trial as well as expanded access programmes, sunitinib is another reasonable option in this setting [II, B]. Sorafenib based on expanded access programmes is another possible alternative [III, B]. It is clear that, for some poor prognosis patients, best supportive care remains the only suitable treatment option. •Evidence that TKIs are active after cytokines has been demonstrated with sorafenib [I, A], pazopanib [II, A] and recently axitinib [I, A] [20.Sternberg C.N. Davis I.D. Mardiak J. et al.Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial.J Clin Oncol. 2010; 28: 1061-1068Crossref PubMed Scopus (2024) Google Scholar, 23.Escudier B. Eisen T. Stadler W.M. et al.Sorafenib in advanced clear-cell renal-cell carcinoma.N Engl J Med. 2007; 356: 125-134Crossref PubMed Scopus (4282) Google Scholar, 24.Rini B.I. Escudier B. Tomczak P. et al.Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.Lancet. 2011; 378: 1931-1939Abstract Full Text Full Text PDF PubMed Scopus (1489) Google Scholar]. Sunitinib also has activity in this setting [III, A]. However, since VEGF-targeted therapy is now the first-line standard of care, the number of patients treated with cytokines is decreasing.•After first-line treatment with VEGF-targeted therapy○Both axitinib [I, B] and everolimus [II, A] are active [24.Rini B.I. Escudier B. Tomczak P. et al.Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised p