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

      Incidence and epidemiology

      Kidney cancer accounts for 5% and 3% of all adult malignancies in men and women, respectively, thus representing the 7th most common cancer in men, and the 10th most common cancer in women [
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics.
      ]. However, available statistics include not only renal parenchymal tumours, but also urothelial cancer of the renal pelvis; renal cell carcinoma (RCC) accounts for ∼80% of all kidney cancers.
      After over two decades of increasing rates, RCC incidence trends worldwide have shown signs of plateauing in recent years. Furthermore, kidney cancer mortality rates overall have levelled. These patterns are consistent with reports of incidental diagnosis and downward shift of tumour stage and size; indeed, the widespread use of non-invasive radiological techniques [e.g. ultrasonography (US), computed tomography (CT)], allows the frequent detection of early and small RCCs, which are potentially curable.
      Beyond well-known risk factors for RCC, such as cigarette smoking, obesity and hypertension, evidence is accumulating to suggest an aetiological or, on the contrary, a protective role, for additional factors [
      • Chow W.H.
      • Dong L.M.
      • Devesa S.S.
      Epidemiology and risk factors for kidney cancer.
      ], such as trichloroethylene. In a recently published case–control study of 699 RCC patients and 1001 frequency-matched controls, consumption of caffeinated coffee was found to be associated with reduced risk of RCC; interestingly, decaffeinated coffee was associated with an increased risk for aggressive clear cell RCC (ccRCC) [
      • Antwi S.O.
      • Eckel-Passow J.E.
      • Diehl N.D.
      • et al.
      Coffee consumption and risk of renal cell carcinoma.
      ].
      Furthermore, RCC also appears to be more common in patients with end-stage renal failure or acquired renal cystic disease, and in patients on dialysis, those who have had kidney transplantation or those with tuberous sclerosis syndrome.
      Approximately 2%–3% of all RCCs 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 (VHL) disease. Patients with multiple and bilateral lesions and/or other related disorders should be tested for these germline mutations since it is important that they are recognised.

      Diagnosis and pathology/molecular biology

      As stated above, >50% of RCCs are currently detected incidentally, making the classical triad of flank pain, gross haematuria and palpable abdominal mass less frequent than in the past. Despite this, RCC remains the ‘Internist’s cancer’ with paraneoplastic syndromes such as hypercalcaemia, unexplained fever, erythrocytosis and Stauffer’s syndrome (signs of cholestasis unrelated to tumour infiltration of the liver or intrinsic liver disease, which typically resolve after kidney tumour resection) still being relatively frequent.
      Suspicion of RCC should prompt laboratory examinations of serum creatinine, haemoglobin, leukocyte and platelet counts, lymphocyte to neutrophil ratio, lactate dehydrogenase, C-reactive protein (CRP) and serum-corrected calcium [IV, B]. Some of these tests are prognostic for survival and are used for risk assessment within different prognostic score systems (see Staging and risk assessment section).
      Most cases of RCC are strongly suspected by imaging. Diagnosis is usually suggested by US and further investigated by CT scan, which allows for assessment of local invasiveness, eventual lymph node involvement or distant metastases. Magnetic resonance imaging (MRI) may provide additional information in investigating local advancement and venous involvement by tumour thrombus.
      For accurate staging of RCC, contrast-enhanced chest, abdominal and pelvic CT is mandatory [III, A]; unless indicated by clinical or laboratory signs or symptoms, the use of bone scan or brain CT (or MRI) is not recommended for routine clinical practice [III, A]. In case of an allergy to CT contrast agent or renal insufficiency, adequate staging should include a high-resolution CT scan of the chest without contrast agent, together with an abdominal MRI. Fluorodeoxyglucose positron emission tomography (FDG-PET) is not a standard investigation in the diagnosis and staging of ccRCC and should not be used. The role of new tracers is under investigation.
      A renal tumour core biopsy provides histopathological confirmation of malignancy with high sensitivity and specificity; it is especially recommended before treatment with ablative therapies [III, B] as well as in patients with metastatic disease before starting systemic treatment [III, B]. Complications (e.g. bleeding or tumour seeding) are rare or even exceptional (as in the case of tumour seeding) [
      • Volpe A.
      • Kachura J.R.
      • Geddie W.R.
      • et al.
      Techniques, safety and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy.
      ], while diagnostic accuracy remains high [
      • Marconi L.
      • Dabestani S.
      • Lam T.B.
      • et al.
      Systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy.
      ]. The final histopathological diagnosis, classification, grading and evaluation of prognostic factors are based on the nephrectomy specimen when available.

       Pathology assessment

      The last edition of the World Health Organization (WHO) histological classification of renal tumours has been reported in 2016 (Table 1), and was based on tumour histology, chromosomal alterations and molecular pathways [
      • Moch H.
      • Cubilla A.L.
      • Humphrey P.A.
      • et al.
      The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.
      ].
      Table 1WHO 2016 classification of renal cell tumours
      Reprinted with permission from [
      • Moch H.
      • Cubilla A.L.
      • Humphrey P.A.
      • et al.
      The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.
      ].
      Clear cell renal cell carcinoma
      Multilocular cystic renal neoplasm of low malignant potential
      Papillary renal cell carcinoma
      Hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma
      Chromophobe renal cell carcinoma
      Collecting duct carcinoma
      Renal medullary carcinoma
      MiT family translocation renal cell carcinomas
      Succinate dehydrogenase-deficient renal cell carcinoma
      Mucinous tubular and spindle cell carcinoma
      Tubulocystic renal cell carcinoma
      Acquired cystic disease-associated renal cell carcinoma
      Clear cell papillary renal cell carcinoma
      Renal cell carcinoma, unclassified
      Papillary adenoma
      Oncocytoma
      MiT, microphthalmia-associated transcription factor; WHO, World Health Organization.
      ccRCCs represent 80% of malignant renal tumours in adults, with the remaining 20% corresponding to several histological subtypes with different histological, molecular and cytogenetic profiles [
      • Hsieh J.J.
      • Purdue M.P.
      • Signoretti S.
      • et al.
      Renal cell carcinoma.
      ]. Papillary and chromophobe RCCs account for 80% of non-ccRCCs.
      Papillary RCCs which represent a heterogeneous disease are characterised by:
      • type 1 RCCs more frequently associated to MET or epidermal growth factor receptor (EGFR) mutations and
      • type 2 RCCs often unique tumours with an aggressive phenotype that are associated with SETD2 mutations, CDKN2A mutations or TFE3 fusions [
        • Linehan W.M.
        • Spellman P.T.
        • et al.
        Cancer Genome Atlas Research Network
        Comprehensive molecular characterization of papillary renal-cell carcinomas.
        ].
      In papillary type 2 with familial history of papillary RCC, a fumarate hydratase (FH) mutation should also be investigated.
      The main goal in diagnosis of chromophobe RCC, especially in the eosinophilic histological subtype, is the differential diagnosis with oncocytoma. Chromophobe RCCs have diffuse positivity for cytokeratin 7 (CK7), whereas oncocytomas are negative or present focal positivity for CK7. Moreover, chromophobe RCCs display more frequent chromosome loss but fewer somatic mutations. The most frequently mutated gene is tumour suppressor protein 53 (TP53) (32%), and the most frequent oncogenic pathways involved in such tumours are mammalian target of rapamycin (mTOR) pathways (23%), including alterations of phosphatase and tensin homologue (PTEN) [
      • Davis C.F.
      • Ricketts C.J.
      • Wang M.
      • et al.
      The somatic genomic landscape of chromophobe renal cell carcinoma.
      ].
      Microphthalmia-associated transcription factor (MiT) family translocation RCCs (tRCCs) must be ruled out in young patients under the age of 40 years, if papillary architecture or complex architecture with clear cells and/or epithelioid cells or psammoma bodies are present. The diagnosis is based on the use of both immunohistochemistry and fluorescent in situ hybridisation (FISH) analysis to demonstrate the presence of TFE3/TFEB rearrangement. Recently, Argani et al. reported cases of TFEB-amplified RCCs that occur in older patients. These tumours presented high-grade eosinophilic cells with necrosis and papillary or pseudopapillary architecture. The expression of melanocytic markers is variable and FISH analyses revealed high levels of TFEB gene amplification. The prognosis of such tumours is poor with usually advanced stage and metastatic outcome [
      • Argani P.
      • Reuter V.E.
      • Zhang L.
      • et al.
      TFEB-amplified renal cell carcinomas: an aggressive molecular subset demonstrating variable melanocytic marker expression and morphologic heterogeneity.
      ].
      Collecting duct carcinoma (CDC) or Bellini duct carcinoma remains a highly aggressive RCC arising from the renal collecting tubules. A recent specific gene expression signature showed that CDC appears to be a unique entity among kidney cancers [
      • Becker F.
      • Junker K.
      • Parr M.
      • et al.
      Collecting duct carcinomas represent a unique tumor entity based on genetic alterations.
      ]. Moreover, these tumours are characterised by an immune profile with an average of 22% of tumour-infiltrating lymphocytes [
      • Malouf G.G.
      • Compérat E.
      • Yao H.
      • et al.
      Unique transcriptomic profile of collecting duct carcinomas relative to upper tract urothelial carcinomas and other kidney carcinomas.
      ].
      The prognostic factors validated by the International Society of Urological Pathology (ISUP) consensus and the WHO 2016 classification of RCC to be reported in routine practice are [
      • 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.
      ]:
      • the tumour histological subtype;
      • the ISUP nucleolar grade (instead of the previous Fuhrman grade) that is only applicable to ccRCC and papillary RCC;
      • a sarcomatoid and/or rhabdoid differentiation that defines a grade 4 tumour;
      • the presence of necrosis;
      • the presence of microscopic vascular invasion;
      • the pathological tumour, node and metastasis (pTNM) staging and
      • description of the non-neoplastic renal tissue.

       Biology

      Beyond the classical one gene–one histology paradigm, a more complex biological classification of RCC (and especially of its clear cell histotype) is emerging [
      • Brugarolas J.
      Molecular genetics of clear-cell renal cell carcinoma.
      ].
      First, RCC proved to be an extremely heterogeneous disease [
      • Gerlinger M.
      • Rowan A.J.
      • Horswell S.
      • et al.
      Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.
      ]; beyond the seminal genetic alteration (mutation, deletion or hypermethylation) of the VHL tumour suppressor gene, which is present in the vast majority of sporadic RCCs, other genetic alterations may occur, especially over time [
      • Gerlinger M.
      • Horswell S.
      • Larkin J.
      • et al.
      Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing.
      ], contributing to worsen the prognosis of patients harbouring these tumours. Notably, three of these other genes (PBRM1, BAP1 and SETD2) are located on the same short arm of chromosome 3 where the VHL gene is also located.
      On the contrary, some RCCs are characterised by mutations in the mTOR pathway, and especially in the highly conserved FAT (FRAP, ATM, TTRAP) and kinase domains of the MTOR gene; these cancers have been defined as metabolic RCCs [
      • Hakimi A.A.
      • Pham C.G.
      • Hsieh J.J.
      A clear picture of renal cell carcinoma.
      ].
      Finally, according to another comprehensive molecular characterisation of papillary RCCs, type 1 and type 2 papillary RCCs were shown to be clinically and biologically distinct. Alterations in the MET pathway were indeed associated with type 1 and activation of the NRF2-ARE pathway was associated with type 2, while CDKN2A loss and a CpG island methylator phenotype in type 2 contributed to convey a poor prognosis [
      • Linehan W.M.
      • Spellman P.T.
      • et al.
      Cancer Genome Atlas Research Network
      Comprehensive molecular characterization of papillary renal-cell carcinomas.
      ].

      Staging and risk assessment

       Staging

      The Union for International Cancer Control (UICC) tumour, node and metastasis (TNM) 8 staging system should be used [
      ] (Table 2).
      Table 2UICC TNM 8 staging of RCC [
      ]
      Reprinted from [
      ] with permission from John Wiley & Sons, Inc.
      • T—primary tumour
      • TX Primary tumour cannot be assessed
      • T0 No evidence of primary tumour
      • T1 Tumour 7 cm or less in greatest dimension, limited to the kidney
      •   T1a Tumour 4 cm or less
      •   T1b Tumour more than 4 cm but not more than 7 cm
      • T2 Tumour more than 7 cm in greatest dimension, limited to the kidney
      •   T2a Tumour more than 7 cm but not more than 10 cm
      •   T2b Tumour more than 10 cm, limited to the kidney
      • T3 Tumour extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia
      •   T3a Tumour extends into the renal vein or its segmental branches, or tumour invades the pelvicalyceal system or tumour invades perirenal and/or renal sinus fat (peripelvic) fat but not beyond Gerota fascia
      •   T3b Tumour extends into vena cava below diaphragm
      •   T3c Tumour extends into vena cava above the diaphragm or invades the wall of the vena cava
      • T4 Tumour invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)
      • N—regional lymph nodes
      • NX Regional lymph nodes cannot be assessed
      • N0 No regional lymph node metastasis
      • N1 Metastasis in regional lymph node(s)
      • M—distant metastasis
      • M0 No distant metastasis
      • M1 Distant metastasis
      • pTNM pathological classification
        The pT and pN categories correspond to the T and N categories.
      • Stage
      • Stage I T1 N0 M0
      • Stage II T2 N0 M0
      • Stage III T3 N0 M0
      •    T1, T2, T3 N1 M0
      • Stage IV T4 Any N M0
      •   Any T Any N M1
      pTNM, pathological tumour, node, metastasis; RCC, renal cell carcinoma; TNM, tumour, node, metastasis; UICC, Union for International Cancer Control.
      a The pT and pN categories correspond to the T and N categories.

       Risk assessment

      The natural clinical course varies in RCC, which has led to the development of different prognostic models for the assessment of the patient’s individual risk. Extent of disease, histology, grading and clinical factors have been recognised as having prognostic value in RCC and may be used in localised or in metastatic disease [
      • Moch H.
      • Cubilla A.L.
      • Humphrey P.A.
      • et al.
      The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.
      ].

       Localised disease

      Different pre- or post-operative scores have been developed to assess prognosis in RCC, and are used for risk-adapted follow-up strategies. Integrated prognostic scores offer some predictive advantages over single tumour characteristics and are used preferentially. These models are composed of histological and clinical factors. The most recent modifications of the stage, size, grade and necrosis (SSIGN) score [
      • Leibovich B.C.
      • Blute M.L.
      • 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.
      ] (Table 3) and the University of California Los Angeles Integrated Staging System (UISS) (Table 4) [
      • 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.
      ] score are frequently used.
      Table 3SSIGN score for localised RCC [
      • Leibovich B.C.
      • Blute M.L.
      • 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.
      ]
      Adapted from [
      • Leibovich B.C.
      • Blute M.L.
      • 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.
      ], with permission from John Wiley & Sons, Inc.
      FeatureScore
      Pathological T category of primary tumour (as per 2002 TNM staging)pT1a0
      pT1b2
      pT23
      pT3a-pT3c4
      pT44
      Regional lymph node status (as per 2002 TNM staging)pNx or pN00
      pN1 or pN22
      Tumour size<10 cm0
      10 cm or more1
      Nuclear grade1 or 20
      31
      43
      Histological tumour necrosisNo0
      Yes1
      ScoresGroup5-year metastasis- free survival rate (%)
      0–2Low risk97.1
      3–5Intermediate risk73.8
      6 or moreHigh risk31.2
      RCC, renal cell carcinoma; SSIGN, size, stage, grade and necrosis; TNM, tumour, node, metastasis.
      Table 4UISS risk groups and 5-year disease-specific survival [
      • 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.
      ]
      Reprinted from [
      • 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.
      ] with permission. © 2004 American Society of Clinical Oncology. All rights reserved.
      Patient groupPrognostic group
      T stageFuhrman gradeECOG status5-year disease-specific survival (%)
      Localised disease (N0, M0)Low risk11–2091.1
      Intermediate risk11–21 or more80.4
      13–4Any
      2AnyAny
      31Any
      32–4Any
      High32–41 or more54.7
      4AnyAny
      Metastatic diseaseLow riskN1M0AnyAny32
      N2M0/M11–20
      Intermediate riskN2M0/M11–21 or more19.5
      30, 1 or more
      40
      HighN2M0/M141 or more0
      ECOG, Eastern Cooperative Oncology Group; UISS, University of California Los Angeles Integrated Staging System.
      However, among different prognostic scores, a concordance of 0.68–0.89 for cancer-specific survival (CSS) and 0.74–0.82 for recurrence-free survival (RFS) was reported [
      • Sun M.
      • Shariat S.F.
      • Cheng C.
      • et al.
      Prognostic factors and predictive models in renal cell carcinoma: a contemporary review.
      ], indicating that a plateau has been reached for prognostication with available models. Hence, no clear preference for a specific prognostic model may be given.

       Advanced disease

      The Memorial Sloan Kettering Cancer Center (MSKCC) system was the gold standard for the risk assessment during cytokine treatment in metastatic RCC (mRCC) [
      • Motzer R.J.
      • Mazumdar M.
      • Bacik J.
      • et al.
      Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma.
      ], and it is still commonly used. Further refinement was introduced with the International Metastatic RCC Database Consortium (IMDC) score, which extended the previous factors to a total number of six in order to increase concordance [
      • Ko J.J.
      • Xie W.
      • Kroeger N.
      • et al.
      The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study.
      ]:
      • Karnofsky performance status (PS) <80%;
      • haemoglobin level below the lower limit of normal;
      • time from diagnosis to treatment <1 year;
      • corrected calcium above the upper limit of normal;
      • platelets greater than the upper limit of normal and
      • neutrophils greater than the upper limit of normal.
      A recent evaluation of this model in second-line treatment underscored its predictive value in previously treated mRCC [
      • 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.
      ] (Table 5). Interestingly, this model is also applicable in further lines of therapy as well as in non-clear cell histology.
      Table 5Median OS estimates in first- and second-line RCC according to IMDC risk groups
      Number of risk factorsRisk categoryMedian OS (months)
      First line [
      • 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.
      ]
      Second line [
      • Ko J.J.
      • Xie W.
      • Kroeger N.
      • et al.
      The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study.
      ]
      0Favourable43.235.3
      1–2Intermediate22.516.6
      3–6Unfavourable7.85.4
      IMDC, International Metastatic RCC Database Consortium; OS, overall survival; RCC, renal cell carcinoma.

       Molecular prognostication and biomarkers

      Gene signatures can be used to detect different risk groups in RCC. ClearCode34 is a 34-gene expression panel that proved able to classify ccRCC into two subtypes, clear cell A (ccA) and clear cell B (ccB), significantly associated with relapse-free survival and CSS, as well as overall survival (OS) [
      • Brooks S.A.
      • Brannon A.R.
      • Parker J.S.
      • et al.
      ClearCode34: a prognostic risk predictor for localized clear cell renal cell carcinoma.
      ]. Another gene signature, based on a 16-gene assay, was shown to improve prediction of RFS in localised RCC when compared with the SSIGN score according to the Leibovich score (concordance: 0.81 versus 0.74) [
      • Rini B.
      • Goddard A.
      • Knezevic D.
      • et al.
      A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies.
      ].
      Some gene mutations have also been reported as prognostic. The University of Texas Southwestern group identified distinct clinical outcomes in mutation-defined subtypes of ccRCC: a high-risk BAP1-mutant group and a favourable PBRM1-mutant group [
      • 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.
      ]. Notably, 80% of patients from both the development and the validation cohorts had localised (or locoregional) disease.
      In the metastatic setting, the immunohistochemical expression of programmed death ligand 1 (PD-L1) is presently under the spotlight, although the results available so far are still controversial. In 2016, a systematic review and meta-analysis of 6 studies and 1323 cases clearly demonstrated a negative prognostic role of elevated level of PD-L1 tumour expression in RCC [
      • Iacovelli R.
      • Nolè F.
      • Verri E.
      • et al.
      Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis.
      ], although discrepancies between PD-L1 expression between the primary tumour and the metastases have been reported. A possible predictive value of PD-L1 expression remains controversial, although recently, PD-L1 tumour expression was shown to be able to identify patients benefiting from a combination of two immune-checkpoint inhibitors [
      • Motzer R.J.
      • Tannir N.M.
      • McDermott D.F.
      • et al.
      Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.
      ]. In addition, angiogenesis, T-effector/interferon (IFN)-γ response and myeloid inflammatory gene expression signatures have been suggested to predict response to vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) and immunotherapy [
      • McDermott D.F.
      • Huseni M.A.
      • Atkins M.B.
      • et al.
      Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.
      ]. As a whole, PD-L1 expression should not be routinely used but is a putative biomarker for future treatment selection because of remaining unanswered issues related to the different tests and cut-offs used, to the cells where PD-L1 expression should be checked and to the role of PD-L1 expression heterogeneity (e.g. between different primary tumour sites, or between primary tumour and its metastases).
      Other putative markers such as circulating DNA, microRNA or DNA methylation status were shown to have prognostic relevance in RCC and warrant future investigation. Overall, these data indicate that molecular analysis may provide additional benefit to already established clinical and histo-anatomical parameters, which may lead to an individual risk assessment in the future. Currently, no specific molecular marker can be recommended for clinical use.

      Management of local/locoregional disease

       Role of surgery and local therapy

       T1 tumours (<7 cm)

      Partial nephrectomy (PN) is recommended as the preferred option in organ-confined tumours measuring up to 7 cm (elective indication). This is based on a systematic review including multiple retrospective studies and a prospective, randomised controlled trial (RCT) which compared radical nephrectomy (RN) with PN in solitary T1a-b N0M0 renal tumours <5 cm with normal contralateral kidney function [I, A] [
      • MacLennan S.
      • Imamura M.
      • Lapitan M.C.
      • et al.
      Systematic review of oncological outcomes following surgical management of localised renal cancer.
      ].
      PN can be carried out via open, laparoscopic or robot-assisted laparoscopic approaches. Laparoscopic RN is recommended if PN is not technically feasible. In patients with compromised renal function, solitary kidney or bilateral tumours, PN is also the standard of care, with no tumour size limitation (imperative indication).
      Systematic reviews comparing surgical management of localised RCC (T1-2N0M0) were unable to identify prospective comparative studies reporting on oncological outcomes for minimally invasive ablative procedures compared with PN [
      • MacLennan S.
      • Imamura M.
      • Lapitan M.C.
      • et al.
      Systematic review of oncological outcomes following surgical management of localised renal cancer.
      ].
      Radiofrequency ablation (RFA), microwave ablation (MWA) or cryoablation (CA) 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. Renal biopsy is recommended to confirm malignancy and subtype in this setting.
      Systematic reviews of RFA and PN suggest a long-term CSS for RFA, equal to PN with a low metastasis rate but slightly higher local recurrence rate compared with PN and CA [
      • MacLennan S.
      • Imamura M.
      • Lapitan M.C.
      • et al.
      Systematic review of oncological outcomes following surgical management of localised renal cancer.
      ]. The quality of the available evidence prevents definitive conclusions regarding morbidity and oncological outcomes for RFA and CA [III].
      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. The growth of renal tumours (mean 3 mm/year) is low in most cases and progression to metastatic disease is reported in 1%–2% [
      • Jewett M.A.
      • Mattar K.
      • Basiuk J.
      • et al.
      Active surveillance of small renal masses: progression patterns of early stage kidney cancer.
      ]. Renal biopsy is recommended to select patients with small masses for active surveillance [III] with high accuracy, especially because of the incidence of non-malignant tumours in this setting [
      • Volpe A.
      • Kachura J.R.
      • Geddie W.R.
      • et al.
      Techniques, safety and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy.
      ,
      • Marconi L.
      • Dabestani S.
      • Lam T.B.
      • et al.
      Systematic review and meta-analysis of diagnostic accuracy of percutaneous renal tumour biopsy.
      ].

       T2 tumours (>7 cm)

      Laparoscopic RN is the preferred option.

       Locally advanced RCC (T3 and T4)

      Open RN remains the standard of care, even though a 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.
      The evidence regarding management of venous tumour thrombus is based on retrospective studies with significant risks of bias and confounding. Resection of venous thrombi is challenging and associated with a high risk of complications. Surgical intervention should be considered, but the most effective approach remains unknown and outcome depends on tumour thrombus level [III].

       Adjuvant therapy

      Several RCTs of adjuvant sunitinib (S-TRAC, ASSURE), sorafenib (ASSURE) and pazopanib (PROTECT) have been reported [
      • Haas N.B.
      • Manola J.
      • Uzzo R.G.
      • et al.
      Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.
      ,
      • Ravaud A.
      • Motzer R.J.
      • Pandha H.S.
      • et al.
      Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy.
      ,
      • Motzer R.J.
      • Haas N.B.
      • Donskov F.
      • et al.
      Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma.
      ]. Only S-TRAC was positive for its primary end point, disease-free survival (DFS) by independent review, but without any OS benefit. This result led to approval of sunitinib by the United States Food and Drug Administration (FDA). The European Medicines Agency (EMA) has not approved adjuvant therapy with any of these drugs because of the imbalance between risk and clinical benefit. A recent pooled analysis of S-TRAC, ASSURE and PROTECT did not reveal a statistically significant effect between adjuvant VEGFR-targeted therapy and an improved DFS or OS in patients with intermediate-/high-risk local or regional fully resected RCC [
      • Sun M.
      • Marconi L.
      • Eisen T.
      • et al.
      Adjuvant vascular endothelial growth factor-targeted therapy in renal cell carcinoma: a systematic review and pooled analysis.
      ]. Improvement in DFS may be more likely with the use of full-dose regimens and in high-risk disease, but adjuvant treatment was associated with high-grade adverse events (AEs).
      Neoadjuvant approaches are experimental and should not be proposed outside of clinical trials. Attempting to downsize venous tumour thrombi with systemic targeted therapy cannot be recommended.

      Management of metastatic disease

       Role of surgery and local therapy

      In the cytokine era, cytoreductive nephrectomy (CN) was recommended in patients with good PS [I, A] [
      • Flanigan R.C.
      • Mickisch G.
      • Sylvester R.
      • et al.
      Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis.
      ]. Two randomised trials (CARMENA and SURTIME) investigated the role and sequence of CN in the era of VEGFR-targeted therapy [
      • Méjean A.
      • Ravaud A.
      • Thezenas S.
      • et al.
      Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma.
      ,
      • Bex A.
      • Mulders P.
      • Jewett M.
      • et al.
      Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial.
      ]. While SURTIME was underpowered, CARMENA demonstrated that upfront CN should no longer be considered the standard of care in MSKCC intermediate- and poor-risk patients with asymptomatic primary tumours when medical treatment is required [I, A]. Upfront CN is associated with morbidity and mortality, and there is no subgroup in these studies in which this approach proved to be superior. Secondary CN in patients with local symptoms due to the primary tumour or near complete responses to systemic therapy remains an option.
      Results of CARMENA and SURTIME should not be used to abandon CN in patients with low volume metastatic disease, a good PS and favourable and intermediate risk, who are candidates for initial observation. In fact, both trials recruited patients with high median metastatic volumes (42% of total tumour burden for CARMENA) who needed to start sunitinib.
      Metastasectomy and other local treatment strategies including whole-brain radiotherapy (WBRT), conventional radiotherapy (RT), stereotactic radiosurgery (SRS), stereotactic body radiotherapy (SBRT), CyberKnife® RT and hypofractionated RT can be considered and carried out for selected patients after multidisciplinary review. A systematic review of 16 studies including 2350 patients sought to identify the evidence base for local treatment strategies of metastases from RCC [
      • Dabestani S.
      • Marconi L.
      • Hofmann F.
      • et al.
      Local treatments for metastases of renal cell carcinoma: a systematic review.
      ]. The results consistently point towards a benefit of complete metastasectomy for OS and CSS, but there is selection bias and the results have to be interpreted with caution. No systemic treatment is recommended after metastasectomy.
      No general guidelines can be given to identify cases to refer for local treatment of metastases. Patient selection should be discussed in a multidisciplinary team. Good PS, solitary or oligometastases, metachronous disease with disease-free interval >2 years, the absence of progression on systemic therapy, low or intermediate Fuhrman grade and complete resection have been associated with favourable outcome after local treatment of metastases from RCC.

       Systemic treatment for ccRCC

      Recommendations mainly relate to clear cell histology, since most of the pivotal trials have been conducted in this common histological subtype. In addition, recommendations will differ according to risk stratification (see above).
      The proper time to start systemic therapy is not well defined. Because of the indolent course of some RCCs, 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]. The safety of observation has been suggested by retrospective studies and confirmed by a prospective study [
      • Rini B.I.
      • Dorff T.B.
      • Elson P.
      • et al.
      Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial.
      ].

       First-line treatment

      An algorithm for first-line systemic treatment in ccRCC is presented in Figure 1. Three vascular endothelial growth factor (VEGF)-targeted agents have demonstrated efficacy in pivotal phase III trials, mostly focused on good and intermediate patients: bevacizumab (combined with IFN), sunitinib and pazopanib [
      • 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.
      ,
      • Motzer R.J.
      • Hutson T.E.
      • Tomczak P.
      • et al.
      Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
      ,
      • 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.
      ]. All three drugs have been registered based on improvement of progression-free survival (PFS) over either IFN or placebo. Furthermore, pazopanib has been shown not to be inferior to sunitinib in a large phase III trial [
      • Motzer R.J.
      • Hutson T.E.
      • Cella D.
      • et al.
      Pazopanib versus sunitinib in metastatic renal-cell carcinoma.
      ]. Efficacy of both sunitinib and pazopanib has been confirmed by real-world evidence studies, and these two TKIs are currently the most commonly used treatments in good- and intermediate-risk patients. In addition, tivozanib, a selective VEGF inhibitor, has been shown to improve PFS and response rate versus sorafenib, especially in good-risk patients [
      • Motzer R.J.
      • Nosov D.
      • Eisen T.
      • et al.
      Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial.
      ], and is EMA-approved for first-line treatment.
      Figure 1
      Figure 1Systemic first-line treatment of ccRCC. aESMO-MCBS scores for new therapies/indications approved by the EMA since 1 January 2016. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. ccRCC, clear cell renal cell carcinoma; EMA, European Medicines Agency; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; IFN, interferon; IL2, interleukin 2; MCBS, Magnitude of Clinical Benefit Scale.
      Temsirolimus has been tested in a phase III study in poor-risk patients only, versus IFN, demonstrating evidence of improved OS in this patient population [
      • Hudes G.
      • Carducci M.
      • Tomczak P.
      • et al.
      Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
      ].
      Recently, a large phase III study demonstrated that the combination of nivolumab and ipilimumab was superior to sunitinib in intermediate- and poor-risk patients, but not in good-risk patients [
      • Motzer R.J.
      • Tannir N.M.
      • McDermott D.F.
      • et al.
      Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.
      ]. In the intermediate- and poor-risk population, the combination improved OS as well as response rate, with a high complete response rate (9.4%). In contrast, both response rates and PFS were higher with sunitinib in the good-risk group.
      In addition to these large phase III trials, some efficacy has been reported with sorafenib, high-dose interleukin-2 (IL2) and low-dose IFN combined with bevacizumab, and such therapies should be considered as possible options when the standard treatments are not available. Similarly, single-agent IFN-α, as the inferior arm of three RCTs, should no longer be regarded as a standard option.
      Finally, based on a randomised phase II study, cabozantinib appeared to be superior to sunitinib in terms of PFS and response rate and has been approved by the EMA in the first-line setting in intermediate- and poor-risk patients [
      • Choueiri T.K.
      • Hessel C.
      • Halabi S.
      • et al.
      Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update.
      ].
      Based on the recent data, it appears useful to provide recommendations based on risk classification [see level of evidence (LoE) in Figure 1].
      In good-risk patients, VEGF-targeted agents should remain the standard of care with sunitinib, pazopanib or bevacizumab combined with IFN. Tivozanib is another standard of care when available.
      In intermediate-risk patients, combination of nivolumab and ipilimumab is the new standard of care. If this combination is not available, VEGF-targeted agents should be recommended as in good-risk patients, with cabozantinib being another option in this patient population.
      In poor-risk patients, similarly, combination of nivolumab and ipilimumab is the new standard of care. Among targeted agents, cabozantinib is an attractive option when available. In this specific patient population, temsirolimus remains an option, as well as TKIs (sunitinib or pazopanib). However, in some poor-risk patients with poor Eastern Cooperative Oncology Group (ECOG) PS, only palliative care should be recommended.

       Second-line treatment

      An algorithm for second-line systemic treatment in ccRCC is presented in Figure 2.
      Figure 2
      Figure 2Second-line treatment of ccRCC. aESMO-MCBS scores for new therapies/indications approved by the EMA since 1 January 2016. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. ccRCC, clear cell renal cell carcinoma; EMA, European Medicines Agency; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; MCBS, Magnitude of Clinical Benefit Scale; TKI, tyrosine kinase inhibitor.
      Evidence that TKIs are active after cytokines has been seen with sorafenib, pazopanib, axitinib and tivozanib. Sunitinib also has activity is this setting. Any of these agents can be used after cytokines. 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 and everolimus are active [
        • 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.
        ,
        • Motzer R.J.
        • Escudier B.
        • Oudard S.
        • et al.
        RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.
        ]. Both drugs have shown significant improved PFS over sorafenib (axitinib) or placebo (everolimus) and
      • based on recent phase III trials, sorafenib can also be used as an option.
      However, second-line treatment has been dramatically modified by the report of two large trials showing improvement in OS with nivolumab and cabozantinib [
      • Motzer R.J.
      • Escudier B.
      • McDermott D.F.
      • et al.
      Nivolumab versus everolimus in advanced renal-cell carcinoma.
      ,
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal-cell carcinoma.
      ,
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.
      ] over everolimus. Both trials showed very significant improvement in OS and response rate, while PFS was improved only in the cabozantinib trial. In both trials, patients could be treated after either one or two TKIs.
      Obviously, availability of these two drugs is still heterogenous, and several situations should be differentiated:
      • if only nivolumab is available, it should be recommended;
      • if both nivolumab and cabozantinib are available, either drug is recommended;
      • the combination of lenvatinib and everolimus showed PFS and OS benefit over everolimus based on a randomised study of 150 patients [
        • Motzer R.J.
        • Hutson T.E.
        • Glen H.
        • et al.
        Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
        ] and is FDA and EMA-approved. However, based on the size of this study, this combination should be considered as an acceptable option, primarily when nivolumab or cabozantinib cannot be delivered;
      • if none of these drugs is available, either everolimus or axitinib can be used.
      The optimal duration of treatment, especially for nivolumab, remains unclear, as well as the benefit of treatment beyond progression.

       Third-line treatment

      An algorithm for third-line systemic treatment in ccRCC is presented in Figure 3. Beyond second-line treatment, enrolment into clinical trials is recommended whenever possible. However, based on recent trials with nivolumab and cabozantinib, different situations should be defined:
      Figure 3
      Figure 3Third-line treatment of ccRCC. aESMO-MCBS scores for new therapies/indications approved by the EMA since 1 January 2016. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. ccRCC, clear cell renal cell carcinoma; EMA, European Medicine Agency; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; MCBS, Magnitude of Clinical Benefit Scale; TKI, tyrosine kinase inhibitor.
      • In patients already treated with two TKIs, either nivolumab or cabozantinib is recommended. If neither of these drugs is available, everolimus remains an acceptable option.
      • In patients previously treated with one TKI and nivolumab, cabozantinib is recommended, if available. In the absence of cabozantinib, either everolimus or axitinib can be used.
      • In patients previously treated with one TKI and cabozantinib, nivolumab is recommended, and either everolimus or axitinib remain acceptable options.
      • In patients previously treated with VEGF-targeted therapy and an mTOR inhibitor, sorafenib has shown activity [
        • Motzer R.J.
        • Porta C.
        • Vogelzang N.J.
        • et al.
        Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial.
        ]. However, nivolumab or cabozantinib can be recommended in this setting. Finally, another TKI or re-challenge with the same TKI is considered as an option.

       Medical treatment for non-ccRCC

      Clinical data are limited in these rare histological subtypes, which are usually excluded from controlled phase III trials. Therefore, enrolment into specific clinical trials is strongly recommended. The current evidence is mainly based on small prospective studies and subgroup analyses from larger trials, which mainly focus on TKI or mTOR inhibitor testing [
      • Armstrong A.J.
      • Halabi S.
      • Eisen T.
      • et al.
      Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial.
      ,
      • Tannir N.M.
      • Jonasch E.
      • Albiges L.
      • et al.
      Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial.
      ]. Although not providing definitive answers, these trials favoured sunitinib over the use of everolimus, indicating a similar pattern as that seen in ccRCC. These results were further supported by data from expanded access programmes, retrospective series and from subgroup analysis of the temsirolimus registration trial. Overall, the most robust data exist for the use of sunitinib. These studies also suggest that patients with non-clear cell histology may benefit from treatment with everolimus, sorafenib, pazopanib or temsirolimus. However, in most of these studies, only patients with papillary and chromophobe tumours were enrolled. More recently, clinical data on checkpoint inhibitors have been reported, which suggest clinical activity in patients with non-ccRCC and support their use in such previously treated patients. An algorithm for first-line systemic treatment in non-ccRCC is presented in Figure 4.
      Figure 4
      Figure 4Systemic first-line treatment of non-ccRCC. Non-ccRCC, non-clear cell renal cell carcinoma.
      After first-line therapy, there is no recommendation possible based on available data. However, at least for papillary tumours, which are the most common non-ccRCCs, the use of the ccRCC algorithm is an acceptable option.
      In addition to these general recommendations, some specific situations should be considered:
      • cMET inhibitors have shown activity in papillary RCC with cMET mutation or amplification [
        • Schöffski P.
        • Wozniak A.
        • Escudier B.
        • et al.
        Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification. EORTC 90101 CREATE trial.
        ]. Crizotinib or other cMET inhibitors such as cabozantinib appear as an acceptable option instead of the usual VEGF TKIs.
      • Some patients with chromophobe RCC may benefit from mTOR inhibitors since mutation on chromosome 7 was shown to lead to a loss of the folliculin gene with upregulation of mTOR [
        • Davis C.F.
        • Ricketts C.J.
        • Wang M.
        • et al.
        The somatic genomic landscape of chromophobe renal cell carcinoma.
        ].
      • Some data suggest that sarcomatoid tumours are very inflamed tumours, usually with poor-risk features, and are sensitive to immune checkpoint inhibitors. Thus, the use of nivolumab/ipilimumab combination should be considered as a good option for these patients.
      • Finally, CDCs (and also medullary carcinomas) were reported to behave more like aggressive urothelial tumours rather than RCCs and may therefore be considered for chemotherapy, although expected results are still poor.
      • None of these ‘genetic’ recommendations can be graded, as data are limited and no clear treatment recommendation can be made for these subgroups with distinct biology.

       Role of radiotherapy and bisphosphonates

      Although radiosensitivity of RCC is not perfect, this is not a radioresistant disease. RT has been shown to provide good symptom palliation and local control in RCC depending on the dose that can be delivered [
      • Khoo V.S.
      • Pyle L.
      Radiotherapy and supportive care.
      ]. There is a developing rationale with emerging data suggesting that the apparent radioresistance of RCC can be overcome through the ceramide pathway with the use of higher dose-per-fraction treatments usually delivered by new high-precision RT methods such as SBRT [IV, B] [
      • De Meerleer G.
      • Khoo V.
      • Escudier B.
      • et al.
      Radiotherapy for renal-cell carcinoma.
      ]. This can be exploited and used in many different clinical situations, particularly for unresectable local recurrences or oligometastatic disease.
      There is no current evidence for the use of RT in the neoadjuvant or adjuvant setting. This is on the basis of four negative ‘old’ trials with two pre-operative and two adjuvant studies. Despite being randomised trials, there are several major limitations in trial design and methodology that included inappropriate case selection, sub-therapeutic RT regimes and inadequate patient numbers. Furthermore, treatment morbidity was substantially increased and the RT techniques used then have now been superseded by improved modern irradiation methods such as intensity-modulated RT (IMRT) or SBRT [II, D].
      RT can be used to treat unresectable local or recurrent disease with the aim of improving local control. For patients in whom surgery cannot be carried out due to poor PS or unsuitable clinical condition, RT can be an alternative if other local therapies such as RFA are not appropriate. Modern image-guided RT techniques are needed to enable a high biological dose to be delivered, such as volumetric-modulated arc therapy (VMAT) or SBRT [IV, B]. As discussed earlier, there is an emerging role for its use in the synchronous or metachronous development of oligometastatic mRCC disease, oligoprogression or in mixed response scenarios with immunotherapy or targeted therapies, although none of these techniques can be graded [IV, B].
      RT is an effective treatment for palliation of local and symptomatic mRCC disease or to prevent the progression of metastatic disease in critical sites such as the bones or brain [I, A]. For symptomatic bone metastasis, local RT (either as a single fraction or fractionated course) can provide good symptom relief in up to two-thirds of cases with complete symptomatic responses in up to 20%–25% [I, A].
      For the management of spinal cord compression, an ambulatory status at diagnosis and limited metastatic disease are favourable prognostic factors in those patients able to undergo surgery. The use of initial surgery and postoperative RT was reported in a randomised trial to improve survival and maintenance of ambulation compared with irradiation alone [I, A] [
      • Patchell R.A.
      • Tibbs P.A.
      • Regine W.F.
      • et al.
      Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial.
      ].
      In the management of mRCC patients with brain metastases, the use of corticosteroids can provide effective temporary relief of cerebral symptoms. WBRT between 20 and 30 Gy in 4–10 fractions, respectively, is effective for symptom control [II, B]. Most trials in brain metastasis include only a small proportion of RCC cases [
      • Andrews D.W.
      • Scott C.B.
      • Sperduto P.W.
      • et al.
      Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial.
      ,
      • Kocher M.
      • Soffietti R.
      • Abacioglu U.
      • et al.
      Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study.
      ,
      • Prabhu R.S.
      • Patel K.R.
      • Press R.H.
      • et al.
      Preoperative vs postoperative radiosurgery for resected brain metastases: a review.
      ]. With the use of SRS delivering larger doses per fraction, the mRCC response outcomes are not thought to differ from other solid tumours. For the subset of good-prognosis patients with a single unresectable brain metastasis, SRS with or without WBRT should be considered [II, A]. There is less reported late cognitive dysfunction using SRS alone compared with the combination therapy [II, A]. Adequate control of brain metastases before initiation of anti-VEGF therapy is recommended (expert opinion).
      Finally, randomised data from two trials support the use of postoperative SRS following resection of one to three brain metastases, although these data should be interpreted with caution.
      Multidisciplinary management is needed to optimise care for mRCC patients suffering from bone metastasis. The approach will need to be individualised to the extent of bone metastasis, its location and potential consequences (see sections above on RT palliation and spinal cord compression). In widespread mRCC bone metastasis, bisphosphonate therapy with zoledronic acid has been shown to significantly reduce skeletal-related events (SREs) in patients and increase time to first SRE [
      • Henry D.H.
      • Costa L.
      • Goldwasser F.
      • et al.
      Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
      ]. The receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor denosumab has been shown in a randomised trial to extend the time to first SRE by 4.3 months and was non-inferior to zoledronic acid [
      • Rosen L.S.
      • Gordon D.
      • Tchekmedyian N.S.
      • et al.
      Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial.
      ]. In addition, denosumab has the convenience of subcutaneous administration with no requirement for renal monitoring or dose adjustment [I, A]. Bone-targeted therapy with either zoledronic acid or denosumab should be considered in mRCC patients with reasonable life expectancy and widespread bony metastasis, weighing the potential benefits of the treatment with the potential harms (risk of osteonecrosis of the jaw) [II, A]. Further trials are ongoing to explore its other applications.

      Personalised medicine

      In this disease setting, more research is needed to identify molecular markers which could lead to advances in personalised medicine. However, there is growing evidence that some biomarkers will have clinical implications in the near future, as suggested above for papillary RCC with cMET mutation.

      Follow-up, long-term implications and survivorship

      So far, there is no evidence that early treatment of metastasis results in better outcome of metastatic disease when compared with delayed treatment. Overall, there is no evidence that any particular follow-up protocol influences the outcome in early RCC as well as in advanced RCC.
      The follow-up scheme for localised RCC following surgery should depend on the therapeutic possibilities upon recurrence. CT scans of thorax and abdomen are routinely carried out, with time intervals depending on risk factors. It is recommended to perform CT scans every 3–6 months in high-risk patients for the first 2 years, while a yearly CT scan is probably sufficient in low-risk patients (expert opinion).
      Long-term follow-up is proposed in some institutions, due to the possibility of late relapse, but its benefit has never been demonstrated [
      • Dabestani S.
      • Beisland C.
      • Stewart G.D.
      • et al.
      Long-term outcomes of follow-up for initially localised clear cell renal cell carcinoma: RECUR database analysis.
      ].
      During systemic therapy in mRCC patients, 2- to 4-month follow-up schemes with CT scan should be advised to determine response and resistance. Although not perfect, Response Evaluation Criteria in Solid Tumours (RECIST) remains the most frequently used method to assess drug efficacy. However, in the case of RECIST-defined disease progression, there is no clinical evidence that this quantity of progression is a clinically valid end point that should require treatment interruption or modification.

      Methodology

      These Clinical Practice Guidelines were developed in accordance with the ESMO standard operating procedures for Clinical Practice Guidelines development http://www.esmo.org/Guidelines/ESMO-Guidelines-Methodology. A summary of recommendations is shown in Table 6. The relevant literature has been selected by the expert authors. An ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) table with MCBS scores is included in Table 7. ESMO-MCBS v1.1 [
      • Cherny N.I.
      • Dafni U.
      • Bogaerts J.
      • et al.
      ESMO-Magnitude of Clinical Benefit Scale version 1.1.
      ] was used to calculate scores for new therapies/indications approved by the EMA since 1 January 2016. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee. LoEs and grades of recommendation (GoRs) have been applied using the system shown in Table 8. Statements without grading were considered justified standard clinical practice by the experts and the ESMO Faculty. This manuscript has been subjected to an anonymous peer review process.
      Table 6Summary of recommendations
      Diagnosis and pathology/molecular biology
      • Laboratory examinations of serum creatinine, haemoglobin, leukocyte and platelet counts, lymphocyte to neutrophil ratio, lactate dehydrogenase, CRP and serum-corrected calcium tests should be carried out to confirm suspicion of RCC [IV, B]
      • For accurate staging, US and contrast-enhanced chest, abdominal and pelvic CT are recommended [III, A]
      • A renal tumour core biopsy is recommended before treatment with ablative therapies and in patients with metastatic disease before starting systemic treatment [III, B]
      • Pathology should be assessed using the 2016 WHO histological classification of renal tumours and ISUP grading
      Staging and risk assessment
      • The UICC TNM 8 staging system should be used
      Management of local/locoregional disease
      • For organ-confined T1 tumours <7 cm, PN is recommended [I, A]. Laparoscopic RN is recommended if PN is not feasible [I, A]
      • In patients with compromised renal function, solitary or bilateral tumours, PN is also recommended with no tumour size limitation
      • RFA, MWA or CA are options in patients with small cortical tumours ≤3 cm, frail patients, high surgical risk, solitary kidney, compromised renal function and hereditary RCC or bilateral tumours [III]
      • Renal biopsy is recommended to confirm malignancy and subtype for these patients
      • Active surveillance for elderly patients with significant comorbidities or those with short life expectancy and solid renal tumours <40 mm; renal biopsy is recommended to select these patients [III]
      • For T2 tumours >7 cm laparoscopic RN is preferred option
      • For T3 and T4 tumours (locally advanced), open RN is the standard of care, although a laparoscopic approach can be considered
      Management of advanced/metastatic disease
      • CN is recommended in patients with good PS [I, A] except in intermediate- and poor-risk patients with asymptomatic primary tumours when medical treatment is required [I, A]
      • RT can be used to treat unresectable local or recurrent disease and in patients unsuitable for surgery due to poor PS or unsuitable clinical condition. RT is an alternative if radioablation is not appropriate
      • Image-guided RT techniques such as VMAT or SBRT are needed to enable a high dose to be delivered [IV, B]
      • RT is an effective treatment for palliation of local and symptomatic mRCC disease or to prevent the progression of metastatic disease in critical sites such as bones or brain [I, A]
      • For mRCC patients with brain metastases, the use of corticosteroids can provide temporary relief of cerebral symptoms. WBRT between 20 and 30 Gy in 4–10 fractions is recommended for effective symptom control [II, B]
      • For good-prognosis mRCC patients with a single unresectable brain metastasis, SRS with or without WBRT should be considered [II, A]
      • For first-line systemic treatment, VEGF-targeted agents and TKIs are recommended options for good- and intermediate-risk patients. Tivozanib is EMA-approved for good-risk patients [II, A; ESMO-MCBS v1.1 score: 1]
      • The combination of nivolumab and ipilimumab is recommended for intermediate- and poor-risk patients [I, A; ESMO-MCBS v1.1 score: 3] but not for the good-risk group
      • Cabozantinib is EMA-approved for intermediate- [II, A; ESMO-MCBS v1.1 score: 3] and poor-risk groups [II, B; ESMO-MCBS v1.1 score: 3]
      • For second-line treatment, following TKIs, nivolumab [l, A; ESMO-MCBS v1.1 score: 5] or cabozantinib [l, A; ESMO-MCBS v1.1 score: 3] is recommended
      • The combination of lenvatinib and everolimus following TKIs is FDA- and EMA-approved [II, B; ESMO-MCBS v1.1 score: 4] and is recommended after the nivolumab/ipilimumab combination [IV, C; ESMO-MCBS v1.1 score: 3]
      • If none of these drugs is available, either everolimus or axitinib can be used
      • In patients already treated with two TKIs, either nivolumab [I, A; ESMO-MCBS v1.1 score: 5] or cabozantinib is recommended
      Follow-up, long-term implications and survivorship
      • Follow-up for high-risk patients includes CT scans of thorax and abdomen every 3–6 months for the first 2 years; an annual CT scan is recommended for low-risk patients
      • For mRCC patients during systemic therapy, 2- to 4-month follow-up with CT scan is advised
      • RECIST is the most frequent used method to assess drug efficacy
      CA, cryoablation; CN, cytoreductive nephrectomy; CRP, C-reactive protein; CT, computed tomography; EMA, European Medicines Agency; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; FDA, Food and Drug Administration; ISUP, International Society of Urological Pathology; mRCC, metastatic renal cell carcinoma; MWA, microwave ablation; PN, partial nephrectomy; PS, performance status; RCC, renal cell carcinoma; RECIST, Response Evaluation Criteria in Solid Tumours; RFA, radiofrequency ablation; RN, radical nephrectomy; RT, radiotherapy; SBRT, stereotactic body radiotherapy; SRS, stereotactic radiosurgery; TKI, tyrosine kinase inhibitor; TNM, tumour, node and metastasis; UICC, Union for International Cancer Control; US, ultrasound; VEGF, vascular endothelial growth factor; VMAT, volumetric-modulated arc therapy; WBRT, whole-brain radiotherapy; WHO, World Health Organization.
      Table 7ESMO-MCBS table for new therapies/indications in renal cell carcinoma
      EMA approvals from January 2016.
      TherapyDisease settingTrialControlAbsolute survival gainHR (95% CI)QoL/ToxicityESMO-MCBS score
      ESMO-MCBS version 1.1 [69]. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee.
      Nivolumab, a PD-1 checkpoint inhibitorAdvanced clear cell renal cell carcinoma previously treated with one or two regimens of antiangiogenic therapy
      • Study of nivolumab versus everolimus in pre-treated advanced or metastatic clear-cell renal cell carcinoma
      • (CheckMate 025) [
        • Motzer R.J.
        • Escudier B.
        • McDermott D.F.
        • et al.
        Nivolumab versus everolimus in advanced renal-cell carcinoma.
        ]
      • Phase III
      • NCT01668784
      • Everolimus
      • Median OS: 19.6 months
      • OS gain:
      • 5.4 months
      OS HR: 0.73 (0.57–0.93)Improved toxicity profile and QoL5 (Form 2a)
      CabozantinibAdvanced renal cell carcinoma in adults following prior vascular endothelial growth factor receptor tyrosine kinase inhibitors
      • A study of cabozantinib (XL184) versus everolimus in subjects with metastatic renal cell carcinoma (METEOR) [
        • Choueiri T.K.
        • Escudier B.
        • Powles T.
        • et al.
        Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.
        ]
      • Phase III
      • NCT01865747
      • Everolimus
      • Median OS: 16.5 months
      • OS gain:
      • 4.9 months
      OS HR: 0.66 (0.53–0.83)3 (Form 2a)
      Lenvatinib in combination with everolimusAdvanced or metastatic renal cell carcinoma following one prior vascular endothelial growth factor-targeted therapy
      • Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial [
        • Motzer R.J.
        • Hutson T.E.
        • Glen H.
        • et al.
        Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
        ]
      • Phase II
      • NCT01136733
      • Everolimus
      • Median OS: 15.4 months
      • OS gain:
      • 10.1 months
      OS HR: 0.51 (0.30–0.88)_4 (Form 2a; secondary end point of OS in a small phase II randomised study)
      Nivolumab in combination with ipilimumabFirst-line therapy for intermediate- and poor-risk advanced metastatic renal cell carcinoma
      • Nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma (CheckMate 214) [
        • Motzer R.J.
        • Tannir N.M.
        • McDermott D.F.
        • et al.
        Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma.
        ,
        • Cella D.
        • Grunwald V.
        • Escudier B.
        • et al.
        Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial.
        ]
      • Phase III
      • NCT02231749
      • Sunitinib
      • Median OS: 26.0 months
      • OS gain:
      • 7.3 months
        Calculated conservative estimate of gain based on upper limit of 95% CI (HR 0.78).
      OS HR: 0.63 (0.44–0.89)QoL benefit reported in exploratory evaluation
      Not eligible for QoL adjustment.
      3 (Form 2a)
      TivozanibRecurrent or metastatic renal cell carcinoma with clear cell component, and prior nephrectomy
      • Tivozanib versus sorafenib in patients with advanced renal cell carcinoma [
        • Motzer R.J.
        • Nosov D.
        • Eisen T.
        • et al.
        Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial.
        ]
      • Phase III
      • NCT01030783
      • Sorafenib
      • Median PFS: 9.1 months
      • PFS gain:
      • 2.8 months
      PFS HR: 0.80 (0.64–0.99)
      • OS NS
      • No QoL benefit
      1 (Form 2b)
      CI, confidence interval; EMA, European Medicines Agency; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; HR, hazard ratio; NS, not significant; OS, overall survival; PD-1, programmed cell death protein 1; PFS, progression-free survival; QoL, quality of life.
      a EMA approvals from January 2016.
      b ESMO-MCBS version 1.1 [
      • Cherny N.I.
      • Dafni U.
      • Bogaerts J.
      • et al.
      ESMO-Magnitude of Clinical Benefit Scale version 1.1.
      ]. The scores have been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee.
      c Calculated conservative estimate of gain based on upper limit of 95% CI (HR 0.78).
      d Not eligible for QoL adjustment.
      Table 8Levels of evidence and grades of recommendation
      adapted from the Infectious Diseases Society of America-United States Public Health Service Grading System
      By permission of the Infectious Diseases Society of America [70].
      Levels of evidence
      IEvidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity
      IISmall randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity
      IIIProspective cohort studies
      IVRetrospective cohort studies or case–control studies
      VStudies without control group, case reports, experts opinions
      Grades of recommendation
      AStrong evidence for efficacy with a substantial clinical benefit, strongly recommended
      BStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended
      CInsufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, etc.), optional
      DModerate evidence against efficacy or for adverse outcome, generally not recommended
      EStrong evidence against efficacy or for adverse outcome, never recommended
      a By permission of the Infectious Diseases Society of America [
      • Dykewicz C.A.
      Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients.
      ].

      Acknowledgements

      AB took part as a practicing urologist and not as the vice chair of the European Association of Urology (EAU) RCC guideline panel to synchronise the surgical recommendations with the surgical recommendations of the EAU RCC guidelines. The ESMO Guidelines Committee would like to thank the ESMO Faculty and other experts who provided critical reviews of these ESMO Clinical Practice Guidelines. They would also like to thank the European Cancer Patient Coalition and the Polish Cancer Patient Coalition for their review.

      Disclosure

      BE has reported honoraria for lectures and advisory boards received from Novartis, Pfizer, Bristol-Myers Squibb, Roche, Ipsen, Eisai, EUSA Pharma and Oncorena; CP has reported honoraria for lectures and advisory boards received from Novartis, Pfizer, Bristol-Myers Squibb, Ipsen, Eisai and Janssen; MS has reported honoraria for lectures and advisory boards from Pfizer, Roche, Novartis, Exelixis, Ipsen, Eisai, Bristol-Myers Squibb, Aveo, Astellas and EUSA Pharma; AB took part in advisory boards for Pfizer, Novartis, Nektar and Eisai; VK has reported honoraria for lectures from Accuray, Astellas, Bayer, Ipsen, Tolmar and advisory boards for Accuray, Astellas and Bayer; VG has reported honoraria from AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, MSD, Merck Serono, Novartis, Pfizer and Roche; advisory role for AstraZeneca, Bristol-Myers Squibb, Ipsen, MSD, Merck Serono, Novartis, Pfizer and Roche; research grants from AstraZeneca, Bristol-Myers Squibb, MSD, Novartis and Pfizer; SG has reported advisory boards and independent data monitoring committees for AAA, Astellas, Bayer, Bristol-Myers Squibb, Cellsearch, Clovis, Curevac, Dendreon, ESSA, Ferring, Innocrin, Janssen, MaxiVAX, Nectar, Orion, ProteoMediX, Roche and Sanofi Aventis; speakers’ bureau participation (compensated) for Janssen and Novartis; speakers’ bureau participation (uncompensated) for Astellas, Janssen and Sanofi Aventis; NRL and AH have declared no potential conflicts of interest.

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