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

•This ESMO Clinical Practice Guideline provides key recommendations for managing renal cell carcinoma.•The guideline covers imaging and diagnosis, staging and risk assessment, treatment and follow-up.•Algorithms for the management of localised and advanced or metastatic disease are provided.•The authors comprise a multidisciplinary group of experts from different institutions and countries.•Recommendations are based on available scientific data and the authors' collective expert opinion. Renal cancer is the 14th most common malignancy worldwide, with >430 000 new cases diagnosed in 2020.1 The incidence varies geographically, with higher incidence in Europe and North America. Renal cell carcinoma (RCC) accounts for ∼90% of all renal cancers.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 2Escudier B. Porta C. Schmidinger M. et al.Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019; 30: 706-720Abstract Full Text Full Text PDF PubMed Scopus (724) Google Scholar, 3Huang J. Leung D.K. Chan E.O. et al.A Global Trend Analysis of Kidney Cancer Incidence and Mortality and Their Associations with Smoking, Alcohol Consumption, and Metabolic Syndrome.Eur Urol Focus. 2022; 8: 200-209Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar While incidence rates of renal cancer have been steadily increasing, including a slow rise over the past decade, mortality rates have slowly declined.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar,2Escudier B. Porta C. Schmidinger M. et al.Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019; 30: 706-720Abstract Full Text Full Text PDF PubMed Scopus (724) Google Scholar This can be explained in part by increased rates of incidental diagnoses on abdominal imaging.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Improvements in treatments are also contributing to the declining mortality rates. There are several established risk factors for RCC such as smoking, obesity, hypertension and chemical exposures, which have been described previously.3Huang J. Leung D.K. Chan E.O. et al.A Global Trend Analysis of Kidney Cancer Incidence and Mortality and Their Associations with Smoking, Alcohol Consumption, and Metabolic Syndrome.Eur Urol Focus. 2022; 8: 200-209Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar An estimated 6%-9% of renal cancers have germline mutations in genes associated with cancer predisposition.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Several autosomal dominant syndromes have been described, including von Hippel–Lindau syndrome (VHL), hereditary leiomyomatosis and RCC (HLRCC) or fumarate hydratase (FH)-deficient RCC, hereditary papillary RCC, tuberous sclerosis complex, Birt–Hogg–Dubé syndrome and succinate dehydrogenase (SDH)-deficient RCC.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar The initial presentation of RCC, based on the classic triad of flank pain, gross haematuria and palpable abdominal mass, has been largely replaced by incidental detection.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar The recommended diagnostic investigations are summarised in Figure 1. Contrast-enhanced computed tomography (CT) of the chest, abdomen and pelvis is required for accurate staging of RCC for tumours of all stages. For advanced disease, neuroimaging [CT or magnetic resonance imaging (MRI)] and bone scan are desirable before starting systemic therapy. Positron emission tomography is not recommended for routine staging or assessment of RCC. Histopathological confirmation of RCC is mandatory for all patients before starting systemic treatment. Core biopsy of the renal tumour or metastatic site, or examination of the nephrectomy sample at surgery, provides histopathological confirmation with high sensitivity and specificity, and negligible risk of tumour seeding.4Leveridge M.J. Finelli A. Kachura J.R. et al.Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy.Eur Urol. 2011; 60: 578-584Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar,5Volpe 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.J Urol. 2007; 178: 379-386Crossref PubMed Scopus (301) Google Scholar Histopathology assessment to establish the underlying subtype (clear-cell versus variant histology) and presence of sarcomatoid or rhabdoid differentiation using established criteria is strongly recommended due to prognostic and therapeutic implications.6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar More recent classification based on molecular analysis techniques that are not currently widely available, while recommended, is not yet mandated. Patients with suspected metastatic relapse after nephrectomy for renal cancer do not necessarily need a repeat biopsy of the metastatic site, but the decision should be made on an individual basis, especially in the case of late relapse, which is common in RCC. The risk of relapse of the primary tumour and the interval between primary surgery and relapse are relevant in this decision. Laboratory assessment of serum creatinine, haemoglobin, leukocyte and platelet counts, lymphocyte to neutrophil ratio and serum-corrected calcium should be carried out. These tests are used in prognostic scoring systems and treatment selection for advanced disease, including the International Metastatic RCC Database Consortium (IMDC) score (see Staging and risk assessment section).7Ko 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.Lancet Oncol. 2015; 16: 293-300Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar Clear-cell RCCs (ccRCCs) represent ∼80% of malignant renal tumours in adults. The remaining 20% consist of several subtypes with different histological, molecular and cytogenetic profiles. Papillary RCC (pRCC) is the most common of these.8Fernández-Pello S. Hofmann F. Tahbaz R. et al.A Systematic Review and Meta-analysis Comparing the Effectiveness and Adverse Effects of Different Systemic Treatments for Non-clear Cell Renal Cell Carcinoma.Eur Urol. 2017; 71: 426-436Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar The fifth edition of the World Health Organization (WHO) classification of urogenital tumours, published in 2022, contains significant revisions.6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar With increasing use of massive parallel sequencing to identify molecular alterations in renal tumours, the WHO has introduced a molecular-driven renal tumour classification with 11 subgroups.6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Molecular-defined renal tumours are those which show very heterogeneous morphological aspects and can therefore not be diagnosed by morphology alone. Such tumours include previously described molecular subtypes (such as microphthalmia transcription factor [MiT] family translocation carcinomas and SDH-deficient RCC), as well as new entities including SMARCB1-deficient medullary RCC, TFEB-altered RCC, ALK-rearranged RCC and ELOC-mutated RCC (Table 1).6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google ScholarTable 1New molecular-defined RCC entities defined by the WHO6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google ScholarRCC subtype (WHO)Genetic alterationCommentsEosinophilic solid and cystic RCCTSC mutation and activation of mTOR pathwayTypically clinically indolentResponses with use of mTOR inhibitors have been reportedELOC-mutated RCCELOC (TCEB1) mutationClear cells with abundant cytoplasm and presence of fibromuscular bandsBased on limited data, seem to behave indolently and are associated with good prognosisALK-rearranged RCCALK rearrangementsTypically morphologically very heterogenousResponses with use of ALK inhibitors have been reportedSMARCB1-deficient medullary RCCSMARCB1 lossHighly aggressive subtypeFrequently occurs in young patients with sickle cell trait (although not required for diagnosis)TFEB-altered RCCTFEB translocation and TFEB amplificationTFEB-translocated RCC is typically clinically indolentTFEB-amplified RCC is typically highly aggressive, tends to occur in older patientsFH-deficient RCCFH loss or mutationMay be associated with HLRCCALK, anaplastic lymphoma kinase; FH, fumarate hydratase; HLRCC, hereditary leiomyomatosis and renal cell carcinoma; mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; WHO, World Health Organization. Open table in a new tab ALK, anaplastic lymphoma kinase; FH, fumarate hydratase; HLRCC, hereditary leiomyomatosis and renal cell carcinoma; mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; WHO, World Health Organization. The incorporation of molecular-driven classification highlights a shift to using genome sequencing to identify actionable mutations for more personalised treatments. Testing for germline mutations is recommended for younger patients, those with multiple or bilateral lesions, those with first- or second-degree relatives who have had RCC, those with related disorders associated with known predisposing conditions and those who have exhausted standard therapeutic options. While molecular techniques are becoming more widely available, many laboratories still lack access to them, and most of the identified targets are not currently actionable. When genome sequencing is not available, pathologists should include comments regarding the possible molecular alterations in their diagnoses, along with a detailed morphological description.6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Currently, the identification of ccRCC as opposed to pRCC or another established subtype (e.g. chromophobe, collecting duct, etc.) remains the priority. The identification of sarcomatoid features, which may be observed in any RCC subtype and are characterised by the presence of spindle or mesenchymal-like cells, has become increasingly important for the consideration of systemic therapy. The latest WHO classification no longer differentiates between type 1 and type 2 pRCC, reducing its importance. The clinical relevance of the new WHO subtypes remains uncertain. •Patients with suspected renal cancer should have appropriate investigations with cross-sectional imaging, histopathology analysis and laboratory tests [I, A].•Neuroimaging (CT or MRI) and a bone scan are desirable before starting systemic therapy for advanced disease [IV, B]•Histopathology analysis should be carried out to determine tumour subtype and results should be available before starting systemic treatment [I, A].•The recent WHO classification is not routinely required; instead, attention should be given to established subtypes with well-defined treatment algorithms, such as ccRCC and pRCC [IV, B].•Genetic assessment is recommended for younger patients, those with multiple or bilateral lesions, those with first- or second-degree relatives who have had RCC, those with related disorders associated with known predisposing conditions and those who have exhausted standard therapeutic options [IV, A]. Staging should follow the eighth edition of the Union for International Cancer Control (UICC) TNM (tumour–node–metastasis) system (Supplementary Tables S1 and S2).9Union for International Cancer Control. TNM Classification of Malignant Tumours. 8th ed. John Wiley & Sons, Ltd; 2017.Google Scholar Given the variable clinical course of RCC, the use of prognostic models is recommended in both localised and metastatic disease for the assessment of individualised risk. Localised disease. The approval of adjuvant pembrolizumab for high-risk RCC makes the TNM prognostic classification used in KEYNOTE-564 clinically relevant; this is now the preferred risk classification for operable disease. As per the trial protocol, intermediate-high risk is defined as pathological (p)T2, grade 4 or sarcomatoid, N0, M0, or pT3, any grade, N0, M0.10Choueiri T.K. Tomczak P. Park S.H. et al.Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.N Engl J Med. 2021; 385: 683-694Crossref PubMed Google Scholar High-risk disease is defined as pT4, any grade, N0, M0, or any pT, any grade, lymph node positive, M0. Other risk models testing pre- and post-operative scores can be used for prognostic purposes.11Leibovich 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.Cancer. 2003; 97: 1663-1671Crossref PubMed Scopus (655) Google Scholar,12Patard 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 (325) Google Scholar Advanced disease. The IMDC score, developed in the vascular endothelial growth factor receptor (VEGFR)-targeted therapy era, is a useful tool for predicting the prognosis of patients with advanced RCC. This scoring system uses six clinical and laboratory risk factors to produce three risk categories: favourable, intermediate and poor.7Ko 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.Lancet Oncol. 2015; 16: 293-300Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar The risk category can be used to estimate prognosis and guide treatment decisions in first-line therapy and beyond.13Heng 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 (1700) Google Scholar It should be noted, however, that this scoring system was validated in the era of VEGFR tyrosine kinase inhibitor (TKI) therapy and its predictive value with immune checkpoint inhibitor (ICI) therapy is less certain. Molecular prognostication and biomarkers. The introduction of the molecular-driven classification for RCC by the WHO highlights the prognostic implications of certain gene mutations, as discussed above. Gene expression panels can identify high-risk disease in operable cases and can potentially identify angiogenic versus immunogenic tumours in advanced disease;14McDermott 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.Nat Med. 2018; 24: 749-757Crossref PubMed Scopus (858) Google Scholar however, these are not applicable for routine use. Programmed death-ligand 1 (PD-L1) has been unreliable as a biomarker in renal cancer, and serum and urine biomarkers are experimental. •Staging should follow the eighth edition of the UICC TNM system [IV, B].•Prognostic scoring systems should be used to assess risk in operable disease (KEYNOTE-564 classification) and advanced disease (IMDC classification) [I, A]. T1 tumours (≤7 cm). Partial nephrectomy (PN) is the preferred option in organ-confined tumours measuring ≤7 cm (elective indication). This recommendation is based on a systematic review of multiple retrospective studies and a prospective, randomised controlled trial comparing radical nephrectomy (RN) with PN in solitary T1a-b N0 M0 renal tumours (<5 cm) with normal contralateral kidney function, which showed that PN was associated with significantly better preservation of renal function.15MacLennan S. Imamura M. Lapitan M.C. 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 (283) Google Scholar PN can be carried out via open, laparoscopic or robot-assisted laparoscopic approaches. Conventional or robot-assisted laparoscopic RN is recommended if PN is not technically feasible. A nephron-sparing strategy, including PN, is the standard of care (SoC) in patients with compromised renal function, solitary kidney or bilateral tumours, with no tumour size limitation (imperative indication). Renal mass biopsy prior to surgery for clinical T1a tumours is recommended, as up to 30% are benign and may not need an intervention; however, a clear consensus has not been reached.16Widdershoven C.V. Aarts B.M. Zondervan P.J. et al.Renal biopsies performed before versus during ablation of T1 renal tumors: implications for prevention of overtreatment and follow-up.Abdom Radiol (NY). 2021; 46: 373-379Crossref Scopus (10) Google Scholar Radiofrequency ablation (RFA), stereotactic body radiotherapy (SBRT), microwave ablation and cryoablation (CA) are non-surgical options, particularly in patients with small cortical tumours. These may be especially appropriate for patients who are frail, present a high surgical risk, have a solitary kidney, compromised renal function, hereditary RCC or multiple bilateral tumours, or decline surgery. Preintervention biopsy is recommended to confirm malignancy and subtype in this setting.17Pierorazio P.M. Johnson M.H. Ball M.W. et al.Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry.Eur Urol. 2015; 68: 408-415Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar Systematic reviews suggest a long-term cause-specific survival with RFA that is equal to PN, with a low metastasis rate but slightly higher local recurrence rate compared with PN and CA.15MacLennan S. Imamura M. Lapitan M.C. 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 (283) Google Scholar The quality of the available evidence prevents definitive conclusions regarding morbidity and oncological outcomes for RFA and CA. Data from meta-analyses as well as prospective and retrospective studies support the efficacy and safety of SBRT, including favourable long-term outcomes.18Siva S. Ali M. Correa R.J.M. et al.5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney).Lancet Oncol. 2022; 23: 1508-1516Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Further randomised trials are needed to define its efficacy; SBRT cannot be strongly recommended without these data. Active surveillance is an option for those with a short life expectancy and for patients with small renal masses (≤4 cm); indeed, the growth rate of renal tumours is low in most cases (mean 3 mm/year) and progression to metastatic disease is reported in 1%-2% of patients.17Pierorazio P.M. Johnson M.H. Ball M.W. et al.Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry.Eur Urol. 2015; 68: 408-415Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar,19Jewett 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 (393) Google Scholar In all cases, a risk–benefit discussion should occur with the patient. Minimally-invasive RN is the preferred option. Other approaches are likely to have similar oncological outcomes. Open RN remains the SoC for complex T3 and T4 tumours, although robotic and laparoscopic approaches can be considered. Routine adrenalectomy or lymph node dissection is not recommended when abdominal CT and intraoperative exploration show no evidence of adrenal or lymph node invasion.20Ljungberg B. Albiges L. Abu-Ghanem Y. et al.European Association of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update.Eur Urol. 2022; 82: 399-410Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar The evidence regarding management of venous tumour thrombus is based on retrospective studies.21Lardas M. Stewart F. Scrimgeour D. et al.Systematic Review of Surgical Management of Nonmetastatic Renal Cell Carcinoma with Vena Caval Thrombus.Eur Urol. 2016; 70: 265-280Abstract Full Text Full Text PDF PubMed Google Scholar 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 uncertain and outcomes depend on tumour thrombus level. There is no established role for neoadjuvant therapies. Unique considerations for VHL-associated RCC. VHL is a rare, autosomal dominant, hereditary disorder caused by germline pathogenic variants in the VHL gene. Approximately 70% of patients with VHL will develop RCC during their lifetime.22Jonasch E. Donskov F. Iliopoulos O. et al.Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.N Engl J Med. 2021; 385: 2036-2046Crossref PubMed Scopus (262) Google Scholar Historic approaches to the management of RCC in this population have mostly relied on surgical or ablative approaches; however, given the propensity of patients with VHL to develop multiple RCCs, this often requires multiple procedures. Belzutifan is a novel hypoxia-inducible factor 2 alpha (HIF-2α) transcription factor inhibitor. A recent phase II, open-label, single-group trial of 61 patients investigated belzutifan in VHL-associated RCC.23Srinivasan R. Iliopoulos O. Rathmell W.K. et al.LBA69 Belzutifan, a HIF-2α Inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: 36 months of follow-up of the phase II LITESPARK-004 study.Ann Oncol. 2022; 33: S1433-S1434Abstract Full Text Full Text PDF Google Scholar The overall response rate (ORR) was 64% and there was a reduction in the need for subsequent intervention. Belzutifan appears to be well tolerated and should be recommended for patients who do not require immediate surgery. The phase III KEYNOTE-564 trial evaluated pembrolizumab (17 cycles of 200 mg three times weekly) versus placebo as adjuvant therapy in 994 patients with ccRCC with intermediate-high or high-risk disease (as defined by the trial protocol), or M1 and no evidence of disease (NED).10Choueiri T.K. Tomczak P. Park S.H. et al.Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.N Engl J Med. 2021; 385: 683-694Crossref PubMed Google Scholar After a median follow-up of 57.2 months, pembrolizumab was associated with improved overall survival (OS) [hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.44-0.87, P = 0.005] and disease-free survival (DFS) (HR 0.72, 95% CI 0.59-0.87) versus placebo.24Choueiri T.K. Tomczak P. Park S.H. et al.Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.N Engl J Med. 2024; 390: 1359-1371Crossref Scopus (2) Google Scholar This is the first adjuvant therapy with proven survival benefit in operable RCC and is recommended in patients with intermediate-high and high-risk (KEYNOTE-564 criteria) ccRCC, after careful patient selection and counselling regarding potential acute and long-term adverse events (AEs). If used, treatment should start within 12 weeks of surgery and continue for up to 1 year. The DFS and reported OS benefits observed in KEYNOTE-564 contrast with other trials of immunotherapy in the adjuvant setting (e.g. atezolizumab25Pal S.K. Uzzo R. Karam J.A. et al.Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial.Lancet. 2022; 400: 1103-1116Abstract Full Text Full Text PDF PubMed Google Scholar and ipilimumab–nivolumab26Motzer R.J. Russo P. Grünwald V. et al.Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial.Lancet. 2023; 401: 821-832Abstract Full Text Full Text PDF PubMed Google Scholar). Differences in trial design, duration of treatment, ICI activity or increased toxicity associated with the use of ipilimumab may offer explanations for the contrasting results. Biomarker data from these trials are also required. Adjuvant VEGFR-targeted therapies have demonstrated inconsistent benefit in phase III randomised trials.27Haas 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.Lancet. 2016; 387: 2008-2016Abstract Full Text Full Text PDF PubMed Google Scholar,28Ravaud A. Motzer R.J. Pandha H.S. et al.Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.N Engl J Med. 2016; 375: 2246-2254Crossref PubMed Scopus (592) Google Scholar An algorithm for the treatment of local and locoregional RCC is shown in Figure 2. •Surgical resection remains the SoC for localised renal cancer [I, A] with either minimally invasive or open approaches preferred depending on tumour size and complexity.•Several nephron-sparing options, ranging from surveillance to PN, are recommended for small renal masses (T1 ≤4 cm) [III, B].•Belzutifan may avoid surgeries and can be considered for patients with germline VHL variants and localised renal cancer [III, A; ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1 score: 3; Food and Drug Administration (FDA) approved, not European Medicines Agency (EMA) approved].•Adjuvant pembrolizumab should be considered for patients with intermediate-high or high-risk operable ccRCC (as defined by the KEYNOTE-564 criteria) after careful patient counselling regarding potential long-term AEs [I, A; ESMO-MCBS v1.1 score: A]. Treatment should start within 12 weeks of surgery and continue for up to 1 year.•Adjuvant VEGFR-targeted therapies are not recommended [I, D]. Upfront cytoreductive nephrectomy (CN) is no longer considered the SoC in unselected patients with intermediate-risk asymptomatic primary ccRCC and all patients with poor-risk asymptomatic primary ccRCC in the advanced and metastatic setting.29Méjean A. Ravaud A. Thezenas S. et al.Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.N Engl J Med. 2018; 379: 417-427Crossref PubMed Scopus (599) Google Scholar Due to the inclusion criteria and subset analysis from the CARMENA trial, CN may still be considered for patients with low-volume single-organ metastatic disease with a large primary tumour, or for patients who have had a near complete response (CR) to upfront systemic therapy.29Méjean A. Ravaud A. Thezenas S. et al.Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.N Engl J Med. 2018; 379: 417-427Crossref PubMed Scopus (599) Google Scholar These patients may be candidates for observation rather than systemic therapy after CN, although data are limited regarding long-term outcomes in this setting. Metastasectomy, thermal ablation, stereotactic radiosurgery, SBRT, CyberKnife radiotherapy (RT) and hypofractionated RT can be considered for selected patients with low metastatic burden after multidisciplinary team (MDT) review, although randomised or robust prospective data to support their use is lacking.3