EAU2025OncologyLast updated 29 May 2026

EAU 2025 Guidelines: Renal Cell Carcinoma

Guideline Summary

A plain-language overview and the key recommendations. The complete recommendation tables are in the Full Guidelines section below.

What This Guideline Covers

The EAU 2025 Renal Cell Carcinoma (RCC) guideline spans the whole pathway: imaging diagnosis and staging, when to biopsy, genetic assessment for hereditary RCC, prognostic models, and treatment across localised, locally advanced, and metastatic disease — surgery (partial and radical nephrectomy), ablation and active surveillance, management of venous tumour thrombus, adjuvant therapy, systemic therapy for metastatic disease, and risk-based follow-up.

Key Recommendations at a Glance

Every Strong-rated EAU recommendation, in plain language. The full recommendation tables (with Weak recommendations and strength ratings) are in the Full Guidelines tab.

Prevention & screening

Encourage physical activity, smoking cessation, and (in obese patients) weight loss to lower RCC risk.

Diagnosis & staging

Use multiphasic contrast-enhanced CT of the abdomen and chest to diagnose and stage renal tumours.
If CT is indeterminate, use MRI or contrast-enhanced ultrasound to further characterise small masses, tumour thrombus, or unclear masses.
Biopsy the tumour before ablation, and before systemic therapy when there is no prior pathology; use a coaxial, core-biopsy technique (not fine-needle aspiration).
Do not biopsy cystic masses unless a significant solid component is visible.
Manage Bosniak type IV cysts the same as localised RCC.

Genetics

Order genetic evaluation for patients ≤46 years, with bilateral/multifocal tumours, a relevant family history, a known pathogenic variant, or suggestive histology — and refer suspected hereditary RCC to a cancer geneticist or specialist centre.

Prognosis & decision-making

Stage with the current TNM system and grade/classify with the WHO/ISUP system.
Use validated prognostic models in localised and metastatic disease; do not rely on molecular markers for prognosis.
Use shared decision-making, and counsel every patient to stop smoking.

Localised disease

Offer surgery for cure; offer partial nephrectomy for T1 tumours.
Do not remove the ipsilateral adrenal gland unless there is evidence of adrenal invasion.
Use laparoscopic or robotic radical nephrectomy for T2 tumours and localised masses not suitable for partial nephrectomy — but do not use minimally invasive radical nephrectomy when partial nephrectomy is feasible, or when a minimally invasive approach would compromise outcomes.

Ablation / active surveillance

Biopsy before (not at the same time as) tumour ablation, and discuss the oncological harms and benefits before offering ablation or active surveillance.

Locally advanced / unresectable

Remove the tumour and thrombus when there is venous involvement in non-metastatic disease.
Discuss unresectable locally advanced RCC within a multidisciplinary team.

Adjuvant therapy

Offer adjuvant pembrolizumab to clear-cell RCC patients at the recurrence risk defined in the KEYNOTE-564 trial (ideally 12–16 weeks after nephrectomy), and discuss the conflicting adjuvant-ICI trial data and the risk of overtreatment when planning it.

Metastatic disease

Do not give chemotherapy for metastatic RCC.
Do not perform cytoreductive nephrectomy in IMDC/MSKCC poor-risk patients.
Do not give a tyrosine kinase inhibitor after metastasectomy when there is no evidence of disease.
First-line for IMDC intermediate/poor-risk clear-cell disease: an immunotherapy combination (nivolumab + ipilimumab, pembrolizumab + axitinib, lenvatinib + pembrolizumab, or nivolumab + cabozantinib).
If immunotherapy cannot be used or tolerated: sunitinib or pazopanib (any risk), or cabozantinib (intermediate/poor risk).
After VEGF-targeted therapy, offer cabozantinib; for ICI-naïve, VEGFR-refractory disease (after 1–2 lines) offer nivolumab or cabozantinib; and for patients who had first-line VEGF therapy alone, offer nivolumab or cabozantinib.
Sequence systemic therapies; do not re-challenge with an immune checkpoint inhibitor stopped for toxicity without expert multidisciplinary support.

Hereditary RCC

Suspect hereditary or syndrome-specific RCC with a positive family history, young onset, or bilateral/multiple tumours.
In von Hippel-Lindau disease, offer surveillance until the largest tumour reaches 3 cm.

Follow-up

Base follow-up after treatment of localised RCC on the risk of recurrence.

Read Full Guidelines

Full Guidelines

Reproduced from the official EAU 2025 publication.

Recommendations

Recommendations for epidemiology, aetiology and screening

Recommendation	Strength rating
Increase physical activity, eliminate cigarette smoking and, in obese patients, reducing weight are the primary preventative measures to decrease risk of RCC.	Strong
Do not routinely screen people for primary RCC.	Weak

Recommendations for the management of other renal tumours

Recommendation	Strength rating
Manage Bosniak type III cysts the same as localised RCC, or offer active surveillance (AS).	Weak
Manage Bosniak type IV cysts the same as localised RCC.	Strong
Offer AS to patients with biopsy-proven oncocytoma or other oncocytic renal tumours as an acceptable alternative to surgery or ablation.	Weak
Treat angiomyolipoma (AML) with selective arterial embolisation or nephron-sparing surgery, in: • large tumours (a recommended threshold of intervention does not exist); • females of childbearing age; • patients for whom follow-up or access to emergency care may be inadequate; • persistent pain or acute or repeated bleeding episodes.	Weak
Offer systemic therapy (everolimus) to patients with surgically unresectable AMLs which are not amenable to embolisation and require therapy.	Weak

Recommendations for the diagnosis of RCC

Recommendation	Strength rating
Use multi-phasic contrast-enhanced computed tomography (CT) of abdomen and chest for the diagnosis and staging of renal tumours.	Strong
Omit chest CT in patients with incidentally noted cT1a disease due to the low risk of lung metastases in this cohort.	Weak
Use magnetic resonance imaging (MRI) to better evaluate venous involvement, reduce radiation or avoid intravenous CT contrast medium.	Weak
Use non-ionising modalities, including MRI and contrast-enhanced ultrasound, for further characterisation of small renal masses, tumour thrombus and differentiation of unclear renal masses, in case the results of contrast-enhanced CT are indeterminate.	Strong
Offer brain CT/MRI in metastatic patients when systemic therapy or cytoreductive nephrectomy is considered.	Weak
Do not routinely use bone scan and/or positron-emission tomography CT for staging of renal cell carcinoma.	Weak
Perform a renal tumour biopsy before ablative therapy and systemic therapy without previous pathology.	Strong
Perform a percutaneous biopsy in select patients who are considering active surveillance.	Weak
Use a coaxial technique when performing a renal tumour biopsy.	Strong
Do not perform a renal tumour biopsy of cystic renal masses unless a significant solid component is visible at imaging.	Strong
Use a core biopsy technique rather than fine needle aspiration for histological characterisation of solid renal tumours.	Strong

Recommendations for the genetic assessment of RCC

Recommendation	Strength rating
Perform a genetic evaluation in patients aged ≤ 46 years, with bilateral or multifocal tumours and/or a first- or second-degree relative with RCC and/or a close blood relative with a known pathogenic variant and/or specific histologic characteristics which suggest the presence of a hereditary form of RCC.	Strong
Refer patients to a cancer geneticist or to a Comprehensive Clinical Care Centre in case of suspected hereditary RCC.	Strong

Recommendations for prognostic factors

Recommendation	Strength rating
Use the current Tumour, Node, Metastasis classification system.	Strong
Use the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grading system and classify renal cell carcinoma type.	Strong
Use prognostic models in localised and metastatic disease.	Strong
Use the 2003 Leibovich scoring model for risk stratification of localised and locally advanced clear cell renal cell carcinoma.	Weak
Use the venous involvement, necrosis, size, stage, and sarcomatoid differentiation (VENUSS) scoring model for risk stratification of localised and locally advanced papillary renal cell carcinoma.	Weak
Do not routinely use molecular markers to assess prognosis.	Strong

Shared decision-making

Recommendation	Strength rating
Employ a shared decision-making approach when deciding on appropriate treatment for RCC.	Strong

Smoking cessation

Recommendation	Strength rating
Counsel RCC patients to stop smoking.	Strong

Recommendations for the treatment of localised RCC

Recommendation	Strength rating
Offer surgery to achieve cure in localised renal cell cancer.	Strong
Offer partial nephrectomy (PN) to patients with T1 tumours.	Strong
Offer PN to patients with T2 tumours and a solitary kidney or chronic kidney disease, if technically feasible.	Weak
Do not perform ipsilateral adrenalectomy if there is no clinical evidence of invasion of the adrenal gland.	Strong
Do not offer an extended lymph node dissection to patients with organ-confined disease.	Weak
Offer embolisation to patients unfit for surgery presenting with massive haematuria or flank pain.	Weak

Recommendations for radical and partial nephrectomy techniques

Recommendation	Strength rating
Offer laparoscopic or robotic radical nephrectomy (RN) to patients with T2 tumours and localised masses not treatable by partial nephrectomy (PN).	Strong
Do not perform minimally invasive RN in patients with T1 tumours for whom a PN is feasible by any approach, including open.	Strong
Do not perform minimally invasive surgery if this approach may compromise oncological-, functional-, and peri-operative outcomes.	Strong
Intensify follow-up in patients with a positive surgical margin, especially in upstaged pT3a patients.	Weak
Do not attempt off-clamp PN unless indicated.	Weak

Recommendations for therapeutic approaches as alternative to surgery

Recommendation	Strength rating
Offer active surveillance (AS) or tumour ablation (TA) to frail and/or comorbid patients with small renal masses.	Weak
Perform a percutaneous renal mass biopsy prior to, and not concomitantly with, TA.	Strong
Discuss the harms/benefits with regards to oncological outcomes and complications when TA or AS is offered.	Strong
Offer stereotactic ablative radiotherapy for patients with non-metastatic growing biopsy proven RCC, unfit for surgery.	Weak
Do not routinely offer radiofrequency ablation for tumours > 3 cm and cryoablation for tumours > 4 cm.	Weak

Recommendations for lymph node dissection, the management of RCC with venous tumour thrombus and unresectable tumours

Recommendation	Strength rating
During nephrectomy, remove clinically enlarged lymph nodes for staging, prognosis and follow-up implications.	Weak
Remove the renal tumour and thrombus in case of venous involvement in non- metastatic disease.	Strong
Discuss treatment options in patients with locally-advanced unresectable RCC (biopsy and/or systemic therapy/deferred resection, or palliative management) within a multi-disciplinary team to determine treatment goal.	Strong

Recommendations for neoadjuvant and adjuvant therapy

Recommendation	Strength rating
Do not use neoadjuvant therapy outside a clinical trial setting.	Weak
Offer adjuvant pembrolizumab to clear cell RCC (ccRCC) patients, preferably within twelve to sixteen weeks post-nephrectomy, with a recurrence risk as defined in the Keynote-564 trial: Intermediate-high risk: • pT2, grade 4 or sarcomatoid, N0 M0 • pT3, any grade, N0, M0 High risk: • pT4, any grade, N0, M0 • any pT, any grade, N+, M0 M1 no evidence of disease (NED): • No evidence of disease after resection of oligometastatic sites within one year from nephrectomy.	Strong
If adjuvant therapy is planned: • Discuss the contradictory results of the available adjuvant ICI trials with the patient to facilitate shared decision making. • Inform the patient about the potential risk of overtreatment and immune related side effects if adjuvant therapy is considered.	Strong
Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell RCC.	Weak
Offer vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR- TKI) to patients developing a recurrence while receiving pembrolizumab or within the first six months after stopping pembrolizumab given for one year.	Weak
Do not offer immune checkpoint inhibitor (ICI) mono- or combination therapy in patients with recurrence during or within six months after adjuvant pembrolizumab.	Weak

Recommendations for local therapy of advanced/metastatic RCC

Recommendation	Strength rating
Do not perform cytoreductive nephrectomy (CN) in IMDC/MSKCC poor-risk patients.	Strong
Do not perform immediate CN in intermediate-risk patients who have an asymptomatic synchronous primary tumour and require systemic therapy.	Weak
Start systemic therapy without CN in intermediate-risk patients who have an asymptomatic synchronous primary tumour and require systemic therapy.	Weak
Discuss delayed CN with patients who derive clinical benefit from systemic therapy.	Weak
Perform immediate CN in patients with a good performance status who do not require systemic therapy.	Weak
Perform immediate CN in patients with oligometastases when complete local treatment of the metastases can be achieved.	Weak

Recommendations for local therapy of metastases in metastatic RCC

Recommendation	Strength rating
To control local symptoms, offer ablative therapy, including metastasectomy, to patients with metastatic disease and favourable disease factors and in whom complete resection is achievable.	Weak
Offer stereotactic radiotherapy for clinically relevant bone- or brain metastases for local control and symptom relief.	Weak
Do not offer tyrosine kinase inhibitor treatment to metastatic RCC patients after metastasectomy and no evidence of disease.	Strong
Perform a confirmatory axial scan of disease status prior to metastasectomy to rule out rapid progressive metastatic disease which requires systemic treatment.	Weak
Before initiating systemic therapy for oligometastases that cannot be resected, discuss with your patient a period of observation until progression is confirmed.	Weak

Recommendation for systemic therapy in advanced/metastatic RCC

Recommendation	Strength rating
Do not offer chemotherapy to patients with metastatic RCC.	Strong

Recommendations for single-agent targeted therapy in metastatic clear-cell RCC

Recommendation	Strength rating
Offer nivolumab or cabozantinib for immune checkpoint inhibitor-naive vascular endothelial growth factor receptor (VEGFR)-refractory clear-cell metastatic renal cell carcinoma (cc-mRCC) after one or two lines of therapy.	Strong
Sequence the agent not used as second- line therapy (nivolumab or cabozantinib) for third-line therapy is recommended.	Weak
Offer VEGF-tyrosine kinase inhibitors as second-line therapy to patients refractory to nivolumab plus ipilimumab or axitinib plus pembrolizumab or cabozantinib plus nivolumab or lenvatinib plus pembrolizumab.	Weak
Offer cabozantinib after VEGF-targeted therapy in cc-mRCC.	Strong
Sequence systemic therapy in treating mRCC.	Strong
Offer immune checkpoint inhibitor combination therapy for advanced cc-mRCC with sarcomatoid features.	Weak
Offer belzutifan as an alternative to everolimus in patients previously treated with second to fourth line therapy for clear cell RCC.	Weak
Intermittent single agent VEGFR tyrosine kinase inhibitor can be offered in case of partial response or stable disease > 6 months.	Weak

Recommendations for immunotherapy in cc-mRCC

Recommendation	Strength rating
First line Treatment for metastatic clear cell RCC patients
Offer nivolumab plus ipilimumab, pembrolizumab plus axitinib, lenvatinib plus pembrolizumab or nivolumab and cabozantinib to patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate- or poor risk-disease.	Strong
Offer pembrolizumab plus axitinib, lenvatinib plus pembrolizumab or nivolumab and cabozantinib or nivolumab plus ipilimumab or sunitinib or pazopanib for IMDC favourable risk disease.	Weak
Offer sunitinib or pazopanib to patients with any IMDC risk who cannot receive or tolerate immune checkpoint inhibition.	Strong
Offer cabozantinib to patients with IMDC intermediate- and poor-risk clear cell metastatic renal carcinoma (cc-mRCC) who cannot receive or tolerate immune checkpoint inhibition.	Strong
Patients who do not receive the full four doses of ipilimumab due to toxicity should continue on single-agent nivolumab, where safe and feasible. Re-challenge with combination therapy requires expert support after discontinuation for toxicity.	Weak
Sequencing systemic therapy for metastatic clear cell RCC
Sequence systemic therapy in treating mRCC.	Strong
Offer carbozantinib or other vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors as second-line therapy to patients refractory to nivolumab plus ipilimumab or axitinib plus pembrolizumab or cabozantinib plus nivolumab or lenvatinib plus pembrolizumab.	Weak
Sequence the agent not used as second- line therapy (nivolumab or cabozantinib) for third-line therapy is recommended.	Weak
Offer nivolumab or cabozantinib for those patients who received first line VEGF targeted therapy alone.	Strong
Treatment past progression can be justified but requires close scrutiny and the support of an expert multi-disciplinary team.	Weak
Do not re-challenge patients who stopped immune checkpoint inhibitors because of toxicity without expert guidance and support from a multi-disciplinary team.	Strong
Do not offer programmed death-ligand 1 (PD-L1) combination therapy after progression after immune checkpoint inhibition combination.	Weak

Recommendation for targeted therapy in RCC with sarcomatoid features

Recommendation	Strength rating
Offer immune checkpoint inhibitor combination therapy for advanced clear cell metastatic RCC with sarcomatoid features.	Weak

Recommendations for systemic therapy in papillary metastatic RCC

Recommendation	Strength rating
Offer cabozantinib to patients with papillary RCC (pRCC) based on a positive randomised controlled trial.	Weak
Offer lenvatinib plus pembrolizumab or nivolumab plus cabozantinib to patients with pRCC based on small single-arm trials.	Weak

Recommendation for systemic therapy in chromophobe and unclassified RCC

Recommendation	Strength rating
Offer sunitinib to patients with other non- clear cell renal cell carcinoma (cc-RCC) subtypes than papillary RCC.	Weak
Offer lenvatinib plus pembrolizumab to patients with non-ccRCC subtypes.	Weak
Offer cabozantinib and nivolumab to patients with non-ccRCC subtypes other than chromophobe RCC.	Weak
Offer nivolumab plus ipilimumab in patients with non-ccRCC.	Weak

Recommendation on locally-recurrent RCC after treatment of localised disease

Recommendation	Strength rating
Offer local treatment of locally-recurrent disease when technically possible and after balancing adverse prognostic features, comorbidities and life expectancy.	Weak
Suspect hereditary or syndrome-specific RCC in patients with positive family history, young onset and bilateral or multiple tumours.	Strong
Suspect hereditary or syndrome-specific RCC in patients with positive family history, young onset and bilateral or multiple tumours.	Weak
Offer germline testing to patients < 46 years.	Weak
Offer surveillance in von Hippel-Lindau (VHL) until the largest tumour reaches 3 cm in diameter.	Strong
Offer belzutifan to patients with VHL related renal and other tumours who are not surgical candidates.	Weak

Recommendations for surveillance following radical nephrectomy or partial nephrectomy or ablative therapies in RCC

Recommendation	Strength rating
Base follow-up after treatment of localised RCC on the risk of recurrence.	Strong
Base risk of recurrence stratification on validated subtype-specific models such as the Leibovich Score for clear cell RCC (ccRCC), or the University of California Los Angeles integrated staging system for non- ccRCC.	Weak
Intensify follow-up in patients after nephron- sparing surgery for tumours > 7 cm or in patients with a positive surgical margin.	Weak
Consider curtailing follow-up when the risk of dying from other causes is double that of the RCC recurrence risk.	Weak
Offer psychological evaluation for all patients diagnosed with RCC to provide timely support for distress, depression, or anxiety.	Weak

Classification & Evidence Tables

TNM Classification

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 > 4 cm but ≤ 7 cm
T2 Tumour > 7 cm in greatest dimension, limited to the kidney
T2a Tumour > 7 cm but ≤ 10 cm
T2b Tumours > 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 invades the pelvicalyceal system or invades peri-renal and/or renal sinus fat, but not beyond Gerota fascia
T3b Tumour grossly extends into the vena cava below diaphragm
T3c Tumour grossly 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 stage grouping
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

Summary of evidence for radical and partial nephrectomy techniques	LE
Laparoscopic radical nephrectomy (RN) has lower morbidity than open RN.	1b
Short-term oncological outcomes for T1-T2a tumours are equivalent for laparoscopic- and open RN.	2a
Partial nephrectomy (PN) can be performed, either by open-, pure laparoscopic- or robot-assisted approach, based on surgeon’s expertise and skills.	2b
Robot-assisted and laparoscopic PN are associated with shorter length of hospital stay and lower blood loss compared to open PN.	2b
Transperitoneal and retroperitoneal laparoscopic PN do not differ in post-operative surgical and medical complications, positive surgical margins (PSMs), and kidney function.	2a
Hospital volume for PN might impact on surgical complications, warm ischaemia time and surgical margins.	3
Immediate completion nephrectomy for PSMs can result in over-treatment in many cases.	3
Off-clamp partial nephrectomy does not improve renal function outcomes in patients with baseline normal renal function.	1b

Summary of evidence for neoadjuvant and adjuvant therapy	LE
Neoadjuvant systemic therapy can reduce vascular thrombus and tumour size in the presurgical setting.	2a
Adjuvant sunitinib, sorafenib, pazopanib, everolimus, girentuximab, or axitinib does not improve overall survival (OS) after nephrectomy.	1b
Adjuvant PD1 inhibition with pembrolizumab defined by the inclusion criteria of the trial* after nephrectomy improves disease-free survival (DFS) and OS.	1b
Adjuvant PD-L1 inhibition with atezolizumab and PD1 inhibition with nivolumab did not improve DFS or OS.	1b

Adjuvant dual PD-1 and CTLA-4 inhibition with nivolumab and ipilimumab did not improve DFS.	1b
Peri-operative treatment with nivolumab did not improve relapse-free survival.	1b
There is uncertainty regarding further systemic therapy in patients who receive adjuvant pembrolizumab and develop a recurrence.	4
The lack of biomarker data is hindering progress in this field.	4

Summary of evidence for local therapy of advanced/ metastatic RCC	LE
Deferred cytoreductive nephrectomy (CN) with pre- surgical sunitinib in intermediate-risk patients with clear cell metastatic RCC shows a survival benefit in secondary endpoint analyses and selects out patients with inherent resistance to systemic therapy.	2b
Sunitinib alone is non-inferior compared to immediate CN followed by sunitinib in patients with MSKCC intermediate and poor risk who require systemic therapy with VEGFR-TKI.	1a
Cytoreductive nephrectomy in patients with simultaneous complete resection of a single metastasis or oligometastases may improve survival and delay systemic therapy.	3
Patients with MSKCC or IMDC poor risk do not benefit from CN.	1a
Patients with their primary tumour in place treated with IO-based combination therapy have better PFS and OS in exploratory subgroup analyses compared to treatment with sunitinib.	2b

Summary of evidence for local therapy of metastases in metastatic RCC	LE
Retrospective comparative studies point towards a benefit of complete metastasectomy in metastatic RCC patients in terms of overall survival, cancer specific survival and delay of systemic therapy.	3
A single-arm prospective and retrospective study support that oligometastases can be observed for up to sixteen months before systemic therapy is required due to progression.	2a

Radiotherapy to bone and brain metastases from RCC can induce significant relief from local symptoms (e.g., pain).	3
Tyrosine kinase inhibitors treatment after metastasectomy in patients with no evidence of disease did not improve relapse-free survival when compared to placebo or observation.	1b

Summary of evidence for single-agent targeted therapy in metastatic clear-cell RCC	LE
Single-agent vascular endothelial growth factor (VEGF)-targeted therapy has been superseded by immune checkpoint-based combination therapy.	1b
Intermittent VEGF therapy can be considered in patients on long term VEGF targeted therapy.	2
Immuno-oncology (IO)-VEGFR tyrosine kinase inhibitors (TKI) combination established a response rate (RR) and progression-free survival (PFS) benefit over single agent VEGFR TKI, but no overall survival (OS) benefit in subgroup analysis.	1a
Pazopanib is non-inferior to sunitinib as first-line management option in metastatic RCC.	1b
Cabozantinib in intermediate- and poor-risk treatment-naive clear cell RCC (ccRCC) leads to better response rates and PFS but not OS when compared to sunitinib.	2b
Tivozanib has been European Medicines Agency approved in first-line setting.	3

Single-agent VEGF-targeted therapies are preferentially recommended after first-line PD-L1-based combinations. Re-challenge with treatments already used should be avoided.	3
Single-agent cabozantinib or nivolumab are superior to everolimus after one or more lines of VEGF-targeted therapy.	1b
Everolimus prolongs PFS after VEGF-targeted therapy when compared to placebo. This is no longer widely recommended before third-line therapy.	1b
Belzutifan has a PFS advantage and no OS benefit over everolimus in second and more lines pretreated ccRCC.	1b
Lenvatinib in combination with everolimus improved PFS over everolimus alone in VEGF-refractory disease. Its role after immune checkpoint inhibitors is uncertain. There is a lack of robust data on this combination making its recommendation challenging.	2a

Summary of evidence for immunotherapy in cc-mRCC	LE
Treatment-naïve patients
Currently, PD-L1 expression is not used for patient selection.	2b
The combination of nivolumab and ipilimumab in treatment-naïve patients with metastatic clear cell RCC (cc-mRCC) of IMDC intermediate- and poor risk demonstrated overall survival (OS) and objective response rate (ORR) benefits compared to sunitinib alone.	1b
The updated OS data for Ipilimumab/Nivolumab in IMDC favourable risk patients demonstrates the long- term benefit for this subgroup of patients.	2b
The combination of pembrolizumab plus axitinib, lenvatinib plus pembrolizumab and nivolumab plus cabozantinib in treatment-naïve patients with cc-mRCC demonstrated progression-free survival (PFS), OS and ORR benefits compared to sunitinib in the intention to treat (ITT) population.	1b
The combination of pembrolizumab plus axitinib, lenvatinib plus pembrolizumab and nivolumab plus cabozantinib in treatment-naïve patients with cc-mRCC in IMDC favorable subgroups demonstrated PFS and ORR benefits compared to sunitinib, without OS improvememt.	2b
The combination of axitinib plus avelumab did not demonstrate significant OS benefit and axitinib plus toripalimab did not demonstrate significant OS benefit yet, as did benmelstobart plus anlotinib.	1b
The triplet combination cabozantinib, nivolumab, and ipilimumab (CABO-NIVO-IPI) demonsrated a PFS benefit over NIVO-IPI.	1b

Sequencing systemic therapy
Nivolumab leads to superior OS compared to everolimus in disease progression after one or two lines of vascular endothelial growth factor (VEGR)- targeted therapy.	1b
Axitinib, cabozantinib or lenvatinib can be continued if immune-related adverse events result in cessation of axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab. Re-challenge with immunotherapy requires expert support.	4
Patients who do not receive the full four doses of ipilimumab due to toxicity should continue on single-agent nivolumab, where safe and feasible. Re-challenge with combination therapy requires expert support.	4
Treatment past progression can be justified but requires close scrutiny and the support of an expert multi-disciplinary team.	1b
Nivolumab plus ipilimumab was associated with 46% grade III-IV toxicity and 1.5% treatment-related deaths. Tyrosine kinase inhibitor-based immune- oncology combination therapies were associated with grade III-V toxicity ranging between 61-72% and 1% of treatment-related deaths.	1b
In the CONTACT 3 study atezolizomab plus cabozantinib offered no benefit compared to cabozantinib alone in patients who’s cancers have previously progressed on immune checkpoint inhibition therapy.	1b

Cabozantinib as a single agent has the most robust data after first line PD1 based combination therapy.	3

Summary of evidence for systemic therapy in papillary metastatic RCC	LE
Cabozantinib improved progression-free survival (PFS) over sunitinib in patients with advanced papillary RCC without additional molecular testing.	2a
Lenvatinib plus pembrolizumab and cabozantinib plus nivolumab demonstrated response rates of 47-54% with median PFS rates > 12 months.	2a
Pembrolizumab resulted in long-term median overall survival in a single-arm study in the papillary RCC subgroup.	2a

Summary of evidence for systemic therapy in chromophobe and unclassified RCC	LE
Both mTOR inhibitors and vascular endothelial growth factor (VEGF)-targeted therapies have limited activity in metastatic non-clear cell RCC (non-cc- mRCC). There is a non-significant trend for improved oncological outcomes for sunitinib over everolimus and for cabozantinib over sunitinib.	2a
In non-cc-mRCC, sunitinib improved progression free survival over everolimus in a systematic review of phase II trials and subgroups of patients.	1a
In non—cc-mRCC lenvatinib plus pemrolizumab demonstrated clinical efficacy in different non-ccRCC subgroups.	2a

In non-cc-mRCC cabozantinib plus nivolumab demonstrated clinical efficacy in different non-ccRCC subgroups except for chromophobe RCC which were excluded from the study.	2a
Overall survival rate at twelve months was significantly higher with nivolumab plus ipilimumab compared to standard of care in non-ccRCC patients.	1b

Summary of evidence	LE
Hereditary RCC syndromes are often suggested by family history, age of onset and presence of other lesions typical for the respective syndromes.	3
Hereditary RCC tumours are predominantly found in the lowest decile, with 70% occurring in individuals aged 46 years or younger.	3
To establish whether gene variants identified in a tumour are germline, germline genetic testing must be performed.	3
In von Hippel-Lindau (VHL) and non-familial hereditary disorders-RCC tumours can be observed until a diameter of 3 cm.	3
Belzutifan leads to an objective response rate of VHL lesions of 64% at 37.8 months.	2
There is currently no approved standard first-line treatment for non-VHL hereditary or syndrom specific RCC.	3

Risk profile (*)	Oncological follow-up after date of surgery
	3 mo	6 mo	12 mo	18 mo	24 mo	30 mo	36 mo	> 3 yr () (*)	> 5 yr () (*)
Low risk of recurrence For ccRCC: Leibovich Score 0-2 For non-ccRCC: pT1a-T1b pNx-0 M0 and histological grade 1 or 2.	-	CT	-	CT	-	CT	-	CT once every two yrs	-
Intermediate risk of recurrence For ccRCC: Leibovich Score 3-5 For non-ccRCC: pT1b pNx-0 and/or histological grade 3 or 4.	-	CT	CT	-	CT	-	CT	CT once yr	CT once every two yrs
High risk of recurrence For ccRCC: Leibovich Score ≥ 6 For non-ccRCC: pT2-pT4 with any histological grade or pT any, pN1 cM0 with any histological grade	CT	CT	CT	CT	CT	-	CT	CT once yr	CT once every two yrs

Summary of evidence for surveillance following radical nephrectomy or partial nephrectomy or ablative therapies in RCC	LE
Functional follow-up after curative treatment for RCC is useful to prevent renal and cardiovascular deterioration.	4
Oncological follow-up can detect local recurrence or metastatic disease while the patient may still be surgically curable.	4
After nephron sparing surgery, there is an increased risk of recurrence for larger (> 7 cm) tumours, or when there is a positive surgical margin.	3
Patients undergoing follow-up have a better overall survival than patients not undergoing follow-up.	3
Prognostic models provide stratification of RCC risk of recurrence based on TNM and histological features.	3
In competing-risk models, risk of non-RCC-related death exceeds that of RCC recurrence or related death in low-risk patients.	3
Life expectancy estimation is feasible and may support counselling of patients on duration of follow- up.	4
Overall survival is reduced in metastatic RCC patients with symptoms of depression and distress.	2a

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