EAU Guidelines on

Renal Cell
Carcinoma
A. Bex (Chair), Y. Abu-Ghanem, J. Bedke (Vice-Chair),
D.J. Breen, U. Capitanio, S. Dabestani, M. Hora, T. Klatte,
T. Kuusk, L. Lund, L. Marconi, G. Pignot, T. Powles,
C. Suárez, M. Tran, P. Zondervan
Patient Representative: S. Bonn, R. Woodward
Guidelines Associates: R. Campi, C. Palumbo
Guidelines Office: N. Schouten

© European Association of Urology 2026

TABLE OF CONTENTS PAGE
[Link] 6
1.1 Aims and scope 6
1.2 Panel composition 6
1.3 Available publications 6
1.4 Publication history and summary of changes 6
1.4.1 Publication history 6
1.4.2 Summary of changes 6

2. METHODS 7
2.1 Data identification 7
2.2 Review 7
2.3 Future goals 7

[Link], AETIOLOGY AND PATHOLOGY 8

3.1 Epidemiology 8
3.2 Aetiology 8
3.3 Screening 9
3.3.1 Summary of evidence and recommendations for epidemiology, aetiology
and screening 9
3.4 Histological diagnosis 9
3.4.1 Clear-cell RCC 11
3.4.1.a Multilocular cystic renal neoplasm of low malignant potential 11
3.4.2 Papillary RCC 11
3.4.3 Chromophobe RCC 11
3.5 Other renal tumours 12
3.5.1 Renal medullary carcinoma (SMARCB1-deficient renal medullary carcinoma) 13
3.5.2 Carcinoma associated with end-stage renal disease; acquired cystic
disease-associated RCC 14
3.5.3 Papillary adenoma 14
3.5.4 Renal oncocytoma 14
3.5.5 Other oncocytic tumours of the kidney 14
3.5.6 Classical angiomyolipoma 14
3.5.6.a Treatment of angiomyolipoma 15
3.5.7 Cystic renal tumours 15
3.6 Summary of evidence and recommendations for the management of other renal
tumours 16

4. STAGING AND CLASSIFICATION SYSTEMS 16

4.1 Staging 16
4.2 Anatomic classification systems 17

[Link] EVALUATION 18
5.1 Symptoms 18
5.1.1 Physical examination 18
5.1.2 Laboratory findings 18
5.2 Imaging investigations 18
5.2.1 Computed tomography 19
5.2.2 Magnetic resonance imaging 19
5.2.3 Other investigations and emerging technologies 20
5.2.4 Radiographic investigations to evaluate RCC metastases 20
5.2.5 Bosniak classification of renal cystic masses 20
5.3 Renal tumour biopsy 21
5.3.1 Indications and rationale 21
5.3.2 Technique 22
5.3.3 Diagnostic yield and accuracy 22
5.3.4 Morbidity 23
5.3.5 Genetic assessment 23

2 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

 5.4 Summary of evidence and recommendations for the diagnostic assessment of RCC 23
5.5 Summary of evidence and recommendations for genetic assessment of RCC 24

[Link] FACTORS 25
6.1 Definition and classification 25
6.2 Anatomical factors 25
6.3 Histological factors 25
6.4 Clinical factors 25
6.4.1 Frailty and comprehensive geriatric assessment 26
6.4.2 Nephrological assessment 28
6.5 Molecular factors 28
6.6 Prognostic models 29
6.7 Summary of evidence and recommendations for prognostic factors 29

[Link] MANAGEMENT 31
7.1 Patient involvement in kidney cancer treatment 31
7.1.1 Recommendation on patient involvement and shared decision making 32
7.1.2 Smoking cessation 32
7.1.2.a Recommendation on smoking cessation 32
7.2 Treatment of localised RCC 32
7.2.1 Introduction 32
7.2.2 Surgical treatment 32
7.2.2.a Nephron-sparing surgery versus radical nephrectomy in localised RCC 32
7.2.2.a.1 T1 RCC 32
7.2.2.a.2 T2 RCC 33
7.2.2.a.3 T3 RCC 33
7.2.2.b Associated procedures 34
7.2.2.b.1 Adrenalectomy 34
7.2.2.b.2 Lymph node dissection for clinically negative lymph
nodes (cN0) 34
7.2.2.b.3 Embolisation 34
7.2.2.b.4 Summary of evidence and recommendations for the
treatment of localised RCC 35
7.2.3 Radical and partial nephrectomy techniques 35
7.2.3.a Radical nephrectomy techniques 35
7.2.3.a.1 Open versus laparoscopic or robotic approach 35
7.2.3.a.2 Laparoscopic versus robotic approach 35
7.2.3.a.3 Laparoscopic single port versus laparoscopic multiport
approach 35
7.2.3.b Partial nephrectomy techniques 36
7.2.3.b.1 Open versus laparoscopic approach 36
7.2.3.b.2 Open versus robotic approach 36
7.2.3.b.3 Open versus hand-assisted approach 37
7.2.3.b.4 Open versus laparoscopic versus robotic approaches 37
7.2.3.b.5 Laparoscopic versus robotic approach 37
7.2.3.b.6 Laparoscopic transperitoneal versus retroperitoneal
approach 37
7.2.3.b.7 Robotic systems 38
7.2.3.b.8 Tumour enucleation, standard partial nephrectomy and
single-port approach 38
7.2.3.b.9 Off-clamp versus on-clamp PN 38
7.2.3.b.10 Use of 3D models for PN planning 38
7.2.3.c Positive surgical margins on histopathological specimens 38
7.2.3.d Hospital volume and outcomes of PN 39
7.2.3.e Placement of a drain 39
7.2.3.f Summary of evidence and recommendations for radical and partial
nephrectomy techniques 39
7.2.4 Therapeutic approaches as alternatives to surgery 40
7.2.4.a Watchful waiting 40
7.2.4.b Active surveillance 40

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 3

 7.2.4.c Role of renal tumour biopsy before active surveillance 41
7.2.4.d Tumour ablation 41
7.2.4.d.1 Role of renal mass biopsy 41
7.2.4.d.2 Cryoablation 42
7.2.4.d.3 Radiofrequency ablation 42
7.2.4.d.4 Microwave ablation 42
7.2.4.d.5 Tumour ablation versus surgery 42
7.2.4.d.6 Stereotactic ablative radiotherapy 43
7.2.4.d.7 Other ablative techniques 44
7.2.4.d.8 Summary of evidence and recommendations for
therapeutic approaches as alternative to surgery 44
7.3 Treatment of locally advanced RCC 45
7.3.1 Introduction 45
7.3.2 Role of lymph node dissection in locally advanced RCC 45
7.3.2.a Management of clinically negative lymph nodes (cN-) in locally
advanced RCC 45
7.3.2.b Management of clinically positive lymph nodes (cN+) in locally
advanced RCC 45
7.3.3 Management of RCC with venous tumour thrombus 45
7.3.4 Management of locally advanced unresectable RCC 46
7.3.4.a Summary of evidence and recommendations for lymph node
dissection, the management of RCC with venous tumour
thrombus and unresectable tumours 48
7.3.5 Neoadjuvant and adjuvant therapy 48
7.3.5.a PD-1 Inhibition: Keynote-564 48
7.3.5.b PD-L1 inhibition: IMmotion010 49
7.3.5.c PD-1 and CTLA-4 inhibition: CheckMate 914 49
7.3.5.d Perioperative PD-1 inhibition: PROSPER 49
7.3.5.e Progression after adjuvant PD-1 therapy 50
7.3.5.f Summary of evidence and recommendations for neoadjuvant
and adjuvant therapy 52
7.4 Advanced/metastatic RCC 53
7.4.1 Local therapy of advanced/metastatic RCC 53
7.4.1.a Cytoreductive nephrectomy 53
7.4.1.a.1 Embolisation of the primary tumour 54
7.4.1.a.2 Summary of evidence and recommendations for local
therapy of advanced/metastatic renal cell carcinoma 55
7.4.2 Therapy of oligometastatic disease 55
7.4.2.a Complete versus no/incomplete metastasectomy 55
7.4.2.b Local therapies for RCC metastases 56
7.4.2.c Adjuvant treatment in cM0 patients after metastasectomy 56
7.4.2.d Summary of evidence and recommendations for local therapy
of metastases in metastatic RCC 56
7.5 Systemic therapy for advanced/metastatic RCC 57
7.5.1 Chemotherapy 57
7.5.1.a Recommendation for systemic therapy in advanced/metastatic RCC 57
7.5.2 Targeted therapies 57
7.5.2.a Tyrosine kinase inhibitors 57
7.5.2.a.1 Sunitinib 57
7.5.2.a.2 Pazopanib 57
7.5.2.a.3 Axitinib 58
7.5.2.a.4 Cabozantinib 58
7.5.2.a.5 Lenvatinib 58
7.5.2.a.6 Tivozanib 58
7.5.2.b Monoclonal VEGF antibody 58
7.5.2.c mTOR inhibitors 58
7.5.2.c.1 Temsirolimus 58
7.5.2.c.2 Everolimus 58
7.5.2.d Small molucule inhibitor. 59
7.5.2.d.1 Belzutifan 59

4 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

 7.5.2.d.2 Vascular endothelial growth factor (VEGF) targeted
therapy 59
7.5.2.e Summary of evidence and recommendations for single-agent
targeted therapy in metastatic clear-cell RCC 59
7.5.3 Immunotherapy 60
7.5.3.a Immune checkpoint inhibitors 60
7.5.3.a.1 Immuno-oncology monotherapy 60
7.5.3.b Immunotherapy/combination therapy 60
7.5.4 Therapeutic strategies 65
7.5.4.a Treatment-naïve patients with clear-cell metastatic RCC 65
7.5.4.a.1 Sequencing systemic therapy in clear-cell metastatic
RCC 65
7.5.4.a.2 Summary of evidence and recommendations for
immunotherapy in cc-mRCC 65
7.5.4.a.3 Renal tumours with sarcomatoid features 68
7.5.4.a.4 Summary of evidence and recommendation for
targeted therapy in RCC with sarcomatoid features 69
7.5.4.b Treatment of patients with non-clear-cell metastatic RCC
(general considerations) 69
7.5.4.b.1 Treatment of patients with papillary metastatic RCC 69
7.5.4.b.2 Summary of evidence and recommendations for
systemic therapy in papillary metastatic RCC 70
7.5.4.b.3 Treatment of patients with metastatic non-ccRCC
other than papillary RCC 70
7.5.4.b.4 Summary of evidence and recommendation for
systemic therapy in chromophobe and
unclassified RCC 70
7.5.4.c Treatment of patients with rare tumours 71
7.5.4.c.1 SMARCB1-deficient renal medullary carcinoma 71
7.5.4.c.2 Other rare tumours 71
7.6 Locally recurrent RCC after treatment of localised disease 72
7.6.1 Locally recurrent RCC after nephron-sparing approaches 72
7.6.2 Locally recurrent RCC after radical nephrectomy 72
7.6.3 Summary of evidence and recommendation on locally recurrent RCC after
treatment of localised disease 74

[Link] AND SYNDROME SPECIFIC RCC 74

8.1 Microphthalmia-associated transcription factors (MiTF) associated translocation
tumours 74
8.2 Management of hereditary and syndrome-specific RCC 76
8.2.1 Von Hippel-Lindau-disease-associated RCC 76
8.2.2 TFE3-rearranged RCC 77
8.2.3 TFEB-altered RCC 77
8.2.4 Combined therapy for TFE3- and TFEB-altered RCCs 77
8.2.5 Summary of evidence and recommendation for hereditary and
syndrome-specific RCC 77

9. FOLLOW-UP IN RCC 78
9.1 Introduction 78
9.2 Which imaging investigations for which patients, and when? 79
9.3 Summary of evidence and recommendations for surveillance following RN or PN
or ablative therapies in RCC 80

10. REFERENCES 81

11. CONFLICT OF INTEREST 124

12. CITATION INFORMATION 125

13. COPYRIGHT AND TERMS OF USE 125

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 5

1. INTRODUCTION
1.1 Aims and scope
The European Association of Urology (EAU) Renal Cell Cancer (RCC) Guidelines Panel has compiled these
clinical guidelines to provide urologists with evidence-based information and recommendations for the
management of RCC.

It must be emphasised that clinical guidelines present the best evidence available to the experts, but following
guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical
expertise when making treatment decisions for individual patients but rather help to focus decisions - also
taking into account personal values and preferences/individual circumstances of patients. Guidelines are not
mandates and do not purport to be a legal standard of care.

1.2 Panel composition

The EAU Guidelines Panel on RCC consists of an international multidisciplinary group of clinicians,
including urological surgeons, oncologists, methodologists, a pathologist and a radiologist, with particular
expertise in the field of renal cancer care. Since 2015, the Panel has included patient advocates to provide
a patient-centred perspective for its Guidelines. All experts involved in the production of this document
have submitted potential conflict of interest statements, which can be viewed on the EAU website Uroweb:
[Link]

1.3 Available publications

A quick reference document, the Pocket Guidelines, is available in print. This is an abridged version which may
require consultation together with the full text version. Several scientific publications are available, and all
documents are accessible through the EAU website Uroweb: [Link]
An EAU Guidelines-based chatbot is available on the EAU website, offering Guideline-derived information that
should not replace clinical expertise or individual judgement.

An EAU Guidelines app for iOS and Android devices is also available containing the Pocket Guidelines,
interactive algorithms and calculators, clinical decision support tools, Guidelines cheat sheets and links to the
extended guidelines.

1.4 Publication history and summary of changes

1.4.1 Publication history
The EAU RCC Guidelines were first published in 2000. This 2026 RCC Guidelines document presents a limited
update of the 2025 publication.

1.4.2 Summary of changes

All chapters of the 2026 RCC Guidelines have been updated, based on the 2025 version of the Guidelines.
References have been added throughout the document. Other key changes incorporated in this publication
include:
• Update throughout Chapter 3, ‘Epidemiology, aetiology and pathology,’ as well as in Table 3.2.
• Update throughout Chapter 4 on anatomic classification systems.
• New subchapter on frailty and comprehensive geriatric assessment in Chapter 6, as well as a new
flowchart and updated Section 6.4.2 on nephrological assessment.
• New summary of evidence (SoE) and recommendations in Section 6.7.
• Update in Section 7.1 regarding patient involvement in kidney cancer provided by the panel patient
representatives.
• Inclusion of new text throughout Section 7.2.3.a on radical nephrectomy and Section 7.2.3.b on partial
nephrectomy techniques, as well as inclusion of new SOE and recommendations in Section 7.2.3.d.
• New Figure 7.2.4.d.7.a on alternatives to surgery, as well as new recommendations in Figure 7.2.4.d.8 on
the therapeutic approaches as alternative to surgery.
• Updated text on the therapy of oligometastatic disease in Section 7.4.2.
• Update of the text, SoE and recommendations in Chapter 9, ‘Follow-up in RCC.

6 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

2. METHODS
2.1 Data identification
For the 2025 RCC Guidelines, new and relevant evidence has been identified, collated and appraised
through a structured assessment of the literature. A broad and comprehensive scoping exercise
covering all areas of the RCC Guidelines was carried out. Databases searched included Medline,
EMBASE, and the Cochrane Libraries, covering a time frame between 1 May 2024 and 1 May 2025.
Databases covered included Medline, EMBASE and the Cochrane Library. After de-duplication, a total
of 1,690 unique records were identified, retrieved and screened for relevance. A search strategy is
published online: [Link]

The Panels develop the recommendations within the Guidelines to prioritise clinically important care
decisions. The strength of each recommendation is determined by the balance between desirable
and undesirable consequences of alternative management strategies, the quality of the evidence
(including certainty of estimates), and the nature and variability of patient values and preferences. This
decision process, which can be reviewed in the strength rating forms which accompany each guideline
statement, addresses a number of key elements:
1. the overall quality of the evidence which exists for the recommendation [1];
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other

statistical or study related factors);
4. the balance between desirable and undesirable outcomes; and
5. the impact and certainty of patient values and preferences on the intervention.

Strong recommendations typically indicate a high degree of evidence quality and/or a favourable
balance of benefit to harm and patient preference. Weak recommendations typically indicate
availability of lower quality evidence, and/or equivocal balance between benefit and harm, and
uncertainty or variability of patient preference [2].

Additional methodology information and a list of associations endorsing the EAU Guidelines can be
found online: [Link]

2.2 Review
All publications ensuing from systematic reviews (SR)s have been peer-reviewed. The 2025 print of
the RCC Guidelines was also peer-reviewed prior to publication.

2.3 Future goals

The RCC Guideline Panel supports the focus on patient-reported outcomes, as well as the
development of clinical quality indicators [3]. The Panel identified potential quality indicators that may
help assessing quality of care:
• the proportion of patients undergoing thorax computed tomography (CT) for staging of
pulmonary metastasis;
• proportion of patients with T1aN0M0 tumours undergoing nephron-sparing surgery (NSS) as
first treatment;
• the proportion of patients with metastatic RCC (mRCC) offered systemic therapy; and
• the proportion of patients who undergo minimally invasive or operative treatment as first
treatment who die within 30 days.

The Panel have set up a database to investigate current practice in follow-up of RCC patients in a
number of European centres. Assessing patterns of recurrence and use of imaging techniques are
primary outcomes for this project.

In addition, the panel has collected data from various European datasets on atypical recurrences
following minimally invasive renal surgery to establish incidence and insight on potential causes, their
management and outcome.

Additionally, a registry for Bosniak III-IV cysts has been established to investigate if diameter of the
cyst or nodule is leading in clinical management. An SR as preparatory step has been published [4].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 7

The panel plan to perform a survey investigating the decision factors and the rate of urologists performing NSS
in patients with T1a N0M0.
The results of ongoing and new SRs will be included in future updates of the RCC Guidelines:
• Systematic review of the treatment modalities in Oligometastatic RCC with and without systemic therapy.

3. EPIDEMIOLOGY, AETIOLOGY AND

PATHOLOGY
3.1 Epidemiology
Renal cell carcinoma ranks 14th on the list of cancers, representing approximately 2% of all cancers, with the
highest incidence occurring in Western countries [5-7]. In 2022, there were an estimated 434,840 [7, 8] new
cases of RCC globally with 155,953 deaths worldwide [9]. Incidence and mortality are the highest in Europe
and Asia, whereas the age-standardised incidence rate per 100,000 person/years (age-standardised rate [ASR]
World) is the highest in Northern America and mortality in Eastern Europe. There is predominance in men over
women ASR of 13.7 and 6.4, respectively, with a higher incidence in the older population [10].

In Europe, incidence of RCC was 145,721 in 2022 with mortality of 52,347 [10], with ASR (European 2013) of 18.9
and 6.9 in 27 European Union (EU) countries [11, 12]. In 2022, Belarus, Latvia and Czechia reported the highest
overall rate of RCC in Europe [12], with estimated ASR (European 2013) for Czechia and Latvia for males being
41.3 and 37.8, respectively, while being the lowest in Cyprus, Luxembourg and Bulgaria (13.9-15.4) [13].

Mortality was lowest amongst 27 EU countries in males in Luxembourg, Cyprus and Finland, with ASR (European
2013) of 4.6, 6.9 and 7.3, respectively. In contrast, the highest mortality rates were reported in the Baltics
followed by Czechia and Slovakia (15.5-16.2, 14.7 and 14.4, respectively) [13].

Overall, there is an ongoing rise in incidence of RCC, however, mortality trends vary. In Europe, there has been a
decrease in mortality since the 1980s in Scandinavian countries and since the early 1990s in France, Germany,
Austria, the Netherlands and Italy [14].

Geographic areas and individual countries with a higher level of human development index have higher RCC
incidence and age-standardised mortality rates (all p < 0.0001) [8].

Based on the expected population growth and ageing, the incidence of RCC is projected to increase in the
coming years. Globally, 745,791 new cases and 304,861 new deaths are predicted by the year 2050. The
estimated increase in both incidence and mortality is consistent across sexes and varies considerably by
geographic area (from +19% in Europe to +106% in Africa for RCC incidence; from +39% in Europe to +103% in
Africa for RCC mortality).

3.2 Aetiology
Established risk factors include lifestyle factors such as smoking (hazard ratio [HR]: 1.23-1.58), obesity body
mass index (BMI) (> 35 vs. < 25), (HR: 1.71 [1.06-2.79]), hypertension (HR: 1.70 [1.30 2.22]) and metabolic
syndrome (relative risk [RR] 1.62 [1.41 1.87]) [6, 11, 15-19]. A total of 50.2% of patients with RCC are current or
former smokers. By histology, the proportions of current or former smokers range from 38% in patients with
chromophobe renal cell carcinoma (chRCC) to 61.9% in those with collecting duct/medullary carcinoma [20]. In an
SR, diabetes was also found to be detrimental [21]. Having a first-degree relative (FDR) with kidney cancer is also
associated with an increased risk of RCC [22]. Having one or more FDR (parents, siblings or children) with RCC
approximately doubles the risk of RCC with a higher risk increase for women than for men [23]. Moderate alcohol
consumption has a protective effect, (RR: 0.85) [24] while any physical activity level also appears to have some
protective effect [6, 8, 11, 21, 25, 26]. A number of other factors have been suggested to be associated with lower
risk of RCC, including specific dietary habits such as vegetables (HR: 0.68), coffee (HR: 0.85), tea (HR: 0.85) and
limited intake of red meat (RR: 1.46) for higher versus lower intake [27]. In contrast, a higher risk of RCC has been
associated with ultra-processed (industrially produced) food (HR: 1.42) [28] and a higher risk and occupational
exposure to specific carcinogens, but no high-quality evidence level exists [15, 29]. The most effective prophylaxis
is to avoid cigarette smoking and reduce obesity [6, 11, 15, 16]. Genetic risk factors are known to play a role in the
development of RCC (see Section 8, ‘Hereditary and syndrome specific RCC).

8 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

3.3 Screening
Despite a growing interest among both patients and clinicians in RCC screening programmes, there is a relative
lack of studies reporting the efficacy, cost-effectiveness and optimal modality for RCC screening. Urinary
dipstick is an inadequate screening tool due to low sensitivity and specificity. In addition, incidence of RCC
with non-visible haematuria is low: 0.58% [30]. No clinically validated urinary or serum biomarkers have as yet
been identified. Computed tomography cannot be recommended due to cost, radiation dose and the increased
potential for other incidental findings. A non-contrast CT in the Yorkshire Kidney Screening Trial (performed in a
prespecified risk group of smokers) ultimately yielded solid renal masses or Bosniak 3/4 cysts in 0.62%. 0.25%
participants were subsequently histologically proven to be RCCs, 0.12% oncocytomas [31]. Based on this study,
the evidence for screening in the general population remains uncertain [31]. Ultrasound (US) could be used and
has acceptable sensitivity and specificity, although it is tumour size and operator-dependant. Major barriers to
population screening include the relatively low prevalence of the disease, the potential for false positives and
overdiagnosis of slow-growing kidney tumours. Targeting high-risk individuals and/or combining detection of
RCC with other routine health screenings may represent pragmatic options to improve the cost-effectiveness
and reduce the potential harms of RCC screening [32-35]. Targeting of high-risk patient groups, e.g. those with
end-stage renal disease (ESRD) which is associated with a tenfold increased risk of developing RCC, may also
be a valid approach (see Section 3.5.2) [36]. People with two FDRs with RCC constitute a small high-risk group
that may benefit from screening [23].There is currently no evidence to support primary screening in the general
population.

3.3.1 Summary of evidence and recommendations for epidemiology, aetiology and screening

Summary of evidence LE
Several verified risk factors have been identified, including smoking, obesity and hypertension. These 2a
are considered definite risk factors for RCC.
There is no evidence to support primary screening for RCC. 4

Recommendations Strength rating

Increase physical activity, eliminate smoking and in patients with obesity reduce weight are Strong
the primary preventative measures to decrease the risk of RCC.
Do not routinely screen people for primary RCC. Weak

3.4 Histological diagnosis

Renal cell carcinomas and other renal tumours comprise a broad spectrum of histopathological entities
described in the 5th edition of the World Health Organization (WHO) classification of urogenital tumours
published in 2022 [37-39]. The 5th edition presents standard morphologic diagnostic criteria, combined with
immunohistochemistry, and relevant molecular tests, and was significantly revised as compared to the 2016
classification [40]. The global application of next-generation sequencing (NGS) will result in a diagnostic
shift from morphology to molecular analyses. Therefore, a molecular-driven renal tumour classification has
been introduced in addition to morphology-based renal tumours (Table 3.1). Examples of molecularly defined
epithelial renal tumours include SMARCB1-deficient renal medullary carcinoma, TFE3- and TFEB-rearranged
RCC, ALK-rearranged RCC and elongin C (ELOC)-mutated RCC. The most profound changes in the 2022 WHO
classification mainly relate to rare kidney tumours.

There are three main RCC types: clear cell (ccRCC), papillary (pRCC, no longer divided into type I and II) and
chRCC. The RCC type classification has been confirmed by cytogenetic and genetic analyses [40, 41] (LE: 2b).
The five-year overall survival (OS) for nonmetastatic (including N0-N1) chromophobe, papillary, clear-cell and
collecting duct RCC is 91%, 82%, 81% and 44%, respectively [42]. Sarcomatoid RCC is not a specific subtype but
essentially represents a pattern of dedifferentiation associated with adverse outcome and poor cancer-specific
survival (CSS), irrespective of the underlying RCC subtype. Sarcomatoid RCC should be graded as grade IV on
the WHO/International Society of Urological Pathology (ISUP) scale. At the time of diagnosis of sarcomatoid
RCC, only 15.3% are localised, 28.9% locally advanced and 55.8% metastatic. The five-year OS was 18.1% for all
patients and 27.1% in patients who underwent surgery [43]. Multilocular cystic renal neoplasm of low malignant
potential is a new subtype of ccRCC in the 2022 classification. A new group, ‘oncocytic and chromophobe
tumours’, encompass oncocytoma, together with chRCC and other oncocytic tumours. Other oncocytic tumours
include tumours that do not strictly fit into either the oncocytoma or chRCC subtypes [37, 44].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 9

In addition to RCC type, histological diagnosis includes evaluation of ISUP nuclear grade, sarcomatoid features,
vascular invasion, tumour necrosis, and invasion of the collecting system and peri-renal fat, pT, or even pN
categories. The four-tiered WHO/ISUP grading system has replaced the Fuhrman grading system [37, 40].

Table 3.1 World Health Organization classification of renal tumours 2022 [37, 38]

WHO classification of renal tumours 2022

1. Renal Cell Tumours
01.I Clear cell renal tumours
Clear cell RCC
Multilocular cystic renal neoplasm of low malignant potential
[Link] Papillary renal tumours
Papillary adenoma
Papillary RCC
[Link] Oncocytic and chromophobe renal tumours
Oncocytoma of the kidney
Chromophobe RCC
Other oncocytic tumours of the kidney
[Link] Collecting duct tumours
Collecting duct carcinoma
01.V Other renal tumours
Clear cell papillary renal cell tumour
Mucinous tubular and spindle cell carcinoma
Tubulocystic RCC
Acquired cystic disease-associated RCC
Eosinophilic solid and cystic (ESC) RCC
RCC Not Otherwise Specified (NOS)
[Link] Molecularly defined renal tumours
TFE3-rearranged RCCs
TFEB-altered RCC (TFEB-rearranged RCC and TFEB amplified RCC)
ELOC (formerly TCEB1)-mutated RCC
Fumarate hydratase-deficient RCC
Succinate dehydrogenase-deficient RCC
ALK-rearranged RCCs
SMARCB1-deficient renal medullary carcinoma
2. Metanephric tumours
Metanephric adenoma
Metanephric adenofibroma
Metanephric stromal tumour
3. Mixed epithelial and stromal tumour family
Mixed epithelial and stromal tumour
Adult cystic nephroma
4. Renal mesenchymal tumours
04.I Adult renal mesenchymal tumours
Classic angiomyolipoma/PEComa of the kidney
Epitheloid angiomyolipoma/epithelioid PEComa of the kidney
Renal haemangioblastoma
Juxtaglomerular cell tumour
Renomedullary interstitial cell tumour
[Link] Paediatric renal mesenchymal tumours

10 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

 Ossifying renal tumour of infancy
Congenial mesoblastic nephroma
Rhabdoid tumour of kidney
Clear cell sarcoma of kidney
5. Embryonal neoplasms of the kidney
Nephroblastic tumours
Nephrogenic rests
Paediatric cystic nephroma
Cystic partially differentiated nephroblastoma
Nephroblastoma
6. Miscellaneous tumours
Germ cell tumours of the kidney

3.4.1 Clear-cell RCC

Overall, ccRCC, representing approximately 70% of RCC [38], is well circumscribed with a pseudocapsule. The
cut surface is golden-yellow, often with haemorrhage and necrosis. Loss of chromosome 3p and mutation of
the Von Hippel-Lindau (VHL) gene at chromosome 3p25 are frequently found. The loss of VHL protein function
contributes to tumour initiation, progression and metastases. The 3p locus harbours additional ccRCC tumour
suppressor genes (UTX, JARID1C, SETD2, PBRM1, BAP1) [37]. For details regarding prognosis, see Section 6.3.

3.4.1.a Multilocular cystic renal neoplasm of low malignant potential

Indolent, exclusively cystic, multiloculated renal tumour devoid of any expansile solid growth, with clear cells
lining and low-grade nuclei. Detection of small solid expansive nodules and tumour necrosis are incompatible
with multilocular cystic renal neoplasm of low malignant potential (MCNLMP). It represents 0.5-2.5% of all
renal tumours and is a benign lesion. Long-term follow-up has shown no reports of progression, metastases or
cancer-related death [37, 38].

3.4.2 Papillary RCC

Papillary RCC is the second-most encountered morphotype of RCC accounting for 13-20% of renal epithelial
tumours. This type of RCC is usually circumscribed and characterised by papillary or tubulopapillary
architecture, without specific features of other RCCs with papillary architecture [37, 38]. Papillary RCC has
traditionally been subdivided into two types: Type I and II pRCC [40]. However, in the new 2022 WHO
classification, the former pRCC type I is now referred to as ‘pRCC of classic pattern.’ Three additional
morphologic patterns of pRCC have been introduced including: a) biphasic (alveolo-squamoid) pattern exhibiting
mostly solid growth, b) papillary neoplasm with reverse nuclear polarity, previously described as ‘oncocytic low-
grade pRCC’, and c) Warthin-like pRCC that exhibits brisk inflammation mimicking Warthin tumour of the salivary
gland.

Genetic changes of pRCC include trisomy and tetrasomy of chromosomes 7 and 17 and loss of Y-chromosome.
Mesenchymal-epithelial Transition (MET) gene mutations are more frequent in low-grade pRCC.

The typical histology of classical pattern pRCC, formerly type I pRCC (narrow papillae without any binding, and
only microcapillaries in papillae), explains its typical clinical signs. Narrow papillae without any binding and a
tough pseudocapsule explain the ideal rounded shape (Pascal’s law) and fragility (specimens have a ‘minced
meat’ structure). Tumour growth causes narcotisation of papillae, which is a source of hyperosmotic proteins
that cause subsequent ‘growth’ of the tumour, fluid inside the tumour and only a serpiginous, contrast-enhancing
margin. Stagnation in the microcapillaries explains the minimal post-contrast attenuation on CT. Classical
pattern pRCC can imitate a pathologically changed cyst (Bosniak IIF or III). The typical signs of classical pattern
pRCC are an ochre colour, frequently exophytic, extrarenal growth and low grade. A risk of renal tumour biopsy
tract seeding exists, probably due to the fragility of the tumour papillae [45, 46].

3.4.3 Chromophobe RCC

Chromophobe RCC is now grouped in ‘Oncocytic and chromophobe tumours.’ Most chRCC are discovered
incidentally in asymptomatic patients [37, 38]. Overall, chRCC presents as a pale tan, relatively homogenous
and tough, well-demarcated mass without a capsule. Most tumours are sporadic. Rare hereditary forms
include Birt-Hogg-Dubé (BHD) syndrome with mutations in folliculin and Cowden syndrome with mutations
in phosphatase and tensin homolog (PTEN) (see Chapter 8 for further information) [37, 38]. Due to its innate

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 11

nuclear atypia, chromophobe RCC cannot be graded using the WHO/ISUP (formerly Fuhrman) grading system.
An alternative grading system has been proposed but has yet to be validated and broadly accepted [37, 38, 47].
Loss of chromosomes Y, 1, 2, 6, 10, 13, 17 and 21 are typical genetic changes [37, 38]. The prognosis is relatively
good, with high five-year recurrence-free survival (RFS), and ten-year CSS. The five- and ten-year RFS rates were
94.3% and 89.2%, respectively. Recurrent disease developed in 5.7% of patients, and 76.5% presented with
distant metastases with 54% of metastatic disease diagnoses involving a single organ, most commonly bone.
Recurrence and death after surgically resected chRCC are rare. For completely excised lesions < pT2a without
coagulative necrosis or sarcomatoid features, the prognosis is excellent [48].

3.5 Other renal tumours

Other renal tumours constitute the remaining renal cortical tumours. These include a variety of uncommon,
sporadic and familial carcinomas/tumours - some only recently described - as well as a group of unclassified
carcinomas. A summary of these tumours is provided in Table 3.1, but some clinically relevant tumours and
extremely rare entities are mentioned in Table 3.2, including a summary on their management. Approximately
15% of excised renal masses are benign [49]. For hereditary and syndrome-specific RCC, see Chapter 8.

Table 3.2: Other renal cortical tumours and recommendations for treatment (strength rating: weak)

Entity Clinical relevant notes Malignant potential Treatment

Collecting duct Formerly Bellini duct carcinoma. High, very aggressive. Surgery. Systemic
carcinoma No hemoglobinopathy or Median survival 30 therapy and surgery in
SMARCB1 abnormality. Rare, months [51]. metastatic disease [52].
often presenting at an advanced
stage (N+ 44% and M1 33%
at diagnosis). The HR CSS in
comparison with ccRCC is 4.49
[37, 38, 50].
Clear-cell papillary renal Patient with ACKD, 100 times Indolent. Surgery, NSS, discuss
cell tumour greater risk compared with active surveillance.
general population [38].
Mucinous tubular and Tumour is associated with the Intermediate. Surgery, NSS.
spindle cell carcinoma loop of Henle. < 1% of renal
neoplasm. Female predilection
(3-4:1) [38].
Tubulocystic RCC Rare (< 1%). Mainly men, imaging Low (90% indolent). Surgery, NSS.
can be Bosniak III or IV.
Eosinophilic solid and Usually, alteration of TCS genes. Rarely metastatic. NSS.
cystic RCC (ESC RCC) Predominantly in adult women.
Some with TSC (tuberous
sclerosis complex) syndrome.
TFE3 re-arranged RCC Gene fusions involving TFE3 with Survival similar to clear Surgery. Systemic
one of many different partner cell RCC. therapy in metastatic
genes. Formerly translocation disease, TKI and
RCC (TRCC) Xp11.2. Appr. 40% immunotherapy [53].
of paediatric RCC and 1.6-4% of
adult RCC [24].
TFEB altered (rearranged Gene fusions involving the TFEB More indolent than the Surgery.
and amplified) RCC transcription factor, typically via TFE3-rearranged RCC, Systemic therapy in
a t(6;11)(p21;q12) translocation with fewer than 10% metastatic - PD-L1
resulting in a MALAT1-TFEB gene of cases resulting in inhibitor therapy [53].
fusion. Formerly translocation patient death.
RCC t(6;11). Less common than
TFE3-rearranged RCC. Appr. 100
cases in the literature [38]. TFEB-
amplified in older patient and has
a worse prognosis.

12 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

ELOC (formerly TCBE1)- Twenty cases described in Indolent. Only two NSS.
mutated RCC literature [37, 38]. Typically, T1. metastatic cases
described.
Fumarate hydratase- Formerly hereditary Often aggressive. Immediate surgery.
deficient RCC [For leiomyomatosis and RCC- »75% of cases In metastatic disease,
more information, associated RCC. Alterations staged as pT3-4 at bevacizumab, erlotinib,
please review Chapter in the FH gene. Autosomal nephrectomy. immunotherapy [53].
8 on hereditary kidney dominant. 21-30% lifetime Genetic counselling
tumours] risk of RCC [54]. Cutaneous in the family. Imaging
leiomyomas, female uterine screening in relatives
leiomyoma or leiomyosarcoma. [54].
More common in males. Median
age 44 years [37, 44, 55].
Succinate Rare. 0.05-0.2 % of all RCCs. A metastatic rate of Surgery, NSS. Long-
dehydrogenase- 11%. term follow-up and
deficient RCC (SDH- surveillance for
deficient RCC) [For other SDH-deficient
more information, neoplasms (i.e.
please review Chapter paraganglioma,
8 on hereditary kidney SDH-deficient
tumours] gastrointestinal stromal
tumour, and pituitary
adenoma) is indicated
for cases associated
with germline mutation
[23].
ALK-rearranged RCC Gene fusions involving anaplastic Low (90% indolent). Surgery, NSS. In
lymphoma kinase gene (ALK) at systemic disease, ALK
chromosome 2p23. Fewer than kinase inhibitors such a
100 cases described. [37, 38]. sentrectinib [53].
Metanephric tumours Divided into metanephric Benign. NSS.
adenoma, adenofibroma and
metanephric stromal tumours.
Mixed epithelial and Encompasses two benign Benign. Active surveillance.
stromal renal tumour lesions - mixed epithelial and NSS.
stromal tumour (MEST) of the
kidney (MEST) and adult cystic
nephroma. Imaging - Bosniak
type III or IIF/IV. Overwhelmingly
in women (7:1).
Renal cysts/cystic Simple cysts are frequently Mostly benign. Treatment or follow-
lesions occurring, while occurring up recommendation
septa, calcifications and solid based on Bosniak
components require follow-up classification.
and/or management.
ACKD: Acquired Cystic Kidney Disease; ALK: Anaplastic Lymphoma Kinase; NSS: Nephron-Sparing Surgery;
SMARCB1: SWI/SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily B, Member 1;
TCS: Tuberous Sclerosis Complex; TFEB: Transcription Factor EB.

3.5.1 Renal medullary carcinoma (SMARCB1-deficient renal medullary carcinoma)

Renal medullary carcinoma (RMC) (referred to as SMARCB1-deficient RMC in the 2022 WHO Classification)
is a very rare tumour, comprising < 0.5% of all RCCs [56], predominantly diagnosed in young adults of African
ancestry (median age 28 years) with sickle haemoglobinopathies (including sickle cell trait). Renal medullary
carcinoma has a male predominance of 2:1 and is mainly centrally located with ill-defined borders. Renal
medullary carcinoma is one of the most aggressive RCCs [57, 58] and most patients (±67%) will present
with metastatic disease [57, 59]. Even patients who present with seemingly localised disease may develop
unequivocal metastases shortly (within weeks) after diagnosis (for treatment, see Chapter 7). Apart from the
RMC described above, some patients present with identical tumours without haemoglobinopathy. Such tumours
have been described as ‘unclassified RCC with medullary phenotype’ [37].

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3.5.2 Carcinoma associated with end-stage renal disease; acquired cystic disease-associated RCC
Cystic degenerative changes (acquired cystic kidney disease [ACKD]) and a higher incidence of RCC, are typical
features of ESRD. Renal cell carcinomas of native end-stage kidneys are found in approximately 4% of patients
with ESRD. Their lifetime risk of developing RCCs is at least ten times higher than in the general population.
Compared with sporadic RCCs, RCCs associated with ESRD are generally multicentric and bilateral, found in
younger patients (mostly male), and are less aggressive. Whether the relatively indolent outcome of tumours in
ESRD is due to the mode of diagnosis or a specific ACKD-related molecular pathway still has to be determined.
Although the histological spectrum of ESRD tumours is like that of sporadic RCC; pRCC occur relatively more
frequently [44, 60]. A specific subtype of RCC occurring only in end-stage kidneys has been described as
‘acquired cystic disease-associated RCC’ (ACD-RCC). Tumours present exclusively in patients with ACKD, usually
after long-term dialysis. The vast majority occur in men. Tumours are often multiple and bilateral and, in most
cases, have an indolent clinical behaviour, although aggressive courses have been documented [37].

3.5.3 Papillary adenoma

These tumours have a papillary or tubular architecture of low nuclear grade and may be up to 15mm in diameter
or smaller, according to the 2022 WHO classification [37].

3.5.4 Renal oncocytoma

Oncocytoma is a benign tumour representing 4-7% of all solid renal tumours and 30% of benign surgically
removed kidney masses are contributed to oncocytomas [40, 61, 62]. The diagnostic accuracy of imaging
modalities (CT, magnetic resonance imaging [MRI]) in renal oncocytoma is limited and histopathology remains
the only reliable diagnostic modality [40, 61]. However, 99mTc-sestamibi (SestaMIBI, MIBI) SPECT/CT has
shown promising initial results for the differentiation between benign and low-grade RCC [63-66]. Standard
treatment for renal oncocytoma is similar to that of other renal tumours: surgical excision by partial or radical
nephrectomy (RN) with subsequent histopathological verification. However, due to the inability of modern
imaging techniques to differentiate benign from malignant renal masses, there is a renewed interest in renal
mass biopsy (RMB) prior to surgical intervention. Oncocytic renal neoplasms diagnosed by RMB were found to
be oncocytoma in 64% of cases, the remainder of the tumours were mainly chRCC (18.7% including 6.3% hybrid
oncocytic/chromophobe tumours, which have now been grouped histologically with chRCC) [37, 38], other RCCs
(12.5%), and other benign lesions (4.2%) [67, 68]. The 2022 WHO classification strictly excludes that a definitive
diagnosis of oncocytoma be performed on a needle-core biopsy (see Section 5.3). The majority of oncocytomas
slowly progress in size with an annual growth rate of approximately 2mm [61]. Preliminary data show that active
surveillance (AS) may be a safe option to manage oncocytoma in appropriately selected patients. There are no
reports of distant metastases or disease-related death for oncocytoma on AS [69]. Potential triggers to change
management of patients on AS are not well defined [70, 71].

3.5.5 Other oncocytic tumours of the kidney

Other oncocytic tumours of the kidney are a heterogeneous group of oncocytic tumours not classifiable as
oncocytoma, chRCC or other tumour types with eosinophilic features. These tumours are typically indolent,
therefore, it is important to distinguish such low-grade tumours from the high-grade unclassified RCCs
that typically behave aggressively. In the setting of BHD syndrome (see Chapter 8), tumours with such
intermediate features (hybrid oncocytic tumours) also exist, typically being multifocal and bilateral. As this is a
heterogeneous tumour group, it is likely that new subtypes of renal neoplasia will emerge. There are already two
emerging entities: eosinophilic vacuolated tumour (EVT) and low-grade oncocytic tumour (LOT) [37].

3.5.6 Classical angiomyolipoma

Classical angiomyolipoma (AML)/perivascular epithelioid cell tumours (PEComas) of the kidney is a benign
mesenchymal tumour, which can occur sporadically or as part of tuberous sclerosis complex [72]. Overall
prevalence is 0.44%, with 0.6% in female and 0.3% in male populations. Only 5% of these patients present
with multiple AMLs [73]. Angiomyolipoma belongs to a family of so-called PEComas, characterised by the
proliferation of perivascular epithelioid cells. Some PEComas can behave aggressively and even metastasise,
while classic AMLs are completely benign [40, 74, 75]. Ultrasound, CT and MRI often lead to the diagnosis of
AMLs due to the presence of adipose tissue. However, in fat-poor AML, diagnostic imaging cannot reliably
identify these lesions. Percutaneous biopsy is rarely useful. Renal tumours that cannot be clearly identified as
benign during the initial diagnostic workup should be treated according to the recommendations provided for
the treatment of RCC. In tuberous sclerosis, AML can be found in enlarged lymph nodes (LNs), which does not
represent metastatic spread but a multicentric spread of AMLs. In rare cases, an extension of a non-malignant
thrombus into the renal vein or inferior vena cava (IVC) can be found, associated with an angiotrophic-type
growth of AML. Epithelioid AML, a very rare variant of AML, consists of at least 80% epithelioid cells and with
mean age of onset of 50 years (range 30-80 years) without gender predilection [74, 75]. Epithelioid AMLs are

14 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

potentially malignant, with a variable proportion of cases with aggressive behaviour [76]. Criteria to predict the
biological behaviour in epithelioid AML were proposed by the WHO 2022 [37, 38]. Angiomyolipoma, in general,
has a slow and consistent growth rate and minimal morbidity [77]. Subtypes of AML are oncocytic AML and
AML with epithelial cysts [37].

In some cases, larger AMLs can cause local pain. The main complication of AMLs is spontaneous bleeding
in the retroperitoneum or into the collecting system, which can be life threatening. Bleeding is caused by
spontaneous rupture of the tumour. Little is known about the risk factors for bleeding, but it is believed to
increase with tumour size and may be related to the angiogenic component of the tumour that includes irregular
blood vessels [77]. The major risk factors for bleeding are tumour size, grade of the angiogenic component, and
the presence of tuberous sclerosis.

3.5.6.a Treatment of angiomyolipoma

Active surveillance is the most appropriate option for most AMLs (48%). In a group of patients on AS, only
11% of AMLs showed growth, and spontaneous bleeding was reported in 2%, resulting in active treatment in
5% of patients [77] (LE: 3). The association between AML size and the risk of bleeding remains unclear, and
the traditionally used 4cm cut-off should not per se trigger active treatment [77]. When surgery is indicated,
if technically feasible, NSS is the preferred option. Main disadvantages of less invasive selective arterial
embolisation (SAE) are more recurrences and a need for secondary treatment (0.85% for surgery vs. 31% for
SAE). For thermal ablation, only limited data are available, and this option is used less frequently [77].

Active treatment (SAE, surgery or ablation) should be instigated in case of persistent pain, ruptured AML (acute
or repeated bleeding) or in case of a very large AML. Specific patient circumstances may influence the choice
to offer active treatment, such as patients at high risk of abdominal trauma, females of childbearing age, or
patients in whom follow-up or access to emergency care may be inadequate. Selective arterial embolisation is
an option in case of life-threatening AML bleeding.

In patients diagnosed with tuberous sclerosis, size reduction of often-bilateral AMLs can be induced by
inhibiting the mTOR pathway using everolimus, as demonstrated in randomised controlled trials (RCTs) [78, 79].
In a small phase II trial (n = 20), efficacy of everolimus was demonstrated in sporadic AML as well. A 25% or
greater reduction in tumour volume at four and six months was demonstrated in 55.6% and 71.4% of patients,
respectively. However, 20% of patients were withdrawn due to toxicities and 40% self-withdrew from the study
due to side effects [80].

3.5.7 Cystic renal tumours

Cystic renal lesions are classified according to the Bosniak classification (see Section 5.2.5). Bosniak I and
II cysts are benign lesions which do not require follow-up [81]. Bosniak IV cysts are mostly (83%) malignant
tumours with pseudo-cystic changes only [82]. Bosniak IIF and III cysts remain challenging for clinicians. The
differentiation of benign and malignant tumour into categories IIF/III is based on imaging - mostly CT - with an
increasing role of MRI and contrast-enhanced US (CEUS). Computed tomography shows poor sensitivity (36%)
and specificity (76%; κ [kappa coefficient] = 0.11) compared with 71% sensitivity and 91% specificity (κ = 0.64)
for MRI and 100% sensitivity and 97% specificity for CEUS (κ = 0.95) [83]. Surgical and radiological cohorts
pooled estimates show a prevalence of malignancy of 0.51 (0.44-0.58) in Bosniak III and 0.89 (0.83-0.92) in
Bosniak IV cysts, respectively. In an SR, less than 1% of stable Bosniak IIF cysts showed malignancy during
follow-up. Twelve percent of Bosniak IIF cysts had to be reclassified to Bosniak III/IV during radiological follow-
up, with 85% of these showing malignancy, which is comparable to the malignancy rates of Bosniak IV cysts
[81]. The updated Bosniak classification strengthens the classification and includes also MRI [84] and even
CEUS diagnostic criteria [85].

The most common histological types for Bosniak III cysts are ccRCC, with pseudo-cystic changes and low
malignant potential [86, 87]; multilocular cystic renal neoplasm of low malignant potential (see Section 3.4.1.a);
classical pattern pRCC (very low malignant potential); benign multilocular cyst; benign group of mixed epithelial
and stromal renal tumour (mixed epithelial and stromal tumour of the kidney and adult cystic nephroma);
and other rare entities. Surgery in Bosniak III cysts will result in overtreatment in 49% of the tumours, which
are lesions with a low malignant potential. In view of the excellent outcome of these patients in general, a
surveillance approach is an alternative to surgical treatment [81, 84, 88, 89]. A SR described AS as a safe initial
strategy for selected patients with cystic renal masses, particularly Bosniak IIF [4].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 15

3.6 Summary of evidence and recommendations for the management of other renal tumours

Summary of evidence LE
A variety of renal tumours exist, approximately 15% of which are benign. 3
The most common renal tumours are three malignant types of RCC (clear cell, papillary and 3
chromophobe) and two benign renal tumours (oncocytoma and angiomyolipoma).
A definitive histopathological diagnosis of oncocytoma cannot be made on a needle-core biopsy, 3
because chRCC can show intratumoural heterogeneity with areas very similar to oncocytoma.
Histological workup and results of AS of Bosniak III cysts shows low risk of malignant potential/course. 2

Recommendations 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 Weak
acceptable alternative to surgery or ablation.
Treat angiomyolipoma (AML) with selective arterial embolisation or nephron-sparing surgery in: Weak
• large tumours (a recommended threshold of intervention does not exist);
• females of childbearing age;
• patients in whom follow-up or access to emergency care may be inadequate;
• persistent pain or acute or repeated bleeding episodes.
Offer systemic therapy (everolimus) to patients with surgically unresectable AMLs which are Weak
not amenable to embolisation and require therapy.

4. STAGING AND CLASSIFICATION SYSTEMS

4.1 Staging
The Tumour Node Metastasis (TNM) classification system is recommended for clinical and scientific use [90].
Tumour size, venous invasion, renal capsular invasion, adrenal involvement, LN and distant metastasis are
included in the TNM classification system (Table 4.1). However, some uncertainties remain:
• The sub-classification of T1a versus T1b tumours using a cut-off of 4cm might not be optimal in NSS for
localised cancer [91]. A cut-off of 3cm has been proposed, particularly for its implications for decision-
making [91].
• The value of size stratification of T2 tumours has been questioned [92], as well.
• Renal sinus fat invasion might carry a worse prognosis than perinephric fat invasion but is nevertheless
included in the same pT3a stage group [93-96] (LE: 3).
• Sub T-stages (pT2b, pT3a, pT3c and pT4) may overlap [97]:
- N status should be better stratified to discriminate by burden of lymph node involvement (size, number
and morphology) with a view to considering extensive local regional lymph node disease as an M status.
- M status would require sub stratification according to the metastatic burden. For adequate M staging,
accurate preoperative imaging (chest and abdominal CT) should be performed [98, 99] (LE: 4).

The TNM classification should not be considered the only criterion for clinical decision-making, but patient’s
condition, comorbidities and wishes are of fundamental importance to select the most optimal treatment.
The EAU panel proposed a clinically guided RCC staging classification in 2022, based on changes observed in
the management of small renal masses (SRM) and locally advanced and metastatic disease [91]. A proposed
imaging analysis of Tumour Contour Irregularity might be a valuable tool to enhance the preoperative staging
between T1 and T3a RCCs for treatment decisions [100], as well.

16 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Table 4.1: 2017 TNM classification system [101]

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 perirenal 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

A help desk for specific questions about TNM classification is available at [Link]
*Adapted based on the American Joint Committee on Cancer (AJCC), 8th Edn. 2017 [94].

4.2 Anatomic classification systems

Objective anatomic classification systems, such as the Preoperative Aspects and Dimensions Used for an
Anatomical (PADUA) classification system, the SPARE score [103] the R.E.N.A.L. nephrometry score, the
C-index, the Arterial Based Complexity (ABC) Scoring System, DAP score [104], and the Zonal NePhRO scoring
system, have been proposed to standardise the description of renal tumours [105-107], while other tools
such as the MAP score [108] assess adherent perinephric fat and predict the risk of intra- and postoperative
complications during partial nephrectomy. These systems include assessment of tumour size, exophytic/
endophytic properties, proximity to the collecting system and renal sinus, and anterior/posterior or lower/upper
pole location. Increasing tumour shape irregularity on imaging is associated with an increased risk of pT3a
upgrading and grade 3-4 disease, but the positive margin rate was similar [109]. In a head-to-head comparison
of all the available anatomical classification systems [110], a dedicated uroradiologist prospectively reviewed
preoperative CT scan to assign points to variables of interest included in RENAL, PADUA, SPARE, C-Index, DAP
and MAP score in 202 RCC surgical candidates. The primary outcome was surgical success, defined as PN
completion, absence of grade > II Clavien-Dindo complications, ischemia time ≤ 20min., and negative surgical
margins. The secondary outcome was PN completion relative to RN. At multivariable analyses, all the scores,

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 17

scores independently predicted both outcomes (p < 0.001). However, the highest predictive accuracy for surgical
success and PN completion was recorded for SPARE (AUC: 0.79 and 0.89) [110].

The use of those anatomic classification systems is helpful. The systems allow a standardised preoperative
assessment, surgical decision support, perioperative risk prediction, patient counselling and outcome
comparison across centres, as well as objective prediction of potential morbidity of NSS and tumour ablation
techniques. However, when selecting the most optimal treatment option, anatomic scores must be considered
together with patient features and surgeon experience.

5. DIAGNOSTIC EVALUATION
5.1 Symptoms
Many renal masses remain asymptomatic until the late disease stages. The majority of RCCs are detected
incidentally by means of non-invasive imaging investigating various non-specific symptoms and other
abdominal diseases [111, 112] (LE: 3). In a retrospective observational cohort study, 60% of patients overall, 87%
of patients with stage T1a renal tumours and 39% of patients with stage III or IV disease presented incidentally
[113]. The classic triad of flank pain, visible haematuria and palpable abdominal mass is rare (0.6%) [113].
Patients who have tumours with local symptoms or systemic symptoms correlate with aggressive histology,
advanced disease and poorer outcomes [114, 115] (LE: 3). The increasing detection of incidental tumours is
found in females and older patients with a better prognosis and lower stage [115]. Paraneoplastic syndromes
(PNS) are found in approximately 33% of patients with symptomatic RCCs, but resolution of PNS occurred
in 52% of patients after nephrectomy [116, 117] (LE: 4). Some symptomatic patients present with symptoms
caused by metastatic disease, such as bone pain or persistent cough [118] (LE: 3).

5.1.1 Physical examination

Physical examination has a limited role in RCC diagnosis. However, the following findings should prompt
radiological examinations:
• palpable abdominal mass;
• palpable cervical lymphadenopathy;
• non-reducing varicocele and bilateral lower extremity oedema, which suggests venous involvement.

5.1.2 Laboratory findings

Commonly assessed laboratory parameters are serum creatinine, estimated glomerular filtration rate (e-GFR),
complete cell blood count, C-reactive protein (CRP) or erythrocyte sedimentation rate, liver function study,
alkaline phosphatase, lactate dehydrogenase (LDH) [119], coagulation study, and urinalysis (LE: 4). For central
renal masses abutting or invading the collecting system, urinary cytology and possibly endoscopic assessment
should be considered to exclude urothelial cancer (LE: 4).

Split renal function should be estimated using renal scintigraphy in the following situations [120, 121] (LE: 2b):
• when renal function is compromised, as indicated by increased serum creatinine or significantly
decreased e-GFR;
• when renal function is clinically important, e.g. in patients with a solitary kidney or multiple or
bilateral tumours.

Renal scintigraphy is an additional diagnostic option in patients at risk of future renal impairment due to
comorbid disorders.

5.2 Imaging investigations

Most renal tumours are diagnosed by abdominal US or CT performed for other medical reasons [113] (LE: 3).
Renal masses are classified as solid or cystic based on imaging findings.

With solid renal masses, the most important criterion for differentiating malignant lesions is the presence of
enhancement [122] (LE: 3). Traditionally, US, CT and MRI are used for detecting and characterising renal masses.
Most renal masses are diagnosed accurately by imaging alone.

18 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

5.2.1 Computed tomography
Imaging must be performed unenhanced, in an early arterial phase, and in a parenchymal phase with
intravenous contrast material to demonstrate enhancement. In CT imaging, enhancement in renal masses is
determined by comparing Hounsfield units (HU) before and after contrast administration. A change of fifteen
HU or more in the solid tumour parts demonstrates enhancement and thus vital tumour parts [123] (LE: 3).
Abdominal CT with contrast provides information on [124]:
• function and morphology of the contralateral kidney [125] (LE: 3);
• primary tumour extension;
• venous involvement;
• enlargement of locoregional LNs;
• condition of the adrenal glands and other solid organs (LE: 3).

Abdominal contrast-enhanced CT (CECT) angiography is useful in selected cases when detailed information
on the renal vascular supply is needed [126, 127]. If the results of CT are indeterminate, CEUS is a valuable
alternative to further characterise renal lesions [128-131] (LE: 1b).

5.2.2 Magnetic resonance imaging

Magnetic resonance imaging may provide additional information on venous involvement if the extent of an
IVC tumour thrombus is poorly defined on CT [132, 133] (LE: 3). In MRI, especially high-resolution, T2-weighted
images provide a superior delineation of the uppermost tumour thrombus, as the inflow of the enhanced blood
may be reduced due to extensive occlusive tumour thrombus growth in the IVC. The T2-weighted image with its
intrinsic contrast allows a good delineation [133].

Magnetic resonance imaging is indicated in patients who are allergic to intravenous CT contrast medium and
in pregnancy without renal failure [133, 134] (LE: 3). Magnetic resonance imaging allows the evaluation of
a dynamic enhancement without radiation exposure. Advanced MRI techniques such as diffusion-weighted
imaging (DWI) and perfusion-weighted imaging are being explored for renal mass assessment [135]. The use of
multiparametric MRI (mpMRI) to diagnose ccRCC by means of a clear cell likelihood score (ccLS) in SRMs was
reported [136]. The ccLS is a five-tier classification that denotes the likelihood of a mass representing ccRCC,
ranging from ‘very unlikely’ to ‘very likely.’ The authors prospectively validated the diagnostic performance of
ccLS in 57 patients with cT1a tumours and found a high diagnostic accuracy. The diagnostic performance of
mpMRI-based ccLS was further validated in a larger retrospective cohort (n = 434) across all tumour sizes and
stages [137], and ccLS was found to be an independent prognostic factor for identifying ccRCC.

For the diagnosis of complex renal cysts (Bosniak IIF-III) MRI may be preferable. The accuracy of CT is limited
in these cases, with poor sensitivity (36%) and specificity (76%; κ = 0.11). Due to a higher sensitivity for
enhancement, MRI showed a 71% sensitivity and 91% specificity (κ = 0.64). Contrast-enhanced US showed high
sensitivity (100%) and specificity (97%), with a negative predictive value of 100% (κ = 0.95) [83].

In younger patients and females who are worried about the radiation exposure of frequent CT scans, MRI
can be offered as alternative, although only limited data exist correlating diagnostic radiation exposure to the
development of secondary cancers [138].

An SR and meta-analysis [139] compared the diagnostic performance of CEUS versus CECT and contrast-
enhanced MRI (CEMRI) in the assessment of benign and malignant cystic and solid renal masses. Sixteen
studies were included in the pooled analysis. The results suggested comparable diagnostic performance
of CEUS compared with CECT (pooled sensitivity 0.96 [95% CI: 0.94-0.98], vs. 0.90 [95% CI: 0.86-0.93], for
studies with a final diagnosis of benign or malignant renal masses by pathology), and CEUS versus CEMRI
(pooled sensitivity 0.98 [95% CI: 0.94-1.0], vs. 0.78 [95% CI: 0.66-0.91] for studies with final diagnosis by
pathology report or reaffirmed diagnosis by follow-up imaging without pathology report). However, there were
significant limitations in the data, including very few studies for CEMRI, clinical and statistical heterogeneity and
inconsistency, and high risks of confounding.

Computed tomography or MRI allows accurate diagnosis of RCC but cannot reliably distinguish oncocytoma and
fat-free AML from malignant renal neoplasms [140-143] (LE: 3).

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 19

5.2.3 Other investigations and emerging technologies
Renal arteriography and inferior venacavography have a limited role in the workup of selected RCC patients (LE:
3). In patients with any sign of impaired renal function, an isotope renogram and total renal function evaluation
should be considered to optimise treatment decision-making [120, 121] (LE: 2a). 18FDG positron-emission
tomography (PET) is not recommended in primary staging. [128, 144] (LE: 1b).

Emerging technologies have a growing body of evidence with regard to prostate-specific membrane antigen
(PSMA) positron emission tomography (PET)-CT [145-148], 99TC sestamibi SPECT/CT [63-66, 149] and 89Zr-DFO-
Girentuximab PET-CT [150] for differentiation of RCC subtypes, differentiation between benign tumours and
RCC, and differentiation between high-grade from low-grade tumours. Additionally, some of these modalities
are being evaluated for staging purposes [65, 147]. Currently, the level of published evidence is not sufficient in
terms of external validation to allow any guideline recommendation to be made.

In an SR and meta-analysis from 64 studies, mainly based on CT scan imaging, AI algorithms showed
acceptable performance compared to clinicians in the detection and classification of RCC [151]. However,
heterogeneity and inconsistency between studies underscore the necessity for cautious interpretation and the
need for further prospective studies. A retrospective observational study showed that deep learning models can
predict the likelihood of malignant and aggressive pathology of a renal mass based on preoperative multiphase
CT images [152].

These novel imaging tools may aid in patient management by providing a comprehensive virtual biopsy with
information on tumour histology and thereby disease prognosis [152].

5.2.4 Radiographic investigations to evaluate RCC metastases

Chest CT is accurate for chest staging [98, 99, 153-155] (LE: 3). The use of nomograms to calculate risk of
lung metastases has been proposed based on tumour size, clinical stage and presence of systemic symptoms
[156, 157]. These are based on large, retrospective datasets, and suggest that chest CT may be omitted
in patients with cT1a and cN0, and without systemic symptoms, anaemia or thrombocythemia, due to the
low incidence of lung metastases (< 1%) in this group of patients [158]. There is a consensus that most
bone metastases are symptomatic at diagnosis. Therefore, routine bone imaging is not generally indicated
[153, 159, 160] (LE: 3). However, bone scan, brain CT or MRI can be used in the presence of specific clinical or
laboratory signs and symptoms [159, 161, 162] (LE: 3). A prospective comparative blinded study involving 92
consecutive mRCC patients treated with first-line vascular endothelial growth factor receptor (VEGFR)-tyrosine
kinase inhibitor (TKI) (median follow-up 35 months) found that whole-body DWI/MRI detected a statistically
significant higher number of bony metastases compared with conventional thoraco-abdominopelvic contrast-
enhanced CT, with higher number of metastases being an independent prognostic factor for progression-free
survival (PFS) and OS [163].

The incidence of brain metastasis without neurological symptoms was retrospectively evaluated in 1,689 mRCC
patients selected to be included in 68 clinical trials between 2001-2013 [164]. All patients had a mandatory
brain screening by CT/MRI. Seventy-two patients (4.3%) were diagnosed with occult brain metastases, of whom
39% multifocal. Most patients (61%) were International Metastatic Renal Cancer Database Consortium (IMDC)
intermediate risk and 26% were favourable risk. A majority (86%) of the patients had > 2 extracranial metastatic
sites, including lung metastases in 92%. After predominantly radiotherapy, performed in 93% of patients, a
median OS of 10.3 months (range 7.0-17.9 months) was observed.

5.2.5 Bosniak classification of renal cystic masses

This system classifies renal cysts into five categories, based on CT imaging appearance, to predict malignancy
risk [165, 166] (LE: 3), and also advocates treatment for each category (Table 5.1). An updated Bosniak
classification (2019) strengthened the classification and included MRI diagnostic criteria [84], however, it
requires further validation. According to two meta-analyses, the risk of malignancy of Bosniak IIF-III may be
higher than with the old classification [167, 168]. The latest meta-analysis, which includes 12 studies reporting
975 cystic renal masses assessed by Bosniak 2019 with histopathology as reference with at least five years of
imaging follow-up, showed malignancy BII 9%, BIIF 26%, B III 80% and B IV 88% [168]. The imaging report should
therefore identify which classification has been used. Lastly, the management of cystic renal tumours is also
discussed in Section 3.5.7.

20 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Table 5.1: Bosniak classification of renal cysts updated 2019 [75]

Bosniak classification / CT MRI

Imaging modality
1 (Benign) Well-defined, thin (≤ 2mm) smooth wall; Well-defined, thin (≤ 2mm) smooth
homogeneous simple fluid (-9 to 20 HU); wall; homogeneous simple fluid (signal
no septa or calcifications; the wall may intensity similar to CSF); no septa or
enhance calcifications; the wall may enhance
2 (Benign) 1. C ystic masses with thin (≤ 2mm) and 1. C
 ystic masses with thin (≤ 2mm)
few (1-3) septa; septa and wall may and few (1-3) enhancing septa; any
enhance; may have calcification of non-enhancing septa; may have
any type calcification of any type
2. Homogeneous hyperattenuating 2. H
 omogeneous masses markedly
(≥ 70 HU) masses at non-contrast CT hyperintense at T2-weighted imaging
3. Homogeneous non-enhancing (similar to CSF) at non-contrast MRI
masses. 20 HU at renal mass protocol 3. H
 omogeneous masses markedly
CT, may have calcification of any hyperintense at T1-weighted
type† imaging (approximately 32.5 normal
4. Homogeneous masses -9 to 20 HU at parenchymal signal intensity) at non-
non-contrast CT contrast MRI
5. Homogeneous masses 21 to 30 HU at
portal venous phase CT
6. Homogeneous low-attenuation
masses that are too small to
characterise
2F (Follow-up, up to Cystic masses with a smooth minimally 1. C ystic masses with a smooth
five years. Some are thickened (3mm) enhancing wall, or minimally thickened (3mm) enhancing
malignant.) smooth minimal thickening (3mm) of wall, or smooth minimal thickening
one or more enhancing septa, or many (3mm) of one or more enhancing
(≥ 4 mm) smooth thin (≤ 2mm) enhancing septa, or many (≥ 4mm) smooth thin
septa (≤ 2mm) enhancing septa
2. C
 ystic masses that are
heterogeneously hyperintense at
unenhanced fat-saturated T1-weighted
imaging
3 (Surgery or AS - see One or more enhancing thick (≥ 4mm One or more enhancing thick (≥ 4mm
Chapter 7. Over 50% are width) or enhancing irregular (displaying width) or enhancing irregular (displaying
malignant.) ≤ 3mm obtusely margined convex ≤ 3mm obtusely margined convex
protrusion[s]) walls or septa protrusion[s]) walls or septa
4 (Surgery. Most are One or more enhancing nodule(s) One or more enhancing nodule(s)
malignant.) (≥ 4mm convex protrusion with obtuse (≥ 4mm convex protrusion with obtuse
margins, or a convex protrusion of any margins, or a convex protrusion of any
size that has acute margins size that has acute margins)
AS: Active Surveillance; CSF: Cerebrospinal Fluid; CT: Computed Tomography; HU: Hounsfield Units; MRI: Magnetic
Resonance Imaging

5.3 Renal tumour biopsy

5.3.1 Indications and rationale
Percutaneous biopsy can reveal histology of radiologically indeterminate renal masses and can be considered in
patients who are candidates for AS of small masses, to obtain histology before ablative treatments, and to select
the most suitable medical and surgical treatment strategy in the setting of metastatic disease [169-174] (LE: 3).

A multicentre study assessing 542 surgically removed SRMs showed that the likelihood of benign findings at
pathology is significantly lower in centres where biopsies are performed (5% vs. 16%), suggesting that biopsies
can reduce surgery for benign tumours and the potential for short-term and long-term morbidity associated
with these procedures [175]. In a series of patients who underwent a percutaneous biopsy for an SRM, active
treatment (surgery or cryotherapy) was avoided in 50/182 patients (27.5%) because of a benign diagnosis at
biopsy [176].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 21

However, the 2022 WHO classification categorically precludes establishing a definitive diagnosis of oncocytoma
on needle-core biopsy, which will impact on the utility of percutaneous biopsy in the diagnostic pathway
for mitigating overtreatment of benign renal lesions. Consequently, the urological community must remain
cognisant of the substantial proportion of benign lesions identified following partial or radical nephrectomy (see
also Section 3.5.4).

Renal biopsy is not indicated in comorbid and frail patients, who can be considered only for conservative
management (watchful waiting [WW]), nor is it necessary in patients for whom surgery is planned, regardless of
biopsy results (LE: 4).

Core biopsies of cystic renal masses have a lower diagnostic yield and accuracy and are not recommended,
unless areas with a solid pattern are present (Bosniak IV cysts) [169, 172, 177] (LE: 2b/3). Histological
characterisation by percutaneous biopsy of undefined retroperitoneal masses at imaging may be useful for
decision-making, especially in the younger patient population.

The use of biopsy in the diagnostic pathway of renal tumours is approximately 20% and remains contentious,
with barriers such as clinician bias and concerns regarding seeding persist in limiting adoption into routine
practice [178]. A modified Delphi consensus statement, coproduced by patients and clinicians, on the current
role of biopsy in SRM identified the need for more evidence that a biopsy changes a patient’s treatment choice
and reduces the number of benign nephrectomies to improve utility [179].

5.3.2 Technique
Percutaneous sampling can be performed under local anaesthesia with needle core biopsy and/or fine
needle aspiration (FNA). Biopsies can be performed under US or CT guidance, with a similar diagnostic yield
[172, 180] (LE: 2b). Eighteen-gauge needles are ideal for core biopsies, as they result in low morbidity and
provide sufficient tissue for diagnosis [169, 173, 181] (LE: 2b). A coaxial technique allowing multiple biopsies
through a coaxial cannula should always be used to avoid potential tumour seeding [169, 173] (LE: 3).

Core biopsies are preferred for the characterisation of solid renal masses, while a combination with FNA can
provide complimentary results and improve accuracy for complex cystic lesions [177, 182, 183] (LE: 2a). An SR
and meta-analysis of the diagnostic performance and complications of renal tumour biopsy was performed by
the Panel, including 57 publications and a total of 5,228 patients. Needle core biopsies were found to have better
accuracy for the diagnosis of malignancy compared with FNA [177]. Other studies showed that solid pattern,
larger tumour size and exophytic location are predictors of a diagnostic core biopsy [169, 172, 180] (LE: 2b).

5.3.3 Diagnostic yield and accuracy

In experienced centres, core biopsies have a high diagnostic yield, specificity and sensitivity for the diagnosis
of malignancy. The above-mentioned meta-analysis showed that sensitivity and specificity of diagnostic core
biopsies for the diagnosis of malignancy are 99.1% and 99.7%, respectively [177] (LE: 2b). However, 0-22.6%
of core biopsies are nondiagnostic (8% in the meta-analysis) [170-174, 180, 181, 184] (LE: 2a). If a biopsy is
nondiagnostic and radiologic findings are suspicious for malignancy, a further biopsy or surgical exploration
should be considered (LE: 4). Repeat biopsies have been reported to be diagnostic in a high proportion of cases
(83-100%) [169, 185-187].

Accuracy of renal tumour biopsies for the diagnosis of tumour histotype is good. The median concordance
rate between tumour histotype on renal tumour biopsy and on surgical specimen following PN or RN was
90.3% in the pooled analysis [177]. A retrospective observational study assessing the diagnostic performance
of 151 renal tumour biopsies performed before robotic PN or RN confirmed that pathology on RTBs is highly
concordant with the presence/absence of malignancy (147/151 = 97%) and the histotype on surgical specimens
(141/151=93%) [188].

Assessment of tumour grade on core biopsies is challenging. In the pooled analysis, the overall accuracy for
nuclear grading was poor (62.5%) but significantly improved (87%) using a simplified two-tier system (high vs.
low grade) [177] (LE: 2a).

The ideal number and location of core biopsies are not defined. However, at least two good quality cores should
be obtained, and necrotic areas should be avoided to maximise diagnostic yield [169, 172, 189, 190] (LE: 2b).
Peripheral biopsies are preferable for larger tumours to avoid areas of central necrosis [191] (LE: 2b). In cT2
or greater renal masses, multiple core biopsies taken from at least four separate solid enhancing areas in the
tumour were shown to achieve a higher diagnostic yield and a higher accuracy to identify sarcomatoid features,
without increasing the complication rate [192].

22 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

5.3.4 Morbidity
Overall, percutaneous biopsies have a low morbidity [177]. Tumour seeding along the needle tract has been
regarded as anecdotal in large series and pooled analyses on renal tumour biopsies. The coaxial technique in
particular has been regarded as a safe method to avoid any seeding of tumour cells. However, authors recently
reported on seven patients in whom tumour seeding was identified on histological examination of the resection
specimen after surgical resection of RCC following diagnostic percutaneous biopsy [193]. Six of the seven cases
were of the pRCC type. The clinical significance of these findings is still uncertain, as the only patient to develop
local tumour recurrence at the site of the previous biopsy was a case treated with an open partial nephrectomy
with positive surgical margins [193].

Spontaneously resolving subcapsular/perinephric haematomas are reported in 4.3% of cases in a pooled

analysis, but clinically significant bleeding is unusual (0-1.4%; 0.7% in the pooled analysis) and generally self-
limiting [177].

Percutaneous biopsy of renal hilar masses is technically feasible with a diagnostic yield similar to that of
cortical masses, but with significantly higher post-procedural bleeding compared with cortical masses [194].

5.3.5 Genetic assessment

Renal cancer can be related to an inherited or de novo monogenic germline alteration and this recognition has
significant implications [195]. Hereditary kidney cancer is thought to account for 5-8% of all kidney cancer cases,
although this number is likely an underestimation since a more recent study found germline mutations in up to
38% of all metastatic kidney cancer patients [196] (see Chapter 8 on hereditary kidney tumours). Patients with
a germline predisposition to kidney cancer often require multidisciplinary approaches. It is therefore critical for
clinicians to be familiar with how and when referral for counselling is warranted, methods of genetic testing,
implications of the findings, screening of at-risk (non-renal) organs, and the screening protocol for family
members. Well-defined RCC management strategies exist, and specific therapeutic strategies are available or
in development (see Chapter 8). Lack of a syndromic manifestation does not exclude a genetic contribution to
cancer development. Moreover, other genetic components or polymorphisms are heritable and may confer a
mildly increased risk. When several risk alleles are present, they can significantly increase cancer risk.

Many factors are associated with an increased risk of hereditary RCC syndromes. For instance, even in the
absence of clinical manifestations and personal/family history, an age of onset of 46 years or younger should
trigger consideration for genetic counselling/germline mutation testing [197]. Moreover, presence of bilateral
or multifocal tumours/cysts and/or a first- or second-degree relative with RCC and/or a close blood relative
with a known pathogenic variant significantly increases the risk to detect hereditary cancer. The presence of
renal cysts can be associated with BHD and VHL and form part of the clinical diagnostic spectrum. Moreover,
specific histologic characteristics can support differential diagnosis of a particular RCC syndrome (e.g. multifocal
papillary histology, hereditary fumarate hydratase-deficient RCC, RCC with fumarate hydratase deficiency, multiple
chromophobe, oncocytoma or oncocytic hybrid, succinate dehydrogenase-deficient RCC histology). Finally,
additional tuberous sclerosis complex criteria should be assessed in individuals with AML [197-206].

If additional risk factors are established in a patient, referral to a comprehensive clinical care centre, or a
hospital with demonstrated expertise in managing hereditary cancer syndromes, will provide a dedicated
working team, tailored clinical decisions, research translational programme, appropriate patient psychosocial
support and prospective collection of clinical data and biological samples. This can contribute to a better
patient’s care and further improvements in cancer care.

5.4 Summary of evidence and recommendations for the diagnostic assessment of RCC

Summary of evidence LE
Contrast enhanced multiphasic CT has a high sensitivity and specificity for characterisation and 2a
detection of RCC, invasion, tumour thrombus and mRCC.
The incidence of lung metastases in cT1a, cN0, without systemic symptoms and normal haemoglobin 3
and thrombocytes is negligible.
Magnetic resonance imaging has a slightly higher sensitivity and specificity for small cystic renal 2a
masses and tumour thrombi as compared to CT.
Contrast-enhanced US has a high sensitivity and specificity for characterisation of renal masses. 2a

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 23

Renal mass biopsies are associated with reduced overtreatment of benign masses and offers patients 3
additional information (i.e. grade, subtype) for an informed decision regarding optimal management.
Ultrasound, Power Doppler US and PET CT have a low sensitivity and specificity for detection and 2a
characterisation of RCC.

Recommendations Strength rating

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

5.5 Summary of evidence and recommendations for genetic assessment of RCC

Summary of evidence LE
Hereditary kidney cancer is thought to account for 5-8% of all kidney cancer cases, though that number 3
is likely an underestimate.
In case of renal cancer, if a patient’s age is 46 years, or younger and/or with bilateral or multifocal 3
tumours and/or with a first- or second-degree relative with RCC and/or with a close blood relative
with a known pathogenic variant and/or with specific histologic characteristics (see text), the risk of
hereditary cancer is significantly higher.
Hereditary RCC detection has unique implications for decision-making and follow-up. 3

Recommendations Strength rating

Perform a genetic evaluation in patients aged ≤ 46 years, with bilateral or multifocal tumours Strong
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.
Refer patients to a cancer geneticist or to a comprehensive clinical care centre in case of Strong
suspected hereditary RCC.

24 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

6. PROGNOSTIC FACTORS
6.1 Definition and classification
Prognostic factors are defined as variables associated with clinical endpoints (i.e. recurrence, progression and
survival) independent of a treatment, thereby reflecting the natural course of the disease. Predictive factors, in
contrast, provide information on the effectiveness (i.e. response, progression, survival) of a specific treatment.
Notably, there is substantial overlap between the two categories, because prognostic factors may also serve
as predictive factors and vice versa. Both can be classified into anatomical, histological, clinical and molecular
factors.

6.2 Anatomical factors

Tumour size, venous invasion and extension, collecting system invasion, perinephric- and sinus fat invasion,
adrenal involvement and LN and distant metastasis are included in the TNM classification system [90, 102] (see
Table 4.1).

6.3 Histological factors

Histological factors include tumour grade, RCC subtype, lymphovascular invasion, tumour necrosis and invasion
of the collecting system [207, 208]. Tumour grade is considered one of the most important histological
prognostic factors. The Fuhrman nuclear grade [209] has now been replaced by the WHO/ISUP grading
classification [210]. This relies solely on nucleolar prominence for grade 1-3 tumours, allowing for less
interobserver variation [211]. It has been shown that the WHO/ISUP grading provides superior prognostic
information compared to Fuhrman grading, particularly for grade 2 and grade 3 tumours [212]. Rhabdoid and
sarcomatoid changes can be found in all RCC types and are equivalent to grade 4 tumours. Sarcomatoid
changes are more often found in chRCC than other subtypes [213]. The percentage of the sarcomatoid
component appears to be prognostic as well, with a larger percentage of involvement being associated with
worse survival. There is no agreement on the optimal prognostic cut-off for subclassifying sarcomatoid changes
[214, 215], although 20% has been suggested to distinguish focal and extensive amount of sarcomatoid features
[216]. The WHO/ISUP grading system is applicable to both ccRCC and pRCC. Grading chRCC is currently not
recommended. However, a study suggested a two-tiered chRCC grading system (low vs. high grade) based
on the presence of sarcomatoid differentiation and/or tumour necrosis, which was statistically significant on
multivariable analysis [217]. Both the WHO/ISUP and chRCC grading systems must be validated for prognostic
systems and nomograms [210].

Renal cell carcinoma subtype is regarded as another important prognostic factor. On univariable analysis,
patients with chRCC vs. pRCC vs. ccRCC had a better prognosis [218, 219] (Table 6.1). However, prognostic
information provided by the RCC type is lost when stratified according to tumour stage [219, 220] (LE: 3).

Table 6.1: Cancer-specific survival by stage [218]

Grade HR (95% CI)

T1N0M0 Referent
T2N0M0 2.71 (2.17-3.39)
T3N0M0 5.20 (4.36-6.21)
T4N0M0 16.88 (12.40-22.98)
N+M0 16.33 (12.89-20.73)
M+ 33.23 (28.18-39.18)
CI = confidence interval; HR = hazard ratio.

6.4 Clinical factors

Clinical factors include performance status (PS), local symptoms, early versus late recurrence, cachexia,
anaemia, platelet count, neutrophil count, lymphocyte count, CRP [229], albumin and various indices deriving
from these factors, such as the neutrophil-to-lymphocyte ratio (NLR) [118, 230-236] (LE: 3). As a marker of
systemic inflammatory response, a high preoperative NLR has been associated with poor prognosis [237], but
there is significant heterogeneity in the data and no agreement on the optimal prognostic cut-off. Even though
obesity is an aetiological factor for RCC, it has also been observed to provide prognostic information. A high
body mass index (BMI) appears to be associated with improved survival outcomes in both non-metastatic and
metastatic RCC [238-240]. This association is linear with regards to cancer-specific mortality (CSM), while RCC
patients with obesity show increasing all-cause mortality with increasing BMI [241]. Evidence is also available

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 25

on the prognostic value of body composition indices measured on cross-sectional imaging, such as sarcopenia
and fat accumulation [235, 242, 243]. Health-related quality of life (HRQoL) at baseline and during treatment of
mRCC may also be prognostic. In CheckMate 214, HRQoL measured by the Functional Assessment of Cancer
Therapy Kidney Symptom Index 19 at baseline and during follow-up was associated with improved OS in both
the ipilimumab+nivolumab and the sunitinib arm [244]. Perioperative blood transfusion is linked to worse
cancer-specific and overall mortality, as well as a higher risk of recurrence. However, receiving one to two units
of packed red blood cells does not significantly impact outcomes compared to receiving three or more units.
Notably, intraoperative transfusion is associated with higher cancer-specific mortality and recurrence, while
postoperative transfusion is not [245].

6.4.1 Frailty and comprehensive geriatric assessment

Frailty is a geriatric syndrome characterised by a decline in individuals’ resilience and physiological functional
reserve across multiple body systems, resulting in increased vulnerability to external stressors [246, 247]. Frailty
is an adverse prognostic factor in older patients with localized RCC, being associated with worse perioperative
outcomes as well as poorer oncological outcomes across different stages [246].

Several instruments have been developed and implemented in clinical practice for the diagnosis and
measurement of frailty [247].

Among these, the G8 (Geriatric 8) health status screening tool, which assesses several patient variables (age,
perceived health status, food intake, weight loss, BMI, mobility, neuropsychology, and polypharmacy), is widely
used in oncogeriatrics to identify older cancer patients who could benefit from geriatric assessment, and has
been validated to predict health outcomes in older cancer patients [247].

The EAU Guidelines Office has endorsed the G8 score as a screening tool for frailty [248-250].

Referral to comprehensive geriatric assessment (CGA), performed by dedicated geriatricians, is advised in

patients with a G8 score ≤ 14/17 [247].

The CGA explores several domains: functional capacity, polypharmacy, performance status, cognition, social
support, psychological status and nutritional status. The CGA can identify frailty and risk of geriatric syndromes,
as well as support clinical decision-making in both localised and metastatic RCC [247, 251]. Multidisciplinary
management of patients characterised as frail after CGA is essential.

26 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

 Elderly patients
Frailty screening Risk for frailty Comprehensive Geriatric Assessment (CGA)
with a renal
(Geriatric Screening Tool 8 (G8) (G8 ≤ 14/17) (by a geriatrician)
mass/RCC

Item Answer options Score Domain Description

1. Has food intake declined over the

Severe decrease 0 Evaluation of nutritional status through specific tools to
past 3 mo due to loss of appetite,
Moderate decrease 1 identify potential malnutrition or dietary deficiencies,
digestive problems, chewing, or Nutritional status
No decrease 2 enabling targeted interventions to optimise nutritional
swallowing difficulties?
intake and support overall health.
>3 kg 0
Does not know 1
2. Weight loss during the last 3 mo? Assessment of an individual's ability to perform daily
1–3 kg 2
No weight loss 3 Functional capacity activities independently, providing insight into overall

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Bed or chair bound physical well-being and autonomy.
Table 6.2 Frailty and geriatric assessment factors

0
Able to get out of bed/chair but
3. Mobility 1 Evaluation of drug use and associated risks, including
does not go out
2 Polypharmacy strategies to prevent and manage drug-related toxicities and
Goes out
pharmacological interactions.
Severe dementia or depression 0
4. Neuropsychological problems Mild dementia or depression 1
Assessment of overall health and ability to engage in
No psychological problems 2 Performance status
activities, guiding treatment decisions and interventions.
<19 0
19–<21 1
5. Body mass index (BMI; kg/m²) Cognitive assessment through specific scores to identify
21–<23 2
Cognition impairments that may affect treatment adherence, decision-
≥23 3
making capacity, and quality of life.
6. Takes more than three Yes 0
prescription drugs per day No 1
Not as good 0 Evaluation of social support networks (family, caregivers) to
7. Compared with other people of Social support estimate available support for coping with illness and
Does not know 0.5
the same age, how does the patient adhering to treatment plans.
As good 1
consider their health status?
Better 2
Assessment of psychological well-being to identify mental
>85 0
Psychological status health concerns (e.g., depression, anxiety) influencing
8. Age 80–85 1
treatment outcomes and quality of life.
<80 2

27
6.4.2 Nephrological assessment
Renal function considerations are key for shared decision-making in patients with localised RCC, considering the
bidirectional relationship between RCC and chronic kidney disease (CKD) [252].

Selected patients who are candidate for treatment for RCC may benefit from nephrological consultation,
including patients with pre-existing stage 3-5 CKD or proteinuria; patients with a solitary kidney, especially
those with borderline/known CKD. Patients with known medical comorbidities that may potentially affect renal
function; and patients whose expected new baseline renal function after surgery is below 45ml/min./1.73m2.

To date, while several models have been proposed for predicting postoperative renal function after RCC surgery,
most relied on retrospective cohorts, had a high risk of bias and high concern regarding the applicability of the
proposed model. As such, most of these models are not ready for routine clinical practice, while a few have been
externally validated [253].

In such patients, nephrological consultation before treatment can recommend further diagnostic tests for CKD,
optimise CKD risk factors (e.g. hypertension, hyperglycaemia, obesity, etc.), recommend specific lifestyle and/or
medical interventions to decrease the risk of acute kidney injury or renal function deterioration after treatment
and improve shared decision-making [254].

6.5 Molecular factors

Numerous molecular markers such as carbonic anhydrase IX (CaIX), VEGF, HIF, Ki67 (proliferation), p53, p21
[255], PTEN (phosphatase and tensin homolog) cell cycle [256], E-cadherin, osteopontin [257] CD44 (cell
adhesion) [258, 259], CXCR4 [260], PD-L1 [261], miRNA, SNPs, gene mutations, and gene methylations have been
investigated (LE: 3) [262]. While the majority of these markers are associated with prognosis and many improve
the discrimination of current prognostic models, very little emphasis has been placed on external validation
studies. Moreover, there is no conclusive evidence on the value of molecular markers for treatment selection in
mRCC [229, 261, 263]. The routine use of molecular markers in clinical practice is therefore not recommended.

Several prognostic and predictive marker signatures have been described for specific systemic treatments in
mRCC. In the JAVELIN Renal 101 trial (NCT02684006), a 26-gene immunomodulatory gene signature predicted
PFS in those treated with avelumab plus axitinib, while an angiogenesis gene signature was associated with
PFS for sunitinib. Mutational profiles and histocompatibility leukocyte antigen types were also associated
with PFS, while programmed death-ligand 1 (PD-L1) expression and tumour mutational burden were not
[264]. In IMmotion151 (NCT02420821), a T effector/IFN-γ-high or angiogenesis-low gene expression signature
predicted improved PFS for atezolizumab plus bevacizumab compared to sunitinib. The angiogenesis-high
gene expression signature correlated with longer PFS in patients treated with sunitinib [265]. In CheckMate214
(NCT02231749), a higher angiogenesis gene signature score was associated with better overall response rates
and PFS for sunitinib, while a lower angiogenesis score was associated with higher overall relative risk in those
treated with nivolumab plus ipilimumab. Progression-free survival > 18 months was more often seen in patients
with higher expression of Hallmark inflammatory response and Hallmark epithelial mesenchymal transition gene
sets [235].

Urinary and plasma Kidney-Injury Molecule-1 (KIM-1) has been identified as a potential diagnostic and
prognostic marker. With KIM-1 concentrations are elevated in RCC patients at least up to five years before
diagnosis and were associated with a shorter survival time [266]. Kidney-Injury Molecule-1 is a glycoprotein
marker of acute proximal tubular injury and therefore mainly expressed in RCC derived from the proximal tubules
such as ccRCC and pRCC [267].

In the CheckMate214 trial comparing ipilimumab plus nivolumab with sunitinib, higher baseline serum KIM-1
levels were associated with shorter OS. A decline in KIM-1 levels correlated with improved PFS and OS in
patients treated with ipilimumab and nivolumab [268]. In a post hoc analysis of the IMmotion010 trial in patients
with high-risk resected RCC, elevated baseline plasma KIM-1 levels were linked to worse disease-free survival
(DFS), but also to improved DFS in those receiving adjuvant atezolizumab versus placebo [269]. These findings
suggest that KIM-1 is a promising biomarker and warrants further investigation.

Another promising marker is the urinary glycosaminoglycan score (GAGome) for detecting recurrence after
curative surgery for ccRCC. In a prospective study (AURORAX-0087A), the score demonstrated 90% sensitivity
and 51% specificity for radiologically confirmed recurrence [270]. A validation study is currently underway.

28 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Several retrospective studies and large molecular screening programmes have identified mutated genes and
chromosomal changes in ccRCC with distinct clinical outcomes. The expression of the BAP1 and PBRM1
genes, situated on chromosome 3p in a region that is deleted in more than 90% of ccRCCs, have shown to be
independent prognostic factors for tumour recurrence [271-274]. These published reports suggest that patients
with BAP1 mutant tumours have worse outcomes compared with patients with PBRM1 mutant tumours [272].
Loss of chromosome 9p and 14q have been consistently shown to be associated with poorer survival [275-277].
The TRACERx renal consortium has proposed a genetic classification based on RCC evolution (punctuated vs.
branched vs. linear), which correlates with tumour aggressiveness and survival [276]. Additionally, a 16-gene
signature was shown to predict DFS in patients with non-metastatic RCC [278]. However, these signatures have
not been validated by independent researchers yet.

6.6 Prognostic models

Prognostic models combining independent prognostic factors have been developed and externally validated
[279-286]. These models are more accurate than TNM stage or grade alone for predicting clinically relevant
oncological outcomes [287] (LE: 3). Before being adopted, new prognostic models should be evaluated and
compared to current prognostic models with regards to discrimination, calibration and net benefit. Pathological
prognostic factors are used in the Leibovich 2003 score/groups for ccRCC [282]. Prognostic models for non-
ccRCC are available, such as the VENUSS score for pRCC [288]. Although both were validated in several studies
and showed superior discrimination to other prognostic models, molecular markers are needed [289-292]. In
metastatic disease, risk groups assigned by the Memorial Sloan Kettering Cancer Centre (MSKCC) (primarily
created in the pre-targeted therapy era and validated in patients receiving targeted therapy) and the IMDC
(initially created in the targeted therapy era) differ in 23% of cases [293]. The IMDC model has been used in most
of the recent RCTs, including those with immune checkpoint inhibitors (ICIs), and may therefore be the preferred
model for clinical practice. The IMDC model has been shown to be of continued use for risk stratifying patients
with mRCC treated with contemporary first-line IO combination therapies [294].

The discrimination of the IMDC models improves by additional variables, such as presence of brain metastasis,
bone metastasis, liver metastasis, NLR and platelet count [295-298]. Tables 6.3 and 6.4 summarise the current,
most-relevant prognostic models.

6.7 Summary of evidence and recommendations for prognostic factors

Summary of evidence LE
In RCC patients, TNM stage, tumour size, grade and RCC subtype provide important prognostic 2a
information.
The 2003 Leibovich score is a validated prognostic model to predict the short- and long-term risk of 2b
metastasis in individual patients with sporadic, unilateral pT1-4 N0/+ M0 ccRCC.
The VENUSS score is a validated prognostic model to predict the short- and long-term risk of disease 2b
recurrence in individual patients with sporadic, unilateral pT1-4 N0/+ M0 pRCC.
Frailty is associated with adverse clinical outcomes in patients undergoing treatment for non- 3
metastatic RCC.
There is a bidirectional relationship between RCC and CKD. 3

Recommendations Strength rating

Use the current Tumour, Node, Metastasis classification system. Strong
Use the WHO/ISUP grading system and classify RCC 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 Weak
clear cell RCC.
Use the VENUSS scoring model for risk stratification of localised and locally advanced Weak
papillary RCC.
Do not routinely use molecular markers to assess prognosis. Strong
Screen elderly patients with a renal mass/RCC with a validated geriatric frailty score to Weak
identify patients at risk for frailty.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 29

Offer comprehensive geriatric assessment in elderly patients whose screening revealed a Weak
risk for frailty.
Offer pre-treatment nephrological consultation in selected patients with or at risk for Weak
impaired renal function (e.g. pre-existing chronic kidney disease or proteinuria; solitary
kidney, known medical comorbidities affecting renal function; new baseline eGFR below
45ml/min./1.73m2)
eGFR = estimated glomerular filtration rate; ISUP = International Society of Urological Pathology; WHO = World
health organisation; VENUSS = venous involvement, necrosis, size, stage and sarcomatoid differentiation.

Table 6.3: Prognostic models for localised RCC

Prognostic model Subtype* Risk factors/prognostic factors

UISS** [299] All 1. ECOG PS

2. T classification
3. N classification (N+ classified as metastatic)
4. Grade

T1N0M0G1-2, ECOG PS 0: low-risk disease

T3N0M0G2-4, ECOG PS ≥ 1 OR T4N0M0: high-risk disease
Any other N0M0: intermediate-risk disease
Leibovich score/ CC 1. T classification (pT1a: 0, pT1b: 2, pT2:3, pT3-4: 4 points)
model 2003 [282] 2. N classification (pNx/N0: 0, pN+: 2 points)
3. Tumour size (< 10 cm: 0, ≥ 10 cm: 1 point)
4. Grade (G1-2: 0, G3: 1, G4: 3 points)
5. Tumour necrosis (absent: 0, present: 1 point)

0-2 points: low-risk disease

3-5 points: intermediate-risk disease
6 or more points: high-risk disease
Leibovich score/ CC, P, CH ccRCC
model 2018 [300] • Progression (nine factors): constitutional symptoms, grade, tumour necrosis,
sarcomatoid features, tumour size, perinephric or sinus fat invasion, tumour
thrombus level, extension beyond kidney, nodal involvement.
• Cancer-specific survival (12 factors): age, ECOG PS, constitutional
symptoms, adrenalectomy, surgical margins, grade, tumour necrosis,
sarcomatoid features, tumour size, perinephric or sinus fat invasion, tumour
thrombus, nodal involvement.
• No risk groups /prognostic groups.

pRCC
• Low risk (group 1): grade 1-2, no fat invasion, no tumour thrombus.
• Intermediate risk (group 2): grade 3, no fat invasion, no tumour thrombus.
• High risk (group 3): grade 4 or fat invasion or any level tumour thrombus.

chRCC
• Low risk (group 1): no fat invasion, no sarcomatoid differentiation, no nodal
involvement.
• Intermediate risk (group 2): fat invasion and no sarcomatoid differentiation
and no nodal involvement.
• High risk (group 3): sarcomatoid differentiation or nodal involvement.
VENUSS score/ P 1. T classification (pT1: 0, pT2: 1, pT3-4: 2 points)
model*** 2. N classification (pNx/pN0: 0, pN1: 3 points)
[288, 289] 3. Tumour size (≤ 4 cm: 0, > 4 cm: 2 points)
4. Grade (G1/2: 0, G3/4: 2 points)
5. Tumour thrombus (absent: 0, present: 2 points)

0-2 points: low-risk disease

3-5 points: intermediate-risk disease
6 or more points: high-risk disease

30 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

GRANT score/ All 1. Age > 60 years
model**** [301] 2. T classification = T3b, pT3c or pT4
3. N classification = pN1
4. (Fuhrman) grade = G3 or G4

0-1 factors: favourable-risk disease

2 or more factors: unfavourable-risk disease
* ccRCC = clear-cell RCC; ECOG = Eastern Cooperative Oncology Group; pRCC = papillary RCC;
chRCC = chromophobe RCC; PS = performance status.
** UUniversity of California Integrated Staging system. Available at
[Link]
*** V
 enous extension, Nuclear grade, Size, Stage. Available at [Link]
**** G
 rade, Age, Nodes and Tumour.
Table 6.4: Prognostic models for metastatic RCC

Prognostic model Subtype Risk factors/prognostic factors

MSKCC [302]** All 1. Karnofsky PS [303]* < 80%
2. Interval from diagnosis to systemic treatment < 1 year
3. Haemoglobin < Lower Limit of Normal
4. Corrected calcium > 10mg/dL/> 2.5mmol/L
5. LDH > 1.5x Upper Limit of Normal

0 factors: favourable-risk disease

1-2 factors: intermediate-risk disease
3-5 factors: poor-risk disease
IMDC [304]*** All 1. Karnofsky PS [303]* < 80%
2. Interval from diagnosis to treatment < 1 year
3. Haemoglobin < lower limit of normal
4. Corrected calcium > upper limit of normal (i.e. > 10.2mg/dL)
5. Neutrophil count > upper limit of normal (i.e. > 7.0×10⁹/L)
6. Platelet count > upper limit of normal (i.e. > 400,000)

0 factors: favourable-risk disease

1-2 factors: intermediate-risk disease
3-6 factors: poor-risk disease
IMDC = International Metastatic Renal Cancer Database Consortium; LDH = lactate dehydrogenase;
MSKCC = Memorial Sloan Kettering Cancer Center; PS = performance status.
* Karnofsky performance status calculator: [Link]
[Link].
** M SKCC: [Link]
cell-carcinoma-rcc.
*** IMDC: [Link]

7. DISEASE MANAGEMENT
7.1 Patient involvement in kidney cancer treatment
A large-scale global survey of patients with RCC performed by the International Kidney Cancer Coalition (IKCC)
identified geographic variations in patient education, experience, awareness, access to care, best practices,
quality of life and unmet psychosocial needs [305]. A total of 1,400 patients from 43 countries revealed that, at
diagnosis, 43% of all respondents had no understanding of their RCC subtype, 29% reported no involvement in
their treatment decision and 96% reported psychosocial impacts, with only 50% disclosing it to their health care
team. Moreover, 90% of patients indicated that they would be interested in participating in clinical trials if asked.
Furthermore, an effort should be made to increase diversity in clinical trial participants, ensuring representation
of the target population.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 31

Shared decision-making ensures that patients are supported in making decisions about their care and treatment
given their own individual needs, personal circumstances, goals, values and beliefs. It is a collaborative
process between patients and healthcare professionals that involves information sharing, collaboration and
problem solving given each patient’s prerequisites [306]. Shared decision-making brings together the healthcare
providers expertise on treatment options, evidence, risks and benefits, and the patient’s individual preferences.
However, to ensure patient participation and build the patient-health care professional relationship, adequate
time is needed [307]. Nurse-led patient engagement interventions have shown positive effects on cancer
patients’ participation in the decision-making process, health literacy, self-efficacy and quality of life (QoL) [308].
More evidence, specifically regarding patients with RCC, has been called for [309]. One RCT has indicated that
patient involvement in reporting their symptoms during management of a variety of metastatic solid tumours
can improve clinical outcomes, including OS [310].

7.1.1 Recommendation on patient involvement and shared decision making

Recommendation Strength rating

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

7.1.2 Smoking cessation

A prospective study on 212 patients with RCC investigated the impact of smoking cessation on the risk of
tumour recurrence/progression, RCC-specific and all-cause mortality. Quitting smoking was associated with
lower all-cause mortality, lower cancer-specific mortality and a lower risk of recurrence/progression.

The beneficial effect of quitting smoking was evident across all RCC stages and all levels of smoking [311] and
avoidance of smoking (any form of tobacco or vaping products) and quitting smoking were included in the WHO
European Code against Cancer [312].

7.1.2.a Recommendation on smoking cessation

Recommendation Strength rating

Counsel RCC patients to stop smoking. Strong

7.2 Treatment of localised RCC

7.2.1 Introduction
Section 7.2.2 is underpinned by an SR that includes all relevant published literature comparing surgical
management of localised RCC (T1-2N0M0). Randomised or quasi-RCTs were included. However, due to the very
limited number of RCTs, non-randomised studies, prospective observational studies with controls, retrospective
matched-pair studies and comparative studies from the databases of well-defined registries were also included.
A SR highlights the heterogeneity of outcome reporting and definitions in studies in localised RCC, supporting
the development of a core outcome set to enable robust evaluation of evidence [313]. Surgery has historically
been the benchmark for the treatment of localised RCC.

7.2.2 Surgical treatment

7.2.2.a Nephron-sparing surgery versus radical nephrectomy in localised RCC
7.2.2.a.1 T1 RCC
Outcome 1: Cancer-specific survival
Most studies comparing the oncological outcomes of PN and RN are retrospective and include cohorts of
varied and, overall, limited size [314, 315]. Only one (prematurely closed) prospective RCT including patients with
organ-confined RCCs of limited size (< 5cm) has been published, showing comparable noninferiority of CSS for
PN versus RN (HR: 2.06 [95% CI: 0.62-6.84]) [316].

Outcomes 2 & 3: Overall mortality and renal function

Partial nephrectomy preserved kidney function better after surgery, thereby potentially lowering the risk of
development of cardiovascular disorders [314, 317] and cardiovascular-specific mortality.

In the only prospectively randomised (prematurely closed and heavily underpowered) trial, PN appears to be less
effective than RN in terms of OS in the intention to treat (ITT) population (HR: 1.50 [95% CI: 1.03-2.16]). However,
in the targeted RCC population of the only RCT, the trend in favour of RN was no longer significant [316].
Considering the limitations of the available evidence (most studies are retrospective with a high risk of bias and
unmeasured confounding), the OS advantage suggested for PN versus RN remains an unresolved issue.

32 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Patients with a normal preoperative renal function and a decreased GFR due to surgical treatment (either RN
or PN), generally present with stable long-term renal function [318]. Adverse OS in patients with a pre-existing
glomerular filtration rate (GFR) reduction does not appear to result from further renal function impairment
following surgery, but rather from other medical comorbidities causing presurgical CKD [319]. However, in
particular in patients with pre-existing CKD, PN is the treatment of choice to limit the risk of development
of ESRD, which requires haemodialysis. A retrospective cohort study found that 26% of patients with newly
diagnosed RCC had an GFR ≤ 60mL/min., even though their baseline serum creatinine levels were in the normal
range [121].

Outcomes 4 & 5: Perioperative outcomes and quality of life

In terms of the intra- and perioperative morbidity/complications associated with PN versus RN, the European
Organisation for Research and Treatment of Cancer (EORTC) randomised trial showed that PN for small, easily
resectable, incidentally discovered RCC, in the presence of a normal contralateral kidney, can be performed
safely with slightly higher complication rates than after RN [320].

Only a limited number of studies are available addressing QoL following PN vs. RN, irrespective of the surgical
approach used (open vs. minimally invasive). Quality of life was ranked higher following PN as compared to RN,
but generally speaking patients’ health status deteriorated following both approaches [320, 321].

In view of the above, and since the oncological outcomes (CSS and RFS) of PN are comparable to those of
RN, PN is the treatment of choice for T1 RCC, because it better preserves kidney function and potentially
limits the long-term incidence of cardiovascular disorders and ESRD. In frail patients, treatment decisions
should be individualised, weighing the risks and benefits of PN versus RN, the increased risk of perioperative
complications with PN and the increased risk of developing or worsening CKD with RN.

7.2.2.a.2 T2 RCC
Very limited evidence is available on the comparative effectiveness of PN and RN for patients with radiologically
defined cT2 renal masses.

Some retrospective comparative studies of PN versus RN for T2 RCC have been published [322]. A trend for
lower tumour recurrence and CSM is reported in PN groups. The estimated blood loss is reported to be higher
for PN groups, as is the likelihood of postoperative complications [322]. A multicentre study compared the
survival outcomes in patients with larger (> 7cm) ccRCC treated with PN versus RN with long-term follow-up
(median 102 months). Compared to the RN group, the PN group had a significantly longer median OS (p = 0.014)
and median CSS (p = 0.04) [323]. Retrospective comparative studies of cT1 and cT2 RCC patients upstaged
to pT3a RCC show contradictory results: some reports suggest similar oncologic outcomes between PN and
RN [324], whilst another report suggests that PN of clinical T1 in pathologically upstaged pT3a of cT1 RCC is
associated with a significantly shorter RFS than RN [325]. Overall, the level of the evidence is low. These studies
including T2 masses all have a high risk of selection bias due to imbalance between the PN and RN groups
regarding patient’s age, comorbidities, tumour size, stage and tumour position. These imbalances in covariation
factors may have a greater impact on patient outcome than the choice of PN or RN. The Panel’s confidence in
the results is limited, and the true effects may be substantially different.

In view of the above, the risks and benefits of PN should be discussed with patients with T2 tumours. In this
setting, PN should be considered, if technically feasible, in patients with a solitary kidney, bilateral renal tumours
or CKD with sufficient parenchymal volume preserved to allow sufficient postoperative renal function.

7.2.2.a.3 T3 RCC
The prevalence of cT1 to pT3a is reported in up to 5.7% of the patients, risk factors include age (OR: 1.03),
tumour size (OR: 1.51) and RENAL score (OR: 2.80) [326].

A meta-analysis of nine articles including 1,278 patients with PN and 2,113 patients with RN for pT3a RCC
showed no difference in CSS, OS, CSM and RFS, indicating that PN techniques can be used for functional
benefits and if technically feasible [327].

Overall, there is lack of high-quality evidence on the comparative effectiveness and safety of PN versus RN
for radiologically cT3 tumours and/or pathologically upstaged cT1-2-pT3 RCC. For this reason, the decision
to perform PN in these patients should carefully balance the potential benefits of PN for renal function
preservation against its potential oncologic risks.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 33

7.2.2.b Associated procedures
7.2.2.b.1 Adrenalectomy
One prospective non-randomised study compared the outcomes of RN with, or without, ipsilateral
adrenalectomy [328]. Multivariable analysis showed that upper pole location was not predictive of adrenal
involvement, but tumour size was. No difference in OS at five or ten years was seen with, or without,
adrenalectomy. Adrenalectomy was justified using criteria based on radiographic and intraoperative findings.
Only 48 of 2,065 patients underwent concurrent ipsilateral adrenalectomy, of which 42 of the 48 interventions
were for benign lesions [328].

7.2.2.b.2 Lymph node dissection for clinically negative lymph nodes (cN0)
The indication for LN dissection (LND) together with PN or RN is still controversial [329]. The clinical
assessment of LN status is based on the detection of an enlargement of LNs either by CT/MRI or intraoperative
palpability of enlarged nodes. Fewer than 20% of suspected metastatic nodes (cN+) are positive for metastatic
disease at histopathological examination (pN+) [330]. Both CT and MRI are unsuitable for detecting malignant
disease in nodes of normal shape and size [331]. For clinically positive LNs (cN+), see Section 7.2.2.

Only one prospective RCT evaluating the clinical value of LND combined with surgical treatment of primary RCC
has been published so far. With an incidence of LN involvement of only 4%, the risk of lymphatic spread appears
to be very low. Recognising the latter, only a staging effect was attributed to LND [330]. This trial included a very
high percentage of patients with pT2 tumours, which are not at increased risk for LN metastases. Only 25% of
patients with pT3 tumours underwent a complete LND and the LN template used by the authors was not clearly
stated.

Contemporary pooled retrospective analyses have confirmed a lack of benefit for LND in low-stage RCC [332].

Smaller retrospective studies have suggested a clinical benefit associated with a more or less extensive LND,
preferably in patients at high risk for lymphogenic spread. In a large retrospective study, the outcomes of RN
with or without LND in patients with high-risk non-mRCC were compared using a propensity score analysis. In
this study, LND was not significantly associated with a reduced risk of distant metastases, cancer-specific or
all-cause mortality. The extent of the LND was not associated with improved oncologic outcomes [333]. The
number of LN metastases (< / > 4), as well as the intra- and extra-capsular extension of intra-nodal metastasis,
correlated with the patients clinical prognosis in some studies [331, 334-336]. Better survival outcomes were
seen in patients with a low number of positive LNs (< 4) and no extranodal extension. Based on a retrospective
Surveillance, Epidemiology and End Results (SEER) database analysis of > 9,000 patients, no effects of an
extended LND (eLND) on the disease-specific survival (DSS) of patients with pathologically confined negative
nodes was demonstrated [337]. However, in patients with pathologically proven lymphogenic spread (pN+), an
increase of 10 for the number of nodes dissected resulted in a 10% absolute increase in DSS.

In addition, a larger cohort of 1,983 patients demonstrated that eLND results in a significant prolongation of
CSS in patients with unfavourable prognostic features (e.g. sarcomatoid differentiation, large tumour size)
[338]. With regard to morbidity related to eLND, a retrospective propensity score analysis from a large single-
centre database showed that eLND is not associated with an increased risk of Clavien grade > 3 complications.
Moreover, LND was not associated with length of hospital stay or estimated blood loss [339].

The optimal extent of LND remains controversial. Retrospective studies suggest that an eLND should involve
the LNs surrounding the ipsilateral great vessel and the inter-aortocaval region from the crus of the diaphragm
to the common iliac artery. Involvement of inter-aortocaval LNs without regional hilar involvement is reported
in up to 35-45% of cases [331, 340, 341]. At least fifteen LNs should be removed [338, 342]. Sentinel LND is an
investigational technique [343, 344].

7.2.2.b.3 Embolisation
Before routine nephrectomy, tumour embolisation has no benefit [345, 346]. In patients unfit for surgery, or with
non-resectable disease, embolisation can control symptoms, including visible haematuria or flank pain [347].
These indications will be revisited in Sections 7.2 and 7.3, with cross-reference to the summary of evidence and
recommendations below.

34 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

7.2.2.b.4 Summary of evidence and recommendations for the treatment of localised RCC

Summary of evidence LE
The oncological outcome in terms of OS following PN equals that of RN in patients with c/p T1 RCC. 1b
Retrospective studies suggest that oncological outcomes are similar following PN versus RN in 3b
patients with larger (≥ 7cm) RCC. Postoperative complication rates are higher in PN patients.
Ipsilateral adrenalectomy during RN or PN has no survival advantage in the absence of clinically evident 3
adrenal involvement.
In patients with localised disease without radiographic evidence of LN metastases, a survival 1b
advantage of LND in conjunction with RN is not demonstrated in RCTs.
Retrospective studies suggest a clinical benefit associated with LND in high-risk patients. 2b
In patients unfit for surgery with massive haematuria or flank pain, embolisation can be a beneficial 3
palliative approach.

Recommendations Strength rating

Offer surgery to achieve cure in localised RCC. 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 Weak
technically feasible.
Do not perform ipsilateral adrenalectomy if there is no clinical evidence of invasion of the Strong
adrenal gland.
Do not routinely perform a lymph node dissection to patients with organ-confined disease. Weak
Offer embolisation to patients unfit for surgery presenting with massive haematuria or flank Weak
pain.

7.2.3 Radical and partial nephrectomy techniques

7.2.3.a Radical nephrectomy techniques
7.2.3.a.1 Open versus laparoscopic or robotic approach
No RCTs have assessed the oncological outcomes of laparoscopic versus open RN. An SR did not demonstrate
any survival difference in laparoscopic RN and open RN [348].

Data from one SR [348] and two non-randomised studies [349, 350] showed a significantly shorter hospital
stay and lower analgesic requirement for the laparoscopic RN group as compared with the open group.
Convalescence time was also significantly shorter [350]. Surgical complication rates were low with very wide
confidence intervals. There was no difference in complications, but operation time was significantly shorter in
the open nephrectomy arm. The QoL and perioperative outcomes were inconsistently defined, measured or
reported [314, 348] (LE: 2b, based on one low quality SR).

7.2.3.a.2 Laparoscopic versus robotic approach

Data from a large retrospective cohort study on robot-assisted laparoscopic versus laparoscopic RN showed
that robot-assisted laparoscopic RN was not associated with increased risk of any or major complications but
had a longer operating time and higher hospital costs compared with laparoscopic RN [351].

A SR comparing the outcomes of robotic surgery to those of laparoscopic and open surgery in patients
undergoing RN for RCC (n =12 studies involving 64,221 patients) found that, compared to laparoscopic RN,
robotic RN was associated with longer operative time (weighted mean difference (WMD) 37.44 min.), shorter
length of stay (WMD -0.84 days) and higher total costs [352]. Compared to open RN, robotic RN was associated
with shorter length of stay, fewer overall complications, lower estimated blood loss and higher total hospital
costs. High heterogeneity was observed across all analyses.

7.2.3.a.3 Laparoscopic single port versus laparoscopic multiport approach

Similar results were seen in observational cohort studies comparing ‘portless’ and three-port laparoscopic RN,
with similar perioperative outcomes [353, 354].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 35

Transperitoneal versus retroperitoneal RN
A SR and pooled analysis compared the safety and efficacy of transperitoneal (TLRN) versus retroperitoneal
laparoscopic RN (RLRN) for the treatment of large-volume (> 7cm) renal masses (including 14 studies, of which
five RCTs and nine retrospective studies) [355]. Most studies were limited by the small number of patients
included, limited/unreported follow-up and moderate-to-high risk of bias.

The merged data showed shorter operating time for RLRN operating time (OT) (MD [mean difference]: -26.57);
less estimated blood loss (EBL) (MD: -20.55); and faster postoperative intestinal exhaust (MD: -0.65). The
two approaches were comparable regarding LOS, blood transfusion, conversion rate, intra- and postoperative
complications, local recurrence rate, positive surgical margins, and distant recurrence rate.

7.2.3.b Partial nephrectomy techniques

7.2.3.b.1 Open versus laparoscopic approach
Two small RCTs have compared the outcomes of open versus laparoscopic PN [356]. Studies comparing
laparoscopic and open PN found no difference in PFS [357-360] and OS [359, 360] in centres with laparoscopic
expertise.

The results for GFR decline are debatable. An RCT reported greater three- to 12-month kidney function reduction
in the open group [356], whilst in a matched-pair comparison, GFR decline was greater in the laparoscopic PN
group in the immediate postoperative period [360], but not after 3.6-years follow-up. In another comparative
study, the surgical approach was not an independent predictor for postoperative CKD [361].

Retroperitoneal and transperitoneal laparoscopic PN have similar perioperative outcomes [362].

The feasibility of laparoendoscopic single-site PN has been shown in selected patients, but larger studies are
needed to confirm its safety and clinical role [363].

7.2.3.b.2 Open versus robotic approach

The prospective, randomised, open-label, multicentre OpeRa trial (NCT03849820) aimed to determine whether
robotic-assisted partial nephrectomy (RAPN) is superior to open partial nephrectomy (OPN) in reducing 30-day
postoperative complications during the treatment of intermediate/high-complexity renal tumours (RENAL score
≥7) [364]. The primary endpoint of the 30-day complication rate did not differ between groups (RAPN 37% vs.
OPN 46%), but a limitation was that the trial failed to fully accrue (240 of 606) and closed prematurely. The
most frequent high-grade complications (CD III-IV) to postoperative day 30 (POD30) were urine leakage [RAPN
4/112 (4%) vs. OPN 2/89 (2%)] and postoperative bleeding [2/117 (2%) versus 1/89 (1%)] [364]. Compared with
OPN, RAPN patients had longer operative and warm ischaemia times, shorter hospital stays and reported better
recovery, less opioid use, less pain and improved QoL up to POD30 [364].

The single-centre, open-label ROBOCOP II RCT assessed the feasibility of recruitment as a primary endpoint and
demonstrated as secondary outcomes that included perioperative and postoperative data. In comparison to
open PN, robot-assisted PN had lower blood loss, less need for opioids and fewer complications according to
the mean Comprehensive Complication Index [365]. Open PN has a shorter operative time and warm ischemia
time. There were no differences between robot-assisted PN and open PN regarding postoperative functional
outcomes [365].

The IRON-1 study collected real world data of RAPN versus Open in single cT1-2N0M0 renal masses [366].
RAPN was associated with lower intraoperative (OR: 0.39, 95% CI: 0.22, 0.68) and Clavien-Dindo 2 postoperative
(OR: 0.29, 95% CI: 0.16, 0.50) complications (both p < 0.05). On multivariable analyses, no differences were
found between the two techniques with respect to functional and oncologic outcomes [366].

In a SR and network meta-analysis [367], the EBL, postoperative complications and length of stay were all
significantly reduced in RAPN when compared with OPN.

One study prospectively compared the perioperative outcomes of a series of robot-assisted and open PN
performed by the same experienced surgeon. Robot-assisted PN was superior to open PN in terms of lower EBL
and shorter hospital stay. Warm ischaemia time, operative time, immediate- early- and short-term complications,
variation in creatinine levels and pathologic margins were similar between groups [368].

36 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

A multicentre French prospective database compared the outcomes of 1,800 patients who underwent open
PN and robot-assisted PN. Although the follow-up was shorter, there was a decreased morbidity in the robot-
assisted PN group with fewer overall complications, fewer major complications, fewer transfusions and a much
shorter hospital stay [369].

An SR and meta-analysis comparing RAPN and OPN demonstrated similar short-term functional outcomes,
however, results are inconsistent [370].

7.2.3.b.3 Open versus hand-assisted approach

Hand-assisted laparoscopic PN (HALPN) is rarely performed. A comparative study of open versus HALPN
showed no difference in OS or RFS at intermediate-term follow-up. The authors observed a lower rate of
intraoperative and all-grade postoperative 30-day complications in HALPN versus open PN patients, but no
significant difference in high Clavien grade complications was observed. Three months after the operation, GFR
was lower in the HALPN than in the open PN group [371].

7.2.3.b.4 Open versus laparoscopic versus robotic approaches

In a retrospective propensity-score-matched study, comparing open-, laparoscopic- and robot-assisted PN, after
five years of median follow-up, similar rates of local recurrence, distant metastasis and cancer-related death
rates were found [372].

An SR comparing the three approaches included 31 studies with a combined 7,869 patients (33.7% OPN, 20.8%
LPN, 45.5% RAPN). There was no difference in ischaemia time, intraoperative complications, positive surgical
margins, operative time or trifecta rate. The estimated blood loss, postoperative complications and length of
stay were all significantly reduced with robot-assisted PN and laparoscopic PN compared to open surgery, with
robot-assisted PN superior to laparoscopic PN in terms of reduced EBL [367]. In PADUA score < 10 lesions,
robotic surgery had higher probability of achieving a modified trifecta than open PN (OR: 1.66; 95% CI: 1.09-
2.53; p = 0.018) and laparoscopy (OR: 1.34; 95% CI: 0.94-1.90; p = 0.11) [367].

7.2.3.b.5 Laparoscopic versus robotic approach

A meta-analysis, including a series of NSS with variable methodological quality compared the perioperative
outcomes of robot-assisted and laparoscopic PN. The robotic group had a significantly lower rate of conversion
to open surgery and to radical surgery, shorter warm ischaemia time, smaller change in estimated GFR after
surgery and shorter length of hospital stay. No significant differences were observed between the two groups
regarding complications, change of serum creatinine after surgery, operative time, estimated blood loss and
PSMs [373].

In another SR and network meta-analysis [367], the outcomes of RAPN and LPN were largely similar except the
significantly reduced EBL in RAPN.

Single-site laparoscopic and single-port robotic approaches for PN

The feasibility of laparoendoscopic, single-site PN has been shown in selected patients [363]. Several studies
have reported on the outcomes of single-port RAPN [374-378] and the current evidence is limited by lack of
prospective RCTs comparing the outcomes of single-port versus multiport RAPN, as well as the high risk of
selection bias and confounding of available retrospective studies.

An SR and meta-analysis assessed the perioperative, functional and oncological outcomes of single-port (SP)
versus multiport (MP) RAPN [379]. Ten studies were included (no RCTs were identified). Most of these studies
were limited by a retrospective design, selection bias, small sample size and moderate-to-high risk of bias. The
meta-analysis did not find significant differences between SP- and MP-RAPN regarding intra- and perioperative
outcomes, with the exception of a significantly longer length of hospitalisation and higher pain score on
postoperative day 1 for MP-RAPN, and a significantly longer warm ischaemia time for SP-RAPN.

7.2.3.b.6 Laparoscopic transperitoneal versus retroperitoneal approach

An SR assessed the outcomes of retroperitoneal versus transperitoneal robotic-assisted PN. Seventeen studies,
published between 2013 and 2021, were retrieved, none of which was an RCT. Among the 6,266 patients
included, 2,261 (36.1%) and 4,005 (63.9%) underwent retroperitoneal versus transperitoneal robotic-assisted PN,
respectively. Both retroperitoneal and transperitoneal robotic-assisted PN offered similar surgical outcomes,
while retroperitoneal robotic-assisted PN was associated with shorter surgical time and length of hospital stay
[380]. The feasibility of a future RCT comparing RRPN versus TRPN has been shown [381].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 37

7.2.3.b.7 Robotic systems
Several novel multiport robotic systems have been developed and introduced into clinical practice for urological
surgery following regulatory approval [382]. The existing literature mostly includes single-arm explorative
studies.

7.2.3.b.8 Tumour enucleation, standard partial nephrectomy and single-port approach

Simple tumour enucleation also had similar PFS and CSS rates compared to standard PN and RN in a large
study [383]. The feasibility of laparoendoscopic single-site PN has been shown in selected patients, but larger
studies are needed to confirm its safety and clinical role [363].

The only prospective multicentre study available to date assessing the impact of resection technique
(enucleation vs. enucleoresection vs. resection) during PN using a standardised reporting score to classify the
resection technique after surgery found that the resection technique significantly impacts surgical complications,
early functional outcomes and positive surgical margins after PN of localised renal masses [384].

An SR and pooled analysis found heterogeneity in the reporting of resection techniques across robotic PN
series [385]. Out of twenty studies retrieved, nine compared ‘standard’ resection versus enucleation. A pooled
analysis did not reveal significant differences in terms of operative time, ischemia time, blood loss, transfusions
or positive margins. Significant differences favouring enucleation were found for clamping management (odds
ratio [OR] for renal artery clamping 3.51, 95% confidence interval [CI] 1.13-10.88; p = 0.03), overall complications
(OR: for occurrence 0.55, 95% CI: 0.34-0.87; p = 0.01) major complications (OR: for occurrence 0.39, 95% CI:
0.19-0.79; p = 0.009), length of stay (WMD -0.72 d, 95% CI: -0.99 to -0.45; p < 0.001), and decrease in eGFR (WMD
-2.64 ml/min., 95% CI: -5.15 to -0.12; p = 0.04). Data from a single-centre prospective randomised noninferiority
trial, supports these findings in the low to intermediate complexity setting [386].

7.2.3.b.9 Off-clamp versus on-clamp PN

The use of an off-clamp and selective-clamping approaches for PN has increased in recent years with the aim
to minimise/avoid warm ischemia time and improve functional outcomes. One RCT (CLOCK study) showed a
comparable safety profile of off-clamp versus on-clamp PN in terms of intra- and perioperative complications, as
well as comparable absolute eGFR variation and split renal function at six months from surgery in patients with
regular baseline function and two kidneys. However, 40% of the patients randomised in the off-clamp group were
intraoperatively shifted to on-clamp (median ischemia time of fifteen minutes) [387, 388]. Due to the selective
inclusion criteria of the RCT, off-clamp techniques may still be indicated in patients with CKD single kidney or
multifocal disease [389, 390].

In a contemporary cohort of 1,359 patients from the prospectively maintained database of the French national
network of research on kidney cancer (UROCCR), PSM rate was not statistically different between the off-clamp
group (5.6%) and the on-clamp group (11%) (p = 0.1). With short median follow-up, no statistical differences
between the two groups were seen in OS, local RFS and metastasis-free survival [391].

7.2.3.b.10 Use of 3D models for PN planning

3D models based on cross-sectional imaging are evolving to facilitate pre- and intra-operative planning of
PN. An SR and meta-analysis found that the use of 3D technology led to a significant reduction in the global
ischemia rate and was associated with less blood loss and transfusion rate. However, 3D guidance did not
impact the risk of conversion to radical nephrectomy, the rate of minor and major complications, the change
in glomerular filtration rate or risk of positive surgical margins [392]. There is lack of evidence regarding
oncological outcomes with use of 3D models.

Several prospective, RCTs evaluating the impact of 3D models on robot-assisted partial nephrectomy (RAPN)
outcomes and patient experience are ongoing [393-395].

7.2.3.c Positive surgical margins on histopathological specimens

A PSM is encountered in approximately 2-8% of T1 PNs [396]. Studies comparing surgical margins with
various surgical approaches (open, laparoscopic, robotic) are inconclusive [397-399]. Most trials showed that
intraoperative frozen section analysis had no influence on the risk of definite PSMs [400]. A PSM status occurs
more frequently in cases in which surgery is imperative (solitary kidneys and bilateral tumours) and in patients
with adverse pathological features (pT2a, pT3a, grade III-IV) [401-404].

38 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

The majority of retrospective analyses reported so far indicated that PSMs do not translate into a higher risk
of metastases or a decreased CSS [402, 403]. On the other hand, another retrospective study of a large single-
institutional series showed that PSMs are an independent predictor of PFS due to a higher incidence of distant
and local relapses [405]. Another retrospective study of 42,114 PN patients with 2,823 PSM patients (6.7%)
showed an increased presence of PSM in upstaged pT3a tumours (14.1%), increased all-cause mortality in PSM
patients and a decreased five-year OS rate in pT3a tumours (PSM: 69% vs. NSM: 90.9%) [406].

However, only a proportion of patients with an uncertain margin status actually harbour residual malignancy.
Local tumour bed recurrences were found in 16% in patients with PSMs compared with 3% in those with
negative margins [401], therefore, RN or re-resection of margins can result in overtreatment in many cases.
Patients with PSMs should be informed that they will need a more intense surveillance (imaging) follow-up
and that they are at increased risk of secondary local therapies [402, 407]. On the other hand, protection from
recurrence is not ensured by negative surgical margins [408], because it is reported in up to 1.5% of cases in this
category of patients [396].

7.2.3.d Hospital volume and outcomes of PN

The EAU RCC Guideline Panel performed a protocol-driven SR of the association between hospital volume (HV)
and oncological, functional and complication outcomes following PN for RCC [409]. Higher HV was associated
with lower complication rates, shorter length of stay, lower PSM rates and lower transfusion rates. Most studies
were judged to have high risk of bias. Apart from better PN outcomes, treatment in higher-volume centres
appears to be associated with closer adherence to Guidelines regarding the management of T1 RCC, with more
frequent use of PN instead of RN [410-413].

7.2.3.e Placement of a drain

Routine drain placement after PN or RN is increasingly being questioned.

A number of SRs and cohort studies have been reported on the clinical impact of using versus omitting surgical
drains after nephrectomy [414-417].

In one review, no differences were found for overall complications (OR: 0.99) or reintervention (OR: 1.16) in
patients undergoing PN [416]. In another review, in RAPN, patients without postoperative drainage had shorter
length of hospital stay (mean difference: -0.84 days) and similar low-grade (P = 0.94) and high-grade (P = 0.31)
complications, urinary leakage (P = 0.49), haemorrhage (P = 0.39), reintervention (P = 0.69) and readmission
(P = 0.20) compared with routinely drained patients [415].

Overall, the available evidence suggests that omitting drain placement after standard PN or RN is not associated
with increased surgical complication rates and may lead to shorter length of hospitalisation. However, the
evidence is limited by lack of randomised trials (in the RAPN era).

7.2.3.f Summary of evidence and recommendations for radical and partial nephrectomy techniques

Summary of evidence LE
Laparoscopic 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 can be performed, either by open, pure laparoscopic or robot-assisted approach, 2b
based on surgeon’s expertise and skills.
Robot-assisted and laparoscopic PN are associated with shorter length of hospital stay and lower 2b
blood loss compared to open PN.
Transperitoneal and retroperitoneal laparoscopic PN do not differ in postoperative surgical and medical 2a
complications, PSMs and kidney function.
Hospital volume for PN might impact on surgical complications, warm ischaemia time and surgical 3
margins.
Immediate completion nephrectomy for PSMs can result in overtreatment in many cases. 3
Off-clamp partial nephrectomy does not improve renal function outcomes in patients with baseline 1b
normal renal function.
The evidence on the impact of resection technique on PN outcomes is limited by lack of standardised 3
reporting and by the retrospective design of most available studies.
The placement or omittance of a drain does not alter the post-surgical course of PN. 3

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 39

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

7.2.4 Therapeutic approaches as alternatives to surgery

7.2.4.a Watchful waiting
Elderly and comorbid patients with incidental SRMs have a low RCC-specific mortality and significant
competing-cause mortality [418, 419].

Watchful waiting is employed in cases where RCC is not expected to significantly impact the patient’s remaining
life expectancy, and when the focus is on managing symptoms rather than attempting a cure.

7.2.4.b Active surveillance

Active surveillance is defined as the initial monitoring of tumour size by serial abdominal imaging (US, CT, or
MRI) with delayed intervention reserved for tumours showing clinical progression during follow-up [420]. The
concept of AS differs from the concept of WW. Unless clinically indicated, WW is reserved for patients whose
comorbidities contraindicate any subsequent active treatment and who do not require follow-up imaging.

Population-based studies compared the oncological outcomes of surgery (RN or PN) and non-surgical
management for tumours < 4cm. The analyses showed a significantly lower CSM in patients treated with
surgery [421-423]. However, the patients assigned to the surveillance arm were older and likely to be frailer and
less suitable for surgery. Other-cause mortality rates in the non-surgical group significantly exceeded that of the
surgical group [422]. Analyses of older patients (> 75 years) failed to show the same benefit in CSM for surgical
treatment [424-426].

Growth rate and metastasis

In the largest reported series of AS, the growth of renal tumours was low and progression to metastatic disease
was reported in only a limited number of patients [427, 428]. An SR of eighteen AS cohorts comprising 2,066
patients (cT1-2 N0M0) with a pooled mean follow-up of 53 months showed that 2.1% (95% CI: 1.0-3.6) of
patients developed metastatic disease during follow-up [429]. For patients with SRMs (nine studies, n = 987), the
pooled metastasis rate was 1.8% (95% CI: 0.5-3.7).

In 136 biopsy-proven SRMs managed by AS, median follow-up of patients who remained on AS was 5.8 years
(interquartile range 3.4-7.5 years). Clear-cell RCC grew faster than papillary type 1 SRMs (0.25 and 0.02 cm/
year on average, respectively, p = 0.0003). Overall, 60 (44.1 %) of the malignant SRMs progressed; 49 (82%) by
rapid growth (volume doubling), seven (12%) increasing to ≥ 4cm, and four (6.7%) by both criteria. Six patients
developed metastases, and all were of ccRCC histology [430].

Overall and cancer-specific survival

A single-institutional comparative study evaluating patients aged > 75 years showed decreased OS for those
who underwent surveillance and nephrectomy relative to NSS for clinically T1 renal tumours. However, at
multivariate analysis, management type was not associated with OS after adjusting for age, comorbidities and
other variables [418]. No statistically significant differences in OS and CSS were observed in another study of RN
versus PN versus AS for T1a renal masses with a follow-up of 34 months [431].

The prospective non-randomised multi-institutional Delayed Intervention and Surveillance for Small Renal
Masses (DISSRM) study enrolled 497 patients with solid renal masses < 4cm who selected either AS or primary
active intervention. Patients who selected AS were older, had worse ECOG scores, more comorbidities, smaller
tumours and more often had multiple and bilateral lesions. In patients who elected AS in this study, the overall

40 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

median SRM growth rate was 0.09cm/year with a median follow-up of 1.83 years. The growth rate and variability
decreased with longer follow-up. No patients developed metastatic disease or died of RCC [432, 433].

Overall survival for primary intervention and AS was 98% and 96% at two years and 92% and 75% at five years
(p = 0.06). At five years, CSS was 99% and 100%, respectively (p = 0.3). Active surveillance was not predictive
of OS or CSS in regression modelling with relatively short follow-up [432]. In the above-mentioned large SR
of 18 AS cohorts, 1.0% (95% CI: 0.3-2.1) died from RCC and 22.6% (95% CI: 15.8-30.2) died from any cause.
For patients with SRMs, RCC-specific mortality was 0.6% (95% CI: 0-2.1) and all-cause mortality was 28.5% (95%
CI: 17.4-41.4) [429].

A study using data from the DISSRM Registry investigated the outcomes of AS in a cohort of patients aged 60
or younger at diagnosis [434]. Of 224 patients with median follow-up of 4.9 years, 30.4% chose surveillance.
There were 20 (29.4%) surveillance progression events, including four elective crossovers, and 13 (19.1%)
patients underwent delayed intervention. Among patients with initial tumour size ≤ 2cm, 15.1% crossed over,
as compared to 33.3% with initial tumour size 2-4cm. Overall survival was similar in primary intervention and
surveillance at seven years (94.0% vs. 90.8%, logrank p = 0.2). The CSS remained at 100% for both groups and
RFS at five years was 96.0% and 100% for primary and delayed intervention, respectively (logrank p = 0.6).

Overall, both short- and intermediate-term oncological outcomes indicate that, in selected patients with
advanced age and/or comorbidities, AS is appropriate for initial monitoring of SRMs, followed, if required, by
treatment for progression [420, 427, 428, 435-438].

Quality of life
A multicentre study assessed QoL of patients undergoing immediate intervention versus AS. Patients
undergoing immediate intervention had higher QoL scores at baseline, specifically for physical health. The
perceived benefit in physical health persisted for at least one year following intervention. Mental health, which
includes domains of depression and anxiety, was not adversely affected while on AS [439].

7.2.4.c Role of renal tumour biopsy before active surveillance

Histological characterisation of SRMs by renal tumour biopsy is useful to select tumours at lower risk of
progression based on grade and histotype, which can be safely managed with AS. Pathology can also help to
tailor surveillance imaging schedules. In the largest cohort of biopsy-proven, small, sporadic RCCs followed with
AS, a significant difference in growth and progression among various RCC subtypes was observed. Clear-cell
RCC SRMs grew faster than papillary type 1 SRMs (0.25 and 0.02cm/year on average, respectively, p = 0.0003)
[430].

7.2.4.d Tumour ablation

7.2.4.d.1 Role of renal mass biopsy
An RMB is required prior to tumour ablation (see Sections 5.3, ‘Renal tumour biopsy’, and 5.4, ‘Summary of
evidence and recommendations for the diagnostic assessment of RCC’). Historically, up to 45% of patients
underwent tumour ablation of a benign or non-diagnostic mass [440, 441]. An analysis of the European multi-
national prospective EuRECA registry (871 patients undergoing cryoablation) showed that the use of pre-
cryoablation biopsy has significantly increased from 42% (65/156) in 2015 to 72% (88/122) in 2019 (p < 0.001),
making treatment for a benign or an unknown histology significantly less likely (OR: 0.64, p < 0.001 and OR: 0.31,
p = 0.044, respectively) [442]. An RMB in a separate session reduces overtreatment significantly, with 80% of
patients with benign lesions opting not to proceed with TA [441]. Additionally, there is some evidence that the
oncological outcome following TA differs according to RCC subtype, which should therefore be factored into
the decision-making process. In a series of 229 patients with cT1a tumours (mean size 2.5cm) treated with
radiofrequency ablation (RFA), the five-year DFS rate was 90% for ccRCC and 100% for pRCC (80 months: 100%
vs. 87%, p = 0.04) [443]. In another series, the total tumour ablation effectiveness rate was 90.9% for ccRCC and
100% for pRCC [444]. A study comparing RFA with surgery suggested worse outcomes of RFA versus PN in cT1b
ccRCC, while no difference was observed in those with non-ccRCC [445]. Moreover, patients with high-grade
RCC or metastasis may choose different treatments over tumour ablation. Finally, patients without biopsy or
a nondiagnostic biopsy are often assumed to have RCC and will undergo potentially unnecessary radiological
follow-up or further treatment.

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7.2.4.d.2 Cryoablation
Cryoablation is performed using either a percutaneous- or a laparoscopic-assisted approach, with technical
success rates of > 95% [446]. In comparative studies, there was no significant difference in the overall
complication rates between laparoscopic- and percutaneous cryoablation [447-449]. One comparative study
reported similar OS, CSS and RFS in 145 laparoscopic patients with a longer follow-up versus 118 patients
treated percutaneously with a shorter follow-up [448]. A shorter average length of hospital stay was found with
the percutaneous technique [448-450]. An SR including 82 articles reported complication rates ranging between
8 and 20% with most complications being minor [451]. Although a precise definition of tumour recurrence is
lacking, the authors reported a lower RFS as compared to that of PN.

Oncological outcomes after cryoablation have generally been favourable for cT1a tumours. In a series of 308
patients with cT1a and cT1b tumours undergoing percutaneous cryoablation, local recurrence was seen in 7.7%
of cT1a tumours versus 34.5% of cT1b tumours. On multivariable regression, the risk of disease progression
increased by 32%, with each 1cm increase in tumour size (HR: 1.32, p < 0.001). Mean decline in eGFR was
11.7mL/min./1.73m2 [452]. In another large series of 220 patients with biopsy-proven cT1 RCC, five-year local
RFS was 93.9%, while metastasis-free survival approached 94.4% [446]. A series of 134 patients with T1 RCC
(median tumour size 2.8cm) submitted to percutaneous cryoablation yielded a ten-year DSF of 94% [453].

For cT1b tumours, local tumour control rates drop significantly. One study showed local tumour control in
only 60.3% at three years [454]. In another series, the PFS rate was 66.7% at twelve months [455]. Moreover,
analyses demonstrated five-year cancer-specific mortality rates of 7.6-9% [456, 457]. On multivariable analysis,
cryoablation of cT1b tumours was associated a 2.5-fold increased risk of death from RCC compared with PN
[456].

Recurrence after initial cryoablation is often managed with recryoablation, but only 45% of patients remain
disease-free at two years [458].

7.2.4.d.3 Radiofrequency ablation

Radiofrequency ablation is performed laparoscopically or percutaneously. Several studies compared patients
with cT1a tumours treated by laparoscopic or percutaneous RFA [459-462]. Complications occurred in up to 29%
of patients but were mostly minor. Complication rates, recurrence rates and CSS were similar in patients treated
laparoscopically and percutaneously.

The initial technical success rate on early (i.e. one month) imaging after one session of RFA is 94% for cT1a and
81% for cT1b tumours [463]. This is generally managed by re-RFA, approaching overall total technical success
rates > 95% with one or more sessions [464].

Long-term outcomes with over five years of follow-up following RFA have been reported. Some studies reported
five-year OS rates of 73-79% [463, 464] due to patient selection. While oncological outcomes have been
favourable for cT1a tumours, important to note is that, within the T1a 3-4cm subpopulation, these outcomes are
less encouraging [465]. A study involving 106 patients treated with radiofrequency ablation, and with a median
follow-up of 79 months, the ten-year DFS rate was 82%, but a notable decline was observed to 68% for tumours
larger than 3cm [464]. In series focusing on clinical T1b tumours (4.1-7.0cm), the five-year DFS rate was 74.5%
to 81% [463, 466]. Oncological outcomes appear to be worse than after surgery, but comparative data are
severely biased (see Section 7.2.4.d.4). In general, most disease recurrences occur locally and recurrences
beyond five years are rare [464, 466].

7.2.4.d.4 Microwave ablation

The best evidence base for these techniques exists for percutaneous microwave ablation. In a study of
185 patients with a median follow-up of 40 months, the five-year local progression rate was 3.2%, while
4.3% developed distant metastases [467]. Results appear to be favourable for cT1b tumours, as well [468].
Overall, current data on cryoablation, RFA and microwave ablation of cT1a renal tumours indicate short-term
equivalence with regards to complications, oncological and renal functional outcomes [469, 470].

7.2.4.d.5 Tumour ablation versus surgery

The Guideline Panel performed a protocol-driven SR of comparative studies (including > 50 patients) of tumour
ablation (TA) with PN for T1N0M0 renal masses [471]. Twenty-six non-randomised comparative studies
published between 2000 and 2019 were included, recruiting a total of 16,780 patients. Four studies compared
laparoscopic TA versus laparoscopic/robotic PN; sixteen studies compared laparoscopic or percutaneous
TA versus open, laparoscopic or robotic PN; two studies compared various TA techniques; and four studies

42 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

compared TA versus PN versus RN. In this SR, TA as treatment for T1 renal masses was found to be safe in
terms of complications and adverse events, but its long-term oncological effectiveness compared with PN
remained unclear. The primary reason for the persisting uncertainty was related to the nature of the available
data - most studies were retrospective observational studies with poorly matched controls or single-arm case
series with short follow-up. Many studies were poorly described and lacked a clear comparator.

There was also considerable methodological heterogeneity. Another major limitation was the absence of clearly
defined primary outcome measures. Even when a clear endpoint such as OS was reported, data were difficult
to interpret because of the varying length and type of follow-up amongst studies. The Panel also appraised the
published SRs based on the AMSTAR 2 tool, which showed ‘Critically Low’ or ‘Low’ ratings [471].

A SR and meta-analysis encompassing 133 studies of ablative therapies for localised RCC was published [472].
Of note, 80% of the included studies were retrospective, while only 8% were comparative. The interventions
evaluated consisted of SBRT, RFA, mWA and cryotherapy, represented in 21, 48, 32 and 43 studies, respectively.
The primary endpoint was local control at one, two and five years, defined as the proportion of patients without
evidence of tumour progression - growth or recurrence - on imaging or biopsy. The review reported high local-
control rates across all ablative modalities. Despite these findings, several methodological limitations warrant
consideration. These include heterogeneity in the definition of local control, the potential for double counting
of patients across studies and the application of the ROBINS-I tool to predominantly single-arm designs,
its suitability for which is uncertain [473]. Moreover, the meta-analytic pooling of heterogeneous, largely
noncomparative datasets may convey an unwarranted impression of statistical precision and evidentiary
robustness that is not supported by the underlying data.

Tumour ablation has been demonstrated to be associated with good long-term survival in several single-arm
non-comparative studies [474, 475]. Due to the lack of controls, this apparent benefit is subject to significant
uncertainties. Whether such benefit is due to the favourable natural history of such tumours or due to the
therapeutic efficacy of TA, as compared to PN, remains unknown. In addition, data is available from comparative
studies suggesting that TA may be associated with worse oncological outcomes in terms of local recurrence
and metastatic progression and CSM [456, 457, 476-480]. However, there appears to be no clinically significant
difference in five-year CSM between TA and AS [423]. A retrospective multicentre study, including 86 partial
nephrectomies and 104 TA, matched for complexities, has shown that PN and cryoablation are comparable
regarding complications within 90 days after treatment [481].

The Panel concluded that the current data are inadequate to reach conclusions regarding the clinical
effectiveness of TA as compared with PN. A cohort-embedded randomised feasibility study suggests that a
larger RCT could be conducted to compare cryoablation to PN [482].

Given these uncertainties in the presence of only low-quality evidence, the panel feels that an RCT is needed.

7.2.4.d.6 Stereotactic ablative radiotherapy

Stereotactic ablative radiotherapy (SABR) has been emerging as a treatment option for medically inoperable
patients with localised cT1a and cT1b tumours [483-486]. A variety of dose-fractionation schedules have been
reported (26-60Gy; single, three and five fractions) [484]. The international society of stereotactic radiosurgery
guidelines suggest the optimal dose fractionation is 25-26 Gy in one fraction for tumours < 4-5cm, or 42-48Gy in
three fractions for larger tumours [487]. Published single-arm studies, mainly including cT1 RCC, with a median
follow-up range of 16.4-34.3 months, reported local control rates of 90-97.2% [484, 488-495]. However, viable
tumour cells are often seen in post-SABR biopsies, although their clinical significance remains unclear [490]. In
the multicentre FASTRACK II phase II clinical trial, 70 patients with a biopsy confirmed primary RCC (medically
inoperable, technically at high risk of complications or declined surgery), received either a single fraction SABR
26Gy or 42Gy in three fractions, according to tumour size. Median tumour size was 4.6cm (IQR 3.7-5.5). Primary
endpoint was local control rate at 12 months, defined by RECIST criteria meaning a 30% increase of tumour
diameter (progressive disease) compared to base line as local failure. Based on this definition, local control
was 100% after 12 months and freedom from distant failure at 12 and 36 months was 97% [496]. Grade 3 or 4
toxicities were reported in 0-9.1% of the patients across studies [484]. In FASTRACK II, the ipsilateral kidney GFR
(determined by SPECT/CT) decreased from baseline by 42% and 39% in the 26Gy/single fraction cohort and by
45% and 62% in the 42 Gy/3 fractions cohort, at 12 and 24 months, respectively [497]. Although early reported
results of SABR look encouraging, more evidence from well-conducted prospective studies with longer follow-up
is needed [487].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 43

7.2.4.d.7 Other ablative techniques
Some studies have shown the feasibility of other ablative techniques, such as high-intensity focused US ablation
and nonthermal irreversible electroporation. However, these techniques are still considered experimental.

Figure 7.2.4.d.7.1: Alternatives to surgery

T1 RCC

Treatment not indicated Indication for treatment

RCC is not expected to significantly No indication for immediate treatment*,
RCC is expected to impact patient’s life
affect the patient’s limited life small sporadic tumours less than 2 cm, expectancy
expectancy*
delayed intervention may be appropriate**

*Highly frail and comorbid * Only applicable for T1a

** Several possible scenarios: Frail/old
patient; Refuses immediate
intervention; Suspected benign lesion; Unfit for Surgery Candidate for Surgery
Severe CKD; Relevant comorbidities but
non-terminal, hereditary syndromes

Watchful Waiting

T1a T1b
Active Surveillance
Cryo, RFA, MWA, SABR

Surgery Surgery
Diagnosis Treatment Follow-up
Alternative: Cryo, RFA, MWA

CKD = Chronic Kidney Disease; Cryo = Cryoablation; MWA = Microwave Ablation; RCC = Renal Cell Carcinoma;
RFA = Radiofrequency Ablation; SABR = Stereotactic Ablative Body Radiotherapy.

7.2.4.d.8 Summary of evidence and recommendations for therapeutic approaches as alternative to surgery

Summary of evidence LE
Most population-based analyses show a significantly lower cancer-specific mortality for patients 3
treated with surgery compared to no intervention.
In AS cohorts, the growth of SRMs is low in most cases and progression to metastatic disease is rare 3
(1-2%).
Low-quality studies suggest higher disease recurrence rates after RFA of tumours > 3cm and after 3
cryoablation of tumours > 4cm.
Low quality studies suggest a higher local recurrence rate for TA therapies compared to PN, but quality 3
of data does not allow definitive conclusions.
Stereotactic ablative radiotherapy in patients with non-metastatic RCC who were unfit for or declined 3
surgery, demonstrated short-term safety and efficacy but long-term and comparative data are lacking.

Recommendations Strength rating

Offer watchful waiting to highly frail and comorbid patients with reduced life expectancy. Weak
Offer active surveillance (AS) to cT1a patients with no indication for immediate treatment Weak
and where delayed intervention may be appropriate.
Offer tumour ablation (TA) or stereotactic ablative radiotherapy (SABR) in patients with cT1 Weak
lesions who have an indication for treatment but are unfit for surgery.
Perform a percutaneous renal mass biopsy prior to, and not concomitantly with, TA. Strong
Discuss the limitations in the clinical evidence, with regards to oncological outcomes and Strong
complications when TA or AS is offered.
Do not routinely offer radiofrequency ablation for tumours > 3cm and cryoablation for Weak
tumours > 4cm.

44 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

7.3 Treatment of locally advanced RCC
7.3.1 Introduction
In addition to the summary of evidence and recommendations outlined in Section 7.2 for localised RCC, certain
therapeutic strategies arise in specific situations for locally advanced disease.

7.3.2 Role of lymph node dissection in locally advanced RCC

In locally advanced RCC, the role of LND is still controversial. The only available RCT demonstrated no survival
benefit for patients undergoing LND, but this trial mainly included organ-confined disease cases [330]. In
the setting of locally advanced disease, several retrospective papers and SRs addressed the topic with
contradictory results. An SR and meta-analyses could not confirm any survival benefit in patients at high risk
of progression treated with LND [498]. Another SR and meta-analyses showed a survival benefit in patients
with locally advanced disease treated with LND [499]. Thirteen studies on patients with LND and non-LND were
identified and included in the analyses. In the subgroup of locally advanced RCC (cT3-T4NxM0), LND showed a
significantly better OS rate in patients who had undergone LND compared to those without LND (HR: 0.73, 95%
CI: 0.60-0.90, p = 0.003), although potential unknown biases could have had an impact on the findings.

7.3.2.a Management of clinically negative lymph nodes (cN-) in locally advanced RCC
In case of cN-, the probability of finding pathologically confirmed LN metastases ranges between 0 and 25%,
depending mainly on primary tumour size and the presence of distant metastases [500]. In case of clinically
negative LNs (cN-) at imaging, removal of LNs is justified only if visible or palpable during surgery [501], at least
for staging, prognosis, adjuvant therapy and follow-up implications, although a benefit in terms of cancer control
has not yet been demonstrated [333, 498].

7.3.2.b Management of clinically positive lymph nodes (cN+) in locally advanced RCC
In case of cN+, the probability to identify pathologically confirmed LN metastases ranges between 10.3%
(cT1 tumours) and up to 54.5% in case of locally advanced disease. In cN+, removal of visible and palpable
nodes during LND is justified [501], at least for staging, prognosis, adjuvant therapy and follow-up implications,
although a benefit in terms of cancer control has not yet been demonstrated [333, 498]. Whether to extend the
LND in case of lymphadenopathy (cN1) remains controversial. Retrospective data showed for resected isolated
macroscopical lymph node metastasis (pN1) that the time to systemic progression was a median of 4.2 months
[502], suggesting that systemic therapy should always be discussed in the presence of lymph node invasion.

7.3.3 Management of RCC with venous tumour thrombus

Tumour thrombus formation in RCC patients accounts for 4-10% of RCC and may involve renal vein (pT3a,
78.3%), subdiaphragmatic inferior vena cava (pT3b, 16.4%) or supradiaphragmatic inferior vena cava (pT3c,
5.3%) [503]. This is a significant adverse prognostic factor with a five-year survival rate of 36% to 57% for
patients without metastatic disease to other organs [504-507]. The majority are ccRCC and sarcomatoid
differentiation are frequent (58%) [508].

Magnetic resonance imaging has been established as the imaging method of choice to determine the upper
extent of the tumour thrombus, the degree of IVC occlusion and to predict IVC wall invasion [133]. However, with
the advent of the multidetector CT (MDCT), MRI may one day be replaced.

Several classifications have been described to distinguish the level of thrombus, the best known being the Mayo
classification (Level 0: Tumour thrombus is limited to the renal vein, Level 1: Tumour thrombus extends into the
IVC, < 2cm above the renal vein, Level 2: > 2cm above the renal vein but below the hepatic veins, Level 3: above
the hepatic veins but below the diaphragm Level 4: above the diaphragm, including atrial thrombus) [509].

Traditionally, patients with venous tumour thrombus undergo surgery to remove the kidney and tumour
thrombus. Aggressive surgical resection is widely accepted as the default management option for patients with
venous tumour thrombus, although the associated surgical mortality is 2-10% [503, 504, 506, 507, 510-512].
Close collaboration with the anaesthesia team is mandatory, as well as a preoperative multidiciplinary team
(MDT) for optimal surgical planning, including, for T3c, thoracic or vascular surgeon to consider the possibility of
cardiopulmonary bypass and cardioplegia (requiring preoperative cardiac catheterisation) [513-515, 465].

A preoperative imaging within one to two weeks of surgery is recommended given the propensity for tumour
thrombus to progress rapidly [513]. Further intraoperative real-time evaluation of the thrombus level using
transoesophageal echocardiography may be helpful [515].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 45

Complete surgical excision should always be attempted because positive vascular wall margins increase local
recurrence rates [516].

The role of neoadjuvant treatment with targeted agents has also been investigated in downstaging of tumour
thrombus within the IVC with limited and controversial results [505, 517, 518]. Further investigations are needed
to better identify which patients with RCC and tumour venous might benefit from neoadjuvant therapy (See also
Section 7.3.5).

Several scores and tools have been proposed to estimate surgical complexity and the risk of complications,
although an external validation is needed [519, 520].

In the largest published study, OS was higher in patients with a level of thrombus in the renal vein compared
to inferior caval vein [521]. Survival was also associated with tumour size, grade, perinephric fat extension,
sarcomatoid features, Eastern Cooperative Oncology Group PS and regional and distant metastases
in multivariate analysis [505, 521]. Therefore, all patients with nonmetastatic disease and venous tumour
thrombus, and an acceptable PS, should be considered for surgical intervention, irrespective of the extent of
tumour thrombus at presentation.

The presence of tumor thrombus in RCC patients represents a key risk factor for worse perioperative, as well as
long-term renal function. Specifically, patients with tumor thrombus harbour a significant and early estimated
GFR decrease. However, despite tumor thrombus, patients show a greater estimated GFR decline after surgery -
they retain acceptable renal function, which remains stable over time [522].

The surgical technique and approach (open versus laparoscopic versus robotic) for each case should be
selected based on patients’ characteristics, surgeon and hospital volumes and the extent of tumour thrombus
and the grade of occlusion of the IVC [517, 523-525].

An SR and meta-analysis regarding surgical approach included 1,375 patients, of which 329 patients were in
single-arm studies and 1,046 patients were in comparative studies [526]. Of the 329 patients who underwent
robotic, 14.7% were level I, 60.9% level II, 20.4% level III and 2.5% level IV thrombus. Compared with open
thrombectomy, robotic approach was associated with a lower blood transfusion rate and fewer overall
complications. Major complication and 30-day mortality rates were similar in both groups.

In a propensity-matched retrospective cohort including 324 patients with renal tumour and venous thrombus,
robotic approach was associated with a shorter operative time, a lower blood loss and transfusion rate, and
a lower complication rate and postoperative hospital stay after matching, while there was no significant
difference in survival [527]. In experienced hands with carefully selected patients, robotic thrombectomy can
be considered. However, an emphasised selection bias limits definitive inference of these results, and optimal
patient selection criteria are necessary: robotic approach is possible for stage 1 and selected stage 2 cases.

In case of venous thrombus, referral to a tertiary care centre/specialised centre is recommended to guarantee a
multidisciplinary evaluation and treatment, especially in case of caval thrombus.

7.3.4 Management of locally advanced unresectable RCC

The management of locally advanced unresectable RCC should be based around systemic therapy [528]. A
multidisciplinary evaluation, including urologists, medical oncologists and radiation therapists is suggested
to maximise cancer control, pain control and the best supportive care. In patients with unresectable disease,
embolisation can control symptoms, including visible haematuria or flank pain [347, 529-531].

46 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

 Patients with suspected locally-advanced RCC

Diagnostic work-up to exclude M1 disease Patients fit for surgery with resectable RCC
(see Guidelines on diagnostic evaluation)
+/-
Preoperative embolisation
cT3-T4 cN0-1 cM0 RCC
Radical nephrectomy
+/- +/- +/- +/-
Pre-treatment assessment
Adrenalectomy LND IVC Resection of
Figure 7.1: Treatment of locally advanced RCC

thrombectomy other organs

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

-Age, comorbidities, performance status
-Frailty and perioperative risk Treatment +/-
-Kidney(s) status and renal function decisions Referral to a specialised centre cardiopulmonary or +/-
-Cardiovascular and respiratory status veno-venous bypass
+/-
Patient
Multi-speciality surgical team

Patients unfit for surgery and/or with unresectable RCC

Provider Tumour Best supportive Individualised

MDT
care management based on
systemic therapy
-Centre/surgeon volume -Size and location
and experience -Histology (if renal biopsy performed) Palliative treatment

CECT = contrast-enhanced computed tomography; IVC = inferior vena cava; LND = lymph node dissection;
- MDT (preferred) -Imaging: CECT, MRI, +/- TEE (SBRT / embolisation) Diagnosis Treatment Follow-up

MDT = multidisciplinary team; MRI = magnetic resonance imaging; TEE = transoesophageal echocardiogram.

47
7.3.4.a Summary of evidence and recommendations for lymph node dissection, the management of RCC
with venous tumour thrombus and unresectable tumours

Summary of evidence LE
In patients with locally advanced disease, the survival benefit of LN dissection is unproven, but LN 3
dissection has significant staging, prognosis, adjuvant therapy and follow-up implications.
Low-quality data suggest that tumour thrombus excision in nonmetastatic disease may be beneficial. 3

Recommendations Strength rating

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

7.3.5 Neoadjuvant and adjuvant therapy

Neoadjuvant therapy is currently under investigation and available in clinical trials. In the presurgical setting,
neoadjuvant TKI and immune checkpoint therapy demonstrated varying response rates between 7 and 59% in
retrospective series and some phase II trials [517, 532, 533].

In a presurgical phase II trial in patients with vascular thrombus, treatment with axitinib demonstrated a
reduction in the level of tumour thrombus in 35% of patients (7/20) [532]. Another presurgical phase II trial
with axitinib showed a median shrinkage of tumour diameter of 1.3cm in complex renal tumours (RENAL Score
10-12) [534] and presurgical nivolumab did not show any primary tumour response in a prospective single arm
trial [535]. There is currently no evidence of a prolonged OS by neoadjuvant treatment and at present, the data
do not support its use outside clinical trials.

There is currently no evidence from an SR (including ten retrospective studies and two RCTs) that adjuvant
radiation therapy increases survival [536]. The impact on OS of adjuvant tumour vaccination in selected patients
undergoing nephrectomy for T3 renal carcinomas remains unconfirmed [537-541] (LE: 1b). A similar observation
was made in an adjuvant trial of girentuximab, a monoclonal antibody against carbonic anhydrase IX (CAIX)
(ARISER Study) [542].

At present, no OS data is available supporting the use of adjuvant VEGFR or mTOR inhibitors. Thus far, several
RCTs comparing VEGFR-TKI or mTOR versus placebo have been published [543-550]. A sub analysis of
EVEREST trial exploring adjuvant everolimus (mTOR) in non-clear cell RCC population did not show oncological
benefit [551]. Only S-TRAC, a trial of adjuvant sunitinib versus placebo demonstrated a DFS benefit that was not
reproduced in ASSURE, a trial of sunitinib and sorafenib versus placebo. Due to an unfavourable AE profile and
no survival advantage, none of these drugs are recommended [550].

7.3.5.a PD-1 Inhibition: Keynote-564

The Keynote-564 trial is the first trial to report positive primary endpoint data on DFS [552, 553] and OS [554].
Keynote-564 evaluated pembrolizumab (17 cycles of three-weekly therapy) versus placebo as adjuvant therapy
in 994 patients with intermediate (pT2, grade 4 or sarcomatoid, N0, M0; or pT3, any grade, N0, M0) or high risk
(pT4, any grade, N0, M0; or pT any stage, and grade, or N+, M0), or M1 (no evidence of disease [NED] after
primary tumour plus soft tissue metastases completely resected < one year from nephrectomy) disease. The
median follow-up, defined as time from randomisation to data cut-off, was 24.1 months. The primary endpoint
of DFS per investigator assessment was significantly improved in the pembrolizumab group vs. (at the primary
analysis HR: 0.68, 95% CI: 0.53-0.87, p = 0.001). The estimated 48-month DFS rate was 64.9% versus 56.6% for
pembrolizumab and placebo, respectively. Benefit occurred across broad subgroups of patients including those
with M1/NED disease post-surgery (n = 58 [6%]). Investigator-assessed DFS was considered preferable to DFS
by central review, due to its clinical applicability. Overall survival was statistically significant with a benefit in
the pembrolizumab arm (HR: 0.62, 95% CI: 0.44-0.87, p = 0.005) and a consistent DFS advantage (HR: 0.72)
after median follow-up of 57.2 months [554]. The estimated overall survival 91.2% in the pembrolizumab group
versus 86.0% in the placebo group at 48 months. The five-year update (median follow-up 69.5 months) showed

48 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

consistency in DFS and OS results [555]. Grade III-V all-cause adverse events occurred in 32% versus 18% of
patients for pembrolizumab and placebo, respectively. Quality of life assessment by FKSI-DRS and QLQ30
did not show a statistically significant or clinically meaningful deterioration in health-related QoL or symptom
scores for either adjuvant pembrolizumab or placebo.

7.3.5.b PD-L1 inhibition: IMmotion010

The IMmotion010 phase III trial was the first adjuvant ICI trial to be developed in RCC to investigate the effect
of a PD-L1 inhibitor on DFS [556]. IMmotion010 evaluated atezolizumab 1200 mg (once every three weeks for
sixteen cycles or one year) versus placebo as adjuvant therapy in 778 patients with increased risk of recurrence
defined as: pT2, grade 4 or sarcomatoid, N0, M0; pT3, grade 3-4, N0, M0; pT3b/c/T4, any grade, N0, M0; pT any
stage and grade, pN1, M0; or M1 no NED after primary tumour plus soft tissue metastases completely resected
either synchronous or if metachronous, > 12 months from nephrectomy.

The minimum follow-up, defined as time from randomisation to data cut-off, was 38.6 months. The primary
endpoint of DFS per investigator assessment was not met in the atezolizumab group versus placebo (HR: 0.93,
95% CI: 0.75-1.15, p = 0.4950) with a median DFS of 57.2 months (95% CI: 44.6, NE) for atezolizumab vs. 49.5
months for placebo (47.4, NE). None of the exploratory subgroups suggested a DFS benefit with atezolizumab,
most notably the M1 NED subgroup (n = 108/13.9%) which was larger than in Keynote-564 (5.8%), the
sarcomatoid subgroup and the subgroup expressing > 1% PD-L1 had a HR of 0.93 (0.58-1.49), 0.77 (0.44-1.36)
and 0.83 (0.63-1.10), respectively.

There were no OS differences. Grade 3-4 all-cause and treatment-related adverse events occurred in 27.2% and
14.1% versus 21.1% and 4.7% of patients for atezolizumab and placebo, respectively. There was no treatment-
related grade 5 adverse events.

7.3.5.c PD-1 and CTLA-4 inhibition: CheckMate 914

CheckMate 914 was the first phase III trial to investigate a combination of nivolumab plus ipilimumab versus
placebo as adjuvant treatment in RCC (part A) [557]. Subsequently, a nivolumab monotherapy arm was also
added to the trial (part B). The following results relate to part A, which evaluated nivolumab 240mg every two
weeks (Q2W) for twelve cycles or six months plus ipilimumab 1mg/kg Q6W for four cycles versus placebo in
816 patients with recurrence risk defined as pT2a, grade 3 or 4, N0, M0; pT2b/T3/T4, any grade, N0, M0; or pT
any stage, any grade, pN1, M0. The median time of follow-up, defined as time from randomisation to data cut-
off, was 37 months. The primary endpoint of DFS per investigator assessment was not met in the nivolumab
plus ipilimumab group versus placebo (HR: 0.92 [0.71-1.19], p = 0.5347). Of the exploratory subgroups, patients
with sarcomatoid tumours (n = 40) and those with > 1% PD-L1 expression (n = 107) had a HR of 0.29 (0.09-0.91)
and 0.46 (0.23-0.94) in favour of the ICI combination, respectively.

All-cause treatment discontinuation due to study drug occurred in 43% and 33% in the nivolumab plus
ipilimumab group versus 11% and 1% in the placebo group. Treatment-related adverse events grade > III were
29% in the nivolumab plus ipilimumab group and 2% in the placebo group with four deaths (1%) considered
related to combination therapy. The high adverse event profile may have contributed to the lack of efficacy and
patient retention. The results of the nivolumab arm are awaited.

The results from Part B, (efficacy and safety of adjuvant NIVO monotherapy versus placebo) did not meet the
primary endpoint, DFS of NIVO versus placebo per blinded independent central review (BICR), was not met
(HR: (95% CI), 0.87 (0.62-1.21) p = 0.3962 with median DFS not reached in both arms) [558, 559].

7.3.5.d Perioperative PD-1 inhibition: PROSPER

PROSPER is a perioperative trial of neoadjuvant nivolumab (one cycle) followed by RN or PN and adjuvant
nivolumab (480mg IV q4 weeks) for nine doses compared to surgery followed by surveillance without a placebo
[560]. Patients with clinical stage > T2 or T any N+ RCC or patients with selected oligometastatic disease were
included if they had no evidence of disease within twelve-weeks post-surgery. A total of 819 patients with clear
cell (87%) and non-ccRCC were included, a biopsy in the nivolumab arm was mandatory. The primary endpoint of
RFS was similar between the arms (HR: 0.97; 95% CI: 0.74-1.28; p = 0.43) and the trial was stopped by the data
and safety monitoring committee. The OS was not statistically different (HR: 1.48; 95% CI: 0.89-2.48; p = 0.93),
although not mature. Grade III-IV adverse events occurred in 20% (nivolumab arm) and 6% (control arm) of
patients, respectively. Fifteen (4%) patients died in the nivolumab arm and eighteen (4%) in the surgery-alone
arm.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 49

The panel reached consensus and issued a strong recommendation for adjuvant pembrolizumab for patients
with high-risk (defined as per study) operable ccRCC as final OS data is now available [554, 561]. This decision
was taken as ICI therapy has a different mode of action than VEGFR-TKI, resulting in complete responses in up
to 16% of patients in PD-1 unselected populations in metastatic disease [562]. Despite immature OS data with
the early OS signal potentially driven by the M1 population, the Panel cannot exclude that a survival benefit will
emerge. This was not the case in the adjuvant sunitinib trial (S-TRAC) [557, 563]. The Panel recommends for
adjuvant pembrolizumab, but the following topics should be considered:
• A high proportion of patients, cured by surgery, are receiving unnecessary treatment.
• The tolerability profile is acceptable, but treatment related grade III-V adverse events were higher, with
18.6% in the pembrolizumab arm versus 1.2% in the placebo arm (occurring in approximately one-third of
patients, all cause). Approximately 21% of patients required treatment discontinuation for adverse events.
• There is a risk of life-changing toxicity.
• Other ICI trials have not shown consistent results.
• Biomarker analysis to predict outcome and adverse events is not available.

The results of IMmotion010, CheckMate 914 and PROSPER need to be discussed with patients [556, 557, 560].
Meta-analysis with these data sets is not recommended due to heterogeneity across the ICI studies. It is likely
that there are several reasons behind these inconsistent results, including study population with potential
heterogeneity independent of TNM risk groups, selection criteria and trial design. To date, pembrolizumab is the
only positive trial [563].

While the results of IMmotion010 may reflect the nonsignificant OS results seen in the metastatic setting with
PD-L1 inhibitors (IMmotion151, Javelin 101), the results of CheckMate 914 and PROSPER are more difficult to
interpret. Nivolumab and ipilimumab leads to durable remission and long-term OS in metastatic disease and
nivolumab has a similar mode of action as pembrolizumab (anti PD-1).

The high treatment discontinuation rate of 33% in CheckMate 914 is of concern and may have had an impact
on the trial effectivity (20% in Keynote-564). The Panel strongly feels that biomarker work on all of these trials
should be carried out to identify patients that do respond to therapy and to give a better explanation for the
inconsistent results with KIM-1 as a potential prognostic factor as shown in IMmotion010 [269]. Treatment of
unselected patients in the adjuvant setting based on the Keynote-564 criteria will result in a large proportion
of patients receiving unnecessary therapy. In the absence of OS data or appropriate biomarkers, the patient
preference should be leading in a shared decision-making process. Patients considering adjuvant therapy
should be aware of all trials and not be presented with only one data set.

7.3.5.e Progression after adjuvant PD-1 therapy

Currently, uncertainty exists regarding further treatment of patients who receive adjuvant therapy with
pembrolizumab and develop a recurrence. Due to the relatively recent approval and recommendation, no
phase III prospective trial data exist in this setting. The Guideline panel believes that there are different patient
categories for patient progressing on or after pembrolizumab:
1. IO-Refractory patients: Progressing within the first three months of adjuvant pembrolizumab.
2. Early progressors: Patient progressing during pembrolizumab therapy.
3. Intermediate progressors: Patient progressing within the first six months after finishing adjuvant
pembrolizumab treatment.
4.  Late progressors: Patient progressing more than twelve months after finishing adjuvant
pembrolizumab treatment.

The CONTACT-03 [564] and TiNivo [565] trial in mRCC patients showed no additional benefit of TKI+IO
combinations over single agent TKI in IO pretreated patients. Therefore, it is likely that the first two groups of
IO-refractory patients and early progressors after adjuvant pembrolizumab will not benefit from a subsequent
TKI+IO combination and should be treated with TKI monotherapy. For late progressors and potentially
intermediate progressing patients, the benefit of an IO combination cannot be excluded, but neither can it be
confirmed.

50 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Table 7.1: Overview phase III trials of PD-1 immune checkpoint inhibitors in adjuvant RCC

Phase III trial of PD-1 immune checkpoint inhibitors in adjuvant RCC

Study N Experimental Primary Risk groups DFS (mo) OS (mo.)
arm endpoint Median (95% CI) Median (95% CI)
HR HR
Keynote-564 994 PEMBRO DFS in the Intermediate- (ITT) (ITT)
NCT03142334 200mg IV ITT by IR high: pT2 grade PEMBRO: NR (NE) PEMBRO: NR (NE)
Median follow-up Q3W (17 4 or sarcomatoid; PLACEBO: 68.3 PLACEBO: NR (NE)
of 69.5 mos. cycles) vs. pT3 any grade (51.7 - NR)
[552, 554, 555] placebo High: pT4 any HR: 0.66 (95% CI:
grade, pN1 HR: 0.71 (95% CI: 0.48-0.90)
M1 NED: cM0 0.59-0.86)) p < 0.005
after resection of P < 0.002
oligometastatic alive at 60 mos.:
disease < 12 mo. DFS at 72 mos.: PEMBRO: 87.7.%
PEMBRO: 58.5% PLACEBO: 82.3%
PLACEBO: 48.7%
IMmotion010 778 ATEZO DFS in the By TNM: (ITT) (ITT)
NCT03024996 1200mg IV ITT by IR pT2 grade 4 or ATEZO: 57.2 ATEZO : NE
Median follow-up Q3W (16 sarcomatoid; (44.6-NE) (59.8-NE)
of 44.7 mos. [556] cycles or 1 yr.) pT3 a grade 3-4; PLACEBO: 49.5 PLACEBO : NE
vs. placebo pT3b/c/T4 any (47.4-NE) (NE-NE)
grade, pN1
M1 NED: cM0 HR: 0.93 (95% CI: HR: 0.97 (95% CI:
after resection of 0.75-1.15) 0.67-1.42)
oligometastatic p = 0.4950
disease alive at 24 mo.: NR
(synchronous or DFS at 24 mos.: NR
>/= 12 mos.)
CheckMate 914 816 NIVO 240 mg DFS in By TNM: (ITT) NR
NCT03138512 IV Q2W the ITT by pT2a grade 3-4; NIVO + IPI: NR (NE)
Median follow-up (× 12 cycles) + BICR pT2b/T3/T4 any PLACEBO: 50.7
of 37.0 mos.[557] ipilimumab 1 grade, pN1 (48.1-NE)
mg/kg IV Q6W
(× 4 cycles vs. HR: 0.92 (95% CI:
placebo) 0.71-1.19)
p = 0.5347

DFS at 24 mos.:
NIVO + IPI: 76.4%
PLACEBO: 74.0%

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 51

Arm B median 825 Nivolumab DFS in By TNM: (ITT) NR
follow-up of 27 Arm 240 mg IV the ITT by pT2a grade 3-4; NIVO: NR (NE)
months [558, 559] B Q2W (× 12 BICR pT2b/T3/T4 any PLACEBO: NR (NE)
cycles) + grade, pN1 HR: 0.87 (95%
placebo Q6W CI:0.62-1.21)
(× 4 doses) p = 0.3962
vs.
placebo IV DFS at 18 months
Q2W (× 12) NIVO: 78.4%
+ placebo IV PLACEBO: 75.4%
Q6W (× 4)
vs. Secondary
Nivolumab endpoint:
240 mg IV NIVO: NR (NE)
Q2W (× 12) + NIVO+IPI: (NR (NE)
ipilimumab 1
mg/kg IV Q6W HR: 1.27 (95% CI:
(× 4) 0.92-1.76)
2:1:1
DFS at 18 months
NIVO: 78.4%
NIVO+IPI: 72.3%
PROSPER 779 Neoadjuvant RFS in the By TNM: (ITT), RFS: (ITT)
NCT03055013 NIVO 240mg ITT by IR >/= cT2 (7 cm) or NIVO: NR (NE) NIVO: NR (NE)
Median follow-up: IV Q2W cT any cN1 Observation: NR Observation : NR
NR [560] (x 2 cycles) (NE) (NE)
followed
by adjuvant HR: 0.94 (95% CI: HR: 1.28 (95% CI:
nivolumab 0.74-1.21) 0.84-1.95)
240mg Q2W p = 0.32 p = 0.26
for 3 mos.
and Q4W for
6 mos. vs.
observation
ATEZO = atezolizumab; BICR = blinded independent central review; CI = confidence interval; DFS = disease-free
survival; HR = hazard ratio; IPI = ipilimumab; IR = investigator review; ITT = intention-to-treat; IV = intravenous;
mos. = months; NE = non-estimable; NED = no evidence of disease; NIVO = nivolumab; NR = not reached; OS = overall
survival; PD-1 = programmed death-receptor 1; PEMBRO = pembrolizumab; PFS = progression free survival;
Q2W = every 2 weeks; Q3W = every 3 weeks.

7.3.5.f Summary of evidence and recommendations for neoadjuvant and adjuvant therapy

Summary of evidence LE
Neoadjuvant systemic therapy can reduce vascular thrombus and tumour size in the presurgical 2a
setting.
Adjuvant sunitinib, sorafenib, pazopanib, everolimus, girentuximab or axitinib does not improve OS after 1b
nephrectomy.
Adjuvant PD1 inhibition with pembrolizumab defined by the inclusion criteria of the trial* after 1b
nephrectomy improves DFS and OS.
Adjuvant PD-L1 inhibition with atezolizumab and PD1 inhibition with nivolumab did not improve DFS or 1b
OS.
Adjuvant dual PD-1 and CTLA-4 inhibition with nivolumab and ipilimumab did not improve DFS. 1b
Perioperative treatment with nivolumab did not improve RFS. 1b
There is uncertainty regarding further systemic therapy in patients who receive adjuvant 4
pembrolizumab and develop a recurrence.
The lack of biomarker data is hindering progress in this field. 4
* pT2 G4 or pT3 any G; pT4 any G; pN+ any G; M1, NED after resection of metastases.

52 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Recommendations Strength rating
Do not use neoadjuvant therapy outside a clinical trial setting. Weak
Offer adjuvant pembrolizumab to ccRCC patients, preferably within 12-16 weeks post- Strong
nephrectomy, following restaging, 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):
• NED after resection of oligometastatic sites within one year from nephrectomy.
If adjuvant therapy is planned: Strong
• D iscuss the contradictory results of the available adjuvant immune checkpoint inhibitor
(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.
Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell renal cell Weak
carcinoma (ccRCC).
Offer vascular endothelial growth factor receptor - tyrosine kinase inhibitor (VEGFR-TKI) to Weak
patients developing a recurrence while receiving pembrolizumab or within the first six months
after stopping pembrolizumab given for one year.
Do not offer ICI mono- or combination therapy in patients with recurrence during or within six Weak
months after adjuvant pembrolizumab.

7.4 Advanced/metastatic RCC

7.4.1 Local therapy of advanced/metastatic RCC
7.4.1.a Cytoreductive nephrectomy
Tumour resection is potentially curative only if all tumour deposits are excised. This includes patients with the
primary tumour in place and single or oligometastatic resectable disease. For most patients with metastatic
disease, cytoreductive nephrectomy (CN) is palliative and systemic treatments are necessary.

Two RCTs [501, 566] and a narrative SR were identified [567]. The narrative SR included both RCTs and ten
non-RCTs. CARMENA, a phase III noninferiority RCT investigating immediate CN followed by sunitinib versus
sunitinib alone, showed that sunitinib alone was not inferior to CN followed by sunitinib with regard to OS [566].
The trial included 450 patients with metastatic ccRCC of intermediate and MSKCC poor risk, of whom 226
were randomised to immediate CN followed by sunitinib and 224 to sunitinib alone. Patients in both arms had
a median of two metastatic sites. Patients in both arms had a tumour burden of a median/mean of 140mL of
measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, of which 80mL accounted
for the primary tumour. The study did not reach the full accrual of 576 patients, and the Independent Data
Monitoring Commission (IDMC) advised the trial steering committee to close the study. In an ITT analysis after
a median follow-up of 50.9 months, median OS with CN was 13.9 months versus 18.4 months with sunitinib
alone (HR: 0.89, 95% CI: 0.71-1.10). This was found in both risk groups. For MSKCC intermediate-risk patients
(n = 256), median OS was 19.0 months with CN and 23.4 months with sunitinib alone (HR: 0.92, 95% CI: 0.60-
1.24), and for MSKCC poor risk (n = 193), 10.2 months and 13.3 months, respectively (HR: 0.86, 95% CI: 0.62-
1.17). Noninferiority was also found in two per-protocol analyses accounting for patients in the CN arm who
either did not undergo surgery (n = 16) or did not receive sunitinib (n = 40), and patients in the sunitinib-only arm
who did not receive the study drug (n = 11). Median PFS in the ITT population was 7.2 months with CN and 8.3
months with sunitinib alone (HR: 0.82, 95% CI: 0.67-1.00). The clinical benefit rate, defined as disease control
beyond twelve weeks, was 36.6% with CN and 47.9% with sunitinib alone (p = 0.022). Of note, 38 patients in the
sunitinib-only arm required secondary CN due to acute symptoms or for complete or near-complete response.
The median time from randomisation to secondary CN was 11.1 months.

The randomised EORTC SURTIME study revealed that the sequence of CN and sunitinib did not affect PFS
(HR: 0.88, 95% CI: 0.59-1.37, p = 0.569). The trial accrued poorly and therefore results are mainly exploratory.
However, in secondary endpoint analysis, a strong OS benefit was observed in favour of the deferred CN
approach in the ITT population with a median OS of 32.4 (range 14.5-65.3) months in the deferred CN arm
versus 15.0 (9.3-29.5) months in the immediate CN arm (HR: 0.57, 95% CI: 0.34-0.95, p = 0.032). The deferred

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 53

CN approach appears to select patients with inherent resistance to systemic therapy [568]. This confirms
previous findings from single-arm phase II studies [567, 569]. Moreover, deferred CN and surgery appear safe
after sunitinib, which supports the findings, with some caution, of the only available RCT. In patients with poor
PS or IMDC poor risk, small primaries, and high metastatic volume and/or a sarcomatoid tumour, CN is not
recommended [570]. These data are confirmed by CARMENA [448] and upfront pre-surgical VEGFR-targeted
therapy followed by CN seems to be beneficial [562].

Meanwhile first-line therapy recommendations for patients with their primary tumour in place have changed
to ICI combination therapy (see Section [Link]) with sunitinib and other VEGFR-TKI monotherapies reserved
for those who cannot tolerate ICI combination or have no access to these drugs. High-level evidence regarding
CN is not available for ICI combinations but up to 30% of patients with primary metastatic disease, treated
with their tumour in place, were included in the pivotal ICI combination trials (Table 7.2). The subgroup HRs,
where available, suggest better outcomes for the ICI combination compared to sunitinib monotherapy. In
mRCC patients without a need for immediate drug treatment, an SR evaluating effects of CN demonstrated an
OS advantage of CN [567]. These data were supported by a nation-wide registry study showing that patients
selected for primary CN had a significant OS advantage across all age groups [571].

Table 7.2: Key trials on immune checkpoint inhibitor combinations for primary metastatic disease

Trial Drug Number and % of Number of patients treated Subgroup analyses

combination patients treated with the primary tumour in (HR with 95% CIs)
with primary place
tumour in place (ICI combination vs.
sunitinib)
ICI sunitinib PFS OS
combination
CheckMate 214 ipilimumab + 187/847 (22%) 84 103 NA 0.63
[572] nivolumab (0.42-0.94)
CheckMate 9ER cabozantinib + 196/651 (30.1%) 101 95 0.63 0.79
[573] nivolumab (0.43-0.92) (0.48-1.29)
Javelin 101 axitinib + 179/886 (20.2%) 90 89 0.75 NA
[574] avelumab (0.48-1.65)
KEYNOTE-426 axitinib + 143/861 (16.6%) 73 70 0.68 0.57
[575] pembrolizumab (0.45-1.03) (0.36-0.89)
CLEAR lenvatinib + 179/714 (25.1%) 97 82 0.38 0.52
[576] pembrolizumab (0.31-0.48) (0.31-0.86)
CI = confidence interval; HR = hazard ratio; ICI = immune checkpoint inhibitor; NA = not available;
PFS = progression-free survival; OS = overall survival.

The results of CARMENA and SURTIME demonstrated that patients who require systemic therapy benefit from
immediate drug treatment. While randomised trials to investigate deferred versus no cytoreductive nephrectomy
with ICI and ICI combinations are ongoing, the exploratory results from the ICI combination trials demonstrate
that the respective Immune-Oncology (IO) + IO or TKI + IO combinations have a superior effect on the primary
tumour and metastatic sites when compared to sunitinib alone (Table 7.2). In accordance with the CARMENA
and SURTIME data, this suggests that mRCC patients and IMDC intermediate- and poor-risk groups with their
primary tumour in place should be treated with upfront IO-based combinations. In patients with a clinical
response to IO-based combinations, a subsequent CN may be considered. Real-world data have demonstrated
durable response and surgical safety with this strategy. However, long-term surveillance is lacking [577-579].
Randomised controlled trials in this setting are ongoing but are unlikely to report soon [580].

7.4.1.a.1 Embolisation of the primary tumour

In patients unfit for surgery or with un-resectable disease, embolisation can control symptoms including visible
haematuria or flank pain [347, 530] (see the recommendations in Section 7.2.2.b.4).

54 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

7.4.1.a.2  ummary of evidence and recommendations for local therapy of advanced/metastatic renal cell
S
carcinoma

Summary of evidence LE
Deferred CN with presurgical sunitinib in intermediate-risk patients with clear cell metastatic RCC 2b
(ccm-RCC) shows a survival benefit in secondary endpoint analyses and selects outpatients with
inherent resistance to systemic therapy.
Sunitinib alone is noninferior compared to immediate CN followed by sunitinib in patients with MSKCC 1a
intermediate and poor risk who require systemic therapy with VEGFR-TKI.
Cytoreductive nephrectomy in patients with simultaneous complete resection of a single metastasis or 3
oligometastases may improve survival and delay systemic therapy.
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 2b
and OS in exploratory subgroup analyses compared to treatment with sunitinib.

Recommendations 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 Weak
synchronous primary tumour and require systemic therapy.
Start systemic therapy without CN in intermediate-risk patients who have an asymptomatic Weak
synchronous primary tumour and require systemic therapy.
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 Weak
systemic therapy.
Perform immediate CN in patients with oligometastases when complete local treatment of Weak
the metastases can be achieved.
IMDC = International Metastatic Renal Cell Carcinoma Database Consortium, MSKCC = Memorial Sloan Kettering
Cancer Centre.

7.4.2 Therapy of oligometastatic disease

Therapy of oligometastatic disease (General considerations)
In patient with low metastatic tumour burden, there is no generally accepted definition of oligometastatic
disease and its various forms of clinical presentation with regard to dynamics, size, numbers and site of
metastasis.

However, two Delphi consensus approaches defined oligometastatic disease as one to five lesions at one side
[581, 582]. Metastatic disease is defined as synchronous or metachronous presentation. A metachronous
interval of < 1 year for recurrences following surgery with curative intent is a poor prognostic factor by IMDC
classification [302, 583]. In addition, local treatment may lead to poorer outcomes compared to systemic
therapy approaches as a relapse within the first 12 months and presentation with synchronous oligometastatic
disease is attributed to the IMDC intermediate risk-group.

Data from the TKI era suggest that patients with oligometastatic disease recurrence can be observed for up to a
median of 16 months before systemic therapy is required and that this practice is common in real-world settings
(30%) [584, 585]. However, the general challenge is that a period of surveillance has never been investigated
versus active local treatment or systemic therapy. Despite this, various modalities for local treatment of
oligometastatic disease have evolved over time.

Two SRs of the local treatment of metastases from RCC [586-588], including metastasectomy, various
radiotherapy modalities, local ablation [589] and no local treatment, did not change the level of evidence due to
the heterogeneity and risk of bias to recommend one over the other. In symptomatic patients, radiotherapy to
brain and bone metastases relieved local symptoms. In non-symptomatic patients, different strategies include:

7.4.2.a Complete versus no/incomplete metastasectomy

An SR of eight studies reported a significantly longer median OS or CSS following complete metastasectomy
[590-597].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 55

7.4.2.b Local therapies for RCC metastases
Various retrospective studies using metastasectomy, SBRT or local ablative therapy reported that local tumour
control can be achieved. Due to the retrospective nature, cohort size and missing comparator, no definitive
conclusion can be made if compared to active surveillance or immediate systemic therapy and with regard to OS.

Prospectively, single arm phase II evaluation of metastasis-directed radiotherapy prolonged the time to
start systemic therapy [598] by 34 months in oligometastatic disease. Several other RCTs with SBRT in
oligometastatic setting are ongoing.

7.4.2.c Adjuvant treatment in cM0 patients after metastasectomy

Patients after metastasectomy and no evidence of disease (cM0) have a high risk of relapse. The results of
nine comparative studies of post-metastasectomy adjuvant treatment requirement, summarised in a recent SR,
concluded that there is no benefit in terms of OS and DFS [599].

Recent attempts to reduce RFS in randomised prospective phase II trials of sorafenib and pazopanib after
metastasectomy did not demonstrate an improvement in RFS [201, 202].

KEYNOTE-564 included a small percentage of patients who were treated by nephrectomy and complete
metastasectomy within one year after primary diagnosis (6% in the experimental arm and 6% in the placebo
arm) [552, 553]. Patients with brain and bone metastases where not included [302, 583]. Systemic therapy based
on immune combinations has higher levels of evidence than surgery in this intermediate/advanced disease
setting [600]. In addition, TKI-driven adjuvant trials after metastasectomy have shown no DFS or OS benefit
[201, 202].

Results for single-agent pembrolizumab post-surgery for metastatic disease are therefore difficult to interpret
due to the small subgroup. The DFS HR of 0.40 (95% CI: 0.20-0.81) and OS HR was 0.51 (95% CI: 0.15-
1.75) in favour of resection of M1 to NED plus pembrolizumab shows that patients with subclinical, but
progressive, disease who were subjected to metastasectomy had a benefit of adjuvant systemic therapy with
pembrolizumab. Based on the current data, it cannot be concluded that for patients with oligo-progressive
disease, metastasectomy within the first year of initial diagnosis of the primary and subsequent adjuvant
pembrolizumab is superior to a period of observation and dual IO-based combination first-line therapy upon
progression.

The Panel therefore does not encourage metastasectomy and adjuvant pembrolizumab in this population with
recurrent disease within one year after primary surgery. A careful reassessment of disease status to rule out
rapid progressive disease should be performed. Data from another adjuvant ICI study with the PD-L1 inhibitor
atezolizumab (IMmotion010) also included an M1 NED subgroup which showed no DFS advantage [556]. This
result underscores the need for caution in the treatment of the M1 NED subgroup. No prospective data is
available for adjuvant therapy after local treatment with radiotherapy of ablation.

7.4.2.d Summary of evidence and recommendations for local therapy of metastases in metastatic RCC

Summary of evidence LE
Retrospective comparative studies point towards a benefit of complete metastasectomy in mRCC 3
patients in terms of OS, CSS and delay of systemic therapy.
A single-arm prospective and retrospective study support that oligometastases can be observed for up 2a
to 16 months before systemic therapy is required due to progression.
Radiotherapy to bone and brain metastases from RCC can induce significant relief from local 3
symptoms (e.g. pain).
Tyrosine kinase inhibitors treatment after metastasectomy in patients with no evidence of disease did 1b
not improve RFS when compared to placebo or observation.

Recommendations Strength rating

To control local symptoms, offer ablative therapy, including metastasectomy, to patients Weak
with metastatic disease and favourable disease factors and in whom complete resection is
achievable.

56 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

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

7.5 Systemic therapy for advanced/metastatic RCC

7.5.1 Chemotherapy
Chemotherapy has proven to be generally ineffective in the treatment of RCC, but can be offered to patients with
collecting duct or medullary carcinoma [203].

7.5.1.a Recommendation for systemic therapy in advanced/metastatic RCC

Recommendation Strength rating

Do not offer chemotherapy to patients with metastatic RCC. Strong

7.5.2 Targeted therapies

In sporadic ccRCC, HIF accumulation due to VHL inactivation results in overexpression of VEGF and platelet-
derived growth factor (PDGF), which promote neoangiogenesis [601-603]. This process substantially contributes
to the development and progression of RCC. Several targeting drugs for the treatment of mRCC are approved in
both the USA and Europe.

Most published trials have selected for clear-cell carcinoma subtypes, therefore, no robust evidence-based
recommendations can be given for non-ccRCC subtypes.

In major trials leading to registration of the approved targeted agents, patients were stratified according to the
IMDC risk model (see Section 6.6 on prognostic models) [304].

7.5.2.a Tyrosine kinase inhibitors

7.5.2.a.1 Sunitinib
Sunitinib is an oral TKI inhibitor and has antitumour and antiangiogenic activity. First-line monotherapy with
sunitinib demonstrated significantly longer PFS compared with Interferon-alpha (IFN-α). Overall survival was
greater in patients treated with sunitinib (26.4 months) versus IFN-α (21.8 months), despite crossover [604].

In the EFFECT trial, sunitinib 50mg/day (four weeks on, two weeks off) was compared with continuous
uninterrupted sunitinib 37.5mg/day in patients with clear cell metastatic renal cell carcinoma (cc-mRCC) [605].
No significant differences in OS were seen (23.1 vs. 23.5 months, p = 0.615). Toxicity was comparable in both
arms. Because of the nonsignificant, but numerically longer time to progression with the standard 50mg dosage,
the authors recommended using this regimen. Alternate scheduling of sunitinib (two weeks on, one week off) is
being used to manage toxicity, but robust data to support its use is lacking [606, 607].

7.5.2.a.2 Pazopanib
Pazopanib is an oral angiogenesis inhibitor. In a trial of pazopanib versus placebo in treatment-naive mRCC
patients and cytokine-treated patients, a significant improvement in PFS and tumour response was observed
[608].

A noninferiority trial comparing pazopanib with sunitinib (COMPARZ) established pazopanib as an alternative to
sunitinib. The results of the trial showed that pazopanib was not associated with significantly worse PFS or OS
compared to sunitinib. The two drugs had different toxicity profiles, and QoL was better with pazopanib [609]. In
another patient-preference study (PISCES), patients preferred pazopanib to sunitinib (70% vs. 22%, p < 0.05) due
to symptomatic toxicity [610]. Both studies were limited in that intermittent therapy (sunitinib) was compared with
continuous therapy (pazopanib).

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 57

7.5.2.a.3 Axitinib
Axitinib is an oral selective second-generation inhibitor of VEGFR-1, -2 and -3. Axitinib was first evaluated as
second-line treatment. In the AXIS trial, axitinib was compared to sorafenib in patients who had previously failed
cytokine treatment or targeted agents (mainly sunitinib) [611].

The overall median PFS was greater for axitinib than sorafenib. Axitinib was associated with a greater PFS
than sorafenib (4.8 vs. 3.4 months) after progression on sunitinib. Axitinib showed grade III diarrhoea in 11%,
hypertension in 16% and fatigue in 11% of patients. Final analysis of OS showed no significant differences
between axitinib or sorafenib [612]. In a randomised phase III trial of axitinib versus sorafenib in first-line
treatment-naive cc-mRCC, a significant difference in median PFS between the treatment groups was not
demonstrated, although the study was underpowered, raising the possibility of a type II error [613]. As a result of
this study, axitinib is not approved for first-line therapy.

7.5.2.a.4 Cabozantinib
Cabozantinib is an oral inhibitor of tyrosine kinase, including MET, VEGF and AXL. Cabozantinib was investigated
in a phase I study in patients resistant to VEGFR and mTOR inhibitors demonstrating objective responses and
disease control [260]. Based on these results an RCT investigated cabozantinib versus everolimus in patients with
ccRCC failing one or more VEGF-targeted therapies (METEOR) [614, 615]. Cabozantinib delayed PFS compared to
everolimus in VEGF-targeted therapy refractory disease (HR: 0.58, 95% CI: 0.45-0.75) [614] (LE: 1b). The median
OS was 21.4 months (95% CI: 18.7 to not estimable) with cabozantinib and 16.5 months (95% CI: 14.7-18.8) with
everolimus in VEGF-resistant RCC. The HR for death was 0.66 (95% CI: 0.53-0.83, p = 0.0003) [500]. Grade III or IV
adverse events were reported in 74% with cabozantinib and 65% with everolimus. Adverse events were managed
with dose reductions; doses were reduced in 60% of the patients who received cabozantinib.

The Alliance A031203 CABOSUN randomised phase II trial comparing cabozantinib and sunitinib in first line
in 157 intermediate- and poor-risk patients favoured cabozantinib for RR and PFS, but not OS [616, 617].
Cabozantinib significantly increased median PFS (8.2 vs. 5.6 months, adjusted HR: 0.66, 95% CI: 0.46-0.95; one-
sided p = 0.012). Objective response rate was 46% (95% CI: 34-57) for cabozantinib versus 18% (95% CI: 10-28)
for sunitinib. All-causality grade III or IV adverse events were similar for cabozantinib and sunitinib. No difference
in OS was seen. Due to limitations of the statistical analyses within this trial, the evidence is inferior to existing
choices.

7.5.2.a.5 Lenvatinib
Lenvatinib is an oral multitarget TKI of VEGFR1, VEGFR2 and VEGFR3, with inhibitory activity against fibroblast
growth factor receptors (FGFR1, FGFR2, FGFR3 and FGFR4), platelet growth factor receptor (PDGFRα), rearranged
during transfection (RET) and receptor for stem cell factor (KIT). It has been investigated in a randomised
phase II study in combination with everolimus versus lenvatinib or everolimus alone (see Section 7.5.4.a.1 for a
discussion of the results) [618].

7.5.2.a.6 Tivozanib
Tivozanib is a potent and selective TKI of VEGFR1, VEGFR2 and VEGFR3 and was compared in two phase III trials
with sorafenib in patients with mRCC [619, 620]. The EMA approved Tivozanib in front-line mRCC. While Tivozanib
was associated with a PFS advantage in both studies, no OS advantage was observed. In view of the choice of
sorafenib as the control arm in the front-line trial, the Panel believes that there is too much uncertainty, and too
many attractive alternatives, to support the use of Tivozanib in this front-line setting.

7.5.2.b Monoclonal VEGF antibody

Bevacizumab is a humanised monoclonal antibody. Initial first-line treatment in combination with IFN-α has been
superseded by more effective therapies [621-623]. Bevacizumab in combination with atezolizumab has not been
approved for treatment of mRCC (see Section 7.5.3.b) [624].

7.5.2.c mTOR inhibitors

7.5.2.c.1 Temsirolimus
Temsirolimus is a specific inhibitor of mTOR [625]. Its use has been superseded as front-line treatment option.

7.5.2.c.2 Everolimus
Everolimus is an oral mTOR inhibitor, which is established in the treatment of VEGF-refractory disease. The
RECORD-1 study compared everolimus plus best supportive care (BSC) versus placebo plus BSC in patients with
previously failed anti-VEGFR treatment (or previously intolerant of VEGF-targeted therapy) [626]. The data showed
a median PFS of 4 versus 1.9 months for everolimus and placebo, respectively [626].

58 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

The Panel believes, even in the absence of conclusive data, that everolimus may present a therapeutic option in
patients who were intolerant to, or previously failed, immune- and VEGFR-targeted therapies (LE: 4). Recent phase
II data suggest adding lenvatinib is attractive.

7.5.2.d Small molucule inhibitor.

7.5.2.d.1 Belzutifan
Belzutifan is an inhibitor of the HIF2a transcription factor with single agent activity ccRCC. Initial Phase I/II trials
in 55 patients confirmed objective response rate was 25% (all partial responses), and the median progression-
free survival was 14.5 months. The most common grade ≥ 3 adverse events were anaemia (27%) and hypoxia
(16%) [627]. In the randomised phase III LITESPARK 005, belzutifan shows a PFS advantage over everolimus in
heavily pretreated ccRCC. Belzutifan also has a favourable adverse event profile and should be considered an
attractive alternative to everolimus in this setting. There was no significant difference in OS. Results of a number
of combination studies are awaited [628]. Belzutifan has also been investigated in combination with cabozantinib
in a single arm phase II trial with two cohorts (treatment-naive and after immunotherapy with up to two lines)
[629]. In second and third line, this combination yielded an objective response rate of 30.8% with one complete
response (2%).

7.5.2.d.2 Vascular endothelial growth factor (VEGF) targeted therapy

Intermittent VEGF-targeted therapy is attractive for patients on long-term therapy, due to the chronic toxicity
associated with long-term therapy such as fatigue. Intermittent VEGF-targeted therapy has been tested with
sunitinib or pazopanib in a phase III study and found to be safe [630]. Patients in the study had stable disease
(or better) for at least six months after starting therapy. The patients were closely followed for progression
with cross-sectional imaging. Cessation of therapy was associated with higher rates of progression, but no
detrimental effect was seen on OS [630]. Intermittent therapy has not been tested with VEFG/PD-1 combinations,
therefore its application in the modern first line setting is unknown, but extrapolation suggests it should be safe.

7.5.2.e Summary of evidence and recommendations for single-agent targeted therapy in metastatic clear-
cell RCC

Summary of evidence LE
Single-agent VEGF-targeted therapy has been superseded by immune checkpoint-based combination 1b
therapy.
Intermittent VEGF therapy can be considered in patients on long-term VEGF-targeted therapy. 2
Immuno-oncology VEGFR TKI combination established an RR and PFS benefit over single agent VEGFR 2b
TKI but no OS benefit in subgroup analysis.
Pazopanib is noninferior to sunitinib as first-line management option in mRCC. 1b
Cabozantinib in intermediate- and poor-risk treatment-naive ccRCC leads to better response rates and 2b
PFS, but not OS when compared to sunitinib.
Tivozanib has been approved by the EMA in the first-line setting; however, it was randomised against 1b
sorafonib, which is no longer a standard of care in the first-line setting.
Single-agent VEGF-targeted therapies are preferentially recommended after first-line PD-L1-based 3
combinations. Rechallenge with treatments already used should be avoided.
Single-agent cabozantinib or nivolumab are superior to everolimus after one or more lines of VEGF- 1b
targeted therapy.
Everolimus prolongs PFS after VEGF-targeted therapy when compared to placebo. This is no longer 1b
widely recommended before third-line therapy.
Belzutifan has a PFS advantage and no OS benefit over everolimus in second and more lines pretreated 1b
ccRCC.
Lenvatinib in combination with everolimus improved PFS over everolimus alone in VEGF-refractory 2a
disease in a phase II trial. Its role after ICIs is uncertain. There is a lack of robust data on this
combination, making its recommendation challenging.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 59

7.5.3 Immunotherapy
7.5.3.a Immune checkpoint inhibitors
7.5.3.a.1 Immuno-oncology monotherapy
Immune checkpoint inhibitor with monoclonal antibodies targets and blocks the inhibitory T-cell receptor PD-1
or cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)-signalling to restore tumour-specific T-cell immunity
[631]. Immune checkpoint inhibitor monotherapy has been investigated as second- and third-line therapy. A
phase III trial of nivolumab versus everolimus after one or two lines of VEGF-targeted therapy for mRCC with a
clear cell component (CheckMate 025, NCT01668784) reported a longer OS, better QoL and fewer grade III or
IV adverse events with nivolumab than with everolimus [632]. Nivolumab has superior OS to everolimus (HR:
0.73, 95% CI: 0.57-0.93, p < 0.002) in VEGF-refractory RCC with a median OS of 25 months for nivolumab and
19.6 months for everolimus with a five-year OS probability of 26% versus 18% [633] (LE: 1b). Patients who had
failed multiple lines of VEGF-targeted therapy were included in this trial, making the results broadly applicable.
The trial included 15% MSKCC poor-risk patients. There was no PFS advantage with nivolumab despite the OS
advantage. Progression-free survival does not appear to be a reliable surrogate of outcome for PD-1 therapy in
RCC. Currently PD-L1 biomarkers are not used to select patients for this therapy.

There are no RCTs supporting the use of single-agent ICI in treatment-naive patients. Randomised phase II
data for atezolizumab versus sunitinib showed an HR of 1.19 (95% CI: 0.82-1.71), which did not justify further
assessment of atezolizumab as single agent as first-line treatment option in this group of patients, despite high
complete response rates in the biomarker-positive population [634]. Single-arm phase II data for pembrolizumab
from the KEYNOTE-427 trial show high response rates of 38% (up to 50% in PD-L1+ patients), but a PFS of 8.7
months (95% CI: 6.7-12.2) [634]. Based on these results and in the absence of randomised phase III data, single-
agent checkpoint inhibitor therapy is not recommended as an alternative in a first-line therapy setting.

In addition, several trials explored the strategy of nivolumab monotherapy in first-line ccRCC, followed by
a salvage strategy with nivolumab plus ipilimumab upon progression or if stable disease was the best
response. Trial results do not support such a strategy, which was frequently infeasible and of limited benefit
[635, 636]. This was confirmed in a pooled analysis of three of these trials [637]. However, recent data suggest
that nivolumab monotherapy may yield extensive treatment-free survival in the IMDC favourable risk patient
population [638].

7.5.3.b Immunotherapy/combination therapy

The phase III trial CheckMate 214 (NCT 02231749) showed a superiority of nivolumab and ipilimumab over
sunitinib. The primary endpoint population focused on the IMDC intermediate- and poor-risk population, where
the combination demonstrated an OS benefit (HR: 0.63, 95% CI: 0.44-0.89), which led to regulatory approval
[572] and a paradigm shift in the treatment of mRCC [639]. Results from CheckMate 214 further established
that the combination of ipilimumab and nivolumab was associated with higher RR (39% in the ITT population),
complete RR (8% in the ITT population [central radiology review]) and duration of response compared to
sunitinib. Progression-free survival did not achieve the predefined endpoint. The exploratory analysis of OS data
in the PD-L1-positive population was 0.45 (95% CI: 0.29-0.41).

An update with median follow-up of more than nine years (111 months) shows ongoing benefits for the immune
combination with independently assessed complete response rates of 12% and an HR for OS in the IMDC
intermediate- and poor-risk group of 0.69 (0.59-0.81) [640, 641]. However, this complete response rate has not
been consistent across trials for this combination (the Cosmic313 study showed complete response rates of 4%
[642, 643]).

In CheckMate 214, the 111-month OS probability was 31% for ipilimumab plus nivolumab versus 20% for
sunitinib, respectively [641, 644]. In this update, the IMDC good-risk group continues to perform better with
sunitinib (HR for OS: 0.80 [95% CI: 0.59-1.09]) [641, 644]. Nivolumab plus ipilimumab was associated with
46% grade III-IV toxicity and 1.5% treatment-related deaths. Nivolumab plus ipilimumab should therefore be
administered in centres with experience with immune combination therapy and appropriate supportive care
within the context of a multidisciplinary team (LE: 4). The PD-L1 biomarker is currently not used to select
patients for therapy.

Subset analysis of the favourable-risk group was not a primary endpoint of the trial. Initial results favoured
sunitinb over nivolumab plus ipilimumab for this population, leading to a recommendation restricted to
intermediate- and poor-risk disease. In updated results, after a median follow-up of 111 months, ipilimumab-
nivolumab was associated with an OS HR: of (HR: for OS: 0.80 [95% CI: 0.59-1.09]) while ORR (30% vs. 52%)
and PFS still favoured sunitinib (HR: 1.78, 95% CI: 1.27-2.50), and improved CR rates (13% vs. 6%) and duration

60 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

of response (49% vs. 50% with ongoing response at five years) were observed with ipilimumab plus nivolumab.
These longer-term results led the Guidelines Panel to change the recommendation towards nivolumab plus
ipilimumab in the IMDC favourable risk patient population [641].

The frequency of steroid use has generated controversy, and further analysis, as well as real-world data, are
required. For these reasons the Panel continues to recommend ipilimumab and nivolumab in the intermediate-
and poor-risk population and as an alternative in the favourable risk population.

The KEYNOTE-426 trial (NCT02853331) reported results for the combination of axitinib plus pembrolizumab
versus sunitinib in 861 treatment-naive cc-mRCC patients [645]. The OS and PFS was assessed by central
independent review in the ITT population and were the co-primary endpoints. Response rates and assessment
in the PD-L1-positive patient population were secondary endpoints. With a minimum follow-up of 35.6 months
(median 42.8 months), this trial demonstrated an ongoing OS benefit for axitinib plus pembrolizumab in the ITT
population (HR: 0.73, 95% CI: 0.60-0.88, p < 0.001). Median OS for axitinib plus pembrolizumab was 45.7 months
(95% CI: 43.6 - NR) versus 40.1 month (95% CI: 34.3-44.2) for sunitinib with a PFS benefit (HR: 0.68, 95% CI: 0.58-
0.80, p < 0.0001), which was shown across all IMDC subgroups for PFS, while OS was similar between axitinib
plus pembrolizumab versus sunitinib in the favourable subgroup with an OS benefit in the IMDC intermediate-
and poor-risk groups. The complete response rate by independent review was 10% in the pembrolizumab plus
axitinib arm and 4% in the sunitinib arm [646]. With an extended median follow-up of 67 months median OS was
47.2 months (43.6-54.8) versus 40.8 months (34.3-47.5; HR: 0.84 95% CI: 0.71-0.99) for sunitib, median PFS
was 15.7 (13.6-20.2) versus 11.1 (8.9-12.5) HR: 0.69 (95% CI: 0.59-0.81) and ORR was 60.6% (CR 11.6%) versus
39.6% (CR 4.0%) [647]. Treatment-related adverse events (≥ grade III) occurred in 63% of patients receiving
axitinib and pembrolizumab versus 58% of patients receiving sunitinib. Treatment-related deaths occurred in
approximately 1% in both arms [647].

The phase III CheckMate 9ER trial randomised 651 patients to nivolumab plus cabozantinib (n = 323) or versus
sunitinib (n = 328) in treatment-naive cc-mRCC patients [456]. The primary endpoint of PFS assessed by central
independent review in the ITT population was significantly prolonged for nivolumab plus cabozantinib (16.6
months) versus sunitinib (8.3 months, HR: 0.51, 95% CI: 0.41-0.64, p < 0.0001). The nivolumab/cabozantinib
combination also demonstrated a significant OS benefit in the secondary endpoint compared with sunitinib
(HR: 0.60, CI: 0.40-0.89, p = 0.0010) after a median follow-up of 18.1 months in the initial report [573]. The
independently assessed ORR was 55.7% versus 27.1% with a complete response rate of 8% for nivolumab plus
cabozantinib versus 4.6% with sunitinib. The efficacy was observed independent of IMDC group and PD-L1
status. Treatment-related adverse events (> grade III) occurred in 61% of patients receiving cabozantinib and
nivolumab versus 51% of patients receiving sunitinib. Treatment-related deaths occurred in one patient in the
nivolumab/cabozantinib arm and in two patients in the sunitinib arm. At 67.6 months - considered to be the final
follow-up - the median OS was 46.5 months (40.5-53.8) in the nivolumab plus cabozantinib patients versus 35.5
months (29.2-42.9) in the sunitinib-treated patients (HR: 0.79 [95% CI: 0.65-0.96). The updated median PFS was
16.6 months (12.5-19.3) versus 8.3 months (7.0-9.7; HR: 0.58 [95% CI: 0.49-0.70], p < 0.0001) [648].

The randomised phase III trial CLEAR (Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab vs. Sunitinib Alone
as Treatment of Advanced RCC) was published [576, 649]. CLEAR randomised a total of 1,069 patients (in
a 1:1:1 ratio) to lenvatinib plus pembrolizumab (n = 355) versus lenvatinib plus everolimus (n = 357) versus
sunitinib (n = 357). The trial reached its primary endpoint of independently assessed PFS at a median of 23.9
versus 9.2 months for lenvatinib plus pembrolizumab versus sunitinib, respectively (HR: 0.39, 95% CI: 0.32-0.49,
p < 0.001). Overall survival significantly improved with lenvatinib plus pembrolizumab versus sunitinib (HR: 0.66,
95% CI: 0.49-0.88, p = 0.005). Objective response for lenvatinib plus pembrolizumab was 71%, with 16% of the
patients having a complete remission. In the final analysis with a median follow-up of 49.8 months, median OS
was 53.7 months (48.7 - not estimable) for lenvatinib plus pembrolizumab versus 54.3 (40.9 - not estimable;
HR: 0.79 95% CI: 0.63-0.99) for sunitinib [649]. Efficacy was observed across all IMDC risk groups independently
of PD-L1 status. Treatment-related adverse events (> grade III) with lenvatinib plus pembrolizumab were 72%.
Treatment-related death occurred in four patients in the lenvatinib plus pembrolizumab arm and in one patient in
the sunitinib arm.

The JAVELIN trial investigated 886 patients in a phase III RCT of avelumab plus axitinib versus sunitinib [574].
The trial met one of its coprimary endpoints (PFS in the PD-L1-positive population at first interim analysis
[median follow up 11.5 months]). At first analysis, hazard ratios for PFS and OS in the ITT population were 0.66
(95% CI: 0.566-0.769) and 0.88 (95% CI: 0.749-1.039), respectively, demonstrating no statistically significant
OS improvement at final analysis after a minimum follow-up of 68 months (median OS 44.8 vs. 38.9 months;
P = 0.0669) [650]. The same applies to the atezolizumab/bevacizumab combination (IMmotion151), which also

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 61

achieved a PFS advantage over sunitinib in the PD-L1-positive population at interim analysis and ITT (HR: 0.74,
95% CI: 0.57-0.96), but has not shown a significant OS advantage at final analysis (HR: 0.91 [95% CI: 0.76-1.08],
p = 0.27) [624, 651]. Therefore, these combinations cannot currently be recommended [650].

A similar combination of a PD-1 inhibitor (toripalimab) with axitinib was investigated in the RENOTORCH trial
in cc-mRCC patients with intermediate and poor IMDC risk. A total of 421 patients were randomised, n = 210
received toripalimab plus axitinib and n = 211 received sunitinib. After a median follow-up of 14.6 months,
toripalimab plus axitinib significantly improved PFS compared with sunitinib (HR: 0.65, 95% CI: 0.49-0.86;
p = 0.0028). Median PFS was 18.0 months in the toripalimab plus axitinib arm, and 9.8 months in the sunitinib
arm. Objective response rate was significantly higher in the toripalimab plus axitinib arm compared with the
sunitinib arm (56.7% vs. 30.8%; P < 0.0001). Overall survival trend favoured toripalimab plus axitinib (HR: 0.61,
95% CI: 0.40-0.92).This combination is available in China [652].

In the ETER100 trial, the combination of the PD-L1 inhibitor benmelstobart plus the TKI anlotinib was
investigated in cc-mRCC patient of all IMDC risk groups. The phase III trial randomised 531 cc-mRCC patients
to benmelstobart plus anlotinib (n = 266) and sunitinb (n = 265). After a median follow-up of 18.7 months, the
primary endpoint of PFS by BICR was significantly prolonged, with benmelstobart plus anlotinib compared
to sunitinib (18.9m vs. 9.8m; HR: 0.53, CI: 0.42-0.67). Objective response rate was significantly higher with
benmelstobart plus anlotinib (71.6% vs. 25.1%, p < 0.001). The OS is still immature, with a trend favouring
benmelstobart plus anlotinib (HR: 0.66, CI: 0.48-0.92). This combination is not available in Europe [653].

In IMDC-favourable patients, the treatment with axitinib+pembrolizumab (Keynote-426), cabozantinib+nivolumab

(CheckMate-9ER) and lenvatinib+pembrolizumab (CLEAR) improved PFS and ORR, but not OS [646-649,
654, 655]. Given the long-term follow-up with no OS improvement by the respective TKI+IO combination versus
sunitinib, TKI monotherapy becomes a standard of care as an additional choice in IMDC-favourable patients.
Although sunitinib was the TKI monotherapy used in these trials, pazopanib is a valid alternative based on the
noninferiority data of the phase III trial COMPARZ [609].

The COSMIC-313 trial is the first RCT to evaluate a triple combination of cabozantinib (40mg) plus nivolumab
plus ipilimumab versus nivolumab plus ipilimumab, a current standard of care, in 855 patients with IMDC
intermediate- and poor-risk [642]. The primary endpoint of PFS improvement, measured in a PFS ITT of 550
patient was met after 249 events occurred with a HR: 0.73 (95% CI: 0.57-0.94, p = 0.013) favouring the triplet
therapy. Median PFS was not reached (14.0-NE) versus 11.3 months (7.7-18.2) in the control arm with a median
follow-up of 20.2 months. Overall survival advantage has not been demonstrated yet. the ORR was 43% versus
36% in the triplet versus the control arm with a complete response rate of 3% in both arms.

With an extended median follow-up of 45 months, an improvement in PFS was maintained 16.6 months (14.0-
22.6) for the triplet and 11.2 (9.3-14.0) (HR:0.82, 95% CI: 0.69-0.98), although OS was not significantly different
between the two groups, 41.9 versus 42 months (HR: 1.02, 95% CI: 0.85-1.23, p = 0.84) and ORR was 46%
(CR 4%) versus 37% (CR 3%) [643].

Treatment-related adverse events (> grade III) with cabozantinib plus nivolumab plus ipilimumab were 73%
versus 41% in the nivolumab plus ipilimumab control arm. The use of high-dose steroids (> = 40mg prednisolone
or equivalent) was 58% (triplet) versus 35% (control). Treatment discontinuation rate of any agent was high in
the triplet arm (45%) compared to the doublet (24%), whilst discontinuation of all treatments due to the same
adverse events was 12% versus 5% in the control arm.

Although the primary endpoint of PFS was met, objective response rates of the triplet combination are modest
as known for TKI + IO doublets. Treatment-related adverse events are high with a high rate of treatment
discontinuation. As the OS rate is currently unknown, the additional benefit of this triplet therapy compared to
standard immune-based doublet therapy is still uncertain.

62 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Table 7.4: First line immune checkpoint inhibitor combination trials for clear-cell RCC
Cross trial comparison is not recommended and should occur with caution

Study N Experimental arm Primary Risk groups PFS (mo) OS (mo)

endpoint Median (95% CI) Median (95% CI)
HR HR
KEYNOTE-426 861 PEMBRO 200 mg. PFS and OS IMDC (ITT) (ITT)
NCT02853331 IV Q3W plus AXI in the ITT FAV 31% PEMBRO + AXI: PEMBRO + AXI:
Median follow- 5mg. PO BID by BICR IMD 56% 15.7 (13.6-20.2) 47.2. (43.6-54.8)
up 67 months vs. POOR 13% SUN: 11.1 (8.9-12.5) SUN: 40.8 (34.3-
[575, 645-647] SUN 50mg PO 47.5)
QD 4/2 wks. MSKCC HR: 0.69 (95% CI: HR: 0.84 (95% CI:
Not 0.59-0.81) 0.71-0.99)
determined p < 0.0001 p = 0.001
JAVELIN Renal 886 AVE 10mg/kg IV PFS in the IMDC (PD-L1+) (PD-L1+)
101 Q2W plus AXI, PD-L1+ FAV 22% AVE + AXI: 13.9 AVE+AXI: 43.2 (36.5-
NCT02684006 5mg PO BID population IMD 62% (11.0-17.8) 51.7)
Median follow- vs. and OS in POOR 16% SUN: 8.2 (6.9-9.4) SUN: 36.2 (29.8-
up 68 months SUN 50mg PO QD the ITT by 44.2)
[574, 650, 656, 4/2 wks. BICR MSKCC HR: 0.57 (95% CI:
657] FAV 23% 0.47-0.7) HR: 0.86 (95% CI:
IMD 66% p < 0.0001 0.70-1.06)
POOR 12% p = 0.0755
IMmotion151 915 ATEZO 1200mg PFS in the IMDC (PD-L1+) (ITT)
NCT02420821 fixed-dose IV plus PD-L1+ Not ATEZO + BEV: 11.2 ATEZO + BEV: 36.1
Median follow- BEV 15mg/kg IV population determined (8.9-15.0) (31.5-42.3)
up 24 months on days 1 and 22 and OS in SUN: 7.7 (6.8-9.7) SUN: 35.3 (28.6-42.1
[624, 651] of each 42-day the ITT by MSKCC NE)
cycle IR FAV 20% HR: 0.74 (95% CI:
vs. IMD 69% 0.57-0.96) HR: 0.91 (95% CI:
SUN 50mg POOR 12% p = 0.0217 0.76-1.08)
PO QD 4/2 wks. p = 0.27
CheckMate214 1096 NIVO 3mg/kg PFS and OS IMDC (IMDC IMD/poor) (IMDC IMD/poor)
NCT02231749 plus ipilimumab in the IMDC FAV 23% NIVO + IPI: 12.4 (8.7- NIVO + IPI: 46.7
Median follow- 1mg/kg IV Q3W inter- IMD 61% 16.8) (35-55.1)
up of 111 for 4 doses then mediate POOR 17% SUN: 8.5 (7-11.1) SUN: 26 (21.8-32.6)
months [572, nivolumab 3mg/ and poor HR: 0.69 (0.59-0.81)
644] kg IV Q2W risk MSKCC HR: 0.73 (0.61-0.87)
vs. population Not
SUN 50mg by BICR determined
CheckMate9ER 651 NIVO 240mg. PFS in the IMDC (ITT) (ITT)
NCT03141177 fixed dose IV ITT by BICR FAV 22% NIVO+CABO: 16.6 NIVO+CABO: 46.5
Median follow- every 2 wks. plus IMD 58% (12.5-19.3) (40.5-53.8)
up of 44 CABO 40mg PO POOR 20% SUN: 8.3 (7.0-9.7) SUN: 35.5 (29.2-
months daily vs. 42.9)
[573, 654] SUN 50mg PO QD MSKCC HR: 0.58 (95% CI:
4/2 wks. Not 0.49-0.70) HR: 0.79 (98.9% CI:
determined p < 0.0001 0.65-0.96)

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 63

CLEAR 712 PEMBRO 200mg PFS in the IMDC (ITT) (ITT)
NCT02811861 IV Q3W plus LEN ITT by BIRC FAV 31% PEMBRO+LEN: 23.9 PEMBRO+LEN: 23.9
Median follow- 20mg PO QD IMD 59% (20.8-27.7) (20.8-27.7)
up of 49.8 vs. POOR 9% SUN: 9.2 (6.0-11.0) SUN: 9.2 (6.0-11.0)
months [576, SUN 50mg PO QD NE 1%
649, 658] 4/2 wks. MSKCC HR: 0.47 (95% CI: HR: 0.47 (95% CI:
FAV 27% 0.38-0.57) p > 0.001 0.38-0.57) p < 0.001
IMD 64%
POOR 9%
RENOTORCH 421 TORI 240mg IV PFS in the IMDC (ITT) (ITT)
NCT04394975 Q3W plus AXI ITT by BIRC IMD 81% TORI+AXI: 18.0 TORI+AXI: N.E. (N.E.-
Median follow- 5mg. PO BID POOR 19% (15.0-N.E) N.E.)
up of 14.6 vs. SUN: 9.8 (8.3-13.8) SUN: 26.8 (24.5-
months [652, SUN 50mg PO N.E.)
653] QD 4/2 wks. or QD HR: 0.65 (95%
2/1wks. CI: 0.49-0.86) HR: 0.61 (95% CI:
p = 0.0028 0.40-0.92)
ETER100 531 BENMEL 1200mg PFS in the IMDC (ITT) (ITT)
NCT04523272 IV Q3W plus ITT by BIRC FAV 14% BENMEL+ANLO: BENMEL+ANLO:
Median follow- ANLO 12mg PO IMD 71% 19.0 (15.3-22.8) N.E. (38.2-N.E.)
up of 18.7 QD 2/1 wks. POOR 15% SUN: 9.8 (8.4-12.4) SUN: N.E. (30.5-N.E.)
months [653] vs.
SUN 50mg PO QD HR: 0.53 (95% CI: HR: 0.66 (95%
4/2 wks. 0.42-0.67) p < 0.001 CI: 0.48-0.92)
p = 0.0673
COSMIC-313 855 NIVO 3mg/kg plus PFS in the IMDC (PITT) NR
Median follow- IPI 1mg/kg IV PITT IMD 75% NIVO+IPI+CABO:
up of 20.2 Q3W for 4 doses population POOR 25% NR (14.0-NE)
months [642] then NIVO 3mg/ (first 550 NIVO+IPI: 11.3 (7.7-
kg IV Q2W + CABO pts. rando- 18.2)
40mg PO QD mised)
vs. NIVO 3mg/kg HR: 0.73 (95% CI:
plus IPI 1mg/kg IV 0.57-0.94) p = 0.013
Q3W for 4 doses
then NIVO 3mg/kg
IV Q2W

ANLO = anlotininib; ATEZO = atezolizumab; AVE = avelumab; AXI = axitinib; BENMEL = benmelstobart;
BEV = bevacizumab; BICR = blinded independent central review; BID = twice a day; CABO = cabozantinib;
CI = confidence interval; FAV = favourable; HR = hazard ratio; IMD = intermediate; IMDC = Metastatic Renal
Cancer Database Consortium; IPI = ipilimumab; IR = investigator review; ITT = intention-to-treat; IV = intravenous;
LEN = lenvatinib; mos. = months; MSKCC = Memorial Sloan Kettering Cancer Center; NE = non-estimable;
NIVO = nivolumab; NR = not reached; OS = overall survival; PEMBRO = pembrolizumab; PFS = profession-free
survival; PITT = PFS intention-to-treat; PO = by mouth; Pts = patients; QD = once a day; Q2W = every 2 weeks;
Q3W = every 3 weeks; SUN = sunitinib; TORI = toripalimab; wks. = weeks.

Patients who stop nivolumab plus ipilimumab because of toxicity require expert guidance and support from
a multidisciplinary team before rechallenge can occur (LE: 1). Patients who do not receive the full four doses
of ipilimumab due to toxicity should continue on single-agent nivolumab, where safe and feasible (LE: 4).
Treatment past progression with nivolumab plus ipilimumab can be justified but requires close scrutiny and the
support of an expert multidisciplinary team [572, 659] (LE: 1).

Patients who stop TKI and IO due to immune-related toxicity can receive single-agent TKI once the adverse
events has resolved (LE: 1). Adverse event management, including transaminitis and diarrhoea, require
particular attention as both agents may be causative. Expert advice should be sought on rechallenge of ICIs
after significant toxicity (LE: 4). Treatment past progression on axitinib plus pembrolizumab or nivolumab plus
cabozantinib requires careful consideration as it is biologically distinct from treatment past progression on
ipilimumab and nivolumab.

64 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Based on panel consensus, nivolumab plus ipilimumab, pembrolizumab plus axitinib and nivolumab plus
cabozantinib and lenvatinib plus pembrolizumab should be administered in centres with experience of immune
combination therapy and appropriate supportive care within the context of a multidisciplinary team (LE: 4).

7.5.4 Therapeutic strategies

7.5.4.a Treatment-naïve patients with clear-cell metastatic RCC
The combination of pembrolizumab plus axitinib as well as nivolumab plus cabozantinib and lenvatinib plus
pembrolizumab is the standard of care in all IMDC-risk patients and ipilimumab plus nivolumab in IMDC
intermediate- and poor-risk patients (see Figure 7.1). Therefore, the role of VEGFR-TKIs alone in front-line mRCC
has been superseded in IMDC intermediate and poor risk. In the IMDC favourable group, in the absence of OS
benefit, both options are acceptable. Sunitinib, pazopanib, tivozanib and cabozantinib (IMDC intermediate- and
poor-risk disease) remain alternative treatment options for patients who cannot receive or tolerate immune
checkpoint inhibition in this setting (see Figure 7.1).

7.5.4.a.1 Sequencing systemic therapy in clear-cell metastatic RCC

The sequencing of targeted therapies is established in mRCC and maximises outcomes [618, 632].
Pembrolizumab plus axitinib, nivolumab plus cabozantinib, lenvatinib plus pembrolizumab and nivolumab plus
ipilimumab are the new standard of care in front-line therapy in IMDC intermediate/poor. The impact of front-line
immune checkpoint inhibition on subsequent therapies is unclear. Randomised data on patients with disease
refractory to either nivolumab plus ipilimumab or TKI plus IO in a first-line setting are limited. Sequencing
immune checkpoint inhibition with atezolizumab did not demonstrate objective response rate, PFS or OS benefit
over single agent TKI in the CONTACT 03 [564, 660]. In addition, in the TiNivo trial, the combination of tivoazanib
plus nicvolumab did not improve PFS, OS and objective response rate over single-agent tivozanib [565].
Moreover, prospective data on cabozantinib, tivozanib [661] and axitinib are available for patients progressing on
immunotherapy, but these studies do not focus solely on the front-line setting, involve subset analyses and are
too small for definitive conclusions [632, 662].

The use of mTOR inhibitors can be considered in VEGF-targeted therapy refractory disease but has been
outperformed by other VEGF-targeted therapies in mRCC and belzutifan [628, 663]. Drug choice in the third-line
setting, after immune checkpoint inhibitor combinations and subsequent VEGF-targeted therapy, is unknown.
The Panel recommends a subsequent agent that is approved in VEGF-refractory disease, with the exception of
rechallenge with immune checkpoint blockade. Cabozantinib is the only agent in VEGF-refractory disease with
RCT data showing a survival advantage and should be used preferentially [664]. Axitinib has positive PFS data
in VEGF-refractory disease. Other agents have outperformed both sorafenib and everolimus in VEGF-refractory
disease and are therefore less attractive [663]. The lenvatinib plus everolimus combination appears superior to
everolimus alone and has been granted EMA regulatory approval based on randomised phase II data. This is an
alternative despite the availability of phase II data only [618]. As shown in a study which also included patients
on ICIs, tivozanib provides PFS superiority over sorafenib in VEGF-refractory disease [665].

7.5.4.a.2 Summary of evidence and recommendations for immunotherapy in cc-mRCC

Summary of evidence LE
Treatment-naïve patients
PD-L1 expression is not currently used for patient selection. 2b
The combination of nivolumab and ipilimumab in treatment-naïve patients with cc-mRCC of IMDC, 1b
intermediate and poor risk demonstrated OS and objective response rate benefits compared to
sunitinib alone.
The updated OS data for IPI/NIVO in IMDC favourable-risk patients demonstrates the long-term benefit 2b
for this subgroup of patients.
The combination of pembrolizumab plus axitinib, lenvatinib plus pembrolizumab and nivolumab plus 1b
cabozantinib in treatment-naïve patients with cc-mRCC demon-strated PFS, OS and objective response
rate benefits compared to sunitinib in the ITT population.
The combination of pembrolizumab plus axitinib, lenvatinib plus pembrolizumab and nivolumab plus 2b
cabozantinib in treatment-naïve patients with cc-mRCC in IMDC-favourable subgroups demonstrated
PFS and objective response rate benefits com-pared to sunitinib, without OS improvement.
The combination of axitinib plus avelumab did not demonstrate significant OS benefit and axitinib plus 1b
toripalimab did not demonstrate significant OS benefit yet, as did benmelstobart plus anlotinib.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 65

Triplet CABO-NIVO-IPI demonstrated 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 1b
of VEGF-targeted therapy.
Axitinib, cabozantinib or lenvatinib can be continued if immune-related adverse events result 4
in cessation of axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus
pembrolizumab. Rechallenge with immunotherapy requires expert support.
Patients who do not receive the full four doses of ipilimumab due to toxicity should continue on single- 4
agent nivolumab, where safe and feasible. Rechallenge with combination therapy requires expert
support.
Treatment past progression can be justified but requires close scrutiny and the support of an expert 1b
multidisciplinary team.
Nivolumab plus ipilimumab was associated with 46% grade III-IV toxicity and 1.5% treatment-related 1b
deaths. Tyrosine kinase inhibitor-based IO combination therapies were associated with grade III-V
toxicity ranging between 61-72% and 1% of treatmentrelated deaths.
In the CONTACT 3 study atezolizomab plus cabozantinib offered no benefit compared to cabozantinib 1b
alone in patients whose cancers have previously progressed on ICI therapy.
Cabozantinib as a single agent has the most robust data after first line PD1 based combination 3
therapy.

Recommendations Strength rating

First line Treatment for metastatic clear cell RCC patients
Offer nivolumab plus ipilimumab, pembrolizumab plus axitinib, lenvatinib plus Strong
pembrolizumab or nivolumab and cabozantinib to patients with International Metastatic
Renal Cell Carcinoma Database Consortium (IMDC) intermediate- or poor-risk disease.
Offer pembrolizumab plus axitinib, lenvatinib plus pembrolizumab or nivolumab and Weak
cabozantinib or nivolumab plus ipilimumab or sunitinib or pazopanib for IMDC favourable
risk disease.
Offer sunitinib or pazopanib to patients with any IMDC risk who cannot receive or tolerate Strong
immune checkpoint inhibition (ICI).
Offer cabozantinib to patients with IMDC intermediate- and poor-risk clear cell metastatic Stronga
renal carcinoma (cc-mRCC) who cannot receive or tolerate ICI.
Patients who do not receive the full four doses of ipilimumab due to toxicity should continue Weak
on single-agent nivolumab, where safe and feasible. Re-challenge with combination therapy
requires expert support after discontinuation for toxicity.
Offer ICI combination therapy for advanced cc-mRCC with sarcomatoid features. Strong
Intermittent single agent vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors Weak
(TKI) can be offered in case of partial response or stable disease for more than six months.
Sequencing systemic therapy for metastatic clear cell RCC
Do not offer ICI monotherapy or combination therapy to patients with recurrence during or Weak
within six months after adjuvant pembrolizumab.
Sequence systemic therapy in treating metastatic RCC. Strong
Offer carbozantinib or other VEGF-TKI as second-line therapy to patients’ refractory to Strong
nivolumab plus ipilimumab or axitinib plus pembrolizumab or cabozantinib plus nivolumab or
lenvatinib plus pembrolizumab.
Sequencing the agent not used as second-line therapy (nivolumab or cabozantinib) for third- Weak
line therapy is recommended.
Offer nivolumab or cabozantinib for those patients who received first line VEGF targeted Strong
therapy alone.
Treatment past progression can be justified but requires close scrutiny and the support of an Weak
expert multidisciplinary team.
Do not re-challenge patients who stopped ICI due to toxicity without expert guidance and Strong
support from a multidisciplinary team.

66 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Do not offer programmed death-ligand 1 (PD-L1) combination therapy after progression after Weak
ICI combination.
Offer belzutifan as an alternative to everolimus in patients previously treated with second- to Weak
fourth-line therapy for clear cell metastatic RCC.
a While this is based on a randomised phase II trial, cabozantinib (weak) looks at least as good as sunitinib in this

population. This justified the same recommendation under exceptional circumstances.

Figure 7.2: Updated EAU Guidelines recommendations for the first-line treatment of cc-mRCC

Alternative in patients who can

Standard of Care not receive or tolerate immune
checkpoint inhibitors

Nivolumab/Cabozantinib [1b]
Pembrolizumab/Axitinib [1b]
Pembrolizumab/Lenvatinib [1b]
IMDC favourable risk Nivolumab/Ipilimumab [2b]
Sunitinib [2b]
Pazopanib [2b]

Nivolumab/Cabozantinib [1b]
Cabozantinib [2a]
IMDC intermediate and Pembrolizumab/Axitinib [1b]
Sunitinib [1b]
poor risk Pembrolizumab/Lenvatinib [1b]
Pazopanib* [1b]
Nivolumab/Ipilimumab [1b]

Diagnosis Treatment Follow-up

IMDC = The International Metastatic Renal Cell Carcinoma Database Consortium.
*pazopanib for intermediate-risk disease only.
[1b] = based on one randomised controlled phase III trial.
[2a] = based on a well-designed study without randomisation, or a subgroup analysis of a randomised controlled
trial.

Figure 7.3: EAU Guidelines recommendations for later-line therapy

Standard of Care Alternative

Cabozantinib [3]
Any VEGF-targeted therapy
Prior TKI+IO
that has not been used
Prior IO+IO
previously in combination
with IO [4]

Nivolumab [1b]
Prior TKI Axitinib [2b]
Cabozantinib [1b]

Several prior lines including Belzutifan [1b]

IO and TKI

Diagnosis Treatment Follow-up

IO = immunotherapy; TKI = tyrosine kinase inhibitors; VEGF = vascular endothelial growth factor.
[1b] = based on one randomised controlled phase III trial.
[2b] = subgroup analysis of a randomised controlled phase III trial.
[4] = expert opinion.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 67

7.5.4.a.3 Renal tumours with sarcomatoid features
Subset analyses have shown improved results for PD-L1 inhibitors combined with CTLA4 or VEGF-targeted
therapy in renal tumours with sarcomatoid features. Ipilimumab/nivolumab, axitinib/pembrolizumab and
lenvatinib/pembrolizumab, avelumab/axitinib can all be recommended instead of VEFG-targeted therapy alone.
These options have OS advantages over sunitinib, sunitinib plus gemicitabine and superseded VEGF-targeted
therapy. Nivolumab/Ipilimumab provided post hoc analysis demonstrating ORR of 61%, including 23% CR rate,
PFS and OS benefit over sunitinb (HR 0.50 and OS HR 0.46 respectively with median OS 48.6 vs. 14.2 month)
[666, 667].

Table 7.5: Subgroup analysis of first-line immune checkpoint inhibitor combinations in RCC patients with
sarcomatoid histology
Cross trial comparison is not recommended and should be done with caution.

Study N Therapy N PFS (mo.) OS (mo.) ORR (%)

(ITT) (sRCC) Median (95% CI) Median (95% CI) (95% CI)
HR HR
KEYNOTE-426 861 PEMBRO + 51 NR NR 58.8
NCT02853331 AXI
Median follow- SUN 54 8.4 NR 31.5
up 12.8 months
[645] HR: 0.54 HR: 0.58
(0.29-1.00) (0.21-1.59)
JAVELIN 101 886 AVE + AXI 47 7.0 (5.3-13.8) NA 46.8 (32.1-61.9)
NCT02684006
[650, 668, 669] SUN 61 4.0 (2.7-5.7) 21.3 (11.9-33.7)

HR: 0.57
(0.33-1.00)
IMmotion151 915 ATEZO + BEV 68 8.3 21.7 49 (36-1)
NCT02420821 (5.4, 12.9) (15.3, NE)
Median follow-
up 13 to 17 SUN 74 5.3 15.4 14 (7-23)
months (3.3, 6.7) (10.4, 19.5)
[670]
HR: 0.52 HR: 0.64
(0.34-0.79) (0.41, 1.01)
CheckMate214 1096 NIVO + IPI IMDC 26.5 (7.2-NE) 48.6 (25.2‒NE) 60.8 (48.8-72.0)
NCT02231749 Intermediate
minimum and poor risk 5.5 (4.1-6.9) 14.2 (9.3‒22.9) 23.1 (13.5-35.2)
follow-up of 60
months SUN 74 HR: 0.50 HR: 0.46
[666] (0.32‒0.80) (0.29‒0.71)
75

CheckMate 9ER 651 NIVO + CABO 34 10.3 (5.6-19.4) NR (22.8-NE) 55.9

NCT03141177 (37.9-72.8)
Median follow- SUN 41 4.2 (2.6-8.3)
up 16 months HR: 0.42 (0.23- 19.7 (8.9-29.5) 22.0
[671] 0.74) HR: 0.36 (10.6-37.6)
(0.17-0.79)
CLEAR 712 PEMBRO + 28 11.1 NE 60.7
NCT02811861 LEN
Median follow- 21 5.5 NE 23.8
up 27 months SUN HR: 0.39 HR: 0.91
[576, 672] (0.18-0.84) (0.32-2.58)

68 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

ATEZO = atezolizumab; AVE = avelumab; AXI = axitinib; BEV = bevacizumab; CABO = cabozantinib; CI = confidence
interval; HR = hazard ratio; IPI = ipilimumab; ITT = intention-to-treat; mo. = months; NA = not available;
NE = non-estimable; NR = not reached; NIVO = nivolumab; OS = overall survival; PEMBRO = pembrolizumab;
PFS = progression-free survival; sRCC = sarcomatoid RCC; SUN = sunitinib.

7.5.4.a.4 Summary of evidence and recommendation for targeted therapy in RCC with sarcomatoid features

Summary of evidence LE
Immune checkpoint inhibitor combination therapy is superior to sunitinib in terms of PFS and OS in trial 2a
subset analysis of clear-cell RCC with sarcomatoid features.

Recommendation Strength rating

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

7.5.4.b Treatment of patients with non-clear-cell metastatic RCC (general considerations)

For the sake of historical purposes, the panel recognises the use of non-cc-mRCC but will, where possible, refer
to the distinct subtype. This is a heterogenous group including papillary, chromophobe and other rare tumours
with a widely differing tumour biology. Patients with non-cc-mRCC should therefore be referred to a clinical trial,
where appropriate. While no phase III trials of patients with non-cc-mRCC have been reported, it is increasingly
recognised to study specific subtypes which have a higher incidence than other non-ccRCC. As pRCC comprise
the majority of tumours defined as non-ccRCC, most of the evidence is available for this subtype, either from
trials specifically selecting pRCC or having included a high percentage.

7.5.4.b.1 Treatment of patients with papillary metastatic RCC

Small single-arm trials have been carried out for sunitinib and everolimus [673-677]. Both these agents have
been widely prescribed in pRCC, but more recent data suggests cabozantinib and other combinations may be
preferable [678-680]. For pRCC, new evidence is available from the SWOG PAPMET randomised phase II trial,
which compared sunitinib to cabozantinib, crizotinib and savolitinib in 152 patients with papillary mRCC [678,
680]. Progression-free survival was longer in patients in the cabozantinib group (median 9.0 months, 95% CI:
6-12) than in the sunitinib group (5.6 months, CI: 3-7; HR for progression or death 0.60 [0.37-0.97, one-sided
p = 0.019]). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p = 0.010). Savolitinib
and crizotinib did not improve PFS compared with sunitinib. Grade III or IV adverse events occurred in 69%
(31/45) of patients receiving sunitinib, 74% (32/43) of patients receiving cabozantinib, 37% (10/27) receiving
crizotinib, and 39% (11/28) receiving savolitinib; one grade V thromboembolic event was recorded in the
cabozantinib group. These results support adding cabozantinib as an option for patients with papillary mRCC
based on superior PFS results compared to sunitinib.

In addition, savolitinib was investigated in the SAVOIR trial [679] as first-line treatment for MET-driven tumours
defined as chromosome seven gain, MET amplification, MET kinase domain variations or hepatocyte growth
factor amplification by DNA alteration analysis (±30% of screened patients were MET-positive). In a limited
patient group, savolitinib (n = 27) was compared with sunitinib (n = 33). The trial was stopped early, largely due
to poor accrual. The efficacy data appeared to favour savolitinib (median PFS 7.0 months, 95% CI: 2.8 months-
NR vs. 5.6 months, 95% CI: 4.1-6.9 months, PFS HR: 0.71, 95% CI: 0.37-1.36, OS HR: 0.51,94% CI: 0.21-1.17, RR:
27% vs. 7%, for savolitinib and sunitinib, respectively). The median OS for savolitinib was not reported, Savolitinib
was better tolerated compared with sunitinib with 42% grade > 3 adverse events compared to 81% with sunitinib.
Trials are ongoing to confirm these findings. The results on these trials are required before recommendations
can be made.

Evidence for TKI + IO based combination is derived from three phase II studies of lenvatinib plus pembrolizumab
and cabozantinib and nivolumab. The Keynote-B61 phase II trial investigated lenvatinib plus pembrolizumab
administered to non-ccRCC patients, of whom 93 patients (59%) with pRCC [681, 682]. The primary endpoint of
objective response was 54% in pRCC patients, with a median follow-up of 14.9 months, providing some evidence
of good efficacy for TKI + IO based combinations. With an extended follow-up of 22.8 months, the ORR was 50%
with 8% patients showing complete response.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 69

The cabozantinib and nivolumab study enrolled 40 patients with papillary and unclassified RCC with a response
rate of 47% and a PFS of 13 (7-16) months [683]. In this trial, chromophobe RCC was excluded and the
percentage of pRCC was 68%.

The CALYPSO trial investigated savolitinib and durvalumab in 41 patients with metastatic papillary carcinoma
in first or second line plus. The confirmed RR was 29% and the primary endpoint of confirmed RR > 50% was
misses. In MET-driven tumours confirmed RR was 53% with a PFS of 12 months while PFS was 4.9 months in
the treated population [684]. Indirect comparisons suggest these data compare to an increased efficacy with
those of VEGFR-TKI monotherapy alone.

Efficacy for pembrolizumab in the pRCC subset (118/165) was RR: 29%, PFS: 5.5 months (95% CI: 3.9-6.1
months) and OS: 31.5 months (95% CI: 25.5 months-NR), but these results are based on a single-arm phase II
study [685]. Pembrolizumab can be considered in this setting due to the high unmet need, although the VEGFR
TKI + IO combination may be preferable.

7.5.4.b.2 Summary of evidence and recommendations for systemic therapy in papillary metastatic RCC

Summary of evidence LE
Cabozantinib improved PFS over sunitinib in patients with advanced pRCC without additional molecular 2a
testing.
Lenvatinib plus pembrolizumab and cabozantinib plus nivolumab demonstrated response rates of 2a
47-54% with median PFS rates > 12 months.
Pembrolizumab resulted in long-term median OS in a single-arm study in the pRCC subgroup. 2a

Recommendations Strength rating

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

7.5.4.b.3 Treatment of patients with metastatic non-ccRCC other than papillary RCC
The evidence surrounding systemic therapy for non-ccRCC tumours other than pRCC is especially weak
and has relied on subset analysis of randomised phase II trials as well as expanded access programmes.
Results consistently demonstrate that the outcome of these patients with targeted therapy is poorer than for
ccRCC. Treatment in non-cc-mRCC has focused on temsirolimus, everolimus, sorafenib, sunitinib, cabozantinib
and pembrolizumab in the past [673, 683, 686-688]. Data from single-arm phase II trials of lenvatinib plus
pembrolizumab demonstrated clinical efficacy of this IO+TKI combinations in different non-ccRCC subgroups
[681, 682, 689]. Median ORR across the non-ccRCC subgroups of 158 patients was 49%, and twelve months PFS
and OS rates were 63% and 82%.

The academic prospective randomised European trial SUNNIFORECAST in therapy-naïve patients with advanced
non-ccRCC entities randomized nivolumab plus ipilimumab (157 pts) or SOC (152 pts.; 124 x TKI, 17 x TKI/IO,
2x others). The study included 178 patients (57.6%) with papillary RCCC, 60 patients (19.4%) with chromophobe
RCC, 12 patients (3.9%) with MIT RCC, nine (2.9%) patients with collecting duct carcinoma and 50 had other
subtypes. Primary endpoint was 12 months OS rate. The trial demonstrated a 12-month OS rate for nivolumab/
ipilimumab (Nivo/Ipi) of 86.9% (95% CI: 80.2%-91.5%) statistically significant superior to the SOC 76.8% (95% CI:
68.6%-83.1%) (p = 0.014). Median OS was 42.4 months for the Ipi/Nivo arm and 33.9 months for the SOC arm
(HR:0.83, CI: 0.59-1.17); median PFS was 5.5m for Ipi/Nivo versus 5.7 months for SOC (HR: 0.99, 95% CI: 0.76-
1.18). The ORR was respectively 32.8% versus 19.6%. [690].

7.5.4.b.4  ummary of evidence and recommendation for systemic therapy in chromophobe and
S
unclassified RCC
Summary of evidence LE
Both mTOR inhibitors and VEGF-targeted therapies have limited activity in non-cc-mRCC. There is 2a
a nonsignificant trend for improved oncological outcomes for sunitinib over everolimus and for
cabozantinib over sunitinib.

70 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

In non-cc-mRCC, sunitinib improved PFS over everolimus in an SR of phase II trials and subgroups of 1a
patients.
In non-cc-mRCC lenvatinib plus pembrolizumab demonstrated clinical efficacy in various non-ccRCC 2a
subgroups.
In non-cc-mRCC cabozantinib plus nivolumab demonstrated clinical efficacy in various non-ccRCC 2a
subgroups except for chromophobe RCC, which were excluded from the study.
OS rate at 12 months was significantly higher with nivolumab plus ipilimumab than with SOC in non- 1b
ccRCC patients.

Recommendations Strength rating

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

7.5.4.c Treatment of patients with rare tumours

7.5.4.c.1 SMARCB1-deficient renal medullary carcinoma
SMARCB1-deficient renal medullary carcinoma (RMC) is one of the most aggressive RCCs [50, 691] and most
patients (±67%) will present with metastatic disease [45, 50] and three-year CSM-free survival of 35.8 % [692].
Even patients who present with seemingly localised disease may develop macro metastases shortly thereafter,
often within a few weeks.

Despite treatment, median OS is thirteen months in the most recent series [57]. Due to the infiltrative nature
and medullary epicentre of RMC, RN is favoured over PN even in very early-stage disease. Retrospective data
indicate that nephrectomy in localised disease results in superior OS (16.4 vs. 7 months) compared with
systemic chemotherapy alone, but longer survival was noted in patients who achieved an objective response
to first-line chemotherapy [57, 693]. There is currently no established role for distant metastasectomy or
nephrectomy in the presence of metastases.

Palliative radiation therapy is an option and may achieve regression in the targeted areas but will not prevent
progression outside the radiation field [694, 695]. Renal medullary carcinoma is refractory to monotherapies
with targeted anti-angiogenic regimens including TKIs and mTOR inhibitors [57, 198]. The mainstay systemic
treatments for RMC are cytotoxic combination regimens that produce partial or complete responses in ±29%
of patients [198]. There are no prospective comparisons between different chemotherapy regimens, but most
published series used various combinations of platinum agents, taxanes, gemcitabine and/or anthracyclines
[57, 58]. High-dose-intensity combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) has
also shown efficacy against RMC [696], although a retrospective comparison did not show superiority of MVAC
over cisplatin, paclitaxel and gemcitabine [58]. Single-agent anti-PD-1 immune checkpoint therapy has produced
responses in a few case reports, although, as yet, insufficient data are available to determine the response rate
to this approach [694, 695]. Whenever possible, patients should be enrolled in clinical trials of novel therapeutic
approaches, particularly after failing first-line cytotoxic chemotherapy.

In a phase II basket trial, no evidence of clinical activity was showed for pembrolizumab in patients with RMC,
irrespective of PD-L1 or TIL (tumour-infiltrating lymphocyte) levels [697].

7.5.4.c.2 Other rare tumours

Knowledge about the systemic treatment of rare tumours is very limited, mostly based on a set of case reports.
For some facts about therapy of renal tumours see Section 3.5 and Table 3.2.

Metastatic collecting duct carcinoma (CDC) has the lowest mortality in concomitant use of cytoreductive
nephrectomy and systemic therapy [698]. Systemic therapy was investigated in BONSAI phase II trial. Nivolumab
showed clinical benefit in 60 % as a second-line therapy after cabozantinib failure [699].

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 71

With Anaplastic lymphoma kinase (ALK)-rearranged RCC, there are some reports of the efficacy of ALK
inhibitors, e.g. alectinib, crizotinib and entrectinib [700, 701]. ELOC (formerly TCEB1)-mutated RCC does not
exhibit clinically aggressive behaviour [700].

No data is available that indicates a recommendation for one treatment over another.

7.6 Locally recurrent RCC after treatment of localised disease

Most studies reporting on local recurrent disease after removal of the kidney have not considered the true
definition of local recurrence after RN, PN and thermal ablation, which are: local recurrence in the tumour-
bearing kidney, tumour growth exclusively confined to the true renal fossa, recurrences within the renal vein, the
ipsilateral adrenal gland or the regional LNs. In the existing literature the topic is weakly investigated and often
regarded as local recurrent disease.

RECUR is a protocol-based multicentre European registry capturing patient and tumour characteristics, risk
of recurrence (RoR), recurrence patterns and survival of those curatively treated for nonmetastatic RCC from
2006 to 2011. Per-protocol resectable disease (RD) recurrence was defined as: (1) solitary metastases, (2)
oligometastases, or (3) renal fossa or renal recurrence after radical or partial nephrectomy, respectively. Within
the RECUR consortium, the authors assessed the effectiveness of local treatment of resectable recurrent
RCC after surgical treatment of the primary kidney tumour [702]. Of 3,039 patients with localised RCC treated
with curative intent, 505 presented with recurrence, including 176 with RD. Of these patients, 97 underwent
local treatment of recurrence (LTR) and 79 no LTR. The median OS was 70.3 mos. versus 27.4 in the LTR
versus no-LTR group (p < 0.001). The LTR effect on survival was consistent across risk groups. OS HR for
high, intermediate and low risks were 0.36 (0.2-0.64), 0.27 (0.11-0.65) and 0.26 (0.08-0.8), respectively. Local
treatment of recurrence was associated with longer survival across groups with a risk of recurrence [702]

7.6.1 Locally recurrent RCC after nephron-sparing approaches

Locally recurrent disease can affect the tumour-bearing kidney after PN or focal ablative therapy such as RFA
and cryotherapy. Local relapse may be due to the incomplete resection of the primary tumour, in a minority of
the cases to the local spread of the tumour by microvascular embolisation, or true multifocality [230, 703].

The prognosis of recurrent disease not due to multifocality is poor, despite salvage nephrectomy [703].
Recurrent tumour growth in the regional LNs or ipsilateral adrenal gland may reflect metachronous metastatic
spread (see Section 7.3). After treatment solely for localised disease, systemic progression is common
[704, 705].

There are reports that minimally invasive approaches (laparoscopic and robotic) show atypical reoccurrence
(e.g. peritoneal, port site, etc.) [706, 707]. Therefore, specific manoeuvres to prevent tumour-cell contamination
should be implemented. Those include the use of extraction bags, minimising trocar CO2 leakage, avoiding
tumour morcellation, cleansing of instruments before reuse, changing of gloves after tumour extraction,
avoiding violation of the tumour’s natural capsule, and cleansing of port sites [706, 707].

A retrospective study relying on inverse probability of treatment weighting (IPTW) and comparing percutaneous
ablation and surgical resection for an isolated local recurrence (LR) following PN [708]. A total of 81
patients with an isolated LR were included and treated with either ablation (30 RFA and 12 cryoablation) or
surgical resection (8 PN and 31 RN). Percutaneous ablation was associated with a significantly lower risk
of postoperative complications (5% with PCA vs. 41% with PN; OR: 0.22; p = 0.006) and a smaller change in
estimated GFR. There were no significant differences in the risk of disease recurrence (HR: 0.72; p = 0.61), new
LR (HR: 1.51; p = 0.59) and distant metastasis (HR: 0.19; p = 0.09) [708].

Following thermal ablation or cryotherapy generally intrarenal, but also perirenal, recurrences have been reported
in up to 14% of cases [709]. Whereas repeat ablation is still recommended as the preferred therapeutic option
after treatment failure, the most effective salvage procedure as an alternative to complete nephrectomy has not
yet been defined.

7.6.2 Locally recurrent RCC after radical nephrectomy

Isolated local fossa recurrence is rare and occurs in about 1-3% after radical nephrectomy. Recurrence is more
common in pT3-4 than pT1-2 and grade III-IV disease. Most patients with local recurrence of RCC are diagnosed
by either CT/MRI scans as part of the postoperative follow-up [710]. The median time to recurrence after RN
was 19-36 months in isolated local recurrence or 14.5 months in the group, including metastatic cases as well
[710-712].

72 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Isolated local recurrence is associated with worse survival [230, 713]. Based on retrospective and
noncomparative data only, several approaches, such as surgical excision, radiotherapy, systemic treatment
and observation, have been suggested for the treatment of isolated local recurrence [714-716]. Among
these alternatives, surgical resection with negative margins remains the only therapeutic option shown to be
associated with improved survival [713]. Open surgery has been successfully reported in studies [717, 718].
One of the largest series including 2,945 patients treated with RN reported on 54 patients with recurrent disease
localised in the renal fossa, the ipsilateral adrenal gland or the regional LNs as sole metastatic sites [714].
Another series identified 33 patients with isolated local recurrences and 30 local recurrences with synchronous
metastases within a cohort of 2,502 surgically treated patients, confirming the efficacy of locally directed
treatment versus conservative approaches (observation, systemic therapy) [719].

The five-year OS with isolated local recurrence was 60% (95% CI: 0.44-0.73) and ten-year OS was 32% (95% CI:
0.15-0.51). Overall survival differed significantly by the time period between primary surgery and occurrence
of recurrence (< 2 years vs. > 2 years: ten-year OS rate 31% (95% CI: 10.2-55.0) versus 45% (95% CI: 21.5-65.8;
HR: 0.26; p = 0.0034) [710]. Metastatic progression was observed in 60 patients (58.8%) after surgery [711].
Patient survival can be linked to the type of treatment received, as shown in a cohort of 96 patients, 45.8% were
metastatic at the time of recurrence; three-year CSS rates after local recurrence were 92.3% ± 7.4%) for those
who were treated with surgery and systemic therapy, 63.2% ± 13.2%) for those who only underwent surgery,
22.7% ± 0.9%) for those who only received systemic therapy and 20.5% ± 10.4%) for those who received no
treatment (p < 0.001) [712]. A retrospective multicentre study of patients with local retroperitoneal recurrence
after RN with or without surgical treatment from 2008 to 2020. Retroperitoneal recurrence of RCC was defined
as an ipsilateral recurrence confined to the renal fossa, adrenal gland or retroperitoneal lymph nodes after prior
nephrectomy, which was diagnosed by cross-sectional imaging. Treatment with retroperitoneal recurrence
surgery resulted in significantly longer CSS than targeted therapy alone (P < 0.001). In multivariable analysis,
high Fuhrman grade, size of retroperitoneal recurrence tumour, mixed type of retroperitoneal recurrence, multiple
recurrence lesions and the absence of retroperitoneal recurrence surgery were associated with a significantly
increased risk of death from RCC, suggesting that an aggressive surgical resection of retroperitoneal recurrence
after RN represents a potentially curative treatment for selected RCC patients without synchronous metastases,
resulting in significantly longer CSS than targeted therapy alone [720].

Minimally invasive approaches, including standard and hand-assisted laparoscopic and robotic approaches
for the resection of isolated RCC recurrences, have been reported. A large surgical cohort published of
robotic surgery in this setting (n = 35) providing a standardisation of the nomenclature, describing the surgical
technique for each scenario and reporting on complications, renal function and oncologic outcomes [721].
Ablative therapies, including cryoablation, radiofrequency and microwave ablation, may also have a role in
managing recurrent RCC patients, but further validation will be needed [722, 723].

In summary, the limited available evidence suggests that, in selected patients, surgical removal of locally
recurrent disease with negative margins can induce durable tumour control, although with expected high
risk of complications. A retrospective review on 51 planned repeat PNs in 47 patients with locally recurrent
disease, reporting a total of 40 peri-operative complications, with temporary urinary extravasation being the
most prevalent [724]. Since local recurrences develop early, with a median time interval of 10-20 months
after treatment of the primary tumour [725], a guideline-adapted follow-up scheme for early detection is
recommended (see Chapter 9, ‘Follow-up’), even though benefit in terms of cancer control has not yet been
demonstrated [726].

Adverse prognostic parameters are a short time interval since treatment of the primary tumour (< 3-12 months)
[727], sarcomatoid differentiation of the recurrent lesion and incomplete surgical resection [714]. If complete
surgical removal is unlikely to be performed or when significant comorbidities are present (especially when
combined with poor prognostic tumour features), palliative therapeutic approaches including radiation therapy
aimed at symptom control and prevention of local complications should be considered (see Sections 7.3 and
7.4). Following metastasectomy of local recurrence after nephrectomy, adjuvant therapy can be considered (see
Section 7.3.5, ‘Neoadjuvant and adjuvant therapy’). Local recurrence combined with other metastases is treated
as a metastatic RCC.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 73

7.6.3 Summary of evidence and recommendation on locally recurrent RCC after treatment of localised
disease

Summary of evidence LE
Isolated recurrence after nephron-sparing procedures or nephrectomy is a rare entity (< 2%). 3
Surgical or percutaneous treatment of local recurrences in absence of systemic progression should be 3
considered, especially in the absence of adverse prognostic parameters and favourable performance
status.
The most optimal modality of local treatment for locally recurrent RCC after nephron sparing 3
procedures or nephrectomy is not defined.

Recommendation Strength rating

Offer local treatment of locally-recurrent disease when technically possible and after Weak
balancing adverse prognostic features, comorbidities and life expectancy.

8. HEREDITARY AND SYNDROME SPECIFIC RCC

Five to eight percent of RCCs are hereditary, although this proportion could be underestimated due to the
limitations of available studies. To date, there are more than ten hereditary RCC syndromes associated with
specific germline mutations, RCC histology and comorbidities. Hereditary RCC syndromes are often suggested
by family history, age of onset and presence of other lesions typical for the respective syndromes. Median age
for hereditary RCC is 37 years; 70% of hereditary RCC tumours are found in the lowest decile (age 46 years or
younger) of all RCC tumours [197].

Hereditary kidney tumours are found in the following entities: VHL syndrome; hereditary papillary RCC (HPRCC);
Birt-Hogg-Dubé syndrome; Fumarate hydratase-deficient RCC (FHD-RCC), previously referred to as hereditary
leiomyomatosis and RCC (HLRCC); tuberous sclerosis complex; Hereditary SDH deficient paraganglioma/
pheochromocytoma (HPP) syndrome; Phosphatase and tensin homolog (PTEN) hamartoma syndrome (PHTS);
and BRCA-1 associated protein 1 (BAP1) tumour predisposition syndrome).

RCC can also be associated with the following syndromes: Hyperparathyroidism-jaw tumour (HJT) syndrome,
Chromosome 3 translocation (Cr3T) syndrome, and MITF-related melanoma and renal cell carcinoma
predisposition syndrome. Renal medullary carcinoma can be included because of its association with hereditary
haemoglobinopathies [74, 728-731].

8.1 Microphthalmia-associated transcription factors (MiTF) associated translocation

tumours
Although not hereditary, somatic fusion translocations of TFE3 and TFEB may affect 15% of patients with RCC
younger than 45 years and 20-45% of children and young adults diagnosed with RCC [732].

Table 8.1: Syndrome-specific RCC hystotypes and extrarenal organ involvement patterns [206, 733, 734]

Syndrome
Lifetime Selected associated extrarenal
(Inheritance, estimated Gene Histology
RCC risk clinical features
prevalence)
Hereditary RCC
Retinal/CNS haemangioblastomas
Pancreatic cysts and
VHL syndrome
neuroendocrine tumours
(autosomal dominant; VHL
30-40% ccRCC Endolymphatic sac tumour
estimated prevalence: 1-9 / (3p25.3)
Pheochromocytoma
100,000)
Epididymal cystoadenomas
Others

74 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

 Hereditary papillary RCC
(HPRCC)
MET
(autosomal dominant; 100% pRCC None
(7q31)
prevalence is unknown;
estimated at 1/500,000)

Birt-Hogg-Dubé (BHD) Fibrofolliculomas and other skin

syndrome Hybrid oncocytic; findings
FLCN
(autosomal dominant; 30% chRCC; Renal and lung cysts
(17p11.2)
estimated prevalence: 1-9 / oncocytoma Parotid gland oncocytomas
1,000,000) Pneumothorax

Fumarate hydratase (FH)-

Cutaneous leiomyomas
deficient RCC
FH Uterine leiomyomas
(FH-RCC) 15-32% FH-deficient RCC
(1p42.1) Leiomyosarcomas
(autosomal dominant;
Adrenal nodules
prevalence is unknown)
Renal AMLs
Angiomyofibromas and
Tuberous sclerosis
other dermatological lesions
complex
Cortical dysplasia
(TSC) TSC1/TSC2 ccRCC; pRCC,
<5% Subependymal giant
(autosomal dominant; (9q34/16p13) chRCC
cell astrocytoma
estimated prevalence: 1-9 /
Lymphangioleiomyomatosis
100,000)
Seizures
Others
Hereditary SDH deficient
paraganglioma/
SDHB/C/D
pheochromocytoma Pheocromocitoma
(1p36/ ccRCC,
(HPP) syndrome <10% Paraganglioma
1q23/ unclassified
(autosomal dominant; GI stromal tumour
11q23)
estimated prevalence: 1-9 /
1,000,000)
Macrocephaly
Phosphatase and
Breast cancer and fibrocystic
tensin homolog (PTEN)
PTEN change Thyroid cancer
hamartoma syndrome ccRCC, pRCC,
(10q23) 10-15% Endometrial cancer
(PHTS) chRCC
Prostate cancer
(autosomal dominant;
Colonic polyps
prevalence is unknown)
Facial trichilemmomas
BRCA-1 associated
Uveal and cutaneous melanoma
protein 1 (BAP1) tumour
BAP-1 Malignant pleural mesothelioma
predisposition syndrome <15% ccRCC
(3p21) Other cancers (cholangiocarcinoma,
(autosomal dominant;
basal cell carcinoma, meningioma)
prevalence is unknown)
Syndrome-related RCC

Hyperparathyroidism-jaw Hyperparathyrodism
tumour (HJT) syndrome CDC73 Parathyroid cancer
<10% RCC and Wilms
(estimated prevalence (1q31.2) Jaw fibroma
<1/1,000,000) Uterine cancer

Chromosome 3
-
translocation (Cr3T)
Trans-
syndrome 30% ccRCC None
locations
(estimated prevalence
3:6; 3:8; 3:11
<1/1000 000)

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 75

 SMARCB1-
Renal medullary carcinoma deficient renal
- - Hereditary haemoglobinopathies
(prevalence is unknown) medullary
carcinoma

MITF-related melanoma
and renal cell carcinoma MITF Pheocromocitoma
MiTF family
predisposition syndrome (3p14) <10% Melanoma
translocation RCC
(estimated prevalence Pancreatic cancer
<1/1000 000)
Data on estimated prevalence/incidence are based on [Link]

Published recommendations for the selection of germline genetic testing panels in patients with cancer,
including RCC [735] stated that germline genetic testing should be distinguished from biomarker testing (i.e.
tumour genomic profiling). To establish whether gene variants identified in a tumour are germline, germline
genetic testing must be performed. With advancements in next-generation sequencing technology, genetic
panels now encompass an expanding list of available genes. Specific recommendations have been set for the
following domains: a) family history collection; b) germline multigene panel testing; c) genes to be included in
multigene panels; and d) germline testing in association with somatic genetic tumour testing [735]. For RCC, the
genes recommended for testing and inclusion in multigene panels are: BAP1, FH, FLCN, MET, SDHA, SDHAF2,
SDHB, SDHC, SDHD PTEN, VHL (more strongly recommended) and TSC1/TSC2 (less strongly recommended).

8.2 Management of hereditary and syndrome-specific RCC

Hereditary RCC often presents with multifocal, de-novo recurring and bilateral tumours, which requires
individualised management.

Patients with hereditary kidney cancer syndromes may require repeated surgical intervention [736, 737]. In most
hereditary RCCs, nephron-sparing approaches are recommended due to risk of CKD [738]. To avoid multiple
repetitive partial nephrectomies, thermal ablation can be considered in the treatment paradigm. A registry based
retrospective analysis of 53 patients with inherited RCC syndromes evaluated percutaneous cryoablation for
primary mean 2.46cm tumours, demonstrating within mean follow-up of 30.4 months, estimated five-year local
recurrence-free survival of 96% (95% CI: 75-99), metastases free survival 96.4% (95% CI: 77-99%), CSS 90.9%
(95% CI: 51-99%) and OS 90.9% (95% CI: 51-99%). Complication rate was 1.7% and 7.4% had more than 25%
reduction in kidney function [739].

The exceptions to nephron-sparing approaches are FHD-RCC and high-grade SDH syndromes for which
immediate surgical intervention is recommended due to the aggressive nature of these tumours. For other
hereditary syndromes such as VHL, surveillance is recommended until the largest tumour reaches 3cm in
diameter - this to limit the number of repeat interventions [740, 741]. Active surveillance for VHL and other
nonaggressive hereditary tumours, should, in individual patients, follow the size, growth rate and location of the
tumours, rather than applying a standardised follow-up interval. Regular screening for both renal and extrarenal
lesions should follow international guidelines for these syndromes [741]. Multidisciplinary and co-ordinated
care should be offered, where appropriate [742]. In FHD-RCC, renal screening in relatives has shown benefit in
detecting early-stage RCCs [54], with HLRCCs appearing to have unique molecular profiles.

In the metastatic setting, systemic therapeutic options for fumarate hydratase-deficient RCC with
high metastatic potential include ICI monotherapies, which offer a better disease control rate than TKI
monotherapies. In a phase II trial, ORR of 51 % of combination of erlotinib and bevacizumab was achieved [700].
Another trial expressed a favourable response to ICI/TKI combinational therapy compared to bevacizumab plus
erlotinib [100].

Succinate dehydrogenase (SDH)-deficient RCC has a low risk of metastasis (12 %) with exception of high-grade
with risk 70 %. Due to rarity of disease, no evidence for systemic therapy [700].

8.2.1 Von Hippel-Lindau-disease-associated RCC

Patients with VHL disease often develop RCC and tumours and cysts in other organs, including adrenal glands,
CNS, retinal haemangioblastomas and pancreas, and commonly undergo several surgical resections in their
lifetime. In VHL disease, belzutifan, a HIF-2α inhibitor, has been approved by the United States Food and Drug
Administration [743] for the treatment of ccRCC and other neoplasms associated with VHL for the treatment of
tumours that do not require immediate surgery. Approval was based on the results from a phase II, open-label,

76 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

single-arm trial in 61 patients with tumours not larger than 3cm [744]. Belzutifan induced partial responses with
an RCC ORR of 67%, and complete response rate of 11% after 41.3 months’ treatment. In total, 18% of patients
reported > grade III adverse events, and eight patients (13.5%) discontinued the treatment. In the treatment
with pazopanib for VHL only, 52% continued with the treatment after 24 weeks [745]. A longer follow-up at 37.8
months, ORR for RCC was increased to 64%, with a median time to response of 11.1 months (range, 2.7 to 30.5).
Median duration of response per Kaplan-Meier estimate was not reached (range 5.4+ to 35.8+ months). Thirty-
four of 39 patients with a confirmed response (87%) remain in response as of the data cut-off date (September
2022) [744].

With favourable efficacy results and with relatively low-grade side effects, belzutifan seems to be a valuable
contribution to the treatment of patients with the VHL disease. Recent data from the largest retrospective
VHL cohort under active surveillance showed that 63% experienced disease progression (without systemic
treatment) and surgical intervention was common: 76% required one renal surgery, and 44% multiple
procedures, resulting in chronic kidney disease in 41% of them [738]. The EMA has conditional approval for
belzutifan for VHL disease.

8.2.2 TFE3-rearranged RCC

TFE3-rearranged RCC showed objective response rate 25% with ICI and 0 % with TKI and more prolonged OS
(62.4 months with ICI vs. 10.3 with TKI). Cabozantinib may be an exception with 16.6% objective response. A
future role of ICI-TKI combination (such as nivolumab plus cabozantinib) and cabozantinib plus belzutifan has
been discussed [700].

8.2.3 TFEB-altered RCC

TFEB-rearranged RCC: There is a general lack of information regarding the response to modern systemic
therapy. A combination of ICI and mTOR inhibitors has been discussed. TFEB-amplified RCC (which occurs in
elderly patients and displays more aggressive behaviour compared to TFEB-rearranged RCC) can be treated with
VEGFR targeting agents or with a VEGFR-TKI combination [700].

8.2.4 Combined therapy for TFE3- and TFEB-altered RCCs

Some studies combine therapy TFE3- and TFEB-altered RCCs (due to the former grouping of both tumours
to MiT family translocation RCCs). Two retrospective studies exhibit efficacy of ICI or ICI-TKI combination
[746, 747]. Other studies provided evidence of the activity of cabozantinib in MiT TRCC, with more durable
responses than those observed historically with other VEGFR-TKIs or ICIs [748].

8.2.5 Summary of evidence and recommendation for hereditary and syndrome-specific RCC

Summary of evidence LE
Hereditary RCC syndromes are often suggested by family history, age of onset and presence of other 3
lesions typical for the respective syndromes.
Hereditary RCC tumours are predominantly found in the lowest decile, with 70% occurring in individuals 3
aged 46 years or younger.
To establish whether gene variants identified in a tumour are germline, germline genetic testing must 3
be performed.
In VHL and non-FHD-RCC, tumours can be observed with a diameter of up to 3cm. 3
Belzutifan leads to an ORR of VHL lesions of 67% at 41.3 months. 2
There is currently no approved standard first-line treatment for non-VHL hereditary or syndrome- 3
specific RCC.

Recommendation Strength rating

Suspect hereditary or syndrome-specific RCC in patients with positive family history, young Strong
onset and bilateral or multiple tumours.
Offer germline testing to patients < 46 years. Weak
Offer surveillance in von Hippel-Lindau (VHL) until the largest tumour reaches 3cm in Strong
diameter.
Offer belzutifan to patients with VHL-related renal and other tumours who are not surgical Weak
candidates.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 77

9. FOLLOW-UP IN RCC
9.1 Introduction
Surveillance after treatment for RCC allows the urologist to monitor or identify the following:
• postoperative complications;
• renal function;
• local recurrence;
• recurrence in the contralateral kidney;
• distant metastases; and
• cardiovascular events.

There is no consensus on follow-up strategies after RCC treatment, with limited evidence suggesting that more
frequent postoperative imaging intervals do not provide any improvement for early detection of recurrence
that would lead to improved survival [726]. As such, intensive radiological surveillance may not be necessary
for all patients. Follow-up is also important to assess functional outcomes and to limit long-term sequelae,
such as renal function impairment, ESRD and cardiovascular events [749]. Referral of patients at risk of CKD/
renal function deterioration after treatment (surgery/ablation) to a nephrologist may minimise the risk of
worsening of renal function; support oncologists in managing treatment-related renal adverse events; assist in
the choice of optimal follow-up radiological procedures (mainly deciding if, when, and how to use CT contrast
media); and deal with oncological patients on dialysis or with kidney transplant (including if and when to start
dialysis, or whether to allow a kidney transplant) (expert opinion) [252]. Patients with pre-existing or treatment-
induced CKD (e.g. patients with new baseline estimated GFR equal to or less than 45ml/min. [750]), and/or
known comorbidities potentially affecting renal function could benefit the most from specialist nephrological
assessment during follow-up (expert opinion).

Currently, the key question is whether any recurrence detection during follow-up and subsequent treatment will
lead to any meaningful change in survival outcome for these patients.

In contrast to high-grade and/or locally advanced disease, the outcome after surgery for T1a low-grade tumours
is almost always excellent. It is therefore reasonable to stratify follow-up, taking into account the risk of each
different RCC to develop a local or distant recurrence. Although there is no randomised evidence, large studies
have examined prognostic factors with long follow-up [220, 751, 752] (LE: 4). One study has shown a survival
benefit in patients who were followed within a structured surveillance protocol versus patients who were not
[753]; patients undergoing follow-up appear to have a longer OS when compared to patients not undergoing
routine follow-up [753].

Moreover, an individualised and risk-based approach to RCC follow-up has recently been proposed [754].
The authors used competing risk models, incorporating patient age, pathologic stage, relapse location and
comorbidities, to calculate when the risk of non-RCC death exceeds the risk of RCC recurrence [755].
For patients with low-stage disease but with a Charlson comorbidity index > 2, the risk of non-RCC death
exceeded that of abdominal recurrence risk already one month after surgery, regardless of patient age. As for
psychological factors, an SR including fifteen studies revealed that psychological distress (defined as anxiety,
depression or psychological distress at any time during treatment or follow-up) is also prevalent among RCC
patients, reaching up to 77% in non-metastatic cases [756].

The RECUR consortium, initiated by this Panel, collects similar data with the aim to provide comparators
for guideline recommendations. Published RECUR data support a risk-based approach; more specifically, a
competing-risk analysis showed that, for low-risk patients, the risk of non-RCC-related death exceeded the risk
of RCC recurrence shortly after the initial surgery. For intermediate-risk patients, the corresponding time point
was reached approximately four to five years after surgery. In high-risk patients, the risk of RCC recurrence
continuously exceeded the risk of non-RCC-related death [757]. In the near future, genetic profiling may refine
the existing prognostic scores and external validation in datasets from adjuvant trials have been promising in
improving stratification of patient’s risk of recurrence [757, 758].

Recurrence after PN is rare, but early diagnosis is relevant, as the most effective treatment is surgery [717, 759].
Recurrence in the contralateral kidney is rare (1-2%) and can occur late (median 5-6 years) [760] (LE: 3). Follow-
up can identify local recurrences or metastases at an early stage. At recurrence, extensive metastatic tumour
growth can hinder the opportunity for surgical resection. In addition, early diagnosis of tumour recurrence may
enhance the efficacy of systemic treatment if the tumour burden is low.

78 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

9.2 Which imaging investigations for which patients, and when?
• The sensitivity of chest radiography and US for detection of small RCC metastases is poor. The sensitivity
of chest radiography is significantly lower than CT-scans, as proven in comparative studies including
histological evaluation [761-763]. Therefore, follow-up for recurrence detection with chest radiography and
US are less sensitive [764].
• Positron-emission tomography and PET-CT as well as bone scintigraphy should not be used routinely in
RCC follow-up, due to their limited specificity and sensitivity [128, 144].
• Surveillance should also include evaluation of renal function and cardiovascular risk factors [749].
• Outside the scope of regular follow-up imaging of the chest and abdomen, targeted imaging should be
considered in patients with organ-specific symptoms, e.g. CT or MRI imaging of the brain in patients
experiencing neurological symptoms [765].

Controversy exists on the optimal duration of follow-up. Some authors argue that follow-up with imaging is
not cost-effective after five years. However, late metastases are more likely to be solitary and justify more
aggressive therapy with curative intent. In addition, patients with tumours that develop in the contralateral kidney
can be treated with NSS if the tumours are detected early. Several authors have designed scoring systems and
nomograms to quantify the likelihood of patients to develop tumour recurrences, metastases and subsequent
death [282, 284, 766, 767]. These models, the most utilised of which are summarised in Chapter 6, ‘Prognosis’,
have been compared and validated [768] (LE: 2). Using prognostic variables, several stage-based follow-up
regimens have been proposed, although, none propose follow-up strategies after ablative therapies [769, 770]. A
postoperative nomogram is available to estimate the likelihood of freedom from recurrence at five years [279].
A preoperative prognostic model based on age, symptoms and TNM staging has been published and validated
[771] (LE: 3).

A follow-up algorithm for monitoring patients after treatment for RCC is needed, recognising not only the
patient’s risk of recurrence profile, but also the efficacy of the treatment given (Table 8.1). These prognostic
systems can be used to adapt the follow-up schedule according to predicted risk of recurrence. Ancillary to the
above, life-expectancy calculations based on comorbidity and age at diagnosis may be useful in counselling
patients on duration of follow-up [772].

An SR evaluated frequency and duration of follow-up. Most studies employ a higher imaging frequency during
FU after treatment for non-metastatic RCC than recommended by the 2022 EAU Guidelines. Survival and
recurrence rates suggest that more frequent imaging than recommended by the EAU may not be advantageous,
although high-quality evidence is needed to further improve guidelines [773].

Referral of patients at risk of CKD or with renal function deterioration after treatment to a nephrologist may
minimise the risk of worsening of renal function, support oncologists in managing treatment-related renal
adverse events, and assist in the choice of optimal follow-up radiological procedures (expert opinion) [252].

Patients with pre-existing or treatment-induced CKD (e.g. patients with new baseline estimated GFR < 45ml/min.
[252]) and/or those with known comorbidities potentially affecting renal function could benefit the most from
specialist nephrological assessment during follow-up (expert opinion).

Table 9.1: Proposed follow-up schedule following treatment for localised RCC, taking into account patient risk
of recurrence profile and treatment efficacy (based on expert opinion [LE: 4])

Risk profile (*) Oncological follow-up after date of surgery

3 6 12 18 24 30 36 > 3 yr (**) (***) > 5 yr (**) (***)
mos. mos. mos. mos. mos. mos. mos.
Low risk of recurrence - CT - CT - CT - CT once every -
two yrs
For ccRCC:
Leibovich Score 0-2

For non-ccRCC:
pT1a-T1b pNx-0 M0 and
histological grade 1 or 2.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 79

Intermediate risk of - CT CT - CT - CT CT once yr CT once
recurrence every
two yrs
For ccRCC:
Leibovich Score 3-5

For non-ccRCC:
pT1b pNx-0 and/or
histological grade 3 or 4
High risk of recurrence CT CT CT CT CT - CT CT once yr CT once
every
For ccRCC: two yrs
Leibovich Score ≥ 6

For non-ccRCC:
pT2-pT4 with any
histological grade
or
pT any, pN1 cM0 with any
histological grade
ccRCC = clear cell renal cell carcinoma; CT = computed tomography; mos. = months; non-ccRCC = non clear cell
renal cell carcinoma; yrs. = years.

The table above provides recommendations on follow-up strategies for low, intermediate and high risk of
recurrence in patients curatively treated for localised RCC either with NSS or RN. Computed tomography in the
table refers to imaging of both chest and abdomen. Alternatively, MRI of the abdomen can be performed instead
of a CT-scan.
* Risk of recurrence profiles should be based on validated prognostic models. The EAU RCC Guidelines Panel
recommends the 2003 Leibovich model for ccRCC [282]. However, physicians can use other validated models,
based on their own national/regional recommendations. In a similar fashion, for curatively treated localised
non-ccRCC, the Panel recommends the use of the University of California Los Angeles integrated staging
system (UISS) to determine risk of recurrence [283].
** F  or all risk of recurrence profiles, functional follow-up - mainly monitoring renal and cardiovascular function -
may continue according to specific clinical needs irrespective of the length of the oncological follow-up.
*** F  or low-risk profiles at > 3 years and intermediate-risk at > 5 years of follow-up, respectively, consider
counselling patients about terminating oncological follow-up imaging based on assessment of comorbidities,
age, life expectancy and/or patient wishes.

9.3 Summary of evidence and recommendations for surveillance following RN or PN or

ablative therapies in RCC

Summary of evidence LE
Functional follow-up after curative treatment for RCC is useful to prevent renal and cardiovascular 3
deterioration.
Oncological follow-up can detect local recurrence or metastatic disease while the patient may still be 4
surgically curable.
After NSS, there is an increased risk of recurrence for larger (> 7cm) tumours, or when there is a PSM. 3
Patients undergoing follow-up have a better OS than patients not undergoing follow-up. 3
Prognostic models provide stratification of RCC risk of recurrence based on TNM and histological 3
features.
In competing-risk models, risk of non-RCC-related death exceeds that of RCC recurrence or related 3
death in low-risk patients.
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
Referral to nephrological evaluation of patients with baseline or treatment-induced CKD and/or with 4
known risk factors for renal function deterioration may minimise the risk of worsening of renal function,
support management decisions, and tailor follow-up schedules.

80 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

Recommendations 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 Weak
Leibovich Score for clear cell renal cell carcinoma (ccRCC), or the University of California Los
Angeles integrated staging system for non-ccRCC.
Intensify follow-up in patients after nephron-sparing surgery with a positive surgical margin. Weak
Consider curtailing follow-up when the risk of dying from other causes is double that of the Weak
RCC recurrence risk.
Offer psychological evaluation for all patients diagnosed with RCC to provide timely support Weak
for distress, depression, or anxiety.
Seek nephrological consultation during follow-up in patients treated for RCC with one or Weak
more of the following conditions:
- pre-existing chronic kidney disease (CKD)
- treatment-induced CKD (e.g. new baseline eGFR < 45ml/min.)
- known comorbidities potentially affecting renal function.

10. REFERENCES
1. Phillips, B. Oxford Centre for Evidence-based Medicine Levels of Evidence. Updated by Jeremy
Howick March 2009. 1998.
[Link]
medicine-levels-of-evidence-march-2009
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11. CONFLICT OF INTEREST
All members of the Renal Cell Cancer Guidelines Panel have provided disclosure statements of all
relationships that they have that might be perceived as a potential source of a conflict of interest. This
information is published below and also publicly accessible through the European Association of Urology
website: [Link]

This Guidelines document was developed with the financial support of the European Association of Urology. No
external sources of funding and support have been involved. The EAU is a non-profit organisation, and funding
is limited to administrative and travel and meeting expenses. No honoraria or other reimbursements have been
provided.

Disclosures: The EAU Guidelines Office certifies that all conflicts of interest, including specific financial interests
and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript
(eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert
testimony, royalties, or patents filed, received, or pending), are the following: A. Bex reported receiving research
support and grants from Pfizer; a trial participant for Roche/Genentech and BMS and a company consultant for
Ipsen. J. Bedke reported serving as a company consultant for Astella, AstraZeneca, BMS, Eisai, Ipsen, Janssen,
Merck Sorono, MSD, Pfizer and Roche; receiving company speaker honoraria from Ispen Pharma GMBh,
BMS, MSD, Pfizer and Seagen; declares trial participation with Astella, AstraZeneca, BMS, Eisai, Ipsen, MSD,
Nektar, Novartis, Pfizer, Roche and Seagen and receiving honoraria from Ipsen. U. Capitanio reported receiving
consultation fees from MSD Italia srl and serving as company speaker and receiving fellowship and travel grants
from Merck Sharp & Dohme S.p.A. S. Dabestani reported serving as a company consultant for Elypta AB. M.
Hora reported serving as a company consultant for MSD, receiving company speaker honorarium from MSD
and consultation fees from Merck Spol. S.R.O. G. Pignot reported receiving company speaker honoraria from
Merck, AstraZeneca, Bouchara Recordati, Pfizer, Ipsen, J&J, Bayer, Bristol Myers Squibb and Astellas; receiving
honoraria or consultation fees from AstraZeneca, Bayer, J&J and Intuitive Surgical; and participating in clinical
trials with J&J and Vitadx International. M. Tran received research support from Boston Scientific and honoraria,
consultation fees from Boston Scientific, Eisai Europe Ltd, Telix Pharmaceuticals and Merck Sharp & Dohme.
R. Campi received consultation fees from Telix pharmaceuticals and Nucleix; fellowship, travel grants from
MSD Italia srl. T. Powles reported receiving honoraria or consultation fees from AstraZeneca, Astellas Pharma,
Bristol Myers Squibb, Eisai Europe Ltd, Exelixis, Inc, F. Hoffmann-La Roche Ltd, Incyte Biosciences, Ipsen, Merck
& Co Inc, Merck KGaA, Merck Sharp & Dohme, Merck Sharp & Dohme LLC, MSD Sharp & Dohme GmbH, Novartis
Pharma AG, Pfizer, and Seattle Genetics; receiving grants or research support from AstraZeneca, Astellas
Pharma, Astellas Pharma US, Bristol Myers Squibb, Eisai Europe Ltd, Exelixis, Inc., F. Hoffmann-La Roche Ltd,
Ipsen, Johnson & Johnson, Merck & Co. Inc., Merck KGaA, Merck Sharp & Dohme, Merck Sharp & Dohme LLC,
Merck Sharp & Dohme International Services, Novartis Pharma AG, Pfizer and Seattle Genetics; and reporting
other relationships with AstraZeneca, F. Hoffmann-La Roche Ltd, Ipsen, MSD Sharp & Dohme GmbH, Merck
Sharp & Dohme LLC and Pfizer. T. Klatte reported receiving fellowship or travel grants from Bristol Myers Squibb
and serving as company consultant for Bristol-Myers Squibb Germany, Medac GmbH and Merck Healthcare
Germany GmbH. C. Suarez reported serving as a company consultant to Vall Hebron Institute of Oncology
(VHIO). Riccardo Campi has had advisory roles and has received travel grants from Telix Pharmaceuticals and
MSD. Patricia Zondervan reported serving as company consultant for Telix pharma and receiving travel grants
from IPSEN, BMS and Pfizer. T. Kuusk reported receiving company speaker honoraria from Telix and served as
an advisory role for Telix. S. Bonn, D. Breen, Y. Abu Ghanem, R. Woodward, C. Palumbo, L. Lund and L. Marconi
all have nothing to declare.

124 RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026

12. CITATION INFORMATION
The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the
citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location
or an ISBN number may vary.

The compilation of the complete Guidelines should be referenced as:

EAU Guidelines. Edn. presented at the EAU Annual Congress London 2026. ISBN 978-94-92671-32-5.

If a publisher and/or location is required, include:

EAU Guidelines Office, Arnhem, The Netherlands. [Link]

References to individual guidelines should be structured in the following way:

Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.

13. COPYRIGHT AND TERMS OF USE

The content of the EAU Guidelines and all products derived from them is made available for personal and
educational use only. No commercial usage is authorised. No part of the EAU Guidelines or any related products
may be translated or reproduced in any form without written permission from the EAU. Furthermore, the EAU
prohibits the usage or upload of its Guidelines, and any material derived from these texts (whether in full or
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The EAU accepts no responsibility for the content, quality or performance of materials, applications and
products derived from the EAU Guidelines and does not endorse or warrant their use. In the event of any
discrepancies, the original language version shall be considered authoritative.

RENAL CELL CARCINOMA - LIMITED UPDATE MARCH 2026 125