.

INTRODUCTION
[Link] and scope
The European Association of Urology (EAU) Renal Cell Carcinoma (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 and judgement when making treatment decisions for
individual patients, but rather help to focus decisions whilst also taking personal values and
preferences/individual circumstances of patients into account. Guidelines are not mandates and do
not purport to be a legal standard of care.
[Link] composition
The RCC Guidelines Panel is an international group of clinicians consisting of urological surgeons,
oncologists, methodologists, a pathologist and a radiologist, with particular expertise in the field of
renal cancer care. Since 2015, the Panel has incorporated a patient advocate to provide a consumer
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]
carcinoma/?type=panel/.
[Link]
The RCC Guidelines Panel is most grateful for the continued methodological and scientific support
provided by [Link]. O. Hes (pathologist, Pilzen, Czech Republic) for two sections of this document:
Histological diagnosis and Other renal tumours.
[Link] publications
A quick reference document (Pocket Guidelines) is available, both in print and as an app for iOS and
Android devices, presenting the main findings of the RCC Guidelines. These are abridged versions
which may require consultation together with the full text version. Several scientific publications are
available, as are a number of translations of all versions of the EAU RCC Guidelines [1]. All
documents can be accessed on the EAU website: [Link]
[Link] history and summary of changes
[Link] history
The EAU RCC Guidelines were first published in 2000. This 2020 RCC Guidelines document presents
a limited update of the 2019 publication.
[Link] of changes
All chapters of the 2020 RCC Guidelines have been updated, based on the 2019 version of the
Guidelines. References have been added throughout the document.
New data have been included in the following sections, resulting in changed recommendations in:
Section 3.4.5 Summary of evidence and recommendations for the management of other renal
tumours
Recommendations Strength
rating
Treat angiomyolipoma (AML) with selective arterial embolisation or nephron- Weak
sparing surgery, in:
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.
Only offer radical nephrectomy to patients with localised renal medullary Weak
carcinoma after a favourable response to systemic therapy.
[Link].7 Summary of evidence and recommendation for therapeutic approaches as alternative to
surgery
Recommendations Strength
rating
When radiofrequency ablation, cryoablation and active surveillance are Weak
offered, inform patients about the higher risk of local recurrence and/or tumour
progression.
[Link] Summary of evidence and recommendations for immunotherapy of metastatic clear-cell RRC
Summary of evidence LE
The combination of pembrolizumab and axitinib in treatment-naïve patients with clear- 1b
cell-mRCC across all IMDC risk groups demonstrated overall survival and ORR benefits
compared to sunitinib.
Currently, PD-L1 expression is not used for patient selection. 2b
Axitinib can be continued if immune-related adverse events results in cessation of 4
axitinib and pembrolizumab. Re-challenge with combination therapy requires expert
support.
Patients who do not receive the full four doses of ipilimumab due to toxicity should 4
continue on single-agent nivolumab, where safe and feasible. Re-challenge with
combination therapy requires expert support.
Treatment past progression can be justified but requires close scrutiny and the support 1b
of an expert multidisciplinary team.
Nivolumab plus ipilimumab and pembrolizumab plus axitinib should be administered in 4
centres with experience of immune combination therapy and appropriate supportive care
within the context of a multidisciplinary team.
Recommendations Strength
rating
Offer pembrolizumab plus axitinib to treatment-naïve patients with any IMDC- Strong
risk clear-cell metastatic RCC (cc-mRCC).
Offer ipilimumab plus nivolumab to treatment-naïve patients with IMDC Strong
intermediate- and poor-risk cc-mRCC.
Patients who do not receive the 4 four doses of ipilimumab due to toxicity Weak
should continue on single-agent nivolumab, where safe and feasible.
Offer axitinib as subsequent treatment to patients who experience treatment- Weak
limiting immune-related adverse events after treatment with the combination of
axitinib and pembrolizumab.
Treatment past progression can be justified but requires close scrutiny and the Weak
support of an expert multidisciplinary team.
Offer sunitinib or pazopanib to treatment-naïve patients with IMDC favourable-, Strong
intermediate-, and poor-risk cc-mRCC who cannot receive or tolerate immune
checkpoint inhibition.
Offer cabozantinib to treatment-naïve patients with IMDC intermediate- and Strong*
poor-risk cc-mRCC who cannot receive or tolerate immune checkpoint
 inhibition.
*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.
7.4.7 Summary of evidence and recommendations for targeted therapy in metastatic RRC
Summary of evidence LE
Single-agent VEGF-targeted therapy has been superseded by immune checkpoint- 1b
based combination therapy.
Pazopanib is non-inferior to sunitinib in front-line metastatic RCC. 1b
Tivozanib has been EMA approved, but the evidence is still considered inferior over 3
existing choices in the front-line setting.
Single-agent VEGF-targeted therapies are preferentially recommended after front- 3
line PD-L1-based combinations. Re-challenge with treatments already used should be
avoided.
Single-agent cabozantinib or nivolumab are superior to everolimus after one or more 1b
lines of VEGF-targeted therapy.
Both mTOR inhibitors and VEGF-targeted therapies have limited activity in non-clear cell 2a
RCC. There is a non-significant trend for improved oncological outcomes for sunitinib
over everolimus.
Lenvatinib in combination with everolimus improved PFS over everolimus alone in 2a
VEGF-refractory disease. Its role after immune checkpoint inhibitors is uncertain. There
is a lack of robust data on this combination making its recommendation challenging.
Recommendations Strength
rating
Offer nivolumab or cabozantinib for immune checkpoint inhibitor-naive Strong
vascular endothelial growth factor receptor (VEGFR)-refractory clear-cell
metastatic renal cell carcinoma (cc-mRCC).
Sequencing the agent not used as second-line therapy (nivolumab or Weak
cabozantinib) for third-line therapy is recommended.
Offer VEGF-tyrosine kinase inhibitors as second-line therapy to patients Weak
refractory to nivolumab plus ipilimumab or axitinib plus pembrolizumab.
Offer cabozantinib after VEGF-targeted therapy in clear-cell-mRCC. Strong
Figure 7.1: Updated European Association of Urology Guidelines recommendations for
the treatment of first-line and following lines in clear-cell metastatic renal cancer
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 one randomised controlled phase II trial.
Figure 7.2: Guidelines Recommendations for later-line therapy

IMDC = The International Metastatic Renal Cell Carcinoma Database Consortium; 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.
 [Link]
[Link] identification
For the 2018 Guidelines, new and relevant evidence has been identified, collated and appraised
through a structured assessment of the literature for the chapters as listed in Table 2.1.
A broad and comprehensive scoping search was performed, which was limited to
studies representing high levels of evidence (i.e. systematic reviews [SRs] with meta-analysis,
randomised controlled trials (RCTs), and prospective non-randomised comparative studies only)
published in the English language. The search was restricted to articles published between June
18th 2018 and April 5th, 2019. Databases covered included Medline, EMBASE, and the Cochrane
Library. After deduplication, a total of 2,225 unique records were identified, retrieved and screened for
relevance.
A total of 49 new references have been included in the 2020 RCC Guidelines
publication. A search strategy is published online: [Link]
type=appendices-publications.
For each recommendation within the guidelines there is an accompanying online strength rating form,
the basis of which is a modified GRADE methodology [2]. Each strength rating form addresses a
number of key elements namely:
1. the overall quality of the evidence which exists for the recommendation, references used in
this text are graded according to a classification system modified from the Oxford Centre for
Evidence-Based Medicine Levels of Evidence [3];
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;
5. the impact of patient values and preferences on the intervention;
6. the certainty of those patient values and preferences.
These key elements are the basis which panels use to define the strength rating of each
recommendation.
The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [4]. 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 nature and variability of patient values and preferences. The strength rating forms will
be available online.
Specific chapters were updated by way of SRs, commissioned and undertaken by the Panel, based
on prioritised topics or questions. These reviews were performed using standard Cochrane SR
methodology: [Link]
Table 2.1: Description of update and summary of review methodology
Chapter Brief description of review
methodology
1. Introduction Not applicable.
2. Methods Not applicable.
3. Epidemiology, aetiology and pathology This chapter was updated by a narrative
review, based on a structured literature
assessment.
4. Staging and grading classification systems This chapter was updated by a narrative
review, based on a structured literature
assessment. Section 3.3.5 Angiomyolipoma
was updated by means of a SR [5].
5. Diagnostic evaluation Section 5.2 (Diagnostic imaging) was revised
based on a SR [6]. The remainder of the
chapter was updated by a structured literature
assessment.
6. Prognosis This chapter was updated by a narrative
review, based on a structured literature
assessment.
7. Treatment (Disease management) Sections 7.1.2 and 7.2.4 (Treatment of
localised and locally advanced disease) were
revised based on an updated SR. Section
[Link] (Non-clear-cell carcinoma) was
updated by means of a SR [7]. The remainder
of the chapter was updated using a structured
literature assessment. Systemic therapy for
metastatic disease: this section was updated
by a SR.
8. Follow-up in RCC & Surveillance following This chapter was updated by a narrative
radical or partial nephrectomy or ablative review, based on a structured literature
therapies assessment. The findings of a prospective
database set up by the RCC Panel have been
included [8,9].
Additional methodology information can be found in the general Methodology section of this print, and
online at the EAU website: [Link] A list of Associations endorsing the EAU
Guidelines can also be viewed on line at the above address.
[Link]
All publications ensuring from SRs have been peer reviewed. The 2019 print of the RCC Guidelines
was peer-reviewed prior to publication.
[Link] goals
For their future updates, the RCC Guideline Panel aims to focus on patient-reported outcomes.
The use of clinical quality indicators is an area of interest for the RCC Panel. A number
of key quality indicators for this patient group have been selected:
 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 treated within six weeks after diagnosis;
 the proportion of patients with metastatic RCC (mRCC) offered systemic therapy;
 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.
The results of ongoing and new SRs will be included in the 2020 update of the RCC Guidelines:
 Ablative therapy vs. partial nephrectomy (PN) for T1-T2 renal cell carcinoma;
 What is the best treatment option for ≥ T2 tumours?;
 Systematic review and meta-analysis of systemic therapy of renal tumours (Cochrane
Review);
 Adjuvant targeted therapy for renal cell carcinoma at high risk for recurrence.
 [Link], AETIOLOGY AND
PATHOLOGY
[Link]
Renal cell carcinoma represents around 3% of all cancers, with the highest incidence occurring in
Western countries [10]. Generally, during the last two decades until recently, there has been an
annual increase of about 2% in incidence both worldwide and in Europe leading to approximately
99,200 new RCC cases and 39,100 kidney cancer-related deaths within the European Union in 2018
[10]. In Europe, overall mortality rates for RCC increased until the early 1990s, with rates generally
stabilizing or declining thereafter [11]. 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. However, in some European countries (Croatia, Estonia, Greece, Ireland, Slovakia), mortality
rates still show an upward trend [10,11].
[Link]
Aetiological factors include lifestyle factors such as smoking, obesity, and hypertension [12,13]. In a
recent SR also diabetes was found to be detrimental [14]. Having a first-degree relative with kidney
cancer is also associated with an increased risk of RCC. A number of other factors have been
suggested to be associated with higher or lower risk of RCC, including specific dietary habits and
occupational exposure to specific carcinogens, but the literature is inconclusive [13,15]. Moderate
alcohol consumption appears to have a protective effect for reasons as yet unknown, while also any
physical activity level seems to have a small protective effect [14,16]. The most effective prophylaxis
is to avoid cigarette smoking and reduce obesity [13].
Renal cell carcinoma is the most common solid lesion within the kidney and accounts for
approximately 90% of all kidney malignancies. It comprises different RCC subtypes with specific
histopathological and genetic characteristics [17]. There is a 1.5:1 predominance in men over women,
with a peak incidence occurring between 60 and 70 years of age [18].
[Link] of evidence and recommendation for epidemiology,
aetiology and pathology

Summary of evidence LE
Several verified risk factors have been identified including smoking, obesity and 2a
hypertension. These are considered definite risk factors for RCC.
Recommendation Strength
rating
Increase physical activity, eliminate cigarette smoking and in obese patients Strong
reduce weight as the primary preventative measures to decrease risk of RCC.
[Link] diagnosis
Renal cell carcinomas comprise a broad spectrum of histopathological entities described in the 2016
World Health Organization (WHO) classification [17]. There are three main RCC types: clear cell
(ccRCC), papillary (pRCC- type I and II) and chromophobe (chRCC). The RCC type classification has
been confirmed by cytogenetic and genetic analyses [17] (LE: 2b). Collecting duct carcinoma and
other rare renal tumours are discussed in Section 3.3.
Histological diagnosis includes, besides RCC type; evaluation of 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 (International Society of
Urological Pathology) grading system has replaced the Fuhrman grading system [17].
[Link]-cell RCC
Overall, clear-cell RCC (ccRCC) is well circumscribed and a capsule is usually absent. 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, including additional
tumour suppressor genes including SETD2, BAP1, and PBRM1; all genes are identified near the VHL
gene within a region that is frequently deleted in ccRCC [19]. In general, ccRCC has a worse
prognosis compared to pRCC and chRCC [20,21] even after stratification for stage and grade [22].
The 5-year cancer-specific-survival (CSS) rate was 91%, 74%, 67% and 32% for TNM stages I, II, III
and IV (patients treated between 1987-1998), respectively [23]. For more details, see Section 6.3 -
Histological factors.
[Link] RCC
Papillary RCC is the second most commonly encountered morphotype of RCC. Papillary RCC has
traditionally been subdivided into two types [17]. Type I and II pRCC, which were shown to be
clinically and biologically distinct; pRCC type I is associated with activating germline mutations
of MET and pRCC type II is associated with activation of the NRF2-ARE pathway and at least three
subtypes [24]. Future substratification is expected, e.g. oncocytic pRCC [17].
A typical histology of pRCC type I (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 necrotisation 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. Only microcapillaries explain the minimal post-contrast
attenuation on CT. Papillary RCC type 1 can imitate a pathologically changed cyst (Bosniak IIF or III).
The typical signs of pRCC type 1 are as follows: an ochre colour, more frequently exophytic,
extrarenal growth, low grade, and low malignant potential; over 75% of these tumours can be treated
by NSS surgery. A substantial risk of renal tumour biopsy tract seeding exists (12.5%), probably due
to the fragility of the tumour papillae [25]. Papillary RCC type I is more common and generally
considered to have a better prognosis than pRCC type II [17,26].
[Link] RCC
Overall, chRCC is a pale tan, relatively homogenous and tough, well-demarcated mass without a
capsule. Chromophobe RCC cannot be graded (by the Fuhrman grading system), because of its
innate nuclear atypia. An alternative grading system has been proposed, but has yet to be validated
[17]. Loss of chromosomes Y, 1, 2, 6, 10, 13, 17 and 21 are typical genetic changes [17]. The
prognosis is relatively good, with high 5-year recurrence-free survival (RFS), and 10-year CSS [27].
The new WHO/ISUP grading system merges former entity hybrid oncocytic chromophobe tumour with
chRCC.
[Link] renal tumours
Other renal tumours constitute the remaining renal cortical tumours. These include a variety of
uncommon, sporadic, and familial carcinomas, 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 below.
[Link] medullary carcinoma
Renal medullary carcinoma (RMC) is a very rare tumour, comprising < 0.5% of all RCCs [28],
predominantly diagnosed in young adults (median age 28 years) with sickle haemoglobinopathies
(including sickle cell trait). It is mainly centrally located with ill-defined borders. Renal medullary
carcinoma is one of the most aggressive RCCs [29,30] and most patients (~67%) will present with
metastatic disease [29,31]. Even patients who present with seemingly localised disease may develop
macrometastases shortly thereafter; often within a few weeks.
[Link].Treatment of renal medullary carcinoma
Despite treatment, median OS is 13 months in the most recent series [29]. Due to the infiltrative
nature and medullary epicentre of RMC, radical nephrectomy (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 deferred treatment
seems to be reasonable [29,32]. 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 it will not prevent progression outside the radiation field [33,34]. Renal medullary carcinoma
is refractory to monotherapies with targeted anti-angiogenic regimens including tyrosine kinase
inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors [29,35,36]. The mainstay
systemic treatments for RMC are cytotoxic combination regimens which produce partial or complete
responses in ~29% of patients [35]. There are no prospective comparisons between different
chemotherapy regimens but most published series used various combinations of platinum agents,
taxanes, gemcitabine, and/or anthracyclines [29,30]. High-dose-intensity combination of methotrexate,
vinblastine, doxorubicin, and cisplatin (MVAC) has also shown efficacy against RMC [37] although a
retrospective comparison did not show superiority of MVAC over cisplatin, paclitaxel, and gemcitabine
(CPG) [30]. Single-agent anti-PD-1 (monoclonal antibodies against programmed death-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 [33,34]. Whenever possible, patients
should be enrolled in clinical trials of novel therapeutic approaches, particularly after failing first-line
cytotoxic chemotherapy.
[Link] 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 end-stage renal disease (ESRD). Renal cell carcinomas of native end-stage
kidneys are found in approximately 4% of patients. 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 [38,39]. 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 [39].
Although the histological spectrum of ESRD tumours is similar to that of sporadic RCC, the
predominant form is pRCC. The remaining tumours are mostly ccRCC [38-40]. A specific subtype of
RCC occurring only in end-stage kidneys has been described as Acquired Cystic Disease-associated
RCC (ACD-RCC) [41] with indolent clinical behaviour, likely due to early detection in patients with
ESRD on periodic follow-up [17].
[Link] adenoma
These tumours have a papillary or tubular architecture of low nuclear grade and may be up to 15 mm
in diameter, or smaller [42], according to the WHO 2016 classification [17].
[Link] kidney tumours
Five to eight percent of RCCs are hereditary; to date there are 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 (< 46 years old) of all RCC tumours [43]. Hereditary kidney
tumours are found in the following entities: VHL syndrome, hereditary pRCC, Birt-Hogg-Dubé
syndrome, hereditary leiomyomatosis and RCC (HLRCC), tuberous sclerosis, germline succinate
dehydrogenase (SDH) mutation, non-polyposis colorectal cancer syndrome, hyperparathyroidism-jaw
tumour syndrome, phosphatase and tensin homolog (PTEN) hamartoma syndrome (PHTS),
constitutional chromosome 3 translocation, and familial nonsyndromic ccRCC. Renal medullary
carcinoma can be included because of its association with hereditary haemoglobinopathies
[41,42,44,45].
Patients with hereditary kidney cancer syndromes may require repeated surgical intervention [46,47].
In most hereditary RCCs nephron-sparing approaches are recommended. The exceptions are
HLRCC and SDH syndromes for which immediate surgical intervention is recommended due to the
aggressive nature of these lesions. For other hereditary syndromes such as VHL, surveillance is
recommended until the largest tumour reaches 3 cm in diameter, to reduce interventions [48]. Active
surveillance (AS) for VHL, BDH and HPRCC should, in individual patients, follow the growth kinetics,
size and location of the tumours, rather than apply a standardised follow-up interval. Regular
screening for both renal and extra-renal lesions should follow international guidelines for these
syndromes. Multi-disciplinary and co-ordinated care should be offered, where appropriate [49].
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 [50].
[Link]
Angiomyolipoma (AML) is a benign mesenchymal tumour, which can occur sporadically or as part of
tuberous sclerosis complex [51]. 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 [52]. Angiomyolipoma belongs to a
family of so-called PEComas (perivascular epithelioid cell tumours), characterised by the proliferation
of perivascular epithelioid cells. Some PEComas can behave aggressively and can even produce
distant metastases. Classic AMLs are completely benign [17,42,53]. Ultrasound (US), CT, and
magnetic resonance imaging (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 work-up should be treated according to the recommendations provided for the
treatment of RCC in these Guidelines. 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 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 [42,53]. Epithelioid AMLs are potentially malignant with
a highly variable proportion of cases with aggressive behaviour [54]. Criteria to predict the biological
behaviour in epithelioid AML were proposed by the WHO 2016 [42,53]. Angiomyolipoma, in general,
has a slow and consistent growth rate, and minimal morbidity [5].
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 [5]. The major risk factors
for bleeding are tumour size, grade of the angiogenic component, and the presence of tuberous
sclerosis [55,56].
[Link].Treatment
Active surveillance is the most appropriate option for most AMLs (48%). In a group of patients on AS,
only 11% of AMLs showed growth, spontaneous bleeding was reported in 2%, resulting in active
treatment in 5% of patients [5,57] (LE: 3). The association between AML size and the risk of bleeding
remains unclear and the traditionally used 4-cm cut-off should not per se trigger active treatment [5].
When surgery is indicated, NSS is the preferred option, if technically feasible. 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 is available, and
this option is used less frequently [5].
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.
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 RCTs [58,59].
 [Link] oncocytoma
Oncocytoma is a benign tumour representing 3-7% of all solid renal tumours and its incidence
increases to 18% when tumours < 4 cm are considered [17,57]. The diagnostic accuracy of imaging
modalities (CT, MRI) in renal oncocytoma is limited and histopathology remains the only reliable
diagnostic modality [17,57]. Standard treatment for renal oncocytoma is similar to that of other renal
tumours; surgical excision by partial- or 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. Accuracy of the
biopsy and management of advanced/progressing oncocytomas need to be considered in this context
since oncocytic renal neoplasms diagnosed by RMB at histological examination after surgery showed
oncocytoma in only 64.6% 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) [17], other RCCs (12.5%), and other benign lesions (4.2%) [60]. The majority of
oncocytomas slowly progress in size with an annual growth rate < 14 mm [61-63]. Preliminary data
show that AS may be a safe way to manage oncocytoma in appropriately selected patients.
Table 3.1: Other renal cortical tumours, and recommendations for treatment (strength rating:
weak) [17]
Entity Clinical relevant Malignant Treatment of
notes potential localised
tumour/metastatic
tumour
Sarcomatoid Sign of high-grade High Surgery. Nivolumab
variants of RCC transformation without and ipilimumab.
being a distinct histological Sunitinib, gemcitabine
entity. plus doxorubicin is
also an option [64].
Multilocular cystic Formerly multilocular cystic Benign Surgery, nephron-
renal neoplasm of RCC sparing surgery
low malignant (NSS).
potential
Carcinoma of the Rare, often presenting at High, very Surgery. Response to
collecting ducts of an advanced stage (N+ aggressive. Median targeted therapies is
Bellini 44% and M1, 33% at survival 30 months poor [66].
diagnosis). The hazard [65].
ratio (HR) CSS in
comparison with ccRCC is
4.49 [21].
Renal medullary Very rare. Mainly young High, very Surgery. Different
carcinoma black men with sickle cell aggressive, median chemotherapy
trait. survival is five regimens,
months [65]. radiosensitive.
Translocation RCC Rare, mainly younger High Surgery. Vascular
(TRCC) Xp11.2 patients < 40, more endothelial growth
common in females. Less factor (VEGF)-
commonly, TFEB located targeted therapy.
on the short arm of
Translocation RCC Low/intermediate Surgery, NSS. VEGF-
chromosome 6 (6p21) [67].
t(6;11) targeted therapy.
Mucinous tubular Tumour is associated with Intermediate Surgery, NSS.
and spindle cell the loop of Henle.
carcinoma
Acquired cystic Low Surgery.
disease-associated
RCC
Clear-cell papillary Also reported as renal Low Surgery, NSS.
RCC angiomyomatous tumour
(RAT).
Hereditary Rare, new entity in the High Surgery.
leiomyomatosis and 2016 WHO classification, No data about
RCC-associated caused by a germline treatment of
RCC mutation of the fumarate metastatic disease.
hydratase gene [17].
Tubulocystic RCC Mainly men, imaging can Low (90% indolent) Surgery, NSS.
be Bosniak III or IV.
Succinate Rare. Variable Surgery.
dehydrogenase-
deficient RCC
Metanephric Divided into metanephric Benign Surgery, NSS.
tumours adenoma, adenofibroma,
and metanephric stromal
tumours.
Cystic Term renal epithelial and Low/benign Surgery, NSS.
nephroma/Mixed stromal tumours (REST) is
epithelial and used as well. Imaging –
stromal tumour Bosniak type III or II/IV.
Oncocytoma 3-7% of all renal tumours. Benign Observation (when
Imaging characteristics histologically
alone are unreliable when confirmed) [62,63,70].
differentiating between NSS.
oncocytoma and RCC.
Histopathological diagnosis
remains the reference
standard [68,69].
Renal cysts Simple cysts are frequently Malignant or benign Treatment or follow-
occurring, while occurring up Recommendation
septa, calcifications and based on Bosniak
solid components require classification.
follow-up and/or See table 5.1
management.
[Link] 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 [71]. Bosniak IV cysts are mostly
malignant tumours with pseudocystic changes only. Bosniak IIF and III cysts remain challenging for
clinicians. The differentiation of benign and malignant tumour in categories IIF/III is based on imaging,
mostly CT, with an increasing role of MRI and contrast enhanced ultrasound (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) [72]. 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
a 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%
showing malignancy, which is comparable to the malignancy rates of Bosniak IV cysts [71]. The
updated Bosniak classification strengthens the classification and includes MRI diagnostic criteria [73].
The most common histological type for Bosniak III cysts is ccRCC with pseudocystic changes and low
malignant potential [74,75]; multilocular cystic renal neoplasm of low malignant potential
([MCRNLMP], formerly mcRCC (see Section 3.2 and Table 3.1); pRCC type I (very low malignant
potential); benign multilocular cyst; benign group of renal epithelial and stromal tumours (REST); 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 may also be an alternative to surgical treatment [71,73,76,77].
[Link] of evidence and recommendations for the
management of other renal tumours

Summary of evidence LE
A variety of renal tumours exist of which approximately 15% are benign. 1b
Recent histological work up of Bosniak III cysts shows low risk of malignant potential. 2
[Link] for the management of other renal tumours

Recommendations Strength
rating
Treat Bosniak type III cysts the same as RCC or offer active surveillance. Weak
Treat Bosniak type IV cysts the same as RCC. Strong
Treat angiomyolipoma (AML) with selective arterial embolisation or nephron- Weak
sparing surgery, in:
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 to patients at need for therapy with surgically Weak
unresectable AMLs not amendable to embolisation or surgery.
Prior to management, perform pre-operative renal mass biopsies in patients with Weak
unclear kidney lesions.
Offer active surveillance to patients with biopsy-proven oncocytomas, as an Weak
acceptable alternative to surgery or ablation.
Only offer radical nephrectomy to patients with localised renal medullary Weak
carcinoma after a favourable response to systemic therapy.
Base systemic therapy for renal medullary carcinoma on chemotherapy Weak
regiments containing cisplatinum such as cisplatin plus gemcitabine.
 [Link] AND CLASSIFICATION
SYSTEMS
[Link]
The Tumour Node Metastasis (TNM) classification system is recommended for clinical and scientific
use [78], but requires continuous re-assessment [17,79]. A supplement was published in 2012, and
the latter’s prognostic value was confirmed in single and multi-institution studies [80,81]. Tumour size,
venous invasion, renal capsular invasion, adrenal involvement, and LN and distant metastasis are
included in the TNM classification system (Table 4.1). However, some uncertainties remain:
 The sub-classification of T1 tumours using a cut-off of 4 cm might not be optimal in NSS for
localised cancer.
 The value of size stratification of T2 tumours has been questioned [82].
 Renal sinus fat invasion might carry a worse prognosis than perinephric fat invasion, but, is
nevertheless included in the same pT3a stage group [83-85] (LE: 3).
 Sub T-stages (pT2b, pT3a, pT3c and pT4) may overlap [81].
 For adequate M staging, accurate pre-operative imaging (chest and abdominal CT) should be
performed [86,87] (LE: 4).
Table 4.1: 2017 TNM classification system [78]
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 grossly extends into the renal vein or its segmental (muscle-containing)
branches, or tumour invades perirenal and/or renal sinus fat (peripelvic 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]
[Link] classification systems
Objective anatomic classification systems, such as the Preoperative Aspects and Dimensions Used
for an Anatomical (PADUA) classification system, the R.E.N.A.L. nephrometry score, the C-index, an
Arterial Based Complexity (ABC) Scoring System and Zonal NePhRO scoring system, have been
proposed to standardise the description of renal tumours [88-90]. 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.
The use of such a system is helpful as it allows objective prediction of potential morbidity
of NSS and tumour ablation techniques. These tools provide information for treatment planning,
patient counselling, and comparison of PN and tumour ablation series. However, when selecting the
most optimal treatment option, anatomic scores must be considered together with patient features and
surgeon experience.

[Link] EVALUATION
[Link]
Many renal masses remain asymptomatic until the late disease stages. More than 50% of RCCs are
detected incidentally by non-invasive imaging investigating various non-specific symptoms and other
abdominal diseases [81,91] (LE: 3). The classic triad of flank pain, visible haematuria, and palpable
abdominal mass is rare (6-10%) and correlates with aggressive histology and advanced disease
[36,92] (LE: 3). Paraneoplastic syndromes are found in approximately 30% of patients with
symptomatic RCCs [93] (LE: 4). Some symptomatic patients present with symptoms caused by
metastatic disease, such as bone pain or persistent cough [94] (LE: 3).
[Link] 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.
[Link] findings
Commonly assessed laboratory parameters are serum creatinine, glomerular filtration rate (GFR),
complete cell blood count, erythrocyte sedimentation rate, liver function study, alkaline phosphatase,
lactate dehydrogenase (LDH), serum corrected calcium [95], 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 in order to exclude urothelial cancer (LE: 4).
Split renal function should be estimated using renal scintigraphy in the following
situations [96,97] (LE: 2b):
 when renal function is compromised, as indicated by increased serum creatinine or
significantly decreased 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.
[Link] investigations
Most renal tumours are diagnosed by abdominal US or CT performed for other medical reasons [91]
(LE: 3). Renal masses are classified as solid or cystic based on imaging findings.
[Link] of enhancement
With solid renal masses, the most important criterion for differentiating malignant lesions is the
presence of enhancement [98] (LE: 3). Traditionally, US, CT and MRI are used for detecting and
characterising renal masses. Most renal masses are diagnosed accurately by imaging alone.
Contrast-enhanced US can be helpful in specific cases [99-101] (LE: 3).
[Link] tomography or magnetic resonance imaging
Computed tomography or MRI are used to characterise renal masses. Imaging must be performed
before, and after, administration of intravenous contrast material to demonstrate enhancement. In CT
imaging, enhancement in renal masses is determined by comparing Hounsfield units (HUs) before,
and after, contrast administration. A change of fifteen, or more, HUs demonstrates enhancement [102]
(LE: 3). Computed tomography or MRI allows accurate diagnosis of RCC, but cannot reliably
distinguish oncocytoma and fat-free AML from malignant renal neoplasms [68,103-105] (LE: 3).
Abdominal CT provides information on [106]:
 function and morphology of the contralateral kidney [107] (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 angiography is useful in selected cases when detailed information
on the renal vascular supply is needed [108,109]. If the results of CT are indeterminate, CEUS is a
valuable alternative to further characterise renal lesions [6] (LE: 1b).
Magnetic resonance imaging may provide additional information on venous involvement if the extent
of an inferior vena cava (IVC) tumour thrombus is poorly defined on CT [110-113] (LE: 3).
Magnetic resonance imaging is indicated in patients who are allergic to intravenous CT
contrast medium and in pregnancy without renal failure [111,114] (LE: 3). Advanced MRI techniques
such as diffusion-weighted and perfusion-weighted imaging are being explored for renal mass
assessment [115].
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); MRI had 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) [72].
In younger patients who are worried about the radiation exposure of frequent CT scans,
MRI may be offered as alternative although only limited data exist correlating diagnostic radiation
exposure to the development of secondary cancers [116].
[Link] investigations
Renal arteriography and inferior venacavography have a limited role in the work-up 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 [96,97] (LE: 2a).
Positron-emission tomography (PET) is not recommended [6,117] (LE: 1b).
[Link] investigations to evaluate RCC metastases
Chest CT is accurate for chest staging [86,87,118-120] (LE: 3). There is a consensus that most bone
metastases are symptomatic at diagnosis; thus, routine bone imaging is not generally indicated
[118,121,122] (LE: 3). However, bone scan, brain CT, or MRI may be used in the presence of specific
clinical or laboratory signs and symptoms [121,123,124] (LE: 3).
[Link] classification of renal cystic masses
This system classifies renal cysts into five categories, based on CT imaging appearance, to predict
malignancy risk [125,126] (LE: 3), and also advocates treatment for each category (Table 5.1). A new
updated Bosniak classification has been proposed that strengthens the classification and includes
MRI diagnostic criteria [73].
Table 5.1: Bosniak classification of renal cysts [125]
Bosniak Features Work-up
category
I Simple benign cyst with a hairline-thin wall without septa, Benign
calcification, or solid components. Same density as water and
does not enhance with contrast medium.
II Benign cyst that may contain a few hairline-thin septa. Fine Benign
calcification may be present in the wall or septa. Uniformly
high-attenuation lesions < 3 cm in size, with sharp margins
without enhancement.
IIF These may contain more hairline-thin septa. Minimal Follow-up, up to
enhancement of a hairline-thin septum or wall. Minimal five years. Some
thickening of the septa or wall. The cyst may contain are malignant.
calcification, which may be nodular and thick, with no contrast
enhancement. No enhancing soft-tissue elements. This
category also includes totally intra-renal, non-enhancing, high
attenuation renal lesions ≥ 3 cm. Generally well-marginated.
III These are indeterminate cystic masses with thickened Surgery or active
irregular walls or septa with enhancement. surveillance – see
Chapter 7. Over
50% are malignant.
IV Clearly malignant containing enhancing soft-tissue Surgery. Most are
components. malignant.
[Link] tumour biopsy
Percutaneous renal tumour 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 [127-132] (LE: 3).
Renal biopsy is not indicated for comorbid and frail patients who can be considered only for
conservative management (watchful waiting) regardless of biopsy results. Due to the high diagnostic
accuracy of abdominal imaging, renal tumour biopsy is not necessary in patients with a contrast-
enhancing renal mass for whom surgery is planned (LE: 4). A multicentre study assessing 542
surgically removed small renal masses 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 [133].
 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 [130,134] (LE: 2b). Eighteen-gauge needles are ideal for core biopsies, as
they result in low morbidity and provide sufficient tissue for diagnosis [127,131,135] (LE: 2b). A
coaxial technique allowing multiple biopsies through a coaxial cannula should always be used to avoid
potential tumour seeding [127,131] (LE: 3).
Core biopsies are preferred for the characterisation of solid renal masses while a
combination with FNA can improve accuracy [136-138] (LE: 2a). An SR and meta-analysis of the
diagnostic performance and complications of renal tumour biopsy was performed by the Panel. Fifty-
seven articles with a total of 5,228 patients were included in the analysis. Needle core biopsies were
found to have better accuracy for the diagnosis of malignancy compared with FNA [138]. Other
studies showed that solid pattern, larger tumour size and exophytic location are predictors of a
diagnostic core biopsy [127,130,134] (LE: 2b).
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 [138] (LE: 2b). However, 0-22.6% of core biopsies are non-diagnostic (8% in the
meta-analysis) [128-132,134,135,139] (LE: 2a). If a biopsy is non-diagnostic, 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%)
[127,140-142].
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 the surgical
specimen of the following PN or RN was 90.3% in the pooled analysis [138].
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) [138] (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 [127,130,143,144] (LE: 2b). Peripheral biopsies are preferable for larger tumours, to avoid areas
of central necrosis [145] (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
[146].
Core biopsies of cystic renal masses have a lower diagnostic yield and accuracy and
are not recommended alone, unless areas with a solid pattern are present (Bosniak IV cysts)
[127,130,138] (LE: 2b).
Combined FNA and core biopsies can provide complementary results, especially for
complex cystic lesions [131,139,140,147,148] (LE: 3).
Overall, percutaneous biopsies have a low morbidity [138]. Tumour seeding along the
needle tract has been regarded as anecdotal in large series and pooled analyses on renal tumour
biopsies. Especially the coaxial technique has been regarded as a safe method to avoid any seeding
of tumour cells. However, authors recently reported on 7 patients in whom tumour seeding was
identified on histological examination of the resection specimen after surgical resection of RCC
following diagnostic percutaneous biopsy [149]. Six of the 7 cases were of the pRCC type. The clinical
significance of these findings is still uncertain but only one of these patients developed local tumour
recurrence at the site of the previous biopsy [149].
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 [138].
 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 [150].
[Link] of evidence and recommendations for the diagnostic
assessment of RCC

Summary of evidence LE
Contrast enhanced multi-phasic CT has a high sensitivity and specificity for 2
characterisation and detection of RCC, invasion, tumour thrombus and mRCC.
Magnetic resonance imaging has a slightly higher sensitivity and specificity for small 2
cystic renal masses and tumour thrombi as compared to CT.
Contrast enhanced ultrasound has a high sensitivity and specificity for characterisation of 2
renal masses.
Ultrasound, power-Doppler US and positron-emission tomography CT have a low 2
sensitivity and specificity for detection and characterisation of RCC.
Recommendations Strength
rating
Use multi-phasic contrast-enhanced computed tomography (CT) of abdomen Strong
and chest for the diagnosis and staging of renal tumours.
Use magnetic resonance imaging to better evaluate venous involvement, reduce Weak
radiation or avoid intravenous CT contrast medium.
Use non-ionising modalities, mainly contrast-enhanced ultrasound, for further Strong
characterisation of small renal masses, tumour thrombus and differentiation of
unclear renal masses.
Do not routinely use bone scan and/or positron-emission tomography CT for Weak
staging of renal cell carcinoma.
Perform a renal tumour biopsy before ablative therapy and systemic therapy Strong
without previous pathology.
Perform a percutaneous biopsy in select patients who are considering active Weak
surveillance.
Use a coaxial technique when performing a renal tumour biopsy. Strong
Do not perform a renal tumour biopsy of cystic renal masses. Strong
Use a core biopsy technique rather than fine needle aspiration for histological Strong
characterisation of solid renal tumours.

[Link] FACTORS
[Link]
Prognostic factors can be classified into: anatomical, histological, clinical, and molecular.
[Link] factors
Tumour size, venous invasion, renal capsular invasion, adrenal involvement, and LN and distant
metastasis are included in the TNM classification system [151] (Table 4.1).
 [Link] factors
Histological factors include tumour grade, RCC subtype, sarcomatoid features, microvascular
invasion, tumour necrosis, and invasion of the collecting system [152,153]. Fuhrman nuclear grade is
the most widely accepted grading system [154]. Although affected by intra- and inter-observer
variability, Fuhrman nuclear grade is an independent prognostic factor [155]. A simplified two- or
three-strata system may be as accurate for prognostication as the classical four-tiered grading
scheme [156,157] (LE: 3). The new WHO/ISUP grading system that will replace the Fuhrman grading,
needs to be validated for prognostic systems and nomograms [158].
In a univariate analysis, patients with chRCC vs. pRCC vs. ccRCC had a better prognosis [159,160].
However, prognostic information provided by the RCC type is lost when stratified to tumour stage
[20,160] (LE: 3). In a cohort study of 1,943 patients with ccRCC and pRCC significant survival
differences were shown, whereas pRCC type I displayed a significantly reduced risk of death
compared with ccRCC and pRCC type II [161]. Differences in tumour stage, grade and CSS between
the RCC types are illustrated in Table 6.1.
Table 6.1: Basic characteristics of three main types of RCC [20,21,162]
Type Percentage Advanced disease Fuhrman CSS (HR)
of RCC (~) at diagnosis (T3-4, grade 3 or
N+, M+) 4 [163]
clear-cell RCC 80-90% 28% 28.5% Referent
papillary RCC 6-15% 17.6% 28.8% 0.64-0.85
chromophobe RCC 2-5% 16.9% 32.7%* 0.24-0.56
* The Fuhrman grading system is validated for ccRCC, but is unreliable for chRCC.
CSS = cancer-specific survival; HR = hazard ratio.
In all RCC types, prognosis worsens with stage and histopathological grade (Tables 6.2 and 6.3). The
5-year overall survival (OS) for all types of RCC is 49%, which has improved since 2006 probably due
to an increase in incidentally detected RCCs and the introduction of TKIs [164,165]. Sarcomatoid
changes can be found in all RCC types and are equivalent to high grade and very aggressive
tumours.
Table 6.2: Cancer-specific survival by stage and histopathological grade in RCCs [21]
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)
Grade 1 Referent
Grade 2 1.16 (0.94-1.42)
Grade 3 1.97 (1.60-2.43)
Grade 4 2.82 (2.08-3.31)
CI = confidential interval. HR = hazard ratio.
Long-term survival in RCC patients treated by RN or PN between 1970 and 2003; for unilateral,
sporadic ccRCC, pRCC or chRCC in a cohort study [162] (Table 6.3).
Table 6.3: Cancer-specific survival of surgically treated patients by RCC type (estimated
survival rate in percentage [95% CI])
Survival time 5 years (%) 10 years (%) 15 years (%) 20 years (%)
clear-cell RCC 71 (69-73) 62 (60-64) 56 (53-58) 52 (49-55)
papillary RCC 91 (88-94) 86 (82-89) 85 (81-89) 83 (78-88)
chromophobe 88 (83-94) 86 (80-92) 84 (77-91) 81 (72-90)
RCC
Two subgroups of pRCC with different outcomes have been identified [166]. Type I have a favourable
prognosis. Type II are mostly high-grade tumours with a propensity for metastases (LE: 3). For more
details, see Section 3.2 - Histological diagnosis. Renal cell carcinoma with Xp 11.2 translocation has a
poor prognosis [167]. Its incidence is low, but it should be systematically addressed in young patients.
Renal cell carcinoma type classification has been confirmed by cytogenetic and genetic analyses
[163,168,169] (LE: 2b).
[Link] factors
Clinical factors include performance status (PS), local symptoms, cachexia, anaemia, platelet
count, neutrophil-to-lymphocyte ratio, C-reactive protein (CRP) and albumin [94,170-174] (LE: 3).
Even though obesity is an aetiological factor for RCC, obesity has also been observed to provide
prognostic information. In a Korean cohort study, obesity appeared to be a favourable prognostic
factor in male, but not in female, patients with non-metastatic RCC [175].
[Link] factors
Numerous molecular markers such as carbonic anhydrase IX (CaIX), VEGF, hypoxia-inducible factor
(HIF), Ki67 (proliferation), p53, p21 [176], PTEN (phosphatase and tensin homolog) cell cycle, E-
cadherin, osteopontin [177] CD44 (cell adhesion) [178,179], CXCR4 [180], and other cell cycle and
proliferative markers are being investigated [181,182] (LE: 3). As yet, none of these markers have
been shown to improve the predictive accuracy of current prognostic systems and, so far, none have
been externally validated. Their routine use in clinical practice is, at present, not recommended. In a
pre-diagnostic study, elevated plasma Kidney Injury molecule-1 (KIM-1) concentrations were found to
predict RCC up to 5 years prior to diagnosis and were associated with a shorter survival time [183].
KIM-1 is a protein which is expressed at low levels in a healthy kidney.
Several retrospective studies and large molecular screening programs have identified mutated genes
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 [184-186]. These published reports suggest that
patients with BAP1-mutant tumours have worse outcomes compared with patients with PBRM1-
mutant tumours [185]. Validated data from surgical series can predict relapse using a 16-gene
signature. This signature is likely to be adopted in clinical trials and may be helpful in the clinical
setting in due time [187].
The recognition of the potential relevance of immunotherapy as an approach to RCC management is
growing. Prognostic information of cytokines and blockade of immune-inhibitory molecules such as
PD-L1 have shown promising therapeutic results. A meta-analysis established a correlation between
PD-L1 expression, poor prognosis and advanced clinicopathological features of RCC [188]. Emerging
evidence of chromosomal alterations, through Genome-Wide Association Studies (GWAS), miRNA,
SNPs and gene methylations all contribute to improving diagnostic and prognostic information. A
number of studies have confirmed prognostic information based on gain of chromosomal regions 7q,
8q and 20q, and chromosomal losses of regions 9p, 9q and 14q, which are associated with poor
survival. CpG-methylation-based assays also independently predict survival in ccRCC [189,190]. An
international collaboration is currently investigating GWAS loci for prognostic information.
[Link] systems and nomograms
Post-operative prognostic systems and nomograms combining independent prognostic factors have
been developed and externally validated [191-197]. These may be more accurate than TNM stage or
Fuhrman grade alone for predicting survival (LE: 3). An advantage of nomograms is their ability to
measure predictive accuracy, allowing all new predictive parameters to be objectively evaluated.
Before being adopted, new prognostic variables or systems should demonstrate that its predictive
accuracy is superior to conventional post-operative prognostic schemes [198]. Recently, new pre-
operative nomograms with excellent predictive accuracy have been designed [199,200].
Table 6.4 summarises the current most relevant prognostic systems.

[Link] of evidence and recommendations for prognostic

factors

Summary of evidence LE
In RCC patients, TNM stage, tumour nuclear grade, and RCC subtype provide important 2
prognostic information [201].
Recommendations Strength
rating
Use the current Tumour, Node, Metastasis classification system. Strong
Use grading systems and classify renal cell carcinoma type. Strong
Use prognostic systems in the metastatic setting. Strong
In localised disease, use integrated prognostic systems or nomograms to assess Strong
risk of recurrence.

[Link] MANAGEMENT
[Link] of localised RCC
[Link]
Sections 7.1.2 and [Link] are underpinned by a SR which 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 (NRS),
prospective observational studies with controls, retrospective matched-pair studies, and comparative
studies from the databases of well-defined registries were also included. Historically, surgery has
been the benchmark for the treatment of localised RCC.
[Link] treatment
[Link].Nephron-sparing surgery versus radical nephrectomy
Most studies comparing the oncological outcomes of PN and RN are retrospective and include
cohorts of varied and, overall, limited size [206]. There is only one prospective RCT including patients
with organ-confined RCCs of limited size (< 5 cm), showing comparable CSS for PN vs. RN [207].
Partial nephrectomy demonstrated to preserve kidney function better after surgery, thereby potentially
lowering the risk of development of cardiovascular disorders [206,208-212].
When compared with a radical surgical approach, several retrospective analyses of large databases
have suggested a decreased cardiovascular-specific mortality [209,213] as well as improved OS for
PN compared to RN. However, in some series this held true only for a younger patient population
and/or patients without significant comorbidity at the time of the surgical intervention [214,215].
A Cochrane review found that PN for clinically localised RCC was associated with a
reduced time-to-death of any cause compared to RN, whereas serious adverse event rates, CSS and
time-to-recurrence were similar between the two groups [216].
An analysis of the Medicare database [217] could not demonstrate an OS benefit for
patients ≥ 75 years of age when RN or PN were compared with non-surgical management. Another
series that addressed this question and also included Medicare patients suggested an OS benefit in
an older RCC patient population (75-80 years) when subjected to surgery rather than non-surgical
management. Shuch et al. compared patients who underwent PN for RCC with a non-cancer healthy
control group via a retrospective database analysis; showing an OS benefit for the cancer cohort
[218]. These conflicting results may be an indication that unknown statistical confounders hamper the
retrospective analysis of population-based tumour registries.
In contrast, the only prospectively randomised, but prematurely closed and heavily
underpowered, trial did not demonstrate an inferiority of RN vs. PN in terms of OS [207]. Taken
together, the OS advantage suggested for PN vs. RN remains an unresolved issue.
Patients with a normal pre-operative renal function and a decreased GFR due to surgical treatment
(either RN or PN), generally present with stable long-term renal function [212]. Adverse OS in patients
with a pre-existing GFR reduction does not seem to result from further renal function impairment
following surgery, but rather from other medical comorbidities causing pre-surgical chronic kidney
disease (CKD) [219]. 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.
Only a limited number of studies are available addressing quality of life (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 in general patients’ health status deteriorated following
both approaches [220,221].
In terms of the intra- and peri-operative morbidity/complications associated with PN vs. RN, an
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 [221].
In view of the above, and since oncological safety (CSS and RFS) of PN has been proven to be
similar for RN, PN is the treatment of choice for T1 RCC since it preserves kidney function better and
in the long term potentially limits the incidence of cardiovascular disorders. Whether decreased
mortality from any cause can be attributed to PN is still unresolved, but in patients with pre-existing
CKD, PN is the preferred surgical treatment option as it avoids further deterioration of kidney function;
the latter being associated with a higher risk of development of ESRD and the need for
haemodialysis.
A study compared the survival outcomes in patients with larger (≥ 7 cm) ccRCC treated with PN vs.
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) [222]. A SR and meta-analysis
of comparative studies of PN vs. RN for cT1b and T2 RCCs observed that the PN group had a lower
likelihood of tumour recurrence (OR 0.6, p < 0.001), cancer-specific mortality (OR 0.58, p = 0.001),
and all-cause mortality (OR 0.67, p = 0.005) compared to the RN group. For T2 tumours the
estimated blood loss was higher for PN (p < 0.001), as was the likelihood of complications (RR: 2.0, p
< 0.001). Both the recurrence rate (RR: 0.61, p = 0.004) and cancer-specific mortality (RR: 0.65, p =
0.03) were lower for PN [223].
[Link].Associated procedures
[Link].[Link]
One prospective NRS compared the outcomes of RN with or without, ipsilateral adrenalectomy [224].
Multivariate analysis showed that upper pole location was not predictive of adrenal involvement, but
tumour size was. No difference in OS at 5 or 10 years was seen with, or without, adrenalectomy.
Adrenalectomy was justified using criteria based on radiographic- and intra-operative findings. Only
48 of 2,065 patients underwent concurrent ipsilateral adrenalectomy of which 42 interventions were
for benign lesions [224].
[Link].[Link] node dissection for clinically negative lymph nodes (cN0)
The indication for LN dissection (LND) together with PN or RN is still controversial [225]. 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. Less than 20% of suspected metastatic nodes (cN+) are
positive for metastatic disease at histopathological examination (pN+) [226]. Both CT and MRI are
unsuitable for detecting malignant disease in nodes of normal shape and size [227]. For clinically
positive LNs (cN+) see Section 7.2.2.
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-metastatic RCC were
compared using a propensity score analysis. In this study LND was not significantly associated with a
reduced risk of distant metastases, or cancer-specific or all-cause mortality. Neither eLND nor the
extent of LND was associated with improved oncologic outcomes [228]. The number of LN
metastases (< / > 4) as well as the intra- and extracapsular extension of intra-nodal metastasis
correlated with the patients´ clinical prognosis in some studies [227,229-231]. Better survival
outcomes were seen in patients with a low number of positive LNs (< 4) and no extranodal extension.
On the basis of a retrospective Surveillance, Epidemiology and End Results (SEER) database
analysis of > 9,000 patients no effects of an extended LND on the disease-specific survival (DSS) of
patients with pathologically confined negative nodes was demonstrated [232]. 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, in a larger cohort of 1,983 patients,
Capitanio et al. demonstrated that extended LND results in a significant prolongation of CSS in
patients with unfavourable prognostic features (e.g., sarcomatoid differentiation, large tumour size)
[233]. As to morbidity related to eLND, a recent 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. Furthermore, LND was not associated with length of hospital stay or estimated blood
loss [234].
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 only 4%, the risk of lymphatic spread
appears to be very low. Recognising the latter, only a staging effect was attributed to LND [226]. This
trial included a very high percentage of patients with pT2 tumours, which are not at increased risk for
LN metastases. Additionally, only 25% of patients with pT3 tumours underwent a complete LND. The
LN template used by the authors was also not clearly stated.
The optimal extent of LND remains controversial. Retrospective studies suggest that an
extended LND 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 [227,235,236]. At least 15 LNs
should be removed [233,237]. Sentinel LND is an investigational technique [238,239].
[Link].[Link]
Before routine nephrectomy, tumour embolisation has no benefit [240,241]. In patients unfit for
surgery, or with non-resectable disease, embolisation can control symptoms, including visible
haematuria or flank pain [242,243]. These indications will be revisited in Sections 7.2 and 7.3 with
cross reference to the summary of evidence and recommendations below.
[Link].[Link] 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 1b
c/p T1 RCC.
Ipsilateral adrenalectomy during RN or PN has no survival advantage in the absence of 3
clinically evident adrenal involvement.
In patients with localised disease without evidence of LN metastases, a survival 2b
advantage of LND in conjunction with RN is not demonstrated in randomised trials.
Retrospective studies suggest a clinical benefit associated with lymphadenectomy in 2b
high-risk patients.
In patients unfit for surgery with massive haematuria or flank pain, embolisation can be a 3
beneficial palliative approach.
Recommendations Strength
rating
Offer surgery to achieve cure in localised renal cell cancer. Strong
Offer partial nephrectomy to patients with T1 tumours. Strong
Do not perform ipsilateral adrenalectomy if there is no clinical evidence of Strong
invasion of the adrenal gland.
Offer an extended lymph node dissection to patients with adverse clinical Weak
features, including a large diameter of the primary tumour.
Offer embolisation to patients unfit for surgery presenting with massive Weak
haematuria or flank pain.
[Link] and partial nephrectomy techniques
[Link].Radical nephrectomy techniques
No RCTs have assessed the oncological outcomes of laparoscopic vs. open RN. A cohort study [244]
and retrospective database reviews are available, mostly of low methodological quality, showing
similar oncological outcomes even for higher stage disease and locally more advanced tumours [245-
247]. Based on a SR, less morbidity was found for laparoscopic vs. open RN [206].
Data from one RCT [246] and two NRSs [248,249] 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 [249]. No difference in the number of
patients receiving blood transfusions was observed, but peri-operative blood loss was significantly
less in the laparoscopic arm in all 3 studies [246,248,249]. 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. Post-operative QoL scores were similar [248].
Some comparative studies focused on the peri-operative outcomes of laparoscopic vs.
RN for renal tumours ≥ T2. Overall, patients who underwent laparoscopic RN were shown to have
lower estimated blood loss, less post-operative pain, shorter length of hospital stay and
convalescence compared to those who underwent open RN [247,249,250]. Intra-operative and post-
operative complications were similar in the two groups and no significant differences in CSS, PFS and
OS were reported [247,249,250] (LE: 2b). Another multi-centre propensity matched analysis
compared laparoscopic- and open surgery for pT3a RCC, showing no significant difference in 3-year
RFS between groups [251]. The best approach for RN was the retroperitoneal or transperitoneal
approach with similar oncological outcomes in two RTCs [251,252] and one quasi-randomised study
[253]. Quality of life variables were similar for both approaches.
Hand-assisted vs. standard laparoscopic RN was compared in one quasi-randomised
study [253] and one database review and estimated 5-year OS, CSS, and RFS rates were
comparable [254]. Duration of surgery was significantly shorter in the hand-assisted approach, while
length of hospital stay and time to non-strenuous activities were shorter for the standard laparoscopic
RN cohort [253,254]. However, the sample size was small.
A SR reported on robot-assisted laparoscopic vs. conventional laparoscopic RN,
showing no substantial differences in local recurrence rates, nor in all-cause cancer-specific mortality
[255]. Similar results were seen in observational cohort studies comparing ‘portless’ and 3-port
laparoscopic RN, with similar peri-operative outcomes [256,257].
[Link].Partial nephrectomy techniques
Studies comparing laparoscopic and open PN found no difference in PFS [258-261] and OS [260,261]
in centres with laparoscopic expertise. However, the oncological safety of laparoscopic vs. open PN
has, so far, only been addressed in studies with relatively limited follow-up. Gill et al. suggested
comparable oncological efficacy even in case of higher stage tumours (pT1b/pT3a). However, the
higher number of patients treated with open surgery in this series might reflect a selection bias by
offering laparoscopic surgery in case of a less complex anatomy [262]. The mean estimated blood
loss was found to be lower with the laparoscopic approach [258,260,263], while post-operative
mortality, deep vein thrombosis, and pulmonary embolism events were similar [258,260]. Operative
time is generally longer with the laparoscopic approach [259-261] and warm ischaemia time is shorter
with the open approach [258,260,263,264]. In a matched-pair comparison, GFR decline was greater
in the laparoscopic PN group in the immediate post-operative period [261], but not after follow-up of
3.6 years. In another comparative study, the surgical approach was not an independent predictor for
post-operative CKD [264]. Retroperitoneal and transperitoneal laparoscopic PN have similar peri-
operative outcomes [265]. Simple tumour enucleation also had similar PFS and CSS rates compared
to standard PN and RN in a large study [266].
Hand-assisted laparoscopic PN (HALPN) is rarely performed. A recent comparative study of open vs.
HALPN showed no difference in OS or RFS at intermediate-term follow-up. The authors observed a
lower rate of intra-operative and all-grade post-operative 30-day complications in HALPN than in open
PN patients, but there was no significant difference in high Clavien grade complications. Three
months after the operation, glomerular filtration rate was lower in the HALPN than in the open PN
group [267].
The feasibility of laparo-endoscopic single-site PN has been shown in selected patients
but larger studies are needed to confirm its safety and clinical role [268].
In a retrospective propensity-score-matched study, comparing open-, laparoscopic- and robot-
assisted PN, with 5 years of median follow-up, similar rates of local recurrence, distant metastasis and
cancer-related death rates were found [269].
One study prospectively compared the peri-operative 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 estimated blood loss and shorter hospital stay. Warm ischaemia time,
operative time, immediate- early- and short-term complications, variation in creatinine levels and
pathologic margins were similar among the groups [270]. Another study included the 50 last patients
having undergone laparoscopic and robotic PN for T1-T2 renal tumours by two different surgeons with
an experience of over 200 procedures each in laparoscopic and robotic PN and robotic-assisted
partial nephrectomy (RAPN), respectively, at the beginning of the study. Peri-operative and short-term
oncological and functional outcomes appeared broadly comparable between RAPN and LPN when
performed by highly experienced surgeons [271].
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 robotic-assisted PN group with less overall complications, less major
complications, less transfusions and a much shorter hospital stay [272].
A meta-analysis, including a series of NSS with variable methodological quality compared the peri-
operative 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 difference
was observed between the two groups regarding complications, change of serum creatinine after
surgery, operative time, estimated blood loss and positive surgical margins [273].
In a recent analysis of 8,753 patients who underwent PN, an inverse non-linear
relationship of hospital volume with morbidity of PN was observed, with a plateauing seen at 35 to 40
cases per year overall, and 18 to 20 cases for the robotic approach [274]. A retrospective study of a
U.S. National Cancer Database looked at the prognostic impact of hospital volume and the outcomes
of robot-assisted PN, including 18,724 cases. This study shows that undergoing RAPN at higher-
volume hospitals may have better peri-operative outcomes (conversion to open and length of hospital
stay) and lower positive surgical margin rates [275]. A French study, including 1,222 RAPN, has
shown that hospital volume is the main predictive factor of Trifecta achievement after adjustment for
other variables, including surgeon volume [276].
[Link].Positive margins on histopathological specimens of resected
tumours
A positive surgical margin is encountered in about 2-8% of PNs [273]. Studies comparing surgical
margins with different surgical approaches (open, laparoscopic, robotic) are inconclusive [277,278].
Most trials showed that intra-operative frozen section analysis had no influence on the risk of definite
positive surgical margins [279]. A positive surgical margin 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) [280-283]. The potential negative impact of a positive
margin status on the oncologic outcome is still controversial [277]. The majority of retrospective
analyses reported so far indicated that positive surgical margins do not translate into a higher risk of
metastases or a decreased CSS [281,282]. On the other hand, another retrospective study of a large
single institutional series showed that positive surgical margins are an independent predictor of PFS
due to a higher incidence of distant and local relapses [284].
However, only a proportion of patients with an uncertain margin status actually harbour residual
malignancy [285]. Local tumour bed recurrences were found in 16% in patients with positive surgical
margins compared with 3% in those with negative margins [280], Therefore, RN or re-resection of
margins can result in overtreatment in many cases. Patients with positive surgical margins 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 [281,286]. On the other hand, protection from recurrence
is not ensured by negative surgical margins [287].
[Link].Summary of evidence and recommendations for radical and partial
nephrectomy techniques

Summary of evidence LE
Laparoscopic radical nephrectomy (RN) has lower morbidity than open nephrectomy. 1b
Short-term oncological outcomes for T1-T2a tumours are equivalent for laparoscopic and 2a
open RN.
Partial nephrectomy can be performed, either by open-, pure laparoscopic- or robot- 2b
assisted approach, based on surgeon’s expertise and skills.
Partial nephrectomy is associated with a higher percentage of positive surgical margins 3
compared to RN.
Recommendations Strength
rating
Offer laparoscopic 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 Strong
PN is feasible by any approach, including open.
Do not perform minimally invasive surgery if this approach may compromise Strong
oncological-, functional- and peri-operative outcomes.
[Link] approaches as alternatives to surgery
[Link].Surgical versus non-surgical treatment
Population-based studies compared the oncological outcomes of surgery (RN or PN) and non-surgical
management for tumours < 4 cm. The analyses showed a significantly lower cancer-specific mortality
in patients treated with surgery [217,288,289]. 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 [288]. Analyses of older patients (> 75
years) failed to show the same benefit in cancer-specific mortality for surgical treatment [290-292].
[Link].Surveillance
Elderly and comorbid patients with incidental small renal masses have a low RCC-specific mortality
and significant competing-cause mortality [293,294]. 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 [295]. The concept of AS differs
from the concept of watchful waiting; watchful waiting is reserved for patients whose comorbidities
contraindicate any subsequent active treatment and do not require follow-up imaging, unless clinically
indicated.
 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 [296,297].
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, a multi-variate analysis, management type was not associated with OS after
adjusting for age, comorbidity, and other variables [293]. No statistically significant difference in OS
and CSS were observed in another study of RN vs. PN vs. AS for T1a renal masses with a follow-up
of 34 months [298].
Results from the multi-institutional Delayed Intervention and Surveillance for Small
Renal Masses (DISSRM) registry were recently published [299]. This prospective NRS enrolled 497
patients with solid renal masses < 4 cm 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
median small renal mass growth rate was 0.09 cm/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 [300].
Overall survival for primary intervention and AS was 98% and 96% at 2 years, and 92%
and 75% at 5 years, respectively (p = 0.06). At 5 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 [299]. Overall, both short- and intermediate-term oncological outcomes indicate that in
selected patients with advanced age and/or comorbidities, AS is appropriate for initially monitoring
small renal masses, followed, if required, by treatment for progression [295-297,301-304].
A multicentre study assessed QoL of patients undergoing immediate intervention vs. 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 [305].
[Link].Ablative therapies
[Link].[Link]
Cryoablation is performed using either a percutaneous or a laparoscopic-assisted approach. In
comparative studies, there was no significant difference in the overall complication rates between
laparoscopic- and percutaneous cryoablation [306-308]. One comparative study reported similar OS,
CSS, and RFS in 145 laparoscopic patients with a longer follow up compared with 118 patients
treated percutaneously with a shorter follow up [307]. A shorter average length of hospital stay was
found with the percutaneous technique [307-309].
A recent systematic review including 82 articles reported complication rates ranging
between 8 and 20% with most complications being minor [310]. Although a precise definition of
tumour recurrence is lacking, the authors reported a lower RFS as compared to that of PN.
[Link].[Link] versus partial nephrectomy
Studies compared open-, laparoscopic- or robotic PN with percutaneous or laparoscopic cryoablation.
Oncological outcomes were mixed, with some studies showing no difference in OS, CSS, RFS,
disease-free survival (DFS), local recurrence or progression to metastatic disease [311,312], with
some showing significant benefit for the PN techniques for some or all of these outcomes [313-316].
Not all studies reported all outcomes listed, and some were small and included benign tumours. No
study showed an oncological benefit for cryoablation over PN.
Peri-operative outcomes, complication rates and other QoL measures were mixed.
Some studies found the length of hospital stay was shorter and surgical blood loss was less with
cryoablation [311-313], whilst also finding no differences in other peri-operative outcomes such as
recovery times, complication rates or post-operative serum creatinine levels. Two studies [315,316]
reported specific Clavien rates, with mostly non-significant differences, which were mixed for intra-
operative vs. post-operative complications. Estimated GFRs were not significantly different in two of
the studies, but in favour of cryoablation in a third [314-316]. Estimates of new CKD were also mixed,
with one study in favour of cryoablation [314], another strongly in favour of PN [315], and the third
showing no difference [316]. One study compared PN with ablation therapy, either cryoablation or
RFA [317], and showed significantly improved DSS at both 5 and 10 years for PN.
A study compared 1,057 patients treated by PN to 180 treated by RFA and 187 treated by
cryoablation for a cT1 tumour and found no difference regarding RFS between the three techniques.
Metastasis-free survival was superior after PN and cryoablation compared to RFA for cT1a patients.
However, follow-up of patients treated by thermal ablations was shorter [214].
[Link].[Link] ablation
Radiofrequency ablation is performed laparoscopically or percutaneously. Four studies compared
patients with T1a tumours treated by laparoscopic or percutaneous RFA [318-321]. Complications
occurred in up to 29% of patients but were mostly minor. Complication rates were similar in patients
treated laparoscopically or percutaneously.
One study with a limited number of patients found a higher rate of incomplete ablation in
patients treated by percutaneous RFA [320]. However, no differences in recurrence or CSS were
found in the three comparative studies.
[Link].[Link] ablation versus partial nephrectomy
Most publications about RFA are retrospective cohort studies with a low number of patients and
limited follow up. Some studies retrospectively compared RFA to surgery in patients with T1a tumours
[322-324].
One study compared T1a patients who underwent either RFA (percutaneous or
laparoscopic) or PN and found no difference in OS and CSS [298]. Another study retrospectively
reviewed 105 T1a patients treated by percutaneous RFA or RN. Cancer-specific survival was 100% in
both groups [322]. Overall survival was lower in the RFA group but patients treated with surgery were
younger [322].
A retrospective evaluation comparing RFA with LPN concluded after a median follow-up
time of 27.5 months that both methods achieved equivalent secondary efficacy rates. Radiofrequency
ablation included several treatment sessions, but session and hospitalisation times were shorter, and
complications were less frequent than for LPN. The differences remained after adjustment for renal
tumour complexity [325].
A meta-analysis reported comparable complication rates and post-operative estimated
glomerular filtration rates (eGFR) between RFA and PN [326]. The local tumour recurrence rate was
higher in the RFA group than in the PN group (OR = 1.81) but there was no difference regarding the
occurrence of distant metastasis.
A retrospective analysis of 264 patients treated with either percutaneous RFA or PN and
a median follow up of 78 months showed that T1b ccRCC patients have less favourable outcomes for
percutaneous RFA as compared to PN. However, percutaneous RFA provides comparable
oncological outcomes to PN in patients with T1b non-ccRCC. The authors conclude that it may be
necessary to take RCC subtypes into consideration when selecting either PN or percutaneous RFA as
a surgical approach to treat T1b RCC [327].
A recent large systematic review and meta-analysis including 3,974 patients who had
undergone an ablative procedure (RFA or cryoablation) or PN showed higher all-cause mortality and
cancer-specific mortality rates for ablation than for PN (HR: 2.11 and 3.84, respectively). No
statistically significant difference in local recurrence rates or risk of metastasis was seen.
Complication rates were lower for ablation than for PN (13% vs. 17.6%, p < 0.05). A significantly
greater decrease in eGFR was observed after PN vs. ablation therapy [328].
[Link].[Link] and thermal ablation versus deferred therapy
An analysis of the SEER registry included 733 patients with histopathologically confirmed localised
T1a ccRCC who either received cryosurgery (n = 315) or thermal ablation (n = 155), as well as
patients who had deferred therapy (n = 263) [329]. Patients treated with cryosurgery and thermal
ablation had a statistically significant CSS benefit compared to those who had deferred therapy
(cryosurgery HR: 0.25, 95% CI: 0.14–0.45, p < 0.001; thermal ablation HR: 0.27, 95% CI: 0.13–0.55,
p < 0.001, after adjustment for age at diagnosis, tumour grade, and size).
However, in a systematic review and meta-analysis of 99 studies representing 6,471
small renal lesions, no statistical differences were detected in the incidence of metastatic progression
regardless of whether the lesions were excised, ablated with cryotherapy or radiofrequency or
observed [330].
[Link].[Link] versus radiofrequency ablation
Two studies compared RFA and cryoablation [331,332]. No significant differences were reported for
OS, CSS, or RFS in either study. For local RFS at 5 years, one study [331] reported improvement with
RFA, while the other [332] reported a benefit with cryoablation. One study [331] reported no
differences in Clavien complication rates between the techniques.
A recent retrospective series including 384 patients (mean age 71 years; range 22-88
years) evaluated the peri-operative outcomes of thermal ablation with microwave, RFA, and
cryoablation for stage T1c RCC. Complication rates and immediate renal function changes were
similar among the three ablation modalities. Microwave ablation was associated with a significantly
decreased ablation time (p < 0.05), procedural time (p < 0.05), and dosage of sedative medication (p
< 0.05) compared with RF ablation and cryoablation. The authors conclude that CT-guided
percutaneous microwave ablation is comparable to RF ablation or cryoablation for the treatment of
stage T1N0M0 RCC with regard to treatment response and is associated with shorter treatment times
and less sedation than RF ablation or cryoablation [333].
[Link].[Link] ablative techniques
Some studies have shown the feasibility of other ablative techniques, such as microwave ablation,
laser ablation, high-intensity focused US ablation and irreversible electroporation. However, these
techniques are considered experimental.
[Link].[Link] of evidence and recommendation for therapeutic
approaches as alternative to surgery

Summary of evidence LE
Most population-based analyses show a significantly lower cancer-specific mortality for 3
patients treated with surgery compared to non-surgical management.
In active surveillance cohorts, the growth of small renal masses is low in most cases and 3
progression to metastatic disease is rare (1-2%).
Quality of the available data does not allow definitive conclusions regarding morbidity and 3
oncological outcomes of cryoablation and radiofrequency ablation.
Low quality studies suggest a higher local recurrence rate for thermal ablation therapies 3
compared to partial nephrectomy.
Recommendation Strength
rating
Offer active surveillance, radiofrequency ablation or cryoablation to frail and/or Weak
comorbid patients with small renal masses.
When radiofrequency ablation, cryoablation and active surveillance are offered, Weak
inform patients about the higher risk of local recurrence and/or tumour
progression.
[Link] of locally advanced RCC
[Link]
In addition to the summary of evidence and recommendations outlined in Section 7.1 for localised
RCC, certain therapeutic strategies arise in specific situations for locally advanced disease.
[Link] of clinically positive lymph nodes (cN+)
In the presence of clinically positive LNs (cN+), LND is always justified [23]. However, the extent of
LND remains controversial [227]. A systematic review and meta-analysis attempted to evaluate the
role of retroperitoneal LND in non-metastatic and mRCC [334]. The review included several studies
which recruited patients at high risk of LN metastases, including cN1 patients. Lymph node dissection
was not associated with any survival benefit.
However, LND may provide additional staging information. A recent analysis also
indicates that LND is not associated with improved oncologic outcomes in patients with radiographic
lymphadenopathy (cN1) and across increasing probability thresholds of pN1 disease [228].
[Link] of locally advanced unresectable RCC
In patients with non-resectable disease, embolisation can control symptoms, including visible
haematuria or flank pain [242,243,335]. The use of systemic therapy to downsize tumours is
experimental and cannot be recommended outside clinical trials.
[Link] of RCC with venous tumour thrombus
Tumour thrombus formation in RCC patients is a significant adverse prognostic factor. 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 [336-344]. However, uncertainties remain as to the best approach for
surgical treatment of these patients.
[Link].The evidence base for surgery in patients with venous tumour
thrombus
Data whether patients with venous tumour thrombus should undergo surgery is derived from case
series only. In one of the largest published studies a higher level of thrombus was not associated with
increased tumour dissemination to LNs, perinephric fat or distant metastasis [341]. Thus, all patients
with non-metastatic 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
surgical technique and approach for each case should be selected based on the extent of tumour
thrombus.
[Link].The evidence base for different surgical strategies
A systematic review was undertaken which included only comparative studies on the management of
venous tumour thrombus in non-metastatic RCC [345,346]. Only 5 studies were eligible for final
inclusion, with high risk of bias across all studies.
Minimal access techniques resulted in significantly shorter operating time compared with
traditional median sternotomy [347,348]. Pre-operative embolisation was associated with increased
operating time, blood loss, hospital stay and peri-operative mortality in patients with T3 RCC [349]. No
significant differences in oncological and process outcomes were observed between cardiopulmonary
bypass with deep hypothermic circulatory arrest or partial bypass under normothermia or single caval
clamp without circulatory support [350].
No surgical method was shown to be superior for the excision of venous tumour
thrombus. The surgical method selected depended on the level of tumour thrombus and the grade of
occlusion of the IVC [345,347,348,350]. The relative benefits and harms of other strategies and
approaches regarding access to the IVC and the role of IVC filters and bypass procedures remain
uncertain.
[Link].Summary of evidence and recommendations for the management of
RCC with venous tumour thrombus

Summary of evidence LE
In patients with locally advanced disease due to clinically enlarged lymph nodes (LNs), 3
the survival benefit of LN dissection is unproven but LN dissection adds staging
information.
Low quality data suggest that tumour thrombus excision in non-metastatic disease may 3
be beneficial.
Tumour embolisation or inferior vena cava filter do not appear to offer any benefits. 3
Recommendations Strength
rating
In patients with clinically enlarged lymph nodes (LNs), perform LN dissection for Weak
staging purposes or local control.
Remove the renal tumour and thrombus in case of venous involvement in non- Strong
metastatic disease.
[Link] therapy
There is currently no evidence from randomised phase III trials that adjuvant therapy offers a survival
benefit.
The impact on OS of adjuvant tumour vaccination in selected patients undergoing nephrectomy for T3
renal carcinomas remains unconfirmed [351-355] (LE: 1b). Results from prior adjuvant trials studying
interferon-alpha (IFN-α) and interleukin-2 (IL-2) did not show a survival benefit [356]. Heat shock
protein-peptide complex-96 (vitespen) may have a benefit in a subgroup of patients but the overall
data from phase III trials were negative [357]. A similar observation was made in an adjuvant trial of
girentuximab, a monoclonal antibody against carboanhydrase IX (CAIX) (ARISER Study) [358]. No
difference in DFS was observed in the overall trial analysis, but a subgroup evaluation of patients with
high CAIX expression suggests a potential benefit of girentuximab in this population. Several trials
investigating adjuvant sunitinib, sorafenib or pazopanib have reported whilst studies investigating
sorafenib, axitinib and everolimus have completed accrual and are expected to report in the next
years.
At present, there is no OS data supporting the use of adjuvant VEGFR or mTOR inhibitors. Thus far,
three RCTs comparing VEGFR-TKI vs. placebo have been published. One of the largest adjuvant
trials compared sunitinib vs. sorafenib vs. placebo (ASSURE). Its interim results published in 2015
demonstrated no significant differences in DFS or OS between the experimental arms and placebo
[359]. The study published its updated analysis on a subset of high-risk patients in 2018, which
demonstrated 5-year DFS rates of 47.7%, 49.9%, and 50.0%, respectively for sunitinib, sorafenib, and
placebo (HR: 0.94 for sunitinib vs. placebo; and HR: 0.90, 97.5% CI: 0.71-1.14 for sorafenib vs.
placebo), and 5-year OS of 75.2%, 80.2%, and 76.5% (HR: 1.06, 97.5% CI: 0.78-1.45, p = 0.66,
sunitinib vs. placebo; and HR: 0.80; 97.5% CI: 0.58-1.11, p = 0.12 for sorafenib vs. placebo). The
results indicated that adjuvant therapy with sunitinib or sorafenib should not be given [360].
The PROTECT study included 1,135 patients between pazopanib (n = 571) and placebo (n = 564) in
a 1:1 randomisation [361]. The primary endpoint was amended after 403 patients were included on
pazopanib 800 mg vs. placebo, to DFS with pazopanib 600 mg. The primary analysis results of DFS
in the intention to treat (ITT) pazopanib 600 mg arm were not significant (HR: 0.86; 95% CI: 0.7-1.06,
p = 0.16). Disease-free survival in the ITT pazopanib 800 mg population was improved (HR: 0.69;
95% CI: 0.61 0.94, 1.06, p = 0.02). No benefit in OS was seen in the ITT pazopanib 600 mg
population (HR: 0.79 [0.57-1.09, p = 0.16]). A subset analysis of these studies suggests that full-dose
therapy is associated with improved DFS. Furthermore, no strong association of DFS with OS has
been established for RCC [362,363].
In contrast, the S-TRAC study included 615 patients randomised to either sunitinib or
placebo [364]. The results showed a benefit of sunitinib over placebo for DFS (HR: 0.76; 95% CI:
0.59-0.98, p = 0.03) but data for OS remained immature. Grade 3/4 toxicity in the study was 60.5% for
patients receiving sunitinib, which translated into significant differences in QoL for loss of appetite and
diarrhoea. The study published its updated results in 2018; the results for DFS had not changed
significantly (HR: 0.74; 95% CI: 0.55-0.99, p = 0.04) and median OS was not reached in either arm
(HR: 0.92, 95% CI: 0.66-1.28, p = 0.6).
In summary, there is conflicting data in the three available studies of adjuvant therapy. A recent
systematic review and meta-analysis combined the results of all three RCTs [365]. The pooled
analysis of VEGFR-TKIs vs. placebo demonstrated that VEGFR-targeted therapy was not statistically
significantly associated with improved DFS (HR: 0.92, 95% CI: 0.82-1.03, p = 0.16) nor OS (HR: 0.98,
95% CI: 0.84-1.15, p = 0.84) compared with placebo. The adjuvant therapy group experienced
significantly higher odds of grade 3-4 adverse events (OR: 5.89, 95% CI: 4.85-7.15, p < 0.001).
In summary, there is currently a lack of proven benefits of adjuvant therapy with
VEGFR-TKIs for patients with high-risk RCC after nephrectomy.
The European Medicines Agency (EMA) has not approved sunitinib for adjuvant
treatment of high-risk RCC in adult patients after nephrectomy.
[Link].Summary of evidence and recommendations for adjuvant therapy

Summary of evidence LE
Adjuvant cytokines do not improve survival after nephrectomy. 1b
After nephrectomy in selected high-risk patients, adjuvant sunitinib improved disease-free 1b
survival (DFS) in one of the two available studies, but not overall survival (OS).
Adjuvant sorafenib, pazopanib or axitinib does not improve DFS or OS after 1b
nephrectomy.
Recommendations Strength
rating
Do not offer adjuvant therapy with sorafenib, pazopanib or axitinib. Strong
Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell Weak
renal cell carcinoma.
[Link]/metastatic RCC
[Link] therapy of advanced/metastatic RCC
[Link].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. In a meta-analysis comparing CN+ INF-based immunotherapy vs. INF-based
immunotherapy only, increased long-term survival was found in patients treated with CN [366].
However, INF-based immunotherapy is no longer relevant in contemporary clinical practice. In order
to investigate the role and sequence of CN in the era of targeted therapy, a structured literature
assessment was performed to identify relevant RCTs and systematic reviews published between July
1st - June 30th 2019. Two RCTs [367,368] and a narrative systematic review were identified [369]. The
narrative systematic review included both RCTs and 10 NRSs. CARMENA, a phase III non-inferiority
RCT investigating immediate CN followed by sunitinib vs. sunitinib alone, showed that sunitinib alone
was not inferior to CN followed by sunitinib with regard to OS [370]. 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 140 mL of
measurable disease by Response Evaluation Criteria In Solid Tumours (RECIST) 1.1, of which 80 mL
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 vs. 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). Non-inferiority 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 12 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: [95% CI: 0.88 [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 vs. 15.0 (9.3-29.5) months in the immediate CN arm (HR: [95% CI]
0.57 [0.34-0.95], p = 0.032). The deferred CN approach appears to select out patients with inherent
resistance to systemic therapy. This confirms previous findings from single-arm phase II studies [371].
Moreover, deferred CN and surgery appears safe after sunitinib which supports the findings, with
some caution, of the only available RCT.
In patients with poor PS or Metastatic Renal Cancer Database Consortium (IMDC) risk,
small primaries and high metastatic volume and/or a sarcomatoid tumour, CN is not recommended
[372]. These data are confirmed by CARMENA [370].
[Link].[Link] of the primary tumour
In patients unfit for surgery or with non-resectable disease, embolisation can control symptoms
including visible haematuria or flank pain [242,243,335] (see recommendations Section [Link].4).
[Link].[Link] of evidence and recommendations for local therapy of
advanced/metastatic RCC

Summary of evidence LE
Deferred CN with pre-surgical sunitinib in intermediate-risk patients with cc-mRCC shows 2b
a survival benefit in secondary endpoint analyses and selects out patients with inherent
resistance to systemic therapy.
Sunitinib alone is non-inferior compared to immediate CN followed by sunitinib in patients 1a
with MSKCC intermediate and poor risk who require systemic therapy with VEGFR-TKI.
Cytoreductive nephrectomy for patients with simultaneous complete resection of a single 3
metastasis or oligometastases may improve survival and delay systemic therapy.
Patients with MSKCC or IMDC poor risk (≥ 4 risk factors) do not benefit from local 1a
therapy.
Recommendations Strength
rating
Do not perform cytoreductive nephrectomy (CN) in MSKCC poor-risk patients. Strong
Do not perform immediate CN in MSKCC intermediate-risk patients who have an Weak
asymptomatic synchronous primary tumour and require systemic therapy with
vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor
(TKI).
Start systemic therapy without CN in MSKCC intermediate-risk patients who Weak
have an asymptomatic synchronous primary tumour and require systemic
therapy with VEGFR-TKI.
Discuss delayed CN in MSKCC intermediate-risk patients under VEGFR-TKI Weak
therapy who derive long-term sustained benefit and/or minimal residual
metastatic burden.
Perform immediate CN in patients with good performance who do not require Weak
systemic therapy.
Perform immediate CN in patients with oligometastases when complete local Weak
treatment of the metastases can be achieved.
[Link] therapy of metastases in metastatic RCC
A SR of the local treatment of metastases from RCC in any organ was undertaken [373]. Interventions
included metastasectomy, various radiotherapy modalities, and no local treatment. The outcomes
assessed were OS, CSS and PFS, local symptom control and adverse events. A risk-of-bias
assessment was conducted [374]. Of the 2,235 studies identified only sixteen non-randomised
comparative studies were included.
Eight studies reported on local therapies of RCC-metastases in various organs [375-382]. This
included metastases to any single organ or multiple organs. Three studies reported on local therapies
of RCC metastases in bone, including the spine [383-385], two in the brain [386,387] and one each in
the liver [388] lung [389] and pancreas [390]. Three studies were published as abstracts only
[378,380,389]. Data were too heterogeneous to meta-analyse. There was considerable variation in
the type and distribution of systemic therapies (cytokines and VEGF-inhibitors) and in reporting the
results.
[Link].Complete versus no/incomplete metastasectomy
An systematic review, including only 8 studies, compared complete vs. no and/or incomplete
metastasectomy of RCC metastases in various organs [375-382]. In one study complete resection
was achieved in only 45% of the metastasectomy cohort, which was compared with no
metastasectomy [382]. Non-surgical modalities were not applied. Six studies [376-378,380-382]
reported a significantly longer median OS or CSS following complete metastasectomy (the median
value for OS or CSS was 40.75 months, range 23-122 months) compared with incomplete and/or no
metastasectomy (the median value for OS or CSS was 14.8 months, range 8.4-55.5 months). Of the
two remaining studies, one [375] showed no significant difference in CSS between complete and no
metastasectomy, and one [379] reported a longer median OS for metastasectomy albeit no p-value
was provided.
Three studies reported on treatment of RCC metastases in the lung [389], liver [388],
and pancreas [390], respectively. The lung study reported a significantly higher median OS for
metastasectomy vs. medical therapy only for both target therapy and immunotherapy. Similarly, the
liver and pancreas study reported a significantly higher median OS and 5-year OS for
metastasectomy vs. no metastasectomy.
[Link].Local therapies for RCC bone metastases
Of the three studies identified, one compared single-dose image-guided radiotherapy (IGRT) with
hypofractionated IGRT in patients with RCC bone metastases [385]. Single-dose IGRT (≥ 24 Gy) had
a significantly better 3-year actuarial local PFS rate, also shown by Cox regression analysis. Another
study compared metastasectomy/curettage and local stabilisation with no surgery of solitary RCC
bone metastases in various locations [383]. A significantly higher 5-year CSS rate was observed in
the intervention group.
After adjusting for prior nephrectomy, gender and age, multi-variate analysis still
favoured metastasectomy/curettage and stabilisation. A third study compared the efficacy and
durability of pain relief between single-dose stereotactic body radiotherapy (SBRT) and conventional
radiotherapy in patients with RCC bone metastases to the spine [384]. Pain, objective response rate
(ORR), time-to-pain relief and duration of pain relief were similar.
[Link].Local therapies for RCC brain metastases
Two studies on RCC brain metastases were included. A three-armed study [386] compared
stereotactic radiosurgery (SRS) vs. whole brain radiotherapy (WBRT) vs. SRS and WBRT. Each
group was further subdivided into recursive partitioning analysis (RPA) classes I to III (I favourable, II
moderate and III poor patient status). Two-year OS and intra-cerebral control were equivalent in
patients treated with SRS alone and SRS plus WBRT.
Both treatments were superior to WBRT alone in the general study population and in the
RPA subgroup analyses. A comparison of SRS vs. SRS and WBRT in a subgroup analysis of RPA
class I showed significantly better 2-year OS and intra-cerebral control for SRS plus WBRT based on
only three participants. The other study compared fractionated stereotactic radiotherapy (FSRT) with
metastasectomy and conventional radiotherapy or conventional radiotherapy alone [387]. Several
patients in all groups underwent alternative surgical and non-surgical treatments after initial treatment.
One-, two- and 3-year survival rates were higher but not significantly so for FSRT as for
metastasectomy and conventional radiotherapy, or conventional radiotherapy alone. Fractionated
stereotactic radiotherapy did not result in a significantly better 2-year local control rate compared with
metastasectomy plus conventional radiotherapy.
[Link].Embolisation of metastases
Embolisation prior to resection of hypervascular bone or spinal metastases can reduce intra-operative
blood loss [391]. In selected patients with painful bone or paravertebral metastases, embolisation can
relieve symptoms [392] (see recommendation Section [Link].4).
[Link].Summary of evidence and recommendations for local therapy of
metastases in metastatic RCC

Summary of evidence LE
All studies included in the Panel systematic review were retrospective non-randomised 3
comparative studies, resulting in a high risk of bias associated with non-randomisation,
attrition, and selective reporting.
With the exception of brain and possibly bone metastases, metastasectomy remains by 3
default the only local treatment for most sites.
Retrospective comparative studies consistently point towards a benefit of complete 3
metastasectomy in mRCC patients in terms of overall survival, cancer-specific survival
and delay of systemic therapy.
Radiotherapy to bone and brain metastases from RCC can induce significant relief from 3
local symptoms (e.g. pain).
Recommendations Strength
rating
To control local symptoms, offer ablative therapy, including metastasectomy, to Weak
patients with metastatic disease and favourable disease factors and in whom
complete resection is achievable.
Offer stereotactic radiotherapy for clinically relevant bone- or brain metastases Weak
for local control and symptom relief.
[Link] therapy for advanced/metastatic RCC
[Link]
Chemotherapy has proven to be generally ineffective in the treatment of RCC but can be offered in
rare patients, with the exception of collecting duct and medullary carcinoma [393].
[Link].Recommendation for systemic therapy in advanced/metastatic RCC

Recommendation Strength
 rating
Do not offer chemotherapy to patients with metastatic renal cell carcinoma. Strong
[Link]
[Link].IFN-α monotherapy and combined with bevacizumab
All studies comparing targeted drugs to IFN-α monotherapy therapy showed superiority for sunitinib,
bevacizumab plus IFN-α, and temsirolimus [394-397]. Interferon-α has been superseded by targeted
therapy in clear-cell-mRCC (cc-mRCC).
Table 7.1: The Metastatic Renal Cancer Database Consortium (IMDC) risk model [398]*
Risk factors** Cut-off point used
Karnofsky performance status < 80%
Time from diagnosis to treatment < 12 months
Haemoglobin < Lower limit of laboratory reference range
Corrected serum calcium > 10.0 mg/dL (2.4 mmol/L)
Absolute neutrophil count (neutrophilia) > upper limit of normal
Platelets (thrombocytosis) > upper limit of normal
*The MSKCC (Motzer) criteria are also widely used in this setting [204].
**Favourable (low) risk, no risk factors; intermediate risk, one or two risk factors; poor (high) risk,
three to six risk factors.
[Link].Interleukin-2
Interleukin-2 has been used to treat mRCC since 1985 with response rates ranging from 7-27%
[397,399,400]. Complete and durable responses have been achieved with high-dose bolus IL-2,
however, this can be achieved at less toxicity with immune checkpoint inhibitor combination therapy
and IL-2 is no longer widely used.
[Link].Immune checkpoint blockade
[Link].[Link]-oncology monotherapy
Immune checkpoint blockade 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 [401]. Immune checkpoint inhibitor monotherapy has been investigated as
second- and third-line therapy. A phase III trial of nivolumab vs. everolimus after one or two lines of
VEGF-targeted therapy (CheckMate 025, NCT01668784) reported a longer OS, better QoL and fewer
grade 3 or 4 adverse events with nivolumab than with everolimus [182]. 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 (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 immune checkpoint blockade in treatment-
naïve patients. Randomised phase II data for atezolizumab vs. sunitinib showed a 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 [402]. 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) [403]. 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.
[Link].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 [404] and a paradigm shift in the treatment of mRCC [1]. Results from
CheckMate 214 further established that the combination of ipilimumab and nivolumab was associated
with higher response rates (RR) (39% in the ITT population), complete response rates (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). Frequency of grade 3-4 adverse events and QoL
data favoured the immune combination.
Nivolumab plus ipilimumab was associated with 15% grade 3-5 toxicity including 1.5%
treatment-related deaths. It should therefore be administered in centres with experience of immune
combination therapy and appropriate supportive care within the context of a multidisciplinary team
(LE: 4). PD-L1 biomarker is currently not used to select patients for therapy.
The frequency of steroid use has generated controversy and further analysis, as well as
real world data, are required.
A recent update with 32-month data shows ongoing benefits for the immune combination with
investigator-assessed CR rates of 11% and an OS HR in the IMDC intermediate- and poor-risk group
of 0.66 (95% CI 0.54-0.80) [406]. The IMDC good-risk group continues to perform well with sunitinib
although this appears less marked than in earlier analyses (HR for OS 1.22 [95% CI: 0.73-2.04]). For
these reasons the Guidelines Panel continues to recommend ipilimumab and nivolumab in the
intermediate- and poor-risk population.
The Keynote-426 trial (NCT02853331) has recently reported results for the combination of axitinib
plus pembrolizumab vs. sunitinib in 861 treatment-naïve cc-mRCC patients [407]. Overall survival and
PFS assessed by central independent review in the ITT population were the co-primary endpoints.
Response rates and assessment in the PD-L1-positive patient population were secondary endpoints.
With a median follow-up of 12.8 months, at first interim analysis both primary endpoints were reached,
The median PFS in the pembrolizumab plus axitinib arm was 15.1 months vs. 11.1 in the sunitinib arm
(HR 0.69; 95% CI: 0.57-0.84, p < 0.001). Median OS has not been reached in either arm, but the risk
of death was 47% lower in the axitinib plus pembrolizumab arm when compared to the sunitinib arm
(OS HR: 0.53; 95% CI: 0.38–0.74, p < 0.0001). Response rates were also higher in the experimental
arm (59.3% vs. 35.7%). Efficacy occurred irrespective of IMDC group and PD-L1 status. Treatment-
related AEs (≥ grade 3) occurred in 63% of patients receiving axitinib and pembrolizumab vs. 58% of
patients receiving sunitinib. Treatment-related deaths occurred in approximately 1% in both arms.
The JAVELIN trial investigated 886 patients in a phase III RCT of avelumab plus axitinib vs. sunitinib
[408]. It met one of its co-primary endpoints (PFS in the PD-L1-positive population at first interim
analysis [median follow up 11.5 months]). Progression-free survival and OS in the ITT population was
HR 0.69 (95% CI: 0.56-0.84) and 0.78 (95% CI: 0.55-1.08), respectively. The same applies to the
atezolizumab/bevacizumab combination which also 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 yet
shown a significant OS advantage (HR: 0.81 [95% CI: 0.63-1.03]) [409]. Results are awaited and the
combination cannot currently be recommended.
Table 7.2: Cross trial comparison is not recommended and should occur with caution
Study N Experimental Primary Risk PFS
arm endpoint groups Median (95% CI)
HR
KEYNOTE- 861 Pembrolizumab PFS and IMDC (ITT)
426 200 mg. IV OS in the FAV 31% PEMBRO + AXI 15.1
NCT02853331 Q3W plus ITT by BICR IMD 56% (12.6-17.7)
[407] axitinib 5 mg. POOR SUN 11.1 (8.7-12.5)
PO BID 13% HR: 0.69 (95% CI: 0.57,
vs. MSKCC 0.84)
Study N Experimental Primary Risk PFS
arm endpoint groups Median (95% CI)
HR
sunitinib 50 mg Not p = < 0.0001
PO QD 4/2 determined
weeks
JAVELIN 101 886 Avelumab 10 PFS in the IMDC (PD-L1+)
NCT02684006 mg/kg IV Q2W PD-L1+ FAV 22% AVE + AXI 13.8 (11.1-
[408] plus axitinib, 5 population IMD 62% NE)
mg PO BID and OS in POOR SUN 7.2 (5.7-9.7)
vs. the ITT by 16% HR: 0.61 (95% CI: 0.475,
sunitinib 50 mg BICR MSKCC 0.790)
PO QD 4/2 FAV 23% p < .0001
weeks IMD 66%
POOR
12%
Immotion 151 915 Atezolizumab PFS in the IMDC (PD-L1+)
NCT02420821 1200 mg fixed PD-L1+ Not ATEZO + BEV 11.2 (8.9-
[409] dose IV plus population determined 15.0)
bevacizumab and OS in MSKCC SUN 7.7 (6.8-9.7)
15 mg/kg IV on the ITT by FAV 20% HR: 0.74 (95% CI: 0.57,
days 1 and 22 IR IMD 70% 0.96)
of each 42-day POOR p = 0.02
cycle 10%
vs.
sunitinib 50 mg.
PO QD 4/2
weeks
Checkmate 1096 Nivolumab 3 PFS and IMDC (IMDC intermediate/poor)
214 mg/kg plus OS in the FAV 23% NIVO + IPI 11.8 (8.7-
NCT02231749 ipilimumab 1 IMDC IMD 61% 15.5)
[405,410] mg/kg IV Q3W intermediate POOR SUN 8.4 (7.0-10.8)
for 4 doses then and poor 17% HR: 0.82 (99.1% CI: 0.64,
nivolumab 3 population MSKCC 1.05)
mg/kg IV Q2W by BICR Not p = 0.03
vs. determined
sunitinib 50 mg.
PO QD 4/2
weeks
ATEZO = atezolizumab; AVE = avelumab; AXI = axitinib; BEV = bevacizumab; BICR = blinded
independent central review; CI = confidence interval; FAV = favourable; HR = hazard ratio; IPI =
ipilimumab; IMD = intermediate; IMDC = Metastatic Renal Cancer Database Consortium; IR =
investigator review; ITT = intention-to-treat; IV = intravenous; NE = non-estimable; NR = not reached;
NIVO = nivolumab; OS = overall survival; PEMBRO = pembrolizumab; PFS = profession-free survival;
PO QD = by mouth, once a day; SUN = sunitinib.
Whilst this table gives a broad overview of the available, data direct cross trial comparisons should be
avoided.
Patients who stop nivolumab plus ipilimumab because of toxicity require expert guidance and support
from a multidisciplinary team before re-challenge occurs (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 [405,410] (LE: 1).
Patients who stop axitinib and pembrolizumab due to immune-related toxicity can
receive single-agent axitinib once the adverse event 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 re-challenge of immune checkpoint inhibitors after
significant toxicity (LE: 4). Treatment past progression on axitinib and pembrolizumab requires careful
consideration as it is biologically distinct from treatment past progression on ipilimumab and
nivolumab.
Generally, the Panel is of the opinion that nivolumab plus ipilimumab and pembrolizumab plus axitinib
should be administered in centres with experience of immune combination therapy and appropriate
supportive care within the context of a multidisciplinary team (LE: 4).
[Link].Summary of evidence and recommendations for immunotherapy in
metastatic RCC

Summary of evidence LE
Interferon-α monotherapy is inferior to VEGF-targeted therapy or mTOR inhibition in 1b
mRCC.
Nivolumab leads to superior OS compared to everolimus in patients failing one or two 1b
lines of VEGF-targeted therapy.
The combination of nivolumab and ipilimumab in treatment-naïve patients with clear-cell- 1b
mRCC (cc-mRCC) of IMDC intermediate and poor risk demonstrated overall survival
(OS) and objective response rate (ORR) benefits compared to sunitinib.
The combination of pembrolizumab and axitinib in treatment-naïve patients with cc- 1b
mRCC across all IMDC risk groups demonstrated OS and ORR benefits compared to
sunitinib.
Currently, PD-L1 expression is not used for patient selection. 2b
Axitinib can be continued if immune-related adverse events results in cessation of axitinib 4
and pembrolizumab. Re-challenge with immunotherapy requires expert support.
Patients who do not receive the full 4 doses of ipilimumab due to toxicity should continue 4
on single-agent nivolumab, where safe and feasible. Re-challenge with combination
therapy requires expert support.
Treatment past progression can be justified but requires close scrutiny and the support of 1b
an expert multidisciplinary team.
Nivolumab plus ipilimumab and pembrolizumab plus axitinib should be administered in 4
centres with experience of immune combination therapy and appropriate supportive care
within the context of a multidisciplinary team.
The combination of nivolumab and ipilimumab in the ITT population of treatment-naïve 2b
unselected patients with cc-mRCC leads to superior survival compared to sunitinib.
Due to the exploratory nature of PD-L1 tumour expression, the small sample size, the 2b
lack of OS data and the premature results in this subpopulation, definitive conclusions
cannot be drawn relative to the usefulness of PD-L1 expression.
Nivolumab plus ipilimumab was associated with 15% grade 3-5 toxicity and 1.5% 1b
treatment-related deaths.
Recommendations Strength
 rating
Offer pembrolizumab plus axitinib to treatment-naïve patients with any IMDC-risk Strong
clear-cell metastatic renal cell carcinoma (cc-mRCC).
Offer ipilimumab plus nivolumab to treatment-naïve patients with IMDC Strong
intermediate- and poor-risk cc-mRCC.
Administer nivolumab plus ipilimumab and pembrolizumab plus axitinib in Weak
centres with experience of immune combination therapy and appropriate
supportive care within the context of a multidisciplinary team.
Patients who do not receive the full 4 doses of ipilimumab due to toxicity should Weak
continue on single-agent nivolumab, where safe and feasible.
Offer axitinib as subsequent treatment to patients who experience treatment- Weak
limiting immune-related adverse events after treatment with the combination of
axitinib and pembrolizumab.
Treatment past progression can be justified but requires close scrutiny and the Weak
support of an expert multidisciplinary team.
Do not re-challenge patients who stopped immune checkpoint inhibitors because Strong
of toxicity without expert guidance and support from a multidisciplinary team.
Offer nivolumab after one or two lines of vascular endothelial growth factor- Strong
targeted therapy in mRCC.
Offer sunitinib or pazopanib to treatment-naïve patients with IMDC favourable-, Strong
intermediate-, and poor-risk cc-mRCC who cannot receive or tolerate immune
checkpoint inhibition.
Offer cabozantinib to treatment-naïve patients with IMDC intermediate- and Stronga
poor-risk cc-mRCC who cannot receive or tolerate immune checkpoint inhibition.
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.
[Link] therapies
In sporadic ccRCC, hypoxia-inducible factor (HIF) accumulation due to VHL-inactivation results in
over-expression of VEGF and platelet-derived growth factor (PDGF), which promote neo-
angiogenesis [411-413]. 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, thus 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 (Table 7.1) [205].
Table 7.3: Median OS and percentage of patients surviving two years treated in the era of
targeted therapy per IMDC risk group*,**
IMDC Model Patients** Median OS* 2-yr OS (95%
n % (months) CI)**

Favourable 157 18 43.2 75% (65-82%)

Intermediate 440 52 22.5 53% (46-59%)
Poor 252 30 7.8 7% (2-16%)
* Based on [205]; ** based on [398].
CI = confidence interval; IMDC = Metastatic Renal Cancer Database Consortium; n = number of
patients; OS = overall survival; yr = year.
[Link].Tyrosine kinase inhibitors
[Link].[Link]
Sorafenib is an oral multi-kinase inhibitor. A trial compared sorafenib and placebo after failure of prior
systemic immunotherapy or in patients unfit for immunotherapy. Sorafenib improved PFS (HR: 0.44;
95% CI: 0.35- 0.55, p < 0.01) [414]. Overall survival improved in patients initially assigned to placebo
who were censored at crossover [415]. In patients with previously untreated mRCC sorafenib was not
superior to IFN-α (phase II study). A number of studies have used sorafenib as the control arm in
sunitinib-refractory disease vs. axitinib, dovitinib and temsirolimus. None showed superior survival for
the study drug compared to sorafenib.
[Link].[Link]
Sunitinib is an oral TKI inhibitor and has anti-tumour and anti-angiogenic activity. First-line
monotherapy with sunitinib demonstrated significantly longer PFS compared with IFN-α. Overall
survival was greater in patients treated with sunitinib (26.4 months) vs. INF-α (21.8 months) despite
crossover [417].
In the EFFECT trial, sunitinib 50 mg/day (4 weeks on/2 weeks off) was compared with
continuous uninterrupted sunitinib 37.5 mg/day in patients with cc-mRCC [418]. 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 non-significant, but numerically longer time to progression with the standard 50 mg
dosage, the authors recommended using this regimen. Alternate scheduling of sunitinib (2 weeks
on/one week off) is being used to manage toxicity, but robust data to support its use is lacking
[419,420].
[Link].[Link]
Pazopanib is an oral angiogenesis inhibitor. In a trial of pazopanib vs. placebo in treatment-naïve
mRCC patients and cytokine-treated patients, a significant improvement in PFS and tumour response
was observed [421].
A non-inferiority trial comparing pazopanib with sunitinib (COMPARZ) established
pazopanib as an alternative to sunitinib. It 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 [422]. In another patient-preference study (PISCES), patients
preferred pazopanib to sunitinib (70% vs. 22%, p < 0.05) due to symptomatic toxicity [423]. Both
studies were limited in that intermittent therapy (sunitinib) was compared with continuous therapy
(pazopanib).
[Link].[Link]
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) [424].
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 3 diarrhoea in 11%, hypertension in 16%, and fatigue in 11% of patients. Final analysis of OS
showed no significant differences between axitinib or sorafenib [425,426]. In a randomised phase III
trial of axitinib vs. sorafenib in first-line treatment-naïve 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 [427]. As a result of this study, axitinib is not approved for first-
line therapy.
[Link].[Link]
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 [180]. Based on these results an RCT investigated
cabozantinib vs. everolimus in patients with ccRCC failing one or more VEGF-targeted therapies
(METEOR) [181,428]. Cabozantinib delayed PFS compared to everolimus in VEGF-targeted therapy
refractory disease (HR: 0.58 95% CI: 0.45-0.75) [181] (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) [428].
Grade 3 or 4 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 cabozatinib and
sunitinib in first-line in 157 intermediate- and poor-risk patients favoured cabozantinib for RR and
PFS, but not OS [429,430]. Cabozantinib significantly increased median PFS (8.2 vs. 5.6 months,
adjusted HR: 0.66; 95% CI: 0.46 to 0.95; one-sided p = 0.012). Objective response rate was 46%
(95% CI: 34-57) for cabozantinib vs. 18% (95% CI: 10-28) for sunitinib. All-causality grade 3 or 4
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 over existing choices.
[Link].[Link]
Lenvatinib is an oral multi-target TKI of VEGFR1, VEGFR2, and VEGFR3, with inhibitory activity
against fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3, and FGFR4), platelet growth
factor receptor [(PDGFR-α), re-arranged during transfection (RET) and receptor for stem cell factor
(KIT). It has recently been investigated in a randomised phase II study in combination with everolimus
vs. lenvatinib or everolimus alone (see Section [Link].1.5 for discussion of results) [431].
[Link].[Link]
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 [432,433]. Tivozanib was approved by the
EMA in front-line mRCC. While it is associated with a PFS advantage in both studies, no OS
advantage was seen. In view of the choice of sorafenib as the control arm in the front-line trial, the
Panel feels there is too much uncertainty, and too many attractive alternatives, to support its use in
this setting.
[Link] antibody against circulating VEGF
[Link].Bevacizumab monotherapy and bevacizumab plus IFN-α
Bevacizumab is a humanised monoclonal antibody.
The double-blind AVOREN study compared bevacizumab plus IFN-α with INF-
α monotherapy in mRCC. Overall response was higher in the bevacizumab plus IFN-α group. Median
PFS increased from 5.4 months with IFN-α to 10.2 months with bevacizumab plus IFN-α. No benefit
was seen in MSKCC poor-risk patients. Median OS in this trial, which allowed crossover after
progression, was not greater in the bevacizumab/IFN-α group (23.3 vs. 21.3 months) [434].
An open-label trial (CALGB 90206) of bevacizumab plus IFN-α vs. IFN-α showed a
higher median PFS for the combination group [435,436]. Objective response rate was also higher in
the combination group. Overall toxicity was greater for bevacizumab plus IFN-α, with significantly
more grade 3 hypertension, anorexia, fatigue, and proteinuria.
Bevacizumab, alone, or in combinations, is not widely recommended or used in mRCC
due to more attractive alternatives.
[Link] inhibitors
[Link].Temsirolimus
Temsirolimus is a specific inhibitor of mTOR [437]. Its use has been superseded as front-line
treatment option.
[Link].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) vs. placebo
plus BSC in patients with previously failed anti-VEGFR treatment (or previously intolerant of VEGF-
targeted therapy) [438]. The data showed a median PFS of 4 vs. 1.9 months for everolimus and
placebo, respectively [438].
The RCC Guidelines Panel consider, 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 levantinib is attractive.
[Link] strategies
[Link].Therapy for treatment-naïve patients with clear-cell metastatic RCC
The combination of pembrolizumab and axitinib as well as nivolumab and ipilimumab is the standard
of care in all IMDC and IMDC intermediate- and poor-risk patients (Figure 7.1). Therefore, the role of
VEGFR-TKIs alone in front-line mRCC has been superseded. Sunitinib, pazopanib, 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 (Figure 7.1).
[Link].[Link] systemic therapy in clear-cell metastatic RCC
The sequencing of targeted therapies is established in mRCC and maximises outcomes
[181,182,431]. Pembrolizumab plus axitinib and nivolumab plus ipilimumab are the new standard of
care for front-line therapy. 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 pembrolizumab plus axitinib in a first-line setting are lacking, and available cohorts are
limited [439]. Prospective data on cabozantinib and axitinib are available for patients progressing on
immune therapy, but these studies do not focus solely on the front-line setting, involve subset
analysis, and are too small for definitive conclusions [181,440].
Retrospective data on VEGFR-TKI therapy after progression on front-line immune combinations exist
but have significant limitations. When considering this data in totality, there is some activity but it is
still too early to recommend one VEGFR-TKI above another after immunotherapy-immunotherapy or
immunotherapy-VEGFR combination (Figure 7.2). After the axitinib plus pembrolizumab combination,
changing the VEGFR-TKI at progression is recommended which may be cabozantinib or any other
TKI not previously used.
The Panel do not favour the use of mTOR inhibitors unless VEGF-targeted therapy is contraindicated
as they have been outperformed by other VEGF-targeted therapies in mRCC [441]. 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 which is approved in VEGF-
refractory disease, with the exception of re-challenge with immune checkpoint blockade. Cabozantinib
is the only agent in VEGF-refractory disease with a survival advantage in an RCT and should be used
preferentially [424]. Axitinib has positive PFS data in VEGF-refractory disease. Both sorafenib and
everolimus have been outperformed by other agents in VEGF-refractory disease and are therefore
less attractive [441]. The Lenvatinib and 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 [431]. Tivozinib has PFS superiority to
sorafenib in VEGF-refractory disease as shown in a study which also included patients on immune
checkpoint inhibitors [442].
[Link].Non-clear-cell metastatic RCC
No phase III trials of patients with non-cc-mRCC have been reported. Expanded access programmes
and subset analysis from RCC studies suggest the outcome of these patients with targeted therapy is
poorer than for ccRCC. Targeted treatment in non-cc-mRCC has focused on temsirolimus,
everolimus, sorafenib, sunitinib and pembrolizomab [396,443-445].
The most common non-clear-cell subtypes are papillary type I and non-type I papillary
RCCs. There are small single-arm trials for sunitinib and everolimus [445-448]. A trial of both types of
pRCC treated with everolimus (RAPTOR) [448], showed a median PFS of 3.7 months per central
review in the ITT population with a median OS of 21.0 months.
However, a randomised phase II trial of everolimus vs. sunitinib (ESPN) with crossover
design in non-cc-mRCC including 73 patients (27 with pRCC) was stopped after a futility analysis for
PFS and OS [449]. The final results showed a non-significant trend favouring sunitinib (6.1 vs. 4.1
months). Based on a systematic review including subgroup analysis of the ESPN, RECORD-3 and
another phase II trial (ASPEN), sunitinib and everolimus remain options in this population, with a
preference for sunitinib [7,139,450]. Patients with non-cc-mRCC should be referred to a clinical trial,
where appropriate. Efficacy for pembrolizumab (n = 165; response rates of 24%, PFS 4.1 months
[95% CI: 2.8-5.6 months] 72% one-year OS) was noted but these results are based on a single-arm
phase II study [403]. Pembrolizumab can be conceded in this setting due to the high unmet need.
Subset analysis has shown impressive results for PD-L1 inhibitors combined with CTLA4 or VEGF-
targeted therapy in renal tumours with sarcomatoid features. Bevacizumab/atezolizumab,
ipilimumab/nivolumab, axitinib/pembrolizumab and avelumab/axitinib can all be recommended instead
of VEFG-targeted therapy alone. These options have impressive OS advantages over sunitinib and
superseded VEGF-targeted therapy.
Collecting-duct cancers and renal medullary cancers are highly resistant to systemic
therapy. Only case reports have been published for a spectrum of treatment options so far and no
clear recommendations can be provided until data from international registries (RARECARE) or
clinical trials become available.
Figure 7.1: Updated European Association of Urology Guidelines recommendations for the
treatment of first-line and following lines in clear-cell metastatic renal cancer

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 one randomised controlled phase II trial.
Figure 7.2: Guidelines Recommendations for later-line therapy

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.
[Link] of evidence and recommendations for targeted therapy
in metastatic RCC

Summary of evidence LE
Single agent VEGF-targeted therapy has been superseded by immune checkpoint based 1b
combination therapy.
Pazopanib is non-inferior to sunitinib in front-line mRCC. 1b
Cabozantinib in intermediate- and poor-risk treatment-naïve clear-cell RCC leads to 2b
better response rates and PFS but not OS when compared to sunitinib.
Tivozanib has been EMA approved, but the evidence is still considered inferior over 3
existing choices in the front-line setting.
Single-agent VEGF-targeted therapies are preferentially recommended after front-line 3
PD-L1-based combinations. Re-challenge with treatments already used should be
avoided.
Single-agent cabozantinib or nivolumab are superior to everolimus after one or more lines 1b
of VEGF-targeted therapy.
Everolimus prolongs PFS after VEGF-targeted therapy when compared to placebo. This 1b
is no longer widely recommended before third-line therapy.
Both mTOR inhibitors and VEGF-targeted therapies have limited activity in non-cc- 2a
mRCC. There is a non-significant trend for improved oncological outcomes for sunitinib
over everolimus.
Lenvatinib in combination with everolimus improved PFS over everolimus alone in VEGF- 2a
refractory disease. Its role after immune checkpoint inhibitors is uncertain. There is a lack
of robust data on this combination making its recommendation challenging.
Recommendations Strength
rating
Offer nivolumab or cabozantinib for immune checkpoint inhibitor-naive vascular Strong
endothelial growth factor receptor (VEGFR)-refractory clear-cell metastatic renal
cell carcinoma (cc-mRCC).
Sequencing the agent not used as second-line therapy (nivolumab or Weak
cabozantinib) for third-line therapy is recommended.
Offer VEGF-tyrosine kinase inhibitors as second-line therapy to patients Weak
refractory to nivolumab plus ipilimumab or axitinib plus pembrolizumab.
Offer cabozantinib after VEGF-targeted therapy in cc-mRCC. Strong
Sequence systemic therapy in treating mRCC. Strong
[Link] RCC
Locally recurrent disease can either affect the tumour-bearing kidney after PN, or focal ablative
therapy such as RFA and cryotherapy, or occur outside the kidney following PN or RN for RCC.
After NSS for pT1 disease, recurrences within the remaining kidney occur in about 1.8-
2.2% of patients [451,452]. Although the impact of positive margins on the clinical prognosis is still
unclear [287,452,453] the preferred management, when technically feasible, is repeat surgical
intervention to avoid the potential risk of tumour recurrence.
 Following thermal ablation or cryotherapy generally intra-renal, but also peri-renal,
recurrences have been reported in up to 14% of cases [454]. 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.
Most studies reporting on the oncological efficacy of surgery for recurrent disease after removal of the
kidney, have not considered the traditional definition of local recurrence after RN, PN and thermal
ablation, which is: “tumour growth exclusively confined to the true renal fossa”. Instead, recurrences
within the renal vein, the ipsilateral adrenal gland or the regional LNs were included under this term.
Isolated tumour recurrence within the true renal fossa only is a rare event. Recurrent tumour growth in
the regional LNs or ipsilateral adrenal gland may reflect metachronous metastatic spread (see Section
7.3).
Only retrospective and non-comparative data on the frequency and efficacy of available
therapeutic options have been reported. 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 [455]. Another recent series identified 33 local
recurrences within a cohort of 2,502 surgically treated patients, confirming the efficacy of surgical
treatment vs. conservative approaches (observation, medical therapy). In a series of 1,955 patients
with clinical T1 RCCs treated with PN, 95 patients (4.9%) had a pT3a upstaging, indicating a high risk
for local and intra-renal recurrence and reduced survival [456]. These data were further confirmed by
an analysis of the SEER database showing that up-staging to pT3a with worse CSS occurred in 4.2%
of cT1a tumours and in 9.5% of cT1b tumours [457].
In summary, the limited available evidence suggests that in selected patients surgical
removal of locally recurrent disease can induce durable tumour control. Since local recurrences
develop early, with a median time interval of 10-20 months after treatment of the primary tumour
[458], a guideline-adapted follow-up scheme for early detection is recommended (see Chapter 8 -
Follow-up). Data show that both adequate pre-operative assessment and careful surgical technique
are crucial in reducing local recurrence risk.
Adverse prognostic parameters are a short time interval (< 3-12 months) since treatment of the
primary tumour [459], sarcomatoid differentiation of the recurrent lesion and an incomplete surgical
resection [455]. In case 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).
[Link] of evidence and recommendation for
advanced/metastatic RCC

Summary of evidence LE
Isolated recurrence in the local renal fossa is rare. 3
In the absence of adverse prognostic factors such as sarcomatoid features or median 3
time interval of < 12 months since treatment of the primary tumour, resection of local
recurrences can induce durable tumour local control.
Most local recurrences develop within the first two years following treatment of the 3
primary tumour. A guideline-adapted follow-up regimen is advised for early detection.
Recommendation Strength
rating
Offer surgical resection of locally recurrent disease when a complete resection is Weak
possible and significant comorbidities are absent.
 [Link]-UP IN RCC
[Link]
Surveillance after treatment for RCC allows the urologist to monitor or identify:
 post-operative complications;
 renal function;
 local recurrence;
 recurrence in the contralateral kidney;
 development of metastases.
There is no consensus on surveillance after RCC treatment, and there is no evidence that early vs.
later diagnosis of recurrences improves survival. Intensive radiological surveillance for all patients is
not necessary. However, follow-up is important to increase the available information on RCC and
should be performed by a urologist who should record the time to recurrence or the development of
metastases. 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 developing recurrence or
metastases. Although there is no randomised evidence, large studies have examined prognostic
factors with long follow-up periods [20,460,461] (LE: 4). One study has shown a survival benefit for
patients who were followed within a structured surveillance protocol vs. patients who were not [462];
patients undergoing follow-up seem to have a longer OS when compared to patients not undergoing
routine follow-up [462].
An individualised, risk-based, approach to RCC surveillance was recently proposed. The
authors use 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 [463].
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. The RECUR database consortium initiated by this Panel collects similar data with the aim
to provide comparators for guideline recommendations. Preliminary data support a risk-based
approach. In the near future, genetic profiles may refine the existing prognostic scores and external
validation in datasets from adjuvant trials were promising [8,464].
Renal function is assessed by the measurement of serum creatinine and eGFR. Repeated long-term
monitoring of eGFR is indicated in case of impaired renal function before, or after, surgery. Renal
function [465,466] and non-cancer survival [208,209,467] can be optimised by performing NSS,
whenever possible, for T1 and T2 tumours [468] (LE: 3). Recurrence after PN is rare, but early
diagnosis is useful, as the most effective treatment is surgery [469,470]. Recurrence in the
contralateral kidney is also rare (1-2%), can occur late (median 5-6 years), and might be related to
positive margins, multifocality, and grade [471] (LE: 3). Surveillance can identify local recurrences or
metastases at an early stage. In metastatic disease, extended tumour growth can limit the opportunity
for surgical resection which is considered the standard therapy in cases of resectable and preferably
solitary lesions. In addition, early diagnosis of tumour recurrence may enhance the efficacy of
systemic treatment if the tumour burden is low.
[Link] investigations for which patients, and when?

 The sensitivity of chest radiography and US for small metastases is poor. The sensitivity of
chest radiography is significantly lower than CT-scans, as proven in histology controlled
comparative trials [472-474].
 Surveillance with these imaging modalities are less sensitive [475].
 In low-risk tumours, surveillance intervals should be adapted taking into account radiation
exposure and benefit. To reduce radiation exposure, MRI can be used outside the thorax.
 When the risk of relapse is intermediate or high, CT of the chest, abdomen and pelvis should
be performed.
  Surveillance should also include evaluation of renal function and cardiovascular risk factors.
 Positron-emission tomography and PET-CT as well as bone scintigraphy should not be used
in RCC surveillance, due to their limited specificity and sensitivity.
 After injection of contrast medium, the risk of acute renal failure seems to be negligible in
patients with a GFR > 20 mL/min and chronic renal impairment [476].
Controversy exists on the optimal duration of follow-up. Some 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. For tumours < 4 cm,
there is no difference between PN and RN with regard to recurrences during follow up [477] (LE: 3).
Several authors have designed scoring systems and nomograms to quantify the likelihood of patients
developing tumour recurrences, metastases, and subsequent death [194,196,478,479]. These
systems have been compared and validated [480] (LE: 2). Using prognostic variables, several stage-
based surveillance regimens have been proposed but none include ablative therapies [481,482]. A
post-operative nomogram is available to estimate the likelihood of freedom from recurrence at five
years [191]. Recently, a pre-operative prognostic model based on age, symptoms and TNM staging
has been published and validated [200] (LE: 3).
A surveillance algorithm for monitoring patients after treatment for RCC is needed,
recognising not only the patient’s risk profile, but also efficacy of the treatment given (Table 8.1).
These prognostic systems can be used to adapt the surveillance schedule according to suspected risk
of recurrence. The most suitable approach to define high-risk patients is the utilisation of nomograms.
Data from adjuvant trials are generally based on the University of California Los Angeles
integrated staging system (UISS) risk stratification which makes it the most widely used and validated
system [360,483].
Table 8.1: Proposed surveillance schedule following treatment for RCC, taking into account
patient risk profile and treatment efficacy (based on expert opinion [LE: 4])
Risk profile Surveillance
6 mo 1 y 2y 3y >3y
Low US CT US CT CT once every 2 years; Counsel about
recurrence risk of ~10%
Intermediate / CT CT CT CT CT once every 2 years
High
CT = computed tomography of chest and abdomen, alternatively use magnetic resonance imaging for
the abdomen; US = ultrasound of abdomen, kidneys and renal bed.
[Link] of evidence and recommendations for surveillance
following RN or PN or ablative therapies in RCC

Summary of evidence LE
Surveillance can detect local recurrence or metastatic disease while the patient is still 4
surgically curable.
After NSS, there is an increased risk of recurrence for larger (> 7 cm) tumours, or when 3
there is a positive surgical margin.
Patients undergoing surveillance have a better overall survival than patients not 3
undergoing surveillance.
Repeated CT scans do not reduce renal function in chronic kidney disease patients. 3
Recommendations Strength
rating
Base follow-up after RCC on the risk of recurrence. Strong
Intensify follow-up in patients after nephron-sparing surgery for tumours > 7 cm Weak
or in patients with a positive surgical margin.
Base risk stratification on pre-existing classification systems such as the Strong
University of California Los Angeles integrated staging
system: [Link] or the SSIGN score.
[Link] priorities
There is a clear need for future research to determine whether follow-up can optimise patient survival.
Further information should be sought at what time point restaging has the highest chance to detect
recurrence. Prognostic markers at surgery should be investigated to determine the risk of relapse over
time.

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