# French AFU Cancer Committee Guidelines u2013
## Update 2024u20132026: Management of kidney cancer

Pierre Bigot, Romain Boissier, Zine Eddine Khene, Laurence Albigès, Jean Christophe Bernhard, Jean Michel Correas, Stéphane de Vergie, Nicolas Doumerc, Matthieu Ferragu, Alexandre Ingels, et al.

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► To cite this version:

Pierre Bigot, Romain Boissier, Zine Eddine Khene, Laurence Albigès, Jean Christophe Bernhard, et al. French AFU Cancer Committee Guidelines u2013 Update 2024u20132026: Management of kidney cancer. The French Journal of Urology, 2024, 34 (12), pp.102735. 10.1016/j.fjurol.2024.102735. hal-04822743

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Recommendations

# French AFU Cancer Committee Guidelines – Update 2024–2026:
## Management of kidney cancer

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Pierre Bigot<sup>a,b,*</sup>, Romain Boissier<sup>a,c</sup>, Zine-Eddine Khene<sup>a,d</sup>, Laurence Albigès<sup>a,e</sup>, Jean-Christophe Bernhard<sup>a,f</sup>, Jean-Michel Correas<sup>a,g</sup>, Stéphane De Vergie<sup>a,h</sup>, Nicolas Doumerc<sup>a,i</sup>, Matthieu Ferragu<sup>a,b</sup>, Alexandre Ingels<sup>a,j</sup>, Gaëlle Margue<sup>a,f</sup>, Idir Ouzaïd<sup>a,k</sup>, Caroline Pettenati<sup>a,l</sup>, Nathalie Rioux-Leclercq<sup>a,m</sup>, Paul Sargos<sup>a,n</sup>, Thibaut Waeckel<sup>a,o</sup>, Philippe Barthelemy<sup>a,p</sup>, Morgan Rouprêt<sup>a,q</sup>

ARTICLE INFO

Keywords:

Kidney cancer

Recommendation

French Association of Urology

A B S T R A C T

**Objective:** To update the French recommendations for the management of kidney cancer.

**Methods:** A systematic review of the literature was conducted for the period from 2014 to 2024. The most relevant articles concerning the diagnosis, classification, surgical treatment, medical treatment, and follow-up of kidney cancer were selected and incorporated into the recommendations. The recommendations have been updated specifying the level of evidence (strong or weak).

**Results:** Kidney cancer following prolonged occupational exposure to trichloroethylene should be considered an occupational disease. The reference examination for the diagnosis and staging of kidney cancer is the contrast-enhanced thoraco-abdominal CT scan. PET scans are not indicated in the staging of kidney cancer. Percutaneous biopsy is recommended in situations where its results will influence therapeutic decisions. It should be used to reduce the number of surgeries for benign tumors, particularly avoiding unnecessary radical nephrectomies. Kidney tumors should be classified according to the pTNM 2017 classification, the WHO 2022 classification, and the ISUP nucleolar grade. Metastatic kidney cancers should be classified according to IMDC criteria. Surveillance of tumors smaller than 2 cm should be prioritized and can be offered regardless of patient age. Robot-assisted laparoscopic partial nephrectomy is the reference surgical treatment for T1 tumors. Ablative therapies and surveillance are options for elderly patients with comorbidities for tumors larger than 2 cm. Stereotactic radiotherapy is an option to discuss for treating localized kidney tumors in patients not eligible for other treatments. Radical nephrectomy is the first-line treatment for locally advanced localized cancers. Pembrolizumab is recommended for patients at high risk of recurrence after surgery for localized kidney cancer. In metastatic patients, cytoreductive nephrectomy can be immediate in cases of good prognosis, delayed in cases of intermediate or poor prognosis for patients stabilized by medical treatment, or as "consolidation" in patients with complete or major partial response at metastatic sites after

<footnote><sup>a</sup> Oncology Committee of the French Urology Association, Kidney Group, Maison de l'Urologie, 11, rue Viète, 75017 Paris, France</footnote>

<footnote><sup>b</sup> Department of Urology, Angers University Hospital, Angers, France</footnote>

<footnote><sup>c</sup> Department of Urology and Kidney Transplantation, Conception University Hospital, Aix-Marseille University, AP-HM, Marseille, France</footnote>

<footnote><sup>d</sup> Department of Urology, Rennes University Hospital, Rennes, France</footnote>

<footnote><sup>e</sup> Department of Cancer Medicine, Gustave-Roussy, Paris-Saclay University, Villejuif, France</footnote>

<footnote><sup>f</sup> Department of Urology, Hôpital Pellegrin, Bordeaux University Hospital, Bordeaux, France</footnote>

<footnote><sup>g</sup> Department of Adult Radiology, Hôpital Necker, University of Paris, AP-HP Centre, Paris, France</footnote>

<footnote><sup>h</sup> Department of Urology, Nantes University Hospital, Nantes, France</footnote>

<footnote><sup>i</sup> Department of Urology and Renal Transplantation, Toulouse University Hospital, Toulouse, France</footnote>

<footnote><sup>j</sup> Department of Urology, UPEC, Hôpital Henri-Mondor, Créteil, France</footnote>

<footnote><sup>k</sup> Department of Urology, Bichat University Hospital, AP-HP, Paris, France</footnote>

<footnote><sup>l</sup> Department of Urology, Hôpital Foch, University of Versailles - Saint-Quentin-en-Yvelines, 40, rue Worth, 92150 Suresnes, France</footnote>

<footnote><sup>m</sup> Department of Pathology, Rennes University Hospital, Rennes, France</footnote>

<footnote><sup>n</sup> Department of Radiotherapy, Hôpital Pellegrin, Bordeaux University Hospital, Bordeaux, France</footnote>

<footnote><sup>o</sup> Department of Urology, Caen University Hospital, Caen, France</footnote>

<footnote><sup>p</sup> Medical Oncology, Institut de Cancérologie Strasbourg Europe, Strasbourg, France</footnote>

<footnote><sup>q</sup> Urology, Hôpital Pitié-Salpêtrière, Predictive Onco-Urology, GRC 5, Sorbonne University, AP-HP, 75013 Paris, France</footnote>

<footnote>* Corresponding author. Oncology Committee of the French Urology Association, Kidney Group, Maison de l'Urologie, 11, rue Viète, 75017 Paris, France.
E-mail address: pibigot@chu-angers.fr (P. Bigot).</footnote>
systemic treatment. Surgical or local treatment of metastases can be proposed for single lesions or oligometastases. Recommended first-line drugs for metastatic clear cell renal carcinoma are combinations of axitinib/ pembrolizumab, nivolumab/ipilimumab, nivolumab/cabozantinib, and lenvatinib/pembrolizumab. Patients with non-clear cell metastatic kidney cancer should be presented to the CARARE Network and prioritized for inclusion in clinical trials.

**Conclusion:** These updated recommendations are a reference that will enable French and French-speaking practitioners to optimize their management of kidney cancer.

© 2024 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license

(http://creativecommons.org/licenses/by/4.0/).

# 1. Epidemiology, risk factors

## 1.1. Epidemiology

Kidney cancer is the 14th most common cancer worldwide. Its incidence varies widely by region, with the highest rates observed in men, those aged 75 years and older, and in the Western Hemisphere, particularly in Europe and North America. [1]. The number of kidney cancers cases has increased in most countries in recent decades, particularly in younger populations (< 50 years) [2]. The reasons for this trend are debated, but possible explanations include increased use of imaging examinations leading to incidental findings, a rise in risk factors like obesity, and an aging population [3]. However, our understanding of this phenomenon is still limited and requires focused attention on a global scale [4].

It is estimated that 17,141 new cases of kidney cancer will be diagnosed in France in 2023, which represents a 199% increase in incidence rates between 1990 and 2023. This increase was particularly pronounced among individuals under the age of 50 and in men. [5]. Notwithstanding the considerable rise in the incidence of kidney cancer in France, mortality rates have remained relatively stable, with 5589 deaths recorded in 2018 [6].

A review of the histological characteristics of kidney cancers reveals that the vast majority (90%) of cases are renal cell carcinomas (RCCs). The principal subtypes are clear cell RCC (70%), papillary RCC (10–15%), and chromophobe RCC (5%). The remaining subtypes are exceedingly rare, with an incidence of less than or equal to 1% [7].

## 1.2. Risk factors

The non-modifiable risk factors for kidney cancer are age, with a peak in incidence after the age of 75 [8] gender, with a male/female incidence ratio of 2/1 [9] and familial forms, which account for 3% to 5% of kidney cancers [10].

Modifiable risk factors are lifestyle-related and can be targeted for primary prevention. These include metabolic syndrome (RR 1.62 [1.41–1.87]), obesity (RR: 2.16 [1.77–2.63]), arterial hypertension (RR: 1.70 [1.30–2.22]) and smoking (RR: 1.39 [1.28–1.51]) [2,11–17]. Additionally, chronic renal failure is also associated with an increased risk of kidney cancer (RR 2.58, 95% CI 1.21–5.50) [7,16]. Chronic end-stage renal disease is associated with bilateral and/or multifocal forms that are generally not highly aggressive [18–21]. The role of diabetes as an independent risk factor for kidney cancer remains a topic of debate [7,14,16].

Since 2021, kidney cancer can be recognized as an occupational disease in the case of exposure to trichloroethylene for more than 10 years, with a waiting period for reimbursement of 40 years. [22]. Trichloroethylene is a chlorinated solvent with a long history of use in industry, mainly for degreasing metal parts and dry-cleaning clothes, but also as a component of paints, varnishes and pesticides. [23]. Its use by private individuals has been restricted in France since 1985, and has been definitively banned in the European Union since 2016 [24,25]. The restrictive list of work recognized by the new table is: “degreasing and cleaning of tools, mechanical or electrical equipment and metal parts before 1995” [22].

For anyone diagnosed with kidney cancer, it is essential to investigate their past employment and exposure circumstances, particularly to carcinogens known to cause kidney cancer, such as trichloroethylene.

Tools may be employed to assess exposure based on industrial toxicology data (INRS), documents from past companies attesting to exposure (exposure certificates, nuisance job sheets or others such as the single document, the occupational health file, Ministry of Labour), or such as job-exposure matrices (Matgéné from Santé publique France direct access).

Patients currently under the care of an occupational health physician or a regional center for occupational and environmental pathology should be referred to these professionals to confirm or rule out exposure and consider subsequent steps, such as compensation, prevention, and potential return to work if appropriate (Recommendation Table 1).

## 1.3. Protective factors and prevention

A physically active lifestyle and a diet rich in vegetables, fruit, and vitamin C may confer protection against kidney cancer [7,26–30]. However, the underlying mechanisms remain poorly described, and there are no high-level studies on this subject. The most effective primary prevention strategy is to promote healthy behaviors, including smoking prevention and cessation, reduction of obesity, and promotion of physical activity [2,7,28,31] (Recommendation Table 2).

## 1.4. Screening

The low prevalence of kidney cancer represents a significant challenge to the effectiveness of systematic screening. To date, no biomarker (blood or urine) or imaging protocol has demonstrated a favorable cost-benefit ratio [31–34]. Nevertheless, an increasing number of studies are examining the potential for integrating CT screening for kidney cancer with lung cancer [35,36].

It seems reasonable to suggest that surveillance of high-risk individuals is an appropriate course of action. In the case of Von Hippel-Lindau disease, the current recommendation is for screening by abdominal MRI every two years from the age of 15 [37]. Other familial forms of hereditary kidney cancer could benefit from screening [38].

**Recommendation Table 1**

Exposure to trichloroethylene and occupational disease.

<table><thead><tr><td>Recommendation</td><td>Grade</td></tr></thead><tbody><tr><td>A patient diagnosed with kidney cancer after more than 10 years' occupational exposure to trichloroethylene should be referred to a specialist in occupational medicine and/or to a regional center for occupational and environmental pathology.</td><td>High</td></tr></tbody></table>

**Recommendation Table 2**

Primary prevention of kidney cancer.

<table><thead><tr><td>Recommendation</td><td>Grade</td></tr></thead><tbody><tr><td>Smoking cessation, physical activity and weight loss in obese patients are recommended as primary prevention to reduce the risk of kidney cancer.</td><td>High</td></tr></tbody></table>
**Recommendation Table 3**

Kidney cancer and screening.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>Kidney cancer screening is not recommended in the general population</td><td>High</td></tr><tr><td>Screening for kidney cancer in certain at-risk populations, such as hereditary kidney cancer, hemodialysis patients and transplant patients, should be discussed with the patient.</td><td>High</td></tr></tbody></table>

Monitoring patients with end-stage renal disease, who have a tenfold increased risk of developing RCC, may also be a valid approach [39]. The Transplantation Committee of the French Urology Association (CTAFU) recommends regular monitoring of native kidneys using appropriate imaging in transplant patients (low grade) [40] (Recommendation Table 3).

## 2. Diagnostic evaluation of a kidney tumour

### 2.1. Imaging techniques: techniques and results

Most renal tumours are discovered incidentally on abdominal ultrasound or computed tomography (CT) scans ordered for other medical reasons [41]. The diagnosis and characterization of renal masses are based on three complementary imaging techniques – Doppler ultrasound, CT and MRI – which can be performed with or without contrast injection (Recommendation Table 4).

#### 2.1.1. Doppler ultrasound

Ultrasound often detects renal masses, incidentally, providing essential characterization elements such as distinguishing between cystic or solid masses, identifying typical or atypical features, and identifying a distinctly hyperechoic appearance suggestive of angiomyolipoma (AML). When combined with Doppler ultrasound, it can assess the vascularization of the mass and evaluate vascular extension into the renal vein or inferior vena cava. Ultrasound is also useful for active surveillance to measure the renal tumor and provides highly effective guidance for biopsies by allowing real-time visualization of the needle's trajectory.

The use of an intravenous contrast agent, such as Sonovue®, enhances the characterization of poorly vascularized solid masses, atypical cystic masses, and venous thrombi, helping differentiate between tumor and cruciate thrombi. It also aids in guiding biopsies toward non-necrotic areas in large tumors [42–44]. The contrast agent is well tolerated in clinical practice, with no contraindication related to renal function [42].

#### 2.1.2. Computed tomography (CT)

2.1.2.1. Iodinated contrast media (ICP). ICPs are less well-tolerated contrast agents, with hypersensitivity reactions occurring in up to 3% of cases, including 0.04% of severe anaphylactic reactions. The risk of renal

function deterioration ranges from 2% to 6%, depending on the route of administration for low osmolality contrast products [45–47]. Patients at risk of contrast-induced nephropathy include those with:

* acute renal failure;

* a glomerular filtration rate (GFR) of less than 45 mL/min/1.73 m² for suprarenal intra-arterial injection or patients hospitalized in intensive care;

* a GFR of less than 30 mL/min/1.73 m² for sub-renal intra-arterial or intravenous injection (e.g., in CT scans).

In patients at risk, alternative imaging modalities such as MRI or ultrasound with contrast injection should be considered, or precautions like ensuring adequate hydration should be taken. It's recommended to space ICP injections at least three days apart, limit the injected dose to the minimum necessary, and monitor creatinine levels 48 to 72 hours post-injection.

Hemodialysis after contrast injection does not reduce renal toxicity from ICPs [47]. However, for dialysis patients, CT with contrast injection is preferable to MRI with injection if the diagnostic benefit is comparable. For diabetic patients on metformin, there is no need to stop the medication due to the risk of lactic acidosis if the GFR is above 30 mL/min/1.73 m². If the GFR is below this threshold, metformin should be discontinued on the day of injection and resumed only after checking creatinine levels at 48 hours, provided there is no significant change in renal function. Lastly, even secretory light chain myeloma is no longer an absolute contraindication to the use of ICPs, depending on renal function [48].

2.1.2.2. Technical. CT is the reference examination for the evaluation of kidney tumors in the absence of contraindications to ICP. The dose of ICP must be sufficient to detect enhancement of hypovascular tumors and Bosniak III and IV cystic masses (0.2 mL/kg of a product containing 350 mg/mL iodine). A CT scan may comprise four phases:

* acquisition without injection, which is essential for defining contrast (> + 20 HU between the tubular phase and acquisition without injection);

* acquisition at the cortical phase, which should occur 30 to 40 seconds after injection;

* acquisition at the nephrogenic phase, which should occur 80 to 100 seconds after injection (this is different from the portal phase, which is acquired 60 seconds after injection and in which the medullary is not yet enhanced);

* late excretory acquisition.

In accordance with the indications, these phases may be combined with the objective of limiting irradiation. The acquisition in the excretory phase is dependent on the indication, with the aim of either searching for late enhancement or studying the relationship between the tumor and the excretory tract [49–51].

**Recommendation Table 4**

Recommendations for imaging kidney tumours.

<table><thead><tr><td>Recommendations for imaging kidney tumours</td><td>Grade</td></tr></thead><tbody><tr><td>The pre-therapeutic assessment of a renal tumour should include an abdominal and pelvic CT scan if there is no contraindication to the use of iodinated contrast products. It should include at least three phases.</td><td>High</td></tr><tr><td>Masses with a cystic component must be analyzed according to the Bosniak classification.</td><td>High</td></tr><tr><td>MRI is an alternative in cases of renal failure, in the exploration of cystic tumours and tumours poorly characterized by other imaging examinations.</td><td>High</td></tr><tr><td>18-FDG PET scans are not recommended for the initial assessment of kidney tumours.</td><td>High</td></tr></tbody></table>
For renal imaging, it is recommended that patients should not fast, and that the digestive tract should not be opacified. Dual-energy and spectral CT is a new technology whose results could be promising for the study of renal pathology [52]. Spectral mode CT imaging is under development and has promising applications in the study of renal pathology. There are various technologies available, involving either the emission of the X-ray beam or the sensors. In current practice, they provide access to single-energy images and iodine mapping (with measurement of iodine concentration). These examinations can be carried out with a lower dose of contrast product (less than 80–100 mL) while reducing the radiation dose. Artefacts associated with pseudo-enhancement of central renal masses and metallic artefacts are reduced. Lowering the keV improves the sensitivity of the technique for detecting low enhancement (papillary carcinomas) [53–55]. In several preliminary studies, improved enhancement detection has led to better characterization of cystic masses [56,57]. Nevertheless, it should be emphasized that these new technologies require a new definition of enhancement thresholds, which must be adapted to the energy levels used for image reconstruction. In the study of solid masses, spectral scanning could make it possible to develop new biomarkers such as the normalized iodine concentration, the measurement of enhancement at a fixed energy (such as 70 keV) and the slope of the spectral energy. These parameters could allow better differentiation between high-grade tumours [58,59].

2.1.2.3. *Results and indications.* CT is the preferred technique for identifying angiomyolipoma (AML), as it is capable of detecting macroscopic islands of fat (density < -20 HU). However, it should be noted that fatty metaplasia associated with calcifications may occur in clear cell carcinomas, albeit exceptionally. In the absence of macroscopic fat, AML may exhibit moderate spontaneous hyperdensity (density > 45 HU) and homogeneous enhancement [60].

Cystic lesions must be analyzed according to the Bosniak classification, which distinguishes five categories according to the risk of malignancy. This classification is applicable to cystic masses in the absence of any infectious context or autosomal polycystic disease. However, there is considerable variability in the rate of malignancy due to differences in diagnostic criteria, study bias, acquisition technique, and imaging method (CT vs. MRI vs. contrast ultrasound).

Additionally, CT provides information regarding the characterization of RCC, specifically whether the enhancement is hypervascular or homogeneous. Nevertheless, these findings are merely indicative and should prompt the patient to undergo a renal puncture biopsy as soon as the nature of the result allows for modification of the management plan.

A computed tomography (CT) examination with an injection is the primary diagnostic tool used in the preoperative assessment of a kidney tumor. The optimal imaging protocol would entail a pre-injection study and three post-injection phases, with multiplanar and maximum intensity projection (MIP) reconstructions. This allows for a precise assessment of the tumor, including its size, location, relationship with the upper excretory tract and vessels, as well as the perirenal fat. The use of grading according to the RENAL or PADUA scores may prove useful in predicting the complexity of partial nephrectomy [61]. In the case of venous thrombosis, the level of the upper portion of the thrombus in relation to the diaphragm and the ostium of the supraepatic veins must be determined. It looks for a synchronous tumour in the contralateral kidney.

### 2.1.3. MRI

Magnetic resonance imaging (MRI) has become a preferred alternative to computed tomography (CT) in cases where IPC injection is contraindicated, such as in patients with renal failure with a glomerular filtration rate (GFR) below 30 mL/min or a history of anaphylactic reaction to PCI injection. It is indicated for characterizing atypical cystic and solid masses that remain undetermined on CT scan, for extension assessment (particularly vascular), and for monitoring patients with familial hereditary cancer. Nevertheless, the pre-therapeutic assessment of kidney tumors continues to rely primarily on CT.

#### 2.1.3.1. Gadolinium-based contrast media (GBM) [46,47].
They are very well tolerated in clinical practice, and systemic nephrogenic fibrosis is now a very rare side effect, and has even disappeared [62]. It used to occur in patients with severe renal insufficiency (GFR < 15 mL/min/1.73 m²) or dialysis, and its incidence was linked to the stability of the Gadolinium chelating complex. In patients at risk, injection is not currently contraindicated if the clinical benefit outweighs the risk, which is the case for kidney cancer, but only products with high stability should be used (Gadobutrol, Gadoterate meglumine and Gadoteridol). PCG can lead to the accumulation of gadolinium in the basal ganglia, though no specific neurological symptoms have been linked to these deposits so far. Additionally, gadolinium can accumulate in bone, liver, and skin. In the skin, this can result in erythematous plaques similar to those seen in systemic nephrogenic fibrosis, although these occurrences are not associated with renal failure.

#### 2.1.3.2. MRI technique.
The multiparametric study includes axial and coronal T2-weighted sequences without and with saturation of the fat signal, T1-weighted gradient echo in phase and phase opposition (detection of intra-tumour fat on the phase opposition sequence), diffusion at high B (800 to 1000), and finally a dynamic sequence after injection of contrast medium with acquisition of late times (study of tumour wash-out, contrast of central stellate fibrosis in oncocytoma).

#### 2.1.3.3. Results and indications.
T2-weighted sequences (with or without saturation of the fat signal) can be used to differentiate between solid tumors and typical (even sub-centimeter-sized) or atypical fluid masses, as well as to a lesser extent, AML (even low-fat) in T2 hyposignal (hemorrhagic suffusions, papillary formations, or muscle cells) [63,64]. Clear cell carcinomas and oncocytic tumours frequently exhibit a hypersignal [65,66]. The dynamic T1-weighted sequence, conducted before and after the injection of PCG, allows for the differentiation of hypervascular and heterogeneous tumors (which correspond to clear cell carcinomas and AML) from homogeneous, less enhanced tumors (which are characteristic of chromophobe carcinomas) or weakly enhanced tumors (which are characteristic of papillary carcinomas). The presence of a signal drop in phase opposition and on fat saturation sequences is not specific to AML with a low fat contingent, as it is described in many carcinomas [67]. MRI can also be used to identify microcystic areas or necrotic-hemorrhagic changes. A central stellate hypovascular zone is compatible with the diagnosis of oncocytoma but may also be found in renal carcinomas [68]. Diffusion imaging is very sensitive for detecting small subcentimetric tumours that are difficult to characterize by other sequences [69]. Diffusion imaging is also very sensitive for the identification of lymph node, adrenal, pancreatic or hepatic metastases during extension work-up or surveillance [70,71].

MRI can provide supplementary data to computed tomography (CT) in the preoperative assessment of renal tumors with venous thrombus. It offers a superior evaluation of the extent of venous wall invasion, which may necessitate surgical reconstruction or the delineation of the upper thrombus limit [72–75].

Although MRI can assist in the identification of different types of solid tumors, it is not a definitive diagnostic tool due to the lack of specificity of the various combined signs. In cases where subsequent treatment may be modified based on the histological results, biopsy remains an essential procedure [76].

### 2.1.4. Metabolic imaging

The fluorine-18-fluorodeoxyglucose positron emission tomography (PET) scanner (18-FDG PET) is a valuable tool for assessing the extent of many cancers. It is not a useful modality for characterizing kidney tumors. Nevertheless, its potential is currently being investigated in the context of the initial extension assessment and post-surgical recurrence detection. The evaluation of additional tracers may facilitate the acquisition of data pertaining to the histological subtypes of kidney tumors. Single-photon
emission tomography with 99mTc sestamibi appears to have good specificity for characterizing the oncocytoma and chromophobe subtypes [77,78]. Girentuximab (cG250), a chimeric anti-CAIX antibody, is used in molecular imaging for PET/CT imaging when labelled with isotopes such as 131I, 124I or 111In, paving the way for radioimmunotherapy (RIT) in clear cell CRC (ccCCR). Lindenberg et al. evaluated the PET/CT potential of 124I-labelled girentuximab in 195 patients surgically treated for renal tumour and concluded that it had a sensitivity and specificity of 86% for the detection of malignant renal tumours [79]. Hekman et al. conducted a study using 89Zr-labelled girentuximab in PET/CT imaging, demonstrating its ability to predict the histological subtype of ccCCR and exclude recurrence in previously treated patients [80]. Minn et al. developed a novel dual-motif ligand, 64Cu-XYIMSR-06, with high affinity for CAIX, facilitating PET/CT imaging programs compared with girentuximab [81]. More recently, the prospective phase 3 ZIRCON trial studied 89Zr-DFO-girentuximab in 300 patients. PET positivity was assessed by 3 independent readers blinded to ccCCR status. Mean sensitivity and specificity were 86% and 87% respectively in the overall population, and 85% and 90% in the subgroup ≤ 4 cm. Sensitivity and specificity for lesions ≤ 2 cm were 90% and 100%, respectively. Inter- and intra-reader agreement was 91% and 100%, respectively. In the subgroup ≤ 4 cm, the positive and negative predictive values were 93.4% and 78%, respectively [82]. Girentuximab PET scans could be used to assess small renal tumours and could be particularly useful for tumours smaller than 2 cm and/or cystic tumours that are inaccessible to biopsy.

### 2.1.5. Outlook

The advent of novel imaging modalities and artificial intelligence, particularly radiomics, should facilitate more precise characterization of tumor subtypes and their propensity for progression [83] and their potential response to treatment [84].

### 2.2. Assessment of extension

The standard extension assessment is based on thoracic and abdominal-pelvic CT scans, both with and without injection. The thoraco-abdominal-pelvic scan is performed concurrently with the arterial nephrography. In the event that a PCI injection is contraindicated, a thoraco-abdominal and pelvic CT scan without injection may be combined with an abdominal MRI scan without and with injection.

In cases of metastatic disease, it is recommended that systematic brain imaging (either MRI or CT) and bone scintigraphy be performed if symptoms are present.

### 2.3. Anatomical classifications

Morphometric classifications have been developed with the objective of aiding clinicians in surgical planning and providing patients with information regarding conservative surgical options [85]. The oldest are the RENAL [61] and PADUA [86] but over the last 10 years, 16 other classifications have been described [87]. The majority of available studies are retrospective. The predictive values of the RENAL and PADUA scores are superior when they are used for categorization, particularly for estimating the risk of overall or major perioperative complications and the duration of renal ischemia. The principal benefit of these scores is that they offer an objective classification of tumor characteristics, facilitating the comparison of scientific literature.

### 2.4. What biological tests are carried out?

#### 2.4.1. Standard biological work-up

The standard biological work-up for a localized renal tumor should include:

* serum creatinine measurement with GFR calculation;

* blood count.

In the case of metastatic cancer, the following additional tests should be conducted:

* liver function tests (AST, ALT, PAL, total and conjugated bilirubin);

* full ionogram, including phosphorus and magnesium levels;

* protein and albumin levels;

* lipasemia;

* calcemia with calculation of corrected calcemia;

* endocrine assessment (necessary before immunotherapy): cortisolemia, ACTH, TSH, T4I;

* serologies (required before immunotherapy): HIV, hepatitis B, and hepatitis C;

* alkaline phosphatases;

* LDH;

* urine dipstick ± 24-hour proteinuria.

The aim of this assessment is to evaluate renal function, to determine the prognostic factors for IMDC [88] (in the metastatic setting), screen for possible paraneoplastic syndrome (anemia, polycythemia, hypercalcemia, cholestasis), monitor and screen for contraindications to immunotherapy [89,90].

#### 2.4.2. Assessment of renal function

The reference technique for estimating glomerular filtration rate is the calculation of creatinine clearance using the Chronic Kidney Disease Epidemiology Collaboration 2009 (CKD EPI) equation. The CKD EPI equation is considered to outperform the Cockroft/Gault and MDRD (Modification of Diet in Renal Disease) methods [91]. However, there are situations in which calculating creatinine clearance does not provide a reliable assessment of renal function: extreme situations of muscle mass (obesity, cachexia), inhibition of renal tubule secretion (trimethoprim and fenofibrate) and extra-renal elimination of creatinine by the microbiota (broad-spectrum antibiotic therapy). In the preoperative assessment, it is advisable to assess separate renal function by scintigraphy in cases of renal insufficiency or bilateral tumours [92]. Performing a DMSA renal scan allows the relative renal function of each kidney to be assessed, which may be important in the surgical strategy for renal preservation.

Recent work has demonstrated the reliability of the estimation of renal function by late-stage CT imaging with a good correlation with the standard method of measuring iohexol clearance [56].

## 3. Histological diagnosis

### 3.1. WHO 2022 classification

In the latest WHO classification (2022, 5th edition), malignant renal tumors in adults have been divided into six groups: clear cell tumors, papillary tumors, oncocytic and chromophobe tumors, collecting duct tumors, tumors with molecular alterations, and a group of new entities (Table 1) [93].

The group of clear cell tumors includes clear cell renal cell carcinoma, which remains the most frequent histological subtype, and multilocular cystic neoplasia of low malignant potential. The latter is a macrocystic tumor on imaging and histologically, with clusters of non-atypical clear cells measuring less than 1 mm in the cyst wall. This allows for differentiation from cystic clear cell renal cell carcinoma [94,95].

In the case of papillary renal cell carcinomas, the former subtypes 1 and 2 have been superseded by the ISUP nucleolar grade. In light of the ongoing clinical trials that include patients according to these two subtypes, it is recommended that subtypes 1 and 2 be retained until the completion of these trials. Moreover, in the context of a papillary carcinoma, particularly if it is of high grade, it is imperative to systematically rule out FH-deficient carcinoma through immunohistochemistry (which may be associated with hereditary leiomyomatosis, necessitating genetic counseling) and carcinoma with a
<table><caption>**Table 1**

WHO 2022 classification of adult renal tumors.</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td><strong>Renal cell tumours</strong></td><td><strong>Metanephric tumours</strong></td></tr><tr><td><u>Tumours with a clear cell component</u></td><td>Metanephric adenoma</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Clear cell carcinoma of the kidney</td><td>Metanephric adenofibroma</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Multilocular cystic neoplasia with low malignant potential</td><td>Metanephric stromal tumour</td></tr><tr><td><u>Papillary tumours</u></td><td><strong>Mixed epithelial and stromal tumours</strong></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Papillary adenoma</td><td>Mixed epithelial and stromal tumour</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Papillary renal cell carcinoma</td><td><strong>Adult mesenchymal tumours</strong></td></tr><tr><td><u>Oncocytic and chromophobic tumours</u></td><td>Angiomyolipoma/pecoma</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Oncocytoma</td><td>Epithelioid angiomyolipoma</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Chromophobe cell carcinoma</td><td>Hemangioblastoma</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Other oncocytic cell tumours</td><td>Juxta glomerular tumour</td></tr><tr><td><u>Collecting duct tumours</u></td><td>Renomedullary interstitial tumour</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Carcinoma of the collecting duct</td><td><strong>Embryonal tumours</strong></td></tr><tr><td><u>Other renal tumours</u></td><td>Nephroblastic tumours</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Papillary clear cell tumour</td><td>Nephrogenic remains</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Tubular and mucinous spindle cell carcinoma</td><td>Partially differentiated cystic nephroblastoma</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Tubulocystic carcinoma</td><td>Nephroblastoma</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Carcinoma associated with acquired cystic disease</td><td><strong>Rare tumours</strong></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Solid and cystic eosinophilic cell carcinoma</td><td>Germ cell tumours</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Renal cell carcinoma NOS</td><td></td></tr><tr><td><u>Renal carcinomas with molecular alterations</u></td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Carcinoma with TFE3 rearrangement</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Carcinoma with TFEB alterations</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Mutated ELOC carcinoma (formerly TCEB1)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Carcinoma fumarate hydratase/FH deficient</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Carcinoma linked to succinate dehydrogenase deficiency (SDHB)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Rearranged ALK carcinoma</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;SMARCB1-deficient medullary carcinoma</td><td></td></tr></tbody></table>

TFE3 translocation through immunohistochemistry and cytogenetic analysis in FISH [96].

The classification of kidney tumors that are still in the process of being dismembered corresponds to that of oncocytic cell tumors, which still includes oncocytoma and chromophobe carcinoma. However, new entities have emerged that are diagnosed based on histological analysis and immunohistochemical markings. These include low-grade oncocytic tumors (LOT), vacuolated eosinophilic tumors (formerly high-grade oncocytic tumor/HOT), and solid and cystic eosinophilic cell carcinoma. These tumors are typically indolent and may be associated with abnormalities in the mTOR pathway or mutations in the TSC1/TSC2 genes [97–99].

The diagnosis of certain histological subtypes of renal cell carcinoma now necessitates the performance of a molecular analysis. These are primarily carcinomas of the MITF family, namely renal cell carcinoma with TFE3 or TFEB translocation and carcinoma with TFEB amplification. These carcinomas must be considered in the differential diagnosis when a particular histology is observed, namely, a papillary and solid architecture with clear and eosinophilic cells. This is particularly relevant when the patient is younger than 40 years of age. Carcinomas with TFEB amplification are the most aggressive, with a stage of at least pT3a at the time of diagnosis, and progress to metastases in more than two-thirds of cases. A diagnosis is made on the basis of immunohistochemical and, most notably, cytogenetic FISH analysis. The remaining histological subtypes associated with a specific molecular anomaly are mutated ELOC carcinoma (formerly mutated TCEB1), which presents as a carcinoma with a clear cell component separated by a leiomyomatous stroma with a mutation in the ELOC/TCEB1 gene, and in FISH cytogenetic analysis, a monosomy 8. The occurrence of SDHB-mutated or ALK-rearranged carcinomas is less frequent, as is that of medullary carcinoma, which is a highly aggressive neoplasm predominantly observed in individuals with sickle cell anemia. This particular carcinoma is distinguished by its deficiency in INI1/SMARCB1 [100–104].

The 2022 WHO classification has identified a group of tumors that are often associated with a favorable prognosis and which are characterized by the presence of a cystic component. These include tubulocystic carcinomas, carcinomas associated with acquired cystic disease, and solid and cystic eosinophilic cell carcinomas [93].

## 3.2. pTNM classification 2017

The Union for International Cancer Control (UICC) pTNM classification has remained unchanged since 2017. In 2019, the American Joint Committee on Cancer (AJCC) conducted a review of the classification, but the two systems remain identical (Table 2) [105–107].

In light of the advent of adjuvant immunotherapies, it is imperative that pathologists exercise caution to avoid overlooking a pT3a stage, regardless of whether it involves infiltration of hilar or perirenal fat, the

<table><caption>**Table 2**

AJCC/UICC pTNM classification 2017 of malignant tumours of the kidney, 8th edition.</caption><thead><tr><th>AJCC/UICC (2017)</th><th>Status</th></tr><tr><th>Tumour (T)</th><th></th></tr></thead><tbody><tr><td>Tx</td><td>Tumour status cannot be defined</td></tr><tr><td>T1a</td><td>Tumour ≤ 4 cm located in the kidney</td></tr><tr><td>T1b</td><td>Tumour > 4 cm and ≤ 7 cm located in the kidney</td></tr><tr><td>T2a</td><td>Tumour located in the kidney > 7 to ≤ 10 cm</td></tr><tr><td>T2b</td><td>Tumour located in the kidney > 10 cm</td></tr><tr><td>T3a</td><td>Invasion of peri-renal adipose tissue and/or hilar adipose tissue but not Gerota's fascia and/or macroscopic thrombus in the renal vein or in one of its branches and/or infiltration of the pyelocaliceal cavities</td></tr><tr><td>T3b</td><td>Thrombus in the vena cava under the diaphragm</td></tr><tr><td>T3c</td><td>Tumour extending into the vena cava above the diaphragm or invading the muscular wall of the vena cava</td></tr><tr><td>T4</td><td>Tumour infiltrating beyond Gerota's fascia and/or contiguous invasion of the adrenal gland</td></tr><tr><th colspan="2">Lymph node metastasis (N)</th></tr><tr><td>Nx</td><td>No assessment of lymph node status</td></tr><tr><td>N0</td><td>No lymph node metastases</td></tr><tr><td>N1</td><td>Regional lymph node metastasis in a single lymph node</td></tr><tr><td>N2</td><td>Regional lymph node metastasis in more than one lymph node</td></tr><tr><th colspan="2">Remote metastasis (M)</th></tr><tr><td>Mx</td><td>No assessment of metastatic status</td></tr><tr><td>M0</td><td>No metastases</td></tr><tr><td>M1</td><td>Remote tissue metastasis</td></tr></tbody></table>
pyelocaliceal cavities, or a thrombus in the renal vein or one of its branches.

### 3.3. What should the pathology report include?

In the case of all kidney cancers, the conclusion of the pathology report must include all the information required for prognostic assessment and patient management. These items have been defined by the Société française de pathologie and the Institut national du cancer (http://www.sfpathol.org/; www.e-cancer.fr).

A typical conclusion for kidney cancer should include the following items [108]:

* type of surgery (partial or radical nephrectomy);

* laterality (right/left);

* histological subtype according to WHO 2022 classification;

* the size of the tumour at its largest diameter in cm. In the case of multiple tumours, enter the size of the largest tumour;

* ISUP nucleolar grade from 1 to 4;

* the presence or absence of a sarcomatoid component and assessment of its %;

* presence or absence of a rhabdoid component and assessment of its %;

* presence or absence of necrosis (focal vs. extensive);

* the presence or absence of microscopic vascular emboli;

* locoregional extension of the tumour according to the UICC/AJCC 2017 pTNM classification;

* the presence or absence of lymph node metastases;

* the quality of surgical margins in the case of lumpectomy/partial nephrectomy and at the level of the renal vein in the case of tumour thrombus;

* the appearance of the non-tumourous kidney and other associated lesions.

**Recommendation Table 5**

### 3.4. Histopronostic factors

The histopronostic factors for kidney cancer described in the WHO 2016 classification have been incorporated into the 2022 version. These include histological subtype (the most aggressive renal carcinomas being medullary carcinomas, collecting-tube carcinomas and clear-cell carcinomas), ISUP nucleolar grade, the presence of necrosis, especially when extensive (except in low-grade papillary carcinomas, formerly subtype 1), pTNM stage, the presence of vascular emboli and especially the presence of a sarcomatoid or rhabdoid component [93,109,110].

The ISUP nucleolar grade 4 sarcomatoid component is indicative of an epithelial-mesenchymal transition, even if it is only present in a minority of cases, in a manner analogous to the rhabdoid component. The presence of this factor in more than 10% of the tumor is associated with a poor prognosis. Furthermore, this factor is relevant in the context of therapeutic management, as it is associated with a diminished response to tyrosine kinase inhibitors and is postulated to be linked to a more favorable response to immunotherapies (Recommendation Table 5).

### 3.5. When should an oncogenetic consultation be requested?

In accordance with the 2020 recommendations of the INCA/Predir network, an oncogenetic consultation should be proposed if one or more of the following criteria are present (Recommendation Table 5).

**Recommendation Table 5**

Anatomopathology and oncogenetics.

<table><thead><tr><th>Recommendations</th><th>Grade</th></tr></thead><tbody><tr><td>The WHO 2022 and pTNM 2017 classifications should be used to describe a renal tumour.</td><td>High</td></tr><tr><td>The main histopronostic factors to be used to describe a kidney tumour are:</td><td></td></tr><tr><td>- Histological subtype</td><td></td></tr><tr><td>- The ISUP nucleolar grade</td><td></td></tr><tr><td>- Tumour necrosis</td><td>High</td></tr><tr><td>- The pTNM stage</td><td></td></tr><tr><td>- The presence of vascular emboli</td><td></td></tr><tr><td>- The presence of a sarcomatoid or rhabdoid component</td><td></td></tr><tr><td>A centralized review by an expert pathologist from the CARARE network should be proposed for kidney cancer:</td><td></td></tr><tr><td>- kidney cancer in young patients &lt; 40 years old</td><td>Low</td></tr><tr><td>- located outside the papilla, chromophobe and clear cells</td><td></td></tr><tr><td>- metastatic non-clear cell</td><td></td></tr><tr><td>An oncogenetic consultation should be offered to all patients with:</td><td></td></tr><tr><td>- diagnosis before the age of 45 years</td><td></td></tr><tr><td>- histological subtype other than clear cell</td><td>Low</td></tr><tr><td>- multiple and/or bilateral tumours</td><td></td></tr><tr><td>- family history of kidney cancer</td><td></td></tr><tr><td>- extra-renal manifestations suggesting a personal or family syndromic form</td><td></td></tr></tbody></table>
The following criteria should be considered for the recommendation of an oncogenetic consultation:

* age of onset of renal tumor before 45 year for clear cell carcinomas;

* routinely, regardless of the patient's age, for all other histological subtypes;

* if the tumors are multiple and/or bilateral;

* if there is a family history of kidney cancer;

* if there are extrarenal manifestations suggestive of a personal or familial syndromic form (www.e-cancer.fr) [111-115].

### 3.6. When should I request a Carare proofreading?

The Carare network, which addresses the rare cancers of the adult kidney, was accredited by the Inca from 2013 to 2018. It is currently undergoing the reaccreditation process. The objective of this initiative is to facilitate a histopathological review of renal cell carcinomas occurring in young adults under the age of 40 years, rare renal cell carcinomas (all except clear cell, chromophobe, and papillary subtypes), and metastatic renal cell carcinomas, excluding clear cell carcinoma, through a national network of pathologists with expertise in kidney tumors. This network relies on the UroCCR network for patient data and on the national network of pathologists, which encompasses 16 professionals distributed across all regions of France. Since the conclusion of 2022, the Carare network has made available a virtual endoscopic retrograde cholangio-pancreatography (eRCP) platform for any practitioner interested in discussing complex cases and/or the management of kidney cancer, whether surgical or oncological. These eRCPs are held every fortnight on Wednesdays at 5:30 p.m. and are led by two oncologists, two urologists who are members of the board of the Association Française d'Urologie (AFU) kidney cancer committee, and two pathologists, all of whom are experts in renal tumor pathology. Cases may be registered up to 24 hours prior to the scheduled eRCP date via the Pulsy website (carare@icans.eu). The dates of the eRCPs and the procedure for registering are available on the GETUG website (https://recherche.unicancer.fr/fr/les-groupes-d-experts/groupe-detude-des-tumeurs-urogenitales-getug/) and the Carare website (www.carare.fr) (Recommendation Table 5).

## 4. The role of biopsy

### 4.1. Technique

The biopsy can be performed under local anesthesia, on an outpatient basis, under ultrasound or CT scan guidance. The CCAFU recommends using a 16-18 G coaxial needle to avoid the risk of tumor spread, avoiding biopsies in necrotic areas and taking at least two samples.

It is recommended that antiaggregant and anticoagulant treatments be suspended and that a hemostasis and coagulation test be performed prior the biopsy.

Cytopuncture is not effective and is no longer recommended [116].

Biopsies should be fixed in 4% buffered formaldehyde for histologic analysis, FISH, and genetic sequencing. Unfixed conditioning for freezing is recommended for pediatric renal tumors, but freezing is optional for adult renal tumors.

### 4.2. Diagnostic performance

In 2016, two systematic reviews of the literature assessed the performance of renal biopsy [116,117]:

* for the diagnosis of malignancy, sensitivity and specificity were > 95%;

* for the determination of the histologic subtype, the concordance between the biopsy and the surgical specimen was 90%.

Diagnosis of oncocytoma by biopsy is difficult. The concordance between the biopsy and the operative specimen when the biopsy concludes to a renal oncocytoma varies from 65% to 91% depending on

the series [118-120]. Discrepancies between biopsy and surgical specimen in the diagnosis of renal oncocytoma mainly concern other tumors in the oncocytic group (18% to 26% chromophobe carcinoma, hybrid tumour, HOT), more rarely clear cell carcinoma (3% to 13%) [118-121].

The performance of renal biopsy for nuclear grading ranged from 43% to 93%. For renal tumors <4 cm, grade concordance was 86% with a simplified high/low grade classification. In the majority of cases, the grade error was an underestimate compared to the surgical specimen [122,123].

The rate of non-contributory biopsies was heterogeneous, ranging from 10% to 20%. The main predictive factors for non-contributory biopsy were skin-to-tumor distance and tumor size [124].

In the case of non-contributory biopsy, a new biopsy was contributory in more than 90% of cases, with a diagnosis of malignancy in the majority of cases [125,126].

### 4.3. Complications

Complications are rare, occurring in only 2-5% of cases. According to the Clavien-Dindo classification, these complications are typically considered low grade [124,127]. The most common complication is hematoma, which occurs early in the post-biopsy period and usually does not require specific treatment [128].

Major complications requiring intervention (such as embolization, drainage of pneumothorax) occur in 0.4 to 2% of biopsies [116,124,129]. Therefore, clinical observation for at least one hour after biopsy is recommended. Tumor seeding in the path of biopsy is exceptional and may manifest late as recurrence in the path of puncture [130,131].

### 4.4. The role of biopsy in small tumors

For tumors ≤ 4 cm, the diagnostic contribution of biopsy is 90% [123,132]. Sensitivity and specificity for the diagnosis of malignancy are > 95%. The concordance is 96% for histologic subtype and 87% for grade [125]. Biopsy series for small renal masses report up to 30% benign pathology [133]. Tumor biopsy reduces the rate of surgery for benign tumors by up to 50%, usually to the benefit of active surveillance [127,134-143]. However, several surveys of urologists report that tumor biopsy is performed for less than 20% of localized kidney tumors [134,144-147]. Finally, performing a biopsy prior to partial nephrectomy does not appear to increase the technical difficulty of surgery or the risk of positive surgical margins or postoperative complications [148,149].

### 4.5. What are the indications?

The practice of biopsy varies widely in France. More and more questions are being asked about the “medico-legal” nature of biopsy, which could prevent a certain number of benign tumours from being removed [127,134-141].

The position of the CCAFU (expert opinion) is to recommend biopsy in the following situations (Recommendation Table 6, Fig. 1):

* prior to medical treatment in the absence of a histologic diagnosis;

* prior to focal treatment (radiofrequency, brachytherapy, or radiotherapy);

* before extended nephrectomy for localized tumor when partial nephrectomy is not considered feasible (cT1, cT2);

* before partial nephrectomy for tumors with high surgical complexity and risk of totalization;

* for single kidney and bilateral tumors;

* in cases of diagnostic uncertainty (lymphoma, metastasis of another cancer, urothelial carcinoma, sarcoma).
<table><caption>**Recommendation Table 6**
Recommendations for kidney biopsies.</caption><thead><tr><th>Recommendations</th><th>Grade</th></tr></thead><tbody><tr><td>It is recommended for renal biopsies:<br>- Control of imaging guidance<br>- Discontinue antiplatelet agents, anticoagulants, and coagulation testing.<br>- Use of 16-18 G coaxial biopsy needles<br>- At least two biopsies, avoiding necrotic areas</td><td>Low</td></tr><tr><td>Renal biopsy is recommended in the following situations<br>- Before medical treatment in the absence of a histologic diagnosis<br>- Before focal treatment<br>- Before extended nephrectomy for localized tumor when partial nephrectomy is not considered feasible (cT1, cT2)<br>- Before partial nephrectomy for tumors with high surgical complexity and risk of totalization<br>- For urgent indications, single kidney and bilateral tumors<br>- In cases of diagnostic uncertainty (lymphoma, metastases from other cancers, urothelial carcinoma, sarcoma)</td><td>High</td></tr><tr><td>Biopsy is not recommended:<br>- If urothelial cancer is suspected<br>- High risk of bleeding<br>- Cystic tumor without solid component<br>- Typical angiomyolipoma appearance</td><td>Low</td></tr></tbody></table>

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** CCAFU recommendations regarding the indication for kidney biopsies.</figcaption></figure>
The position of the CCAFU (expert opinion) is not to propose biopsy in the following situations

* suspicion of urothelial carcinoma;

* high risk of bleeding;

* cystic tumor without solid component;

* typical angiomyolipoma appearance.

# 5. Treatment of small T1a kidney tumours (≤ 4 cm)

## 5.1. Place of partial nephrectomy (PN)

### 5.1.1. Interest and objectives

PN is the surgical technique of choice for small renal masses. It must meet three imperatives: oncologic control, preservation of renal function and limitation of perioperative complications (Recommendation Table 7).

### 5.1.2. Oncology monitoring

Several studies have demonstrated equivalent oncological control in the case of PN or radical nephrectomy (RN) [150,151]. After NP for a T1a tumour, 5-year recurrence-free survival is >95% [152,153]. A positive surgical margin increases the risk of local recurrence but does not appear to have any impact on specific survival [154,155]. In the case of a positive surgical margin, simple surveillance with regular imaging examinations is recommended. Immediate totalization by nephrectomy is not necessary [156,157]. In the case of an aggressive high-grade tumour and/or a large positive margin, totalization may be discussed at the multidisciplinary consultation meeting (RCP). Treatment of local recurrence has been little evaluated. Enlarged nephrectomy, a second partial nephrectomy or ablative treatment may be used depending on the time to recurrence, histological type and grade [157,158]. The UroCCR RePart study, published in 2022, reports on the value of ablathermy for the treatment of local recurrence after PN. Compared with surgical salvage treatment, these percutaneous techniques allow better preservation of renal function and less morbidity [159].

### 5.1.3. Preserving renal function

PN allows optimal preservation of the renal parenchyma, which limits the deterioration of renal function [160]. This functional preservation reduces the risk of cardiovascular events and could increase overall survival compared with RN [161–163]. Renal preservation is also associated with a positive psychological impact and a better quality of life [164].

#### 5.1.3.1. Duration of ischemia
The effect of the duration of ischemia on the decline in renal function is controversial. Renal ischemia may be more detrimental in patients with pre-existing renal insufficiency [165]. Data in the literature are conflicting, but it is advisable to limit the duration of renal pedicle clamping to less than 25 minutes [166–168]. Techniques without clamping or with selective clamping reduce the risk of deterioration in early postoperative renal function but have not been shown to result in better long-term renal preservation compared with total clamping < 25 minutes [169–173].

#### 5.1.3.2. The renorrhaphy technique
Few studies have evaluated the different reconstructive techniques, but some authors suggest that “sutureless” techniques may result in a smaller reduction in GFR in the immediate postoperative period, without demonstrating any difference in terms of GFR in the late postoperative period, morbidity or oncological outcome [174,175].

#### 5.1.3.3. Preservation of parenchymal volume
Preservation of healthy renal parenchyma appears to be the most important factor in maintaining renal function [166,168,176]. Tumour enucleation techniques preserving a minimal margin of healthy tissue do not appear to increase the rate of local recurrence, but their contribution to preserving renal function is uncertain [177,178].

### 5.1.4. Morbidity

There is a significant morbidity associated with PN, which has been reported in the literature to be approximately 20%. The two most feared complications are secondary hemorrhage (false aneurysm) and urinary fistula [179]. The rate of serious complications after NP can be as high as 11%. The risk of complications is influenced by a number of factors: tumour complexity, age, co-morbidities, surgeon's experience, size of center, approach [180–182]. The prospective UroCCR study RoPAN [183] published in 2023 assesses late complications after robotic-assisted PN. Approximately 10% of patients are affected in the first year following surgery. These are mainly vascular, infectious and parietal complications occurring during the first 3 months.

### 5.1.5. Technique: open route vs. laparoscopy vs. robot-assisted laparoscopy

Regardless of the approach (open vs. laparoscopic vs. robotic-assisted) for PN, there is no difference in terms of specific survival and overall survival [184,185].

**Recommendation Table 7**

Recommendations for surgery on small kidney tumours.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>Partial nephrectomy is the recommended first-line surgical treatment for T1a tumours.</td><td>High</td></tr><tr><td>The use of a minimally invasive approach (laparoscopic with or without robotic assistance) is less morbid and should be preferred when performing partial or total nephrectomy for localized tumours.</td><td>High</td></tr><tr><td>Transperitoneal or retroperitoneal routes for partial nephrectomy are equivalent in terms of morbidity, rate of positive surgical margins and renal function.</td><td>Low</td></tr><tr><td>Close monitoring is recommended in the case of positive surgical margins</td><td>Low</td></tr><tr><td>A radical nephrectomy may be proposed for a small renal mass if:<ul><li>non-functioning kidney</li><li>suspected T3a tumour</li><li>complexity deemed too high after confirmation of a second opinion from an expert center</li><li>confirmed histological diagnosis of malignant tumour by biopsy</li></ul></td><td>High</td></tr></tbody></table>
Compared with the open approach, laparoscopy reduces blood loss and length of stay. On the other hand, operating and ischemia times are longer. Postoperative complications and long-term renal function are similar [185-187]. Some teams propose preoperative embolization of tumors to facilitate surgery and reduce postoperative complications [188]. Compared with the open approach, robot-assisted laparoscopy appears superior in terms of blood loss, length of stay, complications and duration of ischemia. The rate of positive margins and residual renal function are similar [189-191]. This reduction in morbidity makes it possible to offer outpatient management for selected patients [192,193]. Compared with the laparoscopic approach, the robot-assisted approach has an advantage in terms of the duration of ischemia and conversion to the open approach [184,194]. There is also an advantage in terms of the rate of conversion to RN, particularly for complex and hilar tumours [185,195].

Robotic assistance coupled with three-dimensional modelling techniques is enabling the development of image-guided surgery, and its value is currently being evaluated. A French study (UroCCR-51) reported an overall improvement in the surgical procedure (trifecta) [196].

### 5.1.6. Transperitoneal vs. retroperitoneal laparoscopic approach

A prospective multicenter observational study showed no significant difference between transperitoneal NP and retroperitoneal NP in terms of postoperative complications, positive surgical margins and functional outcomes (GFR). Shorter operative time and less frequent intraoperative complications favored the transperitoneal approach [197].

### 5.1.7. The center effect in France

A prospective study carried out in France in 2010 in hospital, university and private practice institutions suggested a center effect of PN, with an increase in morbidity and the rate of positive margins in centers with a smaller volume [198]. A CCAFU study also demonstrated better results in high-volume centers for robotic PN [199]. Although it seems difficult to make recommendations on a possible threshold, the CCAFU encourages teams to organize themselves in such a way that the PN activity is concentrated on a few expert surgeons according to the volume of activity.

## 5.2. Place of radical nephrectomy (RN)

### 5.2.1. Interest and objectives

RN is not recommended as a first-line treatment for small kidney tumours. It may be proposed in cases of non-functioning kidney, suspected locally advanced tumour (T3a) or significant complexity. If the

tumour is deemed too complex, it is advisable to seek the advice of an expert center before undergoing RN.

### 5.2.2. Technique: open route vs. laparoscopy vs. robot-assisted laparoscopy

The oncological results of the different approaches are equivalent [200,201]. Laparoscopy is associated with a shorter hospital stay, a reduction in the use of analgesics and a reduction in operative bleeding [202]. Transperitoneal or retroperitoneal laparoscopic approaches have equivalent oncological results and quality of life [203]. Very few studies have compared the robot-assisted technique with standard laparoscopy, whose results appear to be equivalent [204].

## 5.3. Place of ablative therapies (AT)

### 5.3.1. Technique and results

Small renal tumors can be treated with ablative therapies (AT). A biopsy of the lesion is required beforehand. There are several different AT techniques:

* radiofrequency and microwaves;

* cryotherapy;

* irreversible electroporation.

AT may be offered as an option to patients whose tumor can be treated completely. The long-term technical and functional results of TA are good [205-207]. There are no randomized studies comparing TA vs. PN and the published retrospective studies have numerous biases [208]. Several retrospective studies nevertheless suggest inferior local oncological control after TA compared with PN [206,209,210]. TA seems to allow better preservation of renal function compared with PN [211-214] as well as lower overall or major complication rates for TA compared with PN [215-217].

### 5.3.2. How do AT relate to NP?

There are no randomized studies comparing the two techniques. All the recommendations are based on retrospective studies with numerous methodological biases. A meta-analysis of 26 studies and 11 systematic reviews was published by the EAU Kidney Cancer Recommendations Group [208]. It concludes that the level of evidence regarding AT is very low, with current data not allowing conclusions to be drawn regarding its clinical efficacy compared with PN, and that it is therefore difficult in this context to establish recommendations. The CCAFU recommends that patients be informed that TA offers good oncological results, even if they appear to be inferior to those of PN, but that the long-term data are still uncertain (Table of recommendations 8).

**Recommendation Table 8**

Indications for ablative treatments for localized tumours.

<table><thead><tr><th>Recommendations</th><th>Grade</th></tr></thead><tbody><tr><td>The validated indications for ablative treatment are:<br/>- Small renal tumors less than 3 cm in size for which partial nephrectomy appears to be associated with excessive morbidity<br/>- local recurrence following partial nephrectomy</td><td>Low</td></tr><tr><td>Indications to be discussed when ablative treatment is required are:<br/>- localized tumor larger than 3 cm<br/>- cystic tumor<br/>- tumor on kidney transplant</td><td>Low</td></tr><tr><td>Biopsy of the renal mass must be performed prior to ablative treatment and not concurrently (in the absence of prior histologic diagnosis).</td><td>Low</td></tr></tbody></table>
## 5.4. Place of ablative stereotactic radiotherapy

Ablative stereotactic radiotherapy has been evaluated as a therapeutic option in patients with cT1a and cT1b tumours who are inoperable or whose surgery is considered at high risk of complications [218,219]. It has the advantage of being non-invasive and not requiring anesthesia.

There is no consensus on the optimal dose and number of fractions, with delivery methods varying according to the series (26–60 Gy in 1, 3 or 5 fractions) [218–221]. However, the IROCK (International Radiosurgery Oncology Consortium for Kidney) recommendations suggest doses of 25 to 26 Gy in a single fraction for tumours smaller than 4 cm [222].

Several retrospective observational studies, mainly including cT1 tumours, with median follow-up between 16 and 34 months, report local controls between 90 and 97.2% and prolonged survival [218–220,223–226]. The prospective observational FASTRACK II study evaluated the oncological results of stereotactic radiotherapy in 77 inoperable patients with glomerular function > 30 mL/min, with localized kidney tumours of less than 10 cm, 23 of whom had tumours of less than 4 cm without contact with the intestine (organ at risk). The recommended dose was 26 Gy in one fraction for tumours smaller than 4 cm and 42 Gy in 3 fractions for larger tumours. The median age of the patients included was 77 years. Oncological results at 48 months' follow-up showed a local control rate of 100%. The rate of grade 3 toxicities in this study was 10%, mainly pain and nausea/vomiting [227]. The impact on renal function appears to be moderate, with a decrease in GFR estimated at between 5 and 17 mL/min in the years following radiotherapy and stabilization of the loss of renal function after 2 years of follow-up [221,228]. After stereotactic radiotherapy, toxicities appear moderate overall, mainly grade 1 (fatigue, nausea, chest or back pain, diarrhea or gastritis) with 0 to 9% grade 3–4 [218,219,221]. This treatment modality therefore appears to be of interest for frail patients with co-morbidities or on anticoagulants in whom a more invasive treatment (surgery or TA) would be contraindicated [229].

However, more evidence from prospective studies with longer follow-up is still needed to validate this indication in elective situations. Finally, the definition of response to stereotactic radiotherapy needs to be better codified.

### Recommendation Table 9

## 5.5. The role of active surveillance

Active surveillance (AS) is defined as the monitoring of a patient with a small kidney tumour through repeated clinical and imaging examinations (ultrasound, CT or MRI). Patients may be taken off active surveillance, and treatment may therefore be proposed, in the event of clinical progression (increase in volume or tumour becoming symptomatic). This must be distinguished from abstention/surveillance, which consists of clinical surveillance alone in patients with a limited life expectancy or who cannot be operated on because of their comorbidities, with the aim of exclusive symptomatic treatment. AS series report slow and predominantly linear growth of kidney tumours with mean tumour growths varying between 0.09 and 0.37 cm per year [230–233]. There does not appear to be any difference in tumour growth rate between benign and malignant tumours [231]. One series reported faster growth in clear cell carcinomas compared with type 1 tubulopapillary carcinomas (0.25 vs. 0.02 cm/year; *P* < 0.001) but this should be interpreted with caution due to the small number of type 1 papillary carcinoma included

and the wide variability in growth rate [234]. In the main series of small tumours observed, 20 to 30% of tumours did not progress and 10 to 20% of tumours grew rapidly at a rate of more than 0.5 cm/year. The majority of studies included both solid and cystic tumours. It has also been described that the growth rate of small renal masses was faster past the threshold of 3 cm largest diameter [235].

The occurrence of metastatic progression in patients under surveillance for a tumour of less than 4 cm varies from 0 to 6% (up to 7 years of follow-up) [231,233,235–239]. In the vast majority of cases, patients under surveillance had not had a biopsy. High tumour size and rapid growth rate have been found to be associated with an increased risk of local and metastatic progression [235].

The main multicenter DISSRM registry studied the feasibility of AS for tumours ≤ 4 cm and reported similar overall (92% vs. 75%; *P* = 0.06) and specific (99% vs. 100%; *P* = 0.3) survival at 7 years between patients treated upfront (with NP or TA) and those initially monitored [240]. The update of these data at 7 years confirms the feasibility of AS with similar specific survival between PN and AS. In this series, preservation of renal function was superior in patients undergoing AS and psychological tolerance was identical in the 3 groups (PN, TA, AS) [238].

In terms of quality of life, AS was associated with poorer physical health (although these patients were older and more comorbid at the time of inclusion) and greater anxiety than patients managed with immediate intervention (surgery or ablative treatment) [241–243].

Although AS was initially reserved for elderly patients or patients with co-morbidity, recent data suggest that this management is also safe in younger patients. Data from the DISSRM registry showed that there was no difference in cancer-specific survival and overall survival between patients aged under 60 managed with definitive therapy (n = 156) or AS (n = 68). The rate of progression to definitive treatment was lower in patients with tumours less than 2 cm than in those with tumours 2–4 cm (15.1% versus 33.3%) [237].

Follow-up procedures in the different active surveillance cohorts were heterogeneous, both in terms of the type of imaging (MRI, CT, ultrasound) and the frequency of follow-up. Tumour biopsy at inclusion was not systematic. Finally, there was no consensus on thoracic imaging. In the studies, patients were followed up with abdominal imaging every 3 to 6 months for the first year, then every 6 to 12 months if the lesion remained stable. Chest imaging was offered at inclusion and annually.

Biopsy is not compulsory in order to propose AS, but should be considered when the result may alter the patient's management (see chapter 4 – The role of biopsy).

Based on data from historical prospective observational studies, it has been suggested that AS should be discontinued and treatment offered in the event of a growth rate greater than 0.5 cm per year, a symptomatic patient or a tumour size greater than 4 cm (Recommendation Table 10).

## 5.6. Choice of treatment

The choice of treatment for small tumours offered to patients depends mainly on their life expectancy and the size of the tumour. In patients with limited life expectancy, simple, clinically based surveillance may be proposed. For tumours less than 2 cm in size, active surveillance with deferred treatment if necessary is the preferred treatment option, particularly for elderly patients with numerous co-morbidities. For tumours larger than 3 cm, the gold standard remains partial nephrectomy (Fig. 2).

# 6. Treatment of localized kidney tumours > 4 cm

## 6.1. Place of partial nephrectomy (PN)

For cT1b tumors, PN is non-inferior in terms of specific survival to RN [150,162,244–246]. There is only one prospective study, which was stopped early, showing non-inferiority of PN versus RN for localized tumors less than 5 cm [151].

### Recommendation Table 9

Place of stereotactic radiotherapy in the treatment of localized kidney tumours.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>Ablative stereotactic radiotherapy is a treatment option to be discussed for patients with unresectable cT1a and cT1b tumors who are not candidates for ablative treatments.</td><td>High</td></tr></tbody></table>
<table><caption>**Recommendation Table 10**
Monitoring of small kidney tumours.</caption><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>Active surveillance is the preferred strategy for small kidney tumours &lt; 2 cm, given their low growth rate and the low probability of aggressive histology.</td><td>Low</td></tr><tr><td>Active surveillance may be offered as an option to patients with a small kidney tumour measuring 2 to 4 cm.</td><td>Low</td></tr><tr><td>A tumour size greater than 4 cm or annual tumour growth of more than 0.5 cm/year means that the patient must be withdrawn from active surveillance.</td><td>Low</td></tr><tr><td>Simple abstention from monitoring can be proposed to elderly patients with small renal masses and with co-morbidities and/or limited life expectancy.</td><td>Low</td></tr></tbody></table>

For cT2 tumors, the level of evidence from studies concerning optimal surgical treatment is very limited. Retrospective studies comparing PN and RN show a trend in favor of PN in terms of survival and functional results, but with higher blood loss and higher complication rates [245,247,248]. A recent multicenter study demonstrated a benefit of PN vs. RN in terms of specific and overall survival with a median follow-up of 102 months [249].

For pT3a tumors, three retrospective studies reported on the follow-up of patients with tumors initially cT1 and cT2 requalified as pT3a on postoperative pathological analysis. The results were divergent with two studies showing comparable oncological results between PN and RN [250,251]. A third study showed that a pT3a stage after PN was associated with shorter recurrence-free survival [252]. A recent meta-analysis including 1278 patients in the PN group and 2113 patients in the RN group with a pT3a tumor showed no specific difference in survival between the two treatments [253].

The complexity of the tumor can be assessed using morphometric scores (RENAL score, PADUA score, C-Index, etc.). These scores could be useful in predicting renal function impairment and prognosis in the case of tumors > 7 cm [254–256]. An increase in tumor size and complexity is associated with an increased risk of pT3a tumors and local recurrence [251,252,257].

The robot-assisted laparoscopic approach appears to reduce the morbidity of PN for tumors > 4 cm. It is associated with less bleeding, fewer complications and a shorter hospital stay than open surgery [258,259] and less surgical conversion, less warm ischemia and less impairment of renal function than standard laparoscopy [194,260]. Perioperative morbidity remains comparable to that of RN in expert centers [258,259,261].

## 6.2. Place of radial nephrectomy (RN)

### 6.2.1. Laparoscopic radical nephrectomy

No randomized controlled trial has compared the oncologic outcomes of laparoscopic RN versus open RN. A retrospective comparative study showed an advantage in terms of overall survival in the minimally invasive RN group compared with the open approach, as well as in terms of length of hospital stay, readmission rate and mortality at 30 and 90 days [262]. Retrospective systematic reviews and a prospective non-randomized study have shown comparable oncologic outcomes even in locally advanced tumors [202,204,263] with lower morbidity and shorter hospital stays [164,201,263,264].

<figure><img src="image_5.png" /><figcaption>Fig. 2. CCAFU recommendations for the treatment of small kidney tumors.</figcaption></figure>
### 6.2.2. Robot-assisted laparoscopic radical nephrectomy

In a meta-analysis including 1832 patients, robot-assisted RN was non-inferior to standard laparoscopy in terms of perioperative results and complications [265]. Other retrospective studies have confirmed oncological results comparable to other approaches [266,267] but with a significant additional cost [268].

### 6.2.3. Adrenalectomy for cT1b-cT2 cN0 tumors

A single prospective non-randomized study compared RN with or without ipsilateral adrenalectomy. Location at the upper pole of the tumor was not predictive of adrenal invasion. There was no significant difference in overall survival at 10 years [269]. It is not necessary to perform an adrenalectomy except in the case of contiguous invasion detected during the operation or an abnormality suggestive of a secondary lesion on preoperative imaging [269,270].

### 6.2.4. Lymphadenectomy for cT1b-cT2 cN0 tumors

The indications and surgical limits of lymph node dissection associated with RN remain controversial [270–272]. A large retrospective multicenter study published in 2018 analyzed data from 2722 patients. Lymphadenectomy combined with RN did not improve oncological outcomes in terms of progression-free, specific and overall survival [273]. A retrospective analysis of the SEER (Surveillance, Epidemiology and End Results) database of more than 9000 patients showed no effect of extended lymphadenectomy (eLND) on specific survival in cN0 [274]. Only one randomized study evaluating the clinical benefit of lymphadenectomy associated with surgical treatment of a kidney tumor has been published. This EORTC study did not show any benefit of lymph node dissection for cN0 patients and concluded that it was of interest only for staging [275]. In a meta-analysis of 1983 patients, the value of lymph node dissection was demonstrated in terms of specific survival in tumors

with poor prognostic factors such as the presence of sarcomatoid variants or a large tumor volume, without increasing the morbidity of RN [271].

### 6.3. Embolization of cT2 tumours

There is no benefit in performing renal artery embolization before RN [276]. Embolization may be discussed in the event of symptoms (hematuria, pain) in patients not eligible for surgery [277].

### 6.4. Use of thermo-ablative techniques (TA)

Several retrospective studies have reported the results of TA for tumours larger than 4 cm, with short follow-up times and inconsistent results in terms of morbidity and oncological control [209,213,278–282]. An analysis of 5763 patients from the SEER database showed a specific mortality risk multiplied by 2.5 compared with RN for cT1b treated with AT [210].

### 6.5. Place of ablative stereotactic radiotherapy

Some studies suggest that cT1b lesions can be treated effectively with stereotactic radiotherapy. A retrospective study by the IROCK consortium including 95 patients treated with stereotactic radiotherapy for cT1b renal cell carcinomas with a median follow-up of 2.7 years showed a 2.9% failure of local control and a 4-year progression-free survival of 64.9%, with no grade ≥ 3 toxicities reported [283]. In the prospective observational FASTRACK II study, 47 inoperable patients had localized tumours greater than 4 cm and less than 10 cm. In these patients, local control (assessed radiologically by tumour size) was 100% with a median follow-up of 48 months [227]. The treatment modalities recommended by the consortium for tumours > 4 cm are 35 to 45 Gy in 3 fractions or 40 to 50 Gy in 5 fractions [221,222,228] (Recommendation Table 11).

<table><caption>**Recommendation Table 11**

Treatment of cT1b and cT2 kidney tumours.</caption><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>Partial nephrectomy should be proposed for cT1b-T2 tumours when feasible.</td><td>High</td></tr><tr><td>Radical nephrectomy is recommended for localized cT1b-T2 tumours for which partial nephrectomy is not technically feasible or in the case of a non-functioning kidney.</td><td>High</td></tr><tr><td>Laparoscopy is less morbid than the open approach and should be preferred for radical nephrectomy of a cT1b-T2 tumour.</td><td>High</td></tr><tr><td>Partial nephrectomy should be offered to patients with a cT2 tumour and an imperative indication (single kidney, renal failure), if technically feasible.</td><td>High</td></tr><tr><td>Adrenalectomy is not recommended in cases of radical nephrectomy for a cT1b-T2 tumour in the absence of radiological and/or intraoperative signs of invasion.</td><td>High</td></tr><tr><td>Systematic lymph node dissection is not recommended in the case of nephrectomy for a cT1b-T2 cN0 tumour.</td><td>High</td></tr><tr><td>Ablative therapies are not recommended for the treatment of cT1b-T2 tumors, but may be considered on a case-by-case basis in centers of expertise.</td><td>High</td></tr><tr><td>Stereotactic radiotherapy is not recommended for the treatment of cT1b-T2 tumors but may be considered on a case-by-case basis in centers of expertise.</td><td>High</td></tr><tr><td>Renal artery embolization may be proposed in symptomatic inoperable patients to control symptoms.</td><td>Low</td></tr></tbody></table>
# 7. Treatment of locally advanced kidney cancer

## 7.1. Definition of locally advanced kidney cancer

Locally advanced kidney cancers are those that are neither intra-capsular (pT1, pT2) nor metastatic (M1). This definition does not formally include a tumour size criterion. Recent surgical series report 4–15% reclassification of localized tumours ≤ cT2 to pT3a by definitive histology [284–286]. This restaging ≥ pT3a was associated with unfavorable oncological outcomes in terms of recurrence and overall survival compared with tumours ≤ pT2 [284–286]. Within the pT3a group, there appear to be prognostic differences with a worse prognosis from invasion of the renal vein or a segmental branch, versus invasion of sinus fat or peri-renal fat, which appear to have the same prognostic value [287]. Contemporary series of tumours associated with a venous thrombus (T3b and T3c) confirm the prognostic value of the TNM classification with a prognosis significantly correlated with the infra versus supra-diaphragmatic level of the tumour thrombus [288,289].

## 7.2. The principles of extended nephrectomy

### 7.2.1. Technique: open versus laparoscopic and robot-assisted laparoscopic approach

Surgery in this situation is intended as a curative treatment. The main objective, whatever the technique, is to obtain negative surgical margins [290]. The standard approach for locally advanced kidney tumors is the open approach. Several series report the feasibility of the laparoscopic or robotic-assisted laparoscopic approach with favorable perioperative results in selected cases. The minimally invasive approach is possible provided that healthy excision margins can be obtained [291–293].

### 7.2.2. Benefits and indications of lymph node dissection

The value of lymph node dissection during nephrectomy was evaluated in a prospective randomized phase III trial. The lymph node dissection performed in this study was “extensive” (from the diaphragm to the aortic bifurcation, periaortic on the left, latero-caval + pre-caval + inter-aortic-caval on the right). This trial did not demonstrate any oncological benefit from systematic lymphadenectomy. In the absence of adenomegaly seen on preoperative CT or peroperatively, the risk of microscopic lymph node involvement was 4%. A limitation of this study is that it only included 28 and 30% of locally advanced T3–T4 [294]. Even in series of kidney tumours at high risk of recurrence, the rate of pN+ is 4 to 6% [294–297]. Finally, in cN+ patients, up to 58% of reactive hyperplasia without tumour invasion has been reported, particularly in cases of large tumours, tumour necrosis and/or tumour thrombus [298].

Lymph node dissection is recommended in the case of palpable lymph nodes or lymph nodes identified on preoperative imaging [299,300]. In the absence of identified lymph nodes, the usefulness for oncology or tumour stage assessment has not been demonstrated. In the case of lymph node involvement, the survival rate after nephrectomy is 10 to 45% at 5 years, and lymph node dissection is essentially considered to have a staging role [297,300].

## 7.3. What role do neoadjuvant treatments play?

In the neoadjuvant setting, primary tumor responses of 9 to 28% have been observed with targeted anti-angiogenic therapy and tumor volume reductions of up to 35% with immunotherapy [301–307]. In the case of tumor cave thrombus, preoperative systemic treatment is associated with a reduction in thrombus height of up to 35% [308,309].

To date, a neoadjuvant strategy can only be considered in the context of clinical trials or discussed on a case-by-case basis in the tumor setting [310]. The level of evidence is low, the impact on surgical technique

appears to be limited, and the oncologic benefit has not been demonstrated [311].

## 7.4. Special situations

### 7.4.1. In the event of invasion of adjacent organs

Invasion of adjacent organs is difficult to predict [312]. Many cT4 patients are over-staged and may benefit from surgical resection. Survival at this stage is less than 10% at 5 years, and the existence of negative margins is an important prognostic factor [313–315].

### 7.4.2. Tumour thrombus in the vena cava

At present, excision surgery is the reference treatment for kidney tumours with thrombus, whatever the level of thrombus, subject to the following conditions: the tumour and thrombus are technically resectable within a healthy margin and the extension work-up is unequivocal (cM0) [316,317]. Involvement of cN+ lymph nodes on extension is not necessarily contraindicate surgery [316]. In fact, up to 50% of kidney tumours staged as cN+ turn out to be pN0, tumour necrosis and the presence of a venous thrombus being precisely the factors associated with reactive lymph node hyperplasia without tumour invasion [298].

#### 7.4.2.1. Preoperative assessment.
It should be remembered that no metabolic imaging is recommended in the preoperative work-up for nephrectomy, even in the case of a tumor associated with a venous thrombus [316]. Finally, no strategy involving systemic treatment prior to surgery, whether a TKI alone, immunotherapy or a combination of immunotherapy and TKIs, has been shown to have a significant and reproducible impact on reducing the stage of thrombus, facilitating surgery or improving oncological prognosis [316,318,319].

The operability assessment may also be an obstacle to surgery, particularly for the most fragile patients, as thrombus surgery is associated with a mortality rate > 90 days of up to 20% and a complication rate that increases with the level of thrombus [320]. The operability assessment must be adapted to the expected difficulty of the surgery and the type of clamping of the IVC: for the simplest cases of level I thrombus, partial or total but brief clamping of the juxta-renal inferior vena cava is sufficient; clamping of the hepatic hilum and the supra-hepatic veins is necessary for the most complex cases of level 3 to 4 thrombus, or even in certain cases of level 4, beating heart surgery and extra-corporeal circulation. In the case of high-level thrombi, the presence of a disturbance in the liver balance should raise the possibility of Budd-Chiari syndrome or obstruction of the suprahepatic veins [320].

#### 7.4.2.2. Surgical technique.
The surgical technique is determined by the upper level of the thrombus and the risk of invasion of the IVC wall. In most cases, infiltration of the vena cava and adhesion of the thrombus can only be suspected preoperatively. Only the presence of a tumor signal crossing the vena cava on MRI can formally confirm the presence of an adherent thrombus, which requires removal or even prosthetic replacement of the IVC [321–323]. Computed tomography with injection and MRI have a similar overall diagnostic performance with regard to the risk of invasion of the vena cava wall, and the radiological signs most often taken into account are: maximum thrombus diameter > 4 cm and thrombus diameter at the ostium of the renal vein [324]. New dynamic imaging techniques can be used to assess thrombus adhesion to the vena cava, but these are currently being evaluated. The presence of fibrin-cruciate thrombosis of the IVC beneath the thrombus or in the iliac vessels and thrombus invasion of the lumbar veins are factors associated with poor prognosis in oncology.

The initiation of anticoagulation at the time of diagnosis and until surgery is controversial. The benefits of preventive versus curative anticoagulation are currently being studied. In the situation of locally advanced renal tumor with venous thrombus, preventive anticoagulation seems to be a reasonable compromise (expert opinion).
Surgery for vena cava thrombosis is an oncologic emergency, and the progression of the thrombus level is a major concern in surgical planning, especially for high-grade thrombi. Therefore, it is recommended that the thrombus level be rechecked on imaging and that liver function tests be performed in the 24-48 hours prior to surgery. The occurrence of abnormal liver function tests indicates obstruction of the suprahepatic veins (or Budd-Chiari syndrome), which should prompt reconsideration of the indication for surgery, as there is a high risk of intraoperative and postoperative complications and positive margins [325]. In most cases, the thrombus level remains stable or progresses only slightly, and it is preferable to prioritize the safety of the surgical procedure over the delay before surgery.

Cava thrombus surgery, especially at high levels, is a multidisciplinary procedure (vascular, hepatic, and cardiothoracic surgery) that requires not only surgical skill, but also anesthesia expertise and an intensive care unit experienced in major surgery.

Open surgery is the recommended approach for the surgical treatment of cava thrombosis. The minimally invasive approach using robotic surgery has been reported in recent years, with evidence of a reduction in the risk of transfusion and overall complications, but with no significant difference in the occurrence of major complications [326-329].

7.4.2.3. *Postoperative prognosis.* In a contemporary French series, the median time to recurrence after nephrectomy for RCC associated with a tumour thrombus (304 renal vein thrombi [pT3a], 87 infra-diaphragmatic thrombi [pT3b], 18 supra-diaphragmatic thrombi [pT3c]) was 36 months for all stages combined [330]. The predictive factors for recurrence were: tumour necrosis (HR = 2.92), pN + invasion (HR = 2.53) and tumour size > 10 cm (HR = 1.56); adjuvant treatment was a protective factor against recurrence (HR = 0.33) [330].

The Phase III trial (Keynote 564), which randomized a cohort of 994 nephrectomies for kidney tumours at high risk of recurrence to 1 year of adjuvant treatment with Pembrolizumab versus placebo, demonstrated a 37% reduction in the risk of recurrence and a significant benefit in overall survival (HR: 0.64; 95%CI [0.44-0.87]) [331,332]. The proposal of adjuvant treatment following nephrectomy for RCC with tumour thrombus has therefore become the standard approach, provided that the tumour contains at least one clear cell contingent (tubulo-papillary RCC are not eligible for adjuvant treatment) [331,332].

Finally, a recent retrospective study analyzed the distribution of histological subtypes in CRC with tumour thrombus: 89% clear cell, 7% papillary, 4% chromophobe, and highlighted the prognostic value of the histological subtype, with a more unfavorable oncological outcome in papillary RCC compared with clear cell RCC, while the prognosis for

chromophobe RC seemed more favorable [333] (Table of recommendations 12).

# 8. Specific clinical situations

## 8.1. Tumours in an imperative situation

Imperative situations are those where radical nephrectomies would entail a high risk of end-stage renal failure or permanent dialysis: anatomically or functionally unique kidney, bilateral renal tumour, pre-existing renal insufficiency. In this context, partial nephrectomy is the standard treatment. It is recommended that a biopsy be performed prior to any therapeutic decision (Recommendation Table 13).

Retrospective studies suggest that in imperative situations, PN and TA preserve renal function in identical fashion. On the other hand, there is a higher risk of recurrence with TA [334]. A CCAFU study published in 2017 and including 284 patients compared 172 NP with 112 TA in the imperative situation [335]. Recurrence-free survival was better in the PN group despite larger and more complex tumours. On the other hand, morbidity was lower in TA: fewer transfusions, shorter hospital stays and fewer complications despite higher comorbidities.

It is unlikely that randomized studies comparing the two techniques will ever be available. In these imperative situations, NP remains the reference treatment when it is technically feasible. The UroCCR-54 study reported the feasibility of the laparoscopic approach with robotic assistance, in the case of a single kidney, with results equivalent to those of the open approach [336]. In order to maintain optimal renal function, the healthy parenchyma must be preserved as much as possible and ischemia must be limited by early de-clamping or by using ischemia-sparing techniques (no clamping or supra-selective clamping) [337-341]. Given the complexity of these situations, it is advisable to refer these patients to an expert center.

## 8.2. Tumours on renal transplants and native kidneys in chronic renal failure patients

Recommendations have been made by the Transplantation Committee of the French Association of Urology (CTAFU) on this specific subject [342]. Tumours in renal transplants are rare, with a prevalence of between 0.2% and 0.5% [343-345]. These tumours are mostly discovered at a localized stage (T1a) because of the regular monitoring of renal transplant patients by ultrasound-doppler [343,346]. These tumours may be multifocal or bilateral [347,348]. Clear cell renal cell carcinoma is the most common histological type [343,349]. In the case of a non-functioning graft, the lesion tends to be papillary [350]. The management

**Recommendation Table 12**

Recommendations for the treatment of locally advanced tumours.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>In the case of locally advanced tumours, extended radical nephrectomy is recommended if technically feasible with the aim of achieving healthy margins.</td><td>High</td></tr><tr><td>In the case of locally advanced tumours, the therapeutic value of systematic lymph node dissection is uncertain. It is recommended in the case of suspicious lymph nodes identified on preoperative or intraoperative imaging.</td><td>Low</td></tr><tr><td>In the case of tumours with venous thrombus, extended radical nephrectomy combined with surgical thrombectomy is recommended for M0 patients in good general condition.</td><td>High</td></tr><tr><td>No neoadjuvant treatment can be proposed outside of clinical trials.</td><td>High</td></tr><tr><td>For carcinomas with a pT3-4 clear cell component, adjuvant treatment with pembrolizumab is recommended.</td><td>High</td></tr></tbody></table>
**Recommendation Table 13**

Recommendations for the treatment of tumours in imperative situations.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>In imperative cases, it is recommended that a biopsy be performed before any therapeutic decision is taken.</td><td>High</td></tr><tr><td>In imperative cases, partial nephrectomy is the preferred treatment.</td><td>High</td></tr><tr><td>In imperative situations, it is recommended to limit renal ischemia and preserve as much healthy renal parenchyma as possible.</td><td>High</td></tr><tr><td>In imperative situations, percutaneous ablative treatments are an option.</td><td>Low</td></tr><tr><td>In imperative situations not eligible for surgical or ablative treatment, stereotactic radiotherapy may be discussed as an alternative.</td><td>Low</td></tr><tr><td>In imperative situations, it is advisable to refer the patient to an expert center.</td><td>Low</td></tr></tbody></table>

of tumours on renal transplants must be considered as a situation of imperative indication (single functional kidney with pre-existing chronic renal disease). Partial nephrectomy is the standard treatment. Several series have reported experience of conservative surgery, mainly for stage T1a renal transplant tumours, with excellent oncological and functional results [351-354]. Nevertheless, this surgery is potentially complex and morbid, requiring recourse to an expert center [342]. This complexity is mainly related to the dissection of the transplant vessels. Endovascular occlusion of the transplant artery during partial nephrectomy could be of interest in this indication [355]. Transplantectomy may be discussed when renal function is impaired, in cases of locally advanced tumour or symptoms. In published series, the majority of symptomatic or stage ≥T1b tumours were treated by transplantectomy [356,357]. Thermo-ablative treatments (radiofrequency and cryotherapy) can be used for cT1a [342,358]. These treatments appear to be increasingly preferred to PN, particularly in frail, elderly patients and/or when the tumour location is favourable to a percutaneous approach [359,360]. In summary, the management strategy for tumours on kidney transplants must be determined on a case-by-case basis by a multidisciplinary team, considering the expected difficulty of the surgery, the function of the transplant and the technical resources available (Recommendation Table 14).

In the case of lesions in the native kidneys, the reference treatment is laparoscopic total nephrectomy, with a morbidity similar to that of the general population [361,362]. Focal treatment, although not validated in this population, may be discussed if there is a need to preserve residual diuresis [346].

With regard to the waiting period after transplantectomy, the joint CCAFU/CTAFU recommendations do not impose a waiting period for a 2nd transplant in the following cases: papillary histology (low grade, formerly type 1) or clear cell histology (excluding translocation carcinomas), stage <pT3 and low grade ISUP (expert opinion).

In other situations, a minimum waiting period of two years is proposed, to be discussed in a collegial manner [342].

### 8.3. Familial tumours

Tumours arising in the context of a hereditary syndrome (mutations in VHL, MET, FLCN, FH, TSC, SDH or BAP1) are rare (2 to 3% of renal tumours) but are difficult clinical situations because of the frequently multifocal nature of the tumours and their high risk of recurrence. They require discussion within multidisciplinary teams (urologist, oncologist, oncogeneticist, interventional radiologist). Treatment options include active surveillance, multiple tumour resection and ablative therapies. They are discussed on a case-by-case basis depending on the site, size, location and complexity of the tumour, the type of genetic alteration and the technical facilities available.

Historical series suggest an arbitrary threshold of 3 cm above which it is advisable to treat a tumour in the context of a hereditary syndrome. This threshold would make it possible to preserve the renal parenchyma as much as possible while controlling the risk of metastasis for these tumours, which are thought to grow slowly. However, a study of the growth of tumours from hereditary syndromes in 292 patients and 435 tumours suggests different rates of growth depending on the type of mutation. An average tumour growth rate of 0.6 cm per year was reported for BAP1 mutations, 0.37 cm per year for VHL mutations, 0.1 cm per year for FLCN mutations and 0.15 cm per year for MET mutations. Younger patients had faster tumour growth and tumours within the same patient progressed at the same rate. This study suggests caution in monitoring patients with BAP1 [363].

Furthermore, FH mutations described in hereditary leiomyomatosis and succinate dehydrogenase (SDH)-deficient renal cancers in hereditary carcinomas), stage <pT3 and low grade ISUP (expert opinion).

**Recommendation Table 14**

Recommendations for the management of renal lesions in renal transplants and native kidneys in chronic renal failure patients.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>Partial nephrectomy is the standard treatment for small tumours on renal transplants</td><td>Low</td></tr><tr><td>In the case of lesions in the native kidneys, the standard treatment is laparoscopic radical nephrectomy.</td><td>Low</td></tr><tr><td>A temporary contraindication to transplantation should not be imposed in the case of papillary (low grade) or clear cell histology (excluding translocation carcinomas), stage &lt;pT3 and low grade ISUP grade.</td><td>Low</td></tr></tbody></table>
**Recommendation Table 15**

Recommendations for the treatment of kidney tumours arising in the context of hereditary syndromes.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>The management of kidney tumours arising in the context of hereditary syndromes requires multidisciplinary management, including oncogenetic advice.</td><td>High</td></tr><tr><td>Kidney tumours arising in patients with mutations in VHL, MET, FLCN, TSC, SDH or BAP1 should be managed conservatively because of the high risk of contralateral recurrence. Surveillance is a priority option for tumours smaller than 3 cm.</td><td>Low</td></tr><tr><td>Tumours arising in patients with an FH mutation and succinate dehydrogenase (SDH)-deficient RCCs must be treated immediately with the certainty of obtaining negative surgical margins.</td><td>High</td></tr></tbody></table>

paraganglioma/pleochromocytoma syndrome (HPP) are associated with particularly aggressive tumours in young subjects and require immediate management. In this rare situation, it is imperative to obtain negative surgical margins and extended nephrectomy may be considered even for small tumours [364,365] (Recommendation Table 15).

There are no recommendations on systemic treatments for hereditary kidney cancer. In hereditary MET-mutated papillary renal cancer (HPRC), phase II and III studies have demonstrated the efficacy of tyrosine kinase and multikinase inhibitors (MET/VEGFR2) [366,367]. In von Hippel-Lindau disease, a phase II trial demonstrated the clinical activity and good tolerability of belzutifan (an oral inhibitor of HIF-2α), with a phase III trial in progress [368].

## 8.4. Cystic tumours of the kidney

Kidney cancers have a cystic appearance in 5 to 7% of cases. Cystic tumours are generally non-aggressive, low grade and the most common histological subtype is clear cell carcinoma [369,370]. Cross-sectional imaging (CT or MRI) is recommended to best characterize cystic lesions of the kidney. Contrast ultrasound may be performed if CT or MRI is contraindicated. MRI and contrast ultrasonography have better sensitivity and specificity for characterizing a complex cystic tumour (Bosniak IIF or III) [371,372]. Cystic tumours are classified according to the Bosniak classification into 5 stages (I, II, IIF, III, IV), according to six radiological parameters: the appearance of the cyst wall, the contents of the cyst, the presence of partitions and/or calcifications, the presence of vegetations, the enhancement of the cyst wall and/or its contents after injection of contrast medium (Fig. 3) [373–375].

The emergence of artificial intelligence and machine learning may make it possible to improve the assessment of cystic lesions. Ramachandran et al. evaluated three different machine learning algorithms based on the scannographic aspect, enabling better detection of cancerous lesions in a retrospective series of 144 patients. For the moment the level of evidence is not sufficient to recommend them in clinical practice [376].

The risk of malignancy that Bosniak initially reported for each category was updated in a systematic review of the literature [377]. The risk of malignancy was 9% (5–14%) for Bosniak II, 18% (12–26%) for Bosniak IIF, 51% (42–61%) for Bosniak III and 86% (81–89%) for Bosniak IV [377].

In 2018, a CCAFU multicenter study assessed the malignancy rates and histological characteristics of Bosniak III and IV lesions in France among 216 cystic tumours from the national uroCCR database. A central review by experienced pathologists was carried out: the malignancy rates for Bosniak III and IV cysts were 69% and 91% respectively. The tumours were mainly of low stage (86% pT1–2), low grade (68% ISUP grade 1–2) and good prognosis (recurrence 1.1%, specific survival 100%) [369]. In a second national multicenter study, the CCAFU reported the long-term oncological outcome of 152 cystic CRCs, Bosniak IIF (6%), III (53%) and

IV (41%), with a median follow-up of 61 months [370]. Bosniak stage was associated with a higher prevalence of high-grade tumours (36 vs. 12%, $P < 0.01$) [370]. However, Bosniak category was not predictive of oncological outcome, with favourable and similar recurrence-free survival rates for Bosniak III and IV of 92% vs. 92% at 5 years and 84 vs. 83% at 10 years ($P = 0.60$) [370].

The management of cystic tumours is determined by the Bosniak classification. For Bosniak I and II cysts, no treatment or follow-up is recommended. A radiological surveillance period (using cross-sectional imaging) of 5 years is recommended for IIF [377]. This follow-up makes it possible to distinguish stable IIF cysts from IIF cysts that progress to Bosniak $\ge$ III and require surgical removal due to a high risk of malignancy (Fig. 3) [377].

The identification of malignant tumours within Bosniak III cysts is uncertain. The new Bosniak classification including MRI aims to better identify malignant tumours but has not yet been validated [373]. The value of percutaneous biopsy of cystic tumours of the kidney has not been reported apart from the presence of a tissue component (Bosniak IV) [378]. Bosniak III cysts are benign in around 40% of cases and cystic cancers are predominantly of low stage/grade with an excellent long-term prognosis. The CCAFU therefore considers that surveillance is a possible alternative to surgical treatment [369,370,377,379] and can be discussed depending on the complexity of the tumour and the patient's co-morbidities. For Bosniak IV tumours, complete surgical excision is justified by the high risk of malignancy (Recommendation Table 16).

Intraoperative rupture of a cystic tumour is a frequent event, which raises the question of oncological risk. A French multicenter retrospective study reported 50 (18.7%) cases of rupture in a series of 268 cystic tumours operated. No patient developed peritoneal carcinosis. Rupture of the cyst was not associated with a higher risk of recurrence and the results were similar between robot-assisted laparoscopic surgery and open surgery [380]. These results confirm that cystic tumours have a low potential for malignancy. Intraoperative rupture should be avoided as far as possible but appears to have little oncological consequences. However, the CCAFU recommends surgical removal of a cystic tumour without rupturing its wall during the operation, whatever the approach used.

## 8.5. Oncocytoma

Oncocytoma is the most common benign tumour of the kidney, accounting for 3–7% of all kidney tumours and up to 18% of small renal masses ($\le$ 4 cm) [381]. Renal oncocytoma is a solid tumour, more rarely cystic, classically single and more rarely multiple in the context of oncocytosis (multiple oncocytic tumours with renal failure in a potential context of Birt-Hogg-Dubé syndrome) [382,383].

Apart from diagnostic excision surgery, diagnosis can be made on tumour biopsy, but this is becoming increasingly difficult because of the
<figure><img src="image_6.png" /></figure>

<table><caption>Fig. 3. Bosniak classification of cystic kidney tumors.</caption><thead><tr><td>Types</td><td>TDM Signs</td><td>Diagnosis and Management</td></tr></thead><tbody><tr><td>Type I</td><td>Benign cyst with a water density, thin smooth wall, no enhancement, septa, calcification, or contrast medium washout</td><td>No surveillance</td></tr><tr><td>Type II</td><td>Benign cyst that may have enhancing thin septa, thin calcification or daughter cysts</td><td>No surveillance</td></tr><tr><td>Type IIF</td><td>Cyst with smooth thickened enhancing wall, regular calcification or with many enhancing septa</td><td>surveillance with CT every year for 5 years</td></tr><tr><td>Type III</td><td>Solid enhancement, significant thick enhancement of the walls irregular and, or necrosis</td><td>probability of malignancy about 50%, Surgical resection with oncological rules, or surveillance for selected patients</td></tr><tr><td>Type IV</td><td>one or more enhancing septa, nodules</td><td>malignancy cyst, Surgical resection with oncological rules</td></tr></tbody></table>

new emerging entities of oncocytic cell tumours [119,125,384]. The correlation between the biopsy and the operative specimen when the biopsy concludes a renal oncocytoma varies from 65% to 91% depending on the series [118–120,385]. Discrepancies between biopsy and operative

specimen in the diagnosis of renal oncocytoma mainly concern other tumours in the oncocytic tumour group: 18 to 26% of chromophobe carcinomas in their eosinophilic variant, low grade oncocytic tumours/ LOT, vacuolated eosinophilic cell tumours/HOT, hybrid tumours, solid

Recommendation Table 16

Recommendations for the treatment of cystic kidney tumours.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>Cystic kidney lesions should be classified according to the Bosniak classification</td><td>High</td></tr><tr><td>Complete surgical removal is recommended for Bosniak IV cysts.</td><td>High</td></tr><tr><td>Complete surgical removal is recommended as first-line treatment for Bosniak III cysts.</td><td>Low</td></tr><tr><td>Monitoring may be discussed as an option depending on the complexity of the lesion and the co-morbidities of patients with Bosniak III cysts.</td><td>Low</td></tr><tr><td>Bosniak IIF cysts must be monitored regularly; surgical removal is recommended if they progress to category III or IV.</td><td>Low</td></tr><tr><td>Percutaneous biopsy of cystic renal tumours is not recommended unless there is a significant tissue component.</td><td>High</td></tr></tbody></table>
and cystic eosinophilic cell carcinoma, NOS oncocytic tumours and more rarely clear cell carcinoma (3% to 13%) [98,118–121].

A CCAFU systematic review and meta-analysis recently synthesized data from series of biopsied and monitored renal oncocytomas [384], which led to the following conclusions about the natural history of renal oncocytomas:

* the average tumour size at diagnosis is 26 mm (IC95% [17–34.6]) but can exceed 7 cm;

* the average growth rate is 1 to 3 mm/year.

In the case of a small renal mass, it appears that growth rate is not a reliable criterion for distinguishing a malignant tumour from an oncocytoma, as their growth rates are similar. In addition, the growth rate of renal oncocytomas is heterogeneous, with 14% of renal oncocytomas remaining stable in size, while 14% of oncocytomas grow rapidly > 5 mm/year [386].

The strategy for monitoring biopsied oncocytomas is based on a low level of evidence because the series are non-comparative, with an average follow-up of only 3 years (30 to 39 months), and a heterogeneous follow-up methodology, both in terms of the nature of the imaging examinations (ultrasound, CT scan, MRI) and the chronology of these examinations [121,384,387–396].

The rate of conversion from an active surveillance strategy to radical treatment (surgery or ablation) was 5 to 40% at 3 years. The most frequently reported reason (65%) for discontinuing surveillance in favour of surgery was tumour growth (although no threshold rate could be identified). In 13% of cases, the patient's wish to stop surveillance and opt for radical treatment [384,387–396].

Factors associated with conversion from surveillance to surgical management were: age at diagnosis, low Charlson comorbidity score, and tumour size at diagnosis [384,387–396] (Recommendation Table 17).

In these cases, no case of metastatic progression or specific death was reported, either for patients who remained on surveillance or for patients who had deferred treatment after a period of surveillance.

## 8.6. Management of sporadic angiomyolipomas and angiomyolipomas evolving in the context of tuberous sclerosis

Renal angiomyolipoma (AML) is a benign tumor with three components: vascular, fatty and smooth muscle [397]. Most of these tumors are asymptomatic with a sex ratio of 4 women to 1 man [398]. Diagnosis is based on CT (or MRI), which reveals a tumor containing fat with very high sensitivity and specificity, making biopsy unnecessary in typical forms [399]. Fat-poor AMLs are more difficult to diagnose. In this situation, biopsy is often necessary, and their management is similar to that of solid renal masses.

These tumors are sporadic in 80% of cases, but some are part of a genetic syndrome (20%), tuberous sclerosis complex (TSC) [400,401].

The major risk of these tumours is hemorrhagic rupture, which can cause a hematoma of the retroperitoneum. This retroperitoneal hemorrhage, also known as “Wunderlich syndrome”, can exceptionally be so massive as to be life-threatening [402]. The predictive factors for

rupture have not been clearly identified. The risk seems to increase with the size of the tumour and the proportion of the vascular component [403].

Given the benign nature of this tumour, active surveillance (AS) is the treatment of choice [404]. However, more than half of AMLs diagnosed are actively treated, mainly by partial or radical nephrectomy or arterioembolization [398,403]. The over-treatment of these tumours is based on an old dogma, which stated that the risk of bleeding was increased when the tumour size exceeded 4 cm [405]. The relevance of this threshold is highly controversial [403]. Studies evaluating ADT for LMA have shown a minimal rate of serious complications (< 1%) and slow tumour growth (between 0.02 and 0.25 cm/year), confirming the exceptional nature of the much feared cataclysmic hemorrhage [406,407]. Surveillance for tumours larger than 4 cm is a safe option [408]. The modalities of surveillance are not clearly established [406]. Certain situations require active treatment to be discussed: high risk of bleeding from abdominal trauma (contact sports, army, motorcyclists), women of childbearing age, inability to access emergency care in the event of hemorrhagic rupture or refusal of monitoring. The active treatment of choice is partial nephrectomy, which is associated with a lower rate of recurrence than arterioembolization (0.85% vs. 31%) [403]. In the event of a threatening hemorrhage, emergency arterioembolization is indicated. Ablative treatments have been little studied in this indication (Recommendation Table 18).

Epithelioid AMLs are a distinct entity with the potential for malignancy, including the risk of metastasis and death from cancer. These are low-fat tumours. They are often diagnosed on biopsy or after partial nephrectomy. The management of epithelioid AML is similar with the management of localized and metastatic non-clear cell renal cancers [409].

Tuberous sclerosis complex (TSC) is a genetic syndrome with a multi-systemic, autosomal dominant involvement linked, most often, to a mutation of the TSC1 (chromosome 9) and TSC2 (chromosome 16) genes [410]. Its incidence is estimated at 1 in 6500 to 13,520 births [411]. The presence of AML of the kidney in this condition is a major clinical diagnostic criterion [401]. In the event of suspicion, genetic counselling is recommended. Renal assessment and monitoring include MRI (every 1 to 3 years), renal function, testing for hypertension and annual proteinuria. The first-line treatment is medical treatment with mTOR inhibitors, which have demonstrated their efficacy (hemorrhagic complications, preservation of renal function) in this indication. The balance of benefits and adverse effects must be weighed against the progression of the disease [412,413]. Second-line treatments include thermoablation, arterio-embolization and surgical removal (lumpectomy). Radical nephrectomy should be avoided [401].

# 9. Perioperative management

## 9.1. Management of thromboprophylaxis

Open nephrectomy, whether radical or partial, induces a state of hypercoagulability. In 2005, the SFAR recommended prophylactic

<table><caption>**Recommendation Table 17**

Recommendations for the treatment of oncocytomas.</caption><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>Surveillance is an alternative to systematic excision for biopsy-proven renal oncocytomas</td><td>High</td></tr><tr><td>In the absence of surgical excision, a renal oncocytoma must be monitored because of the risk of tumour growth and misdiagnosis of the biopsy.</td><td>High</td></tr><tr><td>In the case of multiple oncocytomas, a genetic investigation should be proposed</td><td>High</td></tr></tbody></table>
<table><caption>**Recommendation Table 18**
Management of angiomyolipomas.</caption><thead><tr><th>Recommendations</th><th>Grade</th></tr></thead><tbody><tr><td>Renal biopsy is not recommended for typical AML.</td><td>High</td></tr><tr><td>Surveillance is the treatment of choice for typical asymptomatic AMLs</td><td>High</td></tr><tr><td>Active treatment by partial nephrectomy or arterioembolization may be discussed if there is a risk of bleeding:<ul><li>Large tumour (no clearly defined intervention threshold)</li><li>women of childbearing age</li><li>non-compliance with surveillance</li><li>no access to a suitable care structure</li><li>risk of abdominal trauma</li></ul></td><td>Low</td></tr><tr><td>In the event of massive hemorrhage, emergency arterioembolization is recommended.</td><td>High</td></tr><tr><td>Tuberous sclerosis requires multidisciplinary care, including genetic counselling.</td><td>High</td></tr><tr><td>Renal assessment and monitoring of patients with tuberous sclerosis includes:<ul><li>MRI every year (if tumour >3 cm) or every 3 years</li><li>Check for high blood pressure every year</li><li>Assessment of renal function every year</li><li>Testing for proteinuria every year</li></ul></td><td>High</td></tr><tr><td>mTOR inhibitors are the first-line treatment for AML associated with tuberous sclerosis.</td><td>High</td></tr><tr><td>Thermoablation, arterioembolization and partial nephrectomy are the second-line treatments for MVA associated with tuberous sclerosis complex</td><td>Low</td></tr><tr><td>Radical nephrectomy should be avoided in patients with AML associated with tuberous sclerosis.</td><td>High</td></tr></tbody></table>

postoperative anticoagulation [414]. However, this recommendation did not distinguish between laparoscopic (± robotic assisted) and open surgery. The advent of these approaches may allow [415] under certain conditions, not to introduce preventive anticoagulation because the thromboembolic complication rate is low (≈ 0.6–0.9%) [416].

Thromboprophylaxis may therefore not be introduced if all the following criteria are met (low grade, expert opinion):

* laparoscopic approach (± robot-assisted);

* age < 75 years;

* BMI < 35;

* no personal or family history of thromboembolism within 1st degree.

## 9.2. Infectious risk management

In January 2024, the SFAR and SPILF, in conjunction with the CIAFU of the AFU, updated their recommendation on intraoperative antibiotic prophylaxis. They concluded that antibiotic prophylaxis should not be used (expert opinion, low grade).

The French multicenter study TOCUS [417], which included 269 nephrectomies, found no significant correlation between the performance of a preoperative ECBU and the risk of postoperative urinary tract infection [OR = 1.2 (0.5–2.7) (P = 0.7)]. Only postoperative non-infectious complications were associated with a higher risk of postoperative UTI [OR = 1.2 (4–37), P < 0.001)]. Furthermore, no study has demonstrated an increased risk of postoperative infection in the case of an untreated positive preoperative UTI. It is therefore not necessary to perform a ECBU prior to nephrectomy in order to prevent postoperative sepsis (expert opinion, low grade).

## 9.3. Enhanced Recovery After Surgery (ERAS)

In June 2022, the AFU issued recommendations on this subject. The introduction of a RAAC program within each establishment, specific to its ecosystem, is recommended. Coordination by paramedical staff plays a central role [418]. The addition of a digital device to the RAAC pathway is currently being evaluated: UROCCR 126 – DiPRU.

These measures can be divided into three parts: preoperative, intraoperative and postoperative (Recommendation Table 19).

### 9.3.1. Preoperative

Particular attention should be paid to informing the patient, especially about possible complications. The AFU leaflets can be used as a basis for these explanations. Treatment with adjuvant immunotherapy should be discussed prior to surgery.

In the event of malnutrition, appropriate nutritional support should be offered. However, immuno-nutrition (such as Oral Impact®) is not recommended (weak evidence, low grade). Fasting may last for only six hours, with the possibility of taking clear liquids up to two hours before surgery. A carbohydrate load of 50 grams the same morning is also recommended [419].

In general, it is advisable to stop smoking and drinking alcohol before surgery (medium level of evidence, high grade).

Radical or partial nephrectomy is also feasible with these measures in elderly patients [420] after possible oncogeriatric optimization and, if possible, adapted physical assistance (APA).

### 9.3.2. Peroperative

Laparoscopic surgery (± robot-assisted) and preservation of the parenchyma by partial nephrectomy is recommended as long as this is
**Recommendation Table 19**

Recommendations for the perioperative management of patients undergoing nephrectomy.

<table><thead><tr><th>Recommendations</th><th>Grade</th></tr></thead><tbody><tr><td>Pre-operative ECBU not recommended before radical and partial nephrectomy</td><td>Low</td></tr><tr><td>It is advisable to encourage patients to stop smoking and drinking alcohol before surgery.</td><td>High</td></tr><tr><td>It is important to be vigilant about the information given to the patient before and after the operation, particularly with regard to the possibility of using adjuvant immunotherapy.</td><td>Low</td></tr><tr><td>Pre-operative immuno-nutrition is not recommended</td><td>Low</td></tr><tr><td>Fasting can last as little as six hours, with the possibility of taking clear liquids up to two hours before surgery. A carbohydrate load of 50 grams that morning is also recommended.</td><td>Low</td></tr><tr><td>Preference should be given to laparoscopy (+/- robot-assisted) and preservation of the renal parenchyma as long as this is technically feasible.</td><td>High</td></tr><tr><td>Antibiotic prophylaxis should not be used</td><td>Low</td></tr><tr><td>Limit morphine and intraoperative filling volumes</td><td>Low</td></tr><tr><td>Limiting postoperative drainage</td><td>Low</td></tr><tr><td>Encourage mobilization and re-feeding on D0</td><td>Low</td></tr><tr><td>Thromboprophylaxis may not be introduced if all the following criteria are met:</td><td></td></tr><tr><td>- laparoscopic approach (+/- robot-assisted)</td><td></td></tr><tr><td>- age &lt; 75</td><td>Low</td></tr><tr><td>- BMI &lt; 35</td><td></td></tr><tr><td>- No personal or family history of thromboembolism in the 1<sup>er</sup> degree range</td><td></td></tr></tbody></table>

technically feasible in view of the oncological results. Anesthesia should limit the use of morphine and filling volumes. In the event of drainage or bladder catheterization, these should be removed as soon as possible.

### 9.3.3. Postoperative care

Early mobilization under multimodal analgesia is an essential part of PAC, and reduces postoperative complications. As a result, light chair feeding is recommended from day 0. Monitoring instructions must be explained and given to patients on discharge.

## 10. Prognostic factors and monitoring after treatment of localized or locally advanced kidney cancer

### 10.1. The benefits of monitoring

There is no real consensus on the modalities of surveillance after kidney cancer treatment [421]. Although some retrospective series suggest a potential benefit of early detection of recurrence, no high-level evidence study has demonstrated an impact on survival with regular follow-up [422,423]. Kidney tumor surgery causes a deterioration in renal function and increases the risk of de novo hypertension whatever the type of surgery, with 19% of de novo hypertension at 6 months after surgery in the prospective VAPANCR-UROCCR study [424].

The aims of follow-up after surgical treatment for non-metastatic kidney cancer are:

* detect local or distant recurrence that may benefit from curative or systemic treatment;

* monitor renal function and blood pressure and implement appropriate nephroprotective measures [424,425].

There is no consensus on the ideal duration of follow-up, which should take into account the patient's age, comorbidities, prognostic factors and life expectancy [426]. The majority of recurrences occur within 5 years, but in the case of poor prognostic factors, the risk remains significant

beyond 5 years (of the order of 20%), justifying prolonged and close follow-up in the early years [427].

### 10.2. Prognostic factors

Prognostic factors include clinico-biological, anatomical, histological and molecular factors.

Clinico-biological factors include performance status (ECOG, Karnofsky index), local symptoms, cachexia, anemia, platelet count, neutrophil count, lymphocyte count, C-reactive protein, albumin and various indices derived from these factors such as neutrophil/lymphocyte ratio (NLR) [428–431]. As a marker of the systemic inflammatory response, a high preoperative NLR appears to be associated with a poor prognosis [431]. However, there is significant heterogeneity in the data and no prognostic threshold can be proposed.

Anatomical factors include tumour size, venous invasion (renal vein, inferior vena cava), overgrowth of the renal capsule and invasion of local lymph nodes. All these factors are considered in the TNM classification.

Histological factors include tumour grade, histological subtype, lymphovascular invasion, tumour necrosis, invasion of the collecting system, rhabdoid and sarcomatoid component [432–435]. The percentage of the sarcomatoid component also seems to have a prognostic value, however, there is no agreement on the optimal prognostic threshold [436,437].

Numerous molecular markers such as expression of carbonic anhydrase IX (CA IX), VEGF and PD-L1 have been studied [438]. However, they have been tested in small cohorts with very little external validation. Their systematic use in clinical practice is therefore not recommended.

### 10.3. Prognostic systems in localized or locally advanced kidney cancer

TNM classification and nuclear grade play a predominant role as prognostic systems in non-metastatic kidney cancer. However, these
systems are often undermined by the sometimes-unpredictable course of kidney cancer.

As a result, several models and nomograms have been developed largely on the basis of retrospective data to predict the risk of death or metastases distant from surgery [439]. However, their ability to predict the risk of recurrence is limited [440] and even the sophisticated models proposed from prospective data by teams of experts show no improvement when evaluated externally [441].

Artificial intelligence (AI) techniques offer an innovative approach to analysis, distinct from traditional methods. These technologies can learn and improve their capabilities autonomously, without the need for explicit programming. In a context where healthcare data is abundant, AI offers a modern and accurate method for estimating individualized survival outcomes, thereby improving healthcare decision-making.

Several studies have used clinico-pathological data to predict post-nephrectomy recurrence, with many results suggesting superior performance of machine learning systems compared with traditional models [442-444].

The UROPREDICT algorithm developed by the CCAFU from prospective UROCCR data is available online (www.uroccr.fr) and can be used to estimate the individual risk of each patient [445].

Although the performance of AI-based models is promising, further steps are needed to improve their interpretability and ensure robust external validation before wider dissemination in clinical practice.

## 10.4. What regimen may be recommended after surgical treatment of localized or locally advanced kidney cancer?

### 10.4.1. Risk stratification

In the absence of a validated scheme, we suggest adapting follow-up to the risk of tumour recurrence, which can be assessed simply using the UISS system (Tables 3 and 4).

The UISS system is simple to use and is applicable to the three most frequent histological subtypes [446,447].

The risk of developing metastases after surgery was estimated at between 30 and 40%, with a median delay of 15 months. The 5-year specific survival after management of localized kidney cancer was estimated according to the UISS score to be 91.1%, 80.4% and 54.7% for patients at low, moderate and high risk [448].

### 10.4.2. Monitoring procedures

Abdominal CT is better than ultrasound for detecting local recurrence [449,450].

The risk of developing a tumour on the contralateral kidney is rare (estimated at 2%) [451].

The primary site of metastatic progression is the lung. CT is superior to radiography in detecting lung lesions [452].

For patients in the low-risk group, the use of irradiating imaging examinations can be limited, with ultrasound or MRI being preferred.

<caption>**Table 3**</caption>

UISS classification algorithm for localized and locally advanced kidney cancer.

<table><thead><tr><th>Stage T</th><th>T1</th><th>T2</th><th>T3</th><th>T4</th></tr></thead><tbody><tr><td>Fuhrman</td><td>1-2</td><td>3-4</td><td>1-4</td><td>1</td><td>2-4</td><td>1-4</td></tr><tr><td>ECOG</td><td>0</td><td>1-3</td><td>0-3</td><td>0</td><td>1-3</td><td>0-3</td></tr><tr><td>Risk</td><td>Low</td><td>Intermediate</td><td></td><td></td><td></td><td>High</td></tr></tbody></table>

## 10.5. What follow-up is required after ablative treatment for localized kidney cancer?

Ablative therapies require monitoring with imaging at 3 months, 6 months, 1 year and then every year for a period that is not clearly defined [453].

If surveillance is based on MRI, the search for secondary lung lesions requires annual lung scans (without iodinated contrast injection). Diagnosis of early local recurrence is often difficult and requires careful comparison with pre-treatment imaging. Given the difficulties in guiding the biopsy, the diagnosis of recurrence is not based on the biopsy, and new treatment may be proposed based on the presence of an oval-shaped contrast enhancement, most often located at the periphery of the lesion in contact with the deep part or non-tumorous renal parenchyma (Table of recommendations 20).

# 11. Adjuvant treatment in kidney cancer

## 11.1. Anti-angiogenic agents

Most randomized trials investigating the value of adjuvant anti-angiogenic therapy in patients at high risk of recurrence after nephrectomy have reported negative results [454]. Only the S-TRAC study, which evaluated the value of sunitinib treatment in patients at high risk of recurrence, showed an improvement in recurrence-free survival but no improvement in overall survival in the sunitinib-treated group [455]. The results of trials conducted with anti-angiogenic agents have not validated in France the indication for adjuvant treatment with anti-angiogenic agents (TKIs and mTOR inhibitors) after surgery for localized kidney cancer [456-461].

## 11.2. The role of immunotherapy

The phase 3 KEYNOTE-564 study evaluated the efficacy of pembrolizumab administered in the adjuvant setting after nephrectomy in patients with localized clear cell renal cancer at intermediate-high and high risk of recurrence, as well as in oligometastatic patients with no visible residual disease after resection of metastases within one year of nephrectomy (M1NED). Adjuvant therapy was initiated within 12 weeks of surgery and for up to 1 year at a dose of 200 mg administered every 3 weeks in ECOG 0 or 1 patients [462]. A total of 994 patients were randomized 1:1 to pembrolizumab or placebo. The study population included patients at risk of recurrence defined as follows: patients at intermediate-high risk of recurrence (pT2 Grade 4 or sarcomatoid, pT3 all grades N0, M0), patients at high risk of recurrence (pT4 all grades N0, M0 or pT all stages, N+, M0) and metastatic patients with no residual

<caption>**Table 4**</caption>

Proposed postoperative follow-up after surgery for localized or locally advanced kidney cancer.

<table><thead><tr><th>Risk</th><th>Low</th><th>Intermediate</th><th>High</th></tr></thead><tbody><tr><td>Terms and conditions</td><td>CT TAP<br>Possible alternation with ultrasound or renal MRI</td><td>CT TAP<br>or<br>Abdominal MRI and thoracic CT scan</td><td>CT TAP<br>Or<br>Abdominal MRI and thoracic CT scan</td></tr><tr><td>Frequency</td><td>At 6 months<br>Then every year for 3 years<br>Final check at 5 years</td><td>Every 6 months for two years<br>Then every year for 4 years<br>Then every two years for 4 years</td><td>Every 3 months for 1 year<br>Then every 6 months for 4 years<br>Then every year for 5 years</td></tr><tr><td>Duration</td><td>5 years</td><td>10 years</td><td>10 years</td></tr></tbody></table>
**Recommendation Table 20**

Recommendations for follow-up after treatment of a localised tumour.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>After treatment for non-metastatic kidney cancer, follow-up thoracic abdominal and pelvic imaging should be carried out.</td><td>High</td></tr><tr><td>The monitoring schedule after treatment for non-metastatic kidney cancer must be adapted to the risk of recurrence and the patient's life expectancy.</td><td>High</td></tr><tr><td>The risk of recurrence can be assessed by predictive nomograms (UISS) or by algorithms using Machine Learning and artificial intelligence.</td><td>Low</td></tr><tr><td>For low-risk diseases, radiation examinations should be limited</td><td>Low</td></tr><tr><td>After surgery or ablative treatment of a localized kidney tumour, renal function and blood pressure should be monitored.</td><td>High</td></tr><tr><td>Patients with post-operative chronic renal failure should be referred to a nephrologist or their General Practitioner for appropriate assessment, given the potentially higher risk of cardiovascular problems.</td><td>High</td></tr></tbody></table>

lesion after resection of all metastases within less than 12 months of nephrectomy (M1 NED – no evidence of disease). With a median follow-up of 57.2 months (47.9–74.5 months), the primary objective was achieved, with a 28% reduction in the risk of recurrence. The 4-year DFS rate was 64.9% in the pembrolizumab group versus 56.6% in the placebo group (HR: 0.72; 95% CI: 0.59–0.87; *P* = 0.001). The benefit existed in all 3 patient subgroups and was more marked in the “metastatic operated (M1NED)” group (HR: 0.40). In addition, adjuvant treatment with pembrolizumab significantly reduced the risk of death by 38%, with overall survival not reached in the 2 arms (HR = 0.62 (95CI: 0.44–0.87); *P* = 0.002). Overall survival at 4 years was 91.2% in the pembrolizumab arm versus 86% in the placebo arm. However, this gain in overall survival was not apparent in the subgroup analysis of high-risk and M1NED patients. Grade 3–4 pembrolizumab-related adverse events occurred in 18.6% of pembrolizumab-treated patients versus 1.2% of placebo-treated patients, leading to permanent discontinuation of treatment in 18.2% of pembrolizumab-treated patients versus 0.8% of placebo-treated patients. There was no death related to treatment side effects. The rate of immun-mediated adverse events requiring high-dose corticosteroid therapy (> 40 mg) was 7.4% in the pembrolizumab group versus 0.6% in the placebo group [463]. Treatment with pembrolizumab did not reduce patients’ quality of life [464].

Based on the improvement in recurrence-free survival and overall survival, pembrolizumab administered in the adjuvant setting for up to 12 months and initiated within 12 weeks of nephrectomy for localized intermediate-high and high-risk clear cell renal cancers as defined by the study (pT2 Grade 4 or sarcomatoid, pT3 all grades N0, M0 and pT4 all grades N0, M0 or pT any stage, N+, M0) is a standard treatment to be offered to patients. Patients should be given clear information about the potential side effects of pembrolizumab (Recommendation Table 21).

For patients in remission after complete resection of metastases, adjuvant treatment with pembrolizumab is recommended. However, it should be pointed out that the reference first-line treatment for metastatic kidney cancer is based on anti-PD1-based combinations, and that these situations of metastases operated on within the first year of diagnosis are exceptional. The cohort of M1 patients operated on in the KEYNOTE 564 study was small (56 pts, 6% in each group) with the majority, but not exclusively, resections of adrenal, proximal lymph node and nephrectomy sites [465–468].

KEYNOTE 564 is the only positive study in the adjuvant treatment of localized clear cell kidney cancer after nephrectomy. The CheckMate

914 study, evaluating nivolumab as a single agent or in combination with ipilimumab, compared with placebo, showed no benefit in terms of recurrence-free survival (HR: 0.87 [0.62–1.21], HR: 0.92 [0.71–1.19] respectively) [469]. The PROSPER study evaluating perioperative nivolumab was negative [469]. The IMmotion 010 study, evaluating atezolizumab vs. placebo, was also negative for recurrence-free survival (HR: 0.93 [0.75–1.15]) [470]. The RAMPART trial (NCT03288532, durvalumab vs. durvalumab + tremelimumab vs. placebo) and the LITESPARK trial (NCT05239728 pembrolizumab vs. pembrolizumab + belzutifan) have completed recruitment and the first results should be available shortly (Recommendation Table 21).

## 12. Treatment of metastatic kidney cancer

### 12.1. IMDC classification (Heng)

The prognostic classification of the International Metastatic RCC Database Consortium [471] (IMDC) is now the most widely used in clinical practice [472]. The prognostic score incorporates the Karnofsky index (< 80%), hemoglobin level (< normal), neutrophil count (> normal), platelet count (> normal), corrected calcium level (> normal) and the time between diagnosis and initiation of systemic therapy. This score has also been validated in second-line treatment [473] in clear cell carcinomas and in non-clear cell carcinomas [474] (Table 5). Median overall survival in the era of targeted therapy is 43, 23, and 8 months in groups with favorable (0 factors), intermediate (1 or 2 factors), and unfavorable (≥ 3 factors) prognosis, respectively [472].

### 12.2. Place of immediate or delayed cytoreductive nephrectomy (CRN) in metastatic renal cancer (mRCC)

#### 12.2.1. In the era of 1st line TKIs

Two long-standing prospective randomized trials (EORTC and SWOG), as well as a third study combining the two trials, have demonstrated an improvement in overall survival after cytoreductive nephrectomy (CRN) prior to IFN-alpha treatment in patients in good general condition with metastatic renal cancer (mRCC) [475].

In the era of single agent 1st line anti-angiogenic treatments, two prospective randomized trials have assessed the value of NCR in MRC: CARMENA and SURTIME. The CARMENA trial assessed the benefit of NCR in addition to sunitinib, while the SURTIME trial looked at the
**Recommendation Table 21**

Recommendations concerning adjuvant treatment after surgery for localized kidney cancer or kidney cancer in remission after removal of metastases.

<table><thead><tr><th>Recommendations</th><th>Grade</th></tr></thead><tbody><tr><td>Adjuvant anti-angiogenic treatment is not recommended after surgery for localized kidney cancer.</td><td>High</td></tr><tr><td>Adjuvant treatment with pembrolizumab is recommended in patients at intermediate-high and high risk of recurrence after nephrectomy for clear cell renal cancer (pT2 Grade 4 or sarcomatoid, pT3 all grades N0, M0 and pT4 all grades N0, M0 or pT all stages, N+, M0).</td><td>High</td></tr><tr><td>Treatment with pembrolizumab is recommended after surgical complete remission of metastases occurring within one year of nephrectomy for clear cell renal cancer.</td><td>Low</td></tr><tr><td>Adjuvant treatment with pembrolizumab is not recommended for non-clear cell renal cell carcinoma.</td><td>High</td></tr><tr><td>The patient must be informed:<br/>- Individual risk of recurrence based on recent prognostic models<br/>- Proven benefits and side effects of treatment</td><td>Low</td></tr></tbody></table>

benefit of immediate NCR versus delayed NCR after treatment with sunitinib.

The CARMENA trial reported non-inferiority of sunitinib alone versus NCR followed by sunitinib (median overall survival: 18.4 versus 13.9 months; HR: 0.89; 95%: 0.71–1.10; non-inferiority limit: ≤ 1.20) in patients with MRC of intermediate or poor prognosis according to the MSKCC model [476]. These data have been updated and confirm the non-inferiority of sunitinib alone in patients with intermediate or poor prognosis MRC using the prognostic criteria of the IMDC (median overall survival: 19.8 vs. 15.6 months; HR: 0.97; 95%CI: 0.79–1.19; *P* = 0.8).

Post-hoc analysis of CARMENA identified a sub-group of patients within the intermediate-risk IMDC population for whom immediate NCR could be discussed: patients with a single risk factor (overall survival benefit in the nephrectomy followed by sunitinib group, non-significant result: 31.4 months versus 25.2 months; HR 1.30, 95%IC 0.85–1.98; *P* = 0.2), patients with a single metastatic site (notably pulmonary with a median overall survival of 44 months [23.2–64.6] versus 31.5 months [14.7–64.4]; HR, 1.4; 95%CI 0.62–2.47) and patients who responded well to sunitinib treatment and underwent secondary surgery (median overall survival of 48.5 months for patients with secondary nephrectomy versus 15.7 months for patients who did not undergo surgery after sunitinib (HR, 0.34; 95%CI 0.22–0.54) [477].

The SURTIME trial showed no benefit in progression-free survival at 28 weeks (amended primary endpoint) in patients with mRCC treated with immediate versus delayed CRN in combination with sunitinib (42%

**Table 5**

IMDC prognostic classification of metastatic kidney cancer.

<table><thead><tr><th colspan="2">IMDC classification</th></tr></thead><tbody><tr><td>Karnofsky index</td><td>Less than 80</td></tr><tr><td>Interval between diagnosis and systemic treatment</td><td>Less than one year</td></tr><tr><td>Hemoglobin level</td><td>Below normal</td></tr><tr><td>Corrected blood calcium</td><td>Above normal</td></tr><tr><td>Platelet count</td><td>Above normal</td></tr><tr><td>Neutrophil count</td><td>Above normal</td></tr><tr><td colspan="2">0 factor: good prognosis<br/>1 or 2 factors: intermediate prognosis<br/>3 or more factors: poor prognosis</td></tr></tbody></table>

versus 43%, *P* = 0.61). In contrast, there was evidence of prolonged overall survival (secondary endpoint) in the delayed CRN arm (32.4 [14.5–65.3] months versus 15 [9.3–29.5] months; [HR: 0.57, 95% CI: 0.34–0.95, *P* = 0.032]). However, the trial enrolled only a small number of patients and lacked power [478].

In the light of these two prospective trials, immediate CRN should no longer be recommended as first-line treatment for patients with an intermediate or poor prognosis.

### 12.2.2. In the era of immunotherapies and 1-line immunotherapy-TKI combinations

Since the publication of CARMENA and SURTIME, combined treatments with checkpoint inhibitors (ICI) have become the reference first-line treatments for metastatic kidney cancer, with anti-angiogenic monotherapies becoming an option in cases where checkpoint inhibitors are contraindicated or unavailable (see the section on systemic treatment). The role of cytoreductive nephrectomy remains undetermined, and the available data are essentially retrospective.

In phase 3 trials of ICI-ICI and ICI-TKI combinations in 1st lines, up to 30% of patients were treated with their primary tumor in place [479–483]. In this group of patients, there was a benefit in progression-free survival and overall survival in favour of combinations with ICI versus sunitinib. A meta-analysis published in 2022 confirmed the benefit of treatment with ICI versus sunitinib in the groups of patients with or without nephrectomy: in overall survival (HR 0.67 [0.59–0.77] and HR 0.69 [0.57–0.85] respectively) and progression-free survival (HR 0.57 [0.44–0.74] and HR 0.63 [0.52–0.77] respectively), suggesting that nephrectomy would not provide any benefit. However, it is important to distinguish between nephrectomies performed before the metastatic stage and cytoreductive nephrectomies performed in synchronous metastatic disease. These data were not available in the various studies analyzed [484].

A retrospective study of the National Cancer Database (NCDB) including 391 patients treated with nephrectomy (immediate or deferred) and immunotherapy (n = 221) or immunotherapy alone (n = 170), reported a benefit in overall survival in favor of the nephrectomy group (median overall survival: NA vs. 11.6 months, HR 0.23 [95% CI 0.15–0.37] (*P* < 0.001). In multivariate analysis, cytoreductive nephrectomy
was the only factor associated with overall survival [485]. Other retrospective studies and meta-analyses concur with these conclusions regarding the overall survival benefit of immediate or delayed nephrectomy. However, these studies all have the bias of retrospective analyses, with patients selected in the nephrectomy group [486–488].

The morbidity of delayed nephrectomy after immunotherapy remains poorly assessed due to the lack of hindsight and the small number of cases reported in the literature. Two initial studies reported the feasibility of total or partial nephrectomy after immunotherapy, with the main surgical complexity being the presence of reactive inflammatory tissue making dissection of the hilum more difficult [489,490]. More recent series report reassuring data in terms of specific postoperative complications [491–493].

In the absence of randomized studies on the role of nephrectomy in the era of immunotherapy, first-line systemic treatment is still recommended in intermediate and poor risk groups.

The role of delayed nephrectomy in good responder patients remains to be determined.

Trials are currently underway to study the benefits of treating the primary tumour at the metastatic stage by delayed nephrectomy (NORDIC SUN [NCT03977571], PROBE [NCT04510597] Cyto-KIK [NCT04322955]) or stereotactic radiotherapy of the primary tumour (CYTOSHRINK [NCT04090710] and NRG-GU012 SAMURAI trial).

First-line medical treatments achieve a complete response to cancer metastases in 8 to 16% of cases [479–483]. On the other hand, response to treatment of the primary tumour is less frequent. In this population of patients with a major response to treatment and a primary tumour in place, delayed nephrectomy, known as “closure nephrectomy”, makes it possible to obtain a status without residual tumour. Once complete remission has been achieved, systemic treatments may be discontinued. This strategy is currently being evaluated, but appears to be a preferred indication for nephrectomy at the metastatic stage (Recommendation Table 22).

### 12.2.3. Special situations

12.2.3.1. Symptomatic patients. In a prospective observational study from 1988 to 2019, 66% of patients with metastatic kidney cancer were symptomatic at diagnosis. A further 37% had symptoms related to the primary tumour. Nephrectomy improved all symptoms in 71% of cases,

and local symptoms in 95% of cases, but was associated with a complication rate of 37% of cases (10% Clavien-Dindo ≥ 3), a mortality rate of 3% and a situation described as deleterious in 4% of cases (non-resolution of symptoms, associated with a major complication). There is also the risk of not being able to administer systemic treatment after nephrectomy in the event of complications or deterioration in the patient's general condition (17.7% of patients in the CARMENA trial were unable to receive sunitinib after nephrectomy). Patients should be informed of this [477,494].

12.2.3.2. Nephrectomy in oligometastatic patients. The KEYNOTE 564 trial demonstrated a benefit in terms of disease-free and overall survival of adjuvant treatment with pembrolizumab in patients undergoing surgery for localized clear cell renal cell carcinoma at high risk of recurrence (see adjuvant chapter) [463,495]. The study included patients with no residual disease after treatment of metastases within 12 months of nephrectomy (M1 NED). In this oligometastatic situation with possible complete treatment of the primary and metastatic sites, immediate nephrectomy may be discussed, accompanied by adjuvant treatment with pembrolizumab.

12.2.3.3. Metastatic non-clear cell kidney cancer. The main studies of cytoreductive nephrectomy (CARMENA, SURTIME) have included clear cell renal cell carcinomas, to the exclusion of other histological types. The same applies to therapeutic trials of checkpoint inhibitors and TKIs in 1st line metastatic renal cell carcinoma. The available studies on cytoreductive nephrectomy of metastatic non-clear cell cancers are essentially retrospective and of low level of evidence. A systematic review published in 2019 found an overall survival benefit in favour of cytoreductive nephrectomy for non-clear cell histological subtypes (analysis based on three observational studies) [496]. A recent retrospective study also found a survival benefit for cytoreductive nephrectomy in a matched population of 222 patients treated for metastatic non-clear cell renal cancer (median overall survival 36.8 months vs. 20.8 months; *P* < 0.01) [497].

In the absence of a strong level of evidence, cytoreductive nephrectomy should be discussed on a case-by-case basis for patients with metastatic non-clear cell renal cancer because of the lower likelihood of response to first-line medical treatments and the possible benefit of

<table><caption>**Recommendation Table 22**

Recommendations for cytoreductive nephrectomy.</caption><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>Immediate cytoreductive nephrectomy is not recommended in patients with intermediate and poor prognosis metastatic renal cancer.</td><td>High</td></tr><tr><td>Immediate cytoreductive nephrectomy can be offered to metastatic patients in good general condition who do not require systemic treatment.</td><td>Low</td></tr><tr><td>Immediate cytoreductive nephrectomy may be discussed in intermediate-risk patients with a single prognostic risk factor and a single metastatic site.</td><td>Low</td></tr><tr><td>Immediate cytoreductive nephrectomy may be proposed in oligometastatic patients in association with local treatment of metastases if the complete remission can be obtained.</td><td>Low</td></tr><tr><td>Delayed cytoreductive nephrectomy may be discussed in patients who have responded well to systemic treatment.</td><td>Low</td></tr><tr><td>Immediate cytoreductive nephrectomy may be discussed for patients with metastatic non-clear cell renal cancer in good general condition.</td><td>Low</td></tr><tr><td>Immediate cytoreductive nephrectomy may be proposed for symptomatic purposes</td><td>Low</td></tr></tbody></table>
nephrectomy. These patients should be discussed at the CARARE multidisciplinary oncological meeting.

## 12.3. Local treatment of metastases

### 12.3.1. Indications

Local treatment of metastases may be justified in several situations:

* for symptomatic purposes;

* to prevent local complications;

* to defer the introduction of systemic treatment;

* to achieve complete remission and consider a therapeutic pause in oligometastatic patients

The aim of targeted treatment of metastases would be to improve patient survival while preserving quality of life, on the one hand by delaying the introduction of or change to systemic treatment, and on the other hand by limiting the complications associated with metastases.

Oligometastatic and oligoprospective situations should be considered at a multidisciplinary meeting in order to discuss the alternatives of surveillance, systemic treatment and/or local surgical or ablative treatment of the metastases (Recommendation Table 23).

### 12.3.2. Surgery

Among the alternatives for local treatment of metastases, surgery has been the most extensively studied. However, survival data for surgical treatment of kidney cancer metastases are based on retrospective series with highly selected patients. The recommendations must therefore be taken with the reservation of a low level of evidence.

#### 12.3.2.1. Metastasectomy versus no surgical treatment of metastases.
Several retrospective studies report a benefit in terms of overall survival, specific survival and progression-free survival in favour of metastasectomy in selected patients and have been the subject of literature reviews [498–501]. This benefit was not found in patients with a poor prognosis [502,503]

#### 12.3.2.2. Complete metastasectomy versus incomplete metastasectomy.
In 2014, a systematic review of surgery for kidney cancer metastases,

including 16 studies with a total of 2,235 patients, concluded that complete treatment of metastases was associated with a specific survival of 41 months compared with 15 months in the absence of treatment and/or incomplete treatment. The gain in survival with complete treatment concerned all metastatic sites (lung, liver, bone, pancreas) and reached in particular 142 vs. 27 months for liver metastases (P = 0.003). [499].

In a series of 586 patients published in 2020, 2-year survival was 84% for complete resection versus 54% for incomplete resection (P < 0.001). Complete surgical resection was the main prognostic factor for survival [504].

According to a 2021 systematic review, incomplete or unperformed metastasectomy had a negative impact on overall survival compared with complete metastasectomy (HR 2.15; P < 0.00001), with synchronous and multiple metastases being associated negative factors [505]. The benefit of complete metastasectomy also seems to be confirmed in the era of immunotherapies [506,507].

#### 12.3.2.3. Other prognostic factors related to metastasectomy.
Other prognostic factors have been put forward, such as the number of metastatic sites and the disease-free interval. The prognostic impact of the organ affected is less clear: the most favourable survival data seem to concern surgery for pulmonary, pancreatic, hepatic, thyroid and adrenal metastases, as opposed to bone, brain and lymph node metastases [498].

#### 12.3.2.4. Morbidity of surgery for metastases.
Surgery for metastases can therefore only be considered when it is thought to be complete, in a patient in good general condition, with a limited number of metastatic sites and slowly progressive disease [498,499,508,509]. However, this should be weighed against the risks involved: according to a study based on the SEER database, the complication rate and intra-hospital mortality after metastasectomy were 55% and 4.6% respectively. In a multicenter series published in 2023, including 740 metastasectomies in 522 patients, 8% of patients had a major complication and 1% died perioperatively. Age, multiple resected sites and pancreatic surgery were associated with the risk of major complication [510].

### Recommendation Table 23

Recommendations for local treatment of kidney cancer metastases.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>In oligometastatic patients, local treatment of metastases may be offered for oncological purposes if it achieves a complete response.</td><td>Low</td></tr><tr><td>Surgery for metastases should only be considered for carcinological purposes if complete surgical resection is possible.</td><td>Low</td></tr><tr><td>Local treatment of metastases can also be proposed in the following cases:<ul><li>Palliative for symptomatic purposes,</li><li>To prevent local complications,</li><li>To defer the introduction of systemic treatment,</li><li>To delay a change in therapeutic line</li><li>To take a therapeutic break from a systemic treatment</li><li>To control dissociated responses</li></ul></td><td>Low</td></tr><tr><td>The modalities for local treatment of metastases should be discussed at the multidisciplinary consultation meeting (RCP). Surgery, radiotherapy and percutaneous ablative therapies are possible.</td><td>Low</td></tr></tbody></table>
### 12.3.3. Stereotactic radiotherapy

Stereotactic radiotherapy (SABR or SBRT) has demonstrated its superiority over conventionally fractionated radiotherapy with a high rate of local control (> 90%) and low morbidity [511-515].

#### 12.3.3.1. In oligometastatic situations (≤ 5 metastases).
Complete treatment of all metastatic sites with stereotactic radiotherapy provides a benefit in terms of progression-free survival and specific survival compared with no treatment or incomplete treatment [516]. A 2019 meta-analysis of 1602 oligometastatic patients treated with stereotactic radiotherapy reported a 1-year local control rate of 89.1% and 90.1% for extracranial and intracranial metastases respectively, and 1-year overall survival of 86.8% and 49.7%. The tolerability of stereotactic radiotherapy was acceptable, with a grade 3-4 toxicity of 0.7% at 1 year. Different radiotherapy regimens were used: 1 fraction of 25 Gy, 36 Gy in 3 fractions or 40 Gy in 5 fractions. However, the inclusion criteria were heterogeneous (oligometastatic, oligoprospective), with heterogeneous and suboptimal concomitant systemic treatment protocols [513].

In selected patients (a single metastasis, metachronous), stereotactic radiotherapy could make it possible in oligometastatic situations to delay the introduction of a first line of systemic treatment [511,517] by just over a year. A 1-year systemic treatment-free survival rate of 82% was reported in a phase II trial. In another trial published in 2022, Hannan et al. reported a 1-year systemic treatment-free rate of 91.3% [518].

#### 12.3.3.2. In situations of oligoprogression.
There may also be a role for stereotactic radiotherapy of metastases (one to 5 metastases), with the aim of delaying switching to a different line of systemic treatment. Several prospective multicenter phase II studies have reported a local control rate at 1 year ranging from 83 to 100% and a median time to change treatment line of around 12 months [514,517-519]. The GETUG-StORM-01 trial (NCT04299646) is currently being enrolled in patients receiving first- or second-line TKI or immunotherapy, with 1 to 3 oligoprospective metastatic sites.

#### 12.3.3.3. Radiotherapy and immunotherapy.
The role of stereotactic radiotherapy is also being studied in the era of immunotherapy, with the hypothesis of an abscopal effect. Current data are based on retrospective studies or studies with a low level of evidence, with the limitations of small numbers and relatively short follow-up. Radiotherapy protocols (doses and fractions) and patient selection criteria have yet to be determined. Randomized trials are underway to determine the benefits of stereotactic radiotherapy for metastatic sites (RADVAX RCC, OligoRARE (NCT04498767), SABR-COMET-3 (NCT03866291), SABR-COMET 10 (NCT03721342).

The single-arm NIVES trial studied nivolumab in second- and third-line metastatic disease, in combination with stereotactic radiotherapy to a single metastatic site. There was no evidence of benefit from combining radiotherapy with immunotherapy in this study [520]. Preliminary results from the RADVAX RCC trial, investigating the combination of nivolumab-ipilimumab with stereotactic radiotherapy at 1-2 metastatic sites (50 Gy in 5 fractions) in intermediate- and high-risk IMDC patients, were reported at ASCO 2020, with an objective response rate of 56% (Hammers et al.). The RAPPORT phase 1-2 trial analyzed the benefit of stereotactic radiotherapy (single 20 Gy fraction) to all metastatic sites (1-5 sites) followed by treatment with pembrolizumab in patients on 1st or 2nd lines of systemic therapy. The objective response rate was 63% with overall survival of 90 and 74% and progression-free survival of 60 and 45% at 1 and 2 years respectively, associated with grade ≥ 3 toxicity of 13% [521].

#### 12.3.3.4. Specificity of brain metastases.
Surgery or stereotactic radiotherapy gives similar or better results than panencephalic radiotherapy [522]. Panencephalic radiotherapy should be reserved for patients with numerous lesions or patients with a poor prognosis [523].

#### 12.3.3.5. Management of systemic treatments during stereotactic radiotherapy.
Continuation of anti-angiogenic treatment during radiotherapy does not appear to increase toxicity or the risk of complications [524,525]. In practice, and according to expert opinion, it is recommended that anti-angiogenic treatments be stopped during radiotherapy for visceral metastases and continued during treatment for bone metastases.

The morbidity of radiotherapy associated with checkpoint inhibitors appears to be acceptable (toxicity grade mostly ≤ 3). [526]. On the basis of expert opinion, it is not necessary to discontinue checkpoint inhibitors during radiotherapy treatment.

### 12.3.4. Radiofrequency and ablative treatments

Few data are available on the use of ablative treatments (radio-frequency (RF) or cryoablation) for metastases. The first retrospective studies focused on pulmonary, hepatic and adrenal sites, with 3-year local control rates of 77% to 91% for pulmonary and adrenal sites, and 3-year recurrence-free survival of 83% for hepatic sites [527-532]. RF can be considered for single or few metastases that are not accessible to surgery in patients with a good or intermediate prognosis. In the treatment of pulmonary metastases, the main complication is pneumothorax (42-89%), which requires pleural drainage in 7-25% of cases [528].

## 12.4. Medical treatments

### 12.4.1. Treatment of metastatic clear cell kidney cancer

#### 12.4.1.1. Results of trials using immunotherapy combinations.
Since the last CCAFU recommendations were published, several updates of the main phase 3 registration studies evaluating combinations of immunotherapies and anti-angiogenic agents have been published.

#### 12.4.1.2. CheckMate-214 (NCT02231749), nivolumab plus ipilimumab versus sunitinib.
The CheckMate 214 study is a prospective randomized phase 3 trial that evaluated the efficacy of the combination of nivolumab-ipilimumab versus sunitinib in first-line locally advanced or metastatic clear cell kidney cancer. Initial results from this study were published in April 2018 [533] and updated in October 2020 [534]. The latest analyses reported at ASCO GU 2024 confirm, with a median follow-up of 99.1 months in patients in the intermediate- and poor-risk groups, the superiority of the immunotherapy combination on overall survival (HR = 0.69; 46.7 vs. 26.0 months; *P* < 0.0001), progression-free survival (HR = 0.73, 0.61-0.87) and objective response rate (42% vs. 27%; *P* = 0.0001). The overall survival benefit was not significant for patients in the favourable risk group (HR = 0.82; 77.8 months vs. 66.7 months). There was also a complete response rate of 12% in the intermediate- and poor-risk patient population for the immunotherapy combination versus 3% for sunitinib. Finally, the median duration of response was achieved with 8.3 months versus 19.8 months for the sunitinib arm in the intermediate/poor prognosis group [535].

#### 12.4.1.3. The Keynote-426 study (NCT02853331), pembrolizumab plus axitinib versus sunitinib.
The Keynote-426 study is a prospective randomized phase 3 trial that evaluated the efficacy of the combination of pembrolizumab-axitinib versus sunitinib in first-line metastatic clear cell kidney cancer. The results of this study were published in March 2019 and updated in 2020 [480,536]. A further update of the study was published in 2023 with a median follow-up of 43 months. Progression-free survival remained unchanged (15.7 vs. 11.1 months, HR = 0.68, *P* < 0.001). Overall survival remained in favour of the combination arm (45.7 vs. 40.1 months, *P* < 0.001, HR = 0.73). The reported objective response rate was 60.4% for the combination arm, including 10% complete responses (vs. 3.5% for sunitinib). The median duration of response was 24 months versus 15 months in the pembrolizumab-axitinib arm versus sunitinib, respectively [537].
12.4.1.4. The CheckMate 9ER study (NCT03141177), nivolumab plus cabozantinib versus sunitinib. The CheckMate 9ER study is a prospective randomized phase 3 trial that evaluated the efficacy of the combination of nivolumab and cabozantinib versus sunitinib as first-line treatment for metastatic clear cell kidney cancer. The results of this study were published in 2021 [479]. The last update with a median follow-up of 55.6 months was at ASCO GU 2024. Progression-free survival remained unchanged (16.4 vs. 8.4 months, HR = 0.58 [0.49–0.70]). Overall survival favoured the combination arm (46.5 vs. 36.0 months, HR = 0.77 [0.63–0.95]). The objective response rate was 55.7% for the combination arm, including 13.6% complete responses (vs. 4.6% for sunitinib). Subgroup analyses reported no benefit in overall survival for patients in the favourable IMDC group (HR 1.10, 52.9 months vs. 58.9 months) with, however, an improvement in progression-free survival (HR = 0.69, 21.4 vs. 12.8 months) and a response rate of 66.2% with 16.2% complete responses [538].

12.4.1.5. The CLEAR study (NCT02811861), pembrolizumab plus lenvatinib versus everolimus plus lenvatinib versus sunitinib. The CLEAR study is a prospective randomized phase 3 trial that evaluated the efficacy of the combination of pembrolizumab and lenvatinib versus sunitinib versus everolimus and lenvatinib as first-line treatment for metastatic clear cell kidney cancer. The results of this study were published in March 2021 [482]. The latest update was reported with 49.8 months median follow-up at ASCO GU 2024. The combination of pembrolizumab and lenvatinib improved overall survival (HR = 0.79, 53.7 months vs. 54.3 months. P = 0.0424), progression-free survival (23.9 vs. 9.2 months; HR = 0.47; P < 0.001) and objective response rate (71.3% vs. 36.7%). The complete response rate was 18.3% vs. 4.8% for the sunitinib arm. Subgroup analyses reported no overall survival benefit for patients in the favourable IMDC arm (HR 0.94; 59.9 months vs. NR) with, however, an improvement in progression-free survival (HR = 0.50; 28.6 vs. 12.9 months) [539].

12.4.1.6. Recommendations for first-line treatment of metastatic disease. In patients with a good prognosis, the following combinations are recommended with a high level of evidence: pembrolizumab-axitinib, pembrolizumab-lenvatinib and nivolumab-cabozantinib. There is no preferred combination of anti-PD1 and anti-VEGFR inhibitors, and comparisons between studies are not recommended. Overall survival data in subgroup analysis for each of the combinations show that overall survival is not superior to sunitinib. However, progression-free survival as well as objective response rates and complete response rates are in favour of the combinations. In patients with a contraindication to immunotherapy, pazopanib or sunitinib are the recommended treatments. Close monitoring with deferred treatment is an option to be discussed by the PCR in this population, whose course is often indolent.

In patients with an intermediate or poor prognosis, the following combinations are recommended with the same high level of evidence: nivolumab-ipilimumab, pembrolizumab-axitinib, pembrolizumab-lenvatinib and nivolumab-cabozantinib. If immunotherapy is contraindicated, pazopanib and sunitinib are the recommended treatments (Table of recommendations 24).

Recommendations for second-line treatment of metastatic disease. In the event of failure of anti-VEGFR treatment, two molecules are recommended: nivolumab [540] and cabozantinib [541]. Axitinib and sorafenib are also possible options.

After double immunotherapy or a combination of immunotherapy and TKIs, there are no randomized data to define the best therapeutic sequence. Treatment options are based on the sequential use of anti-VEGFR targeted therapies not previously used (expert opinion).

The CONTACT 03 study evaluated the value of maintaining immunotherapy after failure of a previous line including immunotherapy. The study randomized 522 patients with metastatic clear cell renal cell carcinoma who had failed prior immunotherapy to cabozantinib (60 mg/

<caption>Recommendation Table 24</caption>

Summary of recommendations for 1st line systemic treatments in clear cell MRC.

<table><thead><tr><th>IMDC prognostic classification</th><th>1st line</th></tr></thead><tbody><tr><td rowspan="3">Favorable</td><td rowspan="2">Standard</td><td>pembrolizumab + axitinib</td></tr><tr><td>nivolumab + cabozantinib</td></tr><tr><td>Options</td><td>pembrolizumab + lenvatinib</td></tr><tr><td rowspan="6">Intermediate</td><td rowspan="3">Standard</td><td>sunitinib</td></tr><tr><td>pazopanib</td></tr><tr><td>nivolumab + ipilimumab</td></tr><tr><td rowspan="3">Options</td><td>pembrolizumab + axitinib</td></tr><tr><td>nivolumab + cabozantinib</td></tr><tr><td>pembrolizumab + lenvatinib</td></tr><tr><td rowspan="3">Poor</td><td rowspan="2">Standard</td><td>sunitinib</td></tr><tr><td>pazopanib</td></tr><tr><td>Options</td><td>nivolumab + ipilimumab</td></tr><tr><td rowspan="3">Standard</td><td>pembrolizumab + axitinib</td></tr><tr><td>nivolumab + cabozantinib</td></tr><tr><td>pembrolizumab + lenvatinib</td></tr><tr><td rowspan="3">Poor</td><td rowspan="2">Standard</td><td>sunitinib</td></tr><tr><td>pazopanib</td></tr><tr><td>Options</td><td>nivolumab + ipilimumab</td></tr></tbody></table>

d) monotherapy (n = 263) or a combination of cabozantinib (60 mg/d) and atezolizumab (1200 mg/3wk). The primary objective was not met with a progression-free survival of 10.8 months for the combination arm and 10.6 months for the cabozantinib alone arm [542]. The study was negative, suggesting that there is no benefit in continuing immunotherapy in this setting. Other studies are underway, in particular the TiNivo-2 study, the results of which are expected shortly. In view of the initial results, this strategy is not currently recommended (expert opinion) (Table of recommendations 25).

### 12.4.2. Treatment of metastatic non-clear cell renal cell carcinoma

12.4.2.1. Main prospective studies evaluating the therapeutic management of metastatic non-clear cell renal cell carcinoma. We report the results of the main prospective studies that have investigated the efficacy of targeted therapies and immunotherapy alone or in combination with targeted therapies. These studies are mostly non-randomized, small in number and heterogeneous in terms of the different histological subtypes and the aggressiveness of the cancer at diagnosis. However, they represent the most objective data available.

#### 12.4.2.1.1. Studies evaluating targeted therapies alone.

12.4.2.1.1. CALYPSO study. The CALYPSO study is a prospective, single-arm phase 2 trial which investigated the efficacy of durvalumab in combination with the MET inhibitor salvolitinib in patients with metastatic papillary cancer. The study included 41 patients and the objective response rate was 29%. Median progression-free survival was 4.9 months (95% CI, 2.5–10) and overall survival was 14.1 months (95% CI, 7.3–30.7). Patients with MET gene alteration had a higher response rate (progression-free survival of 12 months (95% CI 7.3–30.7) and overall survival of 27.4 months (95% CI 9.3 – not achieved) [543].

12.4.2.1.1.2. Study KNOWLEDGE. The SAVOIR study is a multicenter randomized phase 3 trial that compared the efficacy of savolitinib versus sunitinib in patients with tubulopapillary carcinoma with MET gene alteration. The study included 33 patients in the savolitinib arm and 27 patients in the sunitinib arm. The objective response rate was 27% in
**Recommendation Table 25**

Summary of recommendations for 2nd line systemic treatments for clear cell MRC.

<table><thead><tr><th>Treatment received in 1<sup>st</sup> Line</th><th>2<sup>nd</sup> Line</th><th>3<sup>rd</sup> Line</th></tr></thead><tbody><tr><td>sunitinib</td><td>cabozantinib</td><td>nivolumab</td></tr><tr><td>pazopanib</td><td>nivolumab</td><td>cabozantinib</td></tr><tr><td>pembrolizumab + axitinib</td><td rowspan="3">Anti-VEGF TKI not used in 1<sup>st</sup> line</td><td rowspan="3">Other targeted therapy</td></tr><tr><td>pembrolizumab + lenvatinib</td></tr><tr><td>nivolumab + cabozantinib</td></tr><tr><td>nivolumab + ipilimumab</td><td>Anti-VEGF TKI</td><td>Other targeted therapy</td></tr></tbody></table>

the savolitinib arm and 7% in the sunitinib arm. Median progression-free survival was 7 months (95% CI, 2.8 – not achieved) in the savolitinib arm and 5.6 months (95% CI, 4.1–6.9) in the sunitinib arm (P = 0.31). Savolitinib was better tolerated than sunitinib. The study was stopped early due to the lack of a positive signal in favour of savolitinib [544]. 12.4.2.1.1.3. PAPMET study. SWOG's randomized phase 2 study, PAPMET, evaluated cabozantinib (n = 44) versus sunitinib (n = 28) versus savolitinib (n = 29) and crizotinib (n = 28) in metastatic papillary renal cell carcinoma. The arms evaluating savolitinib, a specific MET inhibitor, and crizotinib were discontinued due to futility. The primary endpoint of progression-free survival was significantly improved by cabozantinib (9 months vs. 5.6 months, HR = 0.60 (95% CI 0.37–0.97), P = 0.02). Cabozantinib was associated with a higher response rate (23% vs. 4%) than sunitinib. Overall survival was not significantly improved due to lack of power (20 months vs. 16 months) [545].

12.4.2.1.1.4. ASPEN study. The ASPEN study is a randomized phase 2 trial that investigated the efficacy of sunitinib versus everolimus in patients with metastatic non-clear cell renal cell carcinoma. This study included 108 patients, 76 (70.3%) with tubulo-papillary carcinoma and 16 (14.8%) with chromophobe carcinoma. Sunitinib was associated with superior progression-free survival compared with everolimus (8.3 months [5.8–11.4] vs. 5.6 months [5.5–6.0]; HR: 1.41 [80% CI 1.03–1.92]; P = 0.16). There was heterogeneity in response to treatment across histological subtypes with a better response rate to sunitinib in papillary carcinomas [546].

12.4.2.1.1.5. AXIPAP study. The AXIPAP study is a prospective, single-arm, multicenter phase 2 trial coordinated by GETUG, which investigated the efficacy of axitinib in first-line metastatic papillary carcinoma. This study included 44 patients. The objective response rate was 28.6% (12 partial responses). Median progression-free survival was 6.6 months (95% CI, 5.5–9.2) and overall survival was 18.9 months (95% CI, 12.8 – not reached) [547].

12.4.2.1.1.6. ESPN study. The ESPN study is a prospective randomized phase 2 trial that compared the efficacy of sunitinib versus everolimus with group switching at the time of progression in patients with metastatic non-clear cell renal cell carcinoma. The study included 68 patients, 27 with tubulopapillary carcinoma and 12 with chromophobe carcinoma. The objective response rate was 9% in first-line treatment with sunitinib and 2.8% in first-line treatment with everolimus. First-line progression-free survival was 6.1 months for sunitinib and 4.1 months for everolimus (P = 0.6) [548].

12.4.2.1.1.7. RAPTOR study. The RAPTOR study is a multicenter, single-arm, phase 2 trial which evaluated the efficacy of everolimus in first-line metastatic disease in patients with papillary carcinoma. The study

included 92 patients. The objective response rate was 1% (one partial response). Median progression-free survival was 4.1 months (95% CI 3.6–5.5) [549].

12.4.2.1.1.8. SUPAP study. The SUPAP study is a single-arm, multicenter, phase 2 GETUG study that evaluated the efficacy of sunitinib in patients with metastatic tubulopapillary cancer (PTC). The study enrolled 51 patients, including 14 patients with type 1 PTC and 47 patients with type 2 PTC. The objective response rate was 13% for type 1 PTC and 11% for type 2 PTC. Median progression-free survival for type 1 and type 2 PTC was 6.6 months (95% CI 2.8–14.8) and 5.5 months (95% CI 3.8–7.1), respectively [550].

### 12.4.2.1.2. Study evaluating immunotherapy alone.

12.4.2.1.2.1. KEYNOTE 427 (cohort B). KEYNOTE 427 is a prospective, single-arm study investigating the efficacy of single-agent pembrolizumab as first-line therapy in patients with metastatic renal cell carcinoma. Cohort B studied non-clear cell RCC. The study included 165 patients, 71.5% of whom had tubulopapillary carcinomas, 12.7% chromophobe carcinomas and 15.8% unclassified carcinomas. The objective response rate was 26.7% (28.8% for tubulopapillary carcinomas, 9.5% for chromophobe carcinomas and 30.8% for unclassified carcinomas). Median progression-free survival for the overall cohort, papillary and chromophobe subtypes were 4.2 months (95% CI, 2.9–5.6), 5.5 months (95% CI 3.9–6.9) and 3.9 months (95% CI 2.6–6.9), respectively [551].

### 12.4.2.1.3. Studies evaluating targeted therapies in combination with immunotherapy.

12.4.2.1.3.1. Study Keynote B-61. Keynote B-61 is a prospective, non-randomized, single-arm phase 2 study investigating the efficacy and safety of the combination of pembrolizumab and lenvatinib as first-line therapy in metastatic non-clear cell renal cell carcinoma. The study included 158 patients with a median follow-up of 14.9 months. The disease control rate was 82% and the objective response rate was 49%, including 6% complete response and 44% partial response. The progression-free survival rate was 18 months (95% CI [14 – not achieved]). Grade 3–4 adverse events occurred in 51% of patients, the most common being hypertension (23%). Patient populations were composed of 93 (59%) papillary carcinomas, 29 (18.3%) chromophobe carcinomas, 21 (13%) unclassified carcinomas, 6 (3.7%) translocation carcinomas and 9 (5.6%) other histologies. Patients with collecting-tube carcinoma (Bellini carcinoma) were excluded from this study. Response to treatment was similar in all histological subtypes but this should be interpreted with caution due to the heterogeneity of the population and the small number of patients [552].

12.4.2.1.3.2. Nivolumab plus cabozantinib. This prospective, single-arm, single-center study investigated the efficacy of cabozantinib in
<figure><img src="image_7.png" /></figure>

Non-hierarchical therapeutic options in the absence of randomized phase 3 studies and direct comparison

<caption>Fig. 4. CCAFU recommendations for the treatment of metastatic non-clear cell renal cell cancer.</caption>

combination with nivolumab in first- or second-line metastatic disease (after anti-VEGF) in patients with metastatic non-clear cell renal cell carcinoma. The study enrolled 47 patients, including 40 patients with tubulopapillary carcinoma and 7 patients with chromophobe carcinoma. In patients with tubulopapillary carcinoma, the objective response rate was 48% (19 partial responses) and progression-free survival was 12.5 months (95% CI, 6.3–16.4). In patients with chromophobe carcinoma, no objective response was observed and progression-free survival could not be determined due to the small size of the cohort [553].

12.4.2.1.4. *Studies specific to renal cell carcinoma of the collecting tubes.*

12.4.2.1.4.1. Gemcitabine combined with cisplatin or carbaplatin. This prospective single-arm GETUG trial evaluated the efficacy of gemcitabine combined with cisplatin or carboplatin (in cases of renal failure) in patients with metastatic collecting-tube cancer. The study included 23 patients, 6 (26%) of whom had an objective response to treatment (one complete response and 4 partial responses). Median progression-free and overall survival were 7.1 (95% CI 3–11.3) and 10.5 (95% CI 3.8–17.1) months [554].

12.4.2.1.4.2. Gemcitabine combined with Sorafenib and Cisplatin. This prospective single-arm phase 2 trial evaluated the combination of cisplatin, gemcitabine and sorafenib in 26 patients with metastatic collecting-tube carcinoma. The objective response rate was 30.8%. Median progression-free and overall survival were 8.8 months (95% CI: 6.7–10.9) and 12.5 months (95% CI: 9.6–15.4), respectively [555].

12.4.2.1.4.3. Bonzai study. The Bonzai study is a prospective, single-arm, phase 2 trial which evaluated the efficacy of cabozantinib (60 mg/day) in patients with metastatic collecting-tube carcinoma. The study included 25 patients, 23 of whom were treated. The objective response rate was 35% (one complete response and 7 partial responses). Median progression-free and overall survival were 4 months (95% CI: 3–13) and 7 months (95% CI: 3–31) [556].

12.4.2.1.4.4. BEVABEL study. The BEVABEL study is a single-arm phase 2 GETUG trial which evaluated the efficacy of the combination of gemcitabine, cisplatin and bevacizumab in patients with collecting-tube carcinoma. The study included 34 patients and was stopped early due to lack of efficacy signals and toxicity (82% grade 3–4 toxicity and 2 grade 5). Median overall survival was 11.1 months (95% CI: 7.6–24.2) [557].

12.4.2.2. CARARE multidisciplinary consultation meeting. Given the difficulties of histological diagnosis, it is recommended that a specific anatomopathological review be proposed to the CARARE network of French experts. With regard to systemic management, it is proposed that cases be discussed at the national CARARE RCP and that priority be given to including patients in clinical trials. The CARARE virtual RCP is organized every 15 days. The quorum is made up of two pathologists, two oncologists and two urologists (Recommendation Table 26, Fig. 4).

Recommendation Table 26

Management of non-clear cell MRC.

<table><thead><tr><td>Recommendations</td><td>Grade</td></tr></thead><tbody><tr><td>A centralized review by the CARARE network of expert pathologists is recommended.</td><td>Low</td></tr><tr><td>It is recommended that files be discussed at the CARARE RCP.</td><td>Low</td></tr><tr><td>It is recommended that inclusion in a therapeutic trial be proposed as a priority</td><td>High</td></tr><tr><td>The treatment options are shown in Figure 4.</td><td>Low</td></tr></tbody></table>

Disclosure of interest

Pierre Bigot: MSD, Ipsen, Bms, Astellas, Pfizer.

Philippe Barthelemy: Ipsen, Bms, Pfizer, Astellas, Janssen, Cilag, Amgen, Bayer, Gilead, Astrazeneca, Novartis.

Alexandre Ingels: Ipsen, Bms, Msd, Bayer, Astellas, Intuitive.

Caroline Pettenati: Ipsen, Bms, Astellas, Msd, Janssen.

Jean Michel Correas: Bracco, GUerbet, Johnson et Johnson, Canon, Supersonic, imagine, General electric, Fujifilm, Siemens, Philips.

Nathalie Rioux Leclercq: Ipsen, Bms, Astellas, Msd, Janssen.

Stéphane De Vergie: Astellas, Ipsen, Bms, Msd, Janssen, Intuitive, Lamidey Noury.

Romain Boissier: Ipsen, Merck, Bms, Astellas, Novartis, Bayer, Astrazeneca.

Nicolas Doumerc: Intuitive Surgical, Ipsen, Msd, Pierre Fabre, Ferring.

Morgan Rouprêt: Roche, Bms, Ipsen, Msd, Novartis, Bayer, Astellas, Pfizer, Janssen, Provepharm, Intuitive, Medtronics, Photocure Curium.

Jean Christophe Berhnard: Ipsen, Bms, Msd, Fujifilm, Intuitive.

Idir Ouzaid: Bms, Astellas, Msd, Jansen, Ipsen, Bayer, Novartis.

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