Guidelines

Renal Cell Carcinoma

1. INTRODUCTION

1.1. Aims and scope

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

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

1.2. Panel composition

The RCC Guidelines Panel is an international group of clinicians consisting of urological surgeons, oncologists, methodologists, a pathologist and a radiologist, with particular expertise in the field of renal cancer care. Since 2015, the Panel has incorporated a patient advocate to provide a consumer perspective for its guidelines. All experts involved in the production of this document have submitted potential conflict of interest statements, which can be viewed on the EAU website Uroweb: http://uroweb.org/guideline/renalcellcarcinoma/.

1.3. Acknowledgement

The RCC Guidelines Panel is most grateful for the continued methodological and scientific support provided by Prof.Dr. O. Hes (pathologist, Pilzen, Czech Republic) for two sections of this document: Histological diagnosis and Other renal tumours.

1.4. Available publications

A quick reference document (Pocket Guidelines) is available, both in print and as an app for iOS and Android devices, presenting the main findings of the RCC Guidelines. These are abridged versions which may require consultation together with the full text version. Several scientific publications are available, as are a number of translations of all versions of the EAU RCC Guidelines [1]. All documents can be accessed on the EAU website: http://uroweb.org/guideline/renal-cell-carcinoma/.

1.5. Publication history and summary of changes

1.5.1. Publication history

The EAU RCC Guidelines were first published in 2000. This 2022 RCC Guidelines document presents a substantial update of the 2021 publication.

1.5.2. Summary of changes

All chapters of the 2022 RCC Guidelines have been updated, based on the 2021 version of the Guidelines. References have been added throughout the document.

New data have been included in the following sections, resulting in changed evidence summaries and recommendations in:

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

Recommendations

Strength rating

Offer brain CT/MRI in metastatic patients when systemic therapy or cytoreductive nephrectomy is considered.

Weak

Do not perform a renal tumour biopsy of cystic renal masses unless a significant solid component is visible at imaging.

Strong

5.5 Summary of evidence and recommendations for genetic assessment of RCC

Summary of evidence

LE

Hereditary kidney cancer is thought to account for 5–8% of all kidney cancer cases, though that number is likely an underestimate.

3

In case of renal cancer, if patient’s age is 46 years or younger, and/or with bilateral or multifocal tumours and/or with a first or second-degree relative with RCC and/or with close blood relative with a known pathogenic variant and/or with specific histologic characteristics (see text), the risk or hereditary cancer is significantly higher.

3

Hereditary RCC detection has unique implications for decision-making and follow-up.

3

Recommendations

Strength rating

Perform a genetic evaluation in patients aged < 46 years, with bilateral or multifocal tumours and/or a first or second-degree relative with RCC and/or a close blood relative with a known pathogenic variant and/or specific histologic characteristics which suggest the presence of a hereditary form of RCC.

Strong

Refer patients to a cancer geneticist or to a comprehensive clinical care centre in case of suspected hereditary kidney cancer.

Strong

7.1.2.2.4 Summary of evidence and recommendations for the treatment of localised RCC

Recommendation

Strength rating

Do not offer an extended lymph node dissection to patients with organ-confined disease.

Weak

7.1.3.4 Summary of evidence and recommendations for radical and partial nephrectomy techniques

Summary of evidence

LE

Transperitoneal and retroperitoneal laparoscopic PN do not differ in in post-operative surgical and medical complications, positive surgical margins and kidney function.

2a

Recommendation

Strength rating

Intensify follow-up in patients with a positive surgical margin, especially in upstaged pT3a patients.

Weak

7.2.4.3 Summary of evidence and recommendations for the management of RCC with venous tumour thrombus

Recommendation

Strength rating

During nephrectomy, remove clinically enlarged lymph nodes for staging, prognosis and follow-up implications.

Weak

7.2.5.1 Summary of evidence and recommendations for neoadjuvant and adjuvant therapy

Summary of evidence

LE

Adjuvant TKI therapy does not improve OS after nephrectomy.

1b

Adjuvant pembrolizumab after nephrectomy in patients with high-risk RCC improves disease-free survival.

1b

In one RCT, in selected intermediate/high- or high-risk patients or M1 patients without evidence of disease, adjuvant pembrolizumab improved disease-free survival.

1b

Recommendation

Strength rating

Offer adjuvant pembrolizumab to patients with clear-cell (cc) RCC following surgery with curative intent with a risk of recurrence as defined in the trial.*

Weak

*pT2 G4 or pT3 any G; pT4 any G; pN+ Any G.

7.3.2.6 Summary of evidence and recommendations for local therapy of metastases in metastatic RCC

Summary of evidence

LE

A single-arm prospective and retrospective study support that oligometastases can be observed for up to 16 months before systemic therapy is required due to progression.

2a

Recommendations

Strength rating

Perform a confirmatory axial scan of disease status prior to metastasectomy to rule out rapid progressive metastatic disease which requires systemic treatment.

Weak

Before initiating systemic therapy for oligometastases that cannot be resected, discuss with your patient a period of observation until progression is confirmed.

Weak

7.4.2.4 Summary of evidence and recommendations for targeted therapy in clear-cell metastatic RCC

Recommendation

Strength rating

Offer immune checkpoint inhibitor combination therapy for advanced cc-mRCC with sarcomatoid features.

Weak

7.4.4.1.2 Summary of evidence and recommendations for immunotherapy in clear-cell metastatic RCC

Summary of evidence

LE

Sequencing systemic therapy

Nivolumab plus ipilimumab was associated with 15% grade 3-5 toxicity and 1.5% treatment-related deaths. Tyrosine kinase inhibitor-based IO combination therapies were associated with grade 3-5 toxicity ranging between 61-72% and 1% of treatment-related deaths.

1b

Recommendation

Strength rating

Treatment-naïve patients

Offer nivolumab or cabozantinib for immune checkpoint inhibitor-naïve vascular endothelial growth factor receptor (VEGFR)-refractory clear-cell metastatic renal cell carcinoma (cc-mRCC) after one or two lines of therapy.

Strong

7.4.4.1.3.1 Summary of evidence and recommendation for targeted therapy in RCC with sarcomatoid features

Summary of evidence

LE

Immune checkpoint inhibitor combination therapy was superior to sunitinib in terms of PFS and OS in trial subset analysis of cc-RCC with sarcomatoid features.

2a

Recommendation

Strength rating

Offer immune checkpoint inhibitor combination therapy for advanced cc-mRCC with sarcomatoid features.

Weak

7.4.4.2.1 Summary of evidence and recommendation for targeted therapy in non-clear-cell metastatic RCC

Summary of evidence

LE

Both mTOR inhibitors and VEGF-targeted therapies have limited activity in non-cc-mRCC. There is a non-significant trend for improved oncological outcomes for sunitinib over everolimus.

2a

In non-cc-mRCC, sunitinib improved PFS over everolimus in a systematic review of phase II trials and subgroups of patients.

2a

Recommendation

Strength rating

Offer sunitinib to patients with other non-ccRCC subtypes than papillary RCC.

Weak

7.4.4.3.1 Summary of evidence and recommendations for targeted therapy in papillary metastatic RCC

Summary of evidence

LE

Cabozantinib improved PFS over sunitinib in patients with advanced pRCC without additional molecular testing.

2a

Savolitinib improved PFS over sunitinib in patients with MET-driven advanced pRCC.

2a

Pembrolizumab resulted in long-term median OS in a single arm study in the pRCC subgroup.

2a

Recommendations

Strength rating

Offer cabozantinib to patients with advanced papillary RCC (pRCC) without molecular testing.

Weak

Offer savolitinib to patients with MET-driven advanced pRCC.

Weak

Offer pembrolizumab to patients with advanced pRCC without molecular testing.

Weak

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

Summary of evidence

LE

Surgical or percutaneous treatment of local recurrences in absence of systemic progression should be considered, especially in absence of adverse prognostic parameters and favourable performance status.

3

The most optimal modality of local treatment for locally recurrent RCC after nephron-sparing procedures or nephrectomy is not defined.

3

Recommendation

Strength rating

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

Weak