Renal Cell Carcinoma

Full Text Guidelines Summary of Changes Scientific Publications & Appendices Pocket Guidelines Archive Panel

ISBN 978-94-92671-13-4

B. Ljungberg (Chair), L. Albiges, J. Bedke, A. Bex (Vice-chair), U. Capitanio, R.H. Giles (Patient Advocate), M. Hora, T. Klatte, T. Lam, L. Marconi, T. Powles, A. Volpe
Guidelines Associates: Y. Abu-Ghanem, S. Dabestani, S. Fernández-Pello Montes, F. Hofmann, T. Kuusk, R. Tahbaz

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: https://uroweb.org/guideline/renal-cell-carcinoma/.

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: https://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 2021 RCC Guidelines document presents a substantial update of the 2020 publication.

1.5.2.Summary of changes

All chapters of the 2021 RCC Guidelines have been updated, based on the 2020 version of the Guidelines. References have been added throughout the document.

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

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

Recommendations

Strength rating

Omit chest CT in patients with incidentally noted cT1a disease due to the low risk of lung metastases in this cohort.

Weak

Use non-ionising modalities, including MRI and contrast-enhanced ultrasound, for further characterisation of small renal masses, tumour thrombus and differentiation of unclear renal masses, if the results of contrast-enhanced CT are indeterminate.

Strong

Section 6.7 Summary of evidence and recommendations for prognostic factors

Summary of evidence

LE

In RCC patients, TNM stage, tumour size, grade, and RCC subtype provide important prognostic information.

2

Recommendations

Strength rating

Use the WHO/ISUP grading system and classify renal cell carcinoma type.

Strong

Use prognostic models in localised and metastatic disease.

Strong

Do not routinely use molecular markers to assess prognosis.

Strong

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

Summary of evidence

LE

Retrospective studies suggest that oncological outcomes are similar following PN vs. RN in patients with larger (≥ 7 cm) RCC. Post-operative complication rates are higher in PN groups.

3b

In patients with localised disease without radiographic evidence of LN metastases, a survival advantage of LND in conjunction with RN is not demonstrated in randomised trials.

2b

Recommendations

Strength rating

Offer partial nephrectomy to patients with T2 tumours and a solitary kidney or chronic kidney disease, if technically feasible.

Weak

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

Robotic-assisted and laparoscopic PN are associated with shorter length of stay and lower blood loss compared to open PN.

2b

Hospital volume in PN might impact on surgical complications, warm ischaemia and surgical margins.

3

Radical nephrectomy after positive surgical margins can result in over-treatment in many cases.

3

Recommendation

Strength rating

Intensify follow-up in patients with a positive surgical margin.

Weak

Section 7.1.4.3.7 Summary of evidence and recommendation for therapeutic approaches as alternative to surgery

Summary of evidence

LE

Low quality studies suggest high disease recurrence rates after radiofrequency ablation of tumours > 3 cm and after cryoablation of tumours > 4 cm.

3

Low quality studies suggest a higher local recurrence rate for thermal ablation therapies compared to PN, but the quality of the data does not allow definitive conclusions.

3

Recommendations

Strength rating

Offer active surveillance (AS) or thermal ablation (TA) to frail and/or comorbid patients with small renal masses.

Weak

Perform a percutaneous renal mass biopsy prior to, and not concomitantly with TA.

Strong

When TA or AS are offered, discuss with patients about the harms/benefits with regards to oncological outcomes and complications.

Strong

Do not routinely offer TA for tumours > 3 cm and cryoablation for tumours > 4 cm.

Weak

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

Summary of evidence

LE

In patients with locally advanced disease, the survival benefit of lymph node (LN) dissection is unproven but LN dissection has significant staging, prognosis and follow-up implications.

3

Recommendations

Strength rating

In patients with clinically enlarged lymph nodes (LNs), perform LN dissection to guide staging, prognosis and follow-up.

Weak

In case of metastatic disease, discuss surgery within the context of a multidisciplinary team.

Weak

Section 7.2.5.1 Summary of evidence and recommendations for adjuvant therapy

Summary of evidence

LE

Adjuvant therapy does not improve survival after nephrectomy.

1b

In one single RCT, in selected high-risk patients, adjuvant sunitinib improved disease-free survival (DFS) but not overall survival (OS).

1b

Adjuvant sorafenib, pazopanib, everolimus, girentuximab or axitinib does not improve DFS or OS after nephrectomy.

1b

Adjuvant RCTs are ongoing to evaluate the benefit of adjuvant immunotherapy after nephrectomy in high-risk patients.

1b

Recommendations

Strength rating

Do not offer adjuvant therapy with sorafenib, pazopanib, everolimus, girentuximab or axitinib.

Strong

Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell renal cell carcinoma.

Weak

Section 7.3.1.1.2 Summary of evidence and recommendations for local therapy of advanced/metastatic RCC

Summary of evidence

LE

Patients with their primary tumour in place treated with ICI-based combination therapy have better PFS and OS in exploratory subgroup analyses compared to treatment with sunitinib.

2b

Recommendation

Strength rating

Discuss delayed cytoreductive nephrectomy in patients who derive clinical benefit from systemic therapy.

Weak

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

Summary of evidence

LE

Tyrosine kinase inhibitors treatment after metastasectomy in patients with no evidence of disease did not improve RFS when compared to placebo or observation.

1b

Recommendation

Strength rating

Do not offer tyrosine kinase inhibitor treatment to mRCC patients after metastasectomy and no evidence of disease.

Strong

Section 7.4.2.5 Summary of evidence and recommendations for immunotherapy in metastatic RCC

Summary of evidence

LE

The combination of pembrolizumab plus axitinib, lenvatinib plus pembrolizumab and nivolumab plus cabozantinib in treatment-naive patients with cc-mRCC across all IMDC risk group demonstrated PFS, OS and ORR benefits compared to sunitinib.

1b

Axitinib, cabozantinib or lenvatinib can be continued if immune-related adverse events result in cessation of axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab. Re-challenge with immunotherapy requires expert support.

4

Nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib and lenvatinib plus pembrolizumab should be administered in centres with experience of immune combination therapy and appropriate supportive care within the context of a multidisciplinary team.

4

The combination of nivolumab plus ipilimumab in the IMDC intermediate- and poor-risk population of treatment-naive patients with cc-mRCC leads to superior survival compared to sunitinib while OS was higher in IMDC good-risk patients with sunitinib.

2b

Recommendations

Strength rating

Offer pembrolizumab plus axitinib, lenvatinib plus pembrolizumab or nivolumab plus cabozantinib to treatment-naive patients in clear-cell metastatic renal cell carcinoma (cc-mRCC).

Strong

Administer nivolumab plus ipilimumab, pembrolizumab plus axitinib, lenvatinib plus pembrolizumab and nivolumab plus cabozantinib in centres with experience of immune combination therapy and appropriate supportive care within the context of a multidisciplinary team.

Weak

Offer axitinib, cabozantinib or lenvatinib as subsequent treatment to patients who experience treatment-limiting immune-related adverse events after treatment with the combination of axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab.

Weak

Figure 7.1: Updated EAU Guidelines recommendations for the first-line treatment of metastatic ccRCC

Section 7.4.7 Summary of evidence and recommendations for targeted therapy in metastatic RCC

Recommendations

Strength rating

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

Strong

Offer VEGF-tyrosine kinase inhibitors as second-line therapy to patients refractory to nivolumab plus ipilimumab or axitinib plus pembrolizumab, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab.

Weak

Section 8.3 Summary of evidence and recommendations for surveillance following RN or PN or ablative therapies in RCC

Summary of evidence

LE

Functional follow-up after curative treatment for RCC is useful to prevent renal and cardiovascular deterioration.

4

Oncological follow-up can detect local recurrence or metastatic disease while the patient may still be surgically curable.

4

Prognostic models provide stratification of RCC risk of recurrence based on TNM and histological features

3

In competing-risk models, risk of non-RCC-related death exceeds that of RCC recurrence or related death in low-risk patients.

3

Life expectancy estimation is feasible and may support counselling of patients on duration of follow-up.

4

Recommendations

Strength rating

Perform functional follow-up (renal function assessment and prevention of cardiovascular events) both in nephron-sparing (NSS) and radical nephrectomy (RN) patients.

Weak

Consider curtailing follow-up when the risk of dying from other causes is double that of the recurrence risk of RCC.

Weak

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