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 long-standing 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]*.
1.4. Available publications
A quick reference document (Pocket Guidelines) is available presenting the main findings of the RCC Guidelines. This is an abridged version which may require consultation together with the full text version. 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 2023 RCC Guidelines document presents a substantial update of the 2022 publication.
1.5.2. Summary of changes
All chapters of the 2023 RCC Guidelines have been updated, based on the 2022 version of the Guidelines. References have been added throughout the document.
New data have been included in the following sections, resulting in updates and changes in evidence summaries and recommendations:
3.3.1 Summary of evidence and recommendation for epidemiology, aetiology and screening
Summary of evidence | LE |
There is no evidence to support primary screening for RCC. | 4 |
Recommendation | Strength rating |
Do not routinely screen any population for primary RCC. | Weak |
3.6 Summary of evidence and recommendations for the management of other renal tumours
Summary of evidence | LE |
The most common renal tumours are three malignant types of RCC (clear cell, papillary and chromophobe) and two benign renal tumours: oncocytoma and angiomyolipoma. | 3 |
A definitive histopathological diagnosis of oncocytoma cannot be made on a needle-core biopsy, because chRCC can show intratumoural heterogeneity with areas very similar to oncocytoma. | 3 |
Recent histological work up and results of active surveillance of Bosniak III cysts shows low risk of malignant potential/course. | 2 |
* †Deceased, July 2022.
Recommendations | Strength rating |
Offer AS to patients with biopsy-proven oncocytoma or other oncocytic renal tumours as an acceptable alternative to surgery or ablation. | Weak |
Offer systemic therapy (everolimus) to patients at need for therapy with surgically unresectable AMLs not amendable to embolisation or surgery. | Weak |
7.2.4.3 Summary of evidence and recommendations for lymph node dissection, the management of RCC with venous tumour thrombus and unresectable tumours
Summary of evidence | LE |
In patients with locally-advanced disease, the survival benefit of LN dissection is unproven but LN dissection has significant staging, prognosis, adjuvant therapy and follow-up implications. | 3 |
Recommendation | Strength rating |
Discuss treatment options in patients with locally-advanced unresectable RCC (biopsy and/or systemic therapy/deferred resection, or palliative management) within a multidisciplinary team to determine treatment goal. | Strong |
7.2.5.5 Summary of evidence and recommendations for neoadjuvant and adjuvant therapy
Summary of evidence | LE |
Adjuvant pembrolizumab defined by the inclusion criteria of the trial* after nephrectomy improves DFS. | 1b |
Adjuvant PD-L1 inhibition with atezolizumab did not improve DFS or OS. | 1b |
Adjuvant dual PD-1 and CTLA-4 inhibition with nivolumab and ipilimumab did not improve DFS. | 1b |
Peri-operative treatment with nivolumab did not improve RFS. | 1b |
The lack of biomarker data is hindering progress in this field. Adjuvant RCTs are ongoing to evaluate the benefit of adjuvant immunotherapy after nephrectomy in high-risk patients. | 4 |
*pT2 G4 or pT3 any G; pT4 any G; pN+ any G; M1, NED after resection of metastases.
Recommendation | Strength rating |
Discuss the contradictory results of the available adjuvant ICI trials with patients to facilitate shared decision making. | Strong |
Inform patients about the potential risk of overtreatment and immune-related side effects if adjuvant therapy is considered. | Strong |
Offer adjuvant pembrolizumab to ccRCC patients, preferably within 12–16 weeks post-nephrectomy, with a recurrence risk as defined in the Keynote-564 trial: • Intermediate-high risk: • pT2, grade 4 or sarcomatoid, N0, M0 • pT3, any grade, N0, M0 • High risk: • pT4, any grade, N0, M0 • any pT, any grade, N+, M0 • M1 no evidence of disease (NED): • NED after resection of oligometastatic sites < 1 year from nephrectomy | Weak |
7.3.1.1.2 Summary of evidence and recommendations for local therapy of advanced/metastatic RCC
Summary of evidence | LE |
Patients with MSKCC or IMDC poor risk do not benefit from CN. | 1a |
Recommendation | Strength rating |
Do not perform immediate CN in intermediate-risk patients who have an asymptomatic synchronous primary tumour and require systemic therapy. | Weak |
7.4.4.1.2 Summary of evidence and recommendations for immunotherapy in cc-mRCC
Summary of evidence | LE |
Sequencing systemic therapy | |
Nivolumab plus ipilimumab was associated with 46% grade 3–4 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 treatment with PD1 combinations in centres with experience. | Weak |
Offer either nivolumab plus ipilimumab, pembrolizumab plus axitinib, or lenvatinib plus pembrolizumab, or nivolumab plus cabozantinib to treatment-naive patients with IMDC intermediate- or poor-risk disease. | Strong |
Offer either pembrolizumab plus axitinib, lenvatinib plus pembrolizumab or nivolumab plus cabozantinib to treatment-naïve patients with IMDC favourable risk. | Weak |
Offer sunitinib or pazopanib to treatment-naive patients with IMDC favourable risk. | Weak |
Offer sunitinib or pazopanib to treatment-naive cc-mRCC patients with any IMDC risk who cannot receive or tolerate immune checkpoint inhibition. | Strong |
Patients who do not receive the full four doses of ipilimumab due to toxicity should continue on single-agent nivolumab, where safe and feasible. Re-challenge with combination therapy requires expert support. | Weak |
Sequencing systemic therapy | |
Sequence systemic therapy in treating mRCC. | Strong |
Offer VEGF-tyrosine kinase inhibitors as second-line therapy to patients refractory to nivolumab plus ipilimumab or axitinib plus pembrolizumab or cabozantinib plus nivolumab or lenvatinib plus pembrolizumab. | Weak |
Sequencing the agent not used as second-line therapy (nivolumab or cabozantinib) for third-line therapy is recommended. | Weak |
Offer nivolumab or cabozantinib to those patients who received first-line VEGF targeted therapy alone. | Strong |
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 and for cabozantinib over sunitinib. | 2a |
7.4.4.3.1 Summary of evidence and recommendation for targeted therapy in papillary metastatic RCC
Recommendations | Strength rating |
Offer cabozantinib to patients with papillary RCC (pRCC) based on a positive RCT. | Weak |
Offer pembrolizumab alone or lenvatinib plus pembrolizumab or nivolumab plus cabozantinib to patients with pRCC based on small single-arm trials. | Weak |