Renal Cell Carcinoma

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

2018

All chapters of the 2018 RCC Guidelines have been updated, based on the 2017 version of the Guidelines. References have been added throughout the document.

 

Key changes in this 2018 print:

  • Section 3.3 – Other renal tumours has been expanded, to include:
  • 3.3.1 Renal medullary carcinoma;
  • 3.3.6 Renal oncocytoma;
  • 3.3.7 Cystic renal tumours.

 

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

 

3.4 Summary of evidence and guidelines for the management of other renal tumours

 

Recommendations Strength rating
Offer systemic therapy to patients at need for therapy with surgically unresectable angiomyolipomas not amendable to embolisation. Weak

 

Prior to management, perform pre-operative renal mass biopsies in patients with unclear kidney lesions. Weak

 

Perform radical nephrectomy in patients with renal medullary carcinoma. Weak
Base systemic therapy for renal medullary carcinoma on chemotherapy regiments containing cisplatinum such as gemcitabine plus cisplatin. Weak

 

 

5.4 Summary of evidence and recommendations for the diagnostic assessment of renal cell cancer

 

Recommendations Strength rating
Use MRI to better evaluate venous involvement, reduce radiation or avoid intravenous CT contrast. Weak

 

Use a core biopsy technique rather than fine needle aspiration for histological characterisation for solid renal tumours Strong

 

 

7.1.2.2.4 Summary of evidence and recommendations for the treatment of localised renal cell cancer

 

Summary of evidence LE
Retrospective studies suggest a clinical benefit associated with lymphadenectomy in high-risk patients. 2b

 

Recommendations Strength rating
Offer embolisation in patients unfit for surgery presenting with massive haematuria or flank pain. Weak

 

 

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

 

Recommendations Strength rating
Do not perform minimally invasive surgery if this approach may compromise oncological, functional and peri-operative outcomes. Strong

 

 

7.2.5.1 Summary of evidence and recommendations for adjuvant therapy

 

Recommendations Strength rating
Do not offer adjuvant therapy with sorafenib or pazopanib. Strong
Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell renal cell cancer. Weak

 

7.3.1.1.2 Summary of evidence and recommendation for local therapy of advanced/metastatic renal cell cancer

 

Summary of evidence LE
Deferred cytoreductive nephrectomy with presurgical sunitinib in intermediate-risk patients with clear-cell metastatic RCC leads to a survival benefit in secondary endpoint analysis and selects out patients with inherent resistance to systemic therapy. 2b

 

Patients with IMDC poor risk (≥ 4 risk factors) do not benefit. 2b

 

Recommendations Strength rating
Do not offer cytoreductive nephrectomy in IMDC poor-risk patients with ≥ 4 risk factors. Weak
Perform immediate cytoreductive nephrectomy in patients with oligometastases when complete resection can be achieved. Weak

 

Offer deferred cytoreductive nephrectomy to intermediate-risk patients with clear-cell metastatic RCC who require systemic therapy with sunitinib. Weak

 

 

7.4.2.5 Summary of evidence and recommendations for immunotherapy in metastatic renal cell cancer

 

Summary of evidence LE
The combination of nivolumab and ipilimumab in treatment-naïve patients with clear-cell metastatic RCC of IMDC intermediate and poor-risk leads to superior survival compared to sunitinib. 1b

 

The combination of nivolumab and ipilimumab in the ITT population of treatment-naïve unselected patients with clear-cell metastatic RCC leads to superior survival compared to sunitinib. 2b

 

Due to the exploratory nature of PD-L1 tumour expression, the small sample size, the lack of OS data and the premature results in this subpopulation, definitive conclusions cannot be drawn. 2b

 

Nivolumab plus ipilimumab was associated with 15% grade 3-5 toxicity and 1.5% treatment-related deaths. 1b

 

 

Recommendations Strength rating
Use ipilimumab plus nivolumab in treatment-naïve patients with clear-cell metastatic RCC of IMDC intermediate and poor risk. Strong

 

Do not use bevacizumab plus IFN-α in treatment-naïve clear-cell favourable- and intermediate-risk RCC patients. Weak

 

Do not use PD-L1 tumour expression as a predictive biomarker. Weak
Administer nivolumab plus ipilimumab in centres with experience of immune combination therapy and appropriate supportive care within the context of a multidisciplinary team. Weak

 

Do not rechallenge patients who stop nivolumab plus ipilimumab because of toxicity with the same drugs in the future without expert guidance and support from a multidisciplinary team. Strong

 

 

Figure 7.1:             Updated EAU Guidelines recommendations for the treatment of first-line clear-cell metastatic renal cancer’ has been revised.

 

7.4.6.3 Summary of evidence and recommendations for targeted therapy in metastatic renal cell cancer

 

Summary of evidence LE
Cabozantinib in intermediate- and poor-risk treatment-naïve clear-cell RCC leads to better RR and PFS but not OS when compared to sunitinib. 2a

 

Tivozanib has recently been approved but the evidence is still considered inferior over existing choices. 3
In treatment-naïve patients, bevacizumab in combination with IFN-α has not been tested against nivolumab plus ipilimumab and the evidence for subsequent therapies is unclear. 3

 

In treatment-naïve patients temsirolimus has not been tested against nivolumab plus ipilimumab and the evidence for subsequent therapies is unclear. 3

 

Both mTOR inhibitors (everolimus and temsirolimus) and VEGF-targeted therapies (sunitinib or sorafenib) have limited oncological efficacy in non-clear cell RCC. There is a non-significant trend for improved oncological outcomes for sunitinib, over everolimus. 2a

 

Lenvatinib in combination with everolimus modestly improved PFS over everolimus alone. 2a

 

Recommendations Strength rating
Use cabozantinib in treatment-naïve patients with clear-cell metastatic RCC of IMDC intermediate and poor risk. Weak

 

Do not use bevacizumab plus Interferon (IFN)-α in treatment-naïve clear-cell favourable- and intermediate-risk RCC patients. Weak

 

Do not use tivozanib in treatment-naïve clear-cell metastatic RCC patients. Weak
Do not use temsirolimus in treatment-naïve clear-cell poor-risk RCC patients. Weak
Use VEGF-TKIs in second-line in patients refractory to nivolumab plus ipilimumab. Weak
Do not offer sorafenib as first- or second-line treatment to patients with metastatic RCC. Weak

 

7.5.2 Summary of evidence and recommendation for advanced/metastatic renal cell cancer

Recommendations Strength rating
Offer surgical resection of local recurrent disease, when complete resection is achievable. Weak

 

2017

Summary of changes

All chapters of the 2017 Renal Cell Cancer Guidelines have been updated, based on the 2016 version of the guideline. References have been added throughout the document.

Key changes in the 2017 print:

  • Section 3.3.3 – Hereditary kidney tumours: This section has been expanded
  • Section 5.2 – Imaging evaluations: The findings of a systematic review have been incorporated.

New data and recommendations have been included in the following sections:

5.4 Summary of evidence and recommendations for the diagnostic assessment of renal cell cancer

Summary of evidence LE
Contrast enhanced multi-phasic CT has a high sensitivity and specificity for characterisation and detection of RCC, invasion, tumour thrombus and metastatic RCC. 2
MRI has a slightly higher sensitivity and specificity for small renal masses and tumour thrombus as compared to CT. 2
CEUS has a high sensitivity and specificity for characterisation of renal masses. 2
US, Power-Doppler US and PET-CT have a low sensitivity and specificity for detection and characterisation of RCC. 2

 

Recommendations grade  
Use multi-phasic contrast-enhanced computed tomography (CT) for general staging and detection of renal cell cancer (RCC). strong ↑↑
Use axial abdominal imaging and CT of the chest for staging of RCC. strong ↑↑
Use non-ionising modalities, mainly contrast enhanced ultrasound (CEUS), for further characterisation of small renal masses, tumour thrombus and differentiation of unclear renal masses. weak
Do not use bone scan and/or positron-emission tomography (PET)-CT for staging of RCC. weak
Perform a renal tumour biopsy before ablative therapy and systemic therapy without previous pathology. strong ↑↑
Perform a percutaneous biopsy in select patients who are considered for active surveillance. weak
When performing a renal tumour biopsy technique, use a coaxial technique. strong ↑↑
Do not perform a renal tumour biopsy of cystic renal masses. weak

 

 7.2.5.1     Summary of evidence and recommendations for adjuvant therapy

Summary of evidence LE
Adjuvant cytokines do not improve survival after nephrectomy. 1b
Adjuvant sunitinib improved disease-free survival in one of the two available studies, but not overall survival, after nephrectomy in selected high-risk patients. 1b

 

Recommendations grade  
Do not offer adjuvant therapy with sorafenib. strong ↓↓
Do not offer adjuvant sunitinib following surgically resected high-risk clear-cell renal cell cancer. weak

 

7.3.2.5     Recommendations for local therapy of metastases in metastatic RCC

Recommendation grade  
Consider local therapy for metastatic disease (including metastasectomy) in patients with a favourable risk profile in whom complete resection is achievable or when local symptoms need to be controlled. weak

 

7.4.1.1     Summary of evidence and recommendation for systemic therapy for advanced/metastatic renal cell cancer

Summary of evidence LE
In metastatic RCC, 5-FU combined with immunotherapy has equivalent efficacy to INF-α. 1b
In metastatic RCC, chemotherapy is otherwise not effective with the exception of gemcitabine and doxorubicine in sarcomatoid and rapidly progressive disease. 3

 

Recommendations grade  
Do not offer chemotherapy as first-line therapy in patients with metastatic clear-cell renal cell cancer (RCC). strong ↓↓
Consider offering a combination of gemcitabine and doxorubicin to patients with sarcomatoid or rapidly progressive RCC. weak

 

7.4.6.3     Summary of evidence and recommendations for systemic therapy in metastatic renal cell cancer 

Summary of evidence LE
First line pazopanib is not inferior to sunitinib in clear-cell mRCC patients. 1b
Cabozantinib is superior to everolimus in terms of PFS and OS in patients failing one or more lines of VEGF-targeted therapy. 1b
Everolimus prolongs PFS in patients who have previously failed or are intolerant of VEGF-targeted therapy when compared to placebo. 1b
No combination has proven to be better than single-agent therapy, with the exception of the combination of lenvatinib plus everolimus. 1b

 

Recommendations grade  
Offer sunitinib or pazopanib as first-line therapy for metastatic clear-cell renal cell cancer (ccRCC). strong ↑↑
Consider offering bevacizumab + Interferon (IFN)-α as first-line therapy for metastatic RCC in favourable-risk and intermediate-risk ccRCC. weak
Consider offering temsirolimus as first-line treatment in poor-risk RCC patients. weak
Offer cabozantinib for ccRCC after one or two lines of vascular endothelial growth factor (VEGF)-targeted therapy in metastatic RCC. strong ↑↑
Sunitinib can be offered as first-line therapy for non-clear cell mRCC. weak

 

2016

All chapters of the 2016 Renal Cell Cancer Guidelines have been updated, based on the 2015 version of the guideline.

Conclusions and recommendations have been rephrased and added to, throughout the current document.

Key changes for the 2016 print:

Chapter 3 – Epidemiology, Aetiology and Pathology: the new Vancouver histological classification has been included.

  • Section 7.4.3.1 – Tyrosine kinase inhibitors – A new figure has been included. (Figure 7.1: Recommendations for patients with metastatic clear cell-RCC who have failed one or more lines of VEGF targeted therapy).

New data and recommendations have been included in the following sections.

 3.4 Summary of evidence and recommendations for the management of other renal tumours 

Recommendations GR
In AML > 3 cm not requiring surgical intervention, medical treatment with everolimus can be considered. C
Treat all tumours with the radiologic appearance of RCC in the same way. C

AML = angiomyolipoma.

 7.2.5.1 Summary of evidence and recommendation for adjuvant therapy 

Summary of evidence LE
Adjuvant sunitinib or sorafenib do not improve disease-free and overall survival after nephrectomy. 1b

 

Recommendations GR
Adjuvant therapy with sunitinib or sorafenib should not be given. A

 7.3.2.4     Embolisation of metastases – 7.3.2.5   Summary of evidence and recommendations 

Recommendations GR
Stereotactic radiotherapy for bone metastases and stereotactic radiosurgery for brain metastases may be offered for local control and symptom relief. C

 7.4.1.1     Summary of evidence and recommendation for systemic therapy for advanced/metastatic RCC 

Summary of evidence LE
In mRCC, chemotherapy is otherwise not effective. 3

mRCC = metastatic renal cell cancer. 

7.4.2.5     Summary of evidence and recommendations for immunotherapy in mRCC 

Summary of evidence LE
IFN-α monotherapy is inferior to VEGF-targeted therapy or mTOR inhibition in mRCC 1b
Nivolumab leads to superior OS compared to everolimus in patients failing one or two lines of VEGF-targeted therapy 1b

 

Recommendation GR
Nivolumab is strongly recommended after one or two lines of VEGF-targeted therapy in mRCC. A

INF = interferon; mRCC = metastatic renal cell carcinoma; mTOR = mammalian target of rapamycin inhibitor;

OS = overall survival: VEGF = vascular endothelial growth factor.

 7.4.6.3     Summary of evidence and recommendations for systemic therapy in mRCC 

Summary of evidence LE
Nivolumab is superior to everolimus in terms of OS and adverse events in patients failing one or two lines of VEGF-targeted therapy 1b
Cabozantinib is superior to everolimus in terms of PFS in patients failing one or more lines of VEGF-targeted therapy 1b

 

Recommendations GR
Cabozantinib should be given for ccRCC patients who failed one or two lines of VEGF-targeted therapy based on a PFS advantage over everolimus. A
Nivolumab is strongly recommended for ccRCC patients who failed one or two lines of VEGF-targeted therapy based on and OS advantage over everolimus. A
Axitinib can be given as second-line treatment for mRCC after cytokines or first-line VEGF where other drugs are not safe, tolerable or available. A
Sunitinib or everolimus can be given as first-line therapy for non-clear cell mRCC. B

ccRCC = clear-cell renal cell carcinoma; mRCC = metastatic renal cell carcinoma; OS = overall survival:

PFS = progression-free survival; VEGF = vascular endothelial growth factor.

Table 2.1: Description of update and summary of review methodology 

Chapter   Brief description of review methodology
1.                   Introduction Not applicable
2.                   Methods Not applicable
3.                   Epidemiology, Aetiology and Pathology This chapter was updated based on a traditional narrative review, based on a structured literature assessment.
4.                   Staging and grading classification systems This chapter was updated based on a traditional narrative review, based on a structured literature assessment.
5.                   Diagnostic evaluation Chapters 5.2 and 5.3 were updated by way of a systematic review [4]. The rest of the chapter 2016 was updated using a structured literature assessment.
6.                   Prognosis This chapter was updated based on a traditional narrative review, based on a structured literature assessment.
7.                   Treatment (Disease management) Chapters 7.1.2 and 7.2.4 were updated by way of a systematic review. The remainder of the chapter 2016 was updated using a structured literature assessment.Treatment of localised disease: For 2015 this section was updated using a systematic review mostly based on a literature search from 2000. A new section, ‘Management of RCC with venous thrombus’ has been added which is based on a systematic review [5].Systemic therapy for metastatic disease: For 2015, these sections were updated using a systematic review.
8.                   Surveillance following radical or partial nephrectomy or ablative therapies This chapter was updated based on a traditional narrative review, based on a structured literature assessment.

The findings of a number of SR topics have been incorporated in this 2016 update:

  • What is the best surgical treatment option for clinical ≥ T2, N0M0 tumours? What is the best way of performing this procedure?
  • What is the best treatment for advanced/metastatic non-clear cell RCC?
  • Performance of CT for the initial diagnosis of suspected renal masses.

2015

All chapters of the 2015 RCC Guidelines have been updated, based on the 2014 update. The consistency of the data work-up will differ between sections. An overview is presented in Table 1.1.

Table 1.1: Description of update and summary of review methodology for the 2015 update 

Chapter                 Brief description of review methodology
  1. Introduction
Not applicable
  1. Methods
Not applicable
  1. Epidemiology, Aetiology and Pathology
Updated using a structured data assessment. Of particular note is the inclusion of the new Vancouver Classification in the Histology section [4, 5].
  1. Staging and grading classification systems
Updated using a traditional narrative review.
  1. Diagnostic evaluation
Updated using a systematic review on tumour biopsy. Updated using a structured data assessment [6].
  1. Prognosis
Updated using a traditional narrative review, based on a structured literature search.
  1. Treatment (Disease management)
Updated using a systematic review mostly based on a literature search from 2000. A new section, ‘Management of RCC with venous thrombus’ has been added which is based on a systematic review [7].
A new section on recurrent RCC was added.
  1. Surveillance following radical or partial nephrectomy or ablative therapies
Updated using a traditional narrative review, based on a structured data search.

 

Changed recommendations

Recommendations have been rephrased and added to throughout the current document, not resulting in a change in the grade of recommendation (GR). The sections where changes were made can be found below:

 

3.4 Recommendations for other renal tumours 

Recommendations GR
AMLs, active surveillance is the most appropriate option for most AMLs. Treatment with selective arterial embolization (SAE) or NSS can be considered in:

  • large tumours (recommended threshold of intervention does not exist, the formerly recommended size of > 4 cm wide is disputed);
  • females of childbearing age;
  • patients in whom follow-up or access to emergency care may be inadequate.
C

AML = angiomyolipoma; NSS = nerve-sparing surgery.


7.1.2.2.4 Conclusions and recommendations
 

Recommendation GR
PN should be favoured over RN in patients with T1b tumour, whenever feasible. B

PN = partial nephrectomy; RN = radical nephrectomy.

 

7.2.4.3                              Conclusions and recommendations 

Conclusions LE
In patients with locally advanced disease due to clinically enlarged LNs the survival benefit of LND is unclear. In these cases LND can be performed for staging purposes.

 LN = lymph node; LND = lymph node dissection.
 

7.3.3.8 Conclusions and recommendations for systemic therapy in mRCC 

Recommendation GR
Sunitinib can be recommended as first-line therapy for non-clear cell mRCC. B

mRCC = metastatic renal cell carcinoma.

2014

For this 2014 update the following changes should be noted:

Chapter 2
Epidemiology and aetiology: This chapter has been updated using a structured data assessment

Chapter 3
Diagnosis and staging: This chapter has been updated using a systematic review on tumour biopsy and a traditional narrative review for the other aspects of diagnosis and staging

Chapter 4
Classification and prognostic factors: This chapter has been updated using a structured data assessment

Chapter 5
Other renal tumours: The chapter has been updated using a traditional narrative review, based on a structured literature search. Of particular note is the inclusion of the new Vancouver Classification in the Histology section (3.4).

Chapter 6
Treatment of localised disease: This chapter has been updated using a systematic review, in part based on a literature search from 2000. A new section, ‘Management of RCC with venous thrombus’ has been added which is based on a systematic review.

Chapter 7
Systemic therapy for metastatic disease: This chapter has been updated using a systematic review.

Chapter 8
Surveillance following radical or partial nephrectomy or ablative therapies: This chapter was updated based on a traditional narrative review, based on a structured data search.

2013

For this 2013 update the following changes should be noted:
Chapter 2
Epidemiology and aetiology: The chapter has been updated using a structured data assessment.
Chapter 3
Diagnosis and staging: The chapter has been updated using a systematic review on tumour biopsy and a traditional narrative review for the other aspects of diagnosis and staging.
Chapter 4
Classification and prognostic factors: The chapter has been updated using a structured data assessment.
Chapter 5
Other renal tumours: The chapter has been updated using a traditional narrative review.
Chapter 6
Treatment of localised disease: The chapter has been updated using a systematic review.
Chapter 7
Systematic therapy for metastatic disease: The chapter has been updated using a mixed methods approach. Literature searching, study identification and data abstraction were carried out using systematic review methodology, with 54 studies being deemed eligible for inclusion. Ten of the most important and influential studies, as determined by consensus, were data-abstracted and the review was based on these 10 studies.
Chapter 8
Surveillance following radical or partial nephrectomy or ablative therapies: The chapter has been updated using a traditional narrative review.