Renal cell carcinoma

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

small renal mass or RCC stage 1 or 2

surgical candidate

1st line – surgery

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1st line –

surgery

A small renal mass (SRM) is defined as a renal lesion <4 cm. Early-stage renal cell carcinoma (RCC; stages 1 and 2) is defined as tumour confined to kidney without regional lymph node or distant metastasis.

Many patients with early-stage RCC require surgical resection, which affords the best chance for long-term control and cure.[1][2]

Radical nephrectomy and partial nephrectomy/nephron-sparing surgery (NSS) are effective treatment options for SRMs and early-stage RCC.[61] NSS is preferred whenever clinically feasible, especially for tumours/SRMs <4 cm, to preserve more renal function in the long term.[1][2] Evidence comparing complete nephrectomy to NSS shows no difference in cancer-specific survival; however, there is evidence that radical nephrectomy (compared with NSS) worsens renal function outcomes, which may have non-cancer-related health consequences.[90][91][92]

In the setting of high tumour complexity, no pre-existing chronic kidney disease or proteinuria, and normal contralateral kidney (predicted baseline glomerular filtration rate >45 mL/min/1.73 m²), radical nephrectomy should still be considered.[1][90]

NSS may be particularly important for retaining renal function in patients with multifocal or bilateral tumours (especially those with hereditary syndromes and ongoing RCC risk), a single kidney, renal insufficiency, or at risk of developing chronic kidney disease.[61]

Open, laparoscopic, or robot-assisted surgical techniques may be used for both radical and partial nephrectomies.[61][93][94][95][96][97] Both transperitoneal and retroperitoneal laparoscopic approaches have been evaluated.[98] Ipsilateral adrenalectomy is not recommended if the gland is uninvolved on preoperative imaging studies.[99]

Consider – adjuvant pembrolizumab

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Consider –

adjuvant pembrolizumab

Additional treatment recommended for SOME patients in selected patient group

Adjuvant treatment following nephrectomy has not been shown to be beneficial for most patients with localised disease. However, for some patients with clear cell renal cell carcinoma (RCC) who are at increased risk of recurrence after nephrectomy, such as those with stage 2 RCC with grade 4 tumours, adjuvant therapy with pembrolizumab (a programmed death receptor-1 [PD-1] immune checkpoint inhibitor) may be considered.[61][106][107][108][109]

Clinicians should discuss the potential risks and benefits of adjuvant treatment with the patient during a shared decision-making process.[2][61]

Patients receiving immune checkpoint inhibitors should be monitored closely for treatment-related toxicity and endocrine dysfunction.[110][111][112]

Participation in a clinical trial examining adjuvant therapy may be an alternative option for post-nephrectomy patients.

See local specialist protocols for guidance on dose.

Primary options

pembrolizumab

1st line – local ablation therapy

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1st line –

local ablation therapy

A small renal mass (SRM) is defined as a renal lesion <4 cm. Early-stage RCC (stages 1 and 2) is defined as tumour confined to kidney without regional lymph node or distant metastasis.

Locally ablative techniques are an alternative approach for small tumours.[1][2][90][100] The most commonly utilised of these techniques are radiofrequency ablation (RFA), microwave ablation, and cryoablation. Tumour cell death is achieved by high-temperature ablation in RFA (using high-frequency currents) and microwave ablation (using electromagnetic waves). In cryoablation, cell death is achieved by local freezing. Percutaneous techniques are preferred owing to shorter procedure time and faster recovery compared with laparoscopic ablation.[1]

Evidence shows that local thermal ablation for SRMs can yield good oncological outcomes for tumour masses <3 cm in size.[101][102]

Guidelines recommend percutaneous ablation for stage 1 tumours (T1a and select patients with T1b tumours).[61]

In particular, local ablation may be appropriate for patients whose renal function needs to be preserved (e.g., with hereditary syndromes, multiple bilateral lesions, renal insufficiency, or a single kidney), or for those patients who are not deemed to be good surgical candidates due to comorbidities and/or frailty.[2]

non-surgical candidate: <3 cm and slow-growing

1st line – surveillance

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1st line –

surveillance

Active surveillance of SRMs (particularly those <3 cm) in older patients with significant comorbidity, limited life expectancy, and/or high surgical risk may be the most appropriate strategy.[1][2][6][87]

Renal masses <3.5 cm, even if an RCC is likely, have low metastatic potential over 2-3 years. Biopsy of SRMs may be considered to confirm malignancy and inform treatment decisions.[61]

A well-communicated risk-benefit analysis unique to individual patient circumstances should be part of the patient decision-making process.[1][5] Surveillance of SRMs is not recommended for younger, medically fit patients with operable masses.[1]

Abdominal imaging with CT, MRI, or ultrasound should be performed within 6 months of starting active surveillance, then at least annually.[88]

non-surgical candidate: ≥3 cm or rapidly growing

1st line – surveillance

Back

1st line –

surveillance

A small renal mass (SRM) is defined as a renal lesion <4 cm. Early-stage RCC (stages 1 and 2) is defined as tumour confined to kidney without regional lymph node or distant metastasis.

Active surveillance of SRMs in older patients with significant comorbidity, limited life expectancy, and/or high surgical risk may be the most appropriate strategy.[1][2][6][87]

Biopsy of SRMs may be considered to confirm malignancy and inform treatment decisions.[61]

Abdominal imaging with CT, MRI, or ultrasound should be performed within 6 months of starting active surveillance, then at least annually.[88]

1st line – local ablation therapy

Back

1st line –

local ablation therapy

Evidence shows that local thermal ablation for small renal masses can yield good oncological outcomes for tumour masses <3 cm in size.[101][102] Guidelines recommend percutaneous ablation as an alternative to surgery for stage 1 tumours (T1a and select patients with T1b tumours).[61]

Stereotactic body radiotherapy (SBRT) is considered an ablative therapy, and may be an option for patients with T1a tumours who are not optimal candidates for surgery or percutaneous ablation, or for select patients with T1b or stage 2 tumours who are not optimal candidates for surgery.[61][103][104] One systematic review and meta-analysis found that SBRT may offer improved local control for larger tumours; while microwave ablation, cryoablation, and SBRT are highly effective for small tumours (<4 cm).[105]

Local ablation may be appropriate for patients whose renal function needs to be preserved (e.g., with hereditary syndromes, multiple bilateral lesions, renal insufficiency, or a single kidney), or for those patients who are not deemed to be good surgical candidates due to comorbidities and/or frailty.[2]

RCC stage 3

surgical candidate

1st line – surgery

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1st line –

surgery

Stage 3 tumours extend into major veins, or invade the adrenal gland or perinephric tissue, but do not invade beyond the Gerota fascia. There may be metastasis in a single regional lymph node, but no evidence of distant metastasis.

The standard of care for surgical candidates with locally advanced renal cell carcinoma (RCC), with or without extension into the inferior vena cava, is radical nephrectomy.[2][61] For small, unilateral tumours, partial nephrectomy may be considered if technically feasible.[61] Open, laparoscopic, or robot-assisted approaches may be used.[61][113]

Inferior vena cava invasion can pose a technical challenge, but durable disease response is still possible with advanced surgical techniques.[114] The management of RCC with tumour thrombus in the inferior vena cava requires a multidisciplinary team with expertise in this area.

Consider – adjuvant pembrolizumab

Back

Consider –

adjuvant pembrolizumab

Additional treatment recommended for SOME patients in selected patient group

Adjuvant therapy with pembrolizumab (a programmed death receptor-1 [PD-1] immune checkpoint inhibitor) may be considered for patients with locally advanced clear cell renal cell carcinoma (RCC) who are at increased risk of recurrence after nephrectomy.[2][61][106] Studies show improved overall survival with pembrolizumab compared with placebo in these patients.[107][108][109]

Clinicians should discuss the potential risks and benefits of adjuvant treatment with the patient during a shared decision-making process.[2][61]

Patients receiving immune checkpoint inhibitors should be monitored closely for treatment-related toxicity and endocrine dysfunction.[110][111][112]

See local specialist protocols for guidance on dose.

Primary options

pembrolizumab

non-surgical candidate

1st line – stereotactic body radiotherapy (SBRT) or clinical trial

Back

1st line –

stereotactic body radiotherapy (SBRT) or clinical trial

SBRT may be an option for poor surgical candidates with locally advanced disease.[61][103][104] SBRT may offer improved local control for larger tumours (≥4 cm) compared with thermal ablative techniques.[105]

Neoadjuvant therapy does not have an established role in treating renal cell carcinoma (RCC). However, patients with locally advanced RCC may be considered for neoadjuvant therapy if it is likely to enable complete resection or (for patients requiring renal preservation) partial nephrectomy.[61] One stage 2 trial reported reduction in tumour size and complexity with neoadjuvant axitinib, allowing successful partial nephrectomy in patients with localised RCC.[115] Participation in available clinical trials should be considered for neoadjuvant therapy.[1]

RCC stage 4 (metastatic disease)

limited metastatic disease: suitable for surveillance

1st line – surveillance

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1st line –

surveillance

Highly selected patients with metastatic clear cell renal cell carcinoma may be considered for an initial active surveillance strategy as an alternative to immediate systemic therapy.[61][117][118][119]

Suitable patients may include those with favourable or intermediate risk, with no disease-related symptoms, favourable histology, and a significant interval between nephrectomy and the development of metastasis.[116]

This approach avoids the toxicity of systemic therapy without compromising the benefit of therapy when initiated.[117]

Decisions about surveillance should be made using shared decision-making, including discussion of the benefits and risks.[116] Patients must be closely monitored for disease progression with regular serial imaging, including bone and brain imaging.[116][118]

Consider – local therapy and supportive care

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Consider –

local therapy and supportive care

Additional treatment recommended for SOME patients in selected patient group

Metastasis-directed local therapy may be considered for select patients receiving surveillance.[116]

Metastasectomy, stereotactic body radiotherapy (SBRT), or thermal ablation may be considered to treat oligometastatic disease. The role and optimal timing of metastasis-directed local therapy is uncertain.[61]

Palliative radiotherapy may be considered at any stage of metastatic disease for palliation of symptoms and local control. SBRT is the preferred approach.[61] Radiotherapy is commonly used for patients with bone or brain metastases.[2]

In patients with bone metastases, treatment with zoledronic acid or denosumab can significantly delay skeletal-related events, including pain requiring increased analgesia or radiation, pathological fractures, and progressive bone lesions.[116][155][156] Zoledronic acid or denosumab should be considered for patients with bone metastases.[2][61]

limited metastatic disease: suitable for surgical resection

1st line – surgery

Back

1st line –

surgery

Cytoreductive nephrectomy followed by metastasectomy may be an option for select patients who do not require immediate systemic therapy, example, with a potentially resectable primary tumour, minimal metastatic disease, and good performance status).[61][116]

The role of cytoreductive nephrectomy of the primary tumour in metastatic disease is controversial.[123] The CARMENA trial found that sunitinib (a tyrosine kinase inhibitor) alone was not inferior to nephrectomy followed by sunitinib in patients with intermediate or poor-risk metastatic renal cell carcinoma.[124] There is limited evidence regarding the use of systemic targeted cancer therapies and immune checkpoint inhibitors subsequent to cytoreductive nephrectomy.[123][125][126][127]

Consider – adjuvant pembrolizumab

Back

Consider –

adjuvant pembrolizumab

Additional treatment recommended for SOME patients in selected patient group

After complete resection of disease, adjuvant therapy with pembrolizumab (a programmed death receptor-1 [PD-1] immune checkpoint inhibitor) may be considered within 1 year of nephrectomy in patients with clear cell histology.[61][106][107][108][109]

Clinicians should discuss the potential risks and benefits of adjuvant treatment with the patient during a shared decision-making process.[2][61]

Patients receiving immune checkpoint inhibitors should be monitored closely for treatment-related toxicity and endocrine dysfunction.[110][111][112]

See local specialist protocols for guidance on dose.

Primary options

pembrolizumab

Consider – local therapy and supportive care

Back

Consider –

local therapy and supportive care

Additional treatment recommended for SOME patients in selected patient group

Metastasectomy, stereotactic body radiotherapy (SBRT), or thermal ablation may be considered to treat oligometastatic disease. The role and optimal timing of local therapy for metastatic disease is uncertain.[61]

In patients with bone metastases, treatment with zoledronic acid or denosumab should be considered to delay skeletal-related events, including pain requiring increased analgesia or radiation, pathological fractures, and progressive bone lesions.[2][61][116][155][156]

suitable for systemic therapy: clear cell histology

1st line – immunotherapy and/or targeted therapy

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1st line –

immunotherapy and/or targeted therapy

Treatment of metastatic disease should be individualised, based on symptoms, histology, and extent of metastatic disease. Discussion of palliative intent of therapy upfront is important, along with close symptom management and ongoing discussions about goals of care.

Risk stratification into Memorial Sloan Kettering Cancer Center (MSKCC) or International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk categories is recommended for patients with metastatic disease who require first-line systemic therapy.[61][116] Patients can be categorised as: favourable (0 prognostic factors); intermediate (1 to 2 prognostic factors); poor (3 or more prognostic factors).[62][78]

Systemic therapy with immunotherapies and/or targeted therapies is a first-line treatment option for patients with metastatic disease.[86] Immune checkpoint inhibitor-based combination therapies (dual immune checkpoint inhibitors or an immune checkpoint inhibitor plus a vascular endothelial growth factor tyrosine kinase inhibitor [VEGF-TKI]) are recommended as first-line systemic therapy for patients with metastatic clear cell renal cell carcinoma.[61]

Preferred first-line combination therapies for all risk categories include: pembrolizumab plus axitinib; nivolumab plus cabozantinib; pembrolizumab plus lenvatinib; ipilimumab plus nivolumab.[2][18][61][82][129][130][131][132][133] VEGF-TKI monotherapy with cabozantinib is a further preferred first-line option, recommended for intermediate/poor risk disease.[61][134][135]

A subcutaneous formulation of nivolumab (known as nivolumab/hyaluronidase) may be substituted for intravenous formulations of nivolumab when used in combination with cabozantinib or as monotherapy.[61] However, nivolumab/hyaluronidase is not approved for concurrent use with intravenous ipilimumab.

Studies of immune checkpoint inhibitor-based combinations have shown improved overall and progression-free survival compared with sunitinib for advanced disease, with durable responses.[133][136][137][138] However, there is a lack of head-to-head studies comparing treatment combinations.[86]

If immune checkpoint inhibitor combinations are not available, not tolerated, or contraindicated, sunitinib, pazopanib, or cabozantinib monotherapy may be used as first-line options for patients in all risk categories.[2][18][61][81][82][139][140][141] Axitinib plus avelumab may be considered as a further first-line option.[61][142]

Patients receiving immune checkpoint inhibitors should be monitored closely for treatment-related toxicity and endocrine dysfunction.[110][111][112]

See local specialist protocols for guidance on dose.

Primary options

pembrolizumab

and

axitinib

nivolumab

nivolumab/hyaluronidase

-- AND --

cabozantinib

pembrolizumab

and

lenvatinib

nivolumab

and

ipilimumab

cabozantinib

Secondary options

pazopanib

sunitinib

axitinib

and

avelumab

Consider – cytoreductive nephrectomy

Back

Consider –

cytoreductive nephrectomy

Additional treatment recommended for SOME patients in selected patient group

Deferred nephrectomy following systemic therapy may be considered for some patients (e.g., with large-volume distant metastases or large tumour burden), although evidence from randomised trials using current treatment combinations is lacking.[61][128]

Cytoreductive nephrectomy may also be an option for palliative treatment in patients with haematuria or pain.

Consider – local therapy and supportive care

Back

Consider –

local therapy and supportive care

Additional treatment recommended for SOME patients in selected patient group

2nd line – second-line systemic therapy (based on prior therapy)

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2nd line –

second-line systemic therapy (based on prior therapy)

Optimal second-line and subsequent systemic treatment for metastatic disease is uncertain and data are limited.[82] Recommended next-line options for metastatic clear cell renal cell carcinoma are based on prior treatment and tolerability.[61]

For patients treated previously with any immune checkpoint inhibitor, vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) inhibitor monotherapy with an agent not previously used may be considered (e.g., axitinib, cabozantinib, tivozanib).[134][135][143][146][147][148]

An immune checkpoint inhibitor combination (see first-line options) may be considered for second-line and subsequent systemic therapy if immunotherapy has not been tried previously. Other options include cabozantinib or nivolumab monotherapy, or everolimus plus lenvatinib.[144][149] [ ]

Consider – local therapy and supportive care

Back

Consider –

local therapy and supportive care

Additional treatment recommended for SOME patients in selected patient group

suitable for systemic therapy: non-clear cell histology

1st line – clinical trial or targeted therapy ± immunotherapy

Back

1st line –

clinical trial or targeted therapy ± immunotherapy

Patients with metastatic non-clear cell renal cell carcinoma (RCC) should be considered for relevant clinical trials whenever possible, until further data are obtained for these uncommon RCC histologies.[61]

Guidelines recommend cabozantinib alone, or in combination with nivolumab, as first-line systemic therapy options for non-clear cell metastatic disease.[61][150][151][152][153] Lenvatinib plus pembrolizumab is a further preferred first-line option.[61][154]

A subcutaneous formulation of nivolumab (known as nivolumab/hyaluronidase) may be substituted for intravenous formulations of nivolumab when used in combination with cabozantinib.[61]

Patients receiving immune checkpoint inhibitors should be monitored closely for treatment-related toxicity and endocrine dysfunction.[110][111][112]

See local specialist protocols for guidance on dose.

Primary options

cabozantinib

-- AND --

nivolumab

nivolumab/hyaluronidase

pembrolizumab

and

lenvatinib

Consider – cytoreductive nephrectomy

Back

Consider –

cytoreductive nephrectomy

Additional treatment recommended for SOME patients in selected patient group

Cytoreductive nephrectomy may also be an option for palliative treatment in patients with haematuria or pain.

Consider – local therapy and supportive care

Back

Consider –

local therapy and supportive care

Additional treatment recommended for SOME patients in selected patient group

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Renal cell carcinoma

Treatment algorithm

small renal mass or RCC stage 1 or 2

surgery

adjuvant pembrolizumab

Primary options

local ablation therapy

surveillance

surveillance

local ablation therapy

RCC stage 3

surgery

adjuvant pembrolizumab

Primary options

stereotactic body radiotherapy (SBRT) or clinical trial

RCC stage 4 (metastatic disease)

surveillance

local therapy and supportive care

surgery

adjuvant pembrolizumab

Primary options

local therapy and supportive care

immunotherapy and/or targeted therapy

Primary options

Secondary options

cytoreductive nephrectomy

local therapy and supportive care

second-line systemic therapy (based on prior therapy)

local therapy and supportive care

clinical trial or targeted therapy ± immunotherapy

Primary options

cytoreductive nephrectomy

local therapy and supportive care