Renal cell carcinoma

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

Surgical resection is effective for treating localised disease, and may achieve cure.[61]

Combination therapy (dual immune checkpoint inhibitors or an immune checkpoint inhibitor plus a vascular endothelial growth factor tyrosine kinase inhibitor [VEGF-TKI]) is recommended as first-line treatment for patients with metastatic clear cell renal cell carcinoma (RCC).[61][86]

Prognostic models are used in patients with metastatic disease to guide systemic therapy. Risk groups in the Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models are categorised as:[62][78]

Favourable: 0 prognostic factors
Intermediate: 1-2 prognostic factors
Poor: ≥3 prognostic factors.

Small renal mass/early-stage RCC (stages 1, 2)

Several management strategies are available for clinically localised renal masses suspicious for RCC: active surveillance, radical nephrectomy, partial (nephron-sparing) nephrectomy, thermal ablation, and stereotactic body radiotherapy (SBRT).[1][5][61]

Active surveillance

Active surveillance of small renal masses (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]

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

There is evidence that SRMs (particularly those <2 cm) are more likely to be benign (up to 46% in those <1 cm, and 25% in those <2 cm).[3][5] SRMs followed by surveillance showed slow growth (<0.2 to 0.3 cm/year) and were either more likely to be benign, or, if malignant, less likely to metastasise; it is unclear if these slower-growing lesions are more likely to be of papillary or chromophobe histology, if indeed they are RCC.[3][4] Rate of growth, nonetheless, cannot be used as an absolute predictor of benign versus malignant pathology, as RCC can also demonstrate little or no growth.[89] Overall, masses <3.5 cm, even if an RCC is likely, have low metastatic potential over 2 to 3 years. Biopsy of SRMs may be considered to confirm malignancy and inform treatment decisions.[61]

Surgery

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]

Ablative therapy

Locally ablative techniques are an alternative approach for small tumours.[1][2][90][100] The most commonly utilised of these 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 as an alternative to surgery for stage 1 tumours (T1a and select patients with T1b tumours).[61]

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 radiofrequency thermal ablation (RTA), 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 who are not deemed to be good surgical candidates due to comorbidities and/or frailty.[2]

Adjuvant therapy

Adjuvant treatment following nephrectomy has not been shown to be beneficial for most patients with localised disease. However, for some patients with clear cell 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.

Locally advanced RCC (stage 3)

The standard of care for surgical candidates with locally advanced 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.

Adjuvant therapy

Adjuvant therapy with pembrolizumab may be considered for patients with locally advanced clear cell 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]

Poor surgical candidates

SBRT may be an alternative 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 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 clinical trials should be considered for neoadjuvant therapy.[1]

Metastatic disease (stage 4)

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.

Systemic therapy with immunotherapies and/or targeted therapies is a first-line treatment option for patients with metastatic disease.[86] Active surveillance, cytoreductive nephrectomy, and/or local metastases-directed therapy may be options for select patients.[2][61][116] Tissue biopsy is recommended for histological evaluation and to guide treatment.[61][116]

Active surveillance

Highly selected patients with metastatic clear cell RCC 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] Metastasis-directed local therapy may be considered for select patients receiving surveillance.[116] 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 CNS imaging.[116][118]

Local therapy for oligometastatic disease

Patients with potentially surgically resectable primary tumours and oligometastatic disease may be considered for metastasectomy or SBRT to manage metastases after nephrectomy.[61][120][121][122] Other ablative techniques may be considered as alternatives for select patients who are not candidates for metastasectomy or SBRT.

Cytoreductive nephrectomy

The role of cytoreductive nephrectomy of the primary tumour in metastatic disease is controversial.[123] The CARMENA trial found that sunitinib (a TKI) alone was not inferior to nephrectomy followed by sunitinib in patients with intermediate or poor-risk metastatic RCC.[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]

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

After complete resection of disease, adjuvant therapy with pembrolizumab may be considered within 1 year of nephrectomy in patients with clear cell histology.[61][106][107][108][109]

Cytoreductive nephrectomy may also be an option for palliative treatment in patients with haematuria or pain.[61]

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.[2][61][128]

Systemic therapy for metastatic clear cell RCC

Risk stratification using MSKCC or IMDC prognostic risk categories (favourable, intermediate, and poor) is recommended for patients with metastatic disease who require first-line systemic therapy.[61][62][78][116]

Immune checkpoint inhibitor-based combination therapies (dual immune checkpoint inhibitors or an immune checkpoint inhibitor plus a VEGF-TKI) are recommended as first-line systemic therapy for patients with metastatic clear cell RCC.[61] Preferred first-line combination therapies for all risk categories include:[2][18][61][82][129][130][131][132][133]

Pembrolizumab plus axitinib
Nivolumab plus cabozantinib
Pembrolizumab plus lenvatinib
Ipilimumab plus nivolumab

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.[2][142]

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

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 RCC are based on prior treatment and tolerability.[61] For patients treated previously with any immune checkpoint inhibitor, VEGF-TKI monotherapy with an agent not previously used (e.g., axitinib, cabozantinib, tivozanib) or everolimus plus lenvatinib may be considered.[134][135][143][144][145][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] [ ]

Systemic therapy for metastatic non-clear cell RCC

Patients with metastatic non-clear cell 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]

Local therapy and supportive care

Metastasectomy, 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 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]

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Renal cell carcinoma

Approach

Small renal mass/early-stage RCC (stages 1, 2)

Locally advanced RCC (stage 3)

Metastatic disease (stage 4)