Treatment algorithm

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

1st line – surgery

Back
ONGOING
|
small renal mass or RCC stage 1 or 2
|
surgical candidate
1st line – 

surgery

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

These patients generally require surgical resection, which affords the best chance for long-term control and cure.[1][2]​​ Surgeon, center, and patient factors all determine the ultimate surgical technique.

Consider – consideration for adjuvant therapy (pembrolizumab or clinical trials)

Back
ONGOING
|
small renal mass or RCC stage 1 or 2
|
surgical candidate
Consider – 

consideration for adjuvant therapy (pembrolizumab or clinical trials)

Treatment recommended for SOME patients in selected patient group

Adjuvant therapy may be considered for some patients with RCC who are at increased risk of recurrence following nephrectomy. For selected patients with stage 2 RCC with grade 4 tumors, adjuvant pembrolizumab may be an option.​[64][99]​​​ Clinicians should discuss the potential risks and benefits with the patient before making a shared decision about adjuvant treatment.[64]

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

See local specialist protocols for guidance on dose.

Primary options

pembrolizumab

1st line – local ablation therapy

Back
ONGOING
|
small renal mass or RCC stage 1 or 2
|
surgical candidate
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 tumor confined to kidney without regional lymph node or distant metastasis.

This is an alternative first-line approach for such tumors.[1][2]​​ The most commonly utilized of these techniques are radiofrequency ablation (RFA) and cryoablation. Evidence shows that local ablation for SRMs can yield good oncologic outcomes for tumor masses <3 cm in size, with cryoablation showing better local control, less risk of metastases, and less need for repeat treatments.[101] Local ablation may also be of use to patients whose renal function needs to be preserved (e.g., risk of multiple lesions in von Hippel-Lindau, unilateral kidney).[2] Thermal ablative techniques such as RFA and cryoablation are considered an alternative to surgery.[1]

1st line – surveillance

Back
ONGOING
|
small renal mass or RCC stage 1 or 2
|
nonsurgical candidate: <3 cm and slow-growing
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 tumor confined to kidney without regional lymph node or distant metastasis.

It may be reasonable to adopt surveillance strategies for those who are unfit for surgery (usually due to older age or medical comorbidities). Surveillance of SRMs may be the best option for those patients with limited life expectancy due to other pathologies.[1]​​[2][6]

Abdominal imaging with CT, MRI, or ultrasound should be performed at least annually in these patients.[90]

1st line – surveillance

Back
ONGOING
|
small renal mass or RCC stage 1 or 2
|
nonsurgical candidate: ≥3 cm or rapidly growing
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 tumor confined to kidney without regional lymph node or distant metastasis.

It may be reasonable to adopt surveillance strategies for those who are unfit for surgery (usually due to older age or medical comorbidities). Surveillance of SRMs may be the best option for those patients with limited life expectancy due to other pathologies.[1]​​[2][6]

Abdominal imaging with CT, MRI, or ultrasound should be performed at least annually in these patients.[90]

Consider – local ablation therapy

Back
ONGOING
|
small renal mass or RCC stage 1 or 2
|
nonsurgical candidate: ≥3 cm or rapidly growing
Consider – 

local ablation therapy

Treatment recommended for SOME patients in selected patient group

Locally ablative therapies may be considered for small renal masses.[1][2]​​ The most commonly utilized of these techniques are radiofrequency ablation (RFA) and cryoablation. Evidence shows that local ablation for small renal masses can yield good oncologic outcomes for tumor masses <3 cm in size, with cryoablation showing better local control, less risk of metastases, and less need for repeat treatments.[101]​ Stereotactic body radiation therapy (SBRT) is considered an ablative therapy, and may be an alternative option for poor surgical candidates.[64]

Consider – consideration for clinical trials

Back
ONGOING
|
small renal mass or RCC stage 1 or 2
|
nonsurgical candidate: ≥3 cm or rapidly growing
Consider – 

consideration for clinical trials

Treatment recommended for SOME patients in selected patient group

Participation in clinical trials for neoadjuvant therapy should be considered for patients whose tumors are deemed inoperable on presentation.

RCC stage 3

1st line – surgery

Back
ONGOING
|
RCC stage 3
|
surgical candidate
1st line – 

surgery

Stage 3 tumors 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 RCC is radical nephrectomy.[2] Inferior vena cava invasion can pose a technical challenge, but durable disease response is still possible with advanced surgical techniques.[102]

Consider – adjuvant pembrolizumab

Back
ONGOING
|
RCC stage 3
|
surgical candidate
Consider – 

adjuvant pembrolizumab

Treatment recommended for SOME patients in selected patient group

Targeted adjuvant therapy remains controversial.

Pembrolizumab is approved for use as an adjuvant therapy after surgery for locally advanced RCC in several countries. In one randomized double-blind trial of patients with RCC at high risk of recurrence after nephrectomy, pembrolizumab was associated with significantly greater disease-free survival (at 24 and 30 months) than placebo.[103][104]​​​ Longer term, a significant improvement in overall survival was observed with adjuvant pembrolizumab compared with placebo (alongside continued benefit in disease-free survival). Estimated overall survival at 48 months was 91.2% in the pembrolizumab group compared with 86.0% in the placebo group (consistent across subgroups).[105]

Guidelines recommend consideration of pembrolizumab as an option for adjuvant therapy in patients with RCC who are at increased risk of recurrence after nephrectomy, including those with stage 3 tumors.​[64][99]​​​​ Clinicians should discuss the potential risks and benefits with the patient before making a shared decision about adjuvant treatment.[64]

See local specialist protocols for guidance on dose.

Primary options

pembrolizumab

1st line – consideration for clinical trials

Back
ONGOING
|
RCC stage 3
|
nonsurgical candidate
1st line – 

consideration for clinical trials

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

Patients with locally advanced RCC in whom nephrectomy may be deemed difficult or unsuccessful should be considered for available neoadjuvant clinical trials.

The ability to downsize a tumor with molecular agents (tyrosine kinase inhibitors) as evaluated in some protocols appears to be related to the initial size of tumor (more effective with smaller lesions); however, neoadjuvant therapy is under clinical study and most often advocated for truly locally advanced, unresectable tumors.[97][98][106]

RCC stage 4 (metastatic disease)

1st line – targeted therapy

Back
ONGOING
|
RCC stage 4 (metastatic disease)
1st line – 

targeted therapy

Discussion of palliative intent of therapy upfront is important, along with close symptom management and ongoing discussions about goals of care.

Prognostic models are used in patients with metastatic disease to stratify risk, and can be categorized as:[77]

Favorable: 0 prognostic factors

Intermediate: 1 to 2 prognostic factors

Poor: 3 or more prognostic factors.

Targeted therapy should be supervised by medical oncologists with experience in managing their adverse-effect profiles, and in evaluating the ongoing benefit to patients with the potential for progressive metastatic disease.

Toxicities, patient comorbidities, and patient preference, in addition to efficacy, are important to consider when selecting a treatment regimen.

Combination treatment with pembrolizumab plus axitinib, or nivolumab plus cabozantinib, or pembrolizumab plus lenvatinib is recommended in all treatment-naive patients with clear-cell metastatic RCC.[17][64]​​​[113][114][115][116]​​​​ Ipilimumab plus nivolumab is an alternative option in intermediate- and poor-risk patient groups.[2][17]​​[64][81]​​​[117]

Avelumab plus axitinib has also been approved for use; however, pembrolizumab plus axitinib remains the preferred combination.[81] Nivolumab plus ipilimumab is an alternative option in intermediate- and poor-risk patient groups.[2][17][81][117]

VEGF-therapy with sunitinib or pazopanib is an option for patients with any risk level of metastatic disease who cannot receive or tolerate immune checkpoint inhibition.[17] Cabozantinib is an alternative option for patients in the poor-risk group of metastatic RCC.[2][17][81]

Other second- and third-line treatments may be recommended (e.g., aldesleukin, axitinib monotherapy, lenvatinib plus everolimus, everolimus, sorafenib) in certain circumstances. 

In treating patients with disease progression after combination therapy with pembrolizumab plus axitinib, changing the VEGFR-TKI to cabozantinib or or any other TKI not previously used is recommended.[17] The combination of nivolumab plus ipilimumab is recommended as salvage therapy, after prior VEGFR therapy.[81] Tivozanib, an oral next-generation VEGFR tyrosine kinase inhibitor, is approved for use in relapsed or refractory disease in patients who have received two or more prior treatments.[134][135]

See local specialist protocols for guidance on dose.

Primary options

pembrolizumab

and

axitinib

OR

nivolumab

and

cabozantinib

OR

pembrolizumab

and

lenvatinib

OR

nivolumab

and

ipilimumab

Secondary options

avelumab

and

axitinib

OR

pazopanib

OR

sunitinib

OR

cabozantinib

OR

aldesleukin

Tertiary options

axitinib

OR

lenvatinib

and

everolimus (oncologic)

OR

everolimus (oncologic)

OR

sorafenib

OR

tivozanib

Consider – consideration for surgery

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

consideration for surgery

Treatment recommended for SOME patients in selected patient group

The role of cytoreductive (or debulking) nephrectomy has been challenged in the setting of more targeted therapy.[110][111][112]

Surgery is typically only indicated in patients with good performance status, particularly if patients present with a few isolated sites of distant disease and cytoreductive nephrectomy is still an option for the primary.[64]

Metastasectomy can be done at the same time as renal surgery or on another occasion.

Surgeon, center, and patient factors all determine the ultimate surgical technique.

Consider – consideration for clinical trials

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

consideration for clinical trials

Treatment recommended for SOME patients in selected patient group

All patients with metastatic RCC should be considered for any available clinical studies throughout their treatment course (first-line and beyond).

Patients with nonclear-cell RCC in particular should be considered for relevant clinical trials when possible, at least until further data in these more uncommon RCC histologies accumulate.[141][142]

Consider – consideration for chemotherapy

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

consideration for chemotherapy

Treatment recommended for SOME patients in selected patient group

Chemotherapy has shown little efficacy in metastatic RCC. In one trial, gemcitabine and doxorubicin may have some efficacy, particularly in tumors with sarcomatoid differentiation.[143] However, chemotherapy should only be considered after exhausting targeted treatments and trial options for patients.

See local specialist protocol for guidance on regimen and dose.

Consider – consideration for local radiation

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

consideration for local radiation

Treatment recommended for SOME patients in selected patient group

Palliative radiation can be considered at any stage of metastatic disease if needed for local tumor control/pain.

External beam radiation to the primary tumor can be considered for nonsurgical candidates for palliation of symptomatic metastases to bone or viscera.[146] However, the precise delivery of ultra-high-dose stereotactic ablative body radiation therapy has shown to be effective treatment, particularly in cases of oligometastatic RCC, and is the preferred approach if available.[2][65][147][148]

Consider – bisphosphonate therapy for bone metastases

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

bisphosphonate therapy for bone metastases

Treatment recommended for SOME patients in selected patient group

In patients with metastatic RCC and bone metastases, zoledronic acid therapy can significantly delay skeletal-related events, including pain requiring increased analgesia or radiation, pathologic fractures, and progressive bone lesions.​[108][150]​​ This therapy should be considered for patients with bone metastases and/or hypercalcemia from metastatic RCC, and adequate renal function.

Primary options

zoledronic acid 4 mg injection: 4 mg intravenously every 3-4 weeks or as tolerated

2nd line – surveillance

Back
ONGOING
|
RCC stage 4 (metastatic disease)
2nd line – 

surveillance

Some patients with metastatic clear cell RCC may be offered an initial active surveillance strategy as an alternative to targeted therapy.[138][139][140]​​ These patients may include those with IMDC favorable and intermediate risk, limited or no disease-related symptoms, a favorable histologic profile, a significant interval between nephrectomy and the development of metastasis, or with limited burden of metastatic disease.[108]​

This approach avoids the toxicity of systemic therapy without compromising the benefit of therapy when initiated.[138]​

Metastasis-directed therapy may be considered for select patients on surveillance.[108]​

The benefits (preserving quality of life, delaying or avoiding treatment-related adverse effects) versus the potential for disease progression should be discussed with the patient to incorporate their preferences in the decision-making process.[108]​

Abdominal imaging with CT, MRI, or ultrasound should be performed at least annually in surveillance patients.[90]

Consider – consideration for local radiation

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

consideration for local radiation

Treatment recommended for SOME patients in selected patient group

Palliative radiation can be considered at any stage of metastatic disease if needed for local tumor control/pain.

External beam radiation to the primary tumor can be considered for nonsurgical candidates for palliation of symptomatic metastases to bone or viscera.[146] However, the precise delivery of ultra-high-dose stereotactic ablative body radiation therapy has shown to be effective treatment, particularly in cases of oligometastatic RCC, and is the preferred approach if available.[2][65][147][148]

Consider – bisphosphonate therapy for bone metastases

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

bisphosphonate therapy for bone metastases

Treatment recommended for SOME patients in selected patient group

In patients with metastatic RCC and bone metastases, zoledronic acid therapy can significantly delay skeletal-related events, including pain requiring increased analgesia or radiation, pathologic fractures, and progressive bone lesions.​[108][150]​​ This therapy should be considered for patients with bone metastases and/or hypercalcemia from metastatic RCC, and adequate renal function.

Primary options

zoledronic acid 4 mg injection: 4 mg intravenously every 3-4 weeks or as tolerated

Consider – targeted therapy

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

targeted therapy

Treatment recommended for SOME patients in selected patient group

Discussion of palliative intent of therapy upfront is important, along with close symptom management and ongoing discussions about goals of care.

Prognostic models are used in patients with metastatic disease to stratify risk, and can be categorized as:[77]

Favorable: 0 prognostic factors

Intermediate: 1 to 2 prognostic factors

Poor: 3 or more prognostic factors.

Targeted therapy should be supervised by medical oncologists with experience in managing their adverse-effect profiles, and in evaluating the ongoing benefit to patients with the potential for progressive metastatic disease.

Toxicities, patient comorbidities, and patient preference, in addition to efficacy, are important to consider when selecting a treatment regimen.

Combination treatment with pembrolizumab plus axitinib, or nivolumab plus cabozantinib, or pembrolizumab plus lenvatinib is recommended in all treatment-naive patients with clear-cell metastatic RCC.[17][113][114][115][116]​​​ Ipilimumab plus nivolumab is an alternative option in intermediate- and poor-risk patient groups.[2][17][81][117]

Avelumab plus axitinib has also been approved for use; however, pembrolizumab plus axitinib remains the preferred combination.[81] Nivolumab plus ipilimumab is an alternative option in intermediate- and poor-risk patient groups.[2][17][81][117]

VEGF-therapy with sunitinib or pazopanib is an option for patients with any risk level of metastatic disease who cannot receive or tolerate immune checkpoint inhibition.[17] Cabozantinib is an alternative option for patients in the poor-risk group of metastatic RCC.[2][17][81]

Other second- and third-line treatments may be recommended (e.g., aldesleukin, axitinib monotherapy, lenvatinib plus everolimus, everolimus, sorafenib) in certain circumstances.

In treating patients with disease progression after combination therapy with pembrolizumab plus axitinib, changing the VEGFR-TKI to cabozantinib or or any other TKI not previously used is recommended.[17] The combination of nivolumab plus ipilimumab is recommended as salvage therapy, after prior VEGFR therapy.[81] Tivozanib, an oral next-generation VEGFR tyrosine kinase inhibitor, is approved for use in relapsed or refractory disease in patients who have received two or more prior treatments.[134][135]

See local specialist protocols for guidance on dose.

Primary options

pembrolizumab

and

axitinib

OR

nivolumab

and

cabozantinib

OR

pembrolizumab

and

lenvatinib

OR

nivolumab

and

ipilimumab

Secondary options

avelumab

and

axitinib

OR

pazopanib

OR

sunitinib

OR

cabozantinib

OR

aldesleukin

Tertiary options

axitinib

OR

lenvatinib

and

everolimus (oncologic)

OR

everolimus (oncologic)

OR

sorafenib

OR

tivozanib

Consider – consideration for surgery

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

consideration for surgery

Treatment recommended for SOME patients in selected patient group

The role of cytoreductive (or debulking) nephrectomy has been challenged in the setting of more targeted therapy.[110][111][112]

Surgery is typically only indicated in patients with good performance status, particularly if patients present with a few isolated sites of distant disease and cytoreductive nephrectomy is still an option for the primary.

Metastasectomy can be done at the same time as renal surgery or on another occasion.

Surgeon, center, and patient factors all determine the ultimate surgical technique.

Consider – consideration for clinical trials

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

consideration for clinical trials

Treatment recommended for SOME patients in selected patient group

All patients with metastatic RCC should be considered for any available clinical studies throughout their treatment course (first-line and beyond).

Patients with nonclear-cell RCC in particular should be considered for relevant clinical trials when possible, at least until further data in these more uncommon RCC histologies accumulate.[141][142]

Consider – consideration for chemotherapy

Back
ONGOING
|
RCC stage 4 (metastatic disease)
Consider – 

consideration for chemotherapy

Treatment recommended for SOME patients in selected patient group

Chemotherapy has shown little efficacy in metastatic RCC. In one trial, gemcitabine and doxorubicin may have some efficacy, particularly in tumors with sarcomatoid differentiation.[143] However, chemotherapy should only be considered after exhausting targeted treatments and trial options for patients.

See local specialist protocol for guidance on regimen and dose.

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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

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