Approach

Surgery is the cornerstone for localized disease and may achieve cure.[64]​ The increased detection of small renal masses (SRMs, defined as renal lesions <4 cm) from more widespread use of sensitive imaging modalities may be raising the threshold for surgical intervention.

Locally advanced disease continues to pose surgical challenges in achieving complete tumor resection, which creates a higher risk for relapse both locally and systemically. Preferred systemic therapy for patients with clear cell RCC is a tyrosine kinase inhibitor (TKI of vascular endothelial growth factor receptors [VEGFRs]) plus immune checkpoint inhibitor.[87]

Prognostic models are used in patients with metastatic disease to distinguish between groups of patients with different outcomes. Risk groups in the Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models are categorized as:[77]

  • Favorable: 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 localized renal masses suspicious for RCC: active surveillance, radical nephrectomy, partial (nephron-sparing) nephrectomy, and thermal ablation.[1][5][64]​​​

Cancer-specific survival rates are very high for stage 1 and 2 tumors across all treatment modalities (with a median 5-year cancer-specific survival of 95%).[1][88]

Active surveillance

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 metastasize; 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.

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]​​​ Abdominal imaging with CT, MRI, or ultrasound should be performed at least annually in patients undergoing active surveillance.[90]​ A well-communicated risk-benefit analysis unique to individual patient circumstances should be part of the patient decision making tool.[1][5]​​ Surveillance of SRMs is not recommended for younger, medically fit patients with operable masses.[1]

Surgery

Open radical nephrectomy has historically been the treatment of choice for those in this group of patients who are surgical candidates (biopsy may be indicated preoperatively to establish the presence of malignancy, especially in high-risk surgical candidates). Laparoscopic nephrectomy shows outcomes comparable to open techniques, even for large tumors, and is preferred if technically possible. Both transperitoneal and retroperitoneal laparoscopic approaches have been evaluated.[91] The use of robot-assisted laparoscopic techniques shows promise in early study, but requires ongoing research evaluation.[92][93] Ipsilateral adrenalectomy is no longer recommended if the gland is uninvolved on preoperative imaging studies.[94]

Partial nephrectomy/nephron-sparing surgery (NSS) was previously only done in patients with a single kidney, or if there were concerns about contralateral kidney function; however, this is now generally advocated whenever clinically feasible, especially for tumors/SRMs <4 cm, to preserve more renal function in the long term. Oncologic outcome 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 noncancer-related health consequences.[88][95][96] Whenever technically feasible, efforts should be made to perform NSS as the standard of care over radical nephrectomy in early RCC.[1][2] However, in the setting of high tumor complexity, no pre-existing chronic kidney disease or proteinuria, normal contralateral kidney (predicted baseline glomerular filtration rate >45 ml/min/1.73 m²), radical nephrectomy should still be considered.[1][88] NSS may be particularly important for patients with multifocal or bilateral tumors (especially those with hereditary syndromes and ongoing RCC risk), in order to maintain renal function for as long as possible. There is some early evidence that neoadjuvant therapy with molecular agents (tyrosine kinase inhibitors) may be useful to downsize tumors for potential NSS or ablative techniques; however, this remains experimental.[97][98]

Adjuvant therapy

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.

Ablative techniques

Although surgery remains the standard of care for patients with early-stage RCC, an alternative approach for small tumors is locally ablative techniques.[1][2][88][100]​​ The most commonly utilized of these are radiofrequency ablation (RFA) and cryoablation. Tumor cell death in RFA is caused by coagulation from high-frequency current. In cryoablation, cell death is achieved by local freezing. 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., at risk of multiple lesions in von Hippel-Lindau syndrome, or those with unilateral kidney), or for those patients who are not deemed to be good surgical candidates due to comorbidities.[2] Thermal ablative techniques such as radiofrequency ablation and cryoablation are considered an alternative to surgery for small renal masses.[1]​ Stereotactic body radiation therapy (SBRT) is considered an ablative therapy, and may be an alternative option for poor surgical candidates.[64]

Locally advanced RCC (stage 3)

The standard of care for surgical candidates with locally advanced RCC is radical nephrectomy.[2]​​​ Inferior vena cava (IVC) invasion can pose a technical challenge, but durable disease response is still possible with advanced surgical techniques.​[102]​ The management of RCC with tumor thrombus in the IVC requires a multidisciplinary team with expertise in this area.

Adjuvant therapy

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]

Patients with locally advanced RCC, particularly 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]​

Metastatic disease (stage 4)

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. Metastatic disease can also be resected after relapse of original curative-intent nephrectomy, particularly if there is a low burden of disease relapse and the patient is fit.

Resection of metastases is most often done with curative intent, and is best described for pulmonary lesions. Fit patients who are found to have low-burden metastatic disease on presentation, or who relapse with it after original curative surgery performed more than 1 year previously, should be considered for metastasectomy, particularly if they have pulmonary metastases.[107] However, the role and optimal timing of metastasectomy is debated, and requires further research. TKI treatment following total metastasectomy is generally not recommended due to a lack of clinical benefit.[108]

The role of cytoreductive nephrectomy of the primary tumor in metastatic disease is controversial. The CARMENA trial showed sunitinib (a tyrosine kinase inhibitor) alone was not inferior to nephrectomy followed by sunitinib in patients with intermediate or poor-risk metastatic RCC.[109] Limitations in this trial and changes to recommended therapies, particularly the use of immune checkpoint inhibitors, mean that the role of cytoreductive surgery continues to evolve as the best candidates are yet to be determined.[110][111][112]

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]

Cytokine-based immunotherapy (aldesleukin/interleukin-2 [IL-2])

  • Historically, the only systemic therapies found to have some utility in metastatic RCC. Considered for patients with excellent performance status (Eastern Cooperative Oncology Group [ECOG] score 0-1) and clear cell histology, although it has been suggested that sarcomatoid histologies may also benefit.[118] In the current era of targeted treatments, the use of cytokine-based immunotherapy is less common and is limited to highly selected patients who have excellent performance status and normal organ function.[119]

Targeted molecular therapy includes vascular endothelial growth factor (VEGF) inhibitors and mammalian target of rapamycin (m-TOR) inhibitors.[2]

  • These therapies 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.

  • Tyrosine kinase inhibitors designed to inhibit the VEGF and platelet-derived growth factor receptor (PDGFR) pathways, revolutionized systemic treatment for metastatic RCC; however, have been replaced by immune checkpoint inhibitors except in specific circumstances.

  • These therapies are typically used for patients with good performance status (ECOG score 0-2) and clear cell histology.[2]

  • Evidence regarding their use for non-clear cell RCC histologies does exist, but is very limited and depends on subtype.[81]

VEGF inhibitors

  • VEGF-targeted therapy is reserved for patients where ICI combinations are not available, not tolerated, or contraindicated.[2][17][81]

  • Sunitinib, a TKI, has been confirmed as an effective first-line therapy for patients with advanced RCC in several real-world studies.[80]

  • Pazopanib is another oral TKI. Data from the COMPARZ study, evaluating sunitinib versus pazopanib in the first-line setting, demonstrated that pazopanib is non-inferior to sunitinib with respect to progression-free survival (PFS).[120][121] Quality of life may be improved on first-line pazopanib compared with sunitinib, based on better tolerability.[122] Either TKI is an option for patients in the first-line setting for patients with metastatic RCC of any prognostic risk level who cannot receive or tolerate immune checkpoint inhibition, and treatment choice should be individualized.

  • Sorafenib is also a small-molecule multikinase inhibitor, affecting VEGF, PDGFR, and Ras/Raf/ERK pathways.[123]

  • Bevacizumab is a monoclonal antibody against VEGF. In early trials, it has been shown to be active as a single agent for patients previously treated by immunotherapy. Bevacizumab, either alone or in combination with other drugs, is not widely recommended due to more attractive alternatives.

  • Axitinib is a TKI and is a potent and selective second-generation inhibitor of VEGF receptors. Most licensing authorities have approved axitinib in the second-line metastatic RCC indication (after having progressed on a prior treatment for metastatic disease).[124] However, combination therapy consisting of axitinib and an immune checkpoint inhibitor (pembrolizumab or avelumab) has now been approved for first-line therapy in several regions, shifting treatment options for metastatic RCC significantly.[2][81]

  • Cabozantinib is an oral TKI that inhibits VEGF receptors, mesenchymal-epithelial transition factor (MET), and AXL receptor tyrosine kinase. Cabozantinib in combination with nivolumab in treatment-naive clear-cell RCC improved progression-free survival in patients compared with sunitinib and has been approved for use in several countries.[115] Cabozantinib monotherapy is indicated in treatment-naive adults with intermediate or poor risk, or as a preferred second- (and subsequent-) line therapy in metastatic RCC.[125][126] Because of action at MET and AXL pathways, cabozantinib is also being utilized in trials in non-clear cell RCC.[127]

  • Lenvatinib, a VEGFR-TKI, is approved for use in combination with everolimus, for the treatment of advanced RCC following one prior anti-angiogenic therapy. Approval was based on one phase 2 trial, in which patients received single-agent lenvatinib versus single-agent everolimus versus a combination of lenvatinib plus everolimus after progression of prior VEGFR-TKI.[128] In the CLEAR trial, treatment-naive patients with metastatic RCC who were treated with lenvatinib plus pembrolizumab had significantly improved progression-free survival compared with those in the sunitinib arm.[116]

m-TOR inhibitors

  • The m-TOR pathway is an important target in RCC. However, newer agents have shown superiority to everolimus, so the m-TOR inhibitors have fallen out of favor in first-line and second-line use.

  • Everolimus, in a large randomized controlled trial in the second- or third-line setting, has shown PFS benefit of 3 months in previously treated patients.[129] Some authorities do not recommend it as second-line therapy, as the OS data were only significant through modeling.[130] Use of everolimus combined with lenvatinib is a potential option for use in patients with advanced RCC if they progress on immunotherapy drugs and TKIs.[119] 

Targeted immunotherapy: immune checkpoint inhibitors

  • Tumor expression of checkpoint proteins (PD-L1, PD-1, cytotoxic T-lymphocyte-associated protein-4 [CTLA-4]) is used by cancer cells to avoid detection by the immune system.[38] However, these proteins can be used for targeted immunotherapy. 

  • Nivolumab, pembrolizumab, avelumab, and ipilimumab are checkpoint inhibitors.

  • Nivolumab is a PD-1 antibody that blocks the binding of PD-1 on T cells with its ligands on immune and tumor cells, allowing for immune-mediated attack of cancer cells. In the pivotal CheckMate 025 study, nivolumab was compared to everolimus in patients with metastatic clear cell RCC after progression of prior VEGFR-TKI therapy.[131] Nivolumab showed an improved median OS over everolimus (25.0 months vs. 19.6 months, P=0.002). Nivolumab also had higher ORR (25% vs. 5%) and more tolerable side effect profile. [ Cochrane Clinical Answers logo ]  

  • Ipilimumab is an antibody that blocks CTLA-4. Checkmate 214 showed improved overall survival and progression-free survival with nivolumab plus ipilimumab compared with sunitinib in intermediate or poor-risk patients, with 42% of patients experiencing an objective response, and 10% experiencing complete response with combination therapy.[117] This trial resulted in a paradigm shift in the treatment of metastatic RCC, and nivolumab plus ipilimumab is a first-line option in the intermediate- and poor-risk patient groups.[2][17][81]

  • Pembrolizumab is a PD-1 inhibitor. In an open-label, phase 3 trial of patients randomly assigned to either pembrolizumab plus axitinib versus sunitinib, combination therapy resulted in 47% lower risk of death and 31% lower risk of progression, with 60% of objective response across all risk groups.[113] Pembrolizumab plus axitinib is recommended as first-line treatment for patients with any risk group metastatic RCC.[2][17][81]

  • Avelumab is a PD-L1 inhibitor. In a phase 3 trial of avelumab plus axitinib versus sunitinib, median progression-free survival was improved in the combination arm, compared to the sunitinib arm, in the overall population, irrespective of risk factor and PD-L1 status. However, no overall survival benefit has been demonstrated for this combination.[132] Avelumab plus axitinib has been approved for use. Pembrolizumab plus axitinib remains the preferred combination.[81]

  • As a class, immune checkpoint inhibitors are generally well tolerated, but immune-related adverse events can be insidious and threatening if not dealt with in a prompt manner.[133] Major side effects to monitor for include diarrhea/colitis, transaminitis/hepatitis, rash/dermatitis, and hypophysitis/endocrine abnormalities. Generally, side effects are treated with possible dose interruptions and corticosteroid therapy, though there are many management algorithms that should be carefully consulted. One unique aspect of immune checkpoint inhibition therapy is a prolonged duration of disease control. While ORR are relatively low, those patients who do respond seem to have tumor control longer than typically seen on targeted molecular therapy.

Subsequent systemic therapy for metastatic RCC

  • As the approach to treatment of metastatic RCC has changed with the approval of immune checkpoint inhibitors as first-line therapy, there is considerable uncertainty and limited data on subsequent therapy.[81] In treating patients with disease progression after combination therapy with pembrolizumab plus axitinib, cabozantinib (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-TKI, is approved for use in relapsed or refractory disease in patients who have received two or more prior treatments.[134][135]

Special patient populations

  • Older patients (older than 65 or 70 years) with metastatic RCC have similar benefits as younger patients from targeted molecular treatments; however, as in all patients, special consideration should be made of comorbid illness and organ dysfunction, which may make certain drug toxicities more likely or pronounced.[136] In the first-line setting, one meta-analysis determined that nivolumab plus ipilimumab is the most efficacious treatment for older patients, with cabozantinib offering the best survival outcome in the salvage-line setting.[137]

Active 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]

Consideration for relevant clinical trials

  • Patients with non-clear cell RCC should be considered for relevant clinical trials when possible, at least until further data in these more uncommon RCC histologies accumulate. Some of these patients may still respond to targeted therapies, and the decision to use these treatments in this patient population should be individualized. Several review articles delineate special considerations for each non-clear cell subtype, as these demonstrate unique biologies.[141][142]

Chemotherapy

  • Chemotherapy has shown little efficacy in metastatic RCC. Gemcitabine and doxorubicin are chemotherapeutic agents that may have some efficacy, particularly in tumors with sarcomatoid differentiation.[143] However, chemotherapy did not result in meaningful survival benefit compared with other therapeutic modalities.[144]

Radiation therapy

  • There is no established role for adjuvant radiation in RCC. One meta-analysis of trials showed decreased local regional failure with the addition of postoperative radiation therapy in early RCC, but no impact in overall survival.[145]

  • Conventional (external beam radiation) to the primary tumor, if left in situ, can be considered for palliation of local symptoms.[146] However, the precise delivery of ultra high-dose stereotactic ablative body radiation therapy has shown to be an effective treatment, particularly in cases of oligometastatic RCC, and is the preferred approach if available.[2][65][147][148]

  • There is evidence suggesting that oral TKIs (e.g., sunitinib) may have a radiosensitizing effect, and the combination of these modalities warrants further study.[146][149]

Bisphosphonate therapy

  • 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.

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