Renal Cell Carcinoma Treatment & Management

The therapeutic approach to renal cell carcinoma (RCC) is guided by the probability of cure, which is related directly to the stage or degree of tumor dissemination. ^{[2, 3, 4]} More than 50% of patients with early-stage RCC are cured, but the outcome for stage IV disease is poor.

The American Urological Association guideline for management of clinically localized sporadic renal masses suspicious for RCC in adults recommends reviewing all available treatment options and the associated benefits and risks with the patient. This review should include oncologic issues, kidney function issues, and potential complications. ^[19]

The principal treatment options for RCC are as follows:

• Surgery
• Thermal ablation
• Active surveillance
• Radiation therapy
• Immunotherapy
• Molecular-targeted therapy

Treatment considerations are as follows:

• Surgical resection remains the only known curative treatment for localized RCC, and it also is used for palliation in metastatic disease.
• Radiofrequency ablation by an interventional radiologist can be considered as an alternative for small lesions in carefully selected patients who are not candidates for surgery.
• Targeted therapy and immunomodulatory agents are considered standard of care in patients with metastatic disease.

Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Objective response rates with chemotherapy, either single-agent or combination, are usually lower than 15%. Therefore, various biologic therapies have been evaluated.

RCC is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators have been used successfully, including the following:

• Interferon (IFN) and interleukin-2 (IL-2)
• The programmed cell death–1 (PD-1) protein receptor blocker nivolumab and similar immune checkpoint inhibitors
• Bacillus Calmette-Guérin (BCG) vaccination
• Autologous vaccines
• Lymphokine-activated killer (LAK) cells plus IL-2
• Tumor-infiltrating lymphocytes
• Nonmyeloablative allogeneic peripheral blood stem cell transplantation

About 25-30% of patients have metastatic disease at diagnosis, and fewer than 5% have a solitary metastasis. Surgical resection is recommended in selected patients with metastatic RCC. This procedure may not be curative in all patients but may lead to long-term survival in some cases. The possibility of disease-free survival increases after resection of primary tumor and excision of isolated metastasis.

Surgical resection of a solitary metastasis is recommended in selected patients with good performance status. A large retrospective analysis from a single institution revealed an improved cancer-specific survival advantage, even with resection of more than one metastatic lesion. The study also revealed increased risk of death from RCC in patients who did not undergo surgical resection of metastasis. ^[22] A study by Alt et al found that complete resection of multiple RCC metastases may be associated with long-term survival. ^[23]

Active surveillance may be an acceptable approach to delay or avoid further intervention in the patient at high surgical risk. Candidates for active surveillance include selected patients older than 70 years who have asymptomatic renal masses and slow growth documented on serial imaging. A retrospective single-institution review of 51 patients showed no metastatic spread with a median follow-up of almost 6 years; only 2 patients required surgical intervention for local progression or symptoms. ^[24]

The treatment of metastatic RCC is problematic, so whenever possible, patients should be directed to approved and controlled clinical trials. This applies as well in the adjuvant treatment of surgically resected RCC, for which no therapy has yet been found to offer survival benefit.

Go to Renal Cell Carcinoma Treatment Protocols, Clear Cell Renal Cell Carcinoma, and Sarcomatoid and Rhabdoid Renal Cell Carcinoma for complete information on these topics. To view a multidisciplinary tumor board case discussion, see Memorial Sloan Kettering e-Tumor Boards: Metastatic Clear Cell Renal Cell Carcinoma.

Surgical resection remains the only known effective treatment for localized renal cell carcinoma, and it also is used for palliation in metastatic disease. Partial or radical nephrectomy may be used, depending on tumor and patient characteristics. Open, laparoscopic, or robotic surgical techniques may be used.

Partial Nephrectomy

For a T1a renal mass, the National Comprehensive Cancer Network (NCCN) recommends partial nephrectomy, stating that radical nephrectomy should not be used when nephron-sparing procedures are possible. For T1b tumors, the NCCN guideline states that the standard of care is either radical nephrectomy or partial nephrectomy (when possible). ^[18]

In patients with a T1 renal mass, the AUA management guideline recommends prioritizing partial nephrectomy, as it minimizes the risk of chronic kidney disease (CKD) or CKD progression and is associated with favorable oncologic outcomes, including excellent local control c ^[19]

Thermal ablation is a less invasive treatment option that may be preferable in the patient at high surgical risk, but it is associated with a higher risk of local tumor recurrence compared with surgical excision. Biopsy is recommended for all patients undergoing thermal ablation.

The AUA guideline panel cautions that larger tumors (> 3.5 cm) and those with uneven shape or infiltrative appearance may be linked with increased risk of recurrence when managed with thermal ablation. ^[19] A study by Zagoria et al found that in patients who are poor surgical candidates, radiofrequency ablation can result in durable oncologic control of renal cell carcinomas that are smaller than 4 cm. ^[25]

Radical Nephrectomy

Radical nephrectomy, which remains the most commonly performed standard surgical procedure for treatment of localized renal cell carcinoma, involves complete removal of the Gerota fascia and its contents, including a resection of kidney, perirenal fat, and ipsilateral adrenal gland, with or without ipsilateral lymph node dissection. Radical nephrectomy provides a better surgical margin than simple removal of the kidney, because perinephric fat may be involved in some patients. Approximately 20-30% of patients with clinically localized disease develop metastatic disease after nephrectomy.

AUA guidelines recommend considering radical nephrectomy for patients with a solid or Bosniak 3/4 complex cystic renal mass whenever tumor size, tumor biopsy results (if obtained), and/or imaging suggest increased oncologic potential. In those cases, radical nephrectomy is preferred if all of the following criteria are met ^[19] :

• High tumor complexity and partial nephrectomy would be challenging even in experienced hands
• No preexisting CKD or proteinuria
• Normal contralateral kidney and new baseline eGFR will likely be greater than 45 mL/min/1.73m ² even if radical nephrectomy is performed.

Some surgeons believe that the adrenal gland should not be removed because of the low probability of ipsilateral adrenal metastasis and the morbidity associated with adrenalectomy. The NCCN recommends considering ipsilateral adrenal gland resection for patients with large upper pole tumors or adrenal glands that appear abnormal on CT; if adrenal glands are uninvolved, adrenalectomy can be omitted. ^[18]

In the absence of distant metastatic disease with locally extensive and invasive tumors, adjacent structures such as bowel, spleen, or psoas muscle may be excised en bloc during radical nephrectomy.

At least three common approaches exist for removal of kidney cancer: the transperitoneal approach, the flank approach, and the thoracoabdominal approach. Which approach is used depends on the tumor location and size as well as the body habitus of the patient. The thoracoabdominal approach offers the advantage of palpation of the ipsilateral lung cavity and mediastinum, as well as the ability to resect solitary pulmonary metastases.

Lymph node involvement

Lymph nodes may be involved in 10-25% of patients. The 5-year survival rate in patients with regional node involvement is substantially lower than in patients with stage I or II disease. Regional lymphadenectomy adds little in terms of operative time or risk and should be included in conjunction with radical nephrectomy.

The NCCN guideline states that patients with enlarged lymph nodes (palpable or visible or detected on preoperative imaging) should undergo lymph node dissection. To obtain needed staging information, lymph node dissection may also be performed on patients whose lymph nodes appear normal. Lymph node dissection is described as prognostic rather than therapeutic in the NCCN guideline, which cites a 2009 randomized phase 3 trial in which adding lymph node dissection to radical nephrectomy made no significant difference in time to progression, progression-free survival, or overall survival. ^[18]

Inferior vena cava involvement

Approximately 5% of patients with renal cell carcinoma have inferior vena caval involvement. In these cases, the NCCN guideline states that radical nephrectomy is preferred, and for stage II and III renal tumors, it is the standard of care. ^[18]

Tumor invasion of the renal vein and inferior vena cava usually occurs as a well-vascularized thrombus covered with its own intimal surface. In patients with renal vein involvement without metastases, radical nephrectomy is performed with early ligation of the renal artery but no manipulation of the renal vein. If the inferior vena cava is involved, then vascular control of the inferior vena cava is obtained both above and below the tumor thrombus, and the thrombus is resected intact, with subsequent closure of the vena cava. Patients with actual invasion of the inferior vena caval wall have poor prognoses, despite aggressive surgical approaches.

Laparoscopic Nephrectomy

Laparoscopic nephrectomy is a less invasive procedure than radical nephrectomy, incurs less morbidity, and is associated with shorter recovery time and less blood loss. Although the need for pain medications is reduced, operating room time and costs are higher. Disadvantages include concerns about spillage and technical difficulties in defining surgical margins. Laparoscopic partial nephrectomy can be considered at centers with experience in this procedure for early-stage renal cell cancer.

Palliative Nephrectomy

Palliative nephrectomy should be considered in patients with metastatic disease for alleviation of symptoms such as pain, hemorrhage, malaise, hypercalcemia, erythrocytosis, or hypertension. Several randomized studies have shown improved overall survival in patients presenting with metastatic kidney cancer who have nephrectomy, followed by either interferon or interleukin-2 therapy. If the patient has good physiologic status, then nephrectomy should be performed before immunotherapy.

Reports have documented regression of metastatic renal cell carcinoma after removal of the primary tumor. Adjuvant nephrectomy is not recommended for inducing spontaneous regression; rather, it is performed to decrease symptoms or to decrease tumor burden for subsequent therapy in carefully controlled environments.

Interleukin-2

IL-2 is a T-cell growth factor and activator of T cells and natural killer (NK) cells. IL-2 affects tumor growth by activating lymphoid cells in vivo without affecting tumor proliferation directly. High-dose interleukin-2 (IL-2) can induce durable long-term remission in 10% of patients with advanced kidney cancer, and must be considered for robust patients with excellent cardiopulmonary reserve. This treatment should generally be administered in centers with significant experience in using this agent. Patients who do not have access to high-dose IL-2, who refuse it, or who are not candidates for it should consider one of the approved targeted therapies.

In the initial study by the National Cancer Institute (NCI), bolus intravenous (IV) infusions of high-dose IL-2 combined with lymphokine-activated killer (LAK) cells produced an objective response rate of 33%. In subsequent multicenter trials, not only was the response rate 16%, but LAK cells were shown to add no definite therapeutic benefit and could be eliminated from the treatment. ^[26] A high-dose regimen (600,000-720,000 IU/kg q8h for a maximum of 14 doses) resulted in a 19% response rate with 5% complete responses. The majority of responses to IL-2 were durable, with median response duration of 20 months; 80% of patients who had a complete response to IL-2 therapy were alive at 10 years.

Most patients had a clinical response after the first cycle, and those who did not show a response after the second cycle did not have a response to any further treatment. Therefore, the current recommendation is to continue treatment with high-dose IL-2 to the best response (up to 6 cycles) or until toxic effects become intolerable. Treatment should be discontinued after 2 cycles if the patient has had no regression. Combinations of IL-2 and interferon or other chemotherapeutic agents such as 5-fluorouracil (5-FU) have not been shown to be more effective than high-dose IL-2 alone.

Toxic effects associated with high-dose IL-2 are related to increased vascular permeability and secondary cytokine secretion (eg, IL-1, interferon gamma, tumor necrosis factor, nitric oxide). The management of high-dose IL-2 toxicities requires inpatient monitoring, often in an intensive care unit.

The major toxic effect of high-dose IL-2 is a sepsislike syndrome, which includes a progressive decrease in systemic vascular resistance and an associated decrease in intravascular volume due to capillary leak. Other toxic effects are fever, chills, fatigue, infection, and hypotension.

High-dose IL-2 has been associated with a 1-4% incidence of treatment-related death and should be offered only to patients with no cardiac ischemia or significant impairment of renal or pulmonary functions. Management includes judicious use of fluids and vasopressor support to maintain blood pressure and intravascular volume and at the same time to avoid pulmonary toxicity due to noncardiogenic pulmonary edema from the capillary leak. This syndrome is normally reversible.

Interferons

The interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. These agents have a direct antiproliferative effect on renal tumor cells in vitro, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules. Interferon alfa, which is derived from leukocytes, has an objective response rate of approximately 15% (range, 0-29%).

Interferons have been largely replaced by single-agent molecular targeted therapy. Single-agent interferon therapy is generally no longer used. Currently, the only established role for these agents is the use of interferon alfa in combination with bevacizumab as first- or second-line therapy for metastatic renal cell carcinoma.

The introduction of molecular-targeted therapy has essentially altered the management of advanced renal cell carcinoma (RCC). Molecular-targeted agents approved by the US Food and Drug Administration (FDA) for treatment of metastatic kidney cancer include the following:

• Sunitinib
• Bevacizumab in combination with interferon
• Pazopanib
• Temsirolimus
• Everolimus
• Lenvatinib in combination with everolimus
• Nivolumab (plus ipilimumab or cabozantinib)
• Avelumab in combination with axitinib
• Cabozantinib
• Sorafenib
• Axitinib
• Avelumab
• Pembrolizumab

These targeted agents have gained wide use as first-line, second-line, and subsequent-line therapy. The optimal sequence of their use as targeted agents is not yet defined, however.

The National Comprehensive Cancer Network (NCCN) currently recommends that for relapsed or stage IV clear cell kidney cancer, preferred first-line regimens for systemic therapy in favorable-risk patients are as follows ^[18] :

• Pazopanib
• Sunitinib
• Axitinib + pembrolizumab
• Cabozantinib + nivolumab

NCCN recommendations for poor-risk or intermediate-risk patients are as follows:

• Ipilimumab + nivolumab(category 1)
• Axitinib + pembrolizumab (category 1)
• Cabozantinib + nivolumab
• Cabozantinib

For subsequent therapy, preferred category 1 regimens are cabozantinib or nivolumab. For relapsed or stage IV non–clear cell kidney cancer, the NCCN recommends participation in a clinical trial. Sunitinib is the only preferred regimen.

Individual molecular-targeted agents are discussed below.

Sunitinib

Sunitinib (Sutent) is a multikinase inhibitor approved by the FDA for the treatment of metastatic kidney cancer that has progressed after a trial of immunotherapy. The receptor tyrosine kinases inhibited by sunitinib include vascular endothelial growth factor receptors 1,2, and 3 (VEGFR 1-3), platelet-derived growth factor receptor alpha (PDGFR-alpha), and PDGFR-beta. Approval of sunitinib was based on the high response rate (40% partial responses), a median time to progression of 8.7 months, and an overall survival of 16.4 months. ^[27]

The recommended dose of sunitinib for advanced RCC is one 50 mg oral dose taken once daily, with or without food, on a schedule of 4 weeks on treatment, followed by 2 weeks off treatment. ^[28]

In a phase III study in 750 patients with previously untreated metastatic RCC progression-free survival (PFS) was longer and response rates were higher in patients who received sunitinib than in those receiving interferon alfa (IFN-alfa). ^[29] In final survival analyses, the median overall survival (26.4 mo) and the objective response rate (47%) was greater in the sunitinib group than in the IFN-alfa group (21.8 mo and 12%, respectively). ^[30]

An expanded-access trial that provided sunitinib on a compassionate-use basis to 4564 trial-ineligible patients with RCC from countries where regulatory approval had not been granted suggested that the safety of sunitinib in these patients was manageable and its efficacy was encouraging, particularly in subgroups associated with poor prognosis (eg, those with brain metastases, low performance status, non–clear cell disease, and elderly patients). ^[31] Median PFS was 10.9 months and overall survival was 18.4 months (17.4-19.2 mo).

Hypertension induced by sunitinib may correlate with a significantly higher probability of response and better disease-free and overall survival. ^[32] Likewise, onset of hypothyroidism in patients treated with sunitinib may portend better response. ^[33]

Bevacizumab

The novel combination of bevacizumab (Avastin), which is a neutralizing monoclonal antibody to VEGF, and interferon has been shown to have activity against metastatic RCC. ^[34] A phase III trial by Escudier et al found bevacizumab plus interferon alfa-2a to be effective as first-line treatment in patients with metastatic RCC. ^[35] The FDA approved bevacizumab in combination with interferon alfa for the treatment of patients with metastatic RCC. ^[36]

In 2017, the FDA approved Mvasi (bevacizumab-awwb) as a biosimilar to Avastin (bevacizumab) to treat metastatic RCC, in combination with interferon alfa. The approval was based on supportive evidence from animal study data, human pharmacokinetic and pharmacodynamics data, and clinical immunogenicity data. ^[37]

Pazopanib

Pazopanib (Votrient) is a oral multi-kinase inhibitor that targets VEGFR, PDGFR, and c-Kit (stem cell receptor factor). The FDA approved pazopanib for the treatment of patients with advanced RCC in 2009.

A phase III randomized study of pazopanib 800 mg orally daily confirmed statistically and clinically meaningful improvement of PFS versus placebo (9.2 vs 4.2 months). The study enrolled 435 patients and randomized them to pazopanib or placebo in a 2:1 ratio; 233 (54%) of the patients were treatment naïve and 202 (46%) had prior cytokine therapy. In the treatment-naïve population, the difference in survival was much larger between pazopanib and placebo (11.1 vs 2.8 months).

Although final overall survival results showed no significant difference between the pazopanib and the placebo arms, extensive crossover from placebo to pazopanib confounded this analysis, and post-hoc analyses adjusting for crossover suggest an overall survival benefit with pazopanib. In this study pazopanib was well tolerated, with common adverse events including diarrhea (52%), hypertension (40%), hair color change (38%), nausea (26%), and anorexia (22%). ^[38]

In another phase III study, COMPARZ (Comparing the Efficacy, Safety, and Tolerability of Pazopanib vs Sunitinib) study, pazopanib was associated with a lower median overall survival (28.4 vs 29.3 months) and lower median PFS (8.4 vs 9.5 months) than sunitinib, but the differences were not considered statistically significant. COMPARZ included 1110 treatment-naive patients with clear cell metastatic RCC and measurable disease, who were randomly assigned to treatment with either oral pazopanib 800 mg daily with continuous dosing or oral sunitinib 50 mg daily administered in 6-week cycles (4 weeks on/2 weeks off). ^[39]

The pazopanib group had fewer dose interruptions of 7 days or more than did the sunitinib group (44% vs 49%) and fewer dose reductions (44% vs 51%); however, a higher proportion of patients in the pazopanib group discontinued the drug because of adverse events, primarily abnormalities in liver function tests (6% vs 1%). ^[39] On the other hand, in another phase III trial (PISCES), 70% of patients selected pazopanib due to better quality of life, while 22% preferred sunitinib. ^[40]

Temsirolimus

Temsirolimus (Torisel) inhibits mammalian target of rapamycin (mTOR), which is a serine/threonine kinase important in the regulation of cell growth and division. Genes involved with the response to hypoxia (hypoxia-inducible factor [HIF] pathway) are also upregulated by mTOR and are believed to be central to the pathogenesis of kidney cancers. The FDA has approved temsirolimus for the treatment of advanced RCC at an intravenous (IV) dose of 25 mg weekly until progression.

Temsirolimus has been tested alone and in conjunction with interferon in patients with poor-prognosis, advanced RCC. Temsirolimus monotherapy at an IV dose of 25 mg weekly resulted in longer overall and progression-free survival (median survival, 10.9 mo) compared with interferon (median survival, 7.3 mo). ^[41] There was no significant additive effect of interferon combined with temsirolimus. A second study combining temsirolimus and interferon over a range of dose levels showed overall survival of 18.8 months and PFS of 9.1 months for the combination. ^[42] Partial response was observed in 8% and stable disease in 36% of patients.

Common toxicities of temsirolimus include asthenia, rash, anemia, hypophosphatemia, and hyperlipidemia.

Lenvatinib

In 2016, the FDA approved lenvatinib (Lenvima) in combination with everolimus for advanced RCC following 1 prior antiangiogenic therapy. Approval was based on a randomized, phase II open-label, multicenter trial of 153 patients with advanced clear-cell RCC who had progressed on or within 9 months of stopping VEGF receptor–targeted therapy. PFS was significantly improved with lenvatinib in combination with everolimus compared with everolimus alone (14.5 mo vs 5.5 mo; P=0.0005). When the 2 monotherapies were analyzed, there was a modest improvement in PFS with lenvatinib 7.4 months (P=0.048). ^[43]

Lenvatinib is a small molecule tyrosine kinase inhibitor (TKI) that inhibits the kinase activities of VEGF receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). It also inhibits other tyrosine kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular function.

Everolimus

Everolimus (Afinitor) is a serine-threonine kinase inhibitor of mTOR. This agent is approved for use in advanced RCC after failure of treatment with sunitinib or sorafenib. ^[44]

In a randomized, double-blind, placebo-controlled, multicenter, phase III trial in patients with metastatic RCC that had progressed during sunitinib and/or sorafenib treatment, analysis showed significantly longer median pPFS with everolimus than with placebo. ^{[45, 46]} The median overall survival with everolimus was 14.8 months compared with 14.4 months for placebo; 80% of patients in the placebo arm crossed over to everolimus. ^[45]

A pooled analysis of four prospective, non-interventional studies provided evidence that everolimus can be safe and effective for second-line treatment of metastatic RCC refractory to anti-VEGF therapy. In the analysis, which included a total of 632 patients in whom one or two anti-VEGF therapies had failed, median time to progression was 6.3 months for the overall study population and 6.4 months for patients treated with second-line everolimus. Median PFS was 5.5 months for the overall population and 5.8 months for the everolimus group. ^[47]

The most common toxicities associated with everolimus are stomatitis, infections, asthenia, fatigue, cough, and diarrhea. ^[44]

Nivolumab

Nivolumab (Opdivo) is a monoclonal antibody to programmed cell death–1 protein (PD-1). In 2015, nivolumab gained a new indication in the US for patients with advanced RCC whose disease progressed despite prior antiangiogenic therapy (ie, with VEGF inhibitors). Approval was based on the Checkmate-025 trial, which showed improved overall survival and fewer grade 3 or 4 adverse events than everolimus in a randomized, open-label, study of 821 patients with advanced clear-cell RCC who had received previous treatment with one or two regimens of antiangiogenic therapy. Median overall survival was 25.0 months with nivolumab and 19.6 months with everolimus (hazard ratio, 0.73; P = 0.002). Additionally, the objective response rate was 25% for nivolumab compared with 5% for everolimus (P < 0.001). ^[48]

In 2018, the FDA approved nivolumab plus ipilimumab for intermediate- and poor-risk patients with previously untreated advanced RCC. The combination of nivolumab with ipilimumab yielded significantly higher overall survival and objective response rates, compared with sunitinib, in the phase III CheckMate 214 trial. At a median follow-up of 25.2 months, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70-78%) with nivolumab plus ipilimumab (n=425), compared with 60% (95% CI, 55-65%) with sunitinib (n=422); the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P < 0.001). The objective response rate was 42% versus 27% (P < 0.001), and the complete response rate was 9% versus 1%. ^[49]

Cabozantinib

Cabozantinib (Cabometyx) is a small-molecule tyrosine kinase inhibitor. In 2016, cabozantinib was approved for advanced RCC in patients who have received prior antiangiogenic therapy. Approval was based on a randomized, open-label study of 658 patients with RCC who had progressed after VEGF receptor–targeted therapy. Treatment with the cabozantinib significantly improved progression-free survival compared with everolimus. Median progression-free survival was 7.4 months with cabozantinib treatment versus 3.8 months with everolimus (P< 0.0001). Median overall survival also significantly improved with cabozantinib compared with everolimus (21.4 mo vs 16.5 mo; P=0.0003). However, cabozantinib had significant side effects that necessitated a dose reduction in 60% or more of patients. ^[50]

In 2017, the FDA approved cabozantinib for first-line treatment of advanced RCC. Approval was based on findings from the CABOSUN trial, a randomized, open-label phase II multicenter study. The study enrolled 157 patients with intermediate- and poor-risk previously untreated RCC. Patients received either cabozantinib or sunitinib daily (4 weeks on treatment followed by 2 weeks off) until disease progression or unacceptable toxicity. Estimated median PFS for patients taking cabozantinib was 8.6 months compared with 5.3 months for patients taking sunitinib. ^[51]

METEOR, a randomized phase III trial in patients with advanced RCC after prior antiangiogenic therapy, found that cabozantinib was superior to everolimus in terms of longer PFS  (7.4 vs 3.9 months, respectively; P <  0.0001), overall survival (21.4 vs 16.5 months, respectively; P = 0.0003), and objective response rate. In addition, low baseline levels of hepatocyte growth factor (HGF) was a consistent biomarker for improved PFS or overall survival with either cabozantinib or everolimus. ^[52]

Nivolumab plus cabozantinib

In February 2021, the FDA approved nivolumab plus cabozantinib for first-line treatment of advanced RCC. Approval was based on preliminary data from the phase III CheckMate-9ER trial, which randomized patients (n=651) with previously untreated advanced or metastatic RCC with clear cell histology at any risk level to receive either nivolumab plus cabozantinib or sunitinib. The nivolumab-plus-cabozantinib arm had a higher median PFS (16.6 months [95% CI:12.5-24.9]) compared with the sunitinib-treated arm (8.3 months [95% CI: 7-9.7]). Median overall survival was not reached in either arm. Risk of death in the nivolumab/cabozantinib-treated arm was 40% lower than in the sunitinib-treated arm. ^[53]

Three-year follow-up of CheckMate-9ER continued to demonstrate the superiority of nivolumab plus cabozantinib over sunitinib, with median overall survival of 49.5 months versus 35.5 months, respectively. Median overall survival improved by 11.8 months since the previous data cutoff, at a median follow-up of 32.9 months. The median PFS was 16.6 months with nivolumab plus cabozantinib versus 8.4 months with sunitinib. Benefits of nivolumab plus cabozantinibwere observed regardless of the tumor programmed death ligand 1 (PD-L1) status. ^[54]

Sorafenib

Sorafenib (Nexavar), a small-molecule Raf kinase and VEGF multireceptor kinase inhibitor, is approved by the FDA for the treatment of patients with advanced RCC. This indication was based on the demonstration of improved progression-free survival in a large, multinational, randomized, double-blind, placebo-controlled phase 3 study and a supportive phase 2 study. ^{[55, 56]}

The safety and efficacy of sorafenib were also demonstrated in a nonrandomized, open-label expanded access program in which 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Patients included those with no previous therapy, nonclear cell renal cell carcinoma, brain metastases, and previous bevacizumab treatment; and elderly patients. Median overall survival was 50 weeks. ^[57]

Sorafenib targets serine/threonine and receptor tyrosine kinases, including those of Raf, VEGFR-2, VEGFR-3, PDGFR-beta, c-KIT, fmslike tyrosine kinase–3 (FLT-3); and the glial cell-line–derived neurotrophic factor receptor (RET). A study by Verma et al concluded that the use of tyrosine kinase inhibitors reduces the incidence of brain metastasis among patients with metastatic renal cell carcinoma. ^[58]

The recommended sorafenib dose is 400 mg (two 200-mg tab) twice daily taken either 1 hour before or 2 hours after meals. Adverse events were accommodated by temporary dose interruptions or reductions to 400 mg once daily or 400 mg every other day.

Hypertension is a common side effect of sorafenib treatment, and may be high grade. ^[59] Physicians should be aware of the importance of frequent blood pressure monitoring and management, especially during the first 6 weeks after starting sorafenib.

Sorafenib toxicities (based on an updated phase III study database of 902 patients) include reversible skin rashes in 40% and hand-foot skin reaction in 30%. Diarrhea was reported in 43%, treatment-emergent hypertension in 17%, and sensory neuropathic changes in 13%. Alopecia, oral mucositis, and hemorrhage were also reported more commonly in the sorafenib arm. The incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib group (2.9%) compared with the placebo group (0.4%). Hypothyroidism is another potential toxicity of sorafenib. ^[33]

Axitinib

Axitinib (Inlyta) inhibits tyrosine kinase receptors including VEGFR-1, VEGFR-2, and VEGFR-3. Axitinib is 50-450 times more potent than first-generation VEGF inhibitors in inhibiting those VEGF receptors. The FDA approved axitinib in January 2012 for treatment of advanced RCC after failure of one prior systemic therapy.

The approval was based on a single efficacy study, (AXIS trial), in which axitinib extended PFS by 2 months more than sorafenib (6.7 mo vs 4.7 mo, P < 0.0001) and produced a superior objective response rate (19.4% vs 9.4%). ^[60] AXIS was a randomized, controlled, open-label, multicenter phase III trial in 723 patients with advanced renal cell carcinoma who had failed one previous therapy. Severe toxicity requiring discontinuation of therapy was less prevalent in the axitinib group (4% vs 8%). This study is the only published phase 3 head-to-head comparison of VEGF-targeted agents.

Pembrolizumab

Pembrolizumab (Keytruda), a PD-1 inhibitor, gained accelerated FDA approval in 2019 for first-line treatment of advanced RCC in combination with axitinib.

In the open-label KEYNOTE-426 trial, which included 861 patients, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and PFS, as well as a higher objective response rate, than treatment with sunitinib. The estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab–axitinib group and 78.3% in the sunitinib group (hazard ratio [HR] for death, 0.53; P < 0.0001). Median PFS was 15.1 months in the pembrolizumab–axitinib group and 11.1 months in the sunitinib group (HR for disease progression or death, 0.69; P < 0.001). The objective response rates with pembrolizumab–axitinib and sunitinib were 59.3% versus 35.7%, respectively (P < 0.001). The overall frequency of toxic effects was similar in the two groups. ^[61]  

In November 2021, the FDA approved pembrolizumab for the adjuvant treatment of patients with RCC who are at intermediate-high or high risk of disease recurrence following nephrectomy or nephrectomy and resection of metastatic lesions. Approval was based on interim analysis of results of the KEYNOTE-564 trial that demonstrated statistically significant improvement in disease-free survival compared with placebo. ^[62]

Avelumab

In 2019, the FDA approved the combination of avelumab and axitinib for the frontline treatment of patients with advanced RCC.

Approval was based on the results from the phase 3 JAVELIN Renal 101 study (n=886), in which median PFS was 13.8 months with avelumab plus axitinib, as compared with 8.4 months with sunitinib (HR, 0.69; P < 0.001). Median PFS with avelumab plus axitinib was the same regardless of whether the tumor was PD-L1–positive; with sunitinib, however, median PFS in PD-L1 positive tumors was 7.2 months. In the patients with PD-L1–positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib. ^[63]

Experimental multikinase inhibitors

Lapatinib is an epidermal growth factor receptor (EGFR) and ErbB-2 dual tyrosine kinase inhibitor that appears to have efficacy in the treatment of tumors that overexpress EGFR, including RCC. A phase 3 study in patients with advanced RCC whose disease had failed previous therapy found that lapatinib was well tolerated and had overall efficacy equivalent to that of hormonal therapy. ^[64]

Molecular therapy in early-stage disease

For early-stage RCC, an emerging treatment strategy is to utilize molecular approaches earlier in the adjuvant setting in order to improve overall survival rates. However, interim analysis of a randomized phase 3 trial of sunitinib versus sorafenib versus placebo as adjuvant therapy in patients with resected RCC showed no difference in disease-free or overall survival. The investigators concluded that patients with locally advanced resected renal cell carcinoma should not be given adjuvant treatment. ^[65]

In contrast, another study by S-TRAC investigators demonstrated that patients at high risk for tumor recurrence after nephrectomy may benefit from adjuvant therapy with sunitinib. The median duration of disease-free survival was significantly longer in those who took 50 mg of sunitinib daily for 4 weeks on/2 weeks off schedule for 1 year following nephrectomy. Survival data was not mature at the time of analysis for this study. ^[66]

For patients with stage II or III RCC who have undergone nephrectomy (radical or partial), NCCN recommendations for adjuvant therapy in those with clear cell histology and high-risk features include sunitinib as a category 2B option. However, the NCCN's preferred strategy in those cases is participation in a clinical trial. Surveillance is also an option. ^[18]

The following chemotherapeutic agents all have been used in advanced renal cell cancer (RCC):

• Floxuridine (5-fluoro 2'-deoxyuridine [FUDR])
• 5-fluorouracil (5-FU)
• Vinblastine
• Paclitaxel (Taxol)
• Carboplatin
• Ifosfamide
• Gemcitabine
• Doxorubicin

Floxuridine infusion has a mean response rate of 12%, whereas vinblastine infusion yielded an overall response rate of 7%. 5-FU alone has a response rate of 10%, but when used in combination with interferon, it had a 19% response rate in some studies.

A phase II trial of weekly intravenous (IV) gemcitabine (600 mg/m² on days 1, 8, and 15) with continuous infusion 5-FU (150 mg/m²/d for 21 days in a 28-day cycle) in patients with metastatic RCC produced a partial response rate of 17%. ^[67] No complete responses were noted. Eighty percent of patients had multiple metastases, and 83% had received previous treatment. The mean progression-free survival duration of 28.7 weeks was significantly longer than that of historic controls. ^[67]

RCC is refractory to most chemotherapeutic agents because of multidrug resistance mediated by p-glycoprotein. Normal renal proximal tubules and RCC both express high levels of p-glycoprotein. Calcium channel blockers or other drugs that interfere with the function of p-glycoprotein can diminish resistance to vinblastine and anthracycline in human RCC cell lines.

Other experimental approaches for treatment of renal cell carcinoma (RCC) include the following ^[68] :

• Immunomodulatory drugs (eg, lenalidomide)
• Vaccines
• Nonmyeloablative allogeneic peripheral blood stem-cell transplantation
• Megestrol and antiestrogens

Lenalidomide

The immunomodulator lenalidomide (Revlimid), a derivative of thalidomide, inhibits vascular endothelial growth factor (VEGF), stimulates T and natural killer (NK) cells, and inhibits inflammatory cytokines. This agent has been evaluated extensively in hematologic malignancies. In phase II studies of metastatic RCC, lenalidomide demonstrated an antitumor effect in some cases, with disease stabilization or durable partial response. ^{[69, 70]}

Vaccines

Vaccine trials are in early stages of development. Few antigens have been identified that induce T-cell responses from RCC. One example of vaccine strategy is to induce the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) into autologous cultured renal cell cancer lines by retroviral transduction. Patients are then immunized with irradiated tumor cells secreting large amounts of GM-CSF and are evaluated for immune responses and clinical tumor regression. Other approaches to vaccination include tumor lysates and dendritic cells.

The experimental agent AGS-003 is produced by extracting messenger RNA from a sample of a patient's tumor (obtained at the time of nephrectomy) and incorporating it into the patient's dendritic cells (obtained during a single leukapheresis procedure), thereby providing personalized immunotherapy. In a single-group phase II study of 21 patients with metastatic RCC, combination therapy with AGS-003 and sunitinib prolonged expected survival time. ^[71]

For intermediate-risk patients, median overall survival was 39.5 months, versus 20.7 months reported in a different trial in which sunitinib was used alone; comparable survival figures for poor-risk patients were 9.1 versus 5.8 months. ^[71] This evidence of prolonged survival prompted a larger phase III trial; however, this was terminated due to lack of efficacy.

Autologous vaccine therapy is now being tried in combination with cytokine therapy. A pilot study of vaccinating with the corresponding mutant von Hippel-Lindau peptides demonstrated safety and proved efficacy in generating a specific immune response in patients with advanced renal cell carcinoma. ^[72]

Nonmyeloablative allogeneic stem cell transplantation

Nonmyeloablative allogeneic stem cell transplantation can induce sustained regression of metastatic renal cell carcinoma in patients who have had no response to conventional immunotherapy. In one trial, 19 patients with refractory metastatic renal cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of peripheral blood stem cells from a human leukocyte antigen (HLA) – identical sibling or a sibling with a mismatch of a single HLA antigen. ^[73] Patients with no response received as many as three infusions of donor lymphocytes.

Two patients died of transplantation-related causes, and eight died from progressive disease. In 10 patients (53%), metastatic disease regressed; three patients had a complete response, and seven had a partial response. ^[73] The durations of these responses continue to be assessed. Further trials are needed to confirm these findings and to evaluate long-term benefits.

Megestrol and antiestrogens

Multiple studies have been conducted using megestrol (Megace) in the treatment of renal cell carcinoma. No benefit has been shown except for appetite stimulation, so megestrol is currently not recommended. Antiestrogens such as tamoxifen (100 mg/m²/d or more) and toremifene (300 mg/d) have also been tried, with a response rate as low as that of most chemotherapeutic agents.  With the availability of targeted therapy that improves survival, the role of hormonal therapy is unclear; in the author's opinion, these agents should not be considered as a part of the routine treatment algorithm. 

Radiation therapy may be considered as the primary therapy for palliation in patients whose clinical condition precludes surgery, because of either extensive disease or poor overall condition. A dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy. Preoperative radiation therapy yields no survival advantage.

A study of curative-intent stereotactic body radiaiton therapy (SBRT) in 74 patients with medically inoperable localized renal cell carcinoma reported favorable oncologic outcomes, with a 4-year cumulative incidence of local failure of 7.77%, respectively and a cumulative incidence of distant metastasis at 2 years of 4.24%. The proportion of overall kidney function in the involved kidney decreased from 47% pre-SBRT to 36% at 2 years, but the proportion of contralateral kidney's contribution to kidney function improved correspondingly. ^[74] Stereotactic radiation therapy also has an emerging role in ablation of extracranial oligometastatic renal cell carcinoma. ^[75]

Palliative radiation therapy is often used for local or symptomatic metastatic disease, such as painful osseous lesions or brain metastasis, to halt potential neurologic progression. Surgery should also be considered for solitary brain or spine lesions, followed by postoperative radiotherapy.

About 11% of patients develop brain metastasis during the course of their disease. Renal cell carcinoma is a radioresistant tumor, but radiation treatment of brain metastasis improves quality of life, local control, and overall survival duration. Patients with untreated brain metastasis have a median survival time of 1 month, which can be improved with glucocorticoid therapy and brain irradiation. Stereotactic radiosurgery is more effective than surgical extirpation for local control and can be performed on multiple lesions.

Renal artery embolization with ethanol and gelatin sponge pledgets has been found effective for palliative treatment in patients who are not candidates for surgery, or who refuse surgery. A retrospective study in 8 patients with stage IV disease found that ethanol ablation controlled hematuria and flank pain. ^[76]

It is recommended that patients avoid causative factors such as smoking, obesity, occupational exposures, and other factors, as described in Etiology.

Careful surveillance by ultrasonography and computed tomography scanning is recommended for patients with end-stage renal disease or von Hippel-Lindau disease, those who have undergone kidney transplantation, and other high-risk groups.

According to American Urological Association management guidelines, active surveillance is a reasonable choice for selected patients for management of localized renal masses. For patients with decreased life expectancy or numerous comorbidities that would make them high risk for intervention, active surveillance is recommended as first choice.

For patients who are candidates for intervention, counseling about active surveillance should include a frank discussion of the small but real risk of cancer progression, the lack of curative therapies if metastases develop, the possible loss of a chance for nephron-sparing surgery, and the limited data on active surveillance. Larger tumors (> 3-4 cm) and those with an aggressive appearance (eg, infiltrative growth pattern) may pose increased risk and should be managed in a proactive manner if possible. ^[19]

For stage I and II renal cell carcinoma, a complete history, physical examination, chest radiographs, liver function tests, blood urea nitrogen (BUN) and creatinine levels, and calcium levels are recommended every 6 months for 2 years, then annually for 5 years. Abdominal computed tomography (CT) scanning is recommended once at 4-6 months and then as indicated.

For stage III renal cell carcinoma, physical examination, chest radiographs, liver function tests, BUN and creatinine levels, and calcium levels are recommended every 4 months for 2 years, every 6 months for 3 years, and then annually for 5 years. Abdominal CT scanning should be performed at 4-6 months, then annually or as indicated.

Spontaneous regression has been reported anecdotally in renal cell carcinoma. As many as 10% of patients with metastatic disease show no progression for more than 12 months. All systemic therapies are associated with treatment-related toxicity and low response; therefore, close observation is an option for asymptomatic metastatic disease. Once evidence of progression or symptoms appears, appropriate therapy should be initiated.

Careful surveillance of patients with end-stage renal disease by ultrasonography and CT scanning is recommended. ^[19]