Renal Cell Carcinoma

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Practice Essentials

Renal cell carcinoma (see the image below) is the most common type of kidney cancer in adults.[1] It accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney.



View Image

Typical renal cell carcinoma. CT scan obtained before contrast enhancement has an attenuation measurement of 33.9 HU.

See Renal Cell Carcinoma: Recognition and Follow-up, a Critical Images slideshow, to help evaluate renal masses and determine when and what type of follow-up is necessary.

Signs and symptoms

Renal cell carcinoma may remain clinically occult for most of its course. Only 10% of patients present with the classic triad of flank pain, hematuria, and flank mass.

Other signs and symptoms include the following:

See Clinical Presentation for more detail.

Diagnosis

Lab studies used for diagnosis of renal cell carcinoma include the following:

Imaging studies used to evaluate and stage renal masses may include the following:

See Workup for more detail.

Management

The principal treatment options for renal cell cancer are as follows:

Surgical resection remains the only known curative treatment for localized renal cell carcinoma, and it is also used improve outcome or for palliation in metastatic disease. Targeted therapy and immunomodulatory agents are considered standard of care in patients with metastatic disease. Chemotherapy is used only occasionally, in certain tumor types. Experimental treatment approaches include vaccines and nonmyeloablative allogeneic peripheral blood stem cell transplantation.

See Treatment and Medication for more detail.

Background

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. This disease is characterized by a lack of early warning signs, diverse clinical manifestations (see Presentation), and resistance to radiation and chemotherapy.[2, 3, 4]

Increasingly, renal cell cancers are diagnosed at an earlier stage, and nephron-sparing surgery, thermal ablation, and surveillance are gaining acceptance as a treatment of choice for smaller tumors. Radical nephrectomy is the standard for larger and central tumors. (See Treatment.)

In recent years, multiple agents have been developed for systemic treatment of metastatic disease. Although the optimal treatment strategy continues to evolve, three agents that target angiogenesis (sunitinib, bevacizumab/interferon, and pazopanib) and a mammalian target of rapamycin (mTOR)–targeted therapy (temsirolimus) are approved as front-line agents. For selected patients, cabozantinib or combination therapy with nivolumab plus ipilimumab are also used as first-line treatments. Finally, high-dose interleukin-2 (IL-2) and axitinib can be used in selected patients.

A number of agents are available to be used in second and subsequent lines of therapy, these include anti-angiogenic therapy (if not already used in first-line treatment), nivolumab, cabozantinib, and mTOR inhibitors. Recommendations regarding how to sequence approved agents during subsequent therapy are evolving; more work is needed. Clinical trials are currently exploring future directions, including combinations of approved agents and the optimal sequencing of these agents.

Go to Clear Cell Renal Cell Carcinoma and Sarcomatoid and Rhabdoid Renal Cell Carcinoma for complete information on these topics.

Pathophysiology

The tissue of origin for renal cell carcinoma (RCC) is the proximal renal tubular epithelium. Renal cancer occurs in a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET).

Multiple hereditary syndromes associated with renal cell carcinoma are recognized, as follows:

von Hippel-Lindau syndrome

von Hippel-Lindau syndrome, or von Hippel-Lindau disease, is an autosomal dominant syndrome that confers predisposition to a variety of neoplasms, including the following:

Renal cell carcinoma develops in nearly 40% of patients with von Hippel-Lindau disease and is a major cause of death in these patients. Deletions of chromosome 3p occur commonly in renal cell carcinoma associated with von Hippel-Lindau disease. Chromosome 3p contains several of the genes associated with kidney cancer, including BAP-1 and PBRM-1, among others.  

The VHL gene is mutated in a high percentage of tumors and cell lines from patients with sporadic (nonhereditary) clear cell renal carcinoma. Several kindreds with familial clear cell carcinoma have a constitutional balanced translocation between 3p and either chromosome 6 or chromosome 8.

Mutations of the VHL gene result in the accumulation of hypoxia-inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor (VEGF) and its receptor (VEGFR). VEGF and VEGFR are important new therapeutic targets.

Hereditary papillary renal carcinoma

Hereditary papillary renal carcinoma is an inherited disorder with an autosomal dominant inheritance pattern; affected individuals develop bilateral, multifocal papillary renal carcinoma. Germline mutations in the tyrosine kinase domain of the MET gene have been identified.

Familial renal oncocytoma and Birt-Hogg-Dube syndrome

Individuals affected with familial renal oncocytoma can develop bilateral, multifocal oncocytoma or oncocytic neoplasms in the kidney. Birt-Hogg-Dube syndrome is a hereditary cutaneous syndrome. Patients with Birt-Hogg-Dube syndrome have a dominantly inherited predisposition to develop benign tumors of the hair follicle (ie, fibrofolliculomas), predominantly on the face, neck, and upper trunk, and these individuals are at risk of developing renal tumors, colonic polyps or tumors, and pulmonary cysts.

Hereditary renal carcinoma

Affected individuals with this inherited medical condition have an increased tendency to develop oncocytomas, benign kidney tumors that have a low malignant potential.

Renal carcinoma patients diagnosed at 45 years or younger and those with family history of kidney cancer should receive genetic counseling.

Etiology

A number of environmental and genetic factors have been studied as possible causes for renal cell carcinoma (RCC). Cigarette smoking doubles the risk of renal cell carcinoma and contributes to as many as one third of all cases. The risk appears to increase with the amount of cigarette smoking in a dose-dependent fashion. Smoking has also been associated with advanced disease at presentation. 

Obesity is a risk factor, particularly in women. Increasing body weight has a linear relationship with increasing risk. Hypertension is a possible risk factor.

Occupational exposure to certain chemicals, such as trichloroethylene, has been linked to increased risk for renal cell carcinoma.[1] In addition, the risk of renal cell carcinoma increases with duration of exposure to benzene, benzidine, cadmium, herbicides and vinyl chloride.[5]

A prospective evaluation by Cho et al concluded that longer duration of use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for renal cell cancer.[6] Phenacetin-containing analgesics taken in large amounts may be associated with increased incidence of renal cell carcinoma; this agent is no longer approved for use in the United States.

Patients undergoing long-term renal dialysis have an increased incidence of acquired cystic disease of the kidney, which predisposes to renal cell cancer. In renal transplant recipients, acquired renal cystic disease also predisposes to renal cell cancer. Chronic hepatitis C infection[7]  and, according to meta-analysis of pooled data, kidney stones in males[8] are associated with higher incidences of kidney cancer. 

Genetic disorders associated with renal cell carcinoma include von Hippel-Lindau syndrome, hereditary papillary renal carcinoma, Birt-Hogg-Dube syndrome, and hereditary renal carcinoma. The genetic disease tuberous sclerosis appears to be associated with renal cell carcinoma, although the exact nature of the association is unclear.   

Epidemiology

From 1975 to 2008, the incidence of kidney cancer rose fairly steadily in the United States, from 7 to 16 cases per 100,000 population.[9]  The increase appears to have been due in part to increased incidental detection because of the wider use of medical imaging. More recently, the increase has slowed, with incidence rates increasing by about 1% per year from 2006 to 2015.[1]  

Currently, cancers of the kidney and renal pelvis are the sixth most common cancer in US men, accounting for 5% of cases, and the eighth most common in US women, accounting for 3% of cases. The American Cancer Society estimates that in 2019 there will be 73,820 cases (44,120 in males and 29,700 in females) of malignant tumors of the kidney diagnosed, with 14,770 deaths (9820 in males and 4950 in females).[1] Renal cell carcinoma is expected to account for 80% of this incidence and mortality.

In most of Europe, the incidence of kidney cancer has decreased or stabilized over the past decade, perhaps in part because of reduced tobacco smoking in men. Mortality from kidney cancer has also declined in most of Europe, principally in Scandinavia and other western European countries. In men, the mortality rate per 100,000 population fell from 4.8 in 1990-1994 to 4.1 in 2000-2004; in women, the rate fell from 2.1 to 1.8.[10]

Renal cell carcinoma is more common in people of Northern European ancestry (Scandinavians) and North Americans than in those of Asian or African descent. In the United States, the incidence is slightly higher in blacks than in whites: 25.0 versus 21.9 per 100,000 population in men, and 12.6 versus 11.0 per 100,000 population in women.[9]

The median age at diagnosis from 2010 to 2015 was 64 years. In familial clusters, however, the disease has been reported in younger people.[9]

Prognosis

In the United States, death rates from kidney and renal pelvis cancer have been falling on average 0.7% annually over 2006-2015; these cancers currently constitute the twelfth leading cause of cancer death.[9]  The 5-year survival rates initially reported by Robson in 1969 were 66% for stage I renal carcinoma, 64% for stage II, 42% for stage III, and only 11% for stage IV.[11, 12] Except for stage I, these survival statistics have remained essentially unchanged for several decades.

Survival in renal cell carcinoma

After radical nephrectomy for stage I renal cell carcinoma, the 5-year survival rate is approximately 94%. Patients with stage II lesions have a survival rate of 79%. A tumor confined to the kidney is associated with a better prognosis. A study by Heng et al found that progression-free survival at 3 and 6 months predicted overall survival among patients with metastatic renal cell carcinoma.[13]

By T stage, the 5-year disease-specific survival rates in patients with renal carcinoma are as follows:

Patients with regional lymph node involvement or extracapsular extension have a survival rate of 12-25%. Although renal vein involvement does not have a markedly negative effect on prognosis, the 5-year survival rate for patients with stage IIIB renal cell carcinoma is 18%. In patients with effective surgical removal of the renal vein or inferior vena caval thrombus, the 5-year survival rate is 25-50%.

Unfortunately, 5-year survival rates for patients with stage IV disease are low (0-20%).

Survival prognostic factors

Motzer et al identified 5 prognostic factors for predicting survival in patients with metastatic renal cell carcinoma.[14] These factors were used to categorize patients with metastatic renal cell carcinoma into 3 risk groups. Patients in the favorable-risk group (zero risk factors) had a median survival of 20 months, and patients with intermediate risk (1 or 2 risk factors) had a median survival of 10 months, whereas patients in the poor-risk group (3 or more risk factors) had a median survival of only 4 months. Heng et al validated and further developed risk criteria for metastatic renal cell carcinoma patients treated with vascular endothelial growth factor–targeted therapies and found the following prognostic criteria[15] :

The following are factors associated with increased survival in patients with metastatic disease:

In addition, Albiges and colleagues identified obesity as a favorable prognostic factor in patients with metastatic renal cell carcinoma treated with targeted therapy. In a study of 1975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), median overall survival was 25.6 months in patients with a body mass index (BMI) of 25 kg/m2 or higher, compared with 17.1 months in patients with a BMI of less than 25 kg/m2. The adjusted hazard ratio (HR) for obesity was 0.84.[16, 17]

Review of an external validation cohort of 4657 patients treated for kidney cancer in clinical trials from 2003 to 2013 also demonstrated longer overall survival in obese patients, with median overall survivals of 23.4 months versus 14.5 months for those with low BMI.[16, 17]

The longer survival may relate to the fatty acid synthase (FASN) pathway. FASN acts as a metabolic oncogene and its overexpression has been associated with poor prognosis in renal cell carcinoma and other types of cancers. FASN was downregulated in overweight and obese patients in this study..[16, 17]

Patient Education

Patients with a family history of genetic syndromes associated with increased risk for renal cell carcinoma should be educated about these syndromes, and genetic counseling should be offered to the patients and family members. For example, renal cell carcinoma develops in nearly 40% of patients with von Hippel-Lindau (VHL) disease and is a major cause of death in patients with that disorder/

Patients at high risk should be made aware of the early signs and symptoms of the disease, and the need for early intervention for possible cure should be stressed. For patients with early-stage disease who have undergone treatment, education about possible relapse should be provided.

For patient education information, see the Cancer and Tumors Center, as well as Blood in the Urine and Renal Cell Cancer.

History

Renal cell carcinoma (RCC) may remain clinically occult for most of its course. The classic triad of flank pain, hematuria, and flank mass is uncommon (10%) and is indicative of advanced disease. Twenty-five to thirty percent of patients are asymptomatic, and their renal cell carcinomas are found on incidental radiologic study.

The frequency of the individual components of the classic triad is as follows:

Other signs and symptoms include the following:

Renal cell carcinoma is a unique and challenging tumor because of the frequent occurrence of paraneoplastic syndromes, including hypercalcemia, erythrocytosis, and nonmetastatic hepatic dysfunction (ie, Stauffer syndrome). Polyneuromyopathy, amyloidosis, anemia, fever, cachexia, weight loss, dermatomyositis, increased erythrocyte sedimentation rate (ESR), and hypertension are also associated with renal cell carcinoma.

Cytokine release by tumor (eg, interleukin (IL)-6, erythropoietin, nitric oxide) causes these paraneoplastic conditions. Resolution of symptoms or biochemical abnormalities may follow successful treatment of the primary tumor or metastatic foci. (Go to Paraneoplastic Syndromes for more information.)

Physical Examination

Approximately 30% of patients with renal carcinoma (RCC) present with metastatic disease. The physical examination should include a thorough evaluation for metastatic disease, particularly in the following organs:

The presence of a varicocele and findings of paraneoplastic syndromes should raise clinical suspicion for this diagnosis. In addition, look for hypertension, supraclavicular adenopathy, and a flank or abdominal mass with bruit. However, gross hematuria with vermiform clots suggests upper urinary tract bleeding.

Staging

The following are briefly discussed in this section:

Robson staging system

The Robson modification of the Flocks and Kadesky system is uncomplicated and is commonly used in clinical practice. This system was designed to correlate stage at presentation with prognosis and is as follows:

TNM classification

The TNM classification is endorsed by the AJCC. The major advantage of this system is that it clearly differentiates individuals with tumor thrombi from those with local nodal disease. In the Robson system, stage III disease includes both inferior vena caval involvement (stage IIIA) and local lymph node metastases (stage IIIB). Although patients with Robson stage IIIB renal carcinoma have greatly decreased survival rates, the prognosis for patients with stage Robson IIIA renal carcinoma is not markedly different from that for patients with Robson stage I or II renal carcinoma. The TNM classification system is delineated below.

Primary tumors (T) are defined as the following:

Regional lymph node (N) classification is not affected by laterality and is defined as follows:

Distant metastasis (M) is defined as the following:

AJCC staging system

The AJCC stages are as follows:

The division of patients with renal cell carcinoma into low-, intermediate-, and high-risk groups with or without metastases may be useful in choosing appropriate therapy for these individuals.[2, 18]

For more information, see Renal Cell Carcinoma Staging.

Approach Considerations

With the increasing utilization of imaging studies, renal cell carcinoma (RCC) is increasingly detected incidentally, as a suspicious mass on abdominal computed tomography (CT) or ultrasound.[19] Fewer patients present with symptomatic disease (eg, gross hematuria, flank mass or pain).

RCC is remarkable for the frequent occurrence of paraneoplastic syndromes, including hypercalcemia, erythrocytosis, and nonmetastatic hepatic dysfunction (ie, Stauffer syndrome). Thus, laboratory studies in the evaluation of RCC should include a workup for paraneoplastic syndromes.

A number of imaging modalities are used to evaluate and stage suspected renal cancer, including the following:

Determining whether a space-occupying renal mass is benign or malignant can be difficult. Imaging studies should be tailored to enable further characterization of renal masses, so that nonmalignant tumors can be differentiated from malignant ones.

Contrast-enhanced CT scanning has become the imaging procedure of choice for diagnosis and staging of renal cell cancer and has virtually replaced excretory urography and renal ultrasonography. Ultrasonographic examination can be useful in evaluating questionable cystic renal lesions if CT imaging is inconclusive. Large papillary renal tumors are frequently undetectable by renal ultrasonography.

Excretory urography is not used frequently in the initial evaluation of renal masses because of its low sensitivity and specificity. A small- to medium-sized tumor may be missed by excretory urography.

Renal arteriography is not used in the evaluation of a suspected renal mass as frequently now as it was in the past. When inferior vena cava involvement is suspected, either inferior venacavography or magnetic resonance angiography (MRA) is used. MRA is currently the preferred imaging technique. Knowledge of inferior vena cava involvement is important in planning the vascular aspect of the operative procedure.

Positron emission tomography (PET) imaging remains controversial in kidney cancer. Currently, PET is not considered a standard part of the diagnosis of kidney cancer or in follow-up for evidence of relapse after nephrectomy.[20] PET has a better sensitivity for detecting metastatic lesions than for determining the presence of cancer in the renal primary site.

When clinically indicated, bone scans are used both in inital workup and follow-up. A bone scan is recommended for patients with pain or an elevated alkaline phosphatase level.[20]

For more information, see Renal Cell Carcinoma Imaging.

Initial Laboratory Studies

The following are initial laboratory studies in the evaluation of suspected renal cell carcinoma (RCC):

Computed Tomography and Magnetic Resonance Imaging

Contrast-enhanced computed tomography (CT) scanning has become the imaging procedure of choice for diagnosis and staging of renal cell cancer and has virtually replaced excretory urography and renal ultrasonography. In most cases, CT imaging can differentiate cystic masses from solid masses and supplies information about lymph node, renal vein, and inferior vena cava involvement.

The 2009 American Urological Association (AUA) guideline for the management of the clinical T1 renal mass recommends a high-quality cross-sectional CT or MRI, first without and then with intravenous contrast if renal function is adequate. The objectives are as follows.[21] :

The National Comprehensive Cancer Network (NCCN) guidelines for kidney cancer recommend the following as part of the initial workup[20] :

The NCCN guideline recommends abdominal MRI to assess suspected tumor involvement in the inferior vena cava, or as an alternative to CT for renal mass detection and staging in cases where the use of contrast is contraindicated because of allergy or renal insufficiency.[20]

A study by Sauk et al concluded that multidetector CT imaging characteristics may aid in identifying differences at the cytogenic level among patients with clear cell renal cell carcinomas. Imaging features that proved significant included degree of attenuation and presence of calcifications.[22]

Percutaneous Biopsy

Percutaneous cyst puncture and fluid analysis is used in the evaluation of potentially malignant cystic renal lesions detected by ultrasonography or computed tomography imaging.

According to the 2009 AUA management guideline, a renal mass core biopsy via a percutaneous approach, with or without fine needle aspiration, is indicated in patients for whom the results might affect approach to treatment. Biopsy is especially appropriate in patients with clinical or radiographic evidence of lymphoma, abscess, or metastasis.[21]

Histology

Renal cell carcinoma (RCC) has the following common subtypes in addition to other rare subtypes:

Clear cell carcinoma is characterized by unusually clear cells with a cytoplasm rich in lipids and glycogen, and it is most likely to show 3p deletion. Papillary renal cell carcinomas are divided into type 1 and type 2. Papillary tumors are more likely to be bilateral and multifocal and may have trisomy 7 and/or trisomy 17. Chromophobe carcinoma is characterized by large polygonal cells with pale reticular cytoplasm characterize, and it does not exhibit 3p deletion.

Collecting duct carcinoma is an unusual variant characterized by a very aggressive clinical course. This disease tends to affect younger patients and may present as local or widespread advanced disease. These cells can have three different types of growth patterns: acinar, sarcomatoid, and tubulopapillary.

Sarcomatoid de-differentiation may occur with several subtypes and is associated with a poor prognosis.

Go to Clear Cell Renal Cell Carcinoma and Sarcomatoid and Rhabdoid Renal Cell Carcinoma for complete information on these topics.

Procedures

Cystoscopy and Ureteroscopy if central lesion, to rule out urothelial carcinoma

Biopsy of mass in case of central mass lesions to rule out urothelial carcinoma

Approach Considerations

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, renal functional issues, and potential complications.[21]

The principal treatment options for RCC are as follows:

Treatment considerations are as follows:

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:

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.[23] A study by Alt et al found that complete resection of multiple RCC metastases may be associated with long-term survival.[24]

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.[25]

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.

Surgical Treatment

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).[20]

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[21]

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.[21] A study by Zagoria et al found that radiofrequency ablation can result in durable oncological control in patients with renal cell carcinomas that are smaller than 4 cm who are poor surgical candidates.[26]

Radical Nephrectomy

Radical nephrectomy, which remains the most commonly performed standard surgical procedure today 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.

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.[20]

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.[20]

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.[20]

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 and Interferon

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.[27] 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.

Molecular-Targeted Agents

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:

These targeted agents have gained wide use as first-line, second-line, and subsequent lines of 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 regimens for systemic therapy are as follows:

For subsequent therapy, preferred 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.[28]

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.[29]

In a phase 3 study in 750 patients with previously untreated metastatic RCC progression-free survival was longer and response rates were higher in patients who received sunitinib than in those receiving interferon alfa (IFN-alfa).[30] 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).[31]

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).[32] Median progression-free survival was 10.9 months and overall survival was 18.4 months (17.4-19.2 mo).

Major toxicities (grade II or higher) of sunitinib include the following:

Hypertension induced by sunitinib may correlate with a significantly higher probability of response and better disease-free and overall survival.[33] Likewise, onset of hypothyroidism in patients treated with sunitinib may portend better response.[34]

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.[35] A phase 3 trial by Escudier et al found bevacizumab plus interferon alfa-2a to be effective as first-line treatment in patients with metastatic RCC.[36]  FDA approved bevacizumab in combination with interferon alfa for the treatment of patients with metastatic RCC.[37]

In September 2017, FDA has 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.[38]

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 renal cell carcinoma in 2009.

A phase 3 randomized study of pazopanib 800 mg orally daily confirmed statistically and clinically meaningful improvement of progression-free survival 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%).[39]

In another phase 3 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 progression-free survival (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 renal cell carcinoma 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).[40, 41]

The pazopanib group had fewer dose interruptions of 7 days or more when compared with the sunitinib group (44% and 49%) and fewer reductions in the dose (44% and 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%).[40, 41] On the other hand, when asked in another phase 3 trial (PISCES), 70% of patients selected pazopanib due to better quality of life, while 22% preferred sunitinib.[42]

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 renal cell carcinoma 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 renal cell carcinoma. 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).[43] 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 progression-free survival of 9.1 months for the combination.[44] 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 May 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. Progression-free survival (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).[45]

Lenvatinib is a small molecule tyrosine kinase (TK) inhibitor that inhibits the kinase activities of VEGF receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). It also inhibits other TKs 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 was approved by the FDA in 2009 for use in advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

The recommended everolimus dose for treatment of advanced renal cell carcinoma is 10 mg, to be taken once daily at the same time every day, with or without food.[46] However, the tablets should be swallowed whole, not be chewed or crushed, with a glass of water.

In a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial in patients with metastatic renal cell carcinoma that had progressed during sunitinib and/or sorafenib treatment, analysis showed significantly longer median progression-free survival with everolimus than with placebo.[47, 48] 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.[47]

A pooled analysis of four prospective, non-interventional studies provided evidence that everolimus can be safe and effective for second-line treatment of metastatic renal cell carcinoma 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 progression-free survival was 5.5 months for the overall population and 5.8 months for the everolimus group.[49]

The most common toxicities associated with everolimus are stomatitis, infections, asthenia, fatigue, cough, and diarrhea.[46]

Nivolumab

Nivolumab (Opdivo) is a monoclonal antibody to programmed cell death–1 protein (PD-1). In November 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).[50]

In April 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 3 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%.[51]

Cabozantinib

Cabozantinib (Cabometyx) is a small-molecule tyrosine kinase inhibitor. In April 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.[52]

In December 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 progression-free survival for patients taking cabozantinib was 8.6 months compared with 5.3 months for patients taking sunitinib.[53]

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.[54, 55]

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.[56]

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.[57]

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.[58] 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 3 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.[34]

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 progression-free survival 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%).[59] AXIS was a randomized, controlled, open-label, multicenter phase 3 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 April 2019 for first-line treatment of advanced renal cell carcinoma 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.[60]  

Avelumab

In May 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.[61]

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 renal cell carcinoma. 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.[62]

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.[63]

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.[64]

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.[20]

Chemotherapy

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

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 2 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%.[65] 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.[65]

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.

Experimental Therapeutic Approaches

Other experimental approaches for treatment of renal cell carcinoma (RCC) include the following[66] :

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 2 studies of metastatic RCC, lenalidomide demonstrated an antitumor effect in some cases, with disease stabilization or durable partial response.[67, 68]

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 2 study of 21 patients with metastatic RCC, combination therapy with AGS-003 and sunitinib prolonged expected survival time.[69]

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.[69] This evidence of prolonged survival prompted a larger phase 3 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.[70]

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.[71] 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.[71] 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

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.

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

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.[72]

Prevention of Renal Cell Carcinoma

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

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

Long-Term Monitoring

According to the 2009 AUA management guideline, 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.[21]

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.

As many as one third of patients with clinically localized disease may develop metastatic disease after nephrectomy, so they should be monitored carefully. In 2013, the AUA released a set of new guidelines addressing the follow-up and surveillance of clinically localized renal cancers treated with surgery or renal ablative procedures, biopsy-proven untreated clinically localized renal cancers followed on surveillance, and radiographically suspicious but biopsy-unproven renal neoplasms.[73]

Of the 27 statements in the guideline, the only one considered a standard is that patients with a history of renal neoplasm who present with acute neurological signs or symptoms should undergo prompt neurologic cross-sectional CT or MRI scanning of the head or spine based on localization of symptomatology.[73]

Other recommendations and options outlined in the guideline include the following[73] :

Guidelines Summary

Guidelines Contributor: Bagi RP Jana, MD Associate Professor of Medicine (Genitourinary Oncology), Division of Hematology and Oncology, University of Texas Medical Branch

Classification

In 2016, the World Health Organization released an updated classification of renal cell tumors that expanded the subtypes of renal cell carcinoma (RCC) based on tumor histology, chromosomal alterations, and molecular pathways. The update included the following five newly recognized epithelial renal tumors[74] :

Other revisions to RCC classification included the following[74] :

 

Diagnosis and Staging

Guidelines for the diagnosis and staging of renal cell carcinoma (RCC) have been issued by the following organizations:

American Urological Association recommendations

The 2017 AUA guideline for the management of clinically localized sporadic renal masses suspicious for RCC in adults recommends that in patients with a solid or complex cystic renal mass, clinicians should perform high-quality, multiphase, cross-sectional abdominal imaging to optimally characterize and clinically stage the renal mass.[21] Characterization of the renal mass should include assessment of the following:

According to the AUA guideline, a renal mass biopsy should be considered when a mass is suspected to be hematologic, metastatic, inflammatory, or infectious (Clinical Principle). In the setting of a solid renal mass, biopsy is not required for either of the following (Expert Opinion):

When considering the utility of renal mass biopsy, patients should be counseled regarding its rationale, positive and negative predictive values, potential risks, and nondiagnostic rates (Clinical Principle). For patients with a solid renal mass who elect biopsy, multiple core biopsies are preferred over fine needle aspiration (Moderate Recommendation; Evidence Level: Grade C)

National Comprehensive Cancer Network recommendations

NCCN recommendations are categorized as follows[20] :

All NCCN recommendations are category 2A unless otherwise noted.

The NCCN  guidelines for kidney cancer recommend the following as part of the initial workup[20] :

In addition, the NCCN recommends considering needle biopsy of small lesions if clinically indicated. The NCCN also recommends considering urine cytology and ureteroscopy if urothelial carcinoma is suspected (eg, a central mass is present).

The NCCN guideline recommends lymph node dissection in patients with enlarged lymph nodes (palpable or visible or detected on preoperative imaging). To obtain needed staging information, lymph node dissection may also be performed on patients whose lymph nodes appear normal.

European Society for Medical Oncology recommendations

The ESMO 2019 updated clinical practice guidelines include the following recommendations for the diagnosis and staging of RCC.[75]

Diagnosis is usually suggested by ultrasound and further investigated by CT scan. If RCC is suspected, the following laboratory examinations should be performed:

Contrast-enhanced chest, abdominal, and pelvic CT is mandatory for accurate RCC staging. Bone scan or brain CT (or magnetic resonance imaging) is not recommended for routine clinical practice unless indicated by clinical or laboratory signs or symptoms.

Renal tumor core biopsy has high sensitivity and specificity for histopathologic confirmation of malignancy. It is especially recommended before ablative therapy and in patients with metastatic disease before systemic treatment is started.

The Union for International Cancer Control tumor, node, and metastasis staging system should be used for staging and risk assessment.

Management of Stage I Renal Mass

In patients with a clinical T1a renal mass for which intervention is indicated, the American Urological Association (AUA) 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 (Moderate Recommendation; Evidence Level: Grade B).[21]

Thermal ablation may be considered as an alternate approach for the management of cT1a renal masses < 3 cm in size. Before ablation, a tumor mass biopsy should be performed, to provide pathologic diagnosis and guide subsequent surveillance (Expert Opinion). Counseling about thermal ablation should include information that tumor persistence or local recurrence occurs more commonly after primary thermal ablation than after surgical extirpation, but may be addressed with repeat ablation if further intervention is elected (Strong Recommendation; Evidence Level: Grade B).[21]

Thermal ablation may be performed using radiofrequency or cryoablation. A percutaneous technique is preferred over a surgical approach whenever feasible, to minimize morbidity. (Conditional Recommendation; Evidence Level: Grade C).[21]

For a pathologic T1a renal mass, National Comprehensive Cancer Network (NCCN) lists the following as treatment options[20] :

For pT1b disease, the NCCN recommends either partial or radical nephrectomy.[20]

The 2019 European Society for Medical Oncology (ESMO) guidelines also recommend partial nephrectomy as the preferred option in tumors measuring up to 7 cm. Partial nephrectomy is also recommended in patients with compromised renal function, solitary kidney, or bilateral tumors, with no tumor size limitation.[75]

Active surveillance

AUA recommendations regarding active surveillance include the following[21] :

ESMO guidelines recommend active surveillance as an option in elderly patients with significant comorbidities or with a short life expectancy and tumors measuring < 40 mm.[75]

Management of Clinical Stage II and III Renal Masses

For stage II and III renal tumors, the National Comprehensive Cancer Network (NCCN) guideline recommends radical nephrectomy. in most cases. Partial nephrectomy may be used if clinically indicated, such as in unilateral tumors, where technically feasible, or the following:

The European Society for Medical Oncology (ESMO) guideline recommends laparoscopic radical nephrectomy for T2 tumors (> 7 cm). For locally advanced RCC (T3 and T4), open radical nephrectomy is the standard of care, though a laparoscopic approach can be considered. However, systemic adrenalectomy or extensive lymph node dissection is not recommended when there is no evidence of adrenal or lymph node invasion. There is no recommended adjuvant treatment. Adjuvant and neoadjuvant treatment should not be considered outside of clinical trials.[75]

Primary Treatment of Stage IV Kidney Cancer

National Comprehensive Cancer Network (NCCN) recommendations for primary treatment of patients with stage IV kidney cancer are as follows[20] :

Molecular-Targeted Therapy in Metastatic Renal Cell Carcinoma

For stage IV RCC that is relapsed, includes multiple metastatic sites, or is surgically unresectable, the National Comprehensive Cancer Network (NCCN) guideline gives several targeted therapy agents a category 1 recommendation (ie, based on high-level evidence, with uniform NCCN consensus that the intervention is appropriate) for this group of patients.[20]  For patients with predominantly clear cell cancer, considerations for first-line therapy are best supportive care and one of the following:

For patients with previously treated predominantly clear cell renal cell cancer, NCCN considerations for subsequent therapy include the following:

For patients with non–clear cell histology, NCCN recommendations for systemic therapy include the following:

Long-Term Monitoring for Clinically Localized Renal Neoplasms

Active surveillance

In patients with a clinically localized renal neoplasm who have chosen active surveillance, the American Urological Association (AUA)[73]  and the National Comprehensive Cancer Network (NCCN)[20]  recommend similar follow-up measures. The NCCN monitoring schedule for active surveillance in patients with pT1a disease is as follows[20] :

Followup after renal surgery

As many as one third of patients with clinically localized disease may develop metastatic disease after nephrectomy, so they should be monitored carefully. In 2013, the AUA released a set of new guidelines addressing the follow-up and surveillance of clinically localized renal cancers treated with surgery or renal ablative procedures, biopsy-proven untreated clinically localized renal cancers followed on surveillance, and radiographically suspicious but biopsy-unproven renal neoplasms.[73]  Of the 27 statements in this guideline, the only one considered a grade A recommendation (standard of care) is that patients with a history of renal neoplasm who present with acute neurologic signs or symptoms should undergo prompt neurologic cross-sectional CT or MRI scanning of the head or spine, based on localization of signs and symptoms.[73]

Other recommendations and options outlined in the guideline include the following[73] :

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.[73]

NCCN postoperative guidelines

For stage I renal cell carcinoma, the NCCN recommends a complete history, physical examination, comprehensive metabolic panel, and other laboratory tests as indicated every 6 months for 2 years, then annually for 5 years.

The NCCN recommends a baseline abdominal CT, MRI, or ultrasound scan within 3-12 months postoperatively. If this scan is negative, patients who underwent partial nephrectomy may be considered for abdominal imaging annually for 3 y, based on individual risk factors. For patients who underwent radical nephrectomy, abdominal imaging after 12 mo may be performed at the clinician’s discretion.[20]

For stage II or III renal cell carcinoma, the NCCN recommends following radical nephrectomy with a history and physical examination every 3-6 mo for 3 y, then annually for up to 5 y, then as clinically indicated. A comprehensive metabolic panel (and other tests as indicated) is recommended every 6 mo for 2 y, annually up to 5 y, then as clinically indicated.

Imaging studies are as follows:

For relapsed or stage IV and surgically unresectable disease, the NCCN recommendations are as follows[20] :

Management of Advanced and Metastatic Disease

European Society for Medical Oncology (ESMO) recommendations for management of advanced or metatstatic RCC are as follows[75] :

Medication Summary

The goals of pharmacotherapy in renal cell carcinoma are to induce remission, reduce morbidity, and prevent complications. Selected patients with metastatic disease respond to immunotherapy, but many patients with advanced renal cell disease can be offered only palliative therapy.

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. Targeted therapies that primarily block angiogenesis or cell growth pathways are commonly used for metastatic renal carcinoma.

Renal cell carcinoma is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators have been tried, including the following:

More recently, immune checkpoint inhibitors have been developed and approved for use in metastatic renal carcinoma. Results with these agents and other molecular-targeted therapies continue to emerge, and these agents are being approved for use.

Aldesleukin (Proleukin)

Clinical Context:  Aldesleukin is an interleukin (IL)–2 product that is also known as a T-cell growth factor and activator of T cells and natural killer cells. It has been approved for the treatment of adults with metastatic renal cell carcinoma. This agent affects tumor growth by activating lymphoid cells in vivo, without affecting tumor proliferation directly.

Caution must be exercised in patients with preexisting cardiac, pulmonary, central nervous system (CNS), hepatic, or renal impairment. 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.

Vinblastine

Clinical Context:  Vinblastine is a vinca alkaloid with cytotoxic effects via mitotic arrest. This agent binds to a specific site on tubulin, preventing polymerization of tubulin dimers and inhibiting microtubule formation. Using the intrathecal route of administration may result in death.

Gemcitabine (Gemzar)

Clinical Context:  Gemcitabine is a cytidine analogue. After intracellular metabolism to active nucleotide, this agent inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA.

5-Fluorouracil

Clinical Context:  5-fluorouracil (5-FU) is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and interferes with RNA synthesis and function. This agent has cell-cycle specificity with activity in S phase. 5-FU metabolites can incorporate into DNA and RNA, resulting in changes in DNA synthesis and RNA processing that impair cell turnover.

Paclitaxel

Clinical Context:  Paclitaxel has a mechanism of action that involves tubulin polymerization and microtubule stabilization, which, in turn, inhibits mitosis and may result in breakage of chromosomes.

Carboplatin

Clinical Context:  Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-links and inhibition of DNA replication. Cytotoxicity can occur at any stage of the cell cycle, but the cell is most vulnerable to action of these drugs in the G1 and S phase. It has the same efficacy as cisplatin but with a better toxicity profile.

Ifosfamide (Ifex)

Clinical Context:  Ifosfamide inhibits DNA and protein synthesis and, thus, cell-proliferation, by causing DNA cross-linking and denaturation of the double helix.

Doxorubicin

Clinical Context:  Doxorubicin is a cytotoxic anthracycline antibiotic that blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to the sugar-phosphate backbone of DNA, which causes DNA polymerase inhibition. It binds to nucleic acids, presumably by specific intercalation of the anthracycline nucleus with the DNA double helix. Doxorubicin is also a powerful iron chelator. The iron-doxorubicin complex induces the production of free radicals that can destroy DNA and cancer cells.

Floxuridine

Clinical Context:  Floxuridine is an antineoplastic antimetabolite that is most active during the S phase of the cell cycle. Floxuridine is catabolized to 5-fluorouracil when administered. Floxuridine inhibits DNA and RNA synthesis.

Interferon alfa-2a (Roferon A) and 2b (Intron A)

Clinical Context:  Interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. These agents have a direct antiproliferative effect on renal tumor cells, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules.

Caution should be exercised when administering interferons in patients with brain metastases, severe hepatic or renal insufficiency, seizure disorders, multiple sclerosis, or a compromised CNS.

Class Summary

Few options are available for the systemic therapy of renal cell carcinoma (RCC), and no hormonal or chemotherapeutic regimen is accepted as a standard of care to treat this disease. Objective response rates, either for single or combination chemotherapy, are usually lower than 15%. Multikinase inhibitors induce objective responses in up to 40% of patients, but they are not known to cure patients with metastatic disease.

Nivolumab (Opdivo)

Clinical Context:  Nivolumab is a monoclonal antibody to programmed cell death–1 protein (PD-1). PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells. Nivolumab monotherapy is indicated for patients with advanced RCC who have received prior anti-angiogenic therapy (eg, VEGF inhibitors). It is also indicated in combination with ipilimumab for patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma.

Pembrolizumab (Keytruda)

Clinical Context:  Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks interaction between PD-1 and its ligands, PD-L1 and PD-L2. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells. It is indicated as first-line treatment of advanced RCC in combination with axitinib.

Avelumab (Bavencio)

Clinical Context:  Anti-PD-L1 IgG1 monoclonal antibody. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen-presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. It is indicated in combination with axitinib) for first-line treatment of advanced RCC.

Sorafenib (Nexavar)

Clinical Context:  Sorafenib is indicated for advanced renal cell carcinoma. This agent was the first oral multikinase inhibitor that targeted serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Sorafenib targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases included RAF kinase, vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-beta, stem cell factor receptor (KIT), and Fmslike tyrosine kinase-3 (FLT-3).

Axitinib (Inlyta)

Clinical Context:  Axitinib inhibits receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. It is indicated for treatment of advanced renal cell carcinoma after failure of 1 prior systemic therapy.

Sunitinib (Sutent)

Clinical Context:  Sunitinib is a multikinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. This agent inhibits PDGFRs (ie, PDGFR-alpha, PDGFR-beta), VEGFRs (ie, VEGFR1, VEGFR2, VEGFR3), KIT, FLT3, colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET).

Pazopanib (Votrient)

Clinical Context:  Pazopanib is a multityrosine kinase inhibitor indicated for advanced renal cell carcinoma. This agent selectively inhibits VEGFR-1, -2 and -3, c-kit, and PDGFR, which may result in inhibition of angiogenesis in tumors in which these receptors are upregulated.[58]

Lenvatinib (Lenvima)

Clinical Context:  Tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors for VEGFR-1, -2, -3, FGFR -1, -2, -3, and -4, PDGFR-alpha, KIT and RET pathways. The combination of everolimus and lenvatinib shows increased ant-angiogenesis properties.  The combination is indicated for advanced renal cell carcinoma in patients who have received prior antiangiogenic therapy. It is indicated for advanced RCC in combination with everolimus following 1 prior antiangiogenic therapy.

Cabozantinib (Cabometyx)

Clinical Context:  Tyrosine kinase inhibitor that targets RET, MET, VEGFR-1, -2, and -3, KIT, TrkB, FLT-3, AXL, and TIE-2 pathways. It is indicated for advanced renal cell carcinoma.

Bevacizumab (Avastin, Mvasi)

Clinical Context:  Bevacizumab is a recombinant, humanized monoclonal antibody that inhibits angiogenesis by targeting and inhibiting VEGF. Bevacizumab is indicated for the treatment of metastatic kidney cancer in combination with interferon alfa. Mvasi has been FDA-approved as a biosimilar to Avastin but not as an interchangeable product.

Temsirolimus (Torisel)

Clinical Context:  Temsirolimus is a water-soluble ester of sirolimus that binds with high affinity to immunophilin FKBP (FK506 binding protein) and is indicated for advanced renal cell carcinoma. This complex inhibits mammalian target of rapamycin (mTOR) kinase, a key protein in cells that regulates gene translation responsible for cell cycle regulation. mTOR also reduces cell growth factors (eg, vascular endothelial growth factor [VEGF]) involved in new blood vessel development.

Everolimus (Afinitor)

Clinical Context:  Everolimus is a rapamycin-derivative kinase inhibitor that is indicated for advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. This agent reduces cell proliferation and angiogenesis by inhibition of mTOR pathway.

What is renal cell carcinoma (RCC)?What are the signs and symptoms of renal cell carcinoma (RCC)?Which lab studies are performed in the workup of renal cell carcinoma (RCC)?Which imaging studies are performed in the evaluation and staging of renal cell carcinoma (RCC)?What are the treatment options for renal cell cancer (RCC)?What is the prevalence of renal cell carcinoma (RCC) and how is it characterized?What is the role of surgery in the treatment of renal cell carcinoma (RCC)?What is the first-line therapy for metastatic renal cell carcinoma (RCC)?Which agents are used in second-line therapy for renal cell carcinoma (RCC)?What is the tissue of origin for renal cell carcinoma (RCC)?What are the hereditary syndromes associated with renal cell carcinoma (RCC)?What is von Hippel-Lindau (VHL) syndrome (disease)?What is the prevalence of renal cell carcinoma in von Hippel-Lindau (VHL) syndrome (disease)?What is the role of the VHL gene in the pathogenesis of renal cell carcinoma (RCC)?What is hereditary papillary renal carcinoma (RCC)?What are familial renal oncocytoma and Birt-Hogg-Dube syndrome?What is hereditary renal cell carcinoma (RCC)?What is the role of smoking in the etiology of renal cell carcinoma (RCC)?What is the role of obesity in the etiology of renal cell carcinoma (RCC)?What are the occupational exposure risk factors for renal cell carcinoma (RCC)?Which NSAIDs increase the risk of renal cell carcinoma (RCC)?How does long-term dialysis affect the risk for renal cell carcinoma (RCC)?Which genetic disorders are associated with renal cell carcinoma (RCC)?What is the incidence of renal cell carcinoma (RCC) in the US?What is the incidence of renal cell carcinoma (RCC) in Europe?What is the median age at diagnosis of renal cell carcinoma (RCC)?What is the prognosis of renal cell carcinoma (RCC)?What are the survival rates for renal cell carcinoma (RCC)?What are the T stage 5-year disease-specific survival rates in patients with renal cell carcinoma (RCC)?What is the survival rate of renal cell carcinoma (RCC) with regional lymph node involvement?What is the survival rate of patients with stage IV renal cell carcinoma (RCC)?What are the factors for predicting survival in patients with metastatic renal cell carcinoma (RCC)?What are the factors associated with increased survival in patients with metastatic renal cell carcinoma (RCC)?When is obesity a favorable prognostic factor in renal cell carcinoma (RCC)?How should patients with a family history of genetic syndromes for renal cell carcinoma (RCC) be counseled?What information should be given to patients at high risk for renal cell carcinoma (RCC)?What is the patient history associated with renal cell carcinoma (RCC)?How frequency are the individual components of the classic triad of renal cell carcinoma (RCC) present?What are the nonspecific signs and symptoms of renal cell carcinoma (RCC)?Which paraneoplastic syndromes are comorbid with renal cell carcinoma (RCC)?What causes the paraneoplastic conditions of renal cell carcinoma (RCC)?What should be included in the physical exam of suspected renal cell carcinoma (RCC)?Which physical findings suggest renal cell carcinoma (RCC)?What systems are used to stage renal cell carcinoma (RCC)?What is the Robson staging system for renal cell carcinoma (RCC)?What is the TNM classification for renal cell carcinoma (RCC)?How are primary tumors (T) defined in the TNM staging of renal cell carcinoma (RCC)?How are regional lymph nodes (N) defined in the TNM staging of renal cell carcinoma (RCC)?How is distant metastasis (M) defined in the TNM staging of renal cell carcinoma (RCC)?How is the AJCC stage determined for renal cell carcinoma (RCC)?When is a diagnosis of renal cell carcinoma (RCC) considered based on radiographic findings?How should a renal mass of indeterminate etiology be monitored?Which disorders should be included in the differential diagnosis of renal cell carcinoma (RCC)?What are the signs and symptoms of spinal cord compression in renal cell carcinoma (RCC)?What are the differential diagnoses for Renal Cell Carcinoma?How is renal cell carcinoma (RCC) detected?What should be included in the lab studies for renal cell carcinoma (RCC)?Which imaging studies should be performed in the evaluation and staging of renal cancer (RCC)?How are benign renal masses differentiated from renal cell carcinoma?What is the role of contrast-enhanced CT scanning in the workup of renal cell carcinoma (RCC)?What is the role of excretory urography in the workup of renal cell carcinoma (RCC)?What is the role of renal arteriography in the workup of renal cell carcinoma (RCC)?What is the role of positron emission tomography (PET) in the workup of renal cell carcinoma (RCC)?What is the role of bone scans in the workup of renal cell carcinoma (RCC)?Which lab studies are performed in the initial workup of renal cell carcinoma (RCC)?What is the imaging procedure of choice for diagnosis and staging of renal cell cancer?What are the American Urological Association (AUA) guidelines for imaging in the workup of renal cell carcinoma (RCC)?What are the National Comprehensive Cancer Network (NCCN) guidelines for the initial workup for renal cell carcinoma (RCC)?How is multidetector CT imaging used in the workup of renal cell carcinoma (RCC)?What are the histologic subtypes of renal cell carcinoma (RCC)?What are the histologic characteristics of clear cell carcinoma in renal cell carcinoma (RCC)?What are the histologic characteristics of renal oncocytoma in renal cell carcinoma (RCC)?What are the histologic characteristics of collecting duct carcinoma in renal cell carcinoma (RCC)?Which procedures are performed in the workup of renal cell carcinoma (RCC)?What is the role of percutaneous cyst puncture in the workup of renal cell carcinoma (RCC)?What is the basis for treatment selection in renal cell carcinoma (RCC)?What are the American Urological Association (AUA) recommendations for treatment selection in renal cell carcinoma (RCC)?What are the treatment options for renal cell carcinoma (RCC)?What is the role of chemotherapy in the treatment of renal cell carcinoma (RCC)?Which immune modulators are used in the treatment of renal cell carcinoma (RCC)?What is the role of surgery in the treatment of metastatic renal cell carcinoma (RCC)?What is the efficacy of resection in the treatment of renal cell carcinoma (RCC)?What is the role of active surveillance in the treatment of renal cell carcinoma (RCC)?When is enrollment in clinical trials indicated for the treatment of renal cell carcinoma (RCC)?What is the role of surgical resection in the treatment of renal cell carcinoma (RCC)?What is the NCCN treatment recommendations for a T1a renal mass in renal cell carcinoma (RCC)?What is the AUA treatment recommendations for a T1 renal mass in renal cell carcinoma (RCC)?When is ablation most effective for the treatment of renal cell carcinoma (RCC)?What is the role of radical nephrectomy in the treatment of renal cell carcinoma (RCC)?What are the indications for adrenalectomy in the treatment of renal cell carcinoma (RCC)?When is en bloc excision of adjacent structures during surgery for renal cell carcinoma (RCC) indicated?What are the common surgical approaches used in the treatment of renal cell carcinoma (RCC)?What is the prevalence of lymph node involvement in renal cell carcinoma (RCC)?What are the recommendations of treatment of enlarged lymph nodes in renal cell carcinoma (RCC)?What is the prevalence of inferior vena cava involvement in renal cell carcinoma (RCC)?How is renal vein and inferior vena cava involvement managed in renal cell carcinoma (RCC)?What is the role of laparoscopic nephrectomy in the treatment of renal cell carcinoma?When is palliative nephrectomy considered in the treatment of renal cell carcinoma (RCC)?What is the role of interleukin-2 (IL-2) in the treatment of renal cell carcinoma (RCC)?What is the efficacy of interleukin-2 (IL-2) in the treatment of renal cell carcinoma (RCC)?What are the toxic effects associated with interleukin-2 (IL-2) for treatment of renal cell carcinoma (RCC) and how are they managed?What is the mechanism of action for interferons used to treat renal cell carcinoma (RCC)?What is the role of interferons in the treatment of renal cell carcinoma (RCC)?Which molecular-targeted agents are FDA-approved for treatment of renal cell carcinoma (RCC)?What are the National Comprehensive Cancer Network (NCCN) preferred regimens for systemic therapy in renal cell carcinoma (RCC)?What is the role of nivolumab (Opdivo) in the treatment of renal cell carcinoma (RCC)?What is the optimal sequence for use of targeted agents in the treatment of renal cell carcinoma (RCC)?What are the National Comprehensive Cancer Network (NCCN) guidelines for first-line therapy to treat predominantly clear cell renal cell carcinoma (RCC)?What are the National Comprehensive Cancer Network (NCCN) guidelines for second-line therapy to treat predominantly clear cell renal cell carcinoma (RCC)?What is the role of sunitinib (Sutent) in the treatment of renal cell carcinoma (RCC)?What is the efficacy of sunitinib to treat renal cell carcinoma (RCC)?What are the adverse effects of sunitinib in the treatment of renal cell carcinoma (RCC)?What is the role of bevacizumab in the treatment of renal cell carcinoma (RCC)?What is the role of pazopanib (Votrient) in the treatment of renal cell carcinoma (RCC)?What is the efficacy of pazopanib (Votrient) in the treatment of renal cell carcinoma (RCC)?What is the role of temsirolimus (Torisel) in the treatment of renal cell carcinoma (RCC)?What is the efficacy of temsirolimus (Torisel) in the treatment of renal cell carcinoma (RCC)?What are the adverse effects of temsirolimus in the treatment of renal cell carcinoma (RCC)?What is the role of lenvatinib (Lenvima) in the treatment of renal cell carcinoma (RCC)?What is the role of everolimus (Afinitor) in the treatment of renal cell carcinoma (RCC)?What is the efficacy of everolimus for the treatment of renal cell carcinoma (RCC)?What are the adverse effects of everolimus in the treatment of renal cell carcinoma (RCC)?What is the efficacy of nivolumab (Opdivo) in the treatment of renal cell carcinoma (RCC)?What is the role of cabozantinib (Cabometyx) in the treatment of renal cell carcinoma (RCC)?What is the efficacy of cabozantinib (Cabometyx) in the treatment of renal cell carcinoma (RCC)?What is the role of sorafenib (Nexavar) in the treatment of renal cell carcinoma (RCC)?What is the efficacy of sorafenib in the treatment of renal cell carcinoma (RCC)?What is the mechanism of action for sorafenib in the treatment of renal cell carcinoma (RCC)?What is the recommended dose of sorafenib to treat renal cell carcinoma (RCC)?What are the adverse events of sorafenib treatment for renal cell carcinoma (RCC)?What is the role of axitinib (Inlyta) in the treatment of renal cell carcinoma (RCC)?What is the role of lapatinib in the treatment of renal cell carcinoma (RCC)?What is the role of molecular therapy in the treatment of early-stage renal cell carcinoma (RCC)?What is the efficacy of chemotherapy in the treatment of renal cell carcinoma (RCC)?Which chemotherapy agents have been used in the treatment of renal cell carcinoma (RCC)?Why is renal cell carcinoma (RCC) refractory to most chemotherapeutic agents?What are experimental approaches to treatment of renal cell carcinoma (RCC)?What is the efficacy of lenalidomide (Revlimid) for the treatment of renal cell carcinoma (RCC)?What is the role of vaccines in the treatment of renal cell carcinoma (RCC)?What is the role of autologous vaccine therapy in the treatment of renal cell carcinoma (RCC)?What is the role of nonmyeloablative allogeneic stem cell transplantation (ASCT) in the treatment of renal cell carcinoma (RCC)?What are the complications of nonmyeloablative allogeneic stem cell transplantation (ASCT) for the treatment of renal cell carcinoma (RCC)?What is the role of megestrol and antiestrogens in the treatment of renal cell carcinoma (RCC)?When is radiation therapy considered as the primary therapy for renal cell carcinoma (RCC)?When is radiation therapy considered for palliative care in renal cell carcinoma (RCC)?What is the role of radiation therapy in the treatment of brain metastasis in renal cell carcinoma (RCC)?What is the role of renal artery embolization in the treatment of renal cell carcinoma (RCC)?How is renal cell carcinoma (RCC) prevented?When is active surveillance indicated in the treatment of renal cell carcinoma (RCC)?What are the risks of active surveillance in the treatment of renal cell carcinoma (RCC)?What is included in long-term monitoring for stage I and II renal cell carcinoma (RCC)?What is included in long-term monitoring for stage III renal cell carcinoma (RCC)?What is the frequency of spontaneous regression in renal cell carcinoma (RCC)?What are the surveillance recommendations for patients with end-stage renal disease and renal cell carcinoma (RCC)?What organization has released guidelines for surveillance of clinically localized renal cell carcinoma (RCC)?What are the AUA guidelines for surveillance of clinically localized renal cell carcinoma (RCC)?Who are the renal cell carcinoma guideline contributors?What is the WHO updated classification of renal cell tumors?What are the NCCN recommendations for the workup of renal cell carcinoma (RCC)?What organizations have issued guidelines for the diagnosis and staging of renal cell carcinoma (RCC)?According to AUA guidelines, which characteristics of the renal mass should be assessed in the diagnosis of renal cell carcinoma (RCC)?What are the AUA guidelines for renal mass biopsy in the diagnosis of renal cell carcinoma (RCC)?How are the National Comprehensive Cancer Network (NCCN) recommendations for renal cell carcinoma (RCC) categorized?What is lymph node dissection indicated in the workup of renal cell carcinoma (RCC)?What are the ESMO clinical practice guidelines for the diagnosis and staging of renal cell carcinoma (RCC)?What are the AUA treatment guidelines for stage I renal mass in renal cell carcinoma (RCC)?What are the NCCN recommendations for treatment of treatment stage I renal cell carcinoma (RCC)?What are the ESMO recommendations for partial nephrectomy in the treatment of renal cell carcinoma (RCC)?What are the AUA recommendations for active surveillance of renal cell carcinoma (RCC)?When are the treatment guidelines for stage II and III renal cell carcinoma (RCC)?What are the NCCN recommendations for the primary treatment of stage IV renal cell carcinoma (RCC)?What are the NCCN recommendations for management of non-clear cell stage IV renal cell cancer (RCC)?What are the NCCN recommendations for treatment of relapsed stage IV renal cell carcinoma (RCC)?What are the NCCN recommendations for management of previously treated predominantly clear cell stage IV renal cell cancer (RCC)?What is the NCCN recommended monitoring schedule for active surveillance in patients with pT1a renal cell carcinoma (RCC)?What are AUA guidelines for follow-up following surgery for renal cell carcinoma (RCC)?What are the AUA recommendations for management of asymptomatic metastatic renal cell carcinoma (RCC)?What are NCCN postoperative guidelines for stage I renal cell carcinoma (RCC)?What are NCCN postoperative guidelines for stage II and III renal cell carcinoma (RCC)?What are NCCN postoperative guidelines for stage IV renal cell carcinoma (RCC)?What are the goals of drug treatment for renal cell carcinoma (RCC)?Which immune modulators are used in the treatment of renal cell carcinoma (RCC)?Which medications in the drug class Antineoplastic Agents are used in the treatment of Renal Cell Carcinoma?Which medications in the drug class mTOr Kinase Inhibitor are used in the treatment of Renal Cell Carcinoma?Which medications in the drug class Tyrosine kinase inhibitors and VEGF inhibitors are used in the treatment of Renal Cell Carcinoma?Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Renal Cell Carcinoma?

Author

Kush Sachdeva, MD, Southern Oncology and Hematology Associates, Inspira Health Network

Disclosure: Nothing to disclose.

Coauthor(s)

Bagi RP Jana, MD, Professor of Medicine (Genitourinary Oncology), Division of Hematology and Oncology, University of Texas Medical Branch at Galveston

Disclosure: Nothing to disclose.

Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Cancer Center

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Prometheus Pharmaceuticals, BMS<br/>Received research grant from: Prometheus Pharmaceuticals, Viralytics, MedImmune, BMS, Galectin Therapeutics.

Chief Editor

E Jason Abel, MD, Associate Professor of Urologic Oncology, Department of Urology, Associate Professor of Radiology (Affiliate Appointment), Department of Radiology, University of Wisconsin School of Medicine and Public Health; Attending Urologist, William S Middleton Memorial Veterans Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Wendy Hu, MD Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center

Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Mansoor Javeed, MD, FACP Clinical Assistant Professor of Medicine, University of California, Davis, School of Medicine; Consultant, Sierra Hematology-Oncology Medical Center

Mansoor Javeed, MD, FACP is a member of the following medical societies: American College of Physicians and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Issam Makhoul, MD Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences

Issam Makhoul, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology

Disclosure: Nothing to disclose.

Michael Perry, MD, MS, MACP Nellie B Smith Chair of Oncology Emeritus, Director, Division of Hematology and Medical Oncology, Deputy Director, Ellis Fischel Cancer Center, University of Missouri-Columbia School of Medicine

Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, and Missouri State Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Typical renal cell carcinoma. CT scan obtained before contrast enhancement has an attenuation measurement of 33.9 HU.

Gross image of a bivalved kidney showing renal cell carcinoma in the upper half. The periphery of the carcinoma is yellow (due to high lipid content) with a central gelatinous area of necrosis.

H and E, high power of a clear cell renal cell carcinoma. The tumor cells have abundant pale "clear" cytoplasm.

H and E, low power of a papillary renal cell carcinoma. There are "finger-like" projections of fibrovascular stroma lined by malignant tumor cells that lack the abundant clear cytoplasm seen in a clear cell carcinoma.

H and E, high power of a chromophobe RCC composed of cells with clear, reticular cytoplasm and some with eosinophilic cytoplasm. The cell borders are often more distinct in this carcinoma than others and the nuclei are often smaller and darker.

H and E, high power of a collecting duct carcinoma composed of tubules lined by malignant cells in a background stroma that is fibrotic.

Typical renal cell carcinoma. CT scan obtained before contrast enhancement has an attenuation measurement of 33.9 HU.