Renal cancers

Renal cell cancer, also called renal adenocarcinoma, or hypernephroma, can often be cured if it is diagnosed and treated when still localized to the kidney and to the immediately surrounding tissue. The probability of cure is directly related to the stage or degree of tumor dissemination. Even when regional lymphatics or blood vessels are involved with tumor, a significant number of patients can achieve prolonged survival and probable cure. When distant metastases are present, disease-free survival is poor; however, occasional selected patients will survive after surgical resection of all known tumor. Because a majority of patients are diagnosed when the tumor is still relatively localized and amenable to surgical removal, approximately 73% of all patients with renal cell cancer survive for 5 years. Occasionally, patients with locally advanced or metastatic disease may exhibit indolent courses lasting several years. Late tumor recurrence many years after initial treatment also occasionally occurs.

Renal cell cancer is one of the few tumors in which well-documented cases of spontaneous tumor regression in the absence of therapy exist, but this occurs very rarely and may not lead to long-term survival.

Surgical resection is the mainstay of treatment of this disease. Even in patients with disseminated tumor, locoregional forms of therapy may play an important role in palliating symptoms of the primary tumor or of ectopic hormone production. Systemic therapy has demonstrated only limited effectiveness.

Incidence and Mortality

Estimated new cases and deaths from renal cell (kidney and renal pelvis) cancer in the United States in 2018:
• New cases: 65,340.   • Deaths: 14,970.

Cellular Classification of Renal Cell Cancer

Approximately 85% of renal cell cancers are adenocarcinomas, and most of those are of proximal tubular origin. Most of the remainder are transitional cell carcinomas of the renal pelvis. (Refer to the PDQ summary on Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment for more information.)
Adenocarcinomas may be separated into clear cell and granular cell carcinomas; however, the two cell types may occur together in some tumors. Some investigators have found that granular-cell tumors have a worse prognosis, but this finding is not universal. Distinguishing between well-differentiated renal adenocarcinomas and renal adenomas can be difficult. The diagnosis is usually made arbitrarily on the basis of size of the mass, but size alone should not influence the treatment approach, because metastases can occur with lesions as small as 0.5 centimeter.

Pathology   Staging   Treatment   NCCN Guidelines  

Risk Factors

The following factors may raise a person’s risk of developing kidney cancer:
• Smoking. Smoking tobacco doubles the risk of developing kidney cancer. It is believed to cause about 30% of kidney cancers in men and about 25% in women.
• Gender. Men are 2 to 3 times more likely to develop kidney cancer than women.
• Race. Black people have higher rates of kidney cancer.
• Age. Kidney cancer is typically found in adults and is usually diagnosed between the ages of 50 and 70.
• Nutrition and weight. Research has often shown a link between kidney cancer and obesity, which is generally caused by many years of eating a high-fat diet.
• High blood pressure. Men with hypertension may be more likely to develop kidney cancer.
• Overuse of certain medications. Painkillers containing phenacetin have been banned in the United States since 1983 because of their link to transitional cell carcinoma. Diuretics and analgesic pain pills, such as aspirin, acetaminophen, and ibuprofen, have also been linked to kidney cancer.
• Exposure to cadmium. Some studies have shown a connection between exposure to the metallic element cadmium and kidney cancer. Working with batteries, paints, or welding materials may increase a person’s risk as well. This risk is even higher for smokers who have been exposed to cadmium.
• Chronic kidney disease. People who have decreased kidney function but don’t yet need dialysis may be at higher risk for the development of kidney cancer.
• Long-term dialysis. People who have been on dialysis for a long time may develop cancerous cysts in their kidneys. These growths are usually found early and can often be removed before the cancer spreads.
• Family history of kidney cancer. People who have first-degree relatives with kidney cancer, such as parents, brothers, sisters, or children, have an increased risk of developing the disease. This risk increases if a number of extended family members have been diagnosed with kidney cancer, including grandparents, aunts, uncles, nieces, nephews, grandchildren, and cousins, and if these family members were diagnosed before the age of 50, had cancer in both kidneys, and/or had more than 1 tumor in the same kidney.

Prevention

Different factors cause different types of cancer. Researchers continue to look into what factors cause this type of cancer. Although there is no proven way to completely prevent this disease, you may be able to lower your risk by:
• Quitting smoking.
• Lowering blood pressure.
• Maintaining a healthy body weight.
• Eating a diet high in fruits and vegetables and low in fat.

Screening

Screening information for kidney cancer
Routine screening tests to detect early kidney cancer are not available. Doctors may recommend that people with a high risk of the disease have imaging tests. For people with a family history of kidney cancer, CT scans or renal ultrasounds are sometimes used to search for early-stage kidney cancer. However, CT scans have not been proven to be a useful screening tool for kidney cancer for most people.

Genetic conditions and kidney cancer

Although kidney cancer can run in families, inherited kidney cancers are uncommon, occurring about 5% of the time. Only a few specific genes that increase the risk of developing kidney cancer have been found, and many are linked to specific genetic syndromes. Most of these conditions are associated with a specific type of kidney cancer.

Finding a specific genetic syndrome in a family can help a person and his or her doctor develop an appropriate cancer screening plan and, in some cases, help determine the best treatment options. Only genetic testing can determine whether a person has a genetic mutation.

Genetic conditions that increase a person's risk of developing kidney cancer include:
• Von Hippel-Lindau syndrome (VHL). People with VHL have an increased risk of developing several types of tumors. Most of these tumors are benign. However, 40% of people with this disorder develop kidney cancer, most often clear cell kidney cancer.
• Hereditary non-VHL clear cell renal cell carcinoma. Hereditary non-VHL clear cell renal cell carcinoma is a genetic condition that increases a person's risk of developing clear cell renal cell carcinoma (CCRCC). A family may have hereditary non-VHL CCRCC if more than 1 family member has been diagnosed with CCRCC.
• Hereditary papillary renal cell carcinoma (HPRCC). HPRCC is a genetic condition that increases the risk of type 1 papillary renal cell carcinoma. People who have HPRCC have an increased risk of developing more than 1 kidney tumor and tumors on both kidneys. HPRCC is suspected when 2 or more close relatives have been diagnosed with type 1 papillary renal cell carcinoma.
• Birt-Hogg-Dubé syndrome (BHD). BHD is a rare genetic condition associated with multiple noncancerous skin tumors, lung cysts, and an increased risk of noncancerous and cancerous kidney tumors, specifically chromophobe or oncocytoma. People with BHD may also develop clear cell or papillary kidney cancer.
• Hereditary leiomyomatosis and renal cell carcinoma (HLRCC). HLRCC is associated with an increased risk of developing type 2 papillary renal cell carcinoma and skin nodules called leiomyomata that are found mainly on the arms, legs, chest, and back. Women with HLRCC often develop uterine fibroids known as leiomyomas or, less commonly, leiomyosarcoma.
• Tuberous sclerosis complex (TSC). TSC is a genetic condition associated with changes in the skin, brain, kidney, and heart. People with TSC also have an increased risk of developing angiomyolipomas of the kidney and kidney cancer.

Other genetic conditions may be associated with an increased risk of kidney cancer, and research to find other genetic causes of kidney cancer is ongoing.

 

Types of kidney cancer

There are several types of kidney cancer:

• Renal cell carcinoma. Renal cell carcinoma is the most common type of adult kidney cancer, making up about 85% of diagnoses. This type of cancer develops in the proximal renal tubules that make up the kidney’s filtration system. There are thousands of these tiny filtration units in each kidney.

• Urothelial carcinoma. This is also called transitional cell carcinoma. It accounts for 10% to 15% of the kidney cancers diagnosed in adults. Urothelial carcinoma begins in the area of the kidney where urine collects before moving to the bladder, called the renal pelvis. This type of kidney cancer is treated like bladder cancer because both types of cancer start in the same cells.

• Sarcoma. Sarcoma of the kidney is rare. This type of cancer develops in the soft tissue of the kidney; the thin layer of connective tissue surrounding the kidney, called the capsule; or surrounding fat. Sarcoma of the kidney is usually treated with surgery. However, sarcoma commonly comes back in the kidney area or spreads to other parts of the body. More surgery or chemotherapy may be recommended after the first surgery.

• Wilms tumor. Wilms tumor is most common in children and is treated differently from kidney cancer in adults. This type of tumor is more likely to be successfully treated with radiation therapy and chemotherapy than the other types of kidney cancer when combined with surgery. This has resulted in a different approach to treatment.

• Lymphoma. Lymphoma can enlarge both kidneys and is associated with enlarged lymph nodes, called lymphadenopathy, in other parts of the body, including the neck, chest, and abdominal cavity. In rare cases, kidney lymphoma can appear as a lone tumor mass in the kidney and may include enlarged regional lymph nodes. If lymphoma is a possibility, your doctor may perform a biopsy and recommend chemotherapy instead of surgery.

Types of kidney cancer cells

Knowing which type of cell makes up a kidney tumor helps doctors plan treatment. Pathologists have identified as many as 20 different types of kidney cancer cells. Computed tomography (CT) scans or magnetic resonance imaging (MRI) cannot always distinguish between benign, indolent, or malignant renal cortical tumors before surgery.

The most common types of kidney cancer cells are listed below.

• Clear cell. About 70% of kidney cancers are made up of clear cells. Clear cells range from slow growing (grade 1) to fast growing (grade 4). Immunotherapy and targeted therapy (see Treatment Options) are particularly effective at treating clear cell kidney cancer.

• Papillary. Papillary kidney cancer develops in 10% to 15% of patients. It is divided into 2 different subtypes, called type 1 and type 2. Papillary kidney cancer is currently treated in the same way as clear cell kidney cancer. However, many doctors recommend treatment through a clinical trial because treatment with targeted therapy is often not as successful for people with papillary kidney cancer as it is for people with clear cell kidney cancer.

• Sarcomatoid features. Each of the tumor subtypes of clear cell, chromophobe, and papillary in kidney cancer can show highly disorganized features under the microscope. These are often described by pathologists as “sarcomatoid.” This is not a distinct tumor subtype, but when these features are seen, clinicians are aware that this is a very aggressive form of kidney cancer.

• Medullary/collecting duct. This is a rare and highly aggressive cancer that is closely related to transitional cell carcinoma but is still considered a renal cortical tumor. It is more common in black people and is highly associated with having the sickle cell trait. Sickle cell trait means that a person has inherited the sickle cell gene from a parent. Collecting duct is more likely to occur in people between the ages of 20 and 30. Despite combinations of systemic chemotherapy and surgery, this form of kidney cancer has lower long-term survival rates.

• Chromophobe. Chromophobe is another uncommon cancer that is different from the other types. It may form indolent tumors.

• Oncocytoma. This is a slow-growing type of kidney cancer that rarely, if ever, spreads.

• Angiomyolipoma. Angiomyolipoma is a benign tumor that has a unique appearance on a CT (or CAT) scan and when viewed under a microscope. Usually, it is less likely to grow and spread. It is generally best treated with surgery or, if it is small, active surveillance. An aggressive form of angiomyolipoma, called epithelioid, can in rare instances spread to nearby lymph nodes or organs such as the liver.

 

Stage Information for Renal Cell Cancer

AJCC TNM Definitions

TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
T1 = Tumor ≤7 cm in greatest dimension, limited to the kidney.
T1a = Tumor ≤4 cm in greatest dimension, limited to the kidney.
T1b = Tumor >4 cm but ≤7 cm in greatest dimension, limited to the kidney.
T2 = Tumor >7 cm in greatest dimension, limited to the kidney.
T2a = Tumor >7 cm but ≤10 cm in greatest dimension, limited to the kidney.
T2b = Tumor >10 cm, limited to the kidney.
T3 = Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota's fascia.
T3a = Tumor extends into the renal vein or its segmental branches, or invades the pelvicalyceal system, or invades perirenal and/or renal sinus fat but not beyond Gerota's fascia.
T3b = Tumor extends into the vena cava below the diaphragm.
T3c = Tumor extends into the vena cava above the diaphragm or invades the wall of the vena cava.
T4 = Tumor invades beyond Gerota's fascia (including contiguous extension into the ipsilateral adrenal gland).

NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastasis in regional lymph node(s).

M0 = No distant metastasis
M1 = Distant metastasis.


AJCC Stage Groupings

Stage I:
T1, N0, M0

Stage II:
T2, N0, M0

Stage III:
T1, N1, M0
T2, N1, M0
T3, N0, M0
T3, N1, M0

T3a, N0, M0  ;  T3a, N1, M0
T3b, N0, M0  ;  T3b, N1, M0
T3c, N0, M0  ;  T3c, N1, M0

Stage IV:
T4, Any N, M0
Any T, Any N, M1

 

 

Treatment Options for Renal Cell Cancer

Treatment options and recommendations depend on several factors, including the type, cell type, and stage of cancer, possible side effects, and the patient’s preferences and overall health. Your care plan may also include treatment for symptoms and side effects, an important part of cancer care.
Kidney cancer is most often treated with surgery, targeted therapy, immunotherapy, or a combination of these treatments.
Radiation therapy and chemotherapy are occasionally used. People with kidney cancer that has spread, called metastatic cancer, often receive multiple lines of therapy.
(ASCO)


Treatment Option Overview

Current treatment cures more than 50% of patients with stage I disease, but results in patients with stage IV disease are very poor. Thus, all patients with newly diagnosed renal cell cancer can appropriately be considered candidates for clinical trials, when possible.


Stage I Renal Cell Cancer Treatment

• T1, N0, M0
Surgical resection is the accepted, often curative, therapy for stage I renal cell cancer. Resection may be simple or radical. The latter operation includes removal of the kidney, adrenal gland, perirenal fat, and Gerota fascia, with or without a regional lymph node dissection. Some, but not all, surgeons believe the radical operation yields superior results. In patients who are not candidates for surgery, external-beam radiation therapy (EBRT) or arterial embolization can provide palliation. In patients with bilateral stage I neoplasms (concurrent or subsequent), bilateral partial nephrectomy or unilateral partial nephrectomy with contralateral radical nephrectomy, when technically feasible, may be a preferred alternative to bilateral nephrectomy with dialysis or transplantation. Increasing evidence suggests that a partial nephrectomy is curative in selected cases. A pathologist should examine the gross specimen as well as the frozen section from the parenchymal margin of excision.

Standard treatment options:
1. Radical nephrectomy.
2. Simple nephrectomy.
3. Partial nephrectomy (selected patients).
4. EBRT (palliative).
5. Arterial embolization (palliative).
6. Clinical trials

Stage II Renal Cell Cancer Treatment

• T2, N0, M0
Radical resection is the accepted, often curative, therapy for stage II renal cell cancer. The operation includes removal of the kidney, adrenal gland, perirenal fat, and Gerota fascia, with or without a regional lymph node dissection. Lymphadenectomy is commonly employed, but its effectiveness has not been definitively proven. External-beam radiation therapy (EBRT) has been given before or after nephrectomy without conclusive evidence that this improves survival when compared with the results of surgery alone; however, it may be of benefit in selected patients with more extensive tumors. In patients who are not candidates for surgery, arterial embolization can provide palliation.

Standard treatment options:
1. Radical nephrectomy.
2. Nephrectomy before or after EBRT (selected patients).
3. Partial nephrectomy (selected patients).
4. EBRT (palliative).
5. Arterial embolization (palliative).
6. Clinical trials.

Stage III Renal Cell Cancer Treatment

• T1, N1, M0
• T2, N1, M0
• T3, N0, M0
• T3, N1, M0

Treatment information for patients whose disease has the following classification:
• T3a, N0, M0
Radical resection is the accepted, often curative, therapy for stage III renal cell cancer. The operation includes removal of the kidney, adrenal gland, perirenal fat, and Gerota fascia, with or without a regional lymph node dissection. Lymphadenectomy is commonly employed, but its effectiveness has not been definitively proven. External-beam radiation therapy (EBRT) has been given before or after nephrectomy without conclusive evidence that this improves survival when compared with the results of surgery alone; however, it may be of benefit in selected patients with more extensive tumors. In patients who are not candidates for surgery, arterial embolization can provide palliation. In patients with bilateral stage T3a neoplasms (concurrent or subsequent), bilateral partial nephrectomy or unilateral partial nephrectomy with contralateral radical nephrectomy, when technically feasible, may be a preferred alternative to bilateral nephrectomy with dialysis or transplantation.

• T3b, N0, M0
Radical resection is the accepted, often curative, therapy for this stage of renal cell cancer. The operation includes removal of the kidney, adrenal gland, perirenal fat, and Gerota fascia, with or without a regional lymph node dissection. Lymphadenectomy is commonly employed, but its effectiveness has not been definitively proven. Surgery is extended to remove the entire renal vein and caval thrombus and a portion of the vena cava as necessary. EBRT has been given before or after nephrectomy without conclusive evidence that this improves survival when compared with the results of surgery alone; however, it may be of benefit in selected patients with more extensive tumors. In patients who are not candidates for surgery, arterial embolization can provide palliation. In patients with stage T3b neoplasms who manifest concurrent or subsequent renal cell carcinoma in the contralateral kidney, a partial nephrectomy, when technically feasible, may be a preferred alternative to bilateral nephrectomy with dialysis or transplantation.

• T1, N1, M0
• T2, N1, M0
• T3, N1, M0
• T3a, N1, M0
• T3b, N1, M0
• T3c, N1, M0
This stage of renal cell cancer is curable with surgery in a small minority of cases. A radical nephrectomy and lymph node dissection is necessary. The value of preoperative and postoperative EBRT has not been demonstrated, but EBRT may be used for palliation in patients who are not candidates for surgery. Arterial embolization of the tumor with gelfoam or other materials may be employed preoperatively to reduce blood loss at nephrectomy or for palliation in patients with inoperable disease.

Standard treatment options:
1. Radical nephrectomy with renal vein and, as necessary, vena caval resection (for T3b tumors).[4] Radical nephrectomy with lymph node dissection.
2. Preoperative embolization and radical nephrectomy.
3. EBRT (palliative).
4. Tumor embolization (palliative).
5. Palliative nephrectomy.
6. Preoperative or postoperative EBRT and radical nephrectomy.
7. Clinical trials involving adjuvant interferon-alpha.

 

Stage IV and Recurrent Renal Cell Cancer Treatment

• T4, any N, M0
• Any T, any N, M1

The prognosis for any treated renal cell cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage. Almost all patients with stage IV renal cell cancer are incurable. The question and selection of further treatment depends on many factors, including previous treatment and site of recurrence, as well as individual patient considerations. Carefully selected patients may benefit from surgical resection of localized metastatic disease, particularly if they have had a prolonged, disease-free interval since their primary therapy.

Local Therapy

Tumor embolization, external-beam radiation therapy (EBRT), and nephrectomy can aid in the palliation of symptoms caused by the primary tumor or related ectopic hormone or cytokine production. For patients with metastatic disease, two randomized studies have demonstrated an overall survival (OS) benefit in selected patients who have undergone initial cytoreductive nephrectomy before the administration of interferon-alpha. However, the benefit of such surgery has not been evaluated in an era with available antiangiogenic and other targeted therapies.

In the larger study, 246 patients were randomly assigned to either undergo a nephrectomy followed by interferon-alpha or receive interferon-alpha alone. The median OS was 11.1 months when the primary tumor was removed first (95% confidence interval [CI], 9.2–16.5) compared with 8.1 months in the control arm (95% CI, 5.4–9.5; P = .05). In the smaller study, 85 patients with identical eligibility criteria were randomly assigned to treatment as in the larger study. Patients who underwent nephrectomy before receiving interferon-alpha had a median OS of 17 months compared with an OS of 7 months in patients who received interferon-alpha alone (hazard ratio [HR], 0.54; 95% CI, 0.31–0.94; P = .03).


These studies were restricted to patients who were asymptomatic or minimally symptomatic, with a performance status (PS) of zero or one, according to the Eastern Cooperative Oncology Group (ECOG) rating scale; these patients were also considered to be candidates for postoperative immunotherapy.[2,3][Level of evidence: 1iiA] Whether the benefit of cytoreductive nephrectomy extends to patients who are not subsequently treated with interferon-alpha has not been tested.

Selected patients with solitary or a limited number of distant metastases can achieve prolonged survival with nephrectomy and surgical resection of the metastases. Even patients with brain metastases had similar results. The likelihood of achieving therapeutic benefit with this approach appears enhanced in patients with a long disease-free interval between the initial nephrectomy and the development of metastatic disease.

 

 

Chemotherapy

Responses to cytotoxic chemotherapy generally have not exceeded 10% for any regimen that has been studied in adequate numbers of patients.

Immunotherapy

Immune checkpoint inhibitors
Nivolumab
Nivolumab is the only treatment that has shown prolonged OS in patients who have previously received antiangiogenic therapy. Nivolumab is a fully human antibody that blocks ligand activation of the programmed death receptor 1 (PD-1). By blocking the interaction between PD-1 and PD-1 ligands 1 and 2, nivolumab blocks a pathway that inhibits the cellular immune response and restores cellular immunity.

After a phase II trial showed promising results and no dose response with nivolumab, which was dosed at 0.3 mg/kg, 2 mg/kg, or 10 mg/kg and administered every 3 weeks, a randomized controlled trial compared nivolumab at a dose of 3 mg/kg every 2 weeks with everolimus at a dose of 10 mg daily. The trial randomly assigned 821 patients with metastatic renal cell carcinoma and a clear cell component who had previously received one or two antiangiogenic regimens. The objective response rate was 25% with nivolumab compared with 5% with everolimus (P < .001). The median duration of treatment was 5.5 months with nivolumab compared with 3.7 months with everolimus, and there was no significant difference in PFS (median PFS, 4.6 months with nivolumab vs. 4.4 months with everolimus). However, OS was significantly longer with nivolumab (median OS, 25.0 months vs. 19.6 months; HR, 0.73; 98.5% CI, 0.57–0.93). In the randomized phase II trial, the median survival was 25.5 months with a dose of 2 mg/kg administered every 3 weeks and 24.7 months with a dose of 10 mg/kg administered every 3 weeks. It is not clear whether the phase III dose of 3 mg/kg every 2 weeks offers any advantage over 2 mg/kg every 3 weeks; however, the latter dose offers substantial cost savings.

Cytokine therapy

Interferon-alpha and interleukin-2 (IL-2)
Cytokine therapy with interferon-alpha or IL-2 has been shown to induce objective responses, and interferon-alpha appears to have a modest impact on survival in selected patients. Interferon-alpha has approximately a 15% objective response rate in appropriately selected individuals. In general, these patients have nonbulky pulmonary or soft tissue metastases with excellent PS ratings of 0 or 1, according to the ECOG rating scale, and the patients show no weight loss. The interferon-alpha doses used in studies reporting good response rates have been in an intermediate range (6–20 million units administered 3 times weekly). A Cochrane analysis of six randomized trials, with a total of 963 patients, indicated an HR for survival of 0.78 (CI, 0.67–0.90) or a weighted average improvement in survival of 2.6 months.[Level of evidence: 1iiA]

High-dose IL-2 produces an overall response rate similar to that of interferon-alpha, but approximately 5% of the patients have shown durable complete remissions. No randomized, controlled trial of IL-2 has ever shown a longer survival result. High-dose IL-2 is used because it is the only systemic therapy that has been associated with inducing durable complete remissions, albeit in a small fraction (about 5%) of patients who are eligible for this treatment. The optimum dose of IL-2 is unknown. High-dose therapy appears to be associated with higher response rates but with more toxic effects. Low-dose inpatient regimens show activity against renal cell carcinoma with fewer toxic effects, especially hypotension, but have not been shown to be superior to placebo or any alternative regimen in terms of survival or QOL. Outpatient subcutaneous administration has also demonstrated responses with acceptable toxic effects but, again, with unclear survival or QOL benefit. Combinations of IL-2 and interferon-alpha have been studied, but outcomes have not been better with high-dose or low-dose IL-2 alone.

 

Antiangiogenic and Other Targeted Therapy

A growing understanding of the biology of cancer in general, and renal cell carcinoma in particular, has led to the development and U.S. Food and Drug Administration (FDA) approval of six new agents that target specific growth pathways. Two of the approved targeted therapies block the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth, division, and survival.

Anti-vascular endothelial growth factor (VEGF)
Based on research showing that most clear-cell renal cell carcinomas carried a mutation resulting in constitutive production of cytokines stimulating angiogenesis, several agents that targeted VEGF-mediated pathways were developed. Several of these agents have been shown in randomized, controlled trials to significantly delay progression of clear-cell renal cell carcinoma, but none has resulted in a statistically significant increase in OS as conventionally assessed. Many of these trials allowed crossover upon progression and, in some instances, other agents with similar biological activity were available to patients after they withdrew from the clinical trial. These facts may have made it more difficult to detect an OS benefit. For the clinician, this makes it challenging to determine the real benefit of these drugs to the patient. The four FDA-approved anti-VEGF agents include three oral tyrosine kinase inhibitors: pazopanib, sorafenib, and sunitinib; and an anti-VEGF monoclonal antibody, bevacizumab. Axitinib is a newer, highly selective, and more potent inhibitor of VEGF receptors 1, 2, and 3 and has been approved by the FDA for the treatment of advanced renal cell carcinoma after the failure of one previously received systemic therapy.

Sunitinib
Sunitinib and the combination of bevacizumab plus interferon-alpha have each been associated with longer progression-free survival (PFS) than interferon-alpha alone in randomized, controlled trials. Sunitinib is an orally available multikinase inhibitor (VEGFR-1, VEGFR-2, PDGFR, c-Kit). In 750 previously untreated patients, all of whom had clear cell kidney cancer, a phase III trial compared sunitinib with interferon-alpha. Sunitinib as first-line systemic therapy was associated with a median PFS of 11 months compared with 5 months for interferon-alpha. The HR for progression was 0.42 (95% CI, 0.32–0.54; P < .001).[Level of evidence: 1iiDiii] However, the analysis for OS showed a strong but statistically nonsignificant trend to improved survival (26.4 months vs. 21.8 months, HR, 0.82; 95% CI, 0.669–1.001; P = .051).[Level of evidence: 1iiDiii] Bevacizumab, a monoclonal antibody that binds to and neutralizes circulating VEGF protein, delayed progression of clear-cell renal cell carcinoma when compared with placebo in patients with disease refractory to biological therapy. Similarly, bevacizumab plus interferon-alpha as first-line therapy resulted in longer PFS but not OS compared with interferon-alpha alone in two similarly designed, randomized, controlled trials.

Pazopanib
Pazopanib is an orally available multikinase inhibitor (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, and c-KIT) and has also been approved for the treatment of patients with advanced renal cell carcinoma.

Pazopanib was evaluated in a randomized, placebo-controlled, international trial (VEG015192 [NCT00334282]) that enrolled 435 patients with clear-cell or predominantly clear-cell renal cell carcinoma. Nearly 50% of the patients had previously received cytokine therapy, although the remainder of them were treatment naïve. PFS was significantly prolonged in the pazopanib arm at 9.2 months compared with 4.2 months in the placebo arm. The HR for progression was 0.46 (95% CI, 0.34–0.62; P < .0001), and the median duration of response was longer than 1 year.

Pazopanib was also compared with sunitinib in a randomized, controlled trial (NCT00720941) that enrolled 1,110 patients who had metastatic renal cell carcinoma with a clear-cell component in a 1:1 ratio. The primary endpoint was PFS. The study was powered to assess the noninferiority of pazopanib. Results were reported when there was disease progression in 336 of 557 patients (60%) who received pazopanib and in 323 of 553 patients (58%) who received sunitinib. The median PFS time was 8.4 months for those in the pazopanib arm and 9.5 months for those in the sunitinib arm (HR, 1.05; CI, 0.9–1.22). There was no difference in OS (HR, 0.91; 95% CI, .76–1.08). Although quality of life (QOL) was compared in the study, differences in the scheduled administration of the medications made this comparison difficult to interpret.

A subsequent double-blind, randomized, controlled, cross-over trial compared sunitinib followed by pazopanib with pazopanib followed by sunitinib; the primary endpoint was patient preference for one drug over the other. Patients were treated for 10 weeks with either sunitinib or pazopanib, followed by a 2-week washout period, followed by 10 more weeks of treatment with the other drug. Preference was assessed at the end of the second 10-week treatment period. This study design created possible bias in favor of pazopanib.

Although the typical regimen for administering sunitinib is a 6-week cycle of 4 weeks on the drug and 2 weeks off the drug, the Patient Preference Study of Pazopanib Versus Sunitinib in Advanced or Metastatic Kidney Cancer (PISCES [NCT01064310]) chose a treatment period of 10 weeks rather than 12 weeks. Because of this treatment-period change, the 10 weeks of sunitinib treatment included 4 weeks on the drug, followed by 2 weeks off the drug, followed by 4 more weeks on the drug. Patients assigned to pazopanib followed by sunitinib had their preference for treatment assessed at the end of the second 4-weeks-on-the-drug period during which they took sunitinib daily for 28 days. At that point, the sunitinib side effects became the most severe. The expected result from an assessment conducted at the end of a 6-week treatment cycle versus the 4-week treatment cycle would be greatly abated side effects.

In addition, the 2-week washout period that occurred between the two 10-week treatment periods was a true break from treatment for patients assigned to take pazopanib first; however, for the patients taking sunitinib, the 2-week washout period was actually just the completion of their second 6-week treatment cycle. In other words, patients assigned to pazopanib first had a true 2-week break from treatment, and their drug preference was assessed at the peak period of toxic effects from sunitinib; however, the patients assigned to sunitinib first had no true treatment break before starting pazopanib and may have had less opportunity to recover from the side effects of sunitinib.

Despite these limitations, 70% of the patients preferred pazopanib, and 22% of the patients preferred sunitinib (P < .001). More patients preferred pazopanib regardless of the treatment they received first; however, that difference was greater for the patients who received pazopanib first (80% vs. 11%) compared with the patients who received sunitinib first (62% vs. 32%). The main side effects cited by the patients that contributed to patient preference were diarrhea, health-related QOL, fatigue, loss of appetite, taste changes, nausea and vomiting, hand and foot soreness, stomach pain, and mouth and throat soreness. The patients preferring pazopanib cited less fatigue and better overall QOL as the most common reasons for their preference. The patients preferring sunitinib cited less diarrhea and better QOL as the most common reasons for their preference. Physician preference was a secondary endpoint of the study, and 61% of physicians preferred to continue patient treatment with pazopanib, compared with 22% of physicians who preferred to continue patient treatment with sunitinib.


Cabozantinib
Cabozantinib is an oral tyrosine kinase inhibitor of the MET, AXL, and VEGF receptors. After a phase I trial showed activity against renal cell carcinoma, a phase III trial randomly assigned 658 patients to receive either cabozantinib (60 mg qd) or everolimus (10 mg qd). Doses were reduced in 60% of the patients receiving cabozantinib compared with 25% of the patients assigned to everolimus, and the incidence of grade 3 or 4 adverse events was 68% with cabozantinib compared with 58% with everolimus. The most common high-grade adverse events were hypertension (15%), diarrhea (11%), and fatigue (9%) with cabozantinib, compared with anemia (16%), fatigue (7%), and hyperglycemia (5%) with everolimus.

Dose reductions of cabozantinib were mainly the result of diarrhea, palmar-plantar erythrodysesthesia syndrome, and fatigue. A planned interim analysis for OS showed a trend toward longer survival for patients who received cabozantinib; however, it did not meet the predetermined boundary for statistical significance for interim analysis, and the published survival curves for the two drugs crossed. At the time of publication, median survival for everolimus had not been reached. PFS was longer for cabozantinib (median, 7.4 months vs. 3.8 months; HR for progression or death, 0.58; 95% CI, 0.45–0.75, P < .001).

Axitinib
Axitinib was shown to prolong PFS when used as second-line systemic therapy. A randomized, controlled trial of 723 patients conducted at 175 sites in 22 countries evaluated axitinib versus sorafenib as treatment for renal cell carcinoma with a clear cell component that had progressed during or after first-line treatment with sunitinib (54%), cytokines (35%), bevacizumab plus interferon (8%), or temsirolimus (3%). The primary endpoint was PFS, and the data were analyzed when disease in 88% of the axitinib patients and 90% of the sorafenib patients had progressed, while 58% and 59%, respectively, had died.

Median PFS was 8.3 months for axitinib and 5.7 months for sorafenib (HR, 0.656; 95% CI, 0.552–0.779, P < .0001 for progressiondeath using a one-sided log-rank test and a threshold of P < .025 for significance). Median OS was 20.1 months with axitinib compared with 19.2 months with sorafenib (HR, 0.969; 95% CI, 0.80–1.17, P = .374). However, the largest benefit was seen in patients who received cytokines as first-line therapy and whose median PFS was 12.2 months with axitinib compared with 8.2 months with sorafenib (P < .0001), while median OS was 29.4 months with axitinib compared with 27.8 months with sorafenib (HR, 0.81; 95% CI, 0.5501.19; P = .144). In contrast, in patients who had previously received sunitinib, axitinib was associated with a 2.1-month increase in PFS compared with sorafenib (6.5 months vs. 4.4 months, one-sided P = .002), but median OS was nearly identical: 15.2 months with axitinib compared with 16.5 months with sorafenib (HR, 1.0; 95% CI, 0.782–1.270; P = .49).

Comparing the toxicity of the axitinib and sorafenib regimens is complicated because the axitinib arm included a dose-escalation component, and only those patients who tolerated the lower dose were subsequently given the higher doses. Hypertension, nausea, dysphonia, and hypothyroidism were more common with axitinib, whereas palmar-plantar erythrodysesthesia, alopecia, and rash were more common with sorafenib.

Sorafenib
Sorafenib is an orally available multikinase inhibitor (CRAF, BRAF, KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-β) and has also been approved for the treatment of patients with advanced renal cell carcinoma.

In an international, multicenter, randomized trial with the primary endpoints of PFS and OS, 769 patients were stratified by the Memorial Sloan Kettering Cancer Center prognostic risk category and by country and were randomly assigned to receive either sorafenib (400 mg bid) or a placebo. Approximately 82% of the patients had received IL-2 previously and/or interferon-alpha in both arms of the study. The median PFS for patients randomly assigned to sorafenib was 167 days compared with 84 days for patients randomly assigned to placebo (P < .001). The estimated HR for the risk of progression with sorafenib compared with a placebo was 0.44 (95% CI, 0.35–0.55). There was no significant difference in OS.[Level of evidence: 1iDiii] A subsequent phase II study of 189 patients randomly assigned to either sorafenib or interferon-alpha reported no difference (5.7 months vs. 5.6 months) in PFS, but sorafenib was associated with better QOL than interferon-alpha.


mTOR inhibitors

Temsirolimus
Temsirolimus, an intravenously administered mTOR inhibitor, was shown to result in prolonged OS compared with interferon-alpha in a phase III randomized controlled trial that enrolled intermediate- and poor-risk patients. The trial enrolled patients with a variety of subtypes of renal cell carcinoma and was not restricted to clear cell kidney cancer. The HR for death was 0.73 (95% CI, 0.58–0.92, P = .008), making temsirolimus the only therapy for renal cell carcinoma to clearly show results in longer OS than did interferon-alpha using conventional statistical analysis.

Everolimus
Everolimus is an orally administered mTOR inhibitor that was evaluated in a double-blind, randomized, placebo-controlled phase III trial. The trial enrolled patients with metastatic renal cell carcinoma with a clear cell component that had progressed during or within 6 months of stopping treatment with sunitinib, sorafenib, or both drugs. Median PFS was 4.0 months with everolimus compared with 1.9 months with placebo. No difference in OS was reported.

 

 

Treatment Options

Because of the lack of curative therapy for metastatic disease and the promise of targeted therapies, patients should be considered for the many ongoing clinical trials testing single or combination therapies, including the following:

First-line therapy:
1.Radical nephrectomy (for T4, M0 lesions).
2.Cytoreductive nephrectomy (for any T, M1 lesions).
3.Temsirolimus.
4.Sunitinib.
5.Pazopanib.
6.Bevacizumab with or without interferon-alpha.
7.Interferon-alpha.
8.IL-2.
9.Palliative EBRT.


Second-line therapy:
1.Nivolumab (for patients who have previously been treated with a sunitinib, pazopanib, sorafenib, and/or axitinib).
2.Cabozantinib (for patients who have previously been treated with sunitinib, pazopanib, sorafenib, or axitinib).
3.Axitinib.
4.Everolimus (for patients who have previously been treated with sunitinib and/or sorafenib).
5.Sorafenib.
6.Palliative EBRT.

Current Clinical Trials
1. NCI advanced clinical trial search. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria.
2. General information about clinical trials.

 

 

 

Treatment for kidney cancer (NCCN Guidelines)

Prognostic factors in kidney cancer

Prognostic factors in kidney cancer

Principles of Surgery

Principles of Surgery

 

Treatment for kidney cancer

Treatment for kidney cancer

Adjuvant Trials

Adjuvant Trials

Note: Adjuvant sunitinib improves relapse-free survival, not overall survival



Treatment for stage IV kidney cancer

Treatment for stage IV kidney cancer

Treatment for relapse or stage IV kidney cancer

Treatment for stage IV or Relapse kidney cancer

Therapy for unresectable & stage IV or relapsed kidney cancer

Predominant clear cell histology
First-line therapy Page: KID-3    Copy
Clinical trial (Preferred)
Sunitinib (Category 1, Preferred)
Pazopanib (Category 1, Preferred)
Bevacizumab + Interferon-alpha-2b (Category 1)

Ipilimumab + nivolumab Category 1, Preferred for intermediate- and poor-prognosis risk)
Temsirolimus (Category 1 for poor-prognosis risk group)

Subsequent therapy Page: KID-4    Copy
Clinical trial (Preferred)
Cabozantinib (Category 1, Preferred)
Nivolumab (Category 1, Preferred)
Axitinib (Category 1)
Lenvatinib + everolimus (Category 1)

Non-clear cell histology
First-line therapy Page: KID-5    Copy
Clinical trial (Preferred)
Sunitinib (Category 1, Preferred)
Temsirolimus (Category 1 for poor-prognosis risk group)


Firstline Therapy for stage IV or relapsed kidney cancer

Firstline Therapy for stage IV or relapsed kidney cancer

Firstline Therapy for stage IV or relapsed non-clear cell kidney cancer

Firstline Therapy for stage IV or relapsed non-clear cell kidney cancer

Note: HLRCC: Hereditory leiomyomatosis and renal cell cancer


Primary Treatment of Relapsed or Stage IV Disease and Surgically Unresectable Disease

Cytoreductive nephrectomy before systemic therapy is generally recommended in patients with a potentially surgically resectable primary tumor mass.
Randomized trials showed a benefit of cytoreductive nephrectomy in patients who received IFN-α therapy after surgery. In similar phase III trials, the Southwest Oncology Group (SWOG) and the EORTC randomized patients with metastatic disease to undergo either nephrectomy followed by IFN-α therapy or treatment with IFN-α alone.
A combined analysis of these trials showed that median survival favored the surgery plus IFN-α group (13.6 vs. 7.8 months for IFN-α alone).

Patient selection is important to identify those who might benefit from cytoreductive therapy. Patients most likely to benefit from cytoreductive nephrectomy before systemic therapy are those with lung-only metastases, good prognostic features, and good performance status.
While similar data are not available for patients who are candidates for high-dose IL-2, data from the UCLA renal cancer database and from a variety of publications by other groups suggest that nephrectomy also provides benefit to patients who undergo other forms of immunotherapy.
As for the role of nephrectomy for patients presenting with metastatic disease and considered for targeted therapies, randomized trials are ongoing at this time, but data from the IMDC suggest that cytoreductive nephrectomy continues to play a role in patients treated with VEGF-targeted agents.
Patients with metastatic disease who present with hematuria or other symptoms related to the primary tumor should be offered palliative nephrectomy if they are surgical candidates. In patients whose tumors are surgically unresectable, the NCCN Panel recommends performing tissue sampling to confirm diagnosis of RCC to determine histology and guide subsequent management.

 

First-line Therapy for Patients with Predominantly Clear Cell Carcinoma


High-dose IL-2 as First-line Therapy for Predominantly Clear Cell Carcinoma
According to the NCCN Kidney Cancer Panel, for highly selected patients with relapsed or medically unresectable stage IV clear cell renal carcinoma, high-dose IL-2 is listed as a first-line treatment option with a category 2A designation.

Checkpoint Antibody Therap
Recent studies have shown efficacy of nivolumab checkpoint monotherapy in the second line setting for patients with advanced renal cell carcinoma, described in the Subsequent Therapy for Patients with Predominantly Clear Cell Renal Cell Carcinoma section,

Nivolumab and Ipilimumab in Combination as First-line Therapy forIntermediate- and Poor-Risk Patients with Predominantly Clear Cell Carcinoma
The NCCN Kidney Cancer Panel has listed nivolumab and ipilimumab in combination as a category 1, preferred treatment option for first-line treatment for intermediate- and poor-risk patients with previously untreated, relapsed or medically unresectable, predominantly clear cell, stage IV renal carcinoma.
Due to conflicting data for favorable-risk patients in the phase III compared to the phase I trials, the NCCN Kidney Cancer Panel recommends nivolumab and ipilimumab in combination as a category 2B treatment option for first line treatment in these patients. The FDA approval for nivolumab plus ipilimumab is narrower, only including patients with intermediate- or poor-risk RCC.

Targeted Therapy
Targeted therapy utilizing tyrosine kinase inhibitors (TKIs), and or anti- VEGF antibodies, is widely used in first- and second-line treatments.
Agents targeting the mammalian targeted of rapamycin (mTOR) are also used in this setting.
A number of targeted agents have been approved by the FDA for the treatment of advanced RCC in the first and/or subsequent line of therapy: sunitinib, sorafenib, pazopanib, axitinib, temsirolimus, everolimus, bevacizumab in combination with interferon, cabozantinib, and lenvatinib (plus everolimus).

Targeted therapy

Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells while limiting damage to healthy cells. These drugs are becoming more important in the treatment of kidney cancer.

Recent studies show that not all tumors have the same targets. Many research studies are taking place now to find out more about specific molecular targets and new treatments directed at them.

• Anti-angiogenesis therapy. This type of treatment focuses on stopping angiogenesis, which is the process of making new blood vessels. Clear cell kidney cancer has a mutation of the VHL gene that causes the cancer to make too much of a certain protein, known as vascular endothelial growth factor (VEGF), which controls the formation of new blood vessels. VEGF can be blocked with certain drugs. Because a tumor needs the nutrients delivered by blood vessels to grow and spread, the goal of anti-angiogenesis therapies is to “starve” the tumor. There are 2 ways to block VEGF.

One is an antibody called bevacizumab (Avastin), which has been shown to slow tumor growth for people with metastatic renal carcinoma. Bevacizumab combined with interferon slows tumor growth and spread. A similar drug called bevacizumab-awwb (Mvasi) also has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of kidney cancer.

The other way to block VEGF is with tyrosine kinase inhibitors (TKIs). Axitinib (Inlyta), cabozantinib (Cabometyx), pazopanib (Votrient), sorafenib (Nexavar), and sunitinib (Sutent) are TKIs that may be used for treatment for clear cell kidney cancer. Side effects of TKIs may include diarrhea, high blood pressure, and tenderness and sensitivity in the hands and feet.

• mTOR inhibitors. Everolimus (Afinitor) and temsirolimus (Torisel) are drugs that target a certain protein that helps kidney cancer cells grow, called mTOR. Studies show that these drugs slow kidney cancer growth.

 

cabozantinib
■ For the first-line treatment of metastatic renal cell cancer (RCC).
Oral dosage (tablets only; do not substitute with cabozantinib capsules)

cabozantinib 60 mg by mouth once daily until disease progression or unacceptable toxicity.
Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

First-line treatment with cabozantinib significantly improved median progression free survival (PFS) over sunitinib in intermediate- or poor-risk patients with metastatic RCC in a multicenter, randomized, open-label, phase 2 clinical trial (8.6 months vs. 5.6 months).
The secondary endpoint of ORR was also improved (46% vs. 18%); overall survival data were not mature (30.3 months vs. 21.8 months). Treatments were similarly tolerated.

Note: cabozantinib has shown benefit in this randomized phase 2 trial over sunitinib in achieving progression-free survival.

■ For the treatment of relapsed or refractory advanced renal cell cancer (RCC).
Oral dosage (tablets only; do not substitute with cabozantinib capsules)

cabozantinib 60 mg by mouth once daily on an empty stomach until disease progression or unacceptable toxicity.
Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
In a multicenter, randomized, open-label clinical trial of patients with advanced renal cell cancer (RCC) who had received at least 1 prior anti-angiogenic therapy, the primary outcome of median progression-free survival (PFS) by blinded independent radiology review in the first 375 patients randomized to the study was significantly improved in patients treated with cabozantinib (n = 187) compared with everolimus (n = 188) (7.4 months vs. 3.8 months). In the total study population, median overall survival (21.4 months vs. 16.5 months) and confirmed objective response rate (ORR) (17% vs. 3%) were also significantly improved in cabozantinib-treated patients (n = 330) compared with those who received everolimus (n = 328).

Note: cabozantinib has shown benefit in this randomized trial over everolimus in achieving higher response rate, progression-free survival and overall survival.

everolimus
■ For the treatment of patients with advanced renal cell cancer who have failed treatment with sunitinib or sorafenib.
everolimus 10 mg orally once daily. Continue treatment for as long as clinical benefit is observed or until unacceptable toxicity develops.
Severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of Afinitor.
Dose adjustment is necessary if Afinitor is coadministered with some CYP3A4 inhibitors or inducers. Avoid concomitant use with strong CYP3A4 inhibitors.

■ For the treatment of advanced renal cell cancer (RCC) in combination with lenvatinib, following one prior anti-angiogenic therapy
everolimus 5 mg orally once daily, in combination with lenvatinib 18 mg by mouth once daily; continue until disease progression or unacceptable toxicity.

In a multicenter, open-label, phase 2 clinical trial, patients with advanced or metastatic renal cell carcinoma (RCC) who had received prior anti-angiogenic therapy were randomized to treatment with lenvatinib plus everolimus (combination therapy, n = 51), or everolimus monotherapy (10 mg per day, n = 50).
The primary outcome of investigator-assessed median progression-free survival (PFS) was significantly improved in patients receiving combination therapy compared with everolimus monotherapy (14.6 months vs. 5.5 months; HR 0.37; 95% CI, 0.22 to 0.62);
this was supported by a retrospective independent review of radiographs with an observed hazard ratio of 0.43 (95% CI, 0.24 to 0.75).
Additionally, the median overall survival was 25.5 months with combination therapy compared with 15.4 months in patients treated with everolimus monotherapy (HR 0.67; 95% CI, 0.42 to 1.08) and the objective response rate was 37% versus 6%, respectively; all but one response (in a patient who received combination therapy) were partial responses.

Note: lenvatinib plus everolimus has shown benefit in this randomized trial over everolimus in achieving higher response rate, progression-free survival and overall survival.