lunes, 9 de septiembre de 2019

Renal Cell Cancer Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Renal Cell Cancer Treatment (PDQ®)–Health Professional Version - National Cancer Institute



National Cancer Institute

Renal Cell Cancer Treatment (PDQ®)–Health Professional Version

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General Information About Renal Cell Cancer

Incidence and Mortality

Estimated new cases and deaths from renal cell (kidney and renal pelvis) cancer in the United States in 2019:[1]
  • New cases: 73,820.
  • Deaths: 14,770.

Follow-up and Survivorship

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.[2] 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.[3] 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.

Treatment Modalities

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.

Related Summaries

Other PDQ summaries containing information related to renal cell cancer include the following:
References
  1. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available onlineExit Disclaimer. Last accessed June 7, 2019.
  2. Sene AP, Hunt L, McMahon RF, et al.: Renal carcinoma in patients undergoing nephrectomy: analysis of survival and prognostic factors. Br J Urol 70 (2): 125-34, 1992. [PUBMED Abstract]
  3. National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 14, 2018.

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 the 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.

Stage Information for Renal Cell Cancer

The staging system for renal cell cancer is based on the degree of tumor spread beyond the kidney.[1-3] Involvement of blood vessels may not be a poor prognostic sign if the tumor is otherwise confined to the substance of the kidney. Abnormal liver function test results may be caused by a paraneoplastic syndrome that is reversible with tumor removal, and these types of results do not necessarily represent metastatic disease. Except when computed tomography (CT) examination is equivocal or when iodinated contrast material is contraindicated, CT scanning is as good as or better than magnetic resonance imaging for detecting renal masses.[4]

AJCC Stage Groupings and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define renal cell cancer.[5]
Table 1. Definitions of TNM Stage Ia
StageTNMDefinitionIllustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Kidney. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 739–48.
IT1, N0, M0T1 = Tumor ≤7 cm in greatest dimension, limited to the kidney.
ENLARGEStage I kidney cancer; drawing shows cancer in the left kidney and the tumor is 7 centimeters or smaller. An inset shows 7 centimeters is about the size of a peach. Also shown are fatty tissue and the right kidney.
Stage I kidney cancer. The tumor is 7 centimeters or smaller and is found in the kidney only.
–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.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 2. Definitions of TNM Stage IIa
StageTNMDefinitionIllustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Kidney. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 739–48.
IIT2, N0, M0T2 = Tumor >7 cm in greatest dimension, limited to the kidney.
ENLARGEStage II kidney cancer; drawing shows cancer in the left kidney and the tumor is larger than 7 centimeters. An inset shows 7 centimeters is about the size of a peach. Also shown are the fatty tissue and right kidney.
Stage II kidney cancer. The tumor is larger than 7 centimeters and is found in the kidney only.
–T2a = Tumor >7 cm but ≤10 cm in greatest dimension, limited to the kidney.
–T2b = Tumor >10 cm, limited to the kidney.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 3. Definitions of TNM Stage IIIa
StageTNMDefinitionIllustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Kidney. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 739–48.
IIIT1, N1, M0T1 = Tumor ≤7 cm in greatest dimension, limited to the kidney.
ENLARGEStage III kidney cancer; drawing shows cancer in the left kidney and in a) nearby lymph nodes, b) the renal vein, c) the structures in the kidney that collect urine, and d) the layer of fatty tissue around the kidney. Also shown are the right kidney, vena cava, and right and left adrenal glands.
Stage III kidney cancer. The cancer in the kidney is any size and cancer has spread to a) nearby lymph nodes, b) the blood vessels in or near the kidney (renal vein or vena cava), c) the structures in the kidney that collect urine, or d) the layer of fatty tissue around 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.
N1 = Metastasis in regional lymph node(s).
M0 = No distant metastasis.
T2, N1, M0T2 = 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.
N1 = Metastasis in regional lymph node(s).
M0 = No distant metastasis.
T3, N0, M0T3 = 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.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T3, N1, M0T3 = 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.
N1 = Metastasis in regional lymph node(s).
M0 = No distant metastasis.
Table 4. Definitions of TNM Stage IVa
StageTNMDefinitionIllustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Kidney. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 739–48.
IVT4, Any N, M0T4 = Tumor invades beyond Gerota's fascia (including contiguous extension into the ipsilateral adrenal gland).
ENLARGEStage IV kidney cancer; drawing shows cancer that has spread beyond the layer of fatty tissue around the left kidney to a) the adrenal gland above the left kidney. Also shown are the lymph nodes, right adrenal gland, and right kidney. An inset shows b) other parts of the body where kidney cancer may spread, including the brain, lung, liver, adrenal gland, bone, and distant lymph nodes.
Stage IV kidney cancer. Cancer has spread a) beyond the layer of fatty tissue around the kidney and may have spread into the adrenal gland above the kidney with cancer, or b) to other parts of the body, such as the brain, lung, liver, adrenal gland, bone, or distant lymph nodes.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastasis in regional lymph node(s).
M0 = No distant metastasis.
Any T, Any N, M1TX = 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).
M1 = Distant metastasis.
References
  1. Bassil B, Dosoretz DE, Prout GR: Validation of the tumor, nodes and metastasis classification of renal cell carcinoma. J Urol 134 (3): 450-4, 1985. [PUBMED Abstract]
  2. Golimbu M, Joshi P, Sperber A, et al.: Renal cell carcinoma: survival and prognostic factors. Urology 27 (4): 291-301, 1986. [PUBMED Abstract]
  3. Robson CJ, Churchill BM, Anderson W: The results of radical nephrectomy for renal cell carcinoma. J Urol 101 (3): 297-301, 1969. [PUBMED Abstract]
  4. Consensus conference. Magnetic resonance imaging. JAMA 259 (14): 2132-8, 1988. [PUBMED Abstract]
  5. Kidney. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 739–48.

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

Stage I renal cell cancer is defined by the American Joint Committee on Cancer's TNM classification system:[1]
  • 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's fascia, with or without a regional lymph node dissection. Some, but not all, surgeons believe the radical operation yields superior results.
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.[2] 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.[3]
In patients who are not candidates for surgery, external-beam radiation therapy (EBRT) or arterial embolization can provide palliation.
Standard treatment options:
  1. Radical nephrectomy.[4]
  2. Simple nephrectomy.[4]
  3. Partial nephrectomy (selected patients).[2,4]
  4. EBRT (palliative).[4]
  5. Arterial embolization (palliative).[4,5]
  6. Clinical trials.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Kidney. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 739–48.
  2. Novick AC, Streem S, Montie JE, et al.: Conservative surgery for renal cell carcinoma: a single-center experience with 100 patients. J Urol 141 (4): 835-9, 1989. [PUBMED Abstract]
  3. Thrasher JB, Robertson JE, Paulson DF: Expanding indications for conservative renal surgery in renal cell carcinoma. Urology 43 (2): 160-8, 1994. [PUBMED Abstract]
  4. deKernion JB, Berry D: The diagnosis and treatment of renal cell carcinoma. Cancer 45 (7 Suppl): 1947-56, 1980. [PUBMED Abstract]
  5. Swanson DA, Wallace S, Johnson DE: The role of embolization and nephrectomy in the treatment of metastatic renal carcinoma. Urol Clin North Am 7 (3): 719-30, 1980. [PUBMED Abstract]

Stage II Renal Cell Cancer Treatment

Stage II renal cell cancer is defined by the American Joint Committee on Cancer's TNM classification system:[1]
  • 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's fascia, with or without a regional lymph node dissection.[2] 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.[3]
  2. Nephrectomy before or after EBRT (selected patients).[3]
  3. Partial nephrectomy (selected patients).[3]
  4. EBRT (palliative).[3]
  5. Arterial embolization (palliative).
  6. Clinical trials.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Kidney. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 739–48.
  2. Phillips E, Messing EM: Role of lymphadenectomy in the treatment of renal cell carcinoma. Urology 41 (1): 9-15, 1993. [PUBMED Abstract]
  3. deKernion JB, Berry D: The diagnosis and treatment of renal cell carcinoma. Cancer 45 (7 Suppl): 1947-56, 1980. [PUBMED Abstract]

Stage III Renal Cell Cancer Treatment

Stage III renal cell cancer is defined by the American Joint Committee on Cancer's TNM classification system:[1]
  • 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's fascia, with or without a regional lymph node dissection.[2] 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 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.[3]
In patients who are not candidates for surgery, arterial embolization can provide palliation.
Treatment information for patients whose disease has the following classification:
  • 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's 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.[4] 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 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.[3,5,6]
In patients who are not candidates for surgery, arterial embolization can provide palliation.
Treatment information for patients whose disease has the following classifications:
  • 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.[7,8]
  3. EBRT (palliative).[7]
  4. Tumor embolization (palliative).[8]
  5. Palliative nephrectomy.
  6. Preoperative or postoperative EBRT and radical nephrectomy.[7]
  7. Clinical trials involving adjuvant interferon-alpha.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Kidney. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 739–48.
  2. Phillips E, Messing EM: Role of lymphadenectomy in the treatment of renal cell carcinoma. Urology 41 (1): 9-15, 1993. [PUBMED Abstract]
  3. Novick AC, Streem S, Montie JE, et al.: Conservative surgery for renal cell carcinoma: a single-center experience with 100 patients. J Urol 141 (4): 835-9, 1989. [PUBMED Abstract]
  4. Hatcher PA, Anderson EE, Paulson DF, et al.: Surgical management and prognosis of renal cell carcinoma invading the vena cava. J Urol 145 (1): 20-3; discussion 23-4, 1991. [PUBMED Abstract]
  5. deKernion JB: Management of renal adenocarcinoma. In: deKernion JB, Paulson DF, eds.: Genitourinary Cancer Management. Philadelphia, Pa: Lea and Febiger, 1987, pp 187-217.
  6. Angermeier KW, Novick AC, Streem SB, et al.: Nephron-sparing surgery for renal cell carcinoma with venous involvement. J Urol 144 (6): 1352-5, 1990. [PUBMED Abstract]
  7. deKernion JB, Berry D: The diagnosis and treatment of renal cell carcinoma. Cancer 45 (7 Suppl): 1947-56, 1980. [PUBMED Abstract]
  8. Swanson DA, Wallace S, Johnson DE: The role of embolization and nephrectomy in the treatment of metastatic renal carcinoma. Urol Clin North Am 7 (3): 719-30, 1980. [PUBMED Abstract]

Stage IV and Recurrent Renal Cell Cancer Treatment

Stage IV renal cell cancer is defined by the American Joint Committee on Cancer's TNM classification system:[1]
  • 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

In patients without metastatic disease, resection of the primary tumor, when feasible, is standard practice. In patients with unresectable and/or metastatic cancers, 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.

Cytoreductive nephrectomy

In the era before targeted antiangiogenic therapies and immune checkpoint inhibitors, two randomized studies demonstrated an overall survival (OS) benefit in selected patients who underwent initial cytoreductive nephrectomy before the administration of interferon-alpha.[2,3]
However, the CARMENA (NCT00930033) trial reported no benefit from undergoing cytoreductive nephrectomy before receiving treatment with sunitinib, an oral antiangiogenic tyrosine kinase inhibitor.[4] This study enrolled only patients with intermediate- (57%) and poor-risk (43%) disease, whereas a previous retrospective study found that cytoreductive nephrectomy only benefited good- and intermediate-risk patients in the sunitinib era. Similarly, the positive trials in the interferon era were restricted to patients who were asymptomatic or minimally symptomatic, with a performance status (PS) rating of 0 or 1, according to the Eastern Cooperative Oncology Group (ECOG) rating scale; these patients were also considered fit candidates for postoperative immunotherapy.
There is evidence that undergoing cytoreductive nephrectomy before antiangiogenic therapy does not provide a survival benefit to patients with intermediate- and poor-risk disease. Cytoreductive nephrectomy for good-risk patients has not been studied in a randomized controlled trial in the era of targeted therapies and immunotherapy, but it was shown to be beneficial before these newer agents were available. In addition, there are retrospective nonrandomized studies that suggest a benefit in good-risk patients in the current era of targeted therapies.
A multicenter analysis of 351 patients with metastatic renal cell carcinoma was conducted to assess the impact of cytoreductive nephrectomy. The study evaluated patients who received systemic therapy and compared outcomes of those who underwent cytoreductive nephrectomy with those who did not. The median OS was 38.1 months for patients who underwent nephrectomy compared with 16.4 months for those treated with systemic therapy alone (P = .03). However, the survival benefit was limited to patients with an ECOG PS rating of 0 to 1 and good- or intermediate-risk disease.[5] Interpretation of the study is limited by selection bias because patients were not randomly assigned to the nephrectomy group. Whether there is a benefit from cytoreductive nephrectomy for patients who are not subsequently treated with systemic therapy has not been tested in the current era.
Randomized controlled trials of cytoreductive nephrectomy:
A randomized, controlled, noninferiority trial of 450 patients compared the outcomes of patients who received sunitinib alone with those who received cytoreductive nephrectomy followed by sunitinib. The trial was designed to enroll 576 individuals, so it was underpowered.[4] In this study, 43% of the patients had poor-risk disease and 57% had intermediate-risk disease.
  • With a median follow-up of 50.9 months, and after 326 deaths, the hazard ratio (HR)death was 0.89 (95% confidence interval [CI], 0.71–1.10) in favor of sunitinib alone. Median OS was 18.4 months in the sunitinib-alone arm and 13.9 months in the nephrectomy-followed-by-sunitinib arm, but the difference was not statistically significant.[4][Level of evidence: 1iiA]
Randomized controlled trials of interferon with or without preceding cytoreductive nephrectomy:
Two randomized studies demonstrated an OS benefit in selected patients who underwent initial cytoreductive nephrectomy before the administration of interferon-alpha.[2,3]
  • In the larger study, 246 patients were randomly assigned to either undergo a nephrectomy followed by interferon-alpha or receive interferon-alpha alone.[2]
    • The median OS was 11.1 months when the primary tumor was removed first (95% 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.[3]
    • 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 (HR, 0.54; 95% CI, 0.31–0.94; P = .03).[3][Level of evidence: 1iiA]
Resection of oligometastatic disease
Selected patients with solitary or a limited number of distant metastases can achieve prolonged survival with nephrectomy and surgical resection of the metastases.[6-11] Even patients with brain metastases had similar results.[12] 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.

Combined Immune Checkpoint Inhibitors and Antiangiogenic Targeted Therapies

After immune checkpoint inhibitors and antiangiogenic targeted therapies were found to improve outcomes, the combination of these two approaches has been studied in clinical trials and shown to result in longer OS when compared with monotherapy.

Pembrolizumab plus axitinib

Evidence (pembrolizumab plus axitinib):
  1. An open-label, phase III randomized controlled trial (NCT02853331) comparing sunitinib with the combination of pembrolizumab and axitinib enrolled 861 patients who had received no previous systemic therapy for metastatic disease.[13]
    • With 12.8 months median follow-up, 1-year OS was 90% in the pembrolizumab plus axitinib arm compared with 78% in the sunitinib arm (HR, 0.53; 95% CI, 0.38–0.74; P < .0001).[13][Level of evidence: 1iiA]
    • Median progression-free survival (PFS) was also prolonged (15.1 months vs. 11.1 months; HR, 0.69; 95% CI, 0.57–0.84).
    • The objective response rate was 59.3% with combination therapy compared with 35.7% with sunitinib (P < .001).
    • Grade 3 or higher adverse event rates were similar: 75.8% of the pembrolizumab/axitinib patients compared with 70.6% patients in the sunitinib arm.

Avelumab plus axitinib

Evidence (avelumab plus axtinib):
  1. An open-label phase III randomized trial (NCT02684006) compared the combination of avelumab and axitinib with sunitinib monotherapy in 560 patients with previously untreated stage IV programmed cell death-ligand-1 (PD-L1)–positive renal cell carcinoma (the entire study population was 886 patients, including those who were PD-L1 negative).[14] This trial specified two primary endpoints: PFS and OS among patients with PD-L1-positive tumors. PFS among the entire study population was a secondary endpoint.
    • With a median follow-up of less than 1 year, there was no significant difference in OS between the two arms.
    • PFS among patients with PD-L1-positive tumors was 13.8 months in the combination therapy arm compared with 7.2 months in the sunitinib arm (HR, 0.61; 95% CI, 0.47–0.79).[14][Level of evidence: 1iiDiii]
    • For the entire study population, median PFS was 13.8 months in the combination arm compared with 8.4 months in the sunitinib arm (HR, 0.69; 95% CI, 0.56–0.84).

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.[15]
Sunitinib
Sunitinib and the combination of bevacizumab plus interferon-alpha have each been associated with longer PFS than interferon-alpha alone in randomized, controlled trials. Sunitinib is an orally available multikinase inhibitor (VEGFR-1, VEGFR-2, PDGFR, c-Kit).
Evidence (sunitinib):
  1. In 750 previously untreated patients, all of whom had clear cell kidney cancer, a phase III trial compared sunitinib with interferon-alpha.[16]
    • 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).[16][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).[17][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.[18] 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.[19,20]
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.[21]
Evidence (pazopanib):
  1. 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.[22] 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.
  2. 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.[23] 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.
  3. 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.[24] 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 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 assessed the activity of cabozantinib in the second-line setting in a randomized controlled trial.
Evidence (cabozantinib):
  1. The METEOR (NCT01865747) trial randomly assigned 658 patients who had previously been treated with a VEGF tyrosine kinase inhibitor to receive either cabozantinib (60 mg qd) or everolimus (10 mg qd).[25,26] Doses were reduced in 60% of the patients receiving cabozantinib compared with 25% of the patients assigned to everolimus.
    • 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.
    • With a median follow-up of about 19 months, median OS was 21.4 months for patients who received cabozantinib and 16.5 months for patients who received everolimus (HR, 0.66; 95% CI, 0.53–0.83; P = .0003).
    • These results were confirmed when the prespecified final analysis was performed after 430 deaths had been confirmed. Median survival was 21.4 months with cabozantinib and 17.1 months with everolimus (HR, 0.70; 95% CI, 0.58–0.85).[27]
  2. A subsequent trial compared cabozantinib with sunitinib in the first-line setting, randomly assigning 157 patients with intermediate- or poor-risk metastatic renal cell carcinoma to cabozantinib or sunitinib.[28,29]
    1. Adverse events were seen in more than 95% of the patients.
      • Grade 3 to 4 adverse events were seen in 68% of the patients on the cabozantinib arm and 65% of the patients on the sunitinib arm.
      • Adverse events included hypertension, diarrhea, fatigue, and thrombocytopenia.
      • Grade 5 adverse events occurred in 4% of the patients on the cabozantinib arm and 10% of the patients on the sunitinib arm.
    2. With a median follow-up of 34.5 months, there was no significant difference in OS between the two arms, and the OS curves crossed multiple times.
    3. PFS, however, was longer with cabozantinib (8.6 months vs. 5.3 months [HR, = .48; 95% CI, 0.31–0.74]), demonstrating that PFS is an inadequate surrogate for OS.[28,29][Level of evidence: 1iiDiii]
Axitinib
Axitinib has been shown to prolong PFS when used as second-line systemic therapy.
Evidence (axitinib):
  1. 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%).[15,30] 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).[30]
    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.[15,30]
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.[21]
Evidence (sorafenib):
  1. 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.[21][Level of evidence: 1iDiii]
  2. A subsequent phase II study randomly assigned 189 patients to either sorafenib or interferon-alpha.[31]
    • No difference was reported in PFS (5.7 months vs. 5.6 months), but sorafenib was associated with better QOL than interferon-alpha.

Mammalian target of rapamycin (mTOR) inhibitors

Temsirolimus
Temsirolimus is an intravenously administered mTOR inhibitor.
Evidence (temsirolimus):
  1. A phase III randomized controlled trial enrolled intermediate- and poor-risk patients with a variety of subtypes of renal cell carcinoma. The trial was not restricted to clear cell kidney cancer.
    • Temsirolimus was shown to result in prolonged OS compared with interferon-alpha.
    • The HRdeath 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.[32]
Everolimus
Everolimus is an orally administered mTOR inhibitor.
Evidence (everolimus):
  1. Everolimus was evaluated in a double-blind, randomized, placebo-controlled phase III trial that 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.[33]
    • No difference in OS was reported.

Immunotherapy

Immune checkpoint inhibitors

Immune checkpoint inhibitors are drugs that block certain proteins that inhibit the response to cancer by the immune system. These proteins down-regulate T-lymphocyte activity and can prevent these cells from killing cancer cells. By reducing the activity of these inhibitory proteins, immune checkpoint inhibitors increase the immune response to cancer. Immune checkpoint proteins that are targeted by this class of drugs include programmed cell death-1 (PD-1), PD-L1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).
Ipilimumab plus nivolumab
The combination of ipilimumab and nivolumab was shown to prolong OS when compared with sunitinib as first-line systemic therapy for advanced-stage renal cell carcinoma in a randomized, controlled trial.[34] Both drugs are immune checkpoint inhibitors. Ipilimumab is an antibody that targets CTLA-4. Nivolumab is an antibody that targets PD-1.
Evidence (ipilimumab plus nivolumab):
  1. A randomized controlled trial compared the combination of these two drugs with sunitinib. Nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) were given every 3 weeks for four doses followed by maintenance nivolumab (3 mg/kg) every 2 weeks. Sunitinib was given at a dose of 50 mg once daily for the first 4 weeks of a repeating 6-week cycle (i.e., each cycle consisted of 4 weeks taking the drug followed by a 2-week break). Treatment continued until disease progression unless adverse events or withdrawal of consent led to discontinuation. The coprimary endpoints were OS, PFS, and objective response rate in patients with intermediate- or poor-risk disease. Of note, because there were three primary endpoints, the overall alpha level of 0.05 was divided among the three endpoints. This meant that the P-value cutoffs for significance were 0.001 for response rate, 0.009 for PFS, and 0.04 for OS. The trial enrolled 1,096 patients, and 847 had intermediate- or poor-risk disease.
    • With a median follow-up of 25.2 months for intermediate- and poor-risk patients, 18-month OS was 75% in the ipilimumab-nivolumab arm compared with 60% in the sunitinib arm. Among intermediate- and poor-risk patients, the HRdeath was 0.63 (99.8% CI, 0.44–0.89; P < .001).
    • There was no statistically significant difference in PFS. Median PFS among intermediate- and poor-risk patients was 11.6 months with ipilimumab-nivolumab compared with 8.4 months with sunitinib (HR, 0.82; 99.1% CI, 0.64–1.05).
    • The objective response rate was higher with ipilimumab-nivolumb than with sunitinib (42% vs. 27%, P < .001). In the ipilimumab-nivolumab arm, 40 patients (9%) had complete responses compared with 5 patients (1%) in the sunitinib arm.
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 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.
Evidence (nivolumab):
  1. 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.[35]
    • 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.
  2. 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.[36] 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).[36]
    It is not clear whether the dose of 3 mg/kg every 2 weeks used in the phase III trial offers any advantage over the dose of 2 mg/kg every 3 weeks used in the phase II trial; 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.[37] 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.[37][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.[38-43] 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.[44] Outpatient subcutaneous administration has also demonstrated responses with acceptable toxic effects but, again, with unclear survival or QOL benefit.[45] 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.[46,47]

Chemotherapy

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

Treatment Options

First-line therapy:
  1. Radical nephrectomy (for T4, M0 lesions).
  2. Cytoreductive nephrectomy (for any T, M1 lesions in patients with good-risk disease).[2-5]
  3. Ipilimumab plus nivolumab.[34]
  4. Pembrolizumab plus axitinib.[13]
  5. Cabozantinib for patients with intermediate- or poor-risk disease.[28,29]
  6. Avelumab plus axitinib.[14]
  7. Sunitinib.[16,17,23,24]
  8. Pazopanib.[22-24]
  9. Temsirolimus.[32]
  10. Bevacizumab with or without interferon-alpha.[18-20,48]
  11. Interferon-alpha.[37,47,49,50]
  12. IL-2.[37,43,44]
  13. Palliative EBRT.
Second-line therapy:
  1. Nivolumab (for patients who have previously been treated with a sunitinib, pazopanib, sorafenib, and/or axitinib).[35]
  2. Cabozantinib (for patients who have previously been treated with sunitinib, pazopanib, sorafenib, or axitinib).[25]
  3. Axitinib.[30]
  4. Everolimus (for patients who have previously been treated with sunitinib and/or sorafenib).[33]
  5. Sorafenib.[31,51]
  6. Palliative EBRT.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
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  42. Fyfe G, Fisher RI, Rosenberg SA, et al.: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13 (3): 688-96, 1995. [PUBMED Abstract]
  43. McDermott DF, Regan MM, Clark JI, et al.: Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 23 (1): 133-41, 2005. [PUBMED Abstract]
  44. Yang JC, Topalian SL, Parkinson D, et al.: Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol 12 (8): 1572-6, 1994. [PUBMED Abstract]
  45. Sleijfer DT, Janssen RA, Buter J, et al.: Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis. J Clin Oncol 10 (7): 1119-23, 1992. [PUBMED Abstract]
  46. Atkins MB, Sparano J, Fisher RI, et al.: Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol 11 (4): 661-70, 1993. [PUBMED Abstract]
  47. Negrier S, Perol D, Ravaud A, et al.: Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: results of a randomized controlled trial. Cancer 110 (11): 2468-77, 2007. [PUBMED Abstract]
  48. Escudier B, Bellmunt J, Négrier S, et al.: Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 28 (13): 2144-50, 2010. [PUBMED Abstract]
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Changes to This Summary (09/06/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Stage IV and Recurrent Renal Cell Cancer Treatment
Added Combined Immune Checkpoint Inhibitors and Antiangiogenic Targeted Therapies as a new subsection.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of renal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewer for Renal Cell Cancer Treatment is:
  • Timothy Gilligan, MD (Cleveland Clinic Taussig Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Renal Cell Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389256]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.
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